BackgroundMycobacterium abscessuscomplex (MABSC) is an emerging opportunistic pathogen that causes chronic, difficult-to-treat pulmonary infections, particularly in people with cystic fibrosis (PwCF), leading to rapid lung function decline, morbidity, and mortality. Effective treatment is particularly challenging due to the pathogen’s resistance mechanisms and the need for prolonged multidrug therapy, which is often hindered by poor clinical outcomes, highlighting the urgent need for novel therapeutic strategies.Imipenem/cilastatin/relebactam (IMI/REL), a novel β-lactam-β-lactamase inhibitor combination, demonstratesin vitroactivity against resistant MABSC strains and effective pulmonary penetration. Prior literature indicates synergistic activity of imipenem with various antibiotics againstM. abscessus.MethodsThis study aims to evaluate thein vitroactivity of IMI/REL, alone and in combination with other antibiotics, against MABSC clinical isolates from PwCF (n=28). Susceptibility and synergy were assessed using broth microdilution and checkerboard assays. Extracellular and intracellular time-kill assays were performed to evaluate bactericidal activity of synergistic two- and three-drug combinations.ResultsIMI/REL demonstrated potentin vitroactivity against clinical MABSC isolates, exhibiting substantial synergy with cefuroxime, cefdinir, amoxicillin, and cefoxitin. Rifabutin, azithromycin, moxifloxacin, clofazimine, minocycline, and omadacycline also demonstrated additive effects with IMI/REL. Extracellular time-kill assays identified IMI/REL+cefoxitin+rifabutin/moxifloxacin as the most effective combinations. Rifabutin demonstrated the highest intracellular killing activity, with combination regimens involving moxifloxacin+rifabutin/omadacycline/azithromycin resulting in greater reductions in bacterial load.ConclusionThese findings suggest that IMI/REL may offer a significant advancement in the management of MABSC infections in PwCF. The promising efficacy of multidrug regimens combining IMI/REL with agents like cefoxitin, azithromycin, moxifloxacin, rifabutin, and omadacycline highlights potential therapeutic strategies.
