Inhibition of the β-Lactamase Bla Mab by Avibactam Improves the In Vitro and In Vivo Efficacy of Imipenem against Mycobacterium abscessus.

Autor: Lefebvre AL; INSERM, U1138, LRMA, Equipe 12 du Centre de Recherche des Cordeliers, Paris, France.; Université Pierre et Marie Curie, UMR S 1138, Paris, France.; Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France., Le Moigne V; UMR1173, INSERM, Université de Versailles St. Quentin, Montigny le Bretonneux, France., Bernut A; Centre d'Études d'Agents Pathogènes et Biotechnologies pour la Santé, FR3689, CNRS, Université Montpellier, Montpellier, France., Veckerlé C; INSERM, U1138, LRMA, Equipe 12 du Centre de Recherche des Cordeliers, Paris, France.; Université Pierre et Marie Curie, UMR S 1138, Paris, France.; Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France., Compain F; INSERM, U1138, LRMA, Equipe 12 du Centre de Recherche des Cordeliers, Paris, France.; Université Pierre et Marie Curie, UMR S 1138, Paris, France.; Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France.; Assistance Publique-Hôpitaux de Paris, Service de Microbiologie, Hôpital Européen Georges Pompidou, Paris, France., Herrmann JL; UMR1173, INSERM, Université de Versailles St. Quentin, Montigny le Bretonneux, France., Kremer L; Centre d'Études d'Agents Pathogènes et Biotechnologies pour la Santé, FR3689, CNRS, Université Montpellier, Montpellier, France.; INSERM, CPBS, Montpellier, France., Arthur M; INSERM, U1138, LRMA, Equipe 12 du Centre de Recherche des Cordeliers, Paris, France michel.arthur@crc.jussieu.fr jean-luc.mainardi@crc.jussieu.fr.; Université Pierre et Marie Curie, UMR S 1138, Paris, France.; Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France., Mainardi JL; INSERM, U1138, LRMA, Equipe 12 du Centre de Recherche des Cordeliers, Paris, France michel.arthur@crc.jussieu.fr jean-luc.mainardi@crc.jussieu.fr.; Université Pierre et Marie Curie, UMR S 1138, Paris, France.; Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France.; Assistance Publique-Hôpitaux de Paris, Service de Microbiologie, Hôpital Européen Georges Pompidou, Paris, France.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2017 Mar 24; Vol. 61 (4). Date of Electronic Publication: 2017 Mar 24 (Print Publication: 2017).
DOI: 10.1128/AAC.02440-16
Abstrakt: Mycobacterium abscessus pulmonary infections are treated with a macrolide (clarithromycin or azithromycin), an aminoglycoside (amikacin), and a β-lactam (cefoxitin or imipenem). The triple combination is used without any β-lactamase inhibitor, even though M abscessus produces the broad-spectrum β-lactamase Bla Mab We determine whether inhibition of Bla Mab by avibactam improves the activity of imipenem against M. abscessus The bactericidal activity of drug combinations was assayed in broth and in human macrophages. The in vivo efficacy of the drugs was tested by monitoring the survival of infected zebrafish embryos. The level of Bla Mab production in broth and in macrophages was compared by quantitative reverse transcription-PCR and Western blotting. The triple combination of imipenem (8 or 32 μg/ml), amikacin (32 μg/ml), and avibactam (4 μg/ml) was bactericidal in broth (<0.1% survival), with 3.2- and 4.3-log 10 reductions in the number of CFU being achieved at 72 h when imipenem was used at 8 and 32 μg/ml, respectively. The triple combination achieved significant intracellular killing, with the bacterial survival rates being 54% and 7% with the low (8 μg/ml) and high (32 μg/ml) dosages of imipenem, respectively. In vivo inhibition of Bla Mab by avibactam improved the survival of zebrafish embryos treated with imipenem. Expression of the gene encoding Bla Mab was induced (20-fold) in the infected macrophages. Inhibition of Bla Mab by avibactam improved the efficacy of imipenem against M. abscessus in vitro , in macrophages, and in zebrafish embryos, indicating that this β-lactamase inhibitor should be clinically evaluated. The in vitro evaluation of imipenem may underestimate the impact of Bla Mab , since the production of the β-lactamase is inducible in macrophages.
(Copyright © 2017 American Society for Microbiology.)
Databáze: MEDLINE
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