AUC/MIC is the Pharmacodynamic (PD) Variable for Caspofungin (C) as Determined in a Non-Neutropenic Mouse Model of Candidiasis.

A. LOUIE, M. DEZIEL, W. LIU, M. DRUSANO, T. GUMBO, G.L. DRUSANO

Author address: 

Ordway Research Institute, Albany, NY.

Abstract: 

Background: Candidiasis remains a major concern for patients and has become one of the most common causes of nosocomial infection. C is an echinocandin antifungal agent with potent activity against Candida species. We evaluated the PD of C against C albicans - ATCC 36082. Methods: The C MIC was determined by NCCLS macrobroth dilution method in RPMI-1640 with MOPS. The end point of the mouse model was the number of colonies in the kidney. Mouse PK of C was determined over the range of 0.25-1.5 mg/kg. Drug was assayed in both serum (S) and kidney (K) by HPLC. All data were co-modeled in a population PK analysis employing BigNPAG. AUC estimates in S and K were calculated from the MAP-Bayesian estimates. The infection model fractionation was done over the steep part of the exposure-response curve over a 4 day period. Fractionated doses were administered as the whole dose at 0 h, 1/2 dose at 0 & 48 h, or 1/4 dose at 0, 24, 48 & 72 h. Sacrifice was at 96 h. Results were examined by analysis of variance and also by inhibitory sigmoid Emax modeling with ADAPT II. Results: The MIC for C was 0.2 mg/L. Clearance was linear. The apparent half life of C in K was approximately twice that in S. The doses fractionated were 0.1, 0.2, 0.4 and 1.0 mg/kg. These corresponded, ultimately, to 6.2%, 19.9%, 48.4% and 84.5% of the maximal effect, respectively. ANOVA revealed no significant differences among the fractionation groups. This indicates AUC/MIC is the PD-linked variable. The inhibitory sigmoid Emax model was: Log10 (CFU/g) = 4.82 - (2.22 x (AUC/MIC2.35 / ((AUC/MIC)2.35 + 70.52.35)); r2 = 0.974, p
2003

abstract No: 

A-1572

Full conference title: 

43rd Interscience Conference on Antimicrobial Agents
    • ICAAC 43rd