Pharmacodynamic Comparison of the Carbapenems Against E. coli and Klebsiella spp. Containing Extended spectrum β-lactamases

Abstract

Carbapenems are the treatment of choice for extended-spectrum β-lactamases (ESBLs). Ertapenem is a new member of the carbapenem class, and is often grouped with imipenem and meropenem as a recommended treatment for ESBLs. However, new in vitro data question ertapenem’s inclusion as a first line treatment for these bacteria, suggesting that ertapenem has a lower likelihood of obtaining appropriate pharmacodynamic exposure than other carbapenems. This study-part of the OPTAMA (Optimizing Pharmacodynamic Target Attainment using a Microbiologic Antibiogram) Program-used Monte Carlo simulations to compare cumulative fraction of response (CFR) for carbapenems against ESBL producing isolates of Escherichia coli and Klebsiella species collected in North America. Pharmacokinetic parameters were derived from the literature; MIC distributions were obtained from the 2004 MYSTIC database and two urban teaching hospitals. Pharmacodynamic endpoints evaluated included free drug time above the MIC (fT_>MIC). Ertapenem dosed at 1 gram every 24 hours showed a CFR of 98.1% at 40%fT_>MIC against all ESBLs included in 5,000 trials, versus 100.0% for imipenem and meropenem dosed at 1 gram every 8 hours (p<0.001). Ertapenem also exhibited a lower CFR against E. coli and Klebsiella when modeled against those species individually (96.9% and 98.7%, respectively) than the other carbapenems (100.00% for all regimens) (p<0.001). Ertapenem demonstrated a probability of target attainment at 40%fT_>MIC of 77% against bacteria with MICs of = 2g/ml. All three carbapenems showed high probabilities of achieving bactericidal target attainment against ESBL producing organisms, though ertapenem’s lower CFR suggests that it might be a second choice agent in institutions with high rates of resistance among ESBLs.