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Another approach to prevent amphotericin B nephrotoxicity is to avoid polyene antifungal agents entirely and use alternative agents, such as the azoles and echinocandins.351–355 Azole antifungal agents inhibit sterol synthesis in fungal cell membranes by blocking the activity of the 14-demethylase enzyme essential for ergosterol synthesis. Nephrotoxicity is an unusual event following the use of azole compounds. The echinocandins are beta-glucan inhibitors that interfere with cell-wall synthesis of fungal elements, and have an entirely different mechanism of action from that of amphotericin B. Both the azole compounds (voriconazole, fluconazole, itraconazole, and posaconazole) and the echinocandins (caspofungin, anidulafungin, and micafungin) compare favorably to amphotericin B with respect to their efficacy against a variety of the systemic mycoses. Both classes of antifungal agents have the advantage of lacking the intrinsic nephrotoxicity associated with amphotericin B deoxycholate. Both the azole compounds and echinocandins have proven to be less nephrotoxic than conventional amphotericin B deoxycholate in observational studies, historical control studies, and in small comparative trials.355
An important consideration in using these antifungal agents is their relative efficacy with respect to the likely pathogen that is targeted for treatment. Candida krusei is intrinsically resistant to the azoles and Candida parapsilosis is frequently resistant to the echinocandins. Amphotericin B-resistant strains of selected Aspergillus spp. and Pseudallescheria boydii are well described and require alternative therapies.
There is currently insufficient evidence as to whether the echinocandins, the azoles, or the lipid formulations of amphotericin B differ significantly from each other with respect to the risk of nephrotoxicity. No adequately controlled, large, randomized studies have been reported to date comparing the relative risk of nephrotoxicity amphotericin B lipid formulations with either azole or echinocandin antifungal agents. Such studies face the difficulty of recruiting sufficient numbers of patients with similar baseline risk for drug-induced AKI, and with a balance of exposure to other potentially nephrotoxic agents. Until such time as these studies are completed, no evidence-based recommendations can be given about the relative risk of AKI attributable directly to these antifungal agents.
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