Combination of MexAB-OprM overexpression and mutations in efflux regulators, PBPs and chaperone proteins is responsible for ceftazidime/avibactam resistance in Pseudomonas aeruginosa clinical isolates from US hospitals

Abstract

Abstract Objectives To evaluate ceftazidime/avibactam resistance mechanisms among Pseudomonas aeruginosa clinical isolates and compare with isolates susceptible to this combination. Methods During 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. Results Two 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×. Conclusions Resistance 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.