(28c) Understanding the Mechanism of Daptomycin Removal from the Gastrointestinal Tract Using Ion Exchange Biomaterials

Antimicrobial resistance is among the most worrisome challenges in the healthcare system worldwide. Daptomycin (DAP), a cyclic anionic lipopeptide antibiotic, is an antibiotic of last resort administered intravenously (IV) to treat infections with Gram-positive bacteria including vancomycin-resistant Enterococcus faecium. While this treatment can be effective at the site of infection, approximately 5-10 % of the antibiotic also enters the intestines through biliary excretion, which may drive resistance evolution in the E. faecium located in the gut, which may lead to antibiotic-resistant bacteria that may infect the patient or transmit to other patients. We have previously found that the oral administration of cholestyramine, an ion exchange biomaterial (IXB), reduces the DAP-resistant in this gastrointestinal population of E. faecium by up to 80-fold in mice; however, the underlying mechanisms for the IXB-DAP interactions are still elusive. Here, we investigate the IXB-mediated DAP removal from several aqueous media with well-controlled pH and electrolyte concentrations as well as from simulated intestinal fluid to uncover the molecular and colloidal mechanisms of IXB-DAP interactions in the gastrointestinal (GI) tract. Our findings show that IXB electrostatically adsorbs the anionic DAP via a time-dependent process controlled by diffusion, and the maximum removal capacity is beyond the electric charge stoichiometric ratios as a result of DAP self-assembly. Understanding the underlying DAP removal mechanism in GI tract may help address the problem of off-target bacterial resistance evolution.