TREATMENT STRATEGIES FOR INVASIVE FUNGAL INFECTIONS … pauw presentat… · TREATMENT STRATEGIES...

TREATMENT STRATEGIES FOR INVASIVE FUNGAL INFECTIONS

Part I:EMPIRICAL THERAPY

CAUSES OF DEATH IN PATIENTS WITH MALIGNANCIESNIJMEGEN, THE NETHERLANDS

CAUSES OF DEATH IN PATIENTS WITH MALIGNANCIESNIJMEGEN, THE NETHERLANDS

BACTERIAL INFECTION

FUNGAL INFECTION

MULTIFACTORIAL

HEMORRHAGE

n = 328n = 328

7%

36%

40%

17%

INVASIVE FUNGAL DISEASE AFTER NON-MYELOABLATIVE ALLO-BMT

Fukuda et al. Blood 2003; 102:827-833

INVASIVE FUNGAL DISEASE AFTER NON-MYELOABLATIVE ALLO-BMT

Fukuda et al. Blood 2003; 102:827-833

22% non-relapse mortality

39% mould-related

9% mould-related deaths

n = 163

PROPHYLAXIS EMPIRICAL THERAPY THERAPY PROPHYLAXIS EMPIRICAL THERAPY THERAPY

invasivefungal

infectionNOT

PRESENT

invasivefungal

infectionNOT

PRESENT invasivefungal

infectionNOT

EXCLUDED

invasivefungal

infectionNOT

EXCLUDED invasivefungal

infection

invasivefungal

infection

PROPHYLAXIS EMPIRICAL THERAPY THERAPY PROPHYLAXIS EMPIRICAL THERAPY THERAPY

invasivefungal

infectionNOT

EXCLUDED

invasivefungal

infectionNOT

EXCLUDED

MORTALITY OF INVASIVE ASPERGILLOSISMORTALITY OF INVASIVE ASPERGILLOSIS

Variation due to: •timing of intervention (timely diagnosis)

97%

22%

EVOLUTION OF AN INFECTION AND MORTALITYEVOLUTION OF AN INFECTION AND MORTALITY

FUNGAL BURDEN

97%

22%

RELATION INITIATION ANTIFUNGAL THERAPY AND OUTCOME OF CANDIDEMIA

Morrell et al. Antimicrob Ag Chemother 2005; 49:3640-3645

RELATION INITIATION ANTIFUNGAL THERAPY AND OUTCOME OF CANDIDEMIA

Morrell et al. Antimicrob Ag Chemother 2005; 49:3640-3645

134 cases of candidemia

0%

5%

10%

15%

20%

25%

30%

35%

within12 hrs

12-24hrs

24-48hrs

>48hrs

mortality

ITRACONAZOLE VS AMPHOTERICIN-B FORFUNGAL INFECTIONS IN NEUTROPENIA

UNIVERSITY HOSPITAL NIJMEGEN

ITRACONAZOLE VS AMPHOTERICIN-B FORFUNGAL INFECTIONS IN NEUTROPENIA

UNIVERSITY HOSPITAL NIJMEGEN

n = 64n = 64

DOCUMENTED

PROBABLE

POSSIBLE

OVERALL

ITRACONAZOLE AMPHOTERICIN-BITRACONAZOLE AMPHOTERICIN-BRESPONSE RATESRESPONSE RATESRESPONSE RATESRESPONSE RATES

25%

70%

80%

63%

0%

75%

65%

43%

SURVIVAL OF ASPERGILLOSIS IN RELATION TO PRESUMED RISK FACTORS

Nivoix, Y et al. Clin Infect Dis 2008; 47:1176-1184

SURVIVAL OF ASPERGILLOSIS IN RELATION TO PRESUMED RISK FACTORS

Nivoix, Y et al. Clin Infect Dis 2008; 47:1176-1184 n = 289

prov

en/

pos

sibl

e

SURVIVAL

62%

42%

56%

40%

voriconazole liposomal ampho B

halo no halo probable proven

% f

avor

able

res

pon

se

100

50

0

IMPACT OF EARLY VERSUS LATE INTERVENTION

Greene et al. Clin Infect Dis 2007; 44:373-379Cornely et al. J Antimicrob Chemother 2010; 65:114-117

1980: DIAGNOSTIC DILEMMAS IN THE MANAGEMENT OF FUNGAL INFECTIONS

1980: DIAGNOSTIC DILEMMAS IN THE MANAGEMENT OF FUNGAL INFECTIONS

Clinical symptoms not characteristic

Manifestations on imaging seldom specific

Biopsy often precluded by co-morbidity

ADJUNCTIVE DIAGNOSTIC TESTS FOR DIAGNOSIS OF INVASIVE FUNGAL INFECTIONS

Pagano et al Haematologica 2004; 86

ADJUNCTIVE DIAGNOSTIC TESTS FOR DIAGNOSIS OF INVASIVE FUNGAL INFECTIONS

Pagano et al Haematologica 2004; 86

Review of 391 cases of IFI in patients with

hematological malignancies:

•Not diagnosed ante mortem 21%21%

•BAL culture sensitivity 66%

INVASIVE FUNGUS AT AUTOPSYSinko et al Transpl Infect Dis 2008; 10:106-109INVASIVE FUNGUS AT AUTOPSY

Sinko et al Transpl Infect Dis 2008; 10:106-109

Review of 97 autopsies after

allogeneic bone marrow transplantation:

•Invasive fungus NOT diagnosed ante

mortem:

60%60%

(in spite of galactomannan screening)

AUTOPSY FINDINGS IN NEUTROPENIC PATIENTS

Bodey GP et al. Eur J Clin Microbiol Infect Dis 1992; 11:99-109.

UP TO 30%30% OF PATIENTS WITH

INVASIVE FUNGAL DISEASE

AT AUTOPSY

NEVER RECEIVED ANY

SYSTEMIC ANTIFUNGAL THERAPY

INFECTION -- DISEASEINFECTION -- DISEASE

YIELD OF DIAGNOSTIC PROCEDURES AND EVOLUTION OF FUNGAL INFECTION

YIELD OF DIAGNOSTIC PROCEDURES AND EVOLUTION OF FUNGAL INFECTION

evolution of the infectionevolution of the infection evolution of the infectionevolution of the infection

yield of diagnostic interventionsyield of diagnostic interventions yield of diagnostic interventionsyield of diagnostic interventions

timetime timetime

MAKE YOUR CHOICE!MAKE YOUR CHOICE!

AMPHOTERICIN-B FOR FEVER PERSISTING 4-7 DAYS

AMPHOTERICIN-B FOR FEVER PERSISTING 4-7 DAYS

EORTC EORTC IFICGIFICG

NO AMPHO-B

AMPHO-B

31%

6%

9%

2%

PERCENTAGE OF SYSTEMIC FUNGUSPERCENTAGE OF SYSTEMIC FUNGUS

Pizzo et alAJM 1982

16 vs 18 pat

EORTCAJM 1989

64 vs 68 pat

THE BASIS FOR EMPIRIC ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENICS

Pizzo et al. Am J Med 1982; 72:101-110

THE BASIS FOR EMPIRIC ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENICS

Pizzo et al. Am J Med 1982; 72:101-110

persisting FUOand neutropenia

(n=50)

continuen=16

stop allantibiotics

n=16

add 0.5 mg/kg/day

amphotericin n=18

6%6%

36%

6%

EARLY EMPIRICAL ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENICS

EORTC. Am J Med 1989; 86:668-72

EARLY EMPIRICAL ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENICS

EORTC. Am J Med 1989; 86:668-72

50%50%50%50% 69%69%

continueantibiotics

n=64

continueantibiotics

n=64

add 0.6 mg/kg/day

amphotericin n=68

add 0.6 mg/kg/day

amphotericin n=68

persisting FUO or CDI

and neutropenia

persisting FUO or CDI

and neutropenia

EORTC EORTC IFICGIFICG

61616161

45454545

41414141

6161

7878

7575

with prophylaxis

no prophylaxis

CDI

DEFERVESCENCE

100%

75%

50%

ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO THE COURSE OF NEUTROPENIA

ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO THE COURSE OF NEUTROPENIA

antibacterialsantibacterials

<100GR

AN

ULO

CY

TES

1000

500

>1000

0 10 20 30 days

CHOICES CHOICES CHOICESCHOICES CHOICES CHOICESCHOICES CHOICES CHOICESCHOICES CHOICES CHOICES

Still fever despite

antibiotics


... it can be a

fungus!

SYMPTOMS OF INVASIVE ASPERGILLOSIS IN NEUTROPENIA AND NON-NEUTROPENIA

Cornillet et al. Clin Infect Dis 2006; 43:577-584

SYMPTOMS OF INVASIVE ASPERGILLOSIS IN NEUTROPENIA AND NON-NEUTROPENIA

Cornillet et al. Clin Infect Dis 2006; 43:577-58488 cases

0102030405060708090

100

feve

r

dyspnea

cough

ches

t pain

neurolo

gysk

in

hemop

tysis

bacter

ial

halo si

gn

totalneutropenia

non-neutropenia


... it can be a

fungus!


..so, what can I do?


... it can be a

fungus!

Diagnosis

Change antibiotics

GROWTH OF ASPERGILLUSGROWTH OF ASPERGILLUS

1-2 cm per 24 hours1-2 cm per 24 hours

ONE WEEK LATER….ONE WEEK LATER….


Diagnosis

Change antibiotics


Diagnosis

Empirical antifungal therapy

Change antibiotics

REPORTED NEED FOR EMPIRICAL ANTIFUNGALSREPORTED NEED FOR EMPIRICAL ANTIFUNGALS

0 20 40 60 80

Goodman

Slavin

McMillan

Rotstein

Winston

Mattiuzi

Penack

Harrouseau

Nucci

Behre

Cordonnier 2006 Blood 1995 Ann Hema2000 CID2000 AAC2005 ICAAC2003 Cancer1993 Annals1999 CID2002 Am J Med1995 JID1992 NEJM

RECOMMENDATIONS IDSA 2002Hughes et al. Clin Infect Dis 2002; 34:730-751

RECOMMENDATIONS IDSA 2002Hughes et al. Clin Infect Dis 2002; 34:730-751

UNEXPLAINED FEVER AND NEUTROPENIA

DEFERVESCENCE NO DEFERVESCENCE

antibiotics for 3-5 days

ANTIFUNGAL

PERCEIVED NEED OF

EMPIRICAL THERAPY

(EUROPEAN GUIDELINE EXPERTS)

E.C.I.L.

PERCEIVED NEED OF

EMPIRICAL THERAPY

(EUROPEAN GUIDELINE EXPERTS)

E.C.I.L.

THE DUELTHE DUEL

DIAGNOS

IS

DIAGNOS

ISTHERAPYTHERAPY

97%

22%

NEW DIAGNOSTIC TOOLS?NEW DIAGNOSTIC TOOLS?

FUNGAL BURDEN

diagnostics

HIGH RESOLUTION CT SCAN

GALACTOMANNAN

β-D-GLUCAN

PCR

TRADITIONAL DIAGNOSIS

NEW TOOLS

01 0

2 03 0

4 05 0

6 07 0

8 09 0

1 0 0

IMPACT OF SYSTEMATIC CT-SCAN ON THE OUTCOME OF PULMONARY ASPERGILLOSIS

Caillot et al. J Clin Oncol 1997; 15:139-147

IMPACT OF SYSTEMATIC CT-SCAN ON THE OUTCOME OF PULMONARY ASPERGILLOSIS

Caillot et al. J Clin Oncol 1997; 15:139-147

SURVIVAL 0 50 100 150 200 days

systematic CT-scan

CT-scan on indication

RETROSPECTIVEANALYSIS

n = 37

RETROSPECTIVEANALYSIS

n = 37

DAYS TO DIAGNOSIS FROM FIRST MOMENT OF SUSPICION

7 ± 5

2 ± 1

SYSTEMATIC CT-SCAN BEFORE AFTER

LEVEL OF GALACTMANNAN TITER:INDICATIVE OF FUNGAL MASSMarr et al. J Infect Dis 2004;190:641-649


1106 samples from 79 bone marrow transplant recipients

numberProvenProbable

positive test85

62%40%

Overall



1106 samples from 79 bone marrow transplant recipients

numberProvenProbable

ProvenProbable

ProvenProbable

positive test85

55

75

62%40%

20%17%

88%80%

Overall

On antifungals

No antifungals

COMPARISON SEROLOGICAL TEST FOR THE DETECTION OF ASPERGILLOSISKawazu et al. J Clin Microbiol 2004;42:2733-2741

COMPARISON SEROLOGICAL TEST FOR THE DETECTION OF ASPERGILLOSISKawazu et al. J Clin Microbiol 2004;42:2733-2741

149 epsiodes in 96 patients with hematological malignancy

sensitivity

Galactomannan ELISA (cut-off 0.6)

PCR

Glucan-test

P.P.V. N.P.V.

100%

55%

55%

55%

40%

40%

100%

96%

96%

COMPARISON SEROLOGICAL TESTS FOR THE DETECTION OF ASPERGILLOSIS

Florent et al. J Infect Dis 2006;193:741-747

COMPARISON SEROLOGICAL TESTS FOR THE DETECTION OF ASPERGILLOSIS


201 febrile episodes in patients with hematological malignancy 2x weekly PCR-ELISA and Galactomannan

sensitivity

Galactomannan (cut-off 0.5)

PCR

PCR + galactomannan

75%

88%

100%

P.P.V.

9%

36%

10%

specificity

22%

55%

11%

0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 DAYS 0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 DAYS

55 patients 55 patients

FIRST TEST POSITIVE FOR ASPERGILLOSIS IN HEMATOLOGICAL MALIGNANCIES


FIRST TEST POSITIVE FOR ASPERGILLOSIS IN HEMATOLOGICAL MALIGNANCIES


culturehistology

CT

GMantigen

PCRPCR

SELECTION OF A STRATEGYSELECTION OF A STRATEGY

OPTIMAL DIAGNOSTIC FACILITIESEasy access CT facilitiesWell equipped laboratory

EXTENSIVE EXPERIENCESpecialists in houseCommon patient population

PRE-EMPTIVE APPROACH

OPTIMAL DIAGNOSTIC FACILITIESEasy access CT facilitiesWell equipped laboratory

EXTENSIVE EXPERIENCESpecialists in houseCommon patient population

PRE-EMPTIVE APPROACH

LIMITED DIAGNOSTIC FACILITIES

LIMITED EXPERIENCE

EMPIRICAL APPROACH

LIMITED DIAGNOSTIC FACILITIES

LIMITED EXPERIENCE

EMPIRICAL APPROACH

OUTCOME OF SEROLOGIC TESTSAND IMPLICATIONS FOR TREATMENT

OF INVASIVE FUNGAL INFECTIONS

OUTCOME OF SEROLOGIC TESTSAND IMPLICATIONS FOR TREATMENT

OF INVASIVE FUNGAL INFECTIONS

*NEGATIVE

does not exclude infection

*POSITIVE

does not prove infection

PAY ATTENTION ALWAYS BE CAREFUL !!!!

€€23372337€€22182218

EMPIRICAL OR PRE-EMPTIVE?Cordonnier et al. Clin Infect Dis 2009; 48:1042-1051

EMPIRICAL OR PRE-EMPTIVE?Cordonnier et al. Clin Infect Dis 2009; 48:1042-1051

66%46%46%

143143 150150

9% 3%

95%95% 98%

End of neutropeniainvasive fungus

survivors

End of neutropeniainvasive fungus

survivors

PRE-EMPTIVEPRE-EMPTIVEimaging imaging

clinicsclinicslaboratorylaboratory

PRE-EMPTIVEPRE-EMPTIVEimaging imaging

clinicsclinicslaboratorylaboratory

EMPIRICEMPIRIC

3 days 3 days persisting feverpersisting fever

EMPIRICEMPIRIC

3 days 3 days persisting feverpersisting fever

293neutropenic patients

antifungals

mean costs

empirical62%

pre-emptive29%

targetted9%

TREATMENT STRATEGIES OF ASPERGILLOSIS ARISING DURING AML IN DAILY PRACTICE

Pagano et al. SEIFEM 2008

TREATMENT STRATEGIES OF ASPERGILLOSIS ARISING DURING AML IN DAILY PRACTICE

Pagano et al. SEIFEM 2008

140 probable/proven cases

attributable mortality 27%

BUILDING AN ANTIFUNGAL STRATEGYBUILDING AN ANTIFUNGAL STRATEGYEMPIRICAL ADMINISTRATION ANTIFUNGALSEMPIRICAL ADMINISTRATION ANTIFUNGALS

diagnostics

therapeutic antifungals

VORICONAZOLE FOR ASPERGILLOSIS AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION

Upton et al. Clin Infect Dis 2007; 44:531-540

VORICONAZOLE FOR ASPERGILLOSIS AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION

Upton et al. Clin Infect Dis 2007; 44:531-540

0

25

50

75

100

0 60120

180240

300360

90-9293-9596-9899-0102-04

days

pro

babi

lity

of d

eath

MAMBO DAY NUMBER 5CREATIVE USE OF ANTIFUNGALS

MAMBO DAY NUMBER 5CREATIVE USE OF ANTIFUNGALS

A little bit of lipo for a while

A little bit of Cancidas by my side

A little bit of fluco makes me smile

A little bit of ampho for my pride

Text: Peter Donnelly

INFECTION -- DISEASEINFECTION -- DISEASE

TREATMENT STRATEGIES FOR INVASIVE FUNGAL INFECTIONS … pauw presentat… · TREATMENT STRATEGIES...

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