AbstractObjectivesTo evaluate ceftazidime/avibactam resistance mechanisms among Pseudomonas aeruginosa clinical isolates and compare with isolates susceptible to this combination.MethodsDuring 2015, 2548 P. aeruginosa isolates were collected in 106 US hospitals and 46 (1.8%) were resistant to ceftazidime/avibactam. These isolates were matched with 109 ceftazidime/avibactam-susceptible isolates resistant to other antipseudomonal agents and were evaluated for the presence of β-lactam resistance mechanisms using WGS analysis and quantitative real-time PCR. Results were analysed using logistic regression comparing the isolate groups to understand the mechanisms of ceftazidime/avibactam resistance.ResultsTwo isolates carried the MBLs blaVIM-1 and blaVIM-2 and another three had unique alterations or deletions in the chromosomal AmpC Ω-loop associated with ceftazidime/avibactam resistance. Overexpression of mexA (+27.4%), disruptions in ampP (+21.7%), mexR (+17.1%) and mexZ (+14.6%) and alterations in ctpA (+13.0%), dnaK (+17.8%) and ftsI (+20.8%) were significantly more prevalent among ceftazidime/avibactam-resistant isolates when compared with their susceptible counterparts independently or in combination. The combination of dnaK alterations and mexA overexpression was more common among ceftazidime/avibactam-resistant by 82×; mexR disruptions and mexA overexpression by 45×; and other two- or three-genotype interactions that included alterations/disruptions in dnaK, ftsI, nalD, mexR, mexZ and mexA overexpression by 6.5× to 34×.ConclusionsResistance to ceftazidime/avibactam among P. aeruginosa clinical isolates has been shown to be a complex interplay of resistance mechanisms that can affect ceftazidime and/or avibactam and some similar findings were reported in laboratory isolates exposed to ceftazidime ± avibactam.