Cosgrove, Sara E

Abstract Objectives This study aimed to characterize susceptibility profiles of both currently approved and investigational β-lactam agents against difficult-to-treat resistant Pseudomonas aeruginosa (DTR P. aeruginosa) clinical isolates, including carbapenemase-producing strains. Patients and methods A total of 502 consecutive DTR P. aeruginosa clinical isolates were collected from unique hospitalized patients between 2022 and 2024 across three tertiary care centres. Isolates originated from bloodstream, respiratory, urinary and intra-abdominal infections. Minimum inhibitory concentrations (MICs) for seven β-lactam agents were determined using triplicate reference broth microdilution. Susceptibility interpretations were based on CLSI criteria or, where applicable, investigational breakpoints. Whole-genome sequencing was performed to detect β-lactamase genes. Results Among the 502 isolates, cefepime-zidebactam exhibited the highest in vitro activity (100% susceptibility), followed by cefiderocol-xeruborbactam (98%), cefiderocol (95%), ceftolozane-tazobactam (90%), cefepime-taniborbactam (86%), ceftazidime-avibactam (85%), and imipenem-relebactam (41%). Notably, only 35% of isolates were susceptible to all seven agents. Carbapenemase genes were identified in 4% of isolates, including blaGES (n = 13), blaVIM (n = 7), blaKPC (n = 1) and blaIMP (n = 1). Among carbapenemase-producing isolates, cefepime-zidebactam retained activity against all isolates (100%), exceeding that of other approved β-lactam/β-lactamase inhibitor combinations (0%–24% susceptible), cefiderocol (76%), cefiderocol-xeruborbactam (86%) and cefepime-taniborbactam (81%). Conclusions While currently approved β-lactam agents retained activity against many DTR P. aeruginosa isolates, their performance was markedly compromised in the presence of carbapenemases, with the notable exceptions of cefepime-zidebactam and cefiderocol. Investigational β-lactam/β-lactamase inhibitor combinations exhibited consistently robust activity across resistance phenotypes, including carbapenemase-producing isolates, representing promising options for DTR P. aeruginosa infections.