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bioRxiv · 10.1101/499830

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

Kaushik, A.·Ammerman, N. C.·Lee, J.·Martins, O.·Kreiswirth, B. N.·Lamichhane, G.·Parrish, N. M.·Nuermberger, E.
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Abstract

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

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Kaushik, A., Ammerman, N. C., Lee, J., Martins, O., Kreiswirth, B. N., Lamichhane, G., Parrish, N. M., Nuermberger, E.. 2018-12-19. In vitro activity of the new β-lactamase inhibitors relebactam and vaborbactam in combination with β-lactams against Mycobacterium abscessus complex clinical isolates. https://doi.org/10.1101/499830

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