Empiric Azithromycin in COVID-19 Impacts the Respiratory Microbiome and Antimicrobial Resistome without Anti-inflammatory Benefit

Azithromycin is often prescribed unnecessarily for respiratory infections, many of which are viral. During the COVID-19 pandemic, its use was widespread, in part due to alleged therapeutic benefits, which have since been disproven. Here, we sought to understand the impact of azithromycin exposure on the respiratory microbiome, antimicrobial resistome, and host immune response in a prospective multicenter cohort of 1164 patients hospitalized for SARS-CoV-2 infection. Using longitudinal nasal metatranscriptomics, we compared patients treated with azithromycin (n=366, 31.4%) to those who received no antibiotics (n=474, 40.7%) or antibiotics other than azithromycin (n=324, 27.8%). We found that azithromycin treatment altered the community composition of the nasal microbiome, reducing bacterial relative abundance, increasing fungal relative abundance, and increasing potentially pathogenic taxa such as Klebsiella and Staphylococcus. Azithromycin treatment was most notably associated with increases in the number of detectably expressed macrolide/lincosamide/streptogramin (MLS) antimicrobial resistance genes, as well as their relative proportion in the resistome, with changes observable after one day of exposure. Of the MLS resistance genes, the expression of ermC , msrA and ermX increased the most in patients receiving azithromycin. Correlation analyses demonstrated that MLS resistance gene expression was significantly associated with the abundance of several taxa, including both commensal (e.g., Dolosigranulum, Corynebacterium ) and potentially pathogenic genera (e.g., Streptococcus, Staphylococcus). Assessment of the peripheral blood and upper airway host transcriptome demonstrated no differences in the expression of inflammatory genes. Taken together, our findings demonstrate that azithromycin treatment in COVID-19 leads to dysbiosis of the upper respiratory microbiome and changes in the expression of MLS resistance genes, without apparent anti-inflammatory benefit.