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Antimicrobial Agents and Chemotherapy, May 1998, p. 1105-1109, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Pharmacodynamics of Fluconazole in a Murine Model of Systemic Candidiasis

Arnold Louie,1,2,* George L. Drusano,1,3 Partha Banerjee,1,2 Qing-Feng Liu,1,2 Weiguo Liu,1 Pamela Kaw,1 Mehdi Shayegani,2 Harry Taber,2 and Michael H. Miller1,2

Divisions of Infectious Diseases1 and Clinical Pharmacology,3 Department of Medicine, Albany Medical College, Albany, New York 12208, and the Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York 122012

Received 23 May 1997/Returned for modification 8 October 1997/Accepted 21 January 1998

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.

* Corresponding author. Mailing address: Division of Infectious Diseases, A-49, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208. Phone: (518) 262-5343. Fax: (518) 262-6727. E-mail: arnold_louie_at_amc01-3{at}ccgateway.amc.edu.

Antimicrobial Agents and Chemotherapy, May 1998, p. 1105-1109, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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