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 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.
Andes
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D
Section of Infectious Diseases, Department of Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin 53792, USA. drandes@facstaff.wisc.edu
van Ogtrop
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M
D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D019540:Area Under Curve; D002176:Candida albicans / Q000145:classification / Q000187:drug effects*; D002177:Candidiasis / Q000150:complications / Q000188:drug therapy*; D015169:Colony Count, Microbial; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D015725:Fluconazole / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications
D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D015725:Fluconazole