TOWARDS PRE-EMPTIVE? TRADITIONAL DIAGNOSIS. GALACTOMANNAN Sensitivity 61% Specificity 93% Neg Predict Value >95% β-d-glucan Neg Predict Value 100% PCR

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1 TOWARDS PRE-EMPTIVE? GALACTOMANNAN Sensitivity 61% Specificity 93% Neg Predict Value >95% TRADITIONAL DIAGNOSIS β-d-glucan Neg Predict Value 100% PCR diagnostics FUNGAL BURDEN

2 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

3 METHODS TO DIAGNOSE INVASIVE ASPERGILLOSIS FOR TRIAL INCLUSION Herbrecht et al. ICAAC, San Francisco 2006; Abstract M-896 AmBiload study (n=201) galacto mannan radiology microbiology histology culture

4 ESTIMATING TIME FOR INTERVENTION Aspergillus Persisting fever + very high risk or a suggestive symptom or a suspected sign or any positive test day 1 5 infiltrate antigen 7 12 // 28 > 42

5 EMPIRICAL OR PRE-EMPTIVE? Cordonnier et al. Blood 2006; 108: abstr 2019 PRE-EMPTIVE imaging clinics laboratory neutropenic patients EMPIRICAL 3 days persisting fever 150 9% End of neutropenia invasive fungus 3% 46% antifungals 66% 2218 mean costs % survivors 98%

6 PROPHYLAXIS EMPIRICAL THERAPY invasive fungal disease

7 PROPHYLAXIS invasive aspergillosis POSA CONAZOLE NOT PRESENT EMPIRICAL invasive CASPO fungal FUNGIN aspergillosis LIPOSOMAL NOT AMPHO B EXCLUDED (PRE-EMPTIVE) THERAPY invasive VORI- CONAZOLE aspergillosis

8 THE BEST CHOICE Selection criteria: Established efficacy in proven disease Safety and compatibility / interactions Intravenous and oral formulation

9 OF NOTE! Independent of the indication, the antifungal with the highest efficacy against the presumed pathogen must be administered in optimal doses! fungal burden empiric setting full blown infection setting tissue tissuelevel levelantifungal antifungal tissue level antifungal

10 EORTC IFICG % response RESULTS FIRST LINE TREATMENT OF INVASIVE ASPERGILLOSIS Herbrecht et al N Engl J Med 2002; 347: Cornely et al. Clin Infect Dis 2007; 44: Candoni et al. Eur J Haematol 2005; 75: /133 (32%) 76/144 (53%) Ampho B Voriconazole 53/107 (50%) 18/32 (56%) Lipo-AmB Caspofungin

11 CASPOFUNGIN AS SECONDARY PROPHYLAXIS OF INVASIVE ASPERGILLOSIS IN BMT De Fabritiis et al. Bone Marrow Transpl 2007; 40: patients with invasive aspergillosis BMT with caspofungin Day 30 Day 180

12 HIGH VERSUS STANDARD DOSE LIPO AMPHO-B FOR INVASIVE MOULD INFECTIONS Cornely et al. Clin Infect Dis 2007; 44: liposomal 201 lipos ampho B ampho-b proven & probable 10 mg/kg x 14 Invasive mould infections 3 mg/kg/day followed by 3 mg/kg/day % End of treatment Favorable response 50% 31% nephrotoxicity 14% 30% hypokalaemia 16% 59% Survivors 12 weeks 72%

13 POSACONAZOLE RESULTS FIRST LINE TREATMENT ASPERGILLOSIS

14 CLINICAL FEATURES CANDIDIASIS

15 COMPARISON OF RESULTS FROM CLINICAL TRIALS ON CANDIDEMIA response mortality Fluconazole 400 mg/day 72% 39% Amphotericin B 40% 40% 34% Micafungin Caspofungin Anidulafungin Voriconazole 79% 62% 71% 74% 74% 76% 65% 30% 36%

16 IERI, OGGI, E DOMANI

17 IERI, OGGI, E DOMANI

18 IERI, OGGI, E DOMANI MSG EORTC

19 THERAPEUTIC TOOLS mainly laboratory knowledge increased knowledge amongst clinicians chest X-ray bronchoalveolar lavage chest CT scan galactomannan, PCR β-d-glucan-test? intuition based strategies rational strategies amphotericin B 5-flucytosine surgery voriconazole caspofungin (candins) lipid amphotericin B (posaconazole)

20 KEY ISSUES Mycology for clinical decisions Tools to select a treatment strategy Selection of the appropriate drug Open ends

21 KEY ISSUES Mycology for clinical decisions Tools to select a treatment strategy Selection of the appropriate drug Open ends

22 CONSIDER PROPHYLAXIS IF Martino P, Girmenia C, Venditti M, Girmenia C, Mandelli F. Candida colonization and systemic infection in neutropenic patients. Cancer 1989; 64: THE PATIENT: Shows mucosal damage 30% Is colonized by Candida 70% Receives broad-spectrum antimicrobials 85% TARGETTED PROPHYLAXIS = PRE-EMPTIVE

23 ALGORITHMS?

24 CORTICOSTEROIDS AND SURVIVAL OF ASPERGILLOSIS IN HSCT Cordonnier et al. Clin Infect Dis 2006;42: patients with aspergillosis low dose corticosteroids S U R V I V A L 0 high dose weeks 41 allo HSCT 10 auto

25 DECISIVE BASIC ELEMENTS FOR THE OUTCOME OF INVASIVE FUNGAL INFECTIONS appropriate antifungal recovered host defense system early phase of infection inappropriate deteriorating full blown

26 KEY ISSUES Mycology for clinical decisions Tools to select a treatment strategy Selection of the appropriate drug Open ends

27 ADJUNCTIVE DIAGNOSTIC TESTS FOR DIAGNOSIS OF INVASIVE FUNGAL INFECTIONS Review of 391 cases of IFI in patients with hematological malignancies, Diagnosis made pre mortem 79% CXR sensitivity 77%; CT sensitivity 94% Pagano et al. Haematologica 86 BAL culture sensitivity 66% (2001) 1

28 EVOLUTION OF ASPERGILLUS INFECTIONS AMONGST PATIENTS WITH ACUTE LEUKEMIA Pagano et al. Clin Infect Dis 2007; 44: new antifungals Incidence (%) % 50% 40% 9 30% 6 PCR CT-scan galactomannan % 10% 2006 attributable mortality

29 KEY ISSUES Mycology for clinical decisions Tools to select a treatment strategy Selection of the appropriate drug Open ends

30 SUCCESS - FAILURE PATIENT PATIENT DISEAS E keep alive efficac y DOCTO DOCTOR R THERAP DRU YG

31 invasive aspergillosis YES cyclosporin NO P450 inducers AmBisome liverfunction abnormal caspofungin failure?? G(M)CSF? interferon? combinations?? voriconazole

32 STRATEGY FOR THE TREATMENT OF DISSEMINATED CANDIDIASIS Spellberg et al. Clin Infect Dis 2006; 42: flucon azole Spellberg Filler Edwards invasive candidiasis proven / probable NO (risk of) C.glabrata C.krusei? YES NO hemodynamically unstable? echinocandin lipid ampho-b voriconazole YES

33 KEY ISSUES Mycology for clinical decisions Tools to select a treatment strategy Selection of the appropriate drug Open ends

34 COMBINATION ANTIFUNGAL THERAPY Possible benefits Improve efficacy Reduce toxicity Reduce risk of resistance Possible disadvantages Risk of antagonism Price

35 IERI, OGGI, E DOMANI

36 IERI, OGGI, E DOMANI

37 INDICATIONS FOR ANTIFUNGALS prophylaxis empirical pre-emptive pathogen-driven

38 MULTIPLE MYELOMA PATIENT WITH FDGPET SCAN DEMONSTRATING ASPERGILLUS INFECTION Aspergilloma

39 COURSE OF β-d-glucan TO MONITOR THERAPY OF INVASIVE FUNGAL INFECTIONS Senn et al. Clin Infect Dis 2008;46: patients treated for acute leukemia 190 neutropenic episodes β-d-glucan pg/ml Response No response Time after onset of fever

40 NEW DRUGS Posaconazole? Ravuconazole?? Isavuconazole Micafungin Anidulafungin Immune manipulation

41 TARGETS 2008 Adequate treatment strategies dosing liposomal amphotericin B rescue after voriconazole zygomycetes Improved diagnostics agreement galactomannan PCR evolvement PET scanning Better drugs posaconazole other azoles candins Increased basic knowledge

42 REMEMBER

43 PIERO, GRAZIE!!