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Antimicrobial Agents and Chemotherapy, September 1999, p. 2116-2120, Vol. 43, No. 9
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Characterization and Quantitation of the Pharmacodynamics of Fluconazole in a Neutropenic Murine Disseminated Candidiasis Infection Model

D. Andes1,* and M. van Ogtrop2

Section of Infectious Diseases, Department of Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin,1 and Leiden University Medical Centre, Leiden, The Netherlands2

Received 12 October 1998/Returned for modification 9 March 1999/Accepted 16 June 1999

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 (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 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 ED50 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.

* Corresponding author. Mailing address: Section of Infectious Diseases, Department of Medicine, University of Wisconsin School of Medicine, Room H4/570, 600 Highland Ave., Madison, WI 53792. Phone: (608) 263-1545. Fax: (608) 263-4464. E-mail: drandes{at}facstaff.wisc.edu.

Antimicrobial Agents and Chemotherapy, September 1999, p. 2116-2120, Vol. 43, No. 9
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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