title: In vivo efficacy of human simulated regimens of carbapenems and comparator agents against NDM-1-producing Enterobacteriaceae.
abstract: Doripenem and ertapenem have demonstrated efficacy against several NDM-1-producing isolates in vivo, despite having high MICs. In this study, we sought to further characterize the efficacy profiles of humanized regimens of standard (500 mg given every 8 h) and high-dose, prolonged infusion of doripenem (2 g given every 8 h, 4-h infusion) and 1 g of ertapenem given intravenously every 24 h and the comparator regimens of ceftazidime at 2 g given every 8 h (2-h infusion), levofloxacin at 500 mg every 24 h, and aztreonam at 2 g every 6 h (1-h infusion) against a wider range of isolates in a murine thigh infection model. An isogenic wild-type strain and NDM-1-producing Klebsiella pneumoniae and eight clinical NDM-1-producing members of the family Enterobacteriaceae were tested in immunocompetent- and neutropenic-mouse models. The wild-type strain was susceptible to all of the agents, while the isogenic NDM-1-producing strain was resistant to ceftazidime, doripenem, and ertapenem. Clinical NDM-1-producing strains were resistant to nearly all five of the agents (two were susceptible to levofloxacin). In immunocompetent mice, all of the agents produced ≥1-log10 CFU reductions of the isogenic wild-type and NDM-1-producing strains after 24 h. Minimal efficacy of ceftazidime, aztreonam, and levofloxacin against the clinical NDM-1-producing strains was observed. However, despite in vitro resistance, ≥1-log10 CFU reductions of six of eight clinical strains were achieved with high-dose, prolonged infusion of doripenem and ertapenem. Slight enhancements of doripenem activity over the standard doses were obtained with high-dose, prolonged infusion for three of the four isolates tested. Similar efficacy observations were noted in neutropenic mice. These data suggest that carbapenems are a viable treatment option for infections caused by NDM-1-producing Enterobacteriaceae.
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*; D015780:Carbapenems / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D000077726:Doripenem; D024901:Drug Resistance, Multiple, Bacterial; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology; D004756:Enterobacteriaceae Infections / Q000188:drug therapy; D000077727:Ertapenem; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; D047090:beta-Lactams / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D000077726:Doripenem; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; D000077727:Ertapenem