Studying the Mechanism of Daptomycin Removal Using Ion Exchange Biomaterials

Authors: Shang-Lin Yeh, Naveen Narasimhalu, Landon G. vom Steeg, Joy Muthami, Sean LeConey, Zeming He, Mica Pitcher,

Harrison Cassady, Valerie J. Morley, Sung Hyun Cho, Carol Bator, Roya Koshani, Robert J. Woods, Michael Hickner, Andrew F. Read, and Amir Sheikhi*

Multidrug-resistant Gram-positive bacterial infections arising from vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus have been the most prevalent cause of deadly hospital-acquired infections. Daptomycin (DAP), a cyclic lipopeptide antibiotic, is the most effective treatment for Gram-positive bacterial infections. DAP is typically administrated intravenously; however, 5-10% of the injected dosage ends up in the gastrointestinal (GI) tract through biliary excretion. This is of major concern because it induces resistance evolution to off-target populations of E. faecium bacteria. As a result, if a patient experiences the same infection in the future, DAP cannot be effective because the E. faecium bacteria has acquired resistance leading to the patient death. Previous in vivo findings on mice models have demonstrated the use of cholestyramine, a porous ion exchange biomaterial (IXB) sorbent, as an oral adjuvant to facilitate preventing DAP-resistance in bacteria populations. In this work, we uncover the interfacial interactions between IXB and DAP, and the antibiotic adsorption mechanism. The adsorption of DAP onto IXB was studied in controlled pH and electrolyte solutions as well as simulated intestinal fluid (SIF) to examine colloidal interactions. The results revealed that the cationic IXB electrostatically captures the anionic DAP through a time-dependent diffusion-mediated process. The adsorption kinetics of this interaction were modeled via unsteady-state diffusion-adsorption mass balance. The theoretical maximum removal capacity based on the electric charge stoichiometric ratio was surpassed due to DAP self-assembly. Through revealing the mechanisms of poorly understood interactions between IXB and DAP, the findings of this work open new horizons for the prevention of DAP resistance and the development of new biomaterials for the removal of other off-target antibiotics from the GI tract.