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
diverse resistance mutations that emerged de novo in daptomycin-treated
mice. Whole-genome sequencing revealed that resistance emerged through
multiple genetic pathways, with most candidate resistance mutations
observed in the clsA gene. Additionally, we observed that cholestyramine
was most effective when administration started prior to the first dose of
daptomycin. However, beginning cholestyramine after the first daptomycin
dose reduced the frequency of resistant E. faecium compared to not using
cholestyramine at all. Conclusions and Implications: Cholestyramine
prevented the enrichment of diverse daptomycin-resistance mutations in
intestinal E. faecium populations during daptomycin treatment, and it is a
promising tool for managing transmission of daptomycin-resistant E.
faecium.