Emergence of resistance to novel cephalosporin-β-lactamase inhibitor combinations through the modification of the Pseudomonas aeruginosa MexCD-OprJ efflux pump.

Gomis-Font, María A; Pitart, Cristina; Del Barrio-Tofiño, Ester; Zboromyrska, Yuliya; Cortes-Lara, Sara; Mulet, Xavier; Marco, Francesc; Vila, Jordi; López-Causapé, Carla; Oliver, Antonio

A ceftolozane/tazobactam and ceftazime/avibactam resistant Pseudomonas aeruginosa isolate was recovered after treatment (including azithromycin, meropenem and ceftolozane/tazobactam) from a patient that had developed ventilator associated pneumonia after Covid-19 infection. Whole genome sequencing revealed that the strain, belonging to ST274, had acquired a nonsense mutation leading to a truncated carbapenem porin OprD (W277X), a 7-bp deletion (nt213Δ7) in NfxB (negative regulator of the efflux pump MexCD-OprJ), and two missense mutations (Q178R, S133G) located within the first Large Periplasmic Loop of MexD. Through the construction of mexD mutants and complementation assays with wild-type nfxB, it was evidenced that resistance to the novel cephalosporin-β-lactamase inhibitor combinations was caused by the modification of MexD substrate specificity.