ADEQUATE ANTIFUNGAL USE FOR BLOODSTREAM INFECTIONS

Transcription

1 ADEQUATE ANTIFUNGAL USE FOR BLOODSTREAM INFECTIONS

2 COMMERCIAL RELATIONS DISCLOSURE Astellas Gilead Sciences Pfizer Inc Expert advice Speaker s bureau Speaker s bureau

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

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

5 LIVING IN SYMBIOSIS

6 LIVING IN SYMBIOSIS Hospitalization.increasing colonization So what??

7 FROM COLONIZATION TO INVASION Initial situation compromised defense invasion

8 FUNGI IN THE BLOODSTREAM YEAST Candida species Cryptococcus MOULD Aspergillus species

9 FUNGI IN THE BLOODSTREAM MOULD Aspergillus species

10 ADMISSION TO THE HUMAN BODY

11 FUNGI IN THE BLOODSTREAM MOULD Aspergillus species

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

13 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)

14 YEAST Candida species FUNGI IN THE BLOODSTREAM

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

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

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

18 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

19 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

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

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

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

23 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

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

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

26 MORTALITY OF NOSOCOMIAL BLOODSTREAM INFECTIONS IN MALIGNANCIES Wisplinghoff et al. Clin Infect Dis 2003; 36: SCOPE, ; 2652 patients Coag-neg staphylococci Enterococci Staphylococcus aureus Candida species Escherichia coli Klebsiella species Enterobacter species Pseudomonas species Viridans streptococci Mortality %

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

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

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

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

31 POWER OF RECOMMENDATIONS A I II III B C

32 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%

33 CASPOFUNGIN VERSUS AMPHOTERICIN B FOR CANDIDEMIA Mora-Duarte et al. N Engl J Med 2002; 347: response overall response non-albicans CASPOFUNGIN 70/50 mg/d AMPHOTERICIN B mg/kg/d 100 n = 92 candidemia n =

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

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

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

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

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

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

40 ANIDULAFUNGIN versus FLUCONAZOLE IN CANDIDEMIA AND INVASIVE CANDIDOSIS Reboli et al. N Engl J Med 2007; 356: 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%

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

42 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% 74% 74% 76% 65% 40% 40% 34% 30% 23% 36%

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

44 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

45 THE FUNGINS Casper Anidula Mica Cilo

46 MY CRITERIA TO SELECT A DRUG efficacy price? safety

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

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

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

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

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

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

53 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

54 LINE REMOVAL FOR PARAPSILOSIS C. parapsilosis skin gut

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

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

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

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

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

60 ISAVUCONAZOLE VERSUS VORICONAZOLE IN THE TREATMENT OF INVASIVE ASPERGILLOSIS Astellas, Press Release Data, Sept 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%

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

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

63 WORLD-WIDE SURVEY OF DISSEMINATED FUSARIOSIS THERAPY Nucci et al. Clin Infect Dis 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 // 16

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

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

66 SUSPICION OF OR EVIDENCE FOR A FUNGUS IN THE BLOODSTREAM

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

68 AFTER THE ACUTE PHASE

69