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In vitro activity of the new β-lactamase inhibitors relebactam and vaborbactam in combination with β-lactams against Mycobacterium abscessus complex clinical isolates

By Amit Kaushik, Nicole Ammerman, Jin Lee, Olumide Martins, Barry N Kreiswirth, Gyanu Lamichhane, Nicole M Parrish, Eric Nuermberger

Posted 19 Dec 2018
bioRxiv DOI: 10.1101/499830 (published DOI: 10.1128/aac.02623-18)

Pulmonary disease due to infection with Mycobacterium abscessus complex (MABC) is notoriously difficult to treat, in large part due to MABC’s intrinsic resistance to most antibiotics, including β-lactams. MABC organisms express a broad-spectrum β-lactamase that is resistant to traditional β-lactam-based β-lactamase inhibitors but inhibited by a newer non-β-lactam-based β-lactamase inhibitor, avibactam. Consequently, the susceptibility of MABC to some β-lactams is increased in the presence of avibactam. Therefore, we hypothesized that two new non-β-lactam-based β-lactamase inhibitors, relebactam and vaborbactam, would also increase susceptibility of MABC to β-lactams. The objective of the present study was to evaluate the in vitro activity of various marketed β-lactams alone and in combination with either relebactam or vaborbactam against multidrug-resistant MABC clinical isolates. Our data demonstrate that both β-lactamase inhibitors significantly improved the anti-MABC activity of many carbapenems (including imipenem and meropenem) and cephalosporins (including cefepime, ceftaroline, and cefuroxime). As a meropenem/vaborbactam combination is now marketed and an imipenem/relebactam combination is currently in phase III trials, these fixed combinations may become the β-lactams of choice for the treatment of MABC infections. Furthermore, given the evolving interest in dual β-lactam regimens, our results identify select cephalosporins, such as cefuroxime, with superior activity in the presence of a β-lactamase inhibitor, deserving of further evaluation in combination with these carbapenem/β-lactamase inhibitor products.

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