TREATMENT STRATEGIES FOR INVASIVE FUNGAL INFECTIONS Part I: - - PowerPoint PPT Presentation

TREATMENT STRATEGIES FOR INVASIVE FUNGAL INFECTIONS Part I: EMPIRICAL THERAPY

CAUSES OF DEATH IN PATIENTS WITH MALIGNANCIES NIJMEGEN, THE NETHERLANDS CAUSES OF DEATH IN PATIENTS WITH MALIGNANCIES NIJMEGEN, THE NETHERLANDS

BACTERIAL INFECTION

FUNGAL INFECTION

MULTIFACTORIAL HEMORRHAGE n = 328 n = 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

invasive fungal infection NOT PRESENT invasive fungal infection NOT PRESENT invasive fungal infection NOT EXCLUDED invasive fungal infection NOT EXCLUDED invasive fungal infection invasive fungal infection

PROPHYLAXIS EMPIRICAL THERAPY THERAPY PROPHYLAXIS EMPIRICAL THERAPY THERAPY

invasive fungal infection NOT EXCLUDED invasive fungal infection NOT EXCLUDED

MORTALITY OF INVASIVE ASPERGILLOSIS MORTALITY OF INVASIVE ASPERGILLOSIS

Variation due to:

• timing of intervention

(timely diagnosis)

97% 22%

EVOLUTION OF AN INFECTION AND MORTALITY EVOLUTION 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% within 12 hrs 12-24 hrs 24-48 hrs >48 hrs

mortality

ITRACONAZOLE VS AMPHOTERICIN-B FOR FUNGAL INFECTIONS IN NEUTROPENIA

UNIVERSITY HOSPITAL NIJMEGEN

ITRACONAZOLE VS AMPHOTERICIN-B FOR FUNGAL INFECTIONS IN NEUTROPENIA

UNIVERSITY HOSPITAL NIJMEGEN

n = 64 n = 64 DOCUMENTED PROBABLE POSSIBLE OVERALL ITRACONAZOLE AMPHOTERICIN-B ITRACONAZOLE AMPHOTERICIN-B RESPONSE RATES RESPONSE RATES RESPONSE RATES RESPONSE 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 proven/ possible S U R V I V A L

62% 42% 56% 40% voriconazole liposomal ampho B halo no halo probable proven % favorable response 100 50 IMPACT OF EARLY VERSUS LATE INTERVENTION

Greene et al. Clin Infect Dis 2007; 44:373-379 Cornely 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 AUTOPSY

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

INVASIVE 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 -- DISEASE INFECTION -- DISEASE

YIELD OF DIAGNOSTIC PROCEDURES AND EVOLUTION OF FUNGAL INFECTION YIELD OF DIAGNOSTIC PROCEDURES AND EVOLUTION OF FUNGAL INFECTION

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

yield of diagnostic interventions yield of diagnostic interventions yield of diagnostic interventions yield of diagnostic interventions time time time time

MAKE YOUR CHOICE! MAKE YOUR CHOICE!

AMPHOTERICIN-B FOR FEVER PERSISTING 4-7 DAYS AMPHOTERICIN-B FOR FEVER PERSISTING 4-7 DAYS

EORTC EORTC IFICG IFICG

NO AMPHO-B AMPHO-B 31% 6% 9% 2%

PERCENTAGE OF SYSTEMIC FUNGUS PERCENTAGE OF SYSTEMIC FUNGUS

Pizzo et al AJM 1982 16 vs 18 pat EORTC AJM 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 FUO and neutropenia (n=50)

continue n=16 stop all antibiotics 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%

continue antibiotics n=64 continue antibiotics 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 IFICG IFICG

61 61 61 61 45 45 45 45 41 41 41 41 61 61 78 78 75 75 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 antibacterials antibacterials

<100

GRANULOCYTES

1000 500 >1000

0 10 20 30 days

CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES

Still fever despite antibiotics

CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES

... 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; 43:577-584

88 cases

10 20 30 40 50 60 70 80 90 100 f e v e r d y s p n e a c

• u

g h c h e s t p a i n n e u r

• l
• g

y s k i n h e m

• p

t y s i s b a c t e r i a l h a l

• s

i g n

total neutropenia non-neutropenia

CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES

... it can be a fungus!

CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES

..so, what can I do?

CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES

... it can be a fungus!

Diagnosis Change antibiotics

GROWTH OF ASPERGILLUS GROWTH OF ASPERGILLUS

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

ONE WEEK LATER…. ONE WEEK LATER….

CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES Diagnosis Change antibiotics

CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES CHOICES Diagnosis Empirical antifungal therapy Change antibiotics

REPORTED NEED FOR EMPIRICAL ANTIFUNGALS REPORTED NEED FOR EMPIRICAL ANTIFUNGALS

20 40 60 80

Goodman Slavin McMillan Rotstein Winston Mattiuzi Penack Harrouseau Nucci Behre Cordonnier

2006 Blood 1995 Ann Hema 2000 CID 2000 AAC 2005 ICAAC 2003 Cancer 1993 Annals 1999 CID 2002 Am J Med 1995 JID 1992 NEJM

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

DIAGNOSIS DIAGNOSIS THERAPY THERAPY

97% 22%

NEW DIAGNOSTIC TOOLS? NEW DIAGNOSTIC TOOLS? FUNGAL BURDEN

diagnostics

HIGH RESOLUTION CT SCAN GALACTOMANNAN β-D-GLUCAN PCR TRADITIONAL DIAGNOSIS NEW TOOLS

1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 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

S U R V I V A L 0 50 100 150 200 days systematic CT-scan CT-scan on indication RETROSPECTIVE ANALYSIS n = 37 RETROSPECTIVE ANALYSIS 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 MASS

Marr et al. J Infect Dis 2004;190:641-649

LEVEL OF GALACTMANNAN TITER: INDICATIVE OF FUNGAL MASS

Marr et al. J Infect Dis 2004;190:641-649

1106 samples from 79 bone marrow transplant recipients number Proven Probable positive test 8 5 62% 40% Overall

LEVEL OF GALACTMANNAN TITER: INDICATIVE OF FUNGAL MASS

Marr et al. J Infect Dis 2004;190:641-649

LEVEL OF GALACTMANNAN TITER: INDICATIVE OF FUNGAL MASS

Marr et al. J Infect Dis 2004;190:641-649

1106 samples from 79 bone marrow transplant recipients number Proven Probable Proven Probable Proven Probable positive test 8 5 5 5 7 5 62% 40% 20% 17% 88% 80% Overall On antifungals No antifungals

COMPARISON SEROLOGICAL TEST FOR THE DETECTION OF ASPERGILLOSIS

Kawazu et al. J Clin Microbiol 2004;42:2733-2741

COMPARISON SEROLOGICAL TEST FOR THE DETECTION OF ASPERGILLOSIS

Kawazu 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

Florent et al. J Infect Dis 2006;193:741-747 201 febrile episodes in patients with hematological malignancy 2x weekly PCR-ELISA and Galactomannan

sensitivity Galactomannan (cut-off 0.5) PCR PCR + galacto- mannan 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

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

FIRST TEST POSITIVE FOR ASPERGILLOSIS IN HEMATOLOGICAL MALIGNANCIES

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

culture histology CT GM antigen PCR PCR

SELECTION OF A STRATEGY SELECTION OF A STRATEGY OPTIMAL DIAGNOSTIC FACILITIES Easy access CT facilities Well equipped laboratory EXTENSIVE EXPERIENCE Specialists in house Common patient population PRE-EMPTIVE APPROACH OPTIMAL DIAGNOSTIC FACILITIES Easy access CT facilities Well equipped laboratory EXTENSIVE EXPERIENCE Specialists in house Common patient population PRE-EMPTIVE APPROACH LIMITED DIAGNOSTIC FACILITIES LIMITED EXPERIENCE EMPIRICAL APPROACH LIMITED DIAGNOSTIC FACILITIES LIMITED EXPERIENCE EMPIRICAL APPROACH

OUTCOME OF SEROLOGIC TESTS AND IMPLICATIONS FOR TREATMENT OF INVASIVE FUNGAL INFECTIONS OUTCOME OF SEROLOGIC TESTS AND IMPLICATIONS FOR TREATMENT OF INVASIVE FUNGAL INFECTIONS *NEGATIVE does not exclude infection *POSITIVE does not prove infection PAY ATTENTION ALWAYS BE CAREFUL !!!!

€ €2337 2337 € €2218 2218 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% 143 143 150 150 9% 3% 95% 95% 98% End of neutropenia invasive fungus survivors End of neutropenia invasive fungus survivors PRE-EMPTIVE PRE-EMPTIVE imaging imaging clinics clinics laboratory laboratory PRE-EMPTIVE PRE-EMPTIVE imaging imaging clinics clinics laboratory laboratory EMPIRIC EMPIRIC 3 days 3 days persisting fever persisting fever EMPIRIC EMPIRIC 3 days 3 days persisting fever persisting fever 293 neutropenic patients antifungals mean costs

empirical 62% pre- emptive 29% targetted 9%

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 STRATEGY BUILDING AN ANTIFUNGAL STRATEGY EMPIRICAL ADMINISTRATION ANTIFUNGALS EMPIRICAL 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

25 50 75 100 60 120 180 240 300 360 90-92 93-95 96-98 99-01

02-04

days probability of death

MAMBO DAY NUMBER 5 CREATIVE USE OF ANTIFUNGALS MAMBO DAY NUMBER 5 CREATIVE 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 -- DISEASE INFECTION -- DISEASE