Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model

Antimicrob Agents Chemother. 1999 Sep;43(9):2116-20. doi: 10.1128/AAC.43.9.2116.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antifungal Agents / blood
  • Antifungal Agents / pharmacokinetics
  • Antifungal Agents / pharmacology*
  • Antifungal Agents / therapeutic use*
  • Area Under Curve
  • Candida albicans / classification
  • Candida albicans / drug effects*
  • Candidiasis / complications
  • Candidiasis / drug therapy*
  • Colony Count, Microbial
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / adverse effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Fluconazole / blood
  • Fluconazole / pharmacokinetics
  • Fluconazole / pharmacology*
  • Fluconazole / therapeutic use*
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / adverse effects
  • Injections, Intraperitoneal
  • Kidney / drug effects
  • Mice
  • Mice, Inbred ICR
  • Microbial Sensitivity Tests
  • Neutropenia / chemically induced
  • Neutropenia / complications

Substances

  • Antifungal Agents
  • Immunosuppressive Agents
  • Cyclophosphamide
  • Fluconazole