Phylogenetic analysis of resistance to ceftazidime/avibactam and ceftolozane/tazobactam in piperacillin/tazobactam-resistant Pseudomonas aeruginosa from cystic fibrosis patients. Pseudomonas aeruginosa

Pseudomonas aeruginosa is one of the most important pathogens in cystic fibrosis. In this study we analysed the genetic basis and phylogenetic profile of resistance to ceftazidime/avibactam and ceftolozane/tazobactam in cystic fibrosis P. aeruginosa. The study focussed on a collection of isolates resistant to piperacillin/tazobactam from four hospitals in Scotland since the introduction of these two third-generation cephalosporin/β-lactamase inhibitor combinations. The majority of isolates (55%) were resistant to ceftazidime/avibactam and ceftolozane/tazobactam or both with resistance due to AmpC overexpression or ampC derepression. Most isolates (83%) were also resistant to carbapenems primarily as a result of inactivating mutations in the chromosomal oprD gene. None of the isolates bore class A, B, D plasmid-encoded carbapenemases. Critically, we show that mutational resistance emerged in phylogenetically distant lineages suggesting that the mutations occur independently without seeming to confer a selective advantage to any phylogenetic lineage. Our findings confirm the strong contribution of mutation-driven evolution to the population structure of P. aeruginosa.