An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen

Therapeutic antibiotic use drives the spread of antibiotic resistance, a
major threat to public health. Ideally, clinicians could treat infections
with antibiotics without fueling transmission of resistant pathogens.
Here, we show proof of concept for an adjunctive therapy approach that
allows treatment of target pathogens without the emergence and onward
transmission of resistance. Like many of the bacterial species responsible
for the antimicrobial resistance crisis, vancomycin-resistant Enterococcus
(VRE) is a colonizing opportunistic pathogen and an important cause of
drug-resistant healthcare-associated infections. VRE causes
life-threatening infections in the bloodstream, but spreads via fecal-oral
transmission because it asymptomatically colonizes the gastrointestinal
(GI) tract. Thus, there is a physical separation between the VRE targeted
by treatment (those in the blood) and the VRE contributing to onward
transmission (those in the GI tract). An oral adjuvant that could
eliminate or inactivate antibiotic in the GI tract would make possible
intravenous patient treatment without promoting transmissible resistance.
We tested this idea in a mouse model of VRE GI tract colonization using
cholestyramine, which we show binds daptomycin, one of the few remaining
front-line antibiotics against VRE. Adjunctive cholestyramine therapy
reduced the fecal shedding of daptomycin-resistant VRE by up to 80-fold in
mice treated with daptomycin. These results provide proof-of-concept for
an approach that could reduce the spread of antibiotic resistance for many
important hospital pathogens.