Lefebvre, A.-L., Le Moigne, V., Bernut, A. orcid.org/0000-0002-1928-8329 et al. (6 more authors) (2017) Inhibition of the β-lactamase BlaMab by avibactam improves the in vitro and in vivo efficacy of imipenem against mycobacterium abscessus. Antimicrobial Agents and Chemotherapy, 61 (4). e02440-16. ISSN 0066-4804
Abstract
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 BlaMab. We determine whether inhibition of BlaMab 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 BlaMab 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-log10 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 BlaMab by avibactam improved the survival of zebrafish embryos treated with imipenem. Expression of the gene encoding BlaMab was induced (20-fold) in the infected macrophages. Inhibition of BlaMab 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 BlaMab, since the production of the β-lactamase is inducible in macrophages.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 American Society for Microbiology. This is an author-produced version of a paper subsequently published in Antimicrobial Agents and Chemotherapy. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | β-lactamase inhibitor; avibactam; Mycobacterium abscessus; cystic fibrosis; imipenem |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 29 Apr 2019 11:30 |
Last Modified: | 29 Apr 2019 11:30 |
Status: | Published |
Publisher: | American Society for Microbiology |
Refereed: | Yes |
Identification Number: | 10.1128/aac.02440-16 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:145419 |