Journal
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
Volume 53, Issue 6, Pages 774-780Publisher
ELSEVIER
DOI: 10.1016/j.ijantimicag.2019.02.022
Keywords
Pseudomonas aeruginosa; Cystic fibrosis; Ceftazidime/avibactam; Ceftolozane/tazobactam; ampC; AmpD
Funding
- NHS Grampian Endowment Fund through the Clinical Microbiology Fund [NER11553]
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Pseudomonas aeruginosa is one of the most important pathogens in cystic fibrosis. This study was conducted to analyse the genetic basis and phylogenetic profile of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in cystic fibrosis P. aeruginosa isolates. Whole genome sequence analysis was conducted of isolates resistant to piperacillin/tazobactam collected from seven hospitals in Scotland since the introduction of these two cephalosporin/beta-lactamase inhibitor combinations. Ceftazidime resistance was primarily related to AmpC induction, as tested by cloxacillin inhibition assays, while high-level ceftazidime resistance not reversed by cloxacillin was associated with amino acid variations in AmpC. 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. This study showed that mutational resistance emerged in phylogenetically distant lineages, which indicates the mutations occur independently without conferring a selective advantage to any phylogenetic lineage. These findings confirm the strong contribution of mutation-driven evolution to the population structure of P. aeruginosa. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
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