In Vitro Activity of the New β-Lactamase Inhibitors Relebactam and Vaborbactam in Combination with β-Lactams against Mycobacterium abscessus Complex Clinical Isolates

Abstract

Pulmonary disease due to infection withMycobacterium abscessuscomplex (MABC) is notoriously difficult to treat, in large part due to the intrinsic resistance of MABC strains 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 members 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 the susceptibility of MABC organisms to β-lactams. The objective of the present study was to evaluate thein vitroactivity 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 that are deserving of further evaluation in combination with these carbapenem–β-lactamase inhibitor products.

New β-Lactamase Inhibitors Nacubactam and Zidebactam Improve the In Vitro Activity of β-Lactam Antibiotics Against Mycobacterium abscessus Complex Clinical Isolates

“…Nacubactam and zidebactam were procured from MedKoo Biosciences, Inc., NC, USA (purity >98%). A total of twenty-six β-lactam antibiotics (Table 1), including penicillins, cephalosporins and carbapenems, were purchased from commercial sources as previously described (10). The purity of all β-lactams was >95%.…”

“…Twenty-eight clinical isolates of MABC were collected at Johns Hopkins Hospital, Baltimore, MD, USA from 2005 to 2015 and described previously (8, 10). M. abscessus ATCC 19977 was purchased from the American Type Culture Collection (Manassas, VA, USA) and used as a reference strain.…”

“…Despite the outstanding contribution of β-lactam antibiotics to treatment of infectious diseases, their utility against MABC organisms is limited by a chromosomally encoded, broad-spectrum, Ambler class A β-lactamase, BlaMab, which is the major determinant of intrinsic β-lactam resistance in MABC (6). While older β-lactam-based β-lactamase inhibitors (BLIs) such as clavulanate, tazobactam and sulbactam are ineffective against BlaMab and do not improve the in vitro activity of β-lactam antibiotics against MABC organisms (7, 8), we and others have shown that the new diazabicyclooctane-based BLIs avibactam and relebactam, developed to treat multidrug-resistant Gram-negative bacteria (9), do improve the in vitro activity of many β-lactam antibiotics against MABC organisms, particularly carbapenems and cephalosporins (8, 10–12). Avibactam and relebactam have been developed with ceftazidime and imipenem, respectively.…”

“…Avibactam and relebactam have been developed with ceftazidime and imipenem, respectively. However, ceftazidime has poor intrinsic activity against MABC organisms, as evidenced by high MICs despite combination with avibactam or relebactam (10, 12), while imipenem has relatively high intrinsic activity and MICs are only modestly lower in the presence of these BLIs (8, 10). Newer diazabicyclooctane-based BLIs being developed for treatment of challenging Gram-negative infections, including nacubactam and zidebactam (13, 14), may offer advantages over avibactam and relebactam.…”

Combining amoxicillin and relebactam provides new therapeutic potential for Mycobacterium abscessus infection

“…Very recently, a number of studies have been published demonstrating a number of β -lactam combinations displaying high levels of in vitro synergistic activity against M. abscessus complex (Pandey et al 2019) (Story-Roller et al 2019). Furthermore, a recent study identified the in vitro activity of two new non- β -lactam β -lactamase inhibitors, namely relebactam and vaborbactam, demonstrating synergistic activity between imipenem and relebactam as well as meropenem and vaborbactam (Kaushik et al 2019).…”