Evaluation of Voriconazole Pharmacodynamics Using Time-Kill Methodology

Abstract

Voriconazole is an investigational azole antifungal agent with activity against a variety of fungal species, including fluconazole-susceptible and -resistant Candida species and Cryptococcus neoformans . In this study, we employed in vitro time-kill methods to characterize the relationship between concentrations of voriconazole and its fungistatic activity against Candida albicans , Candida glabrata , Candida tropicalis , and C. neoformans . Isolates were exposed to voriconazole concentrations ranging from 0.0625 to 16 times the MIC, and the viable colony counts were determined over time. The 50 and 90% effective concentrations (EC ₅₀ and EC ₉₀ , respectively) were determined at 8, 12, and 24 h following the addition of voriconazole. At each time point, near-maximal fungistatic activity, as indicated by the EC ₉₀ , was noted at a drug concentration of approximately three times the MIC. Additionally, EC ₅₀ and EC ₉₀ did not change over time, thus suggesting that the rate of activity was not improved by increasing concentrations. Voriconazole exhibits non-concentration-dependent pharmacodynamic characteristics in vitro.