BackgroundCarbapenem-resistant bacteria are an increasing problem in clinical practice; thus, it is important to identify β-lactamase inhibitors (e.g., relebactam) that can restore carbapenem susceptibility. We report analyses of relebactam enhancement of imipenem activity against both imipenem-nonsusceptible (NS) and imipenem-susceptible (S)Pseudomonas aeruginosaand Enterobacterales. Gram-negative bacterial isolates were collected for the ongoing Study for Monitoring Antimicrobial Resistance Trends global surveillance program. Clinical and Laboratory Standards Institute–defined broth microdilution minimum inhibitory concentrations (MIC) were used to determine the imipenem and imipenem/relebactam antibacterial susceptibilities ofP. aeruginosaand Enterobacterales isolates.ResultsBetween 2018 and 2020, 36.2% ofP. aeruginosa(N= 23,073) and 8.2% of Enterobacterales (N= 91,769) isolates were imipenem-NS. Relebactam restored imipenem susceptibility in 64.1% and 49.4% of imipenem-NSP. aeruginosaand Enterobacterales isolates, respectively. Restoration of susceptibility was largely observed amongK. pneumoniaecarbapenemase-producing Enterobacterales and carbapenemase-negativeP. aeruginosa. Relebactam also caused a lowering of imipenem MIC among imipenem-SP. aeruginosaand Enterobacterales isolates from chromosomal Ambler class C β-lactamase (AmpC)–producing species. For both imipenem-NS and imipenem-SP. aeruginosaisolates, relebactam reduced the imipenem MIC mode from 16 μg/mL to 1 μg/mL and from 2 μg/mL to 0.5 μg/mL, respectively, compared with imipenem alone.ConclusionsRelebactam restored imipenem susceptibility among nonsusceptible isolates ofP. aeruginosaand Enterobacterales and enhanced imipenem susceptibility among susceptible isolates ofP. aeruginosaand isolates from Enterobacterales species that can produce chromosomal AmpC. The reduced imipenem modal MIC values with relebactam may result in a higher probability of target attainment in patients.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12866-023-02864-3.