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

We determined the pharmacodynamic parameter and the magnitude of that param eter that was predictive of the efficacy of fluconazole in the treatment of disseminated candidiasis. We used a neutropenic murine model of disseminat ed Candida albicans infection to characterize the time course of activity o f fluconazole. Quantitation of colony counts in Kidneys after 24 h of thera py with a wide range of doses and three dosing intervals was used to determ ine the dose required to achieve 50% of the maximal effect (ED50), The ED50 was similar for each of the dosing intervals studied, supporting the area under the concentration-time curve (AUC) MIC ratio as the parameter that pr edicts the efficacy of fluconazole. Similar studies were performed with C. albicans strains for which fluconazole MICs are in the susceptible-dose-dep endent range (MICs, 16 to 32 mg/liter). We found that the magnitude of the AUC/MIC ratio required to reach the ED,, was similar for all three organism s studied, ranging from 12 to 25. When the pharmacokinetics of fluconazole in humans are considered, these AUC/MIC ratios would support in vitro susce ptibility breakpoints of 8 mg/liter for dosages of 200 mg/day and susceptib ility breakpoints of 16 to 32 mg/liter for dosages of 400 to 800 mg/day.