TREATMENT STRATEGIES FOR INVASIVE FUNGAL INFECTIONS. Part I: EMPIRICAL THERAPY

Transcription

1 TREATMENT STRATEGIES FOR INVASIVE FUNGAL INFECTIONS Part I: EMPIRICAL THERAPY

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

3 INVASIVE FUNGAL DISEASE AFTER NON-MYELOABLATIVE ALLO-BMT Fukuda et al. Blood 2003; 102: % non-relapse mortality 9% o m 39% mould-related e r uld e t la n = 163 e d d s h at

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

5 PROPHYLAXIS EMPIRICAL THERAPY invasive fungal infection NOT EXCLUDED THERAPY

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

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

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

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

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

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

12 1980: DIAGNOSTIC DILEMMAS IN THE MANAGEMENT OF FUNGAL INFECTIONS Clinical symptoms not characteristic Manifestations on imaging seldom specific Biopsy often precluded by co-morbidity

13 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% BAL culture sensitivity 66%

14 INVASIVE FUNGUS AT AUTOPSY Sinko et al Transpl Infect Dis 2008; 10: Review of 97 autopsies after allogeneic bone marrow transplantation: Invasive fungus NOT diagnosed ante mortem: 60% (in spite of galactomannan screening)

15 AUTOPSY FINDINGS IN NEUTROPENIC PATIENTS Bodey GP et al. Eur J Clin Microbiol Infect Dis 1992; 11: UP TO 30% OF PATIENTS WITH INVASIVE FUNGAL DISEASE AT AUTOPSY NEVER RECEIVED ANY SYSTEMIC ANTIFUNGAL THERAPY

16 INFECTION -- DISEASE

17 YIELD OF DIAGNOSTIC PROCEDURES AND EVOLUTION OF FUNGAL INFECTION time evolution of the infection yield of diagnostic interventions

18 MAKE YOUR CHOICE!

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

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

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

22 ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO THE COURSE OF NEUTROPENIA 100% antibacterials GRANULOCYTES 75% 50% > < days

23 CHOICES CHOICES CHOICES Still fever despite antibiotics

24 CHOICES CHOICES CHOICES... it can be a fungus!

25 SYMPTOMS OF INVASIVE ASPERGILLOSIS IN NEUTROPENIA AND NON-NEUTROPENIA Cornillet et al. Clin Infect Dis 2006; 43: cases ba ct er ia ha l lo si gn si s op ty sk in he m y ne ur ol og pa in h ch es t co ug ea sp n dy fe ve r total neutropenia non-neutropenia

26 CHOICES CHOICES CHOICES... it can be a fungus!

27 CHOICES CHOICES CHOICES..so, what can I do?

28 CHOICES CHOICES CHOICES... it can be a fungus! Diagnosis Change antibiotics

29 GROWTH OF ASPERGILLUS 1-2 cm per 24 hours

30 ONE WEEK LATER.

31 CHOICES CHOICES CHOICES Diagnosis Change antibiotics

32 CHOICES CHOICES CHOICES Empirical antifungal therapy Diagnosis Change antibiotics

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

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

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

36 THE DUEL SIS O GN A I D THE RAP Y

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

38 IMPACT OF SYSTEMATIC CT-SCAN ON THE OUTCOME OF PULMONARY ASPERGILLOSIS Caillot et al. J Clin Oncol 1997; 15: RETROSPECTIVE ANALYSIS n = 37 S U 60 R V 30 I 20 V 10 0 A 0 L systematic CT-scan CT-scan on indication 50 DAYS TO DIAGNOSIS days SYSTEMATIC CT-SCAN BEFORE AFTER FROM FIRST MOMENT OF SUSPICION 7±5 2±1

39 LEVEL OF GALACTMANNAN TITER: INDICATIVE OF FUNGAL MASS Marr et al. J Infect Dis 2004;190: samples from 79 bone marrow transplant recipients Overall Proven Probable number 8 5 positive test 62% 40%

40 LEVEL OF GALACTMANNAN TITER: INDICATIVE OF FUNGAL MASS Marr et al. J Infect Dis 2004;190: samples from 79 bone marrow transplant recipients number 8 5 positive test 62% 40% On antifungals Proven Probable % 17% No antifungals Proven Probable % 80% Overall Proven Probable

41 COMPARISON SEROLOGICAL TEST FOR THE DETECTION OF ASPERGILLOSIS Kawazu et al. J Clin Microbiol 2004;42: epsiodes in 96 patients with hematological malignancy sensitivity P.P.V. N.P.V. 100% 55% 100% PCR 55% 40% 96% Glucan-test 55% 40% 96% Galactomannan ELISA (cut-off 0.6)

42 COMPARISON SEROLOGICAL TESTS FOR THE DETECTION OF ASPERGILLOSIS Florent et al. J Infect Dis 2006;193: febrile episodes in patients with hematological malignancy 2x weekly PCR-ELISA and Galactomannan sensitivity specificity P.P.V. Galactomannan (cut-off 0.5) 75% 22% 9% PCR 88% 55% 36% 100% 11% 10% PCR + galactomannan

43

44 FIRST TEST POSITIVE FOR ASPERGILLOSIS IN HEMATOLOGICAL MALIGNANCIES Florent et al. J Infect Dis 2006;193: GM antigen CT culture histology PCR DAYS 55 patients

45 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 LIMITED DIAGNOSTIC FACILITIES LIMITED EXPERIENCE EMPIRICAL APPROACH

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

47 EMPIRICAL OR PRE-EMPTIVE? Cordonnier et al. Clin Infect Dis 2009; 48: PRE-EMPTIVE imaging clinics laboratory neutropenic patients EMPIRIC 3 days persisting fever 150 9% End of neutropenia invasive fungus 3% 46% antifungals 66% 2218 mean costs 95% survivors %

48 TREATMENT STRATEGIES OF ASPERGILLOSIS ARISING DURING AML IN DAILY PRACTICE Pagano et al. SEIFEM probable/proven cases targetted 9% preemptive 29% attributable mortality 27% empirical 62%

49 BUILDING AN ANTIFUNGAL STRATEGY EMPIRICAL ADMINISTRATION ANTIFUNGALS therapeutic diagnostics antifungals

50 VORICONAZOLE FOR ASPERGILLOSIS AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION probability of death Upton et al. Clin Infect Dis 2007; 44: days

51 MAMBO DAY NUMBER 5 CREATIVE USE OF ANTIFUNGALS A little bit of fluco makes me smile A little bit of ampho for my pride A little bit of lipo for a while A little bit of Cancidas by my side Text: Peter Donnelly

52

53 INFECTION -- DISEASE