Abstract
The overuse of carbapenems has driven the rise of carbapenem-resistant Pseudomonas aeruginosa (CRPA) and Enterobacterales (CRE), against which ceftazidime-avibactam (CAZ-AVI) offers an alternative treatment. This study phenotypically determined resistance profiles of P. aeruginosa (PA), Escherichia coli (EC), and Klebsiella pneumoniae (KP) clinical isolates to CAZ-AVI and investigated molecular resistance mechanisms genotypically. A total of 394 PA, 90 EC, and 84 KP isolates were collected from the American University of Beirut Medical Center. Antimicrobial susceptibility testing (AST) and whole-genome sequencing (WGS) were performed on 30 isolates per species. Results showed that 100% of KP, 63% of EC, and 100% of PA isolates were carbapenem-resistant. Among these, 73% of KP, 79% of EC, and 60% of PA were CAZ-AVI-resistant. WGS revealed diverse sequence types, plasmids, and antimicrobial resistance genes. Additionally, 100% of KP, 93% of EC, and 89% of PA isolates produced metallo-β-lactamases (MBLs). Mutations in ampD, ampR, and mexR were identified in CAZ-AVI-resistant, non-MBL-producing PA, whereas mutations in ompC, marR, and ampC were detected in CAZ-AVI-resistant, non-MBL-producing EC. While CAZ-AVI remains effective against most CRE and CRPA lacking MBLs, resistance to CAZ-AVI is multifactorial, commonly involving overexpression of efflux pumps and AmpC β-lactamases, loss of porin channels, and the presence of oxacillinases.