Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model

Abstract

We determined the pharmacodynamic parameter and the magnitude of that parameter that was predictive of the efficacy of fluconazole in the treatment of disseminated candidiasis. We used a neutropenic murine model of disseminated Candida albicans infection to characterize the time course of activity of fluconazole. Quantitation of colony counts in kidneys after 24 h of therapy with a wide range of doses and three dosing intervals was used to determine the dose required to achieve 50% of the maximal effect (ED(50)). The ED(50) was similar for each of the dosing intervals studied, supporting the area under the concentration-time curve (AUC) MIC ratio as the parameter that predicts the efficacy of fluconazole. Similar studies were performed with C. albicans strains for which fluconazole MICs are in the susceptible-dose-dependent range (MICs, 16 to 32 mg/liter). We found that the magnitude of the AUC/MIC ratio required to reach the ED(50) was similar for all three organisms studied, ranging from 12 to 25. When the pharmacokinetics of fluconazole in humans are considered, these AUC/MIC ratios would support in vitro susceptibility breakpoints of 8 mg/liter for dosages of 200 mg/day and susceptibility breakpoints of 16 to 32 mg/liter for dosages of 400 to 800 mg/day.

FIG. 1

Serum fluconazole concentrations after administration of doses of 100, 25, and 6.25 mg/kg in neutropenic infected mice. Each symbol represents the geometric mean ± standard deviation of the levels in the sera of three mice.

FIG. 2

In vivo PAE of fluconazole after administration of doses of 12.5 and 3.13 mg/kg against C. albicans K-1 in neutropenic mice. Each symbol represents the mean ± standard deviation for two mice. The widths of the bars reflect the duration of time that the serum fluconazole levels exceeded the MIC.

FIG. 3

Relationship between 24-h dose and log₁₀ CFU per kidney for fluconazole administered at different dosing intervals in a neutropenic murine model of disseminated candidiasis. Each symbol represents data for two mice. The solid diamond symbol represents organism counts for untreated animals at 24 h. q 24 h, q 12 h, and q 6 h, dosing every 24, 12, and 6 h, respectively.

FIG. 4

Relationship between 24-h AUC/MIC ratio and log₁₀ CFU per kidney for fluconazole against C. albicans organisms for which MICs varied. Each symbol represents data for two mice.