https://orcid.org/0000-0003-4601-5673
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Sanjay Singh, Tawanda Gumbo, Jann-Yuan Wang, Gunavanthi D Boorgula, Andrew Burke, Hung-Ling Huang, Pamela J McShane, Rodolfo Amaro-Galvez, Jane E Gross, Santosh Aryal, Scott K Heysell, Shashikant Srivastava, Imipenem Pharmacokinetics/Pharmacodynamics in Preclinical Hollow Fiber Model, Dose Finding in Virtual Patients, and Clinical Evidence of Efficacy for Mycobacterium abscessus Lung Disease, The Journal of Infectious Diseases, 2024;, jiae601, https://doi.org/10.1093/infdis/jiae601
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ABSTRACT
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.
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.
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.
Imipenem demonstrated biologic effect in the HFS-Mab and in patients. Imipenem-relebactam doses of 1 g every 6 hours are recommended.
