In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa
Abstract 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 no...
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doaj-74bfca45a65f4093988417ba76437c532020-11-25T03:28:21ZengBMCBMC Microbiology1471-21802019-07-0119111410.1186/s12866-019-1522-7In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosaKatherine Young0Ronald E. Painter1Susan L. Raghoobar2Nichelle N. Hairston3Fred Racine4Douglas Wisniewski5Carl J. Balibar6Artjohn Villafania7Rumin Zhang8Daniel F. Sahm9Timothy Blizzard10Nicholas Murgolo11Milton L. Hammond12Mary R. Motyl13Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.IHMAMerck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Abstract 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.http://link.springer.com/article/10.1186/s12866-019-1522-7β-Lactamase inhibitorCarbapenem-resistantCarbapenemaseMultidrug-resistantMK-7655Imipenem/relebactam |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Katherine Young Ronald E. Painter Susan L. Raghoobar Nichelle N. Hairston Fred Racine Douglas Wisniewski Carl J. Balibar Artjohn Villafania Rumin Zhang Daniel F. Sahm Timothy Blizzard Nicholas Murgolo Milton L. Hammond Mary R. Motyl |
spellingShingle |
Katherine Young Ronald E. Painter Susan L. Raghoobar Nichelle N. Hairston Fred Racine Douglas Wisniewski Carl J. Balibar Artjohn Villafania Rumin Zhang Daniel F. Sahm Timothy Blizzard Nicholas Murgolo Milton L. Hammond Mary R. Motyl In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa BMC Microbiology β-Lactamase inhibitor Carbapenem-resistant Carbapenemase Multidrug-resistant MK-7655 Imipenem/relebactam |
author_facet |
Katherine Young Ronald E. Painter Susan L. Raghoobar Nichelle N. Hairston Fred Racine Douglas Wisniewski Carl J. Balibar Artjohn Villafania Rumin Zhang Daniel F. Sahm Timothy Blizzard Nicholas Murgolo Milton L. Hammond Mary R. Motyl |
author_sort |
Katherine Young |
title |
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_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_sort |
in vitro studies evaluating the activity of imipenem in combination with relebactam against pseudomonas aeruginosa |
publisher |
BMC |
series |
BMC Microbiology |
issn |
1471-2180 |
publishDate |
2019-07-01 |
description |
Abstract 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. |
topic |
β-Lactamase inhibitor Carbapenem-resistant Carbapenemase Multidrug-resistant MK-7655 Imipenem/relebactam |
url |
http://link.springer.com/article/10.1186/s12866-019-1522-7 |
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