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bioRxiv · 10.1101/2024.12.10.627836

In Vitro Activity of Imipenem/Relebactam Alone and in Combination Against Cystic Fibrosis Isolates of Mycobacterium abscessus

Sanders, M.·Shinde, A.·Kim, S. W.·Quach, E.·Beringer, P.
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Abstract

Structured SynopsisO_ST_ABSBackgroundC_ST_ABSMycobacterium abscessus complex (MABSC) is an opportunistic pathogen that causes chronic, difficult-to-treat pulmonary infections, particularly in people with cystic fibrosis (PwCF), leading to rapid lung function decline, and increased morbidity and mortality. Treatment is particularly challenging due to the pathogens resistance mechanisms and the need for prolonged multidrug therapy, which is characterized by poor clinical outcomes and highlights the urgent need for novel therapeutic strategies. Imipenem/relebactam, a novel {beta}-lactam-{beta}-lactamase inhibitor combination, demonstrates in vitro activity against resistant MABSC strains and effective pulmonary penetration. Prior literature indicates synergistic activity of imipenem with various antibiotics against M. abscessus. ObjectivesThis study aims to evaluate the in vitro activity of imipenem/relebactam, alone and in combination with various antibiotics, against MABSC clinical isolates from PwCF (n=28). MethodsSusceptibility and synergy were assessed using broth microdilution and checkerboard assays. Extracellular time-kill assays were performed to evaluate the bactericidal activity of synergistic three-drug combinations containing imipenem/relebactam. ResultsImipenem/relebactam demonstrated potent in vitro activity against clinical MABSC isolates, exhibiting substantial synergy with cefuroxime, cefdinir, amoxicillin, and cefoxitin. Rifabutin, azithromycin, moxifloxacin, clofazimine, and minocycline also demonstrated additive effects with imipenem/relebactam. Extracellular time-kill assays identified imipenem/relebactam+cefoxitin+rifabutin and imipenem/relebactam+cefoxitin+moxifloxacin as the most effective combinations. ConclusionsThese findings suggest that imipenem/relebactam may offer a significant advancement in the management of MABSC infections in PwCF. The promising efficacy of multidrug regimens combining imipenem/relebactam with agents like cefoxitin, azithromycin, moxifloxacin, clofazimine, and rifabutin highlights potential therapeutic strategies.

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Sanders, M., Shinde, A., Kim, S. W., Quach, E., Beringer, P.. 2024-12-16. In Vitro Activity of Imipenem/Relebactam Alone and in Combination Against Cystic Fibrosis Isolates of Mycobacterium abscessus. https://doi.org/10.1101/2024.12.10.627836

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