Which drugs?

Mode of action of antifungals ergosterol polyenes e.g. amphotericin B polyenes azoles e.g. fluconazole azoles nucleosides e.g. 5-flucytosine nucleosides squalenes lanosterol K + Mg 2+ allylamines e.g. terbinafine allylamines acetyl-Co-A echinocandins e.g. caspofungin echinocandins nikkomycinsnikkomycins nucleic acid synthesis glucan synthesis chitin synthesis

Therapeutic window of antifungal agents ergosterol nucleic acid synthesis glucan synthesis chitin synthesis nucleic acid synthesis cholesterol protein synthesis mannan synthesis humanfungus

AmBisome

Related azole antifungal agents (1)

Echinocandins

Comparative spectrum of activity in-vitro FungusAMBFCZITZVCZPCZRCZCF MFAF Candida albicans Candida tropicalis Candida parapsilosis Candida krusei Candida glabrata Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidiodes immitis Paracoccidiodes brasiliensis Pneumocystis carinii Aspergillus fumigatus  Mucor spp Rhizopus spp Fusarium spp FungusAMBFCZITZVCZPCZRCZCF MFAF Candida albicans Candida tropicalis Candida parapsilosis Candida krusei Candida glabrata Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidiodes immitis Paracoccidiodes brasiliensis Pneumocystis carinii Aspergillus fumigatus  Mucor spp Rhizopus spp Fusarium spp azolescandins

Comparative spectrum of activity in-vitro FungusAMBFCZITZVCZPCZRCZCF MFAF Candida albicans Candida tropicalis Candida parapsilosis Candida krusei Candida glabrata Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidiodes immitis Paracoccidiodes brasiliensis Pneumocystis carinii Aspergillus fumigatus  Mucor spp Rhizopus spp Fusarium spp FungusAMBFCZITZVCZPCZRCZCF MFAF Candida albicans Candida tropicalis Candida parapsilosis Candida krusei Candida glabrata Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidiodes immitis Paracoccidiodes brasiliensis Pneumocystis carinii Aspergillus fumigatus  Mucor spp Rhizopus spp Fusarium spp azolescandins Pneumocystis carinii

Comparative spectrum of activity in-vitro FungusAMBFCZITZVCZPCZRCZCF MFAF Candida albicans Candida tropicalis Candida parapsilosis Candida krusei Candida glabrata Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidiodes immitis Paracoccidiodes brasiliensis Pneumocystis carinii Aspergillus fumigatus  Mucor spp Rhizopus spp Fusarium spp FungusAMBFCZITZVCZPCZRCZCF MFAF Candida albicans Candida tropicalis Candida parapsilosis Candida krusei Candida glabrata Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidiodes immitis Paracoccidiodes brasiliensis Pneumocystis carinii Aspergillus fumigatus  Mucor spp Rhizopus spp Fusarium spp Cryptococcus neoformans azolescandins

Mode of action of antifungals ergosterol polyenes e.g. amphotericin B polyenes azoles e.g. fluconazole azoles squalenes lanosterol K + Mg 2+ acetyl-Co-A echinocandins e.g. caspofungin echinocandins glucan synthesis

Available broad-spectrum drugs polyenespolyenes azolesazoles echinocandinsechinocandins caspofungin amphotericin B AmBisomeAbelcetAmphocil/Amphotec itraconazolevoriconazole

How good is the evidence?

Prophylaxis

Days after transplant Granulocytes (log 10 x10 9 /l) 0 Allogeneic HSCT recipient treatment Disease likelihood Prophylaxis remote Temperature (°C)

Prophylaxis most often initiated when a patient falls into a risk group –expected to develop prolonged, profound neutropenia –measurable risk of developing invasive fungal infection High-risk but no evidence

Prophylaxis - candidosis Candida parapsilosis Candida albicans Candida parapsilosis Candida albicans Candida tropicalis Candida albicans Candida tropicalis Candida albicans Candida glabrata Candida krusei Candida albicans Candida glabrata Candida krusei YeastYeast Fluconazole Effective & safe

Fluconazole - HSCT recipients Fluconazoleplacebo 3 27 Invasive candidiasis 2% 15% Empirical antifungal 56%66% 5546 Death - all causes 31%26% Goodman et al. N Eng J Med mg/d

Slavin et al. J. Infect. Dis. 1995; Fluconazole - HSCT recipients Fluconazoleplacebo 1127 Invasive disease 7% 18% 5882 Empirical antifungal 38%55% 2031 Death - all causes 13%21% 400 mg/d

Fluconazole - neutropenic patients Fluconazoleplacebo 5 32 Invasive disease 6% 24% 8067 Empirical antifungal 57%50% 28 Death - fungal 1%6% Rotstein et al 1999 Clin Infect Dis mg/d

Winston et al. Ann Intern Med Fluconazole - neutropenic patients Fluconazoleplacebo 5 10 Invasive disease 4% 8% 7997 Empirical antifungal 64%74% 2624 Death - all causes 21%18% 400 mg/d

Candida parapsilosis Candida albicans Candida parapsilosis Candida albicans Candida tropicalis Candida albicans Candida tropicalis Candida albicans Candida glabrata Candida krusei Candida albicans Candida glabrata Candida krusei YeastYeast itraconazole not proven Prophylaxis - candidosis

itraconazoleplacebo 59 Invasive disease 3% 5% 4259 Empirical antifungal 21%29% 15 Death - fungal 1%3% Itraconazole- neutropenic patients Menichetti et al.. Clin Infect Dis 1999;28 250

MouldsMoulds Aspergillus fumigatus amphotericin B inhalation Prophylaxis - aspergillosis

Amphotericin B inhalation study of prophylaxis  nil 1011 aspergillosis 4% 7% 7362 Empirical antifungal 32%40% 3015 Death - all causes 13%10% Schwartz et al. Blood pp

MouldsMoulds Aspergillus fumigatus itraconazole Prophylaxis - aspergillosis

Itraconazole study of prophylaxis itraconazole amphotericin B po 59 aspergillosis 2% 3% Empirical antifungal 41%48% 1823 Death - all causes 6%8% Harrassou et al. Antimicrob Ag Chemother

Itraconazole study of prophylaxis itraconazoleFluconazole 38 aspergillosis 4% 12% 2234 Empirical antifungal 31%51% 3228 Death - all causes 45%42% Winston et al. Ann Intern Med

Itraconazole study of prophylaxis Winston et al. Ann Intern Med Time to development of invasive fungal infection - all patients

Itraconazole study of prophylaxis Winston et al. Ann Intern Med Time to development of invasive fungal infection - GVHD