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

Abstract

Background and ObjectivesPreviously, 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?MethodologyMice 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.ResultsCholestyramine 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 ImplicationsCholestyramine 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.

Ion exchange biomaterials to capture daptomycin and prevent resistance evolution in off-target bacterial populations

“…We previously demonstrated that the oral administration of cholestyramine IXB concurrent with systemic DAP treatment very substantially prevented the up selection and shedding of DAP resistant VREfm. 8,9 In this study, we The DAP removal efficacy of IXB in the FaSSIF was slightly higher than in the FeSSIF as a result of lower bile acid concentration. This work lays the foundations for optimizing the use of ion exchange sorbents, such as cholestyramine, as adjuvant therapy to prevent daptomycin resistance, as well as designing next generation biomaterials that could combat the emergence of antimicrobial resistance in the GI tract.…”

“…We previously demonstrated that the oral administration of cholestyramine IXB concurrent with systemic DAP treatment very substantially prevented the up selection and shedding of DAP resistant VRE fm . 8, 9 In this study, we shed light on the mechanism and engineering aspects of IXB-mediated DAP removal. DAP tends to self-assemble into micelles or aggregates in aqueous solutions and re-assemble to form SLBs upon contacting the IXB, which triggers the time-dependent molecular diffusion of DAP inside the IXB pores.…”

“…Direct experimental evidence of off-target selection comes from mouse models: systemic DAP treatment enriched for DAP-resistant VRE fm in the GI tract and up-selected a variety of de novo resistance mutations that confer DAP resistance. 8, 9 This raises the prospect that inactivation of DAP in the GI tract would prevent the evolution of DAP resistance without interfering with the capacity of DAP to treat bloodstream infections. This would reduce the risk that patients would acquire DAP-resistant VRE fm from their carriage populations in their own GI tract, as well as prevent the onward transmission of DAP resistance in this important hospital-acquired infection.…”

“…We have previously shown that feeding mice with an ion exchange biomaterial (IXB) sorbent, cholestyramine, reduced DAP-induced enrichment and shedding of DAP-resistant VRE fm by 80-fold 16 and completely prevented the emergence and shedding of de novo resistance mutations. 8, 9 However, the mechanism by which this oral adjuvant prevents DAP activity is unclear.…”

Ion Exchange Biomaterials to Capture Daptomycin and Prevent Resistance Evolution in Off-Target Bacterial Populations

“…This is consistent with off-target selection for resistance, where antibiotic use causes resistance evolution in a population of bacteria that are not the therapeutic target. Direct experimental evidence of off-target selection comes from mouse models: systemic DAP treatments enriched DAP-resistant VRE fm in the GI tract and up-selected a variety of de novo resistance mutations that confer DAP resistance. , This raises the prospect that inactivation of DAP in the GI tract would prevent the evolution of DAP resistance without interfering with the capacity of DAP to treat bloodstream infections. This would reduce the risk that patients would acquire DAP-resistant VRE fm from their carriage populations in their own GI tract, as well as prevent the onward transmission of DAP resistance in this important hospital-acquired infection.…”