Efficacy of Humanized Carbapenem Exposures against New Delhi metallo-beta-lactamase (NDM-1) Producing Enterobacteriaceae in a Murine Infection Model.
Antimicrob Agents Chemother. 2013 Jun 3;
Authors: Wiskirchen DE, Nordmann P, Crandon JL, Nicolau DP
Enterobacteriaceae producing the novel carbapenemase, NDM-1 are emerging worldwide. While these organisms often display high levels of in vitro resistance to multiple antibiotics, in vivo efficacy data are lacking. Herein, the activity of humanized ertapenem and doripenem exposures were characterized against a wild-type K. pneumoniae and its derived isogenic strains harboring either an NDM-1 or KPC-2 plasmid in immunocompetent mice. In addition, four clinical isolates expressing NDM-1 were evaluated. Human simulated regimens of ertapenem 1 g every 24 h and high-dose, prolonged infusion doripenem 2 g every 8 h as a 4 h infusion were evaluated over 24 h and efficacy was determined by the change in bacterial density compared to 24 h growth controls. Greater than 1 log CFU reductions in bacterial density were observed against the wild-type strain as well as the derived isogenic NDM-1 strain, while no reduction was observed against the derived KPC-2 strain. Post-exposure MICs confirmed the in vitro maintenance of ertapenem resistance marker in both the NDM-1 or KPC-2 strains. Similar to the isogenically derived NDM-1 strain, bacterial density was reduced at 24 h against all four clinical NDM-1 isolates showing variable levels of MICs for carbapenems, with near maximal activity of both agents occurring when doripenem MIC was ≤ 8 μg/mL. While carbapenem monotherapy does not appear to be an option against KPC based infections, these data suggest that carbapenem monotherapy may be a viable option for treating NDM-1 producing Enterobacteriaceae under certain conditions, and warrants further in vivo exploration.
PMID: 23733463 [PubMed - as supplied by publisher]