PROGRESSI NELLA TERAPIA ANTIFUNGINA. A tribute to Piero Martino

Transcription

1 PROGRESSI NELLA TERAPIA ANTIFUNGINA A tribute to Piero Martino

2 ITALIAN ICONS

3 IERI, OGGI, E DOMANI

4 IERI, OGGI, E DOMANI

5 IERI, OGGI, E DOMANI 1961

6 CAUSES OF DEATH IN PATIENTS WITH MALIGNANCIES NIJMEGEN, 1988 n = 328 BACTERIAL INFECTION FUNGAL INFECTION 7% 36% MULTIFACTORIAL 40% HEMORRHAGE 17%

7 CRUCIAL FACTORS more complex interventions higher age more co-morbidity less mortality from other causes -underlying disease -better antibacterial therapy

8 NATURE DEPENDS ON RENEWAL

9 NATURE DEPENDS ON RENEWAL

10 NATURE DEPENDS ON RENEWAL

11 CLEANING UP NATURE.

12 WELCOME TO MYCOLOGY YEAST *candida *cryptococcus conidia septate hyphae hyphae pseudohyphae MOULD conidium *aspergillus *fusarium *(mucormycosis)

13 LETHALITY OF THE VARIOUS INVASIVE FUNGAL INFECTIONS s u ll i g r e 42% p s A 33% 61% 53% m u i r sa Zy go m yc et es number of cases Pagano et al. Haematologica 2006; 91: Fu 50% 29% s on a u d c r i o c d n co sp a o ho C t p ic y r Cr T cases casualties

14 IERI, OGGI, E DOMANI

15 IERI, OGGI, E DOMANI 1990 mainly laboratory knowledge chest X-ray bronchoalveolar lavage intuition based strategies amphotericin B 5-flucytosine surgery TOOLS TO MANAGE INVASIVE FUNGUS DISEASE

16 RESPONSE TO TREATMENT FOR ASPERGILLOSIS IN NORMAL PRACTICE Patterson et al. Medicine 2000;79: n P A T I E N T S ampho B 32%

17 PROBLEMS High morbidity and mortality Difficult to diagnose Antifungals are toxic Low numbers in single centers MULTICENTER TRIALS

18 INTERNATIONAL COLLABORATION EORTC IFIG Chairman: Ben de Pauw Secretary: Pietro Martino

19 TARGETS 1994 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

20 ALGORITHMS + -

21 PROPHYLAXIS invasive fungal infection NOT PRESENT EMPIRICAL THERAPY invasive fungal infection NOT EXCLUDED THERAPY invasive fungal infection (INCIPIENT)

22 IERI, OGGI, E DOMANI INDICATIONS FOR ANTIFUNGALS prophylaxis empirical pre-emptive pathogen-driven

23 PROPHYLAXIS invasive fungal infection NOT PRESENT EMPIRICAL THERAPY invasive fungal infection NOT EXCLUDED THERAPY invasive fungal infection (INCIPIENT)

24 PROPHYLAXIS invasive fungal infection NOT PRESENT EMPIRICAL THERAPY

25 PROPHYLAXIS WITH FLUCONAZOLE IN BONE MARROW TRANSPLANTATION Goodman et al. N Engl J Med 1992; 326: 845 FLUCONAZOLE n = 179 INVASIVE FUNGUS 3% CANDIDIASIS PLACEBO n = % 0% 10% SUPERFICIAL 8% 33% FATAL FUNGUS 1% 6%

26 FLUCONAZOLE vs AMPHOTERICIN-B PROPHYLAXIS IN NEUTROPENIA Menichetti et al. Ann Int Med 1994 n = 708 FLUCONAZOLE NEED FOR I.V. ANTIFUNGALS PROVEN/PROBABLE FUNGAL INFECTION AMPHO-B ORALLY 15% 17% 3% 3%

27 IERI, OGGI, E DOMANI

28 COLONIZATION-INVASION Martino P, Girmenia C, Venditti M, Girmenia C, Mandelli F. Candida colonization and systemic infection in neutropenic patients. Cancer 1989; 64: Initial situation colonization invasion

29 RISK FACTOR SELECTION Martino P, Girmenia C, Venditti M, Girmenia C, Mandelli F. Candida colonization and systemic infection in neutropenic patients. Cancer 1989; 64: Risk factors Infection fever Underlying disease selection antibacterials colonization chemical & physical damage mucosa instruments + knife puncture skin gut

30 GROUPS BENEFITTING FROM FLUCONAZOLE PROPHYLAXIS IN NEUTROPENIA Rotstein et al. Clin Infect Dis 1999;28:331 overall antibacterial prophylaxis induction therapy -aggressive -moderate consolidation therapy rapid marrow recovery colonization

31 INVENTARISATION USE OF ANTIFUNGAL PROPHYLAXIS IN STEM CELL TRANSPLANTS Trifilio et al. Bone Marrow Transpl 2004; 33: centers (USA) 2001 >3000 transplant recipients fluconazole itraconazole ampho B iv none autologous allogeneic

32 ITRACONAZOLE VERSUS PLACEBO FOR PROPHYLAXIS IN HAEMATONCOLOGY Menichetti et al. Clin Infect Dis 1999;28:250 double blind ITRACONAZOLE PLACEBO solution 2dd2.5mg/kg n = 201 n = 204 PROVEN / PROBABLE INVASIVE ASPERGILLUS 2% 1% CANDIDA 1% 4% 1% 3% 18% 13% FUNGUS ASSOCIATED DEATH CESSATION DUE TO SIDE EFFECTS

33 POSACONAZOLE vs FLU AS PROPHYLAXIS IN ALLO STEM CELL TRANSPLANTATION Ullmann et al. N Engl J Med 2007; 356: allo HSCT, double-blind 16 weeks FLUCONAZOLE POSACONAZOLE 400 mg/day iv/po n = 299 INVASIVE FUNGUS 200 mg/day tid n = 301 7% 2% 6% 1% 4% 1% OVERALL MORTALITY 28% 25% ADVERSE EVENTS 38% 36% ASPERGILLOSIS FATAL FUNGUS

34 POSACONAZOLE vs AZOLES AS PROPHYLAXIS IN MYELOID MALIGNANCIES Cornely et al. N Engl J Med 2007; 356: Randomized; AML, MDS 12 weeks AZOLES 400 mg/day iv/po n = 298 POSACONAZOLE 200 mg/day tid n = 304 INVASIVE FUNGUS 8% 2% ASPERGILLOSIS 7% 1% FATAL FUNGUS 5% 2% 22% 16% SERIOUS ADVERSE EVENTS 2% 6% OVERALL MORTALITY

35 PUTATIVE ANTIFUNGAL STRATEGY start PROPHYLAXIS EMPIRICAL (PRE-EMPTIVE) THERAPY P E T End of treatment episode DIAGNOSTICS start ULLMANN CORNELY REPORTS P E DIAGNOSTICS T End of treatment Aspergillosis Fungal death Overall mortality

36 POSACONAZOLE ASPERGILLOSIS PROPHYLAXIS STUDIES (1) Cornely et al - Ullmann et al. N Engl J Med 2007 CORNELY FATAL FUNGUS COMPARATOR POSACONAZOLE ULLMANN FATAL FUNGUS DIAGNOSTICS?? AUTOPSY - BIOPSY - GALACTOMANNAN -- 5% 2% 4% 1% NOT MENTIONED NOT MENTIONED SUPPRESSED BY POSACONAZOLE!

37 DEATH AS A PARAMETER OF OUTCOME DEATH AND SURVIVAL DEPEND ON TREATMENT UNDERLYING DISEASE TREATMENT OF COMPLICATIONS INCLUDING INFECTIONS SURVIVAL OF INFECTIONS DEPENDS ON EARLY DIAGNOSIS TIMELY INTERVENTION SELECTION OF ADEQUATE ANTI-INFECTIVES DEATH AND SURVIVAL ARE ENDPOINTS OF A COMPLETE STRATEGY DURING THE RISK EPISODE

38 PROPHYLAXIS EMPIRICAL THERAPY invasive fungal infection NOT EXCLUDED THERAPY

39 ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO THE COURSE OF NEUTROPENIA 100% antibacterials GRANULOCYTES 75% 50% >1000 Empirical antifungals < days

40 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

41 OUTCOME TRIALS EMPIRICAL ANTIFUNGAL THERAPY Walsh et al. N Engl J Med TREATMENT SUCCESS AMBISOME AMPHO-B 50% 49% DIFFERENCE +1% AMBISOME VORICONAZOLE TREATMENT SUCCESS TREATMENT SUCCESS 31% 26% AMBISOME CASPOFUNGIN 34% 34% -5% 0%

42 PERCEIVED NEED FOR PARENTERAL ANTIFUNGALS AFTER PROPHYLAXIS IN NEUTROPENIC PATIENTS perceived need for empirical antifungals fungus %

43 INCIDENCE AND INTENTION

44 IMPACT OF SYSTEMATIC CT-SCAN ON THE OUTCOME OF PULMONARY ASPERGILLOSIS Caillot et al. J Clin Oncol 1997; 15: RETROSPECTIVE1 0 0 ANALYSIS 90 n = 37 S 8 0 U R V 30 I 20 V 10 0 A 0 L systematic CT-scan CT-scan on indication days SYSTEMATIC CT-SCAN BEFORE AFTER DAYS TO DIAGNOSIS FROM HOSPITAL ADMISSION FROM FIRST MOMENT OF SUSPICION 31 ± 9 7±5 21 ± 5 2±1

45 HALO SIGN Patterson et al. ICAAC 2000;abstract 1324.