Journal article

In Vivo Efficacy of Human Simulated Regimens of Carbapenems and Comparator Agents against NDM-1-Producing Enterobacteriaceae

  • Wiskirchen, Dora E. University of Saint Joseph, School of Pharmacy, Hartford, Connecticut, USA
  • Nordmann, Patrice Emerging Antibiotic Resistance, INSERM U914, Le Kremlin-Bicêtre, France - Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science, University of Fribourg, Switzerland
  • Crandon, Jared L. Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA
  • Nicolau, David P. Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA
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Published in:
  • Antimicrobial Agents and Chemotherapy. - 2014, vol. 58, no. 3, p. 1671-1677
English 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.
Faculté des sciences et de médecine
Médecine 3ème année
  • English
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