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 language | English |
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Pages (from-to) | 774-780 |
Number of pages | 7 |
Journal | International Journal of Antimicrobial Agents |
Volume | 53 |
Issue number | 6 |
Early online date | 2 Mar 2019 |
DOIs | |
Publication status | Published - Jun 2019 |
Bibliographical note
ACKNOWLEDGEMENTSWe thank the staff of the Medical Microbiology Laboratory at Aberdeen Royal Infirmary for their dedicated support to this study. We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant reference 203141/Z/16/Z) for the generation and initial processing of the sequencing data.
FUNDING
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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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Karolin Hijazi
- School of Medicine, Medical Sciences & Nutrition, Dental Education - Clinical Chair
- Institute of Medical Sciences
Person: Clinical Academic