Bactericidal Activities of Meropenem and Ertapenem against Extended-Spectrum-{szligbeta}-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae in a Neutropenic Mouse Thigh Model

• Published in: Antimicrobial agents and chemotherapy Vol. 51; no. 4; pp. 1481 - 1486
• Main Authors: DeRyke, CAndrew, Banevicius, Mary Anne, Fan, Hong Wei, Nicolau, David P
• Format: Journal Article
• Language: English
• Published: 01.04.2007
• Subjects: Escherichia coli; Klebsiella pneumoniae
• ISSN: 0066-4804; 1098-6596

The purpose of this study was to examine the in vivo efficacies of meropenem and ertapenem against extended-spectrum-{szligbeta}-lactamase (ESBL)-producing isolates with a wide range of MICs. Human-simulated dosing regimens in mice were designed to approximate the free drug percent time above the MIC (fT>MIC) observed for humans following meropenem at 1 g every 8 h and ertapenem at 1 g every 24 h. An in vivo neutropenic mouse thigh infection model was used to examine the bactericidal effects against 31 clinical ESBL Escherichia coli and Klebsiella pneumoniae isolates and 2 non-ESBL isolates included for comparison at a standard 10 super(5) inoculum. Three isolates were examined at a high 10 super(7) inoculum as well. Meropenem displayed greater in vitro potency, with a median MIC (range) ( mu g/ml) of 0.125 (0.03 to 32), than did ertapenem, with 0.5 (0.012 to 128). Seven of the 31 ESBL isolates were removed from the efficacy analysis due to their inability to establish infection in the mouse model. When MICs were less than or equal to 1.5 mu g/ml for ertapenem ( less than or equal to 0.5 mu g/ml for meropenem), similar reductions in CFU ( approximately 2-log kill) were observed for both ertapenem (fT>MIC greater than or equal to 23%) and meropenem (fT>MIC greater than or equal to 75%). Ertapenem showed bacterial regrowth for seven of eight isolates, with MICs of greater than or equal to 2 mu g/ml (fT>MIC less than or equal to 20%), while meropenem displayed antibacterial potency that varied from a static effect to a 1-log bacterial reduction in these isolates (fT>MIC = 30 to 65%). At a 10 super(7) inoculum, both agents eradicated bacteria due to adequate exposures (fT>MIC = 20 to 45%). Due to low MICs, no difference in bacterial kill was noted for the majority of ESBL isolates tested. However, for isolates with raised ertapenem MICs of greater than or equal to 2 mu g/ml, meropenem displayed sustained efficacy due to its greater in vitro potency and higher resultant fT>MIC.