Derivation of an In Vivo Drug Exposure Breakpoint for Flucytosine against Candida albicans and Impact of the MIC, Growth Rate, and Resistance Genotype on the Antifungal Effect
- 1 November 2006
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 50 (11), 3680-3688
- https://doi.org/10.1128/aac.00369-06
Abstract
Drug exposure or pharmacodynamic breakpoints refer to a magnitude of drug exposure which separates a population into groups with high and low probabilities of attaining a desired outcome. We used a pharmacodynamic model of disseminated candidiasis to define an in vivo drug exposure breakpoint for flucytosine (5FC) against Candida albicans . The results were bridged to humans by using population pharmacokinetics and Monte Carlo simulation. An in vivo drug exposure breakpoint for 5FC was apparent when serum levels were above the MIC for 45% of the dosing interval. The Monte Carlo simulations suggested that using a human dose of 100 mg/kg of body weight/day in four divided doses, 5FC resistance was defined at an MIC of 32 mg/liter. Target attainment rates following administration of 25, 50, and 100 mg/kg/day were similar, suggesting that the use of a lower dose of 5FC is possible. Using six isolates of C. albicans with MICs ranging from 0.06 to >64 mg/liter, we also explored the influence that the MIC, the fraction of the dosing interval that the serum levels of 5FC remained above the MIC (T>MIC), the 5FC resistance genotype, and the in vivo growth rate had on the response to 5FC. The MIC and T>MIC were both critical measures affecting the generation of a drug effect but had no bearing on the magnitude of the maximal kill induced by 5FC. The in vivo growth rate was a critical additional determinant of the exposure-response relationship. There was a relationship between the 5FC resistance genotype and the exposure-response relationship.Keywords
This publication has 25 references indexed in Scilit:
- Surface Response Modeling to Examine the Combination of Amphotericin B Deoxycholate and 5‐Fluorocytosine for Treatment of Invasive CandidiasisThe Journal of Infectious Diseases, 2005
- Relationship between In Vitro Activities of Amphotericin B and Flucytosine and pH for Clinical Yeast and Mold IsolatesAntimicrobial Agents and Chemotherapy, 2005
- Application of an In Vitro Infection Model and Simulation for Reevaluation of Fluoroquinolone Breakpoints for Salmonella enterica Serotype TyphiAntimicrobial Agents and Chemotherapy, 2005
- Relationship between Fluoroquinolone Area under the Curve:Minimum Inhibitory Concentration Ratio and the Probability of Eradication of the Infecting Pathogen, in Patients with Nosocomial PneumoniaThe Journal of Infectious Diseases, 2004
- In Vivo Pharmacokinetics and Pharmacodynamics of a New Triazole, Voriconazole, in a Murine Candidiasis ModelAntimicrobial Agents and Chemotherapy, 2003
- Method for the determination of minimum inhibitory concentration (MIC) by broth dilution of fermentative yeastsClinical Microbiology & Infection, 2003
- Population Pharmacokinetics of Flucytosine: Comparison and Validation of Three Models Using STS, NPEM, and NONMEMTherapeutic Drug Monitoring, 2000
- The Rate of Killing of Escherichia coli by -Lactam Antibiotics Is Strictly Proportional to the Rate of Bacterial GrowthMicrobiology, 1986
- A Comparison of Amphotericin B Alone and Combined with Flucytosine in the Treatment of Cryptoccal MeningitisNew England Journal of Medicine, 1979
- A unifying model for the G1 period in prokaryotes and eukaryotesNature, 1979