Relative inhibitory activities of newly developed diazabicyclooctanes, boronic acid derivatives, and penicillin-based sulfone β-lactamase inhibitors against broad-spectrum AmpC β-lactamases

Le Terrier, Christophe; Mlynarcik, Patrik; Sadek, Mustafa; Nordmann, Patrice; Poirel, Laurent

doi:10.1128/aac.00775-24

Antimicrob Agents Chemother

2024

DOI: 10.1128/aac.00775-24

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Relative inhibitory activities of newly developed diazabicyclooctanes, boronic acid derivatives, and penicillin-based sulfone β-lactamase inhibitors against broad-spectrum AmpC β-lactamases

Christophe Le Terrier,

Patrik Mlynarcik,

Mustafa Sadek

et al.

Abstract: The relative inhibitory activities of diazabicyclooctanes (avibactam, relebactam, zidebactam, nacubactam, durlobactam), boronic acid derivatives (vaborbactam, taniborbactam, xeruborbactam), and penicillin-based sulfone derivative enmetazobactam were evaluated against several intrinsic and acquired class C β-lactamases. By contrast to vaborbactam and enmetazobactam, taniborbactam, xeruborbactam, and all diazabicyclooctanes demonstrated effective activities against most AmpC enzymes. Notably, durlobactam exhibit… Show more

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Cited by 2 publications

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In-vitro activity of newly-developed β-lactamase inhibitors avibactam, relebactam and vaborbactam in combination with anti-pseudomonal β-lactam antibiotics against AmpC-overproducing clinical Pseudomonas aeruginosa isolates

Le Terrier,

Raro,

Saad

et al. 2024

Eur J Clin Microbiol Infect Dis

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Purpose Overproduction of the intrinsic chromosomally-encoded AmpC β-lactamase is one of the main mechanisms responsible for broad-spectrum β-lactam resistance in Pseudomonas aeruginosa. Our study aimed to evaluate the in-vitro activity of anti-pseudomonal β-lactam molecules associated with the recently-developed and commercially-available β-lactamase inhibitors, namely avibactam, relebactam and vaborbactam, against P. aeruginosa isolates overproducing their AmpC. Methods MIC values of ceftazidime, cefepime, meropenem, imipenem and ceftolozane with or without β-lactam inhibitor were determined for 50 AmpC-overproducing P. aeruginosa clinical isolates. MIC breakpoints for resistance were retained at 8 mg/L for β-lactams and β-lactam/β-lactamase inhibitor combinations containing ceftazidime, cefepime and meropenem, while 4 mg/L was used for those containing imipenem and ceftolozane. The concentration of all β-lactamases inhibitors was fixed at 4 mg/L, except for vaborbactam (8 mg/L). Results The rates of isolates not being resistant to ceftazidime, cefepime, meropenem, imipenem and ceftolozane were found at 12%, 22%, 34%, 8% and 74%, respectively. When combined with avibactam, those rates increased to 60%, 62%, 60%, 46%, and 80%, respectively. The highest rates were found with relebactam-based combinations, being 76%, 64%, 66%, 76% and 84%, respectively. By contrast, associations with vaborbactam did not lead to significantly increased “non-resistance” rates. Conclusion Our results showed that all combinations including relebactam led to higher “non-resistance” rates against AmpC-overproducing P. aeruginosa clinical isolates. The best activity was achieved by combining ceftolozane and relebactam, that might therefore be considered as an excellent clinical alternative against AmpC overproducers.

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In-vitro activity of newly-developed β-lactamase inhibitors avibactam, relebactam and vaborbactam in combination with anti-pseudomonal β-lactam antibiotics against AmpC-overproducing clinical Pseudomonas aeruginosa isolates

Le Terrier,

Raro,

Saad

et al. 2024

Eur J Clin Microbiol Infect Dis

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In-vitro activity of the novel β-lactam/β-lactamase inhibitor combinations and cefiderocol against carbapenem-resistant Pseudomonas spp. clinical isolates collected in Switzerland in 2022

Le Terrier,

Bouvier,

Kerbol

et al. 2024

Eur J Clin Microbiol Infect Dis

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To evaluate the in-vitro activity of the novel commercially-available drugs, including meropenem-vaborbactam (MEV), ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), imipenem-relebactam (IPR) as well as cefiderocol (FDC), against carbapenem-resistant Pseudomonas spp. (CRP) isolates. All CRP isolates collected at the Swiss National Reference Laboratory (NARA) over the year 2022 (n = 170) have been included. Most of these isolates (n = 121) were non-carbapenemase producers. Among the 49 carbapenemase producers, 47 isolates produced metallo-β-lactamases (MBL) including NDM-1 (n = 11), VIM-like (n = 28), IMP-like (n = 7), and both NDM-1 and VIM-2 (n = 1) and two isolates produced the class A carbapenemase GES-5. Susceptibility testing was determined by broth microdilution method (BMD), or disk diffusion test, and results interpreted following EUCAST guidelines. The susceptibility rates for MEV, CZA, C/T and IPR were found to be 41%, 45%, 59% and 58%, respectively, for the whole set of isolates tested. Among non-carbapenemase producers, susceptibility rates for these β-lactam/β-lactamase inhibitors (BL/BLI) combinations were higher, determined at 55%, 61%, 83%, and 82%, respectively. The overall susceptibility of carbapenemase-producing Pseudomonas spp. to novel BL/BLI was relatively low, while 80% of these isolates demonstrated susceptibility to FDC, with a similar proportion (79%) observed among MBL producers. A total of 10 MBL-producing isolates (6%), mainly NDM-1, were found to exhibit resistance to all drugs tested, with the exception of colistin. FDC exhibited an excellent in-vitro activity against this collection of CRP recovered from Switzerland in 2022, including MBL producers. The new BL/BLI combinations displayed significant activity against non-carbapenemase CRP, with IPR and C/T showing the highest susceptibility rates.

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Relative inhibitory activities of newly developed diazabicyclooctanes, boronic acid derivatives, and penicillin-based sulfone β-lactamase inhibitors against broad-spectrum AmpC β-lactamases

Cited by 2 publications

References 21 publications

In-vitro activity of newly-developed β-lactamase inhibitors avibactam, relebactam and vaborbactam in combination with anti-pseudomonal β-lactam antibiotics against AmpC-overproducing clinical Pseudomonas aeruginosa isolates

In-vitro activity of newly-developed β-lactamase inhibitors avibactam, relebactam and vaborbactam in combination with anti-pseudomonal β-lactam antibiotics against AmpC-overproducing clinical Pseudomonas aeruginosa isolates

In-vitro activity of the novel β-lactam/β-lactamase inhibitor combinations and cefiderocol against carbapenem-resistant Pseudomonas spp. clinical isolates collected in Switzerland in 2022

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