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Dimercaptosuccinic acid in combination with carbapenems against isogenic strains of Escherichia coli producing or not producing a metallo-β-lactamase in vitro and in murine peritonitis

  • Cheminet, G. Université de Paris, IAME, UMR 1137 INSERM, F-75018 Paris, France
  • de Lastours, V. Université de Paris, IAME, UMR 1137 INSERM, F-75018 Paris, France - Médecine interne, Hôpital Beaujon, AP-HP Nord, Université de Paris, F-92110 Clichy, France
  • Poirel, Laurent IAME, UMR 1137 Laboratoire Européen Associé INSERM, Université de Fribourg, Fribourg, Switzerland - Microbiologie Médicale et Moléculaire, Département de Médecine, Faculté des Sciences et de Médecine, Centre de Référence des Résistances Emergentes aux Antibiotiques (NARA), Université de Fribourg, Fribourg, Switzerland
  • Chau, F. Université de Paris, IAME, UMR 1137 INSERM, F-75018 Paris, France
  • Peoc’h, K. Université de Paris, CRI, UMR 1149 INSERM, F-75018 Paris, France - Laboratoire de biochimie, Hôpital Beaujon, AP-HP Nord, F-92110 Clichy, France
  • Massias, L. Université de Paris, IAME, UMR 1137 INSERM, F-75018 Paris, France - Laboratoire de pharmacologie et toxicologie, AP-HP Nord, Hôpital Bichat-Claude Bernard, F-75018 Paris, France
  • Fantin, B. Université de Paris, IAME, UMR 1137 INSERM, F-75018 Paris, France - Médecine interne, Hôpital Beaujon, AP-HP Nord, Université de Paris, F-92110 Clichy, France
  • Nordmann, Patrice IAME, UMR 1137 Laboratoire Européen Associé INSERM, Université de Fribourg, Fribourg, Switzerland - Microbiologie Médicale et Moléculaire, Département de Médecine, Faculté des Sciences et de Médecine, Centre de Référence des Résistances Emergentes aux Antibiotiques (NARA), Université de Fribourg, Fribourg, Switzerland
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    01.12.2020
Published in:
  • Journal of Antimicrobial Chemotherapy. - 2020, vol. 75, no. 12, p. 3593–3600
carbapenem
peritoneal fluid
imipenem
peritonitis
plasma
succimer
infections
mice
spleen
zinc
escherichia coli
beta-lactamase ndm-1
malnutrition-inflammation-cachexia syndrome
English Background: Carbapenemase-producing Enterobacterales represent a major therapeutic challenge. MBLs, requiring zinc at their catalytic site, could be inhibited by meso-dimercaptosuccinic acid (DMSA), a heavy metal chelator already widely used for treating lead intoxication.Objectives: To evaluate the activity of carbapenems alone or combined with DMSA against MBL-producing Escherichia coli in a severe murine peritonitis model.Methods: Isogenic strains of wild-type E. coli CFT073 producing the MBLs NDM-1, VIM-2 and IMP-1, and the control serine carbapenemases OXA-48 and KPC-3 were constructed. MIC determinations and time–kill assays were performed for imipenem, meropenem and ertapenem alone or in combination with DMSA. Infected mice were treated intraperitoneally for 24 h with imipenem, DMSA or their combination. Bacterial counts in peritoneal fluid and spleen were assessed at 24  h.Results: DMSA in combination with each carbapenem caused a significant decrease in the MICs for all MBL-producing strains, in a concentration-dependent manner, but did not provide benefit against non-MBL strains. In mice infected with the NDM-1- producing strain, the combination of imipenem and DMSA significantly reduced bacterial counts in peritoneal fluid (P = 0.0006) and spleen (P < 0.0001), as compared with imipenem alone, with no benefit against the KPC-3-producing and CFT073 strains. DMSA concentrations in plasma of mice were comparable to those obtained in humans with a standard oral dose.Conclusions: DMSA restores the activity of carbapenems against MBL-producing strains, and its combination with carbapenems appears to be a promising strategy for the treatment of NDM-producing E. coli infections.
Faculty
Faculté des sciences et de médecine
Department
Médecine 3ème année
Language
  • English
Classification
Biological sciences
License
License undefined
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https://folia.unifr.ch/unifr/documents/309105
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