Impact of the anti-inflammatory macrolide glasmacinal on the gut microbiota of healthy adults: an open-label trial.

Glasmacinal (EP395) is an oral macrolide, with immunomodulatory properties like antibiotic macrolides (such as azithromycin), but with negligible in vitro antimicrobial activity, which is being developed as a potential treatment to reduce exacerbations in respiratory conditions. In an open-label healthy participant trial (ClinicalTrials.gov: NCT06118684), with the primary objective of assessing potential drug-drug interactions of glasmacinal, faecal samples were collected to evaluate the impact on the gut microbiota of daily doses of glasmacinal for 2 weeks, using both phenotypic and 16S rRNA gene sequencing. Glasmacinal produced modest effects: reduced phylogenetic richness (p < 0.0001), but not evenness, and altered beta-diversity (PERMANOVA R2 = 0.104 p.adj=0.0018 after 1 week, and R2 = 0.059, p.adj=0.028 after 2 weeks) with reductions in Clostridiaceae, Enterobacteriaceae, and Sutterellaceae abundance. The community shift was approximately 10% after 1-week glasmacinal, and 6% after 2-weeks. With quantitative culture, only Enterobacterales was impacted. No increase or selection of resistance to azithromycin in Enterobacterales and Bacteroides, nor increase in Candida spp. or Clostridioides difficile, were detected. Overall, glasmacinal induced limited restructuring of the gut microbiome (without the defining hallmarks of antibiotic-like dysbiosis), core anaerobic phyla of the gut (Firmicutes and Bacteroidetes) were preserved, and there was no selection of antimicrobial resistance.