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Antimicrobial Agents and Chemotherapy, April 2000, p. 938-942, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

In Vivo Characterization of the Pharmacodynamics of Flucytosine in a Neutropenic Murine Disseminated Candidiasis Model

D. Andes1,* and M. van Ogtrop2

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

Received 9 November 1998/Returned for modification 10 October 1999/Accepted 10 January 2000

In vivo pharmacodynamic parameters have been characterized for a variety of antibacterial agents. These parameters have been studied in correlation with in vivo outcomes in order to determine (i) which dosing parameter is predictive of outcome and (ii) the magnitude of that parameter associated with efficacy. Very little is known of the pharmacodynamics of antifungal agents. We used a neutropenic murine model of disseminated candidiasis to correlate the pharmacodynamic parameters (percentage of time above the MIC, area under the concentration-time curve [AUC]/MIC and peak level/MIC) for flucytosine (5-FC) in vivo with efficacy as measured by organism number in homogenized kidney cultures after 24 h of therapy. The pharmacokinetics of 5-FC in infected mice were linear. Serum half-lives ranged from 0.36 to 0.43 h. Infection was achieved by intravenous inoculation of 106 CFU of yeast cells per ml via the lateral tail vein of neutropenic mice. Groups of mice were treated with fourfold escalating total doses of 5-FC ranging from 1.56 to 400 mg/kg of body weight/day divided into one, two, four, or eight doses over 24 h. Increasing doses produced minimal concentration-dependent killing ranging from 0 to 0.9 log10 CFU/kidneys. 5-FC did, however, produce a dose-dependent suppression of growth after levels in serum had fallen below the MIC. The fungistatic dose increased from 6 to 8 mg/kg with dosing every 3 and 6 h to 70 mg/kg at with dosing every 24 h. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. Time above the MIC was the parameter best predictive of outcome, while AUC/MIC was only slightly less predictive (time above MIC, R2 = 85%; AUC/MIC, R2 = 77%; peak level/MIC, R2 = 53%). Maximal efficacy was observed when levels exceeded the MIC for only 20 to 25% of the dosing interval. If one considers drug kinetics in humans, these results suggest reevaluation of current dosing regimens.

* Corresponding author. Mailing address: Department of Medicine, Section of Infectious Diseases, 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, April 2000, p. 938-942, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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