Chapter 22

Antifungals: Drug Class, Mechanisms of Action, Pharmacokinetics/Pharmacodynamics, Drug-Drug Interactions, Toxicity, and Clinical Use

Jeniel E. Nett

Jeniel E. Nett

Department of Medicine, Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53792

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David R. Andes

David R. Andes

Department of Medicine, Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53792

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First published: 07 December 2011

Summary

Antifungal therapeutic outcomes have been historically suboptimal, in part, due to a relatively small number of safe and effective antifungal drugs. There are many important characteristics of antifungal drugs to consider in treatment of invasive fungal infection. Among these traits, spectrum of activity, pharmacokinetics, pharmacodynamics, potential drug-drug interactions, and toxicities are the most critical. This chapter focuses on these antifungal traits for available systemic agents for treatment of Candida infection. The main toxicities include renal damage, electrolyte abnormalities from renal toxicity, hepato-toxicity, and infusion-related reactions. The majority of the drug-drug interactions are related to potentiation of the electrolyte disturbances and renal dysfunction typical of amphotericin B. For example, the risk of renal toxicity is increased if amphotericin B is used concomitantly with the organ transplant immuno-suppressants cyclosporine and tacrolimus. In addition, lipid-based amphotericin B formulations are preferred for treatment of pregnant patients due to gestational toxicity with the triazole drug class. Studies have found the primary toxicity of flucytosine, bone marrow toxicity, to be associated with high peak concentrations. The fact that the pharmacodynamic drivers of success and toxicity are different provides an opportunity to design dosing strategies to both optimize treatment efficacy and reduce toxicity. The major toxicities of flucytosine include bone marrow suppression and hepato-toxicity. The major route of elimination for echinocandins is non-enzymatic degradation to inactive molecules which are excreted primarily in the bile.

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