Bactericidal activities of meropenem and ertapenem against extended-spectrum-beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae in a neutropenic mouse thigh model

Abstract

The purpose of this study was to examine the in vivo efficacies of meropenem and ertapenem against extended-spectrum-beta-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(5) inoculum. Three isolates were examined at a high 10(7) inoculum as well. Meropenem displayed greater in vitro potency, with a median MIC (range) (microg/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<or=1.5 microg/ml for ertapenem (<or=0.5 microg/ml for meropenem), similar reductions in CFU (approximately 2-log kill) were observed for both ertapenem (fT>MIC>or=23%) and meropenem (fT>MIC>or=75%). Ertapenem showed bacterial regrowth for seven of eight isolates, with MICs of>or=2 microg/ml (fT>MIC<or=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(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>or=2 microg/ml, meropenem displayed sustained efficacy due to its greater in vitro potency and higher resultant fT>MIC.

FIG. 1.

Comparison of concentration-time profiles of meropenem and ertapenem in healthy human volunteers and mice. (A) Meropenem dosing in mice involved three cycles of 60, 30, 20, and 5 mg/kg administered at 0, 1.5, 3, and 5 h every 8 h, and the human regimen represents meropenem 1 g every 8 h. (B) Ertapenem dosing in mice was 50 mg/kg every 6 h, and the human regimen represents 1 g every 24 h.

FIG. 2.

Bacterial growth (measured as density) for the change in log₁₀ CFU/thigh for 24-h-growth control mice compared to that for 0-h control mice for each ESBL isolate tested (n = 31). Each bar represents the mean ± standard deviation of between three and six mice. Isolates marked with asterisks represent inadequately established infections. Mice infected with E. coli 118 were processed at 18 h. EC, E. coli; KP, K. pneumoniae.

FIG. 3.

Change in log₁₀ CFU/thigh measured in density for meropenem (A) and ertapenem (B) at 24 h compared to 0-h controls.