Synergistic Efficacy of β-Lactam Combinations against Mycobacterium abscessus Pulmonary Infection in Mice

Mycobacterium abscessus is an emerging pathogen capable of causing invasive pulmonary infections in patients with chronic lung diseases. These infections are difficult to treat, necessitating prolonged multidrug therapy, which is further complicated by extensive intrinsic and acquired resistance exhibited by clinical M. abscessus isolates. Therefore, development of novel treatment regimens effective against drug-resistant strains is crucial. Prior studies have demonstrated synergistic efficacy of several beta-lactams against M. abscessus in vitro; however, these combinations have never been tested in an animal model of M. abscessus pulmonary disease. We utilized a recently developed murine system of sustained M. abscessus lung infection delivered via an aerosol route to test the bactericidal efficacy of four novel dual beta-lactam combinations and one beta-lactam/beta-lactamase inhibitor combination. All five of the novel combinations exhibited synergy and resulted in at least 6-log(10) reductions in bacterial burden in the lungs of mice at 4 weeks compared to untreated controls (P = 0.038).