ADEQUATE ANTIFUNGAL USE FOR BLOODSTREAM INFECTIONS

COMMERCIAL RELATIONS DISCLOSURE 2500 9000 15000 Astellas Gilead Sciences Pfizer Inc Expert advice Speaker s bureau Speaker s bureau

OUTLINE OF THE PRESENTATION Pathophysiology of fungemia Selection of drugs for candidemia Selection of drugs for moulds Concluding remarks

LIVING IN SYMBIOSIS

LIVING IN SYMBIOSIS Hospitalization.increasing colonization So what??

FROM COLONIZATION TO INVASION Initial situation compromised defense invasion

FUNGI IN THE BLOODSTREAM YEAST Candida species Cryptococcus MOULD Aspergillus species

FUNGI IN THE BLOODSTREAM MOULD Aspergillus species

ADMISSION TO THE HUMAN BODY

FUNGI IN THE BLOODSTREAM MOULD Aspergillus species

SITE OF INFECTION IN ASPERGILLOSIS Lungs only Remainder CNS sinus Disseminated including lung 595 patients PATTERSON et al. Medicine 2000;79:250-60

IMPORTANCE OF EARLY TREATMENT OF INVASIVE ASPERGILLOSIS Patterson et al. Medicine 2000 Type of infection Survival Pulmonary only 40% (n=330) Disseminated 18% (n=144)

YEAST Candida species FUNGI IN THE BLOODSTREAM

SEPARATION OF THE BODY FROM THE ENVIRONMENT external population skin our body mucosa

INVASIVE INFECTIONS IN RELATION TO MUCOSAL DAMAGE external population damaged skin our body mucosa

INVASIVE INFECTIONS IN RELATION TO MUCOSAL DAMAGE after antibiotics damaged skin our body mucosa

RISK FACTORS FOR CANDIDA INFECTIONS Edwards jr JE et al. Ann Intern Med 1978 USE OF: antibiotics immunosuppressants hyperalimentation polyethylene catheters prosthetic devices heroin I AM HERE TO HELP YOU!!! abdominal surgery

COLONIZATION WITH CANDIDA SPECIES C parapsilosis ~5% ~60% C tropicalis C albicans ~50% ~60% C krusei C glabrata

CANDIDEMIA AND COLONIZATION IN EUROPE Tortorano et al. Eur J Clin Microbiol Infect Dis 2004; 23:317-322 2089 cases albicans glabrata parapsilosis tropicalis krusei others 68% 30% 81% 81% prior colonization

SPECTRUM OF INVASIVE CANDIDA INFECTIONS (modified from John Rex) candidemia organ infection acute Candida septicemia candidemia acute disseminated candidiasis hepatosplenic candidiasis

SPECTRUM OF INVASIVE CANDIDA INFECTIONS (modified from John Rex) candidemia organ infection acute Candida septicemia candidemia acute disseminated candidiasis hepatosplenic candidiasis prompt eliminate risk factor prompt specific cover empirical cover specific cover empirical cover beware of toxicity

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

RELATION INITIATION FLUCONAZOLE THERAPY AND OUTCOME OF CANDIDEMIA Garey et al. Clin Infect Dis 2006; 43:25-31 230 cases of candidemia 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% day 0 day 2 day 3 day 4 mortality start fluconazole

MORTALITY OF NOSOCOMIAL BLOODSTREAM INFECTIONS IN MALIGNANCIES Wisplinghoff et al. Clin Infect Dis 2003; 36:1103-10 SCOPE, 1995-2001; 2652 patients Coag-neg staphylococci Enterococci Staphylococcus aureus Candida species Escherichia coli Klebsiella species Enterobacter species Pseudomonas species Viridans streptococci Mortality % 33 34 23 45 35 24 28 36 16

OUTLINE OF THE PRESENTATION Pathophysiology of fungemia Selection of drugs for candidemia Selection of drugs for moulds Concluding remarks

REQUIRED PROPERTIES ANTIFUNGALS FOR ACUTE BLOODSTREAM INFECTIONS Broad spectrum Reliable kinetics Intravenous formulation Low resistance rate Minimal interactions Cheap

BASIS OF RECOMMENDATIONS A I II III RANDOMIZED TRIAL CONSISTENT SERIES EXPERT / CONSENSUS SOLID CLINICAL EVIDENCE B REASONABLE CLINICAL EVIDENCE C TRIVIAL CLINICAL EVIDENCE

POWER OF RECOMMENDATIONS A I II III B C

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

CASPOFUNGIN VERSUS AMPHOTERICIN B FOR CANDIDEMIA Mora-Duarte et al. N Engl J Med 2002; 347:2020-2029 response overall response non-albicans CASPOFUNGIN 70/50 mg/d AMPHOTERICIN B 0.6-1.0 mg/kg/d 100 n = 92 candidemia n = 94 80 60 40 20 0

MICAFUNGIN vs AMBISOME FOR CANDIDEMIA AND INVASIVE CANDIDOSIS Kuse et al. Lancet 2007; 369:1519-1527 Double-blind comparison, n = 541 Rate of 100 Favorable 80 Response 60 40 20 90% 90% neutropenia 0 micafungin 100 mg/d (n=264) AmBisome 3 mg/day (n=267)

MICAFUNGIN vs AMBISOME FOR CANDIDEMIA AND INVASIVE CANDIDOSIS Kuse et al. Lancet 2007; 369:1519-1527 83% 89% 92% 83% micafungin 88% 87% 89% albicans glabrata tropicalis krusei parapsilosis 86% 95% 80% liposomal amphotericin B

MICAFUNGIN versus AMBISOME IN CHILDREN WITH INVASIVE CANDIDOSIS Queiroz-Telles et al. Pediatr Infect Dis J 2008;27:820-827 Double-blind comparison, n = 98 Rate of 100 Favorable 80 Response 60 40 20 premature 73% 70% 76% premature 67% 0 micafungin 2mg/kg/d (n=48) AmBisome 3 mg/day (n=50)

MICAFUNGIN versus LS-AMB FOR CANDIDEMIA AND INVASIVE CANDIDOSIS Kuse et al. Lancet 2007; 369:1519-1527 Double-blind comparison, n = 541 change Glomerular Filtration Rate 40 20 0-20 -40-60 micafungin 100 mg/d (n=264) liposomal amb 3 mg/day (n=267)

MICAFUNGIN versus CASPOFUNGIN FOR CANDIDEMIA AND INVASIVE CANDIDOSIS Pappas et al. Clin Infect Dis 2007; 45:883-893 Double-blind comparison, n = 593 Rate of 100 Favorable 80 Response 60 40 76% 71% 72% 20 0 100 mg (n=199) micafungin 150 mg (n=202) caspofungin 50/70 mg/day (n=192)

MICAFUNGIN versus CASPOFUNGIN FOR CANDIDIASIS OUTCOME PER SPECIES Pappas et al. Clin Infect Dis 2007; 45:883-893 75% 68% 77% 85% micafungin 77% 64% 74% albicans glabrata tropicalis krusei parapsilosis 75% 75% 67% caspofungin

ANIDULAFUNGIN versus FLUCONAZOLE IN CANDIDEMIA AND INVASIVE CANDIDOSIS Reboli et al. N Engl J Med 2007; 356:2772-2782 Non-neutropenics double-blind FLUCONAZOLE 400 mg/day iv/po n = 118 ANIDULAFUNGIN 200->100 mg/day n = 127 SUCCESS AT END OF TREATMENT AT 6 WEEKS ERADICATION OVERALL MORTALITY 60% 44% 76% 31% 76% 56% 88% 23%

ANIDULAFUNGIN versus FLUCONAZOLE IN CANDIDEMIA AND INVASIVE CANDIDOSIS Reboli et al. N Engl J Med 2007; 356:2772-2782 87% 76% 69% 95% albicans glabrata tropicalis parapsilosis anidulafungin 81% 88% 64% 60% fluconazole

IDSA STRATEGY FOR THE TREATMENT OF DISSEMINATED CANDIDIASIS Pappas et al. Clin Infect Dis 2009; 48:503-535 fluconazole invasive candidiasis proven / probable NO (risk of) C.glabrata C.krusei? NO hemodynamically unstable? YES candin lipid ampho-b voriconazole YES

RANKING OF ANTI-CANDIDA DRUGS I II III A B ampho B LS-ampho B candins voriconazole fluconazole G(M)-CSF C itraconazole posaconazole combinations insufficient data on neutropenics

THE FUNGINS Casper Anidula Mica Cilo

MY CRITERIA TO SELECT A DRUG efficacy price? safety

EPIDEMIOLOGY AND OUTCOME OF CANDIDEMIA IN 2019 PATIENTS Horn et al. Clin Infect Dis 2009; 48:1695-1703 USA data base 2002-2008 36% 38% 24% 41% 53% 33% use of antifungals 12 weeks mortality (overall 35%) candins ampho B vori fluconazole

LESSONS FROM CANDIDEMIA TRIALS Rex et al. Clin Infect Dis 2003; 36:1221-1228 eliminate risk factor specific cover Why does 10-15% of candidemia persist in spite of apparently adequate antifungal therapy?

OUTCOME OF CANDIDEMIA IN THE UK 1997-99 IMPACT OF CATHETER MANAGEMENT Kibbler et al. J Hosp Infect 2003; 54:18-24 58% No treatment (n=31) No line removal + antifungal (n=29) Day 30 mortality overall (n = 163) 31% 26% Line removal + antifungal (n=91) 14%

SURVEY OF CANDIDEMIA AND OUTCOME OF ANTIFUNGAL THERAPY Nguyen et al. Arch Int Med 1995;155:2429-35 427 episodes Mortality at 30 days catheter in (n=102) 41% catheter out (n=258) 21% Mortality: Treated: 27% //Untreated (n=58) 74%

MODEL FOR INVASIVE CANDIDIASIS Blijlevens, Donnelly, De Pauw. Brit J Haematol 2002;117:259 Central venous catheter GI tract

MODEL FOR INVASIVE CANDIDIASIS Blijlevens, Donnelly, De Pauw. Brit J Haematol 2002;117:259 Central venous catheter insult GI tract infection translocation

HANDLING OF A CENTRAL LINE IN PATIENTS WITH CANDIDEMIA Nucci & Anaissie. Clin Infect Dis 2002; 34:591-9 R E M O V E T H E L I N E NO LINE NEEDED? YES 1 line >1 line Insertion easy? YES NO Tunneled? NO YES case by case Inspect Tunneled? YES NO

LINE REMOVAL FOR PARAPSILOSIS C. parapsilosis skin gut

Percent resistant CANDIDA GLABRATA: EMERGENCE OF RESISTANCE TO ECHINOCANDINS 2001-2010 Alexander et al. Clin Infect Dis 2013; 56:1724-1732 293 cases C.glabrata candidemia (30% breakthrough) 30 25 20 15 fluconazole Response candins susceptible: 96% resistant: 31% 10 5 echinocandins 0 2001/2 2003/4 2005/6 2007/8 2009/10

BREAKTHROUGH INVASIVE FUNGAL DISEASE DURING CANDIN THERAPY Chan TSY et al. Ann Hematol 2014; 93:493-498 534 hematological patients Anidulafungin n=173 Caspofungin n= 55 Micafungin n=306 8 breakthrough infections (2%) Fusarium Candida parapsilosis possible

OUTLINE OF THE PRESENTATION Pathophysiology of fungemia Selection of drugs for candidemia Selection of drugs for moulds Concluding remarks

EORTC IFICG RESULTS FIRST LINE TREATMENT OF INVASIVE ASPERGILLOSIS Herbrecht et al N Engl J Med 2002; 347:408-415 Cornely et al. Clin Infect Dis 2007; 44:1289-1297 Viscoli et al. J Antimicrob Chemother 2009; 64:1274-1281 % response 60 50 40 30 20 10 42/133 (32%) 76/144 (53%) 53/107 (50%) 25/51 (49%) 0 Ampho B Voriconazole Lipo-AmB Caspofungin

ISAVUCONAZOLE VERSUS VORICONAZOLE IN THE TREATMENT OF INVASIVE ASPERGILLOSIS Astellas, Press Release Data, Sept 2013 516 proven/probable IA VORICONAZOLE double-blind ISAVUCONAZOLE 36% response (partial+complete) 35% 60% 60% without control CT 20% 12 weeks mortality 19% drug-related adverse events 60% 42%

LEVEL OF EVIDENCE I II III A voriconazole isavuconazole B L-AmB caspofungin ABLC posaconazole C itraconazole G(M)-CSF ABCD ampho B

STRANGE DUCKS IN THE IMMUNOSUPPRESSED POND Malassezia furfur Saccharomyces cerevisiae Pseudallescheria boydii Mucor/ Rhizopus Alternaria Scedosporium Trichosporon

WORLD-WIDE SURVEY OF DISSEMINATED FUSARIOSIS THERAPY Nucci et al. Clin Infect Dis 2013 233 cases from all continents Factors associated with a poor outcome Corticosteroids OR 2.7 Dissemination 3.5 Factors associated beneficial outcome Vori as initial Rx OR 0.35 0.4 0.2 1 2 3 4 // 16

OUTLINE OF THE PRESENTATION Pathophysiology of fungemia Selection of drugs for candidemia Selection of drugs for moulds Concluding remarks

SUSPICION OF OR EVIDENCE FOR A FUNGUS IN THE BLOODSTREAM

APPROPRIATE DRUGS candin ampho B azole Candins Azoles Liposomal ampho B Voriconazole Isavuconazole Itraconazole Fluconazole

AFTER THE ACUTE PHASE