In Vitro Activity of Bedaquiline and Imipenem against Actively Growing, Nutrient-Starved, and Intracellular Mycobacterium abscessus.

Mycobacterium abscessus lung disease is difficult to treat due to intrinsic drug resistance and the persistence of drug-tolerant bacteria. Currently, the standard of care is a multidrug regimen with at least 3 active drugs, preferably including a ß-lactam (imipenem or cefoxitin). These regimens are lengthy and toxic and have limited efficacy. The search for more efficacious regimens led us to evaluate bedaquiline, a diarylquinoline licensed for treatment of multidrug-resistant tuberculosis. We performed in vitro time-kill experiments to evaluate the activity of bedaquiline alone and in combination with the first-line drug imipenem against M. abscessus under various conditions. Against actively growing bacteria, bedaquiline was largely bacteriostatic and antagonized the bactericidal activity of imipenem. Contrarily, against nutrient-starved persisters, bedaquiline was bactericidal, while imipenem was not, and bedaquiline drove the activity of the combination. In an intracellular infection model, bedaquiline and imipenem had additive bactericidal effects. Correlations between ATP levels and the bactericidal activity of imipenem and its antagonism by bedaquiline were observed. Interestingly, the presence of Tween 80 in the media affected the activity of both drugs, enhancing the activity of imipenem and reducing that of bedaquiline. Overall, these results show that bedaquiline and imipenem interact differently depending on culture conditions. Previously reported antagonistic effects of bedaquiline on imipenem were limited to conditions with actively multiplying bacteria and/or the presence of Tween 80, whereas the combination was additive or indifferent against nutrient-starved and intracellular M. abscessus, where promising bactericidal activity of the combination suggests it may have a role in future treatment regimens.

In Vitro Activity of New Tetracycline Analogs Omadacycline and Eravacycline against Drug-Resistant Clinical Isolates of Mycobacterium abscessus.

Tigecycline is used in multidrug regimens for salvage therapy of Mycobacterium abscessus infections but is often poorly tolerated and has no oral formulation. Here, we report similar in vitro activity of two newly approved tetracycline analogs, omadacycline and eravacycline, against 28 drug-resistant clinical isolates of M. abscessus complex. Since omadacycline and eravacycline appear to be better tolerated than tigecycline and since omadacycline is also formulated for oral dosing, these tetracycline analogs may represent new treatment options for M. abscessus infections.

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

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