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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                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009366) with those who received no antibiotics (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009474) or other antibiotics (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009324). 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.\n                  <\/jats:p>","DOI":"10.1038\/s41564-026-02285-8","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T10:02:20Z","timestamp":1773655340000},"page":"1100-1112","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Empiric azithromycin alters the upper respiratory microbiome and resistome without anti-inflammatory benefit in 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Bitbucket https:\/\/bitbucket.org\/kleinstein\/impacc-public-code\/src\/master\/azithromycin_manuscript\/ (2026)."}],"container-title":["Nature Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41564-026-02285-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41564-026-02285-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41564-026-02285-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T15:02:31Z","timestamp":1775574151000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41564-026-02285-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,16]]},"references-count":52,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["2285"],"URL":"https:\/\/doi.org\/10.1038\/s41564-026-02285-8","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-6875205\/v1","asserted-by":"object"}]},"ISSN":["2058-5276"],"issn-type":[{"value":"2058-5276","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,16]]},"assertion":[{"value":"29 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines, influenza virus vaccines and influenza virus therapeutics, which list F. Krammer as co-inventor and F. Krammer has received royalty payments from some of these patents. V.S. is listed on the SARS-CoV-2 serology assay patent. Mount Sinai has spun out a company, Castlevax, to develop SARS-CoV-2 vaccines. F. Krammer is co-founder and scientific advisory board member of Castlevax. F. Krammer has also consulted for Merck, GSK, Sanofi, Gritstone, Curevac, Seqirus and Pfizer, and is currently consulting for 3rd Rock Ventures and Avimex. The Krammer laboratory is also collaborating with Dynavax on influenza vaccine development. O.L. is a named inventor on patents held by Boston Children\u2019s Hospital relating to vaccine adjuvants and human in vitro platforms that model vaccine action. His laboratory has received research support from GlaxoSmithKline (GSK) and he is a co-founder of and advisor to ARMR Sciences (formerly Ovax, Inc.) that develops technologies to detect illicit substances and prevent overdose. He is also an advisor to GSK. C.B.C. serves as a consultant to bioMerieux and is funded by a grant from the Bill and Melinda Gates Foundation. J.A.O. is a consultant at Knocean Inc. J.L.-S. serves as a scientific advisor of Precion Inc. S.R.H., G.M. and K.W. are employees of Metabolon Inc. V.S.-M. is a current employee of MyOwnMed. N. Rouphael reports grants or contracts with Merck, Sanofi, Pfizer, Vaccine Company, Quidel, Lilly, and Immorna, and has participated on data safety monitoring boards for Moderna, Sanofi, Seqirus, Pfizer, EMMES, ICON, BARDA, Imunon, CyanVac, and Micron. N. Rouphael has also received support for meetings\/travel from Sanofi and Moderna, and honoraria from Virology Education. A.R. is a current employee of Immunai Inc. S.H.K. is a consultant related to ImmPort data repository for Peraton. D.A.H. has received research funding from Bristol\u2013Myers Squibb, Novartis, Sanofi, and Genentech. He has been a consultant for Bayer Pharmaceuticals, Repertoire Inc., Bristol\u2013Myers Squibb, Compass Therapeutics, EMD Serono, Genentech, Novartis Pharmaceuticals, and Sanofi Genzyme. A.I. is a consultant for 4BIO, Blue Willow Biologics, Revelar Biotherapeutics, RIGImmune, Xanadu Bio, and Paratus Sciences. M.K. receives research funds paid to her institution from NIH, ALA, Sanofi, and Astra-Zeneca for work in asthma; serves as a consultant for Astra-Zeneca, Sanofi, Chiesi, and GSK for severe asthma; and is a co-founder and CMO for RaeSedo, Inc., a company created to develop peptidomimetics for treatment of inflammatory lung disease. E. Melamed received research funding from Babson Diagnostics and honorarium from the Multiple Sclerosis Association of America, and has served on the advisory boards of Genentech, Horizon, Teva, and Viela Bio. C.C. receives research funding from NIH, FDA, DOD, Roche-Genentech and Quantum Leap Healthcare Collaborative, and also provides consulting services for Janssen, Vasomune, Gen1e Life Sciences, NGMBio, and Cellenkos. G.A.M. received research grants from Redhill, Cognivue, Pfizer, and Genentech, and served as a research consultant for Gilead, Merck, Viiv\/GSK, and Jenssen. L.N.G. received research funding paid to her institution from Pfizer, Inc. E.F.R. serves as a consultant for Biogen and Regeneron for clinical trials advancing therapies in transplant alloimmunity. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}