2. ANTIFUNGAL DRUGS PHARM 514 Douglas Black, Pharm.D. Associate Professor School of Pharmacy University of Washington dblack@u.washington.edu

3. THESE CATEGORIES ARE A CONVENIENT WAY TO ORGANIZE THE KINGDOM OF FUNGI IN YOUR HEAD YeastsDimorphic fungiMolds Candida*BlastomycesAspergillus CryptococcusCoccidioidesFusarium TrichosporonHistoplasmaRhizopus SporothrixMucor Absidia Pseudallescheria (Scedosporium) = Zygomycetes *C. albicans, C. tropicalis, C. glabrata are common species

4. WE SEE ALL OF THESE SPECIES OF CANDIDA EVERY YEAR C. albicans C. tropicalis C. parapsilosis C. kefyr C. glabrata C. krusei C. guillermondii C. lusitaniae

5. DRUGCLASSYR APPROVED NystatinPolyene1954 Amphotericin B deoxycholatePolyene1958 GriseofulvinInhibitor of mitosis1959 Miconazole, clotrimazoleImidazole1969 FlucytosineSubstituted pyrimidine1972 KetoconazoleImidazole1981 FluconazoleTriazole1990 Itraconazole (capsules)Triazole1992 Terbinafine (topical)Allylamine1993 Terbinafine (oral)Allylamine1996 Amphotericin B lipid complexPolyene1996 Liposomal amphotericin BPolyene1997 Itraconazole (oral solution)Triazole1997 CaspofunginEchinocandin2001 VoriconazoleTriazole2002 MicafunginEchinocandin2004 AnidulafunginEchinocandin2006 PosaconazoleTriazole2006

6. MOST OF OUR ANTIFUNGAL DRUGS HAVE AN ONGOING LOVE AFFAIR WITH ERGOSTEROL NOTE: voriconazole probably inhibits additional pathways

7. THE AZOLE ANTIFUNGALS MAKE ORAL TREATMENT OF SERIOUS FUNGAL INFECTIONS POSSIBLE Four systemic drugs: Ketoconazole (Nizoral) … obsolete Fluconazole (Diflucan) … now generic Itraconazole (Sporanox) … almost obsolete Voriconazole (Vfend) … doing great Generally considered fungistatic Many topical azoles are available to treat vulvovaginal candidiasis (VVC); there are few clinically significant differences among these products. All topical azole antifungals are considered safe in pregnancy, but the systemic drugs should be avoided.

8. FLUCONAZOLE IS PRETTY GOOD AND IT IS NOW DIRT CHEAP An effective drug for yeast (Candida); not useful for molds Resistance is becoming a problem in some situations Oral, IV (1:1 dosing conversion) Excellent pharmacokinetics, easy-to-use drug –good absorption, unaffected by gastric pH –half-life 20-30 hours –eliminated by the kidneys One of the least toxic antifungals we have Drug interactions (inhibition of metabolism) are of minor significance unless the dose is escalated Pregnancy category C (animal data shows toxicity, human studies inadequate, benefit outweighs risk) Really cheap: 400 mg IV $11.30, 400 mg PO $0.94

9. VORICONAZOLE IS SO AWESOME WE ARE WILLING TO PUT UP WITH ITS CRAP An enormously successful drug that is active against many molds (e.g. Aspergillus) and yeast. The big hole is the class of fungi known as the Zygomycetes. Oral, IV (not a simple conversion) Lousy pharmacokinetics –half-life only 6 hours –nonlinear –wide interpatient variability (e.g. 15-20% of Asians are expected to be slow metabolizers) Significant drug interactions (CYP2C19 substrate, inhibitor of CYP3A4) Unusual side effect: visual disturbances in 8-44% of patients Pregnancy category D (evidence of human risk, but benefits may outweigh) Expensive: 400 mg IV $200, 200 mg PO $33

10. ONYCHOMYCOSIS IS A CHALLENGE TO TREAT Pathogen: Trichophyton rubrum Griseofulvin was DOC for decades (lots of ADR, took a year of therapy at least) Best drug now is oral terbinafine (Lamisil) –good nail distribution –not active vs Candida, otherwise better than itraconazole –dose 250 mg po qd (6 wks for fingers, 12 wks for toes) –ADR: HA, GI, rash, LFT abnormalities –the only oral antifungal to be category B

11. YOU CAN TRY TERBINAFINE FOR THAT NAIL INFECTION, BUT DON’T EXPECT MIRACLES Terbinafine (Lamisil): drug of choice for onychomycosis (tinea unguium), usually caused by Trichophyton rubrum (not effective for Candida) Highly lipophilic, well concentrated in skin, fat, nails More effective than itraconazole (Sporanox), and much more effective than the nail lacquer Penlac. Far from 100% effective, however. Serious (but rare) hepatotoxicity has been reported; avoid terbinafine in patients with chronic or active liver disease. Liver function tests should be monitored. 250 mg po qd x6 weeks for fingernails, x12 weeks for toenails Pregnancy category B (the only oral antifungal with this rating)

12. SOPHIE WANTS TO KNOW IF YOU HAVE ANY QUESTIONS.