Airway 'Resistotypes' and Clinical Outcomes in Bronchiectasis

Micheál Mac Aogáin, Fransiskus Xaverius Ivan, Tavleen Kaur Jaggi, Hollian Richardson, Amelia Shoemark, Jayanth Kumar Narayana, Alison J Dicker, Mariko Siyue Koh, Ken Cheah Hooi Lee, Ong Thun How, Mau Ern Poh, Ka Kiat Chin, Albert Lim Yick Hou, Puah Ser Hon, Teck Boon Low, John Arputhan Abisheganaden, Katerina Dimakou, Antonia Digalaki, Chrysavgi Kosti, Anna GkousiouPhilip M Hansbro, Francesco Blasi, Stefano Aliberti, James D Chalmers, Sanjay H Chotirmall (Lead / Corresponding author)

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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.

Original languageEnglish
Number of pages79
JournalAmerican Journal of Respiratory and Critical Care Medicine
Early online date24 Jan 2024
DOIs
Publication statusE-pub ahead of print - 24 Jan 2024

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