Logo image
Back
In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model
Journal article   Open access   Peer reviewed

In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model

D Andes, D J Diekema, M A Pfaller, R A Prince, K Marchillo, J Ashbeck and J Hou
Antimicrobial agents and chemotherapy, Vol.52(2), pp.539-550
02/2008
DOI: 10.1128/AAC.01061-07
PMCID: PMC2224754
PMID: 18070979
url
https://doi.org/10.1128/AAC.01061-07View
Published (Version of record) Open Access

Abstract

Multiple in vivo studies have characterized the pharmacodynamics of drugs from the triazole and polyene antifungal drug classes. Fewer studies have investigated these pharmacodynamic relationships for the echinocandin drug class. We used a neutropenic murine model of disseminated Candida albicans, Candida tropicalis, and Candida glabrata infection to characterize the time course of activity of the new echinocandin anidulafungin. The pharmacokinetic-pharmacodynamic (PK-PD) indices (the percentage of time that the drug concentration was above the MIC, the ratio of the area under the concentration-time curve from 0 to 24 h [AUC(0-24)] to the MIC, and the ratio of the maximum serum drug concentration [C(max)] to the MIC) were correlated with in vivo efficacy, as measured by organism numbers in kidney cultures after 96 h of therapy. The kinetics following intraperitoneal anidulafungin dosing in neutropenic infected mice were monitored. Peak levels and AUCs were linear over the 16-fold dose range studied. The drug elimination half-life in serum ranged from 14 to 24 h. Single-dose postantifungal-effect studies demonstrated prolonged suppression of organism regrowth after serum anidulafungin levels had fallen below the MIC. Of the four dosing intervals studied, treatment with the more widely spaced dosing regimens was most efficacious, suggesting the C(max)/MIC ratio as the PK-PD index most predictive of efficacy. Nonlinear regression analysis suggested that both the C(max)/MIC and AUC/MIC ratios were strongly predictive of treatment success. Studies were then conducted with 13 additional C. albicans, C. tropicalis, and C. glabrata isolates with various anidulafungin susceptibilities (MICs of anidulafungin for these strains, 0.015 to 2.0 microg/ml) to determine if similar C(max)/MIC and AUC(0-24)/MIC ratios for these isolates were associated with efficacy. The anidulafungin exposures associated with efficacy were similar among Candida species.
 Antifungal Agents - pharmacology Area Under Curve Echinocandins - pharmacokinetics Humans Treatment Outcome Candidiasis - microbiology Mice, Inbred ICR Antifungal Agents - therapeutic use Echinocandins - administration & dosage Microbial Sensitivity Tests Neutropenia - complications Candida - classification Animals Candida - pathogenicity Candidiasis - drug therapy Antifungal Agents - pharmacokinetics Echinocandins - therapeutic use Female Mice Candida - drug effects Antifungal Agents - administration & dosage Echinocandins - pharmacology Disease Models, Animal

Details

Metrics

21 Record Views
114 Times Cited - Web of Science
Logo image