Empiric azithromycin alters the upper respiratory microbiome and resistome without anti-inflammatory benefit in COVID-19

Azithromycin is a widely used antibiotic and was frequently used to treat hospitalized patients during the COVID-19 pandemic. The impact of empiric azithromycin use on the respiratory microbiome in patients with viral respiratory infections is unclear. Here we used longitudinal metatranscriptomics on nasal swabs from a prospective multicentre cohort of 1,164 patients hospitalized for COVID-19. We compared the upper respiratory microbiome, resistome and systemic immune response in patients treated with azithromycin (n = 366) with those who received no antibiotics (n = 474) or other antibiotics (n = 324). We found that azithromycin altered microbiome composition and increased the expression and relative proportion of macrolide/lincosamide/streptogramin (MLS) resistance genes. These changes occurred after 1 day of exposure and persisted for over a week. MLS resistance gene expression was associated with commensals and potential pathogens, while there were no differences in host inflammatory gene expression in blood and airways. This demonstrates that empiric azithromycin treatment impacts the upper respiratory microbiome and resistome without apparent anti-inflammatory benefit.

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Journal
Nature Microbiology
Published
2026-03-16
DOI
https://doi.org/10.1038/s41564-026-02285-8
Primary Topic
Gut microbiota and health
Type
article
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0.00

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article

Empiric azithromycin alters the upper respiratory microbiome and resistome without anti-inflammatory benefit in COVID-19

Grace A. McComsey, Nicolas C. Issa, Luz Torres Altamirano, Jeremy P. Gygi et al.
Nature Microbiology
Gut microbiota and health
article

Empiric azithromycin alters the upper respiratory microbiome and resistome without anti-inflammatory benefit in COVID-19

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article en

Abstract

Azithromycin is a widely used antibiotic and was frequently used to treat hospitalized patients during the COVID-19 pandemic. The impact of empiric azithromycin use on the respiratory microbiome in patients with viral respiratory infections is unclear. Here we used longitudinal metatranscriptomics on nasal swabs from a prospective multicentre cohort of 1,164 patients hospitalized for COVID-19. We compared the upper respiratory microbiome, resistome and systemic immune response in patients treated with azithromycin (n = 366) with those who received no antibiotics (n = 474) or other antibiotics (n = 324). We found that azithromycin altered microbiome composition and increased the expression and relative proportion of macrolide/lincosamide/streptogramin (MLS) resistance genes. These changes occurred after 1 day of exposure and persisted for over a week. MLS resistance gene expression was associated with commensals and potential pathogens, while there were no differences in host inflammatory gene expression in blood and airways. This demonstrates that empiric azithromycin treatment impacts the upper respiratory microbiome and resistome without apparent anti-inflammatory benefit.

Nature Microbiology
Broad Institute (US), Brigham and Women's Hospital (US), Boston Children's Hospital (US), La Jolla Institute for Immunology (US), Harvard University (US), University of Arizona (US), Emory University (US), University of California, Los Angeles (US), Oregon Health & Science University (US), Palo Alto University (US), University of California, San Francisco (US), Baylor College of Medicine (US), University of Washington (US), University of South Florida (US), University Hospitals of Cleveland (US), Yale University (US), University of Florida (US), Jacksonville University (US), The Coordinating Center (US), Immunai (United States) (US), Chan Zuckerberg Initiative (United States) (US), Metabolon (United States) (US), Prevention of Organ Failure (CA), National Institute of Allergy and Infectious Diseases (US), Ludwig Boltzmann Institute Applied Diagnostics (AT), OU Health, University of Oklahoma Health Sciences Center (US), Case Western Reserve University (US), Drexel University (US), Medical University of Vienna (AT), The University of Texas at Austin (US), Stanford University (US), Icahn School of Medicine at Mount Sinai (US)
Yale University, Emory University, University of Washington, Case Western Reserve University, Drexel University, Broad Institute, Universität Wien, Medizinische Universität Wien, School of Medicine, Stanford University, University of California, Los Angeles, Emerging Pathogens Institute, University of Florida, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 21%
Gut microbiota and health
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