PHARMACODYNAMICS OF FLUCONAZOLE IN A MURINE MODEL OF SYSTEMIC CANDIDIASIS

In this study we defined the pharmacodynamic parameter that optimizes outcome in deep-seated Candida albicans infections treated with flucon azole, Using a murine model of systemic candidiasis, we conducted sing le-dose dose-ranging studies with fluconazole to determine the dosage of this drug that resulted in a 50% reduction in fungal densities (50% effective dose [ED50]) in kidneys versus the fungal densities in the kidneys of untreated controls. We found that the ED50 of fluconazole g iven intraperitoneally was 4.56 mg/kg of body weight/day (95% confiden ce interval, 3.60 to 5.53 mg/kg/day), and the dose-response relationsh ip was best described by an inhibitory sigmoid maximal effect (E-max) curve. To define the pharmacodynamics of fluconazole, we gave dosages lower than, approximating, and higher than the ED50 of fluconazole (ra nge, 3.5 to 5.5 mg/kg/day, equivalent to the ED16 to the ED75) to vari ous groups of infected animals using three dose-fractionation schedule s. For each total dose of fluconazole examined, the dose-fractionation schedules optimized the ratio of the area under the concentration-tim e curve (AUC) to the MIC (the AUC/MIC ratio), the ratio of the maximum concentration of drug in serum (C-max) to the MIC, and the time that the drug remained above the MIC for the infecting C, albicans isolate. Similar reductions in fungal densities in kidneys were seen between g roups that received the same total dose of fluconazole in one, two, or four equally divided doses. Thus, dose-fractionation studies demonstr ated that the pharmacodynamic parameter of fluconazole that best predi cted outcome was the AUC/MIC ratio.