title: Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model.
abstract: 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.
authors.affiliation: Section of Infectious Diseases, Department of Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin 53792, USA. drandes@facstaff.wisc.edu
authors.forename: D
authors.initials: D
authors.lastname: Andes
authors.forename: M
authors.initials: M
authors.lastname: van Ogtrop
mesh_terms: 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
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D015725:Fluconazole