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Am. J. Respir. Crit. Care Med. · Jul 2024
Multicenter StudyAirway '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 Gkousiou, Philip M Hansbro, Francesco Blasi, Stefano Aliberti, James D Chalmers, and Sanjay H Chotirmall.
- Biochemical Genetics Laboratory, Department of Biochemistry, St. James's Hospital, Dublin, Ireland.
- Am. J. Respir. Crit. Care Med. 2024 Jul 1; 210 (1): 476247-62.
AbstractRationale: Chronic infection and inflammation shapes the airway microbiome in bronchiectasis. Utilizing whole-genome shotgun metagenomics to analyze the airway resistome provides insight into interplay between microbes, resistance genes, and clinical outcomes. Objectives: To apply whole-genome shotgun metagenomics to the airway microbiome in bronchiectasis to highlight 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 multicenter cross-sectional Cohort of Asian and Matched European Bronchiectasis 2 (CAMEB 2) study (n = 251) and two independent cohorts, one describing patients experiencing acute exacerbation and a further cohort of patients undergoing Pseudomonas aeruginosa eradication treatment. Sputum was subjected to metagenomic sequencing, and the bronchiectasis resistome was evaluated in association with clinical outcomes and underlying host microbiomes. Measurements and Main Results: The bronchiectasis resistome features a unique resistance gene profile and increased counts of aminoglycoside, bicyclomycin, phenicol, triclosan, and multidrug 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 multidrug resistance genes, associate with shorter intervals to the next exacerbation, whereas 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 multidrug resistance, and P. aeruginosa. Successful targeted eradication in P. aeruginosa-colonized individuals mediated reversion from RT2 to RT1, a more clinically favorable resistome profile demonstrating reduced resistance gene diversity. Conclusions: 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.
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