Imipenem Pharmacokinetics/Pharmacodynamics in Preclinical Hollow Fiber Model, Dose Finding in Virtual Patients, and Clinical Evidence of Efficacy for Mycobacterium abscessus Lung Disease.
Journal
The Journal of infectious diseases
Journal Volume
231
Journal Issue
6
Start Page
1521
End Page
1531
ISSN
1537-6613
Date Issued
2025-07-11
Author(s)
Singh, Sanjay
Gumbo, Tawanda
Boorgula, Gunavanthi D
Burke, Andrew
Huang, Hung-Ling
McShane, Pamela J
Amaro-Galvez, Rodolfo
Gross, Jane E
Aryal, Santosh
Heysell, Scott K
Srivastava, Shashikant
Abstract
Background 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.
Subjects
mycobacterium abscessus
Hollow fiber system
Monte Carlo experiments
imipenem
relebactam
Type
journal article