AmpC β-lactamase induction by avibactam and relebactam

David M. Livermore*, Dorota Jamrozy, Shazad Mushtaq, Wright W. Nichols, Katherine Young, Neil Woodford

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Background: Diazabicyclooctanes, e.g. avibactam and relebactam, are a new class of β-lactamase inhibitors. Their spectrum includes AmpC enzymes, but it is important to understand whether they also induce these enzymes. Methods: Levels of ampC mRNA were measured by RT-PCR during 4 h of exposure of Enterobacter cloacae, Citrobacter freundii and Pseudomonas aeruginosa (n=5 strains per species) to avibactam, relebactam and cefoxitin at 0, 1, 4 and 32 mg/L. The method had low precision compared with conventional specific-activitybased induction assays, which are impracticable for inhibitors. Accordingly, induction was only considered to be significant if induction ratios > 10 were found at two consecutive time intervals, with 'strong induction' if one or more of these ratios was > 100. Results: Cefoxitin, as expected, gave concentration-dependent induction for all strains, with strong induction for 13/15. At the other extreme, relebactam caused no significant induction for any strain. Avibactam gave strainvariable results, with strong concentration-dependent induction for 2/5 E. cloacae and 2/5 P. aeruginosa, but little or no induction for the other strains, including all the C. freundii strains. Conclusions: Avibactam, but not relebactam, had some strain-variable ability to induce AmpC enzymes, though at concentrations (32 mg/L) above those reached in the patient.

Original languageEnglish
Pages (from-to)3342-3348
Number of pages7
JournalJournal of Antimicrobial Chemotherapy
Volume72
Issue number12
DOIs
Publication statusPublished - 1 Dec 2017

Bibliographical note

Funding Information:
D. M. L.: Advisory Boards or ad-hoc consultancy for Accelerate, Achaogen, Adenium, Allecra, AstraZeneca, Auspherix, Basilea, BioVersys, Centauri, Discuva, Inhibox, Meiji, Pfizer, Roche, Shionogi, Tetraphase, VenatoRx, Wockhardt, Zambon and Zealand, paid lectures for Astellas, AstraZeneca, Cardiome, Cepheid, Merck and Nordic, and relevant shareholdings in Dechra, GSK, Merck, PerkinElmer and Pfizer collectively amounting to ,10% of portfolio value. W. W. N.: AstraZeneca employee at the time of the study, and AstraZeneca shareholder. K. Y.: Merck employee. All others: no personal interests to declare. However, PHE’s Antimicrobial Resistance and Healthcare Associated Infections Reference Unit has received financial support for conference attendance, lectures, research projects or contracted evaluations from numerous sources, including: Achaogen, Allecra, Amplex, AstraZeneca, AusDiagnostics, Becton Dickinson, BSAC, Cepheid, Check-Points, Cubist Pharmaceuticals, Department of Health, Enigma Diagnostics, Food Standards Agency, GlaxoSmithKline Service, Henry Stewart Talks, IHMA Ltd, Merck Sharpe & Dohme, Meiji Seika Kiasya, Momentum Biosciences, Nordic, Norgine, Rempex, Rokitan Ltd, Smith & Nephew, VenatoRx and Wockhardt Ltd.

Publisher Copyright:
© The Author 2017.

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