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

Roxana Zamudio, Karolin Hijazi (Corresponding Author), Chaitanya Joshi, Emma Aitken, Marco R. Oggioni, Ian M. Gould

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Abstract

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.
Original languageEnglish
Pages (from-to)774-780
Number of pages7
JournalInternational Journal of Antimicrobial Agents
Volume53
Issue number6
Early online date2 Mar 2019
DOIs
Publication statusPublished - Jun 2019

Keywords

  • Pseudomonas aeruginosa
  • cystic fibrosis
  • ceftazidime/avibactam
  • ceftolozane/tazobactam
  • ampC
  • AmpD
  • oprD
  • mutation-driven evolution
  • Ceftolozane/tazobactam
  • Cystic fibrosis
  • Ceftazidime/avibactam

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