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يدي يدي إليه إليهأصغيت.. .. أو ببصري تأملته أصغيت.. .. أو أو ببصري تأملته أو

بأذني بأذني إليه إليه

Invasive Fungal Infections Management

Updates Ahmed Saad MD. FACP.

Ass Prof .Cairo university

Review

• Different types of Invasive fungi

• Changing local epidemiology

• Risk factors

• Clinical picture

• Diagnosis

• Treatment & prophylaxis

Incidence of Systemic Infections: Bacterial vs Fungal

Martin GS, et al. N Engl J Med. 2003;348(16):1546-1554.

No.

of C

ases

of S

epsi

s

1991 1993 1995 1997 1999 2001

225,000

150,000

75,000

25,000

15,000

10,000

5000

0

Gram-positive bacteriaGram-negative bacteriaFungi

Year

Nosocomial Bloodstream Infections in US Hospitals: 1995-2002

CoNS, coagulase-negative staphylococci; BSI, blood stream infection.Surveillance and Control of Pathogens of Epidemiological Importance (SCOPE) study.Wisplinghoff H, et al. Clin Infect Dis. 2004;39:309-317.

9

Patients withcandidal bloodstream

infections

Adapted from Edmond MB et al Clin Infect Dis 1999;29:239–244.

0

5

10

15

20

25

30

35

40

45

40%

25%

Perc

ent o

f P

atie

nts

Patients with bacterial (non-candidal)

bloodstream infections

Invasive Candidiasis

Mortality Associated with Candidemia

Impact of delayed treatment on mortalityImpact of delayed treatment on mortality

Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005;49: 3640–5.

Epidemiology of Invasive Mycosis

Pfaller & Diekema, 2007, Clin. Micro. Rev. 20:133-163

Review

• Different types of Invasive fungi

• Changing epidemiology

• Clinical picture

• Risk factors

• Diagnosis

• Treatment & prophylaxis

Infections Caused by Non-Infections Caused by Non-albicans Candidaalbicans Candida Are IncreasingAre Increasing

Pfaller MA, et al. Clin Microbiol Rev. 2007;20(1):133-163.

0

10

20

30

40

50

60

70

80

90

100

1997-1998 1999 2000 2001 2002 2003

C. kruseiC. parapsilosis

C. tropicalisC. glabrataC. albicansOther

Neither C. glabrata nor C. krusei showed a consistent increase or decrease in isolation rates overall Increased rates of isolation of C. tropicalis (4.2% to 7.5% increase) and C. parapsilosis (4.6% to 7.3% increase)

were observed between 1997 and 2003 over 134,000 consecutive isolates of Candida from cases of invasive candidiasis at 127 medical centers

in 39 countries

Candida Species:Incidence vs Mortality

%

Candida Species

Incidence of Candida albicans, 45.6%; incidence of non-albicans Candida, 54.4%*

*This study is based on data for the 2019 patients (pediatric and adult) enrolled from July 1, 2004 through March 5, 2008 from 23North American centers who received a diagnosis of proven candidemia, including 2.1% other non-albicans Candida [C. lusitaniae,C. dubliniensis, C. guilliermondii, other (not specified), and unknown].

Horn DL, et al. Clin Infect Dis. 2009;48(12):1695-1703.

Invasive Fungal Infections

Aspergillus Candida

Kidney & liver 1.4–14% 0–10% 90–100%

Heart 5–20% 77–91% 8–23%

Lungs/Heart-Lungs 15–35% 25–50% 43–72%

Small Intestine 40–59% 0–3.6% 80–100%

Gabardi S. et al. Transplant Int 2007;20:993–1015, Singh N. Clin Infect Dis 2000:31;545–53.

Incidence of Fungal Infections after SOT

Denning Denning DWDW

Clin Infect Clin Infect DisDis

till 1995till 1995

Paterson DL, Paterson DL, Singh NSingh NMedicineMedicine

1987-19971987-1997

Lin QYLin QYClin Infect Clin Infect

DisDis1995-19991995-1999

Bone marrowBone marrow 90 % 92 % 86.7 %

AIDS/HIVAIDS/HIV 81 % - 85.7 %

Liver Liver transplant.transplant.

93 %93 % 87 %87 % 67.6 %67.6 %

Kidney Kidney transplant.transplant.

70 % 75 % 62.5 %

Lung Lung Transplant.Transplant.

77 % 55 % 62.5 %

Heart Heart transplant.transplant.

50 % 78 % 43.6 %

Pancreas Pancreas transplanttransplant

100 % -

Invasive Aspergillose : Mortality

Review

• Different types of Invasive fungi

• Our local data

• Clinical picture

• Risk factors

• Diagnosis

• Treatment & prophylaxis

Our local data For Candida fungogram for Candida Isolates (In-patient) March 2011- June 2012

CandidaAlbicans

Candida Tropicalis

CandidaGlabrata

CandicaParapsilosis

Candica Krusei

CandidaLusitaniae

Candida Dubliniensis

No. of Isolates 73 23 7 5 2 1 5Caspufugen 100 100 100 100 100 100 100Amphotericin B 96 98 100 100 100 100 100Flucytosine 97 100 100 100 50 100 66Fluconazole 97 89 66 100 0 100 100Voriconazole 100 100 66 100 100 100 100Caspofungin 100 100 100 100 100 100 100

Dr Erfan & Bagedo Hospital Data 2010

• Aspergillus +ve in 3 sputum samples & 24 environmental samples

sample Candida Parapsiliosis

Candida

Albicans

Candida Tropicalis

Candida

Glabrata

Candida

Krusie

Blood 8 6 6 1 1

BAL 9 1

Sputum 4

Urine 1 1

No of Candidal isolates (115) in 18 monthes

Candida albicans63.5%

Candida tropicalis20.0%

Candida glabrata6.1%

Candida parapsilosis4.3%

Candida krusei1.7%

Candida dublinensis4.3%

Candida Albicans

Amph

oter

icin

B

Flucyto

sine

Flucon

azole

Vorico

nazo

le

Caspo

fung

in0

20

40

60

80

100

120

Candida tropicalis

0

20

40

60

80

100

120

Candida Glabrata

Amph

oter

icin

B

Flucyto

sine

Flucon

azole

Vorico

nazo

le

Caspo

fung

in0

20

40

60

80

100

120

Candida parapsislosis

Amph

oter

icin

B

Flucyto

sine

Flucon

azole

Vorico

nazo

le

Caspo

fung

in0

20

40

60

80

100

120

Candida Krusei

0

20

40

60

80

100

120

Candida Dubliniensis

Amph

oter

icin

B

Flucyto

sine

Flucon

azole

Vorico

nazo

le

Caspo

fung

in0

20

40

60

80

100

120

Review

• Different types of Invasive fungi

• Epidemiology

• Risk factors

• Clinical picture

• Diagnosis

• Treatment & prophylaxis

Risk Factors for Invasive Candidiasis In ICU

3 antibiotics• Antibiotics 4 d• Time 4 d in ICU• Mechanical vent >48• Major Abd surgery• CVP• TPN

• Neutropenia• Immunosuppression• Concomitant infection• Diabetes mellitus• Candida coloniz 2 sites• Candiduria (>100,000

colonies)

Pappas PG et al. Clin Infect Dis 2004;38:161-189; Ostrosky-Zeichner L et al. Crit Care Med 2006;34:857-63

Invasive Aspergillosis: Risk factors Post liver transplant

Early IA < 3 months

OR (95% CI)p

Renal failure after SOT 4.9(2.4 -9.8) < 0.0001

Hemodialysis after SOT 3.2(1.3 - 8.1) 0.014

> 1 episode of bacterial infection

3.2(3.2 - 17.4) < 0.006

CMV disease 2.3(1.1 - 4.9) < 0.029

Gavaldà J et al, Clin Inf Dis 2005; 41:52-9

Reintervention is also risk factor

• High doses or prolonged duration of corticosteroids

• Graft failure requiring Hemodialysis

• Potent immunosuppressive therapy for rejection

Risk factors of IA after Renal transplantation

Singh N et al, Am J Transplant 2009, 9, S180-S191 .

• Isolation of Aspergillus from respiratory tract cultures

• Reintervention

• CMV disease

• Hemodialysis

Risk factors of IA after Heart transplantation

Munoz P et al, Curr Opin Infect Dis 2006; 19: 365-370 Singh N et al, Am J Transplant 2009, 9, S180-S191 .

Fungal Infection Post Biologics

Fungal Infection Post Biologics

Fungal Infection Post Biologics

• Till 2007 ,281 reports of invasive fungal infections (IFIs) associated with the 3 anti-TNF- alpha agents, ie, infliximab, etanercept, and adalimumab

• 226 (80%) were associated with infliximab, 44 (16%) with etanercept, and 11 (4%) with adalimumab

• Histoplasmosis (n=84 [30%]), candidiasis (n=64 [23%]), and aspergillosis (n equals 64 [23%]).

• Infliximab induces apoptosis memory T cells, whereas etanercept is antiapoptotic

Review

• Different types of Invasive fungi

• Epidemiology

• Clinical picture

• Risk factors

• Diagnosis

• Treatment & prophylaxis

SPECTRUM OF INVASIVE CANDIDA INFECTIONS

SPECTRUM OF INVASIVE CANDIDA INFECTIONS

candidemiacandidemia

organ infectionorgan infection

candidemia candidemia acuteacute

disseminateddisseminated candidiasis candidiasis

‘ ‘hepato-hepato- splenic’splenic’

candidiasis candidiasis

Candida: Infection sites

C. parapsilosisC. parapsilosisC. parapsilosisC. parapsilosis C. tropicalisC. tropicalisC. tropicalisC. tropicalis

C. albicansC. albicansC. albicansC. albicans

C. kruseiC. kruseiC. kruseiC. krusei

C. glabrataC. glabrataC. glabrataC. glabrata

Candida: Hepatosplenic candidiasis

FEVERFEVER

ALKALINE PHOSPHATASEALKALINE PHOSPHATASE

NEUTROPHILSNEUTROPHILS

DISSEMINATIONDISSEMINATION MICROCOLONIESMICROCOLONIES ‘BULLS EYE’‘BULLS EYE’

Renal candidiasis

Baseline After caspofunginCourtesy of John Rex, MD

Esophageal Candidiasis

Candida Retinitis

Candida Endocarditis

Interaction of Interaction of AspergillusAspergillus with the host with the host

A unique microbial-host interactionA unique microbial-host interaction

Immune dysfunction

Frequency

of a

sperg

illosis

Immune hyperactivity

Frequency

of

asp

erg

illosi

s

Acute IA

Subacute IA

AspergillomaChronic cavitaryChronic fibrosing

ABPAAllergic sinusitis

. www.aspergillus.man.ac.ukwww.aspergillus.man.ac.uk

TimeframesTimeframes

IPA days/1-4 weeks

Subacute IPA weeks/2-3 months

CCPA months/years

Aspergilloma months/years

AspergillomaAspergilloma

Patient RTDecember 2002

Cough (mild) &tired

Wythenshawe Hospital

Aspergilloma – may be mobile in the Aspergilloma – may be mobile in the cavitycavity

Upright Prone

Severo on www.aspergillus.man.ac.uk

AspergillomaAspergilloma

Severo on www.aspergillus.man.ac.uk

Fungal Sinusitis

Fungal Sinusitis

Aspergillus Endocarditis

Zygomycosis in SOT

• Rhinocerebral form

• 76% diabetes and corticosteroids

• 56% mortality

Review

• Different types of Invasive fungi

• Epidemiology

• Clinical picture

• Risk factors

• Diagnosis

• Treatment & prophylaxis

Invasive aspergillosis diagnosis

• Radiology: chest X-ray and CT• Microbiology

– Respiratory secretions: BAL/biopsy• Direct microscopy• culture

• PCR

Ergin et al. Transplant International 2003; 16: 280-286

IA in solid-organ transplant recipients

Diagnosis of Pulmonary Aspergillosis

•Pulmonary Infection

– Peripheral infiltrates

– "halo" sign on chest CT scan

– Broncho-alveolar lavage ++

• Direct exam, Culture, Ag, PCR

Halo sign ??

Fungal Pneumonia

Serology

• 1,3-,D-glucan is a component of fungal

cell walls that can be detected by serology

• One way to effectively use the 1,3-,D-glucan or galactomannan assays may be to serially screen patients who are at high risk for IFIs and/or use them to monitor response to therapy .

Review

• Different types of Invasive fungi

• Epidemiology

• Clinical picture

• Risk factors

• Diagnosis

• Treatment & prophylaxis

Antifungal Agents

Cell Membrane Active Antifungals

Cell membrane • Polyene antibiotics - Amphotericin B, lipid formulations

• Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole -Posaconazole

DNA/RNA synthesis Inhibitors Cell membrane • Polyene antibiotics • Azole antifungals

DNA/RNA synthesis • Pyrimidine analogues - Flucytosine

Cell wall • Echinocandins -Caspofungin acetate (Cancidas)

Cell Wall Active Antifungals

Cell membrane • Polyene antibiotics • Azole antifungals

DNA/RNA synthesis • Pyrimidine analogues - Flucytosine

Cell wall • Echinocandins -Caspofungin acetate - micafungin

Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001

Amphotericin B (Fungizone™) • Binds ergosterols in fungal cell membrane forming pores

in the membrane & interferes with permeability and transport functions.

• Broad spectrum antifungal

• Lipid formulations facilitate drug insertion within the fungal cytoplasmic membrane while reducing uptake in human cells, so limiting toxicity.

Lipid Amphotericin B Formulations

Ribbon-like particlesRibbon-like particlesCarrier lipids: DMPC, Carrier lipids: DMPC, DMPGDMPG (1:1)(1:1)Particle size Particle size (µm): 1.6-: 1.6-11 11

Abelcet Abelcet ®® ABLC ABLC Amphotec Amphotec ®® ABCD ABCD Ambisome Ambisome ®® L-AMB L-AMB

Disk-like particlesDisk-like particlesCarrier lipids: Cholesteryl Carrier lipids: Cholesteryl sulfate sulfateParticle size Particle size (µm): 0.12-: 0.12-0.14 0.14

UnilaminarUnilaminar liposomeliposomeCarrier lipids: HSPC, Carrier lipids: HSPC, DSPG, cholesterolDSPG, cholesterol(1:9)(1:9)Particle size Particle size (µm) : 0.08 : 0.08

DMPC-Dimyristoyl phospitidylcholineDMPG- Dimyristoyl phospitidylcglycerol

HSPC-Hydrogenated soy phosphatidylcholineDSPG-Distearoyl phosphitidylcholine

Lipid AMB Formulations-Summary

• Efficacy– Lipid formulation > AMB-deoxy

• Nephrotoxicity– L-AMB < ABLC < ABCD << AMB-deoxy

• Infusion related toxicity– L-AMB < ABLC < ABCD < AMB-deoxy

• Product cost (AWP)– L-AMB > ABLC > ABCD > AMB-deoxy

Amphotericin B - Nephrotoxicity

• Renovascular and tubular mechanisms– Vascular-(decrease in renal blood flow) leading to drop

in GFR, azotemia– Tubular-distal tubular ischemia, wasting of potassium,

sodium, and magnesium

• Sodium loading-> blunt the vasoconstriction and tubular-glomerular feedback– Administration of 500 ml of NaCl before and after

amphotericin B infusion

Azole Antifungals for Systemic Infections

• Itraconazole (Sporanox)• Fluconazole (Diflucan)• Voriconazole (Vfend)

Triazoles (3N)

“2nd generationtriazole”

Fluconazole Ketoconazole

Azoles - Mechanism

• Azoles bind to (fungal P450 enzymes) lanosterol 14-demethylase inhibiting the production of ergosterol– Some cross-reactivity is seen with

mammalian cytochrome p450 enzymes

• Drug Interactions• Impairment of steroidneogenesis

(ketoconazole, itraconazole)

Fluconazole

• Well tolerated• IV/PO formulations• Favorable

pharmacokinetics• Good activity against

C. albicans and Cryptococcus

• Fungistatic• Resistance is

increasing• Narrow spectrum• (Drug interactions)• Not in biofilm

Advantages Disadvantages

Key Biopharmaceutical Characteristics of the Triazole Antifungals

Fluconazole Voriconazole

Spectrum vs. Candida and Aspergillus

C. albicans, C. tropicalis +/-

No Aspergillus

Broad, includes most Candida spp., Aspergillus, Fusarium sp. Not Zygomycoses

Oral formulation

(% bioavailibility)

Tablet (>90%) Tablet (>90%)

Intravenous formulation

Available, no solubilizer Available, cyclodextrin

R.E. Lewis 2002. Exp Opin Pharmacother 3:1039-57.

Voriconazole –Dose & Side Effects

• Dose 6mg/kg 1st day 6mg/kg bid then 4mg/kg bid

• Visual disturbances (~ 30%)– Decreased vision, photophobia, altered color

perception and ocular discomfort– IV > oral– No evidence of structural damage to retina

The Fungal Cell Wall

mannoproteins

1,6glucans

1,3

chitin

ergosterol

1,3 glucansynthase

Cellmembrane

Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001

Echinocandins inhibition of ß-(1,3)glucan synthaseosmotic fragility

Echinocandins - spectrum

Highly activeCandida albicans, Candida glabrata,Candida tropicalis, Candida krusei

Low MIC ,with fungicidal activity and good in-vivo

Very activeCandida parapsilosisCandida gulliermondiiAspergillus fumigatusAspergillus flavus

Low MIC, but without fungicidal activity in most instances.

Echinocandins  Caspofungin Micafungin Anidulafungin

Absorption Not orally absorbed. IV only

Metabolism spontaneous degradation, hydrolysis and N-acetylation

Chemical degradated Not hepatically

metabolized

Elimination Limited urinary excretion. Not dialyzable

Half-life 9-23 hours 11-21 hours 26.5 hours

Dose 70 mg IV on day1, then 50 mg IVdaily thereafter

100 mg IVonce daily

200 mg IV on day 1,then 100 mg IVdaily thereafter

Dose Adjustment

Child-Pugh B70 mg IV on day 1, then 35 mg IV daily

thereafter

None None

Review

• Different types of Invasive fungi

• Changing epidemiology

• Risk factors

• Clinical picture

• Diagnosis

• Treatment &prophylaxis

• Updated guidelines

Candidemia• If species is unknown, either fluconazole (800mg loading dose, 400 mg

daily) or an echinocandin is appropriate initial therapy for most adult patients (AI)

• An echinocandin is favored if

– Moderately severe to severe illness.

– Recent azole use for treatment or prophylaxis (AIII), or

– Isolate is known to be C. glabrata or C. krusei (BIII)

• Fluconazole for patients who are

– less critically ill and

– who have no recent azole exposure (AIII).

• Remove or exchange intravenous catheters

• Treat for two weeks after clearance of bloodstream

IDSA Guidelines 2010.

Treatment optionsof blood candidal infections in adults

Treatment options of invasive fungal infections in adults 2010

Candidemia: catheter removal

• Removal of central venous line – is a consensus recommendation for the

non-hematological patients II A- in hematology patients the quality of

evidence is lower IIIB- removal is always recommended when

C parapsilosis is isolated II A

IDSA Guidelines 2010.

Duration of antifungal therapy in candidemia : recommendations

Non-neutropenic adults: at least 14 days after the last +ve

blood culture and resolution of signs and symptoms : III B

Neutropenic patients: at least 14 days after the last +ve

blood culture and resolution of signs and symptoms and

resolved neutropenia: III C

IDSA Guidilines 2010.

Invasive pulmonary aspergillosis :1st line

Agent Grade Comments

Voriconazole I A 2 x 6 mg/kg D1 then 4 mg/kg BID

Ambisome I B 3 – 5 mg/kg

Caspofungin I C

Amphotericin B I D

IDSA Guidelines 2010.

Treatment optionsof aspergillus infections

Treatment options of invasive fungal infections in adults 2010

Aspergillosis

• Surgery (CIII) in case of

– Lesion near to a large vessel

– Hemoptysis from a single lesion (embolization is an alternative)

– Localized extrapulmonary lesion including central nervous system lesion

– Fungal sinusitis

Empirical antifungal treatment in ICU

Clinical Prediction Rule Clinical Prediction Rule (CPR)(CPR)• All of

– [(day 1–3 of ICU stay): mechanical ventilation,

– broad spectrum antibiotics

– And central venous catheter CVC

• And ONE of– TPN (total parentral neutrition) (d1-3)

– Dialysis (d1-3)

– Major surgery (d-7-0),

– Pancreatitis (d-7-0),

– Steroids (d-7-3),

– Other immunosuppressive agents (d-7-0)].

sensitivity of 90%, a specificity of 48%

Ostrosky-Zeichner L, et al. 2007. Eur J Clin Microbiol Infect Dis, 26:271–6.Ostrosky-Zeichner L, et al. Mycoses. 2011 Jan;54

The Candida ScoreThe Candida Score• Parenteral nutrition ................................................. (+1)

• Prior surgery ............................................................ (+1)

• Multifocal Candida colonization *........................... (+1)

• Severe sepsis ........................................................... (+2)

The authors concluded that a “Candida score” of 2.5 could accurately select patients who would benefit from early antifungal treatment

Empirical antifungal treatment in ICU

Leon C, et al. 2006. Crit Care Med, 34:730–7.Leon C, et al. 2009 Crit Care Med 37:1624–1633.

• Lipid formulation of AmB (II 2)– 3-5 mg/kg/day

• Or an Echinocandin (II 3)

• Duration 3-4 weeks or until resolution of risk factors

Prophylaxis of high-risk patients after Liver

transplantation (Recommendations of the AST Infectious disease Community of

Practice)

Singh N et al, Am J Transplant 2009, 9, S180-S191 .

Prophylaxis for high-risk patients after Lung transplantation (recommendations of the AST Infectious disease Community of

Practice) • Inhaled lipid formulations of amphotericin B

– Nebulized L-AmB• 25 mg three times per week x 2 months

• In high-risk patients

– Voriconazole* : 400 mg/day x 4 months

Singh N et al, Am J Transplant 2009, 9, S180-S191 .

• Voriconazole– 200mg BID for 50-150 days

Prophylaxis for high-risk patients after

Heart transplantation (Recommendations of the AST Infectious disease Community of

Practice)

Singh N et al, Am J Transplant 2009, 9, S180-S191 .

Antifungal prophylaxis in haematology patients

3rd European Conference on Infections in Leukaemia (ECIL-3)

CLINICAL MICROBIOLOGY AND INFECTION April 2012