Singh, SanjaySanjaySinghGumbo, TawandaTawandaGumboJANN-YUAN WANGBoorgula, Gunavanthi DGunavanthi DBoorgulaBurke, AndrewAndrewBurkeHuang, Hung-LingHung-LingHuangMcShane, Pamela JPamela JMcShaneAmaro-Galvez, RodolfoRodolfoAmaro-GalvezGross, Jane EJane EGrossAryal, SantoshSantoshAryalHeysell, Scott KScott KHeysellSrivastava, ShashikantShashikantSrivastava2025-09-102025-09-102025-07-11https://scholars.lib.ntu.edu.tw/handle/123456789/731970Background Guideline-based therapy (GBT) for Mycobacterium abscessus (Mab) lung disease achieves sputum culture conversion (SCC) rates of 35%. This poor GBT efficacy is mirrored in the hollow fiber system model of Mab (HFS-Mab). While imipenem is part of GBT, its biologic effect, with or without β-lactamase inhibitors, is unproven. Methods We performed imipenem-relebactam minimum inhibitory concentration (MIC) in 122 Mab isolates, and an exposure-response study in the HFS-Mab using human intrapulmonary pharmacokinetics. The percentage of time that concentration persisted above the MIC (TMIC), mediating maximal effect in the HFS-Mab, was used as the exposure target for dose finding in a Monte Carlo experiment including 10 000 virtual patients. For real-world evidence, we performed a patient, intervention (imipenem), comparison (no β-lactam), and outcome (SCC) (PICO) analysis. Results Imipenem killed 1.32 log10 colony-forming units/mL below the day 0 level in HFS-Mab. The average target exposure for imipenem was a TMIC of 47.9% (SD, 9.77%). Infusion of 1 g every 6 hours achieved the target in >90% of virtual patients in Monte Carlo experiments. The pharmacokinetic-pharmacodynamic MIC break point was 1 mg/L. In PICO analyses, the median time to SCC was 470 days in comparators, 311 days for imipenem added on to a failing regimen, and 37 days in newly treated patients (P =. 049). The odds ratio for SCC when imipenem was part of the initial regimen, versus comparators, was 12.5 (95% confidence interval, 1.47 - 84.55). No patients receiving imipenem experienced treatment-limiting adverse events, compared with 2 of 7 comparators (P =. 046). Middlebrook 7H9 broth MIC distribution, read at 24 hours, was better correlated with patient responses than cation-adjusted Mueller-Hinton broth. Conclusions Imipenem demonstrated biologic effect in the HFS-Mab and in patients. Imipenem-relebactam doses of 1 g every 6 hours are recommended.enmycobacterium abscessusHollow fiber systemMonte Carlo experimentsimipenemrelebactam[SDGs]SDG3journal article10.1093/infdis/jiae60139688388