In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa

BACKGROUND: The prevalence of antibiotic resistance is increasing, and multidrug-resistant Pseudomonas aeruginosa has been identified as a serious threat to human health. The production of β-lactamase is a key mechanism contributing to imipenem resistance in P. aeruginosa. Relebactam is a novel β-la...

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Autores principales: Young, Katherine, Painter, Ronald E., Raghoobar, Susan L., Hairston, Nichelle N., Racine, Fred, Wisniewski, Douglas, Balibar, Carl J., Villafania, Artjohn, Zhang, Rumin, Sahm, Daniel F., Blizzard, Timothy, Murgolo, Nicholas, Hammond, Milton L., Motyl, Mary R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610938/
https://www.ncbi.nlm.nih.gov/pubmed/31272373
http://dx.doi.org/10.1186/s12866-019-1522-7
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author Young, Katherine
Painter, Ronald E.
Raghoobar, Susan L.
Hairston, Nichelle N.
Racine, Fred
Wisniewski, Douglas
Balibar, Carl J.
Villafania, Artjohn
Zhang, Rumin
Sahm, Daniel F.
Blizzard, Timothy
Murgolo, Nicholas
Hammond, Milton L.
Motyl, Mary R.
author_facet Young, Katherine
Painter, Ronald E.
Raghoobar, Susan L.
Hairston, Nichelle N.
Racine, Fred
Wisniewski, Douglas
Balibar, Carl J.
Villafania, Artjohn
Zhang, Rumin
Sahm, Daniel F.
Blizzard, Timothy
Murgolo, Nicholas
Hammond, Milton L.
Motyl, Mary R.
author_sort Young, Katherine
collection PubMed
description BACKGROUND: The prevalence of antibiotic resistance is increasing, and multidrug-resistant Pseudomonas aeruginosa has been identified as a serious threat to human health. The production of β-lactamase is a key mechanism contributing to imipenem resistance in P. aeruginosa. Relebactam is a novel β-lactamase inhibitor, active against class A and C β-lactamases, that has been shown to restore imipenem susceptibility. In a series of studies, we assessed the interaction of relebactam with key mechanisms involved in carbapenem resistance in P. aeruginosa and to what extent relebactam might overcome imipenem non-susceptibility. RESULTS: Relebactam demonstrated no intrinsic antibacterial activity against P. aeruginosa, had no inoculum effect, and was not subject to efflux. Enzymology studies showed relebactam is a potent (overall inhibition constant: 27 nM), practically irreversible inhibitor of P. aeruginosa AmpC. Among P. aeruginosa clinical isolates from the SMART global surveillance program (2009, n = 993; 2011, n = 1702; 2015, n = 5953; 2016, n = 6165), imipenem susceptibility rates were 68.4% in 2009, 67.4% in 2011, 70.4% in 2015, and 67.3% in 2016. With the addition of 4 μg/mL relebactam, imipenem susceptibility rates increased to 87.6, 86.0, 91.7, and 89.8%, respectively. When all imipenem–non-susceptible isolates were pooled, the addition of 4 μg/mL relebactam reduced the mode imipenem minimum inhibitory concentration (MIC) 8-fold (from 16 μg/mL to 2 μg/mL) among all imipenem–non-susceptible isolates. Of 3747 imipenem–non-susceptible isolates that underwent molecular profiling, 1200 (32%) remained non-susceptible to the combination imipenem/relebactam (IMI/REL); 42% of these encoded class B metallo-β-lactamases, 11% encoded a class A GES enzyme, and no class D enzymes were detected. No relationship was observed between alleles of the chromosomally-encoded P. aeruginosa AmpC and IMI/REL MIC. CONCLUSIONS: IMI/REL exhibited potential in the treatment of carbapenem-resistant P. aeruginosa infections, with the exception of isolates encoding class B, some GES alleles, and class D carbapenemases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12866-019-1522-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-66109382019-07-16 In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa Young, Katherine Painter, Ronald E. Raghoobar, Susan L. Hairston, Nichelle N. Racine, Fred Wisniewski, Douglas Balibar, Carl J. Villafania, Artjohn Zhang, Rumin Sahm, Daniel F. Blizzard, Timothy Murgolo, Nicholas Hammond, Milton L. Motyl, Mary R. BMC Microbiol Research Article BACKGROUND: The prevalence of antibiotic resistance is increasing, and multidrug-resistant Pseudomonas aeruginosa has been identified as a serious threat to human health. The production of β-lactamase is a key mechanism contributing to imipenem resistance in P. aeruginosa. Relebactam is a novel β-lactamase inhibitor, active against class A and C β-lactamases, that has been shown to restore imipenem susceptibility. In a series of studies, we assessed the interaction of relebactam with key mechanisms involved in carbapenem resistance in P. aeruginosa and to what extent relebactam might overcome imipenem non-susceptibility. RESULTS: Relebactam demonstrated no intrinsic antibacterial activity against P. aeruginosa, had no inoculum effect, and was not subject to efflux. Enzymology studies showed relebactam is a potent (overall inhibition constant: 27 nM), practically irreversible inhibitor of P. aeruginosa AmpC. Among P. aeruginosa clinical isolates from the SMART global surveillance program (2009, n = 993; 2011, n = 1702; 2015, n = 5953; 2016, n = 6165), imipenem susceptibility rates were 68.4% in 2009, 67.4% in 2011, 70.4% in 2015, and 67.3% in 2016. With the addition of 4 μg/mL relebactam, imipenem susceptibility rates increased to 87.6, 86.0, 91.7, and 89.8%, respectively. When all imipenem–non-susceptible isolates were pooled, the addition of 4 μg/mL relebactam reduced the mode imipenem minimum inhibitory concentration (MIC) 8-fold (from 16 μg/mL to 2 μg/mL) among all imipenem–non-susceptible isolates. Of 3747 imipenem–non-susceptible isolates that underwent molecular profiling, 1200 (32%) remained non-susceptible to the combination imipenem/relebactam (IMI/REL); 42% of these encoded class B metallo-β-lactamases, 11% encoded a class A GES enzyme, and no class D enzymes were detected. No relationship was observed between alleles of the chromosomally-encoded P. aeruginosa AmpC and IMI/REL MIC. CONCLUSIONS: IMI/REL exhibited potential in the treatment of carbapenem-resistant P. aeruginosa infections, with the exception of isolates encoding class B, some GES alleles, and class D carbapenemases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12866-019-1522-7) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-04 /pmc/articles/PMC6610938/ /pubmed/31272373 http://dx.doi.org/10.1186/s12866-019-1522-7 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Young, Katherine
Painter, Ronald E.
Raghoobar, Susan L.
Hairston, Nichelle N.
Racine, Fred
Wisniewski, Douglas
Balibar, Carl J.
Villafania, Artjohn
Zhang, Rumin
Sahm, Daniel F.
Blizzard, Timothy
Murgolo, Nicholas
Hammond, Milton L.
Motyl, Mary R.
In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa
title In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa
title_full In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa
title_fullStr In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa
title_full_unstemmed In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa
title_short In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa
title_sort in vitro studies evaluating the activity of imipenem in combination with relebactam against pseudomonas aeruginosa
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610938/
https://www.ncbi.nlm.nih.gov/pubmed/31272373
http://dx.doi.org/10.1186/s12866-019-1522-7
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