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 as well as carbapenems in cystic fibrosis P. aeruginosa isolates. We conducted whole genome sequence analysis of a collection of isolates resistant to piperacillin/tazobactam from seven hospitals in Scotland since the introduction of these two cephalosporin/β-lactamase inhibitor combinations. Ceftazidime resistance was primarily related to AmpC induction, as tested by cloxacillin inhibition assays, while amino acid variations in AmpC were associated with high-level ceftazidime resistance not reversed by cloxacillin. Only isolates resistant to both ceftazidime/avibactam and ceftolozane/tazobactam carried AmpD mutations, likely resulting in ampC overexpression. All isolates resistant to ceftazidime/avibactam and/or ceftolozane/tazobactam were resistant to carbapenems and showed 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 conferring a selective advantage to any phylogenetic lineage. Our findings confirm the strong contribution of mutation-driven evolution to the population structure of P. aeruginosa.
- Pseudomonas aeruginosa
- cystic fibrosis
- mutation-driven evolution
- Cystic fibrosis
Zamudio, R., Hijazi, K., Joshi, C., Aitken, E., Oggioni, M. R., & Gould, I. M. (2019). Phylogenetic analysis of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in piperacillin/tazobactam-resistant Pseudomonas aeruginosa from cystic fibrosis patients. International Journal of Antimicrobial Agents, 53(6), 774-780. https://doi.org/10.1016/j.ijantimicag.2019.02.022