Whole-genome sequencing for predicting clarithromycin resistance in mycobacterium abscessus

Samuel Lipworth*, Natasha Hough, Laura Leach, Marcus Morgan, Katie Jeffery, Monique Andersson, Esther Robinson, E. Grace Smith, Derrick Crook, Tim Peto, Timothy Walker

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Mycobacterium abscessus is emerging as an important pathogen in chronic lung diseases, with concern regarding patient-to-patient transmission. The recent introduction of routine whole-genome sequencing (WGS) as a replacement for existing reference techniques in England provides an opportunity to characterize the genetic determinants of resistance. We conducted a systematic review to cata-logue all known resistance-determining mutations. This knowledge was used to construct a predictive algorithm based on mutations in the erm(41) and rrl genes which was tested on a collection of 203 sequentially acquired clinical isolates for which there were paired genotype/phenotype data. A search for novel resistance-determining mutations was conducted using a heuristic algorithm. The sensitivity of existing knowledge for predicting resistance in clarithromycin was 95% (95% confidence interval [CI], 89 to 98%), and the specificity was 66% (95% CI, 54 to 76%). The subspecies alone was a poor predictor of resistance to clarithromycin. Eight potential new resistance-conferring single nucleotide polymorphisms (SNPs) were identified. WGS demonstrated probable resistance-determining SNPs in regions that the NTM-DR line probe cannot detect. These mutations are potentially clinically important, as they all occurred in samples that were predicted to be inducibly resistant and for which a macrolide would therefore currently be indicated. We were unable to explain all resistance, raising the possibility of the involvement of other as yet unidentified genes.

Original languageEnglish
Article numbere01204-18
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number1
DOIs
Publication statusPublished - Jan 2019
Externally publishedYes

Bibliographical note

Funding Information:
The research was supported by the National Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England (PHE) and by Oxford NIHR Biomedical Research Centre. T. Peto is a NIHR Senior Investigator. The report presents independent research funded by NIHR. The views expressed in this publication are those of the authors and not necessarily those of the NHS, NIHR, the Department of Health, or Public Health England.

Funding Information:
No specific funding was acquired for this work. All sequencing data were created as part of the routine PHE clinical diagnostic service. The research was supported by the National Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England (PHE) and by Oxford NIHR Biomedical Research Centre. T. Peto is a NIHR Senior Investigator. The report presents independent research funded by NIHR. The views expressed in this publication are those of the authors and not necessarily those of the NHS, NIHR, the Department of Health, or Public Health England.

Publisher Copyright:
Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords

  • Macrolides
  • Nontuberculous mycobacteria
  • Whole-genome sequencing

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