title: Efficacy of humanized carbapenem exposures against New Delhi metallo-β-lactamase (NDM-1)-producing enterobacteriaceae in a murine infection model.
abstract: Enterobacteriaceae producing the novel carbapenemase New Delhi metallo-β-lactamase (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. Here, the activities 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 at 1 g every 24 h and high-dose, prolonged infusion of doripenem at 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 that in 24-h growth controls. CFU reductions in bacterial density of greater than 1 log unit 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. Postexposure MICs confirmed the in vitro maintenance of the ertapenem resistance marker in both the NDM-1 and KPC-2 strains. Similar to the case for 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 the 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 this warrants further in vivo exploration.
authors.affiliation: University of Saint Joseph, School of Pharmacy, Hartford, Connecticut, USA.
authors.forename: Dora E
authors.initials: DE
authors.lastname: Wiskirchen
authors.forename: Patrice
authors.initials: P
authors.lastname: Nordmann
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D058491:Bacterial Load; D015780:Carbapenems / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D000077726:Doripenem; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial; D000077727:Ertapenem; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy*; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000473:pathology; D013997:Time Factors; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*; D047090:beta-Lactams / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D047090:beta-Lactams; D000077726:Doripenem; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; D000077727:Ertapenem