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 CAUSES OF DEATH IN PATIENTS WITH MALIGNANCIES NIJMEGEN, THE NETHERLANDS NIJMEGEN, THE NETHERLANDS n = 328 n = 328 BACTERIAL INFECTION 7% FUNGAL INFECTION 36% MULTIFACTORIAL 40% HEMORRHAGE 17%

INVASIVE FUNGAL DISEASE AFTER INVASIVE FUNGAL DISEASE AFTER NON-MYELOABLATIVE ALLO-BMT NON-MYELOABLATIVE ALLO-BMT Fukuda et al. Blood 2003; 102:827-833 Fukuda et al. Blood 2003; 102:827-833 22% non-relapse mortality n = 163 9% mould-related deaths 39% mould-related

PROPHYLAXIS EMPIRICAL THERAPY THERAPY PROPHYLAXIS EMPIRICAL THERAPY THERAPY invasive invasive fungal fungal infection infection NOT NOT invasive invasive PRESENT PRESENT fungal fungal infection infection NOT NOT EXCLUDED EXCLUDED invasive invasive fungal fungal infection infection

PROPHYLAXIS EMPIRICAL THERAPY THERAPY PROPHYLAXIS EMPIRICAL THERAPY THERAPY invasive invasive fungal fungal infection infection NOT NOT EXCLUDED EXCLUDED

MORTALITY OF INVASIVE ASPERGILLOSIS MORTALITY OF INVASIVE ASPERGILLOSIS 97% 22% Variation due to: • timing of intervention (timely diagnosis)

EVOLUTION OF AN INFECTION AND MORTALITY EVOLUTION OF AN INFECTION AND MORTALITY 97% 22% FUNGAL BURDEN

RELATION INITIATION ANTIFUNGAL THERAPY RELATION INITIATION ANTIFUNGAL THERAPY AND OUTCOME OF CANDIDEMIA AND OUTCOME OF CANDIDEMIA Morrell et al. Antimicrob Ag Chemother 2005; 49:3640-3645 Morrell et al. Antimicrob Ag Chemother 2005; 49:3640-3645 134 cases of candidemia 35% 30% 25% 20% 15% mortality 10% 5% 0% within 12-24 24-48 >48 12 hrs hrs hrs hrs

ITRACONAZOLE VS AMPHOTERICIN-B FOR ITRACONAZOLE VS AMPHOTERICIN-B FOR FUNGAL INFECTIONS IN NEUTROPENIA FUNGAL INFECTIONS IN NEUTROPENIA UNIVERSITY HOSPITAL NIJMEGEN UNIVERSITY HOSPITAL NIJMEGEN n = 64 n = 64 RESPONSE RATES RESPONSE RATES RESPONSE RATES RESPONSE RATES ITRACONAZOLE AMPHOTERICIN-B ITRACONAZOLE AMPHOTERICIN-B DOCUMENTED 25% 0% PROBABLE 70% 75% POSSIBLE 80% 65% OVERALL 63% 43%

SURVIVAL OF ASPERGILLOSIS IN RELATION SURVIVAL OF ASPERGILLOSIS IN RELATION TO PRESUMED RISK FACTORS TO PRESUMED RISK FACTORS Nivoix, Y et al. Clin Infect Dis 2008; 47:1176-1184 Nivoix, Y et al. Clin Infect Dis 2008; 47:1176-1184 n = 289 possible proven/ S U R V I V A L

IMPACT OF EARLY VERSUS LATE INTERVENTION Greene et al. Clin Infect Dis 2007; 44:373-379 Cornely et al. J Antimicrob Chemother 2010; 65:114-117 100 voriconazole liposomal ampho B % favorable response 56% 62% 50 40% 42% 0 halo no halo probable proven

1980: DIAGNOSTIC DILEMMAS IN THE 1980: DIAGNOSTIC DILEMMAS IN THE MANAGEMENT OF FUNGAL INFECTIONS MANAGEMENT OF FUNGAL INFECTIONS  Clinical symptoms not characteristic  Manifestations on imaging seldom specific  Biopsy often precluded by co-morbidity

ADJUNCTIVE DIAGNOSTIC TESTS FOR ADJUNCTIVE DIAGNOSTIC TESTS FOR DIAGNOSIS OF INVASIVE FUNGAL INFECTIONS DIAGNOSIS OF INVASIVE FUNGAL INFECTIONS Pagano et al Haematologica 2004; 86 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 INVASIVE FUNGUS AT AUTOPSY Sinko et al Transpl Infect Dis 2008; 10:106-109 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 . 30% OF PATIENTS WITH UP TO 30% INVASIVE FUNGAL DISEASE AT AUTOPSY NEVER RECEIVED ANY SYSTEMIC ANTIFUNGAL THERAPY

INFECTION -- DISEASE INFECTION -- DISEASE

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

MAKE YOUR CHOICE! MAKE YOUR CHOICE!

AMPHOTERICIN-B FOR EORTC AMPHOTERICIN-B FOR EORTC IFICG IFICG FEVER PERSISTING 4-7 DAYS FEVER PERSISTING 4-7 DAYS Pizzo et al EORTC AJM 1982 AJM 1989 16 vs 18 pat 64 vs 68 pat PERCENTAGE OF SYSTEMIC FUNGUS PERCENTAGE OF SYSTEMIC FUNGUS NO AMPHO-B 31% 9% AMPHO-B 6% 2%

THE BASIS FOR EMPIRIC ANTIFUNGAL THE BASIS FOR EMPIRIC ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENICS THERAPY IN FEBRILE NEUTROPENICS Pizzo et al. Am J Med 1982; 72:101-110 Pizzo et al. Am J Med 1982; 72:101-110 persisting FUO and neutropenia (n=50) add 0.5 stop all mg/kg/day antibiotics continue amphotericin n=18 n=16 n=16 6% 6% 6% 36%

EORTC EORTC IFICG IFICG EARLY EMPIRICAL ANTIFUNGAL THERAPY EARLY EMPIRICAL ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENICS IN FEBRILE NEUTROPENICS EORTC. Am J Med 1989; 86:668-72 EORTC. Am J Med 1989; 86:668-72 add 0.6 add 0.6 persisting persisting continue continue mg/kg/day mg/kg/day antibiotics antibiotics FUO or CDI FUO or CDI amphotericin amphotericin n=64 n=64 n=68 n=68 and neutropenia and neutropenia 50% 69% 50% 69% 50% 50% DEFERVESCENCE with prophylaxis 61 61 61 61 61 61 78 45 78 45 45 no prophylaxis 45 75 41 75 41 41 41 CDI

ADMINISTRATION OF ANTIMICROBIALS IN ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO THE COURSE OF NEUTROPENIA RELATION TO THE COURSE OF NEUTROPENIA 100% antibacterials antibacterials 75% 50% GRANULOCYTES >1000 1000 500 <100 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 SYMPTOMS OF INVASIVE ASPERGILLOSIS IN NEUTROPENIA AND NON-NEUTROPENIA NEUTROPENIA AND NON-NEUTROPENIA Cornillet et al. Clin Infect Dis 2006; 43:577-584 Cornillet et al. Clin Infect Dis 2006; 43:577-584 88 cases 100 total 90 neutropenia 80 non-neutropenia 70 60 50 40 30 20 10 0 r a n n s n h y l a e i e i g i g g s a k i v n o r i u y p s s e e p l o t o f t p t o s c c r s o y l u a e a d m b e h h n e c h

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 Empirical antifungal therapy Diagnosis Change antibiotics

REPORTED NEED FOR EMPIRICAL ANTIFUNGALS REPORTED NEED FOR EMPIRICAL ANTIFUNGALS 2006 Blood Cordonnier 1995 Ann Hema Behre 2000 CID Nucci 2000 AAC Harrouseau Penack 2005 ICAAC Mattiuzi 2003 Cancer 1993 Annals Winston 1999 CID Rotstein McMillan 2002 Am J Med Slavin 1995 JID Goodman 1992 NEJM 0 20 40 60 80

RECOMMENDATIONS IDSA 2002 RECOMMENDATIONS IDSA 2002 Hughes et al. Clin Infect Dis 2002; 34:730-751 Hughes et al. Clin Infect Dis 2002; 34:730-751 UNEXPLAINED FEVER AND NEUTROPENIA antibiotics for 3-5 days DEFERVESCENCE NO DEFERVESCENCE ANTIFUNGAL

PERCEIVED PERCEIVED NEED OF NEED OF EMPIRICAL EMPIRICAL THERAPY THERAPY ( EUROPEAN ( EUROPEAN GUIDELINE GUIDELINE EXPERTS ) EXPERTS ) E.C.I.L. E.C.I.L.

THE DUEL THE DUEL DIAGNOSIS DIAGNOSIS THERAPY THERAPY

NEW DIAGNOSTIC TOOLS? NEW DIAGNOSTIC TOOLS? TRADITIONAL HIGH RESOLUTION DIAGNOSIS CT SCAN 97% NEW GALACTOMANNAN TOOLS β-D-GLUCAN PCR 22% diagnostics FUNGAL BURDEN

IMPACT OF SYSTEMATIC CT-SCAN ON THE IMPACT OF SYSTEMATIC CT-SCAN ON THE OUTCOME OF PULMONARY ASPERGILLOSIS OUTCOME OF PULMONARY ASPERGILLOSIS Caillot et al. J Clin Oncol 1997; 15:139-147 Caillot et al. J Clin Oncol 1997; 15:139-147 RETROSPECTIVE RETROSPECTIVE ANALYSIS ANALYSIS 1 0 0 n = 37 n = 37 systematic CT-scan 9 0 S 8 0 U 7 0 R 6 0 CT-scan on indication 5 0 V 4 0 I 3 0 2 0 V 1 0 A 0 L 0 50 100 150 200 days SYSTEMATIC CT-SCAN BEFORE AFTER DAYS TO DIAGNOSIS FROM FIRST MOMENT OF SUSPICION 7 ± 5 2 ± 1