Table 36–1 summarizes the major properties of currently available antifungal agents. Two different lipid-based amphotericin B formulations are used to treat systemic invasive fungal infections. Their principal advantage appears to be substantially reduced nephrotoxicity, allowing administration of much higher doses. Three agents of the echinocandin class, caspofungin, anidulafungin, and micafungin are approved for use. The echinocandins have relatively few adverse effects and are useful for the treatment of invasive Candida infections, although resistance has emerged clinically; C glabrata in particular has shown resistance to this class of antifungals. Caspofungin is also approved for use in refractory cases of invasive aspergillosis. Voriconazole has excellent activity against a broad range of fungal pathogens and has been FDA approved for use in invasive Aspergillus, Fusarium and Scedosporium infections, Candida esophagitis, deep Candida infections, and candidemia. Posaconazole has good activity against a broad range of filamentous fungi, including the Mucorales. Therapeutic drug monitoring is recommended in individuals with severe invasive fungal infections receiving azole therapy because of unreliable serum levels due to either metabolic alterations as a result of genetic polymorphisms (voriconazole) or erratic absorption (itraconazole and posaconazole). A delayed-release tablet preparation of posaconazole provides more reliable pharmacokinetics compared to the oral solution. Isavuconazole is approved for the treatment of aspergillosis and mucormycosis, although the data for use in the latter are sparse; a trial of isavuconazole versus caspofungin failed to establish noninferiority of this agent for candidemia. Advantages of isavuconazole include the availability of an intravenous form that does not utilize the cyclodextrin carrier like previous azoles as well as an oral form with relatively reliable pharmacokinetic properties and effective shortening of the QT interval. As a result of their more frequent and sometimes extended use, newly recognized adverse drug effects are being recognized with the azoles, including peripheral neuropathy (itraconazole and voriconazole), fluoride excess resulting in periostitis and alkaline phosphatase elevations (voriconazole), and pseudohyperaldosteronism (itraconazole and posaconazole). A long-acting echinocandin (rezafungin) has demonstrated efficacy in clinical trials and in vitro, but its clinical use is not established. Additional, novel therapeutic approaches, including vaccination, continue to warrant investigation.
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