Echinocandins exhibit concentration-dependent effects on Candida species, and preclinical studies support the administration of large, infrequent doses. The current report examines the pharmacokinetics/pharmacodynamics of two multicenter, randomized trials of micafungin dosing regimens that differed in both dose level and dosing interval. Analysis demonstrates the clinical relevance of the dose level and area under the concentration-time curve (AUC). Better, although not statistically significant (P ؍ 0.056), outcomes were seen with higher maximum concentrations of drug in serum (C max ) and large, infrequent doses. The results support further clinical investigation of novel micafungin dosing regimens with large doses but less than daily administration. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00666185 and NCT00665639.) U nderstanding the pharmacodynamics driver of antimicrobial efficacy provides a means to identify the optimal dosing strategy (1, 2). Ideal dosing of antimicrobials for which the maximum concentration of drug in serum (C max ) and MIC are most closely linked to the desired effect would involve the infrequent administration of large doses. Conversely, when the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) is best predictive of outcome, it is the total amount of compound rather than the dosing frequency that impacts the treatment strategy. The clinical utility of this information has long been recognized with the C max -linked aminoglycoside drug class, for which once-daily administration both improves efficacy and reduces toxicity (3, 4). More recently, clinical studies have identified enhanced efficacy for extended and continuous infusion of beta-lactams in the critical care setting, an approach to dosing which optimizes the percentage of time above the MIC, the pharmacokinetic/pharmacodynamic (PK/PD) index associated with efficacy (5-7).The majority of the data available to determine the ideal pharmacodynamic dosing strategy is the product of preclinical in vitro and in vivo dose fractionation studies. While clinical studies may use different dose levels, the evaluation of more than a single dosing interval is uncommon. The goal of the present analysis was to utilize an existing clinical data set for an antifungal agent, micafungin, in which both the dose and the dosing interval were varied in order to identify the optimal dosing strategy.Experimental infection models have consistently found concentration-dependent killing and prolonged postantifungal effects for the echinocandin class (8-18). Dose fractionation and pharmacokinetic/pharmacodynamic (PK/PD) index analysis have demonstrated the importance of both the C max/ MIC and AUC/MIC indices to predict efficacy.In the present investigation, micafungin PK and efficacy were explored using pooled data from two multicenter, double-blind, randomized clinical trials in which adult patients were treated for esophageal candidiasis. The two studies ...