PROGRESSI NELLA TERAPIA ANTIFUNGINA A tribute to Piero Martino 1946-2007
ITALIAN ICONS
IERI, OGGI, E DOMANI
IERI, OGGI, E DOMANI
IERI, OGGI, E DOMANI 1961
CAUSES OF DEATH IN PATIENTS WITH MALIGNANCIES NIJMEGEN, 1988 n = 328 BACTERIAL INFECTION FUNGAL INFECTION 7% 36% MULTIFACTORIAL 40% HEMORRHAGE 17%
CRUCIAL FACTORS more complex interventions higher age more co-morbidity less mortality from other causes -underlying disease -better antibacterial therapy
NATURE DEPENDS ON RENEWAL
NATURE DEPENDS ON RENEWAL
NATURE DEPENDS ON RENEWAL
CLEANING UP NATURE.
WELCOME TO MYCOLOGY YEAST *candida *cryptococcus conidia septate hyphae hyphae pseudohyphae MOULD conidium *aspergillus *fusarium *(mucormycosis)
LETHALITY OF THE VARIOUS INVASIVE FUNGAL INFECTIONS 400 300 200 100 0 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; 91:1068-1075 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
IERI, OGGI, E DOMANI
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
RESPONSE TO TREATMENT FOR ASPERGILLOSIS IN NORMAL PRACTICE Patterson et al. Medicine 2000;79:250-260 n P A T I E N T S 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ampho B 32%
PROBLEMS High morbidity and mortality Difficult to diagnose Antifungals are toxic Low numbers in single centers MULTICENTER TRIALS
INTERNATIONAL COLLABORATION EORTC IFIG Chairman: Ben de Pauw Secretary: Pietro Martino
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
ALGORITHMS + -
PROPHYLAXIS invasive fungal infection NOT PRESENT EMPIRICAL THERAPY invasive fungal infection NOT EXCLUDED THERAPY invasive fungal infection (INCIPIENT)
IERI, OGGI, E DOMANI INDICATIONS FOR ANTIFUNGALS prophylaxis empirical pre-emptive pathogen-driven
PROPHYLAXIS invasive fungal infection NOT PRESENT EMPIRICAL THERAPY invasive fungal infection NOT EXCLUDED THERAPY invasive fungal infection (INCIPIENT)
PROPHYLAXIS invasive fungal infection NOT PRESENT EMPIRICAL THERAPY
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 = 177 16% 0% 10% SUPERFICIAL 8% 33% FATAL FUNGUS 1% 6%
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%
IERI, OGGI, E DOMANI
COLONIZATION-INVASION Martino P, Girmenia C, Venditti M, Girmenia C, Mandelli F. Candida colonization and systemic infection in neutropenic patients. Cancer 1989; 64: 2030-2034. Initial situation colonization invasion
RISK FACTOR SELECTION Martino P, Girmenia C, Venditti M, Girmenia C, Mandelli F. Candida colonization and systemic infection in neutropenic patients. Cancer 1989; 64: 2030-2034. Risk factors Infection fever Underlying disease selection antibacterials colonization chemical & physical damage mucosa instruments + knife puncture skin gut
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 0 1 2 3 4 5 6 7
INVENTARISATION USE OF ANTIFUNGAL PROPHYLAXIS IN STEM CELL TRANSPLANTS Trifilio et al. Bone Marrow Transpl 2004; 33:735-739 31 centers (USA) 2001 >3000 transplant recipients fluconazole itraconazole ampho B iv none autologous allogeneic
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
POSACONAZOLE vs FLU AS PROPHYLAXIS IN ALLO STEM CELL TRANSPLANTATION Ullmann et al. N Engl J Med 2007; 356:335-347 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
POSACONAZOLE vs AZOLES AS PROPHYLAXIS IN MYELOID MALIGNANCIES Cornely et al. N Engl J Med 2007; 356:348-359 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
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
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!
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
PROPHYLAXIS EMPIRICAL THERAPY invasive fungal infection NOT EXCLUDED THERAPY
ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO THE COURSE OF NEUTROPENIA 100% antibacterials GRANULOCYTES 75% 50% >1000 Empirical antifungals 1000 500 <100 0 10 20 30 days
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 0 20 40 60 80
OUTCOME TRIALS EMPIRICAL ANTIFUNGAL THERAPY Walsh et al. N Engl J Med 1999-2005 TREATMENT SUCCESS AMBISOME AMPHO-B 50% 49% DIFFERENCE +1% AMBISOME VORICONAZOLE TREATMENT SUCCESS TREATMENT SUCCESS 31% 26% AMBISOME CASPOFUNGIN 34% 34% -5% 0%
PERCEIVED NEED FOR PARENTERAL ANTIFUNGALS AFTER PROPHYLAXIS IN NEUTROPENIC PATIENTS perceived need for empirical antifungals fungus 5 10 20 30 40 50 60%
INCIDENCE AND INTENTION
IMPACT OF SYSTEMATIC CT-SCAN ON THE OUTCOME OF PULMONARY ASPERGILLOSIS Caillot et al. J Clin Oncol 1997; 15:139-147 RETROSPECTIVE1 0 0 ANALYSIS 90 n = 37 S 8 0 U 70 60 R 50 40 V 30 I 20 V 10 0 A 0 L systematic CT-scan CT-scan on indication 50 100 150 200 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
HALO SIGN Patterson et al. ICAAC 2000;abstract 1324.