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.
Keywords: Enterococcus faecium; antimicrobial resistance; antimicrobial stewardship; daptomycin; evolutionary biology; evolutionary medicine; mouse.
Antibiotics are essential for treating infections. But their use can inadvertently lead to the emergence of antibiotic-resistant bacteria that do not respond to antibiotic drugs, making infections with these bacteria difficult or impossible to treat. Finding ways to prevent antibiotic resistance is critical to preserving the effectiveness of antibiotics. Many bacteria that cause infections in hospitals live in the intestines, where they are harmless. But these bacteria can cause life-threatening infections when they get into the bloodstream. When patients with bloodstream infections receive antibiotics, the bacteria in their intestines are also exposed to the drugs. This can kill off all antibiotic-susceptible bacteria, leaving behind only bacteria that have mutations that allow them to survive the drugs. These drug-resistant bacteria can then spread to other patients causing hard-to-treat infections. To stop this cycle of antibiotic treatment and antibiotic resistance, Morley et al. tested whether giving a drug called cholestyramine with intravenous antibiotics could protect the gut bacteria. In the experiments, mice were treated systemically with an antibiotic called daptomycin, which caused the growth of daptomycin-resistant strains of bacteria in the mice’s intestines. In the laboratory, Morley et al. discovered that cholestyramine can inactivate daptomycin. Giving the mice cholestyramine and daptomycin together prevented the growth of antibiotic-resistant bacteria in the mice's intestines. Moreover, cholestyramine is taken orally and is not absorbed into the blood. It therefore only inactivates the antibiotic in the gut, but not in the blood. The experiments provide preliminary evidence that giving cholestyramine with antibiotics might help prevent the spread of drug resistance. Cholestyramine is already used to lower cholesterol levels in people. More studies are needed to determine if cholestyramine can protect gut bacteria and prevent antibiotic resistance in people.
© 2020, Morley et al.