Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, United States
Scott A Showalter
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, United States; Department of Chemistry, The Pennsylvania State University, University Park, United States
Manjunath P Pai
Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States
Robert J Woods
Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, United States
Center for Infectious Disease Dynamics, Department of Biology, The Pennsylvania State University, University Park, United States; Huck Institutes for the Life Sciences, The Pennsylvania State University, University Park, United States; Department of Entomology, The Pennsylvania State University, University Park, United States
A key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and onward transmission of resistance. We repurposed the FDA-approved bile acid sequestrant cholestyramine, which we show binds the antibiotic daptomycin, as an ‘anti-antibiotic’ to disable systemically-administered daptomycin reaching the gut. We hypothesized that adjunctive cholestyramine could enable therapeutic daptomycin treatment in the bloodstream, while preventing transmissible resistance emergence in opportunistic pathogens colonizing the gastrointestinal tract. We tested this idea in a mouse model of Enterococcus faecium gastrointestinal tract colonization. In mice treated with daptomycin, adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistant E. faecium by up to 80-fold. These results provide proof of concept for an approach that could reduce the spread of antibiotic resistance for important hospital pathogens.
