Airway 'Resistotypes' and Clinical Outcomes in Bronchiectasis

Mac Aogáin M 1 , Xaverius Ivan F 2 , Jaggi TK 2 , Richardson H 3 , Shoemark A 4 , Narayana JK 2 Show all authors , Dicker AJ 5 , Koh MS 6 , Lee KCH 7 , Thun How O 6 , Poh ME 8 , Chin KK 8 , Hou ALY 9 , Ser Hon P 10 , Low TB 11 , Abisheganaden JA 12 , Dimakou K 13 , Digalaki A 13 , Kosti C 14 , Gkousiou A 13 , Hansbro PM 15 , Blasi F 16 , Aliberti S 17 , Chalmers JD 18 , Chotirmall SH 19

Affiliations 

  • 1 Saint James's Hospital, 58024, Biochemistry, Dublin, Ireland
  • 2 Lee Kong Chian School of Medicine, Translational Respiratory Research Laboratory, Singapore, Singapore
  • 3 University of Dundee School of Medicine, 85326, Dundee, United Kingdom of Great Britain and Northern Ireland
  • 4 Royal Brompton Hospital, EM Unit, London, United Kingdom of Great Britain and Northern Ireland
  • 5 University of Dundee, Scottish Centre for Respiratory Research, Dundee, United Kingdom of Great Britain and Northern Ireland
  • 6 Singapore General Hospital, 37581, Department of Respiratory and Critical Care Medicine, Singapore, Singapore
  • 7 Singapore General Hospital, 37581, Respiratory and Critical Care Medicine, Singapore, Singapore
  • 8 University of Malaya, 37447, Department of Medicine, Kuala Lumpur, Wilayah Persekutuan, Malaysia
  • 9 Tan Tock Seng Hospital, 63703, Respiratory and Critical Care Medicine, Singapore, Singapore
  • 10 Tan Tock Seng Hospital, 63703, Singapore, Singapore
  • 11 Changi General Hospital, 26674, Respiratory and Critical Care Medicine, Singapore, Singapore
  • 12 Tan Tock Seng Hospital, Respiratory and Critical Care Medicine, Singapore, Singapore
  • 13 "Sotiria" Chest Hospital, 5th Pulmonary Department, Athens, Greece
  • 14 National and Kapodistrian University of Athens - Faculty of Medicine, 68989, 1st department of Critical care and pulmonary medicine, Athens, Greece
  • 15 University of Technology Sydney, 1994, Sydney, New South Wales, Australia
  • 16 University of Milano, Dipartimento Toraco-Polmonare e Cardiovascolare, Milan, Italy
  • 17 Humanitas University, 437807, Department of Biomedical Sciences, Pieve Emanuele, Italy
  • 18 University of Dundee, 3042, Dundee, United Kingdom of Great Britain and Northern Ireland
  • 19 Lee Kong Chian School of Medicine, Translational Respiratory Research Laboratory, Singapore, Singapore; schotirmall@ntu.edu.sg
Am J Respir Crit Care Med, 2024 Jan 25.
PMID: 38271608 DOI: 10.1164/rccm.202306-1059OC

Abstract

INTRODUCTION: Application of whole-genome shotgun metagenomics to the airway microbiome in bronchiectasis highlights a diverse pool of antimicrobial resistance genes: the 'resistome', the clinical significance of which remains unclear.

METHODS: Individuals with bronchiectasis were prospectively recruited into cross-sectional and longitudinal cohorts (n=280) including the international multicentre cross-sectional Cohort of Asian and Matched European Bronchiectasis 2 study (CAMEB 2; n=251) and two independent cohorts, one describing patients experiencing acute exacerbation and a further cohort of patients undergoing P. aeruginosa eradication treatment. Sputum was subjected to metagenomic sequencing and the bronchiectasis resistome evaluated in association with clinical outcomes and underlying host microbiomes.

RESULTS: The bronchiectasis resistome features a unique resistance gene profile and elevated counts of aminoglycoside, bicyclomycin, phenicol, triclosan and multi-drug resistance genes. Longitudinally, it exhibits within-patient stability over time and during exacerbations despite between-patient heterogeneity. Proportional differences in baseline resistome profiles including increased macrolide and multi-drug resistance genes associate with shorter intervals to next exacerbation, while distinct resistome archetypes associate with frequent exacerbations, poorer lung function, geographic origin, and the host microbiome. Unsupervised analysis of resistome profiles identified two clinically relevant 'resistotypes' RT1 and RT2, the latter characterized by poor clinical outcomes, increased multi-drug resistance and P. aeruginosa. Successful targeted eradication in P. aeruginosa-colonized individuals mediated reversion from RT2 to RT1, a more clinically favourable resistome profile demonstrating reduced resistance gene diversity.

CONCLUSION: The bronchiectasis resistome associates with clinical outcomes, geographic origin, and the underlying host microbiome. Bronchiectasis 'resistotypes' link to clinical disease and are modifiable through targeted antimicrobial therapy. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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