Pharmacodynamics of fluconazole in a murine model of systemic candidiasis

Abstract

In this study we defined the pharmacodynamic parameter that optimizes outcome in deep-seated Candida albicans infections treated with fluconazole. Using a murine model of systemic candidiasis, we conducted single-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 given intraperitoneally was 4.56 mg/kg of body weight/day (95% confidence interval, 3.60 to 5.53 mg/kg/day), and the dose-response relationship was best described by an inhibitory sigmoid maximal effect (Emax) curve. To define the pharmacodynamics of fluconazole, we gave dosages lower than, approximating, and higher than the ED50 of fluconazole (range, 3.5 to 5.5 mg/kg/day, equivalent to the ED16 to the ED75) to various groups of infected animals using three dose-fractionation schedules. For each total dose of fluconazole examined, the dose-fractionation schedules optimized the ratio of the area under the concentration-time curve (AUC) to the MIC (the AUC/MIC ratio), the ratio of the maximum concentration of drug in serum (Cmax) 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 groups that received the same total dose of fluconazole in one, two, or four equally divided doses. Thus, dose-fractionation studies demonstrated that the pharmacodynamic parameter of fluconazole that best predicted outcome was the AUC/MIC ratio.

FIG. 1

Relationship between single-dose fluconazole and C_max (A) and AUC (B) for selected doses of fluconazole. The drug was given i.p. as a single dose 5 h after the mice were infected i.v. with C. albicans.

FIG. 2

Pilot dose-ranging study demonstrating the dose-response relationship between the dose of fluconazole administered to infected mice and C. albicans density in kidneys (mean ± 1 standard deviation). Fluconazole was given i.p. as a single dose 5 h after the mice were inoculated with fungus i.v., and quantitative cultures of kidneys were conducted 24 h after drug administration. There were eight mice per group.

FIG. 3

Expanded dose-ranging validation study demonstrating a more complete delineation of the inhibitory sigmoid E_max dose-response curve. The study methods are described in the legend to Fig. 2. The ED₅₀ of 4.56 mg/kg was similar to the ED₅₀ of 4.87 mg/kg that was derived from the smaller number of doses of fluconazole used in the pilot dose-ranging study.