In vivo activity of human-simulated regimens of imipenem alone and in combination with relebactam against Pseudomonas aeruginosa in the murine thigh infection model

Background: Imipenem/relebactam is a carbapenem/beta-lactamase inhibitor combination with in vitro activity against Pseudomonas aeruginosa and Enterobacterales, including KPC producers. Objectives: To provide translational data to support the clinical utility of the imipenem/relebactam 500/250mg q6h regimen using a human-simulated regimen (HSR) of imipenem/relebactam, compared with imipenem alone, against a phenotypically and genotypically diverse population of P. aeruginosa. Methods: Twenty-nine P. aeruginosa isolates, including KPC (n = 6), PDC (n = 9), PAO (n = 4), GES (n = 5) and VIM (n = 1) producers, were used for the in vivo efficacy studies. Neutropenic mice were thigh-inoculated and randomized to receive HSRs of either imipenem 500mg q6h, imipenem 1 g q8h, imipenem/relebactam 500/250mg q6h or saline. Results: Twenty-seven of the 29 isolates examined were imipenem resistant, with 24/29 isolates showing imipenem MICs of similar to 32 mg/L. The addition of relebactam decreased the MICs up to 64-fold; imipenem/relebactam MICs ranged from 0.25 to >32 mg/L. Efficacies of the imipenem monotherapies and the imipenem/relebactam therapy were comparable for the two imipenem-susceptible organisms. Among the imipenem-resistant isolates, an increased mean growth was observed in the imipenem 500mg q6h HSR and 1 g q8h HSR treatment groups of 1.31 +/- 1.01 and 0.18 +/- 1.67 log(10) cfu/thigh, respectively. In contrast, a similar to 2 log reduction in bacterial density was observed in 27/29 (93%) of the imipenem-resistant isolates subjected to imipenem/relebactam 500/250mg q6h HSR. Conclusions: The imipenem/relebactam 500/250mg q6h HSR demonstrated superior in vivo activity compared with the conventionally employed imipenem regimens against MDR P. aeruginosa over a wide range of imipenem/relebactam MICs.