23rd ECCMID, 27-30 Apr 2013 - Berlin - Amazon S3 · Prof. Sevtap Arikan-Akdagli, MD . Hacettepe...
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Prof. Sevtap Arikan-Akdagli, MD Hacettepe University Medical School Department of Medical Microbiology Ankara Turkey www.flickr.com 23rd ECCMID, 27-30 Apr 2013 - Berlin
Transcript of 23rd ECCMID, 27-30 Apr 2013 - Berlin - Amazon S3 · Prof. Sevtap Arikan-Akdagli, MD . Hacettepe...
Prof Sevtap Arikan-Akdagli MD
Hacettepe University Medical School
Department of Medical Microbiology Ankara Turkey
wwwflickrcom
23rd ECCMID 27-30 Apr 2013 - Berlin
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Dermatophytes amp dermatophytosis
Epidemiology of dermatophytosis
bull Among the most frequent human infections bull Affects gt 20-25 of worldrsquos population bull Increase in incidence bull Geographical variations- Homogeneous
distribution vs geographical restriction for some species
bull Changes in epidemiology overtime (migrations life style socioeconomics comorbidities)
Havlickova et al Mycoses 2008 51(Suppl 4) 2 Ameen et al Clin Dermatol 2010 28 197
Italy
Gradual decrease in frequency
Tinea cruris
Italy
Tinea corporis
Tinea capitis
Progressive increase in frequency
Tinea unguium
Tinea pedis
Increase in isolation
T rubrum
Progressive decrease in isolation
T violaceum M canis
E floccosum
Epidemiology of IFIs General Perspective
bull Geographical and temporal variability
bull Local epidemiological trends
bull Changes in incidence and the infecting species in the last two decades
bull Changes in antifungal susceptibility profiles
bull Poor outcome
Montagna et al Infection 2013 March 6 Epub
Median excess cost of 15 509 US $ Prolonged length of stay of 13 days
All-cause inpatient mortality 38x higher
for the scedosporiosis cases as compared to control patients with comparable underlying hematologic disorders
Transplantation Cancer
Opportunistic IFIs THE HOST and the associated risk factors
Immunosupressed Debilitated postoperative
Severely-ill
Bille et al Curr Opin Infect Dis 2005 18 314
ICU
Major changes in IFIs in the last decades
- More mucosal and invasive fungal infections
- Infections due to more resistant species and strains
- Infections due to uncommon genera and species
- More antifungal drugs in clinical practice
Groll et al J Infect 19963323 Marr et al Clin Infect Dis 200234909
Fridkin and Jarvis Clin Microbiol Rev 19969499 Montagna et al Infection 2013 March 6 Epub
Emerged andor Newly recognized
Altered hosts Fungi
Selective antifungal pressure
Changes in environmental
conditions
Emerging fungal infection
Walsh TJ Groll AH Transpl Infect Dis 19991247
More isolates belonging to uncommon genera amp species
Opportunistic IFI Causative agents
CANDIDA
ASPERGILLUS
OTHERS
Mucormycetes C neoformans
Fusarium Scedosporium Dematiaceous moulds
1985
1990
1995
2000s
Trichosporon
Fusarium Mucormycetes P marneffei
C immitis
Azole-R C albicans
Non-albicans Candida
Acremonium Paecilomyces
Trichoderma
Scopulariopsis
Malassezia
B capitatus
Hansenula
Walsh amp Groll Transpl Infect Dis 19991247 Walsh et al Clin Microbiol Infect 20041048 Alastruey-Izquierdo et al ICAAC 2012 abst No M-321
Emerging fungal pathogens in immunocompromised patients
Emergence and awareness of resistant Aspergillus
helliphelliphellip
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Dermatophytes amp dermatophytosis
Epidemiology of dermatophytosis
bull Among the most frequent human infections bull Affects gt 20-25 of worldrsquos population bull Increase in incidence bull Geographical variations- Homogeneous
distribution vs geographical restriction for some species
bull Changes in epidemiology overtime (migrations life style socioeconomics comorbidities)
Havlickova et al Mycoses 2008 51(Suppl 4) 2 Ameen et al Clin Dermatol 2010 28 197
Italy
Gradual decrease in frequency
Tinea cruris
Italy
Tinea corporis
Tinea capitis
Progressive increase in frequency
Tinea unguium
Tinea pedis
Increase in isolation
T rubrum
Progressive decrease in isolation
T violaceum M canis
E floccosum
Epidemiology of IFIs General Perspective
bull Geographical and temporal variability
bull Local epidemiological trends
bull Changes in incidence and the infecting species in the last two decades
bull Changes in antifungal susceptibility profiles
bull Poor outcome
Montagna et al Infection 2013 March 6 Epub
Median excess cost of 15 509 US $ Prolonged length of stay of 13 days
All-cause inpatient mortality 38x higher
for the scedosporiosis cases as compared to control patients with comparable underlying hematologic disorders
Transplantation Cancer
Opportunistic IFIs THE HOST and the associated risk factors
Immunosupressed Debilitated postoperative
Severely-ill
Bille et al Curr Opin Infect Dis 2005 18 314
ICU
Major changes in IFIs in the last decades
- More mucosal and invasive fungal infections
- Infections due to more resistant species and strains
- Infections due to uncommon genera and species
- More antifungal drugs in clinical practice
Groll et al J Infect 19963323 Marr et al Clin Infect Dis 200234909
Fridkin and Jarvis Clin Microbiol Rev 19969499 Montagna et al Infection 2013 March 6 Epub
Emerged andor Newly recognized
Altered hosts Fungi
Selective antifungal pressure
Changes in environmental
conditions
Emerging fungal infection
Walsh TJ Groll AH Transpl Infect Dis 19991247
More isolates belonging to uncommon genera amp species
Opportunistic IFI Causative agents
CANDIDA
ASPERGILLUS
OTHERS
Mucormycetes C neoformans
Fusarium Scedosporium Dematiaceous moulds
1985
1990
1995
2000s
Trichosporon
Fusarium Mucormycetes P marneffei
C immitis
Azole-R C albicans
Non-albicans Candida
Acremonium Paecilomyces
Trichoderma
Scopulariopsis
Malassezia
B capitatus
Hansenula
Walsh amp Groll Transpl Infect Dis 19991247 Walsh et al Clin Microbiol Infect 20041048 Alastruey-Izquierdo et al ICAAC 2012 abst No M-321
Emerging fungal pathogens in immunocompromised patients
Emergence and awareness of resistant Aspergillus
helliphelliphellip
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Dermatophytes amp dermatophytosis
Epidemiology of dermatophytosis
bull Among the most frequent human infections bull Affects gt 20-25 of worldrsquos population bull Increase in incidence bull Geographical variations- Homogeneous
distribution vs geographical restriction for some species
bull Changes in epidemiology overtime (migrations life style socioeconomics comorbidities)
Havlickova et al Mycoses 2008 51(Suppl 4) 2 Ameen et al Clin Dermatol 2010 28 197
Italy
Gradual decrease in frequency
Tinea cruris
Italy
Tinea corporis
Tinea capitis
Progressive increase in frequency
Tinea unguium
Tinea pedis
Increase in isolation
T rubrum
Progressive decrease in isolation
T violaceum M canis
E floccosum
Epidemiology of IFIs General Perspective
bull Geographical and temporal variability
bull Local epidemiological trends
bull Changes in incidence and the infecting species in the last two decades
bull Changes in antifungal susceptibility profiles
bull Poor outcome
Montagna et al Infection 2013 March 6 Epub
Median excess cost of 15 509 US $ Prolonged length of stay of 13 days
All-cause inpatient mortality 38x higher
for the scedosporiosis cases as compared to control patients with comparable underlying hematologic disorders
Transplantation Cancer
Opportunistic IFIs THE HOST and the associated risk factors
Immunosupressed Debilitated postoperative
Severely-ill
Bille et al Curr Opin Infect Dis 2005 18 314
ICU
Major changes in IFIs in the last decades
- More mucosal and invasive fungal infections
- Infections due to more resistant species and strains
- Infections due to uncommon genera and species
- More antifungal drugs in clinical practice
Groll et al J Infect 19963323 Marr et al Clin Infect Dis 200234909
Fridkin and Jarvis Clin Microbiol Rev 19969499 Montagna et al Infection 2013 March 6 Epub
Emerged andor Newly recognized
Altered hosts Fungi
Selective antifungal pressure
Changes in environmental
conditions
Emerging fungal infection
Walsh TJ Groll AH Transpl Infect Dis 19991247
More isolates belonging to uncommon genera amp species
Opportunistic IFI Causative agents
CANDIDA
ASPERGILLUS
OTHERS
Mucormycetes C neoformans
Fusarium Scedosporium Dematiaceous moulds
1985
1990
1995
2000s
Trichosporon
Fusarium Mucormycetes P marneffei
C immitis
Azole-R C albicans
Non-albicans Candida
Acremonium Paecilomyces
Trichoderma
Scopulariopsis
Malassezia
B capitatus
Hansenula
Walsh amp Groll Transpl Infect Dis 19991247 Walsh et al Clin Microbiol Infect 20041048 Alastruey-Izquierdo et al ICAAC 2012 abst No M-321
Emerging fungal pathogens in immunocompromised patients
Emergence and awareness of resistant Aspergillus
helliphelliphellip
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Epidemiology of dermatophytosis
bull Among the most frequent human infections bull Affects gt 20-25 of worldrsquos population bull Increase in incidence bull Geographical variations- Homogeneous
distribution vs geographical restriction for some species
bull Changes in epidemiology overtime (migrations life style socioeconomics comorbidities)
Havlickova et al Mycoses 2008 51(Suppl 4) 2 Ameen et al Clin Dermatol 2010 28 197
Italy
Gradual decrease in frequency
Tinea cruris
Italy
Tinea corporis
Tinea capitis
Progressive increase in frequency
Tinea unguium
Tinea pedis
Increase in isolation
T rubrum
Progressive decrease in isolation
T violaceum M canis
E floccosum
Epidemiology of IFIs General Perspective
bull Geographical and temporal variability
bull Local epidemiological trends
bull Changes in incidence and the infecting species in the last two decades
bull Changes in antifungal susceptibility profiles
bull Poor outcome
Montagna et al Infection 2013 March 6 Epub
Median excess cost of 15 509 US $ Prolonged length of stay of 13 days
All-cause inpatient mortality 38x higher
for the scedosporiosis cases as compared to control patients with comparable underlying hematologic disorders
Transplantation Cancer
Opportunistic IFIs THE HOST and the associated risk factors
Immunosupressed Debilitated postoperative
Severely-ill
Bille et al Curr Opin Infect Dis 2005 18 314
ICU
Major changes in IFIs in the last decades
- More mucosal and invasive fungal infections
- Infections due to more resistant species and strains
- Infections due to uncommon genera and species
- More antifungal drugs in clinical practice
Groll et al J Infect 19963323 Marr et al Clin Infect Dis 200234909
Fridkin and Jarvis Clin Microbiol Rev 19969499 Montagna et al Infection 2013 March 6 Epub
Emerged andor Newly recognized
Altered hosts Fungi
Selective antifungal pressure
Changes in environmental
conditions
Emerging fungal infection
Walsh TJ Groll AH Transpl Infect Dis 19991247
More isolates belonging to uncommon genera amp species
Opportunistic IFI Causative agents
CANDIDA
ASPERGILLUS
OTHERS
Mucormycetes C neoformans
Fusarium Scedosporium Dematiaceous moulds
1985
1990
1995
2000s
Trichosporon
Fusarium Mucormycetes P marneffei
C immitis
Azole-R C albicans
Non-albicans Candida
Acremonium Paecilomyces
Trichoderma
Scopulariopsis
Malassezia
B capitatus
Hansenula
Walsh amp Groll Transpl Infect Dis 19991247 Walsh et al Clin Microbiol Infect 20041048 Alastruey-Izquierdo et al ICAAC 2012 abst No M-321
Emerging fungal pathogens in immunocompromised patients
Emergence and awareness of resistant Aspergillus
helliphelliphellip
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Italy
Gradual decrease in frequency
Tinea cruris
Italy
Tinea corporis
Tinea capitis
Progressive increase in frequency
Tinea unguium
Tinea pedis
Increase in isolation
T rubrum
Progressive decrease in isolation
T violaceum M canis
E floccosum
Epidemiology of IFIs General Perspective
bull Geographical and temporal variability
bull Local epidemiological trends
bull Changes in incidence and the infecting species in the last two decades
bull Changes in antifungal susceptibility profiles
bull Poor outcome
Montagna et al Infection 2013 March 6 Epub
Median excess cost of 15 509 US $ Prolonged length of stay of 13 days
All-cause inpatient mortality 38x higher
for the scedosporiosis cases as compared to control patients with comparable underlying hematologic disorders
Transplantation Cancer
Opportunistic IFIs THE HOST and the associated risk factors
Immunosupressed Debilitated postoperative
Severely-ill
Bille et al Curr Opin Infect Dis 2005 18 314
ICU
Major changes in IFIs in the last decades
- More mucosal and invasive fungal infections
- Infections due to more resistant species and strains
- Infections due to uncommon genera and species
- More antifungal drugs in clinical practice
Groll et al J Infect 19963323 Marr et al Clin Infect Dis 200234909
Fridkin and Jarvis Clin Microbiol Rev 19969499 Montagna et al Infection 2013 March 6 Epub
Emerged andor Newly recognized
Altered hosts Fungi
Selective antifungal pressure
Changes in environmental
conditions
Emerging fungal infection
Walsh TJ Groll AH Transpl Infect Dis 19991247
More isolates belonging to uncommon genera amp species
Opportunistic IFI Causative agents
CANDIDA
ASPERGILLUS
OTHERS
Mucormycetes C neoformans
Fusarium Scedosporium Dematiaceous moulds
1985
1990
1995
2000s
Trichosporon
Fusarium Mucormycetes P marneffei
C immitis
Azole-R C albicans
Non-albicans Candida
Acremonium Paecilomyces
Trichoderma
Scopulariopsis
Malassezia
B capitatus
Hansenula
Walsh amp Groll Transpl Infect Dis 19991247 Walsh et al Clin Microbiol Infect 20041048 Alastruey-Izquierdo et al ICAAC 2012 abst No M-321
Emerging fungal pathogens in immunocompromised patients
Emergence and awareness of resistant Aspergillus
helliphelliphellip
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Epidemiology of IFIs General Perspective
bull Geographical and temporal variability
bull Local epidemiological trends
bull Changes in incidence and the infecting species in the last two decades
bull Changes in antifungal susceptibility profiles
bull Poor outcome
Montagna et al Infection 2013 March 6 Epub
Median excess cost of 15 509 US $ Prolonged length of stay of 13 days
All-cause inpatient mortality 38x higher
for the scedosporiosis cases as compared to control patients with comparable underlying hematologic disorders
Transplantation Cancer
Opportunistic IFIs THE HOST and the associated risk factors
Immunosupressed Debilitated postoperative
Severely-ill
Bille et al Curr Opin Infect Dis 2005 18 314
ICU
Major changes in IFIs in the last decades
- More mucosal and invasive fungal infections
- Infections due to more resistant species and strains
- Infections due to uncommon genera and species
- More antifungal drugs in clinical practice
Groll et al J Infect 19963323 Marr et al Clin Infect Dis 200234909
Fridkin and Jarvis Clin Microbiol Rev 19969499 Montagna et al Infection 2013 March 6 Epub
Emerged andor Newly recognized
Altered hosts Fungi
Selective antifungal pressure
Changes in environmental
conditions
Emerging fungal infection
Walsh TJ Groll AH Transpl Infect Dis 19991247
More isolates belonging to uncommon genera amp species
Opportunistic IFI Causative agents
CANDIDA
ASPERGILLUS
OTHERS
Mucormycetes C neoformans
Fusarium Scedosporium Dematiaceous moulds
1985
1990
1995
2000s
Trichosporon
Fusarium Mucormycetes P marneffei
C immitis
Azole-R C albicans
Non-albicans Candida
Acremonium Paecilomyces
Trichoderma
Scopulariopsis
Malassezia
B capitatus
Hansenula
Walsh amp Groll Transpl Infect Dis 19991247 Walsh et al Clin Microbiol Infect 20041048 Alastruey-Izquierdo et al ICAAC 2012 abst No M-321
Emerging fungal pathogens in immunocompromised patients
Emergence and awareness of resistant Aspergillus
helliphelliphellip
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Median excess cost of 15 509 US $ Prolonged length of stay of 13 days
All-cause inpatient mortality 38x higher
for the scedosporiosis cases as compared to control patients with comparable underlying hematologic disorders
Transplantation Cancer
Opportunistic IFIs THE HOST and the associated risk factors
Immunosupressed Debilitated postoperative
Severely-ill
Bille et al Curr Opin Infect Dis 2005 18 314
ICU
Major changes in IFIs in the last decades
- More mucosal and invasive fungal infections
- Infections due to more resistant species and strains
- Infections due to uncommon genera and species
- More antifungal drugs in clinical practice
Groll et al J Infect 19963323 Marr et al Clin Infect Dis 200234909
Fridkin and Jarvis Clin Microbiol Rev 19969499 Montagna et al Infection 2013 March 6 Epub
Emerged andor Newly recognized
Altered hosts Fungi
Selective antifungal pressure
Changes in environmental
conditions
Emerging fungal infection
Walsh TJ Groll AH Transpl Infect Dis 19991247
More isolates belonging to uncommon genera amp species
Opportunistic IFI Causative agents
CANDIDA
ASPERGILLUS
OTHERS
Mucormycetes C neoformans
Fusarium Scedosporium Dematiaceous moulds
1985
1990
1995
2000s
Trichosporon
Fusarium Mucormycetes P marneffei
C immitis
Azole-R C albicans
Non-albicans Candida
Acremonium Paecilomyces
Trichoderma
Scopulariopsis
Malassezia
B capitatus
Hansenula
Walsh amp Groll Transpl Infect Dis 19991247 Walsh et al Clin Microbiol Infect 20041048 Alastruey-Izquierdo et al ICAAC 2012 abst No M-321
Emerging fungal pathogens in immunocompromised patients
Emergence and awareness of resistant Aspergillus
helliphelliphellip
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Transplantation Cancer
Opportunistic IFIs THE HOST and the associated risk factors
Immunosupressed Debilitated postoperative
Severely-ill
Bille et al Curr Opin Infect Dis 2005 18 314
ICU
Major changes in IFIs in the last decades
- More mucosal and invasive fungal infections
- Infections due to more resistant species and strains
- Infections due to uncommon genera and species
- More antifungal drugs in clinical practice
Groll et al J Infect 19963323 Marr et al Clin Infect Dis 200234909
Fridkin and Jarvis Clin Microbiol Rev 19969499 Montagna et al Infection 2013 March 6 Epub
Emerged andor Newly recognized
Altered hosts Fungi
Selective antifungal pressure
Changes in environmental
conditions
Emerging fungal infection
Walsh TJ Groll AH Transpl Infect Dis 19991247
More isolates belonging to uncommon genera amp species
Opportunistic IFI Causative agents
CANDIDA
ASPERGILLUS
OTHERS
Mucormycetes C neoformans
Fusarium Scedosporium Dematiaceous moulds
1985
1990
1995
2000s
Trichosporon
Fusarium Mucormycetes P marneffei
C immitis
Azole-R C albicans
Non-albicans Candida
Acremonium Paecilomyces
Trichoderma
Scopulariopsis
Malassezia
B capitatus
Hansenula
Walsh amp Groll Transpl Infect Dis 19991247 Walsh et al Clin Microbiol Infect 20041048 Alastruey-Izquierdo et al ICAAC 2012 abst No M-321
Emerging fungal pathogens in immunocompromised patients
Emergence and awareness of resistant Aspergillus
helliphelliphellip
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Major changes in IFIs in the last decades
- More mucosal and invasive fungal infections
- Infections due to more resistant species and strains
- Infections due to uncommon genera and species
- More antifungal drugs in clinical practice
Groll et al J Infect 19963323 Marr et al Clin Infect Dis 200234909
Fridkin and Jarvis Clin Microbiol Rev 19969499 Montagna et al Infection 2013 March 6 Epub
Emerged andor Newly recognized
Altered hosts Fungi
Selective antifungal pressure
Changes in environmental
conditions
Emerging fungal infection
Walsh TJ Groll AH Transpl Infect Dis 19991247
More isolates belonging to uncommon genera amp species
Opportunistic IFI Causative agents
CANDIDA
ASPERGILLUS
OTHERS
Mucormycetes C neoformans
Fusarium Scedosporium Dematiaceous moulds
1985
1990
1995
2000s
Trichosporon
Fusarium Mucormycetes P marneffei
C immitis
Azole-R C albicans
Non-albicans Candida
Acremonium Paecilomyces
Trichoderma
Scopulariopsis
Malassezia
B capitatus
Hansenula
Walsh amp Groll Transpl Infect Dis 19991247 Walsh et al Clin Microbiol Infect 20041048 Alastruey-Izquierdo et al ICAAC 2012 abst No M-321
Emerging fungal pathogens in immunocompromised patients
Emergence and awareness of resistant Aspergillus
helliphelliphellip
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Emerged andor Newly recognized
Altered hosts Fungi
Selective antifungal pressure
Changes in environmental
conditions
Emerging fungal infection
Walsh TJ Groll AH Transpl Infect Dis 19991247
More isolates belonging to uncommon genera amp species
Opportunistic IFI Causative agents
CANDIDA
ASPERGILLUS
OTHERS
Mucormycetes C neoformans
Fusarium Scedosporium Dematiaceous moulds
1985
1990
1995
2000s
Trichosporon
Fusarium Mucormycetes P marneffei
C immitis
Azole-R C albicans
Non-albicans Candida
Acremonium Paecilomyces
Trichoderma
Scopulariopsis
Malassezia
B capitatus
Hansenula
Walsh amp Groll Transpl Infect Dis 19991247 Walsh et al Clin Microbiol Infect 20041048 Alastruey-Izquierdo et al ICAAC 2012 abst No M-321
Emerging fungal pathogens in immunocompromised patients
Emergence and awareness of resistant Aspergillus
helliphelliphellip
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Opportunistic IFI Causative agents
CANDIDA
ASPERGILLUS
OTHERS
Mucormycetes C neoformans
Fusarium Scedosporium Dematiaceous moulds
1985
1990
1995
2000s
Trichosporon
Fusarium Mucormycetes P marneffei
C immitis
Azole-R C albicans
Non-albicans Candida
Acremonium Paecilomyces
Trichoderma
Scopulariopsis
Malassezia
B capitatus
Hansenula
Walsh amp Groll Transpl Infect Dis 19991247 Walsh et al Clin Microbiol Infect 20041048 Alastruey-Izquierdo et al ICAAC 2012 abst No M-321
Emerging fungal pathogens in immunocompromised patients
Emergence and awareness of resistant Aspergillus
helliphelliphellip
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
1985
1990
1995
2000s
Trichosporon
Fusarium Mucormycetes P marneffei
C immitis
Azole-R C albicans
Non-albicans Candida
Acremonium Paecilomyces
Trichoderma
Scopulariopsis
Malassezia
B capitatus
Hansenula
Walsh amp Groll Transpl Infect Dis 19991247 Walsh et al Clin Microbiol Infect 20041048 Alastruey-Izquierdo et al ICAAC 2012 abst No M-321
Emerging fungal pathogens in immunocompromised patients
Emergence and awareness of resistant Aspergillus
helliphelliphellip
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Search of
Worldwide Database for
nosocomial outbreaks
amp
PubMed-Medline
Reports 16 (Yeasts) 7 (Mucormycosis) 2 (Hyalohyphomycosis ndash Acremonium ndashFusarium) 2 (Phaeohyphomycosis - Curvularia-Exophiala) 2 Dermatophytosis (Microsporum) 5 (pneumocystosis) Common genera (Candida Aspergillus) excluded
OUTBREAK gt2 more nosocomial unusual fungal infs diagnosed in a short period
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Supported by unrestricted grants from Astellas Pharma MerckMSD Gilead Sciences Pfizer
Culture Banking G Fischer A Hamprecht Molecular Biology S De Hoog Pharmacokinetics C Mueller F Farowski
Chair OA Cornely Coordination MJGT Vehreschild K Wahlers Clinicalsurveysnet JJ Vehreschild Documentation S Proske
ISHAM and ECMM Working Group
wwwfungiscopenet
GOALS Collect epidemiological amp clinical data
Develop an evidence-based approach for diagnosis
and treatment of IFIs due to emerging fungi
Courtesy of Prof Oliver Cornely
Vehreschild et al ICAAC 2012 abst no M-338
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Web-based electronic case form for registry Collection of clinical data amp infecting strains
Courtesy of Prof Oliver Cornely
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
March 2013 328 valid cases
Courtesy of Prof Oliver Cornely
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
LIFE- Leading International Fungal Education) ldquoLIFE is a growing organisation Leading International Fungal Infection (LIFE) has grown from the 20 year old charity the Fungal Research Trust and is dedicated to improving health in those with fungal disease (infection and allergy) The overall goal is to greatly improve fungal infection outcomes in patients through awareness improved diagnosis and access to appropriate antifungal therapies worldwiderdquo Leaded by Prof David Denning
wwwlife-worldwideorg
27 April 2013 1530-1630 - -POSTER SESSION ldquoGlobe trotting The burden of serious fungal infectionsrdquo
P1034 ndash P1045 (in association with the LIFE program)
23rd ECCMID 2013-Berlin
PUBLICATION ONLY ldquoFungal Infectionsrdquo
R2855 R2873 (in association with the LIFE program)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Fig 2 Timing of invasive fungal infections in allogeneic stem-cell transplant recipients Reprinted with permission (Warnock David 2003 personalcommunication)
Maschmeyer G Int J Antimicrob Agents 27S (2006) S3
Allogeneic HSCT - - Timing of IFI with respect to the infecting mould
HSCT
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Marr et al CID 2002 34 909
Timing of IFI for non-Aspergillus moulds HSCT
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Cohort-retrospective study
Years 1999-2003
3228 cases of HSCT
(1249 allo 1979 oto) General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEM-2004 Study
HSCT
Italy
11 Transplantation Units
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
983 IFIs among 875 HSCT recipients
HSCT
IA 43 IC 28 Mucormycosis 8
One-year cumulative incidences based on the first IFI 77 cases 100 tx (matched unrelated allogeneic) 81 cases 100 tx (mismatched-related allogeneic) 58 cases 100 tx (matched-related allogeneic) 12 cases 100 tx (autologous HSCT)
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
TRANSNET Cumulative incidence for each IFI
HSCT
Highest for aspergillosis Followed by candidiasis
Non-Asp Non-Muc
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Neofytos et al Transplant Infect Dis 2010
SOT
Which fungus for which SOT
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
SOT
1208 IFIs among 1063 organ tx recipients
IC 53 IA 19 Cryptococcosis 8 Non-Asp moulds 8 Endemic fungi 5 Mucormycosis 2
One-year cumulative incidences per each tx type and based on the first IFI
116 (Small bowel tx) 86 (Lung tx) 47 (Liver tx) 4 (Heart tx) 34 (Pancreas tx) 13 (Kidney tx)
March 2001-March 2006
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
TRANSNET Cumulative incidence for each IFI
SOT
6 and 12 months after tx
Non-ASP
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
SOT
Slight increase in cumulative incidence of IFI in general from 2002 to 2005 Incidence of IA remains unchanged
TRANSNET
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Shoham et al J Intensive Care Med Dec 1 2009
Risk factors and infecting fungi ICU
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
IA
17-26 in lung tx recipients
5-24 in acute leukemia patients
5-15 in allogenic bone marrow tx patients
2-13 in heart tx recipients
1-3 in lymphoma patients
Patterson et al Transpl Infect Dis 2000 2 22 Kontoyiannis amp Bodey Eur J Clin Microbiol Infect Dis 2002 21 161 Meersseman et al CID 2007 45 205
(LeuvenBelgium-Univ Hosp)
58 in Medical ICU
(COPD liver failure)
Incidence of IA in ICU ICU
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
AURORA Project Southern Italy 18 ICUs
(observational study) Febr 2007-Aug 2008
Montagna et al Infection 2013 March 6 Epub
124
12 Asp 1 Scedo
23 cases 1000 admissions Mortality 615
ICU
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Aspergillus strains isolated
from resp samples
paranasal sinus aspirates blood
cultures and biopsies
277 strains isolated
EUCAST method and
brkpts
Species
56 A fumigatus sensu stricto
9 A flavus
9 A terreus
8 A tubingensis
75 A niger
3 A nidulans
75 Other species
Alastruey-Izquierdo et al
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Lass-Floumlrl et al Mycoses 2009 52 197
Incidence of aspergillosis in Europe
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
3228 cases of HSCT
(1249 allo 1979 oto)
Italy
11 Transplantation Units General IFI incidence 37
Infecting fungi Aspergillus (86 episodes)
Candida (30 episodes)
78 of the episodes in cases of allo HSCT
12 o f the episodes in cases of auto HSCT
Pagano et al CID 2007 45 1161
Incidence of IA
SEIFEMB-2004 Study
HSCT
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
bull July 2005 bull Five previously
healthy women bull Asp meningitis
following anesthesia for CS
helliphellip
Possibly due to suboptimal storage conditions during the 6-month period after the tsunami disaster
Sri Lanka
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Outbreak of fungal infection due to contaminated methylprednisolone injection
Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy mdash United States 2012 Weekly October 19 2012 61(41)839-842
CDC
USA
14000 persons potentially exposed to medications from at least one of the contaminated lots
Four categories of cases
following injection 1 Fungal
meningitis 2 Basilar stroke
3 Spinal osteomyelitis or epidural abscess
at the site of injection
4 Septic arthritis or osteomyelitis
following injection of that
joint
Evidence of a fungal inf in 26 (37) cases (Culture histopath or PCR)
Fungal identification in 14 cases Exserohilum spp n=13 Aspergillus
fumigatus n=1
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Nonimmunocompromised postoperative patients
High A fumigatus airborne conidia levels
Spain
Seven patients
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
0
05
1
15
2
25
3
AMB Itra Vori Caspo
fumigatusflavusnidulansterreusustusniger
CLSI 24 h Geo mean MIC (μgml) (MEC for Caspo)
Arikan et al Antimicrob Agents Chemother 2001 45 327 Arikan et al Antimicrob Agents Chemother 2002 46 3084 Arikan et al J Clin Microbiol 1999 37 3946 Meletiadis et al J Clin Microbiol 2002 40 2876 Kanj et al Medicine 1996 75 142 Iwen et al J Clin Microbiol 1998 36 3713 Denning et al Antimicrob Agents
Chemother 1997 41 1364 Cuenca-Estrella et al ICAAC 2012 San Francisco M-321
Antifungal Susceptibility
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
ICAAC 2012 San Francisco Abst no M-321 Population-Based Program of Aspergillus spp Antifungal Resistance in Spain (FILPOP STUDY)
Seven Spanish Hospitals Freq of antifungal resistance in two different periods
Oct 2010 May 2011
Resistance reported for EUCAST
method and brkpts
Alastruey-Izquierdo et al
Average prevalence of R lt 8
Resistance rate in crypticsibling species gt50
AMB resistance
A alliaceus A fumigatiaffinis
A insuetus A westerdijikiae A lentulus (66) A flavus (22)
A terreus (27)
Azole resistance Section Usti (all azoles)
A lentulus (Itra all isolates) A fumigatiaffinis (Itra all isolates)
A tubingensis (Itra one isolate) A fumigatus (Posa one isolate)
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Soil decaying vegetation manure foodstuff
INHALATION of the
aerosolized spores
Entry of spores through the
disrupted SKIN following
traumaburn
INGESTION of contaminated
foodstuff
Renovation
Routes of entry ndashOrder Mucorales
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Figure 2 Frequency of non-Aspergillus mould infections at Fred Hutchinson Cancer Research Center (Seattle) The number of patients who developed proven or probable infection with Fusarium species () Zygomycetes () and Scedosporium species () from 1985 through 1999 are shown
Fusarium
Zygomycetes
Scedosporium
Marr et al CID 2002 34 909
Any increase in non-Aspergillus moulds
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
0
2
4
6
8
10
12
14
16
18
20
1989-1993 1994-1998
cases100 000 admissions
Kontoyiannis et al Clin Infect Dis 2000 30851
MD Anderson Cancer Center Houston TX
Underlying
reason
Any increase in incidence of mucormycosis
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Imhof et al Clin Infect Dis 200439743
Chronic GVHD
Prophylactic vori
Histopathologic evidence
Vori for IA
Histopathologic evidence
Chronic GVHD
Prophylactic vori
Rhizopus microsporus
Vori for IA
Cunninghamella spp
Acute GVHD
Vori for IA
Rhizopus arrhizus
Vori for inv fusariosis
Histopathologic
evidence
Invasive Mucormycosis in HSCT Recipients Receiving Voriconazole
Siwek GT et al Clin Infect Dis 200439584
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Receiving voriconazole prophylaxis
Marty FM et al New Engl J Med 2004350950
bull Four cases of invasive mucormycosis (HSCT recipients)
bull Receiving immunosuppressive therapy for presumed GVHD
bull Three receiving voriconazole prophylaxis
bull One receiving empirical voriconazole therapy
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
13 European countries
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Maravi-Poma et al Intensive Care Med 200430724 Linder et al Am J Perinatol 19981535 Mathews et al J Med Vet Mycol 19973561 Mitchell et al Lancet 1996 17348441 Patterson et al Yale J Biol Med 1986 59453 Boyce et al South
Med J 1981741132 Mead et al JAMA 1979 20 242272
o Contaminated wooden tongue depressors o Contaminated elastic bandages o Nonsterile wound dressings o Postsurgical
Gastric mucormycosis
Primary cutaneous mucormycosis
Necrotizing fasciitis
Nosocomial mucormycosis
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
CONCLUSIONS Wooden tongue depressors contaminated by R microsporus var rhizopodiformis used to prepare oral medications (to be given through a NG catheter) caused an outbreak of fungal gastritis with an attributable mortality of 40
12-bed ICU Gastric mucormycosis-an outbreak of 5 patients
(4 pneumonia 1 polytrauma)
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
May-September 2004 Burns Unit
Admission 27 patients Burn wounds
Infected with Absidia 5 Colonized with Absidia 2
(attack rate 259100)
Christiaens et al J Hosp Infect 2005 61 88
Absidia corymbifera was cultured from a new brand of nonsterile elastoplast bandages which were in use for burns patients
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
ldquoCutaneous zygomycosis following attempted radial artery cannulationrdquo Kapadia amp Polenakovik Skinmed 2004 3 336
A 70-year-old man was seen in a hospital consultation for evaluation of cellulitis of
the left arm The patient had multiple medical problems including advanced liver
disease due to alcohol diabetes mellitus congestive heart failure atrial fibrillation
chronic renal in sufficiency and hypopituitarism requiring steroid replacement
Most recently he was admitted to the intensive care unit where he required
intubation and mechanical ventilation support following respiratory failure secondary to pneumonia At that time an attempt was also made to place an arterial line in the left radial artery A large bulla was found on the lateral aspect of the left wrist several days after the attempted arterial line placement Subsequently the lesion drained serosanguineous fluid and during the next 2 days
it ulcerated with necrosis extending around the wrist and to the elbowSmall
tissue clippings were taken from the edge of the lesion and placed on culture plates
By the next morning the patients tissue culture grew a mold later identified as
Rhizopus
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
0
5
10
15
20
25
30
35
40
Rhizopus Mucor Absidia Rhizomucor Cunninghamella Apophysomyces
Itra
Posa
Vori
Terbi
AMB
Dannaoui et al J Antimicrob Chemother 2003 51 45 Sun et al Antimicrob Agents Chemother 2002 46 1581 Tawara et al Antimicrob Agents Chemother 2000 44 57 Sun et al Antimicrob Agents Chemother 2002 46 2310 Sancak et al 3rd National Congress of Fungal Diseases and
Clinical Mycology S-13 378
CLSI 24 h Geo mean MIC
Antifungal susceptibility
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
AFST
Routine testing Not indicated
Clinical relevance unknown In vitro-in vivo correlation
R oryzae amp R microsporus
Posaconazole more effective in infs due to strains with MICs of 025 microgml as compared to those with MICs of 2 microgml
MIC
MFC High posaconazole MFC Clinical failure (R oryzae single strain)
CLSI M38-A2 EUCAST Def Doc EDef 91 Rodriguez et al AAC 2009 53 5022 Rodriguez et al AAC 2010 54 1665 Spreghini et al JAC 2010 65 2158
Mucorales
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Epidemiologic knowledge Genus- species- amp strain-based variations
AFST
Mucor Relatively high posaconazole
MICs
Rhizopus amp Mucor Species-based
differences in azole susceptibility
Rhizopus oryzae Strain-based variations in posaconazole susceptibility
Sun et al AAC 2002 46 1581 Dannaoui et al JAC 2003 51 45 Almyroudis et al AAC 2007 51 2587 Arikan et al Med Mycol 2008 46 567 Rodriguez et al AAC 2009 53 5022 Alastruey-Izuierdo et al AAC 2009 53 1686 Pastor et al AAC 2010 54 4550 Rodriguez et al AAC 2010 54 1665 Vitale et al JCM 2012 50 66
Drogari-Apiranthitou et al JAC 2012 67 1937
Cunninghamella Relatively high posaconazole
MICs (spec for C echinulata)
C bertholletiae Posaconazole
MICs lower than AMB MICs
Mucorales
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Italy Multicenter SEIFEM-2004 project
Hematological malignancy
Pagano et al Hematologica 2006 91 1068
Fusarium infections - Incidence
234 HSCT recs 250 IFIs
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Fusarium infections - Incidence North America Multicenter PATH Project
HSCT
Neofytos et al CID 2009 48 (1 Febr) 265
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Girmenia et al
Trends in epidemiology of fusariosis
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Courtesy of Prof Oliver Cornely
Risk factors for fusariosis
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Assessment of airborne mycoflora in critical areas of the Principal Hospital of Cumanaacute state of Sucre Venezuela [Article in Spanish] Centeno S Machado S Invest Clin 2004 Jun45(2)137-44
Surveillance of nosocomial fungal infections in a burn care unit Infection 1992 May-Jun20(3)132-5 India Chakrabarti A Nayak N Kumar PS Talwar P Chari PS Panigrahi D
(Portugal)
Fusarium is isolated during monitorization of airborne fungi in ICUs
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
283 hospital water system samples
(water tanks water showers sinks and swabs from sink shower heads and wall)
57
43
Fusarium spp (+)
Fusarium spp (-)
Anaissie et al CID 2001 33 1871 Anaissie et al Blood 2003 101 2542
Molecular match of strains of 8 fusariosis patients (F solani) with an environmental or another patientrsquos isolate
Hospital water system as the reservoir for Fusarium
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Inhalation of spores
primarily from air
secondarily by aerosolization from water
Nosocomial fusariosis Possible routes of acquisition
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
In vitro susceptibility
CLSI M38 microdilution24h
F solani F oxysporum
AMB 185-104 (1gt16) 238-19 (2-gt16)
Itra gt16 (gt16) 011 (003-025)
Vori 192-34 (025-8) 05-16 (025-2)
Posa 193 (1-gt16) 1 (1)
Ravu 274 (4-gt16) 56 (4-8)
Caspo (16-gt16) (16-gt16)
Arikan et al J Clin Microbiol 1999 37 3946 Arikan et al Antimicrob Agents Chemother 2002 46 245 Paphitou et al Antimicrob Agents Chemother 2002 46 3298 Pfaller et al Antimicrob Agents Chemother 2002 46 1032 Clancy et al EJ Clin Microbiol ID 1998 17 573
Macromicrodil adapted
from CLSI method
F proliferatum F verticilloides
AMB 1ndash2 1
Vori 1ndash2 05ndash2
Ravu 05ndashgt16
MIC range (microgml)
GM MIC (range) (microgml)
Clancy CJ Nguyen MH Eur J Clin Microbiol Infect Dis 199817573ndash5 Minassian B et al Clin Microbiol Infect 200391250ndash2 Lionakis MS et al Antimicrob Agents Chemother 2003473252ndash9
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Fsolani high azole MICs F verticillioides low posa MICs
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
BAL from 4 ICU patients grew F solani
The bronchoscope was in use only in ICU
The origin of the contamination of the bronchoscope could not be established
Fusarium was isolated from the water supply of the endoscopy department However water entering the endoscope washer-disinfector is passed through a 02 microm filter and rinse water cultures from the washer-disinfector were negative
J Hosp Infec 2008 1
Ireland
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Khor et al
Chang et al
Donnio et al Am J Ophthalmol 2007 143 356
Gorscak et al
Asia North America France Switzerland
Contact lens-associated fusarium keratitis in Switzerland Kaufmann et al Klin Monbl Augenheilkd 2008225418
Cornea 2007 26 1187
Gaujoux et al
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Inhalation
Trauma
Air-borne outbreak of nosocomial S prolificans infection has been reported
(leukemic patients in the same ward in rooms without HEPA filterslaminar airflows)
Guerrero et al Lancet 2001 357 1267
Scedosporium Routes of Entry ndash Airborne outbreaks
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Two fatal infections in immunocompromised patients caused by Scedosporium inflatum (prolificans)
Two fatal infections caused by Scedosporium inflatum in
immunocompromised patients are described One patient
developed peritonitis with this fungus 3 mths post renal
transplantation After a stormy course in the intensive care unit
he eventually died The other patient was suffering from non-
Hodgkins lymphoma and showed persistent neutropenia
Progressive deterioration occurred and disseminated fungal
infection was found at post mortem Both isolates were resistant
to all commonly available antifungal agents
Wise et al Pathology 1993 25 187
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Caira et al
Still very rare
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
2007 13 1170 Cooley et al
renovation
No significant change in the incidence of S apiospermum infections in time
renovation
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Grenouillet et al
But increased incidence in some centers
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
0
10
20
30
40
50
60
70
miconazole voriconazole albaconazole nystatin
apiospermum
prolificans
MIC90
(microgml)
Meletiadis et al Antimicrob Agents Chemother 2002 46 62 Meletiadis et al Antimicrob Agents Chemother 2003 47 106
Scedosporium In vitro antifungal susceptibility
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
AAC 2012 56 2635
N=332 CLSI M38-A2
Lowest MICs (MIC90 lt 2 microgml) of voriconazole as compared to to other drugs against P apiosperma and P boydii
AMB Itra Vori Posa Isavu Caspo Mica Anidula
Voriconazole being the only drug with meaningful activity against S aurantiacum (MIC90 = 1 microgml)
Bimodal distribution of MICs in general (except for voriconazole) rendering species-based susceptibility predictions difficult
Moderate activity of posaconazole and micafungin against a number of Scedosporium strains
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Resistance noted for AMB (some cases)
Azoles (Fluconazole) Flucytosine
Strabelli et al Rev Soc Bras Med Trop 1990 23 233 Fung-Tomc et al Antimicrob Agents Chemother 1998 42 313 Ioakimidou et al DMID 2013 75 313
Acremonium
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit Ioakimidou et al DMID 2013 75 313 Greece
Acremonium skin and soft tissue infection in a kidney transplant recipient
Israel et al Transplantation 2013 95 e20 USA
Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Roehm et al Int J Pediatr Otorhinolaryngol 2012 761387 USA
Acremonium kiliense reappraisal of its clinical significance (- peritonitis - CAPD) Khan et al JCM 2011 49 2342 Kuwait
Catheter-Related Acremonium kiliense Fungemia in a Patient with Ulcerative Colitis under Treatment with Infliximab Diacuteaz-Couselo amp Zylberman Case Rep Infect Dis 20112011710740 Argentina
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Resistance noted for
AMB (P lilanicus) Fluconazole itraconazole flucytosine (P lilanicus)
Aguilar et al Antimicrob Agents Chemother 1998 42 1601 Fung-Tonc et al Antimicrob Agents Chemother 1998 42 313
Paecilomyces Paecilomyces
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections Case Presentation and Review of Published Literature Rimawi et al Mycopathologia 2013 175 3459 (-Immcompromised host) USA
Simultaneous cutaneous infection due to Paecilomyces lilacinus and Alternaria in a heart transplant patient Lavergne et al Transpl Infect Dis 201214E156 France
Paecilomyces lilacinus peritonitis in a peritoneal dialysis patient Wolley et al Perit Dial Int 201232364
A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host Presenting as a Subcutaneous Swelling Permi et al J Lab Physicians 2011346 India
Paecilomyces lilacinus in transplant patients an emerging infection Rosmaninho et al Eur J Dermatol 2010 20 643 Portugal
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Resistance noted for
Fluconazole Flucytosine Itraconazole
Munoz et al J Clin Microbiol 1997 35 499 Richter et al J Clin Microbiol 1999 37 1154 Chouaki et al Clin Infect Dis 2002 35 1360
Cases of invasive infections hematologic malignancy organ transplant rec
MIC (μgml)
AMB 1-2
Itra 16
Vori 2
Trichoderma
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis Santillan Salas et al J Med Microbiol 2011 60(Pt 12)1869 USA
First case of Trichoderma longibrachiatum infection in a renal transplant recipient in Tunisia and review of the literature Trabelsi et al Tunis Med 2010 88 52 Tunisia
Fatal Trichoderma harzianum infection in a leukemic pediatric patient Kantarcıoğlu et al Med Mycol 2009 47 207 Turkey
Trichoderma fungaemia in a neutropenic patient with pulmonary cancer and HIV infection Lagrange-Xelot et al CMI 2008 14 1190 France
Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin Alanio et al CID 2008 46e116 France
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Resistance noted for
Fluconazole Flucytosine
Alternaria
Bipolaris Cladosporium
Husain et al Clin Infect Dis 2003 37 221 Mc Ginnis et al J Clin Microbiol 1998 36 2353 Sharkey et al J Am Acad Dermatol 1990 23 577 Mc Ginnis et al Med Mycol 1998 36 243
Dematiaceous moulds other than S prolificans
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
helliphellip Though they are uncommon causes of disease melanized fungi have been increasingly recognized as important pathogens with most reports occurring in the past 20 years The spectrum of diseases with which they are associated has also broadened and includes allergic disease superficial and deep local infections pneumonia brain abscess and disseminated infection For some infections in immunocompetent individuals such as allergic fungal sinusitis and brain abscess they are among the most common etiologic fungi Melanin is a likely virulence factor for these fungi hellipTriazoles such as voriconazole posaconazole and itraconazole have the most consistent in vitro activityhellip
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Courtesy of Prof Oliver Cornely
Risk factors for infections due to dematiaceous fungi
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Background information amp moulds as causative agents of infections
Diversity of epidemiology per the risk factor
HSCT amp hematological malignancies
Organ tx
ICU
Mould infections (Changing ) epidemiology reported outbreaks and in vitro susceptibility
Aspergillosis
Mucormycosis
Fusariosis
Scedosporiosis
Other emerging mould infections in high risk patients
Conclusions
Agenda
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Epidemiology of mould infections displays a variable trend
Increase in incidence of some of these infections is reported in some centers Among these genera that are less-susceptible or resistant to antifungal drugs do exist
Surveillance of local epidemiological trends remains of major significance in rational direction of antifungal
therapy
Conclusions
Thank you
Thank you
