Oral cholestyramine prevents the enrichment of diverse daptomycin-resistance mutations in intestinal Enterococcus faecium populations

Background and Objectives: Previously, we showed proof-of-concept in a mouse model that oral administration of cholestyramine prevented enrichment of daptomycin-resistant Enterococcus faecium in the gastrointestinal (GI) tract during daptomycin therapy. Cholestyramine binds daptomycin in the gut, which removes daptomycin selection pressure and so prevents the enrichment of resistant clones. Here, we investigated two open questions related to this approach: 1) can cholestyramine prevent the enrichment of diverse daptomycin mutations emerging de novo in the gut? 2) how does the timing of cholestyramine administration impact its ability to suppress resistance? Methodology: Mice with GI E. faecium were treated with daptomycin with or without cholestyramine, and E. faecium was cultured from feces to measure changes in daptomycin susceptibility. A subset of clones was sequenced to investigate the genomic basis of daptomycin resistance. Results: Cholestyramine prevented the enrichment of diver...