Introduction to antifungal drugs.

In the United States, only 10 antifungal drugs are currently approved by the Food and Drug Administration (FDA) for the therapy of systemic fungal infections. As shown in table 1, these drugs belong to 3 principal classes: polyenes, pyrimidines, and azoles. Drugs that belong to other classes are also approved as topical antifungal drugs, but will not be considered further here. Although conventional amphotericin B (Fungizone) remains the standard therapy for many invasive or life-threatening mycoses, this polyene drug is associated with significant toxicity, including infusion-related events, such as chills, fever, headache, nausea and vomiting, and dose-limiting nephrotoxicity [1]. In addition, the clinical efficacy of amphotericin B in some settings (e.g., mold disease such as invasive aspergillosis in severely immunocompromised patients) is suboptimal. Consequently, 3 new lipid formulations of amphotericin B (amphotericin B lipid complex, amphotericin B cholesteryl sulfate, and liposomal amphotericin B) have been developed and recently approved by the FDA. These lipid formulations offer several advantages over conventional amphotericin B, including increased daily dose of the parent drug (up to 10-fold), high tissue concentrations in the primary reticuloendothelial organs (lungs, liver, and spleen), decrease in infusion-associated side effects (especially liposomal amphotericin B), and marked decrease in nephrotoxicity [2–3]. Although the therapeutic : toxic ratio of these compounds is clearly improved, superiority in clinical efficacy has not been definitively established in headto-head comparative trials, either a lipid formulation versus conventional amphotericin B or 1 lipid formulation versus another lipid formulation [4–11]. Moreover, these lipid formulations of amphotericin B are considerably more expensive than conventional amphotericin B, ranging from 10to 20-fold higher in cost per dose [3]. In addition, the optimum daily or total dose of these lipid compounds has not been established. Accordingly, unanswered questions and controversy abound about several issues relating to these 3 lipid agents [11]. For example, is 1 drug superior by pharmacologic and efficacy pa-