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Analysis of Paradoxical Efficacy of Carbapenems against carbapenemase-producing Escherichia coli in a Murine Model of Lethal Peritonitis

Abstract : The clinical benefit of carbapenems against carbapenemase-producing (CPE) remains in question. MICs of imipenem (IMP) and ertapenem (ERT) against isogenic derivatives of the wild-type strain CFT073 producing KPC-3, OXA-48, or NDM-1 were 0.25, 2, 16, and 64 mg/liter for IMP and 0.008, 0.5, 8, and 64 mg/liter for ERT, respectively. Swiss ICR-strain mice with peritonitis were treated for 24 h with IMP or ERT. Despite a limited duration of time during which free antibiotic concentrations were above the MIC (down to 0% for the NDM-1-producing strain), IMP and ERT significantly reduced bacterial counts in spleen and peritoneal fluid at 24 h ( < 0.005) and prevented mortality. Several possible explanations were investigated. Addition of 4% albumin or 50% normal human serum did not modify IMP activity. Bacterial fitness of resistant strains was not altered and virulence did not decrease with resistance. In the presence of subinhibitory concentrations of ERT, growth rates of OXA-48, KPC-3, and NDM-1 strains were significantly decreased and filamentation of the NDM-1 strain was observed. The expression of was not decreased compared to No zinc depletion was observed in infected mice compared with Mueller-Hinton broth. In conclusion, a paradoxical efficacy of IMP and ERT against highly resistant carbapenemase-producing was confirmed. Alternative mechanisms of antibacterial effects of subinhibitory concentrations of carbapenems may be involved to explain activity. These results are in agreement with a potential clinical benefit of carbapenems to treat CPE infections, despite high carbapenem MICs.
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Submitted on : Monday, June 15, 2020 - 5:04:14 PM
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Ariane Roujansky, Victoire de Lastours, François Guerin, Françoise Chau, Geoffrey Cheminet, et al.. Analysis of Paradoxical Efficacy of Carbapenems against carbapenemase-producing Escherichia coli in a Murine Model of Lethal Peritonitis. Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2020, 64 (8), pp.e00853-20. ⟨10.1128/AAC.00853-20⟩. ⟨hal-02635122⟩

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