1. Which drugs?

2. 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

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

4. AmBisome

5. Related azole antifungal agents (1)

7. Echinocandins

8. 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

9. 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

10. 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

11. 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

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

13. How good is the evidence?

14. Prophylaxis

15. -7071421283542495663-14 0.1 1 10 Days after transplant Granulocytes (log 10 x10 9 /l) 0 Allogeneic HSCT recipient treatment Disease likelihood Prophylaxis remote 36 37 38 39 4041 Temperature (°C)

16. 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

17. 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

18. Fluconazole - HSCT recipients 356 179177 Fluconazoleplacebo 3 27 Invasive candidiasis 2% 15% 101116 Empirical antifungal 56%66% 5546 Death - all causes 31%26% Goodman et al. N Eng J Med. 1992 326 845 400 mg/d

19. Slavin et al. J. Infect. Dis. 1995;171 1545 Fluconazole - HSCT recipients 301 152149 Fluconazoleplacebo 1127 Invasive disease 7% 18% 5882 Empirical antifungal 38%55% 2031 Death - all causes 13%21% 400 mg/d

20. Fluconazole - neutropenic patients 274 141133 Fluconazoleplacebo 5 32 Invasive disease 6% 24% 8067 Empirical antifungal 57%50% 28 Death - fungal 1%6% Rotstein et al 1999 Clin Infect Dis 28 331 400 mg/d

21. Winston et al. Ann Intern Med 1993. 118 495 Fluconazole - neutropenic patients 256 123132 Fluconazoleplacebo 5 10 Invasive disease 4% 8% 7997 Empirical antifungal 64%74% 2624 Death - all causes 21%18% 400 mg/d

22. 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

23. 405 201204 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

24. MouldsMoulds Aspergillus fumigatus amphotericin B inhalation Prophylaxis - aspergillosis

25. Amphotericin B inhalation study of prophylaxis  227115 nil 1011 aspergillosis 4% 7% 7362 Empirical antifungal 32%40% 3015 Death - all causes 13%10% Schwartz et al. Blood. 93. 1999 pp. 3654-3661

26. MouldsMoulds Aspergillus fumigatus itraconazole Prophylaxis - aspergillosis

27. Itraconazole study of prophylaxis 557 281276 itraconazole amphotericin B po 59 aspergillosis 2% 3% 114132 Empirical antifungal 41%48% 1823 Death - all causes 6%8% Harrassou et al. Antimicrob Ag Chemother. 44. 2000 1887

28. Itraconazole study of prophylaxis 140 7167 itraconazoleFluconazole 38 aspergillosis 4% 12% 2234 Empirical antifungal 31%51% 3228 Death - all causes 45%42% Winston et al. Ann Intern Med 2003. 138 705

29. Itraconazole study of prophylaxis Winston et al. Ann Intern Med 2003. 138 705 Time to development of invasive fungal infection - all patients

30. Itraconazole study of prophylaxis Winston et al. Ann Intern Med 2003. 138 705 Time to development of invasive fungal infection - GVHD