ABSTRACTThe role of novel β-lactam/β-lactamase inhibitor combinations in ceftazidime-nonsusceptible (CAZ-NS) and imipenem-nonsusceptible (IPM-NS)Pseudomonas aeruginosahas not been fully elucidated. This study evaluated thein vitroactivity of novel β-lactam/β-lactamase inhibitor combinations againstPseudomonas aeruginosaclinical isolates, determined how avibactam restored ceftazidime activity, and compared the activity of ceftazidime-avibactam (CZA) and imipenem-relebactam (IMR) against KPC-producingP. aeruginosa. Similar high susceptibility rates for CZA, IMR, and ceftolozane-tazobactam (88.9% to 89.8%) were found for 596P. aeruginosaclinical isolates from 11 hospitals in China, and a higher susceptibility rate to ceftazidime than imipenem was observed (73.5% versus 63.1%). For CAZ-NS and IPM-NS isolates, susceptibility rates for CZA, ceftolozane-tazobactam, and IMR were 61.5% (75/122), 54.9% (67/122), and 51.6% (63/122), respectively. For CAZ-NS, IPM-NS but CZA-susceptible isolates, 34.7% (26/75) harbored acquired β-lactamases with KPC-2 predominant (n= 19), and 45.3% (34/75) presented overexpression of chromosomal β-lactamaseampC. Among 22 isolates carrying KPC-2 carbapenemase alone, susceptibility rates to CZA and IMR were 86.4% (19/22) and 9.1% (2/22), respectively. Notably, 95% (19/20) of IMR-nonsusceptible isolates had an inactivating mutation ofoprDgene. In conclusion, CZA, ceftolozane-tazobactam, and IMR exhibit high activity againstP. aeruginosa, and CZA is more active than IMR against CAZ-NS and IPM-NS isolates as well as KPC-producingP. aeruginosa. Avibactam overcomes ceftazidime resistance engendered by KPC-2 enzyme and overexpressed AmpC.IMPORTANCEThe emergence of antimicrobial resistance poses a particular challenge globally, and the concept ofP. aeruginosawith “difficult-to-treat” resistance (DTR-P. aeruginosa) was proposed. Here,P. aeruginosaclinical isolates were highly susceptible to three β-lactamase inhibitor combinations, CZA, IMR, and ceftolozane-tazobactam. The combination of KPC-2 enzyme and nonfunctional porin OprD contributed to IMR resistance inP. aeruginosa, and CZA was more active than IMR in fighting against KPC-2-producingP. aeruginosa. CZA also showed good activity against CAZ-NS and IPM-NSP. aeruginosa, primarily by inhibiting KPC-2 enzyme and overproduced AmpC, supporting the clinical use of CZA in the treatment of infections caused by DTR-P. aeruginosa.