Azoles - The azoies (imidazoles and triazoles) are fungistatic agents that inhibit fungal cytochrome P-450 3A-dependent C14-a-demethylase (ERG11), an essential enzyme responsible for the conversion of lanosterol to ergosterol which then leads to the depletion of the ergosterol in the fungal cell membrane (41). The introduction of azoles as an NCE significantly advanced the treatment of fungal infections and recent reviews depicting clinical isolates, structure activity relationships, and azole resistance in fungi are available (42,43). Ketoconazole (20), a phenethyl imidazole with a wide spectrum of antifungal activity, was the first orally available azole currently approved for treating serious fungal infections. Transdermal patches and use in combination with herbal essential oils were reported in 2002 to be active against Candida spp. (44,45). Itraconazole (21), was initially introduced in the 1980's as an alternative to ketoconazole showing reduced toxicity with better pharmacokinetics and a broader spectrum of antifungal activity. Recently, resistance to itraconazole has been reported (46,47). Fluconazole (Diflucan, 22) is a water-soluble bis-triazole derivative that was first approved in 1990 and exhibited good pharmacokinetics and therapeutic activity in several fungal infections (48). Fluconazole was recently reported in intensive care facilities to prevent Candida infection; however, emerging resistance has been observed (49,50). Strains of C. neoformans expressing heteroresistance to fluconazole were tested to characterize the heteroresistant phenotypes using 107 clinical isolates where fluconazole showed MICs ranging from 0.25 to 32 ng/mL (51).
Voriconazole (Vfend, 23), approved May 2002 by the FDA, is a broad-spectrum triazole available as film-coated tablets for oral administration, and as a lyophilized powder for intravenous infusion for the treatment of invasive Aspergillosis (52,53). Voriconazole was also approved in Europe for treatment of serious infections caused by Aspergillus, Fusarium, Scedosporium, and drug resistant Candida spp. (C. albicans an MICgo of 0.06 ng/mL) (54,55). Animal studies and clinical data shows Vfend to be safe and well tolerated, but a non-sight-threatening visual disturbance and drug-drug interactions require monitoring (56).
CS-758 (R-120758, 24) shows potent and broad-spectrum activity against Candida spp., Aspergillus spp. and C. neoformans and in vitro and in vivo activity profile comparisons were made versus fluconazole, itraconazole and amphotericin B (57). Against Candida spp., CS-758 was reported as superior to fluconazole and at least comparable to itraconazole and amphotericin B, with MIC values ranging from < 0.008 ng/mL up to 1 ng/mL. CS-758 displayed excellent activity against Aspergillus spp. and C. neoformans. In vivo studies were performed in mice with systemic infections caused by C. albicans, C. neoformans, A. fumigatus and A. flavus, and the compound exhibited strong efficacy with ED5o values of 0.41-5.0 mg/kg/day after per os once daily for 10 days (58).
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