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

Abstract

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.

Oral cholestyramine prevents enrichment of diverse daptomycin-resistance mutations in intestinal Enterococcus faecium

“…Here, we have shown that cholestyramine can prevent enrichment of resistance following the de novo emergence of daptomycin-resistance in E. faecium populations colonizing the intestines (Experiment 1, Fig 1). Previously, we had shown that cholestyramine could prevent the enrichment of preexisting resistant clones [1] (a result we saw again in Experiment 2; Figure 3). These results further show the promise of cholestyramine treatment for preventing off-target resistance evolution emerging via multiple genetic pathways during daptomycin treatment.…”

“…In the experiment testing the timing of cholestyramine administration, we also used the daptomycin-resistant strain BL00239-1-R (MIC c = 8.6). This resistant strain was isolated from a mouse colonized with BL00239-1 after experimental daptomycin treatment, as previously described [1].…”

“…One isolate (M3.5-5) was excluded from downstream analysis due to poor sequence quality. Trimmed reads were mapped against the BL00239-1 reference genome (generated previously [1]) and the E. faecium DO reference genome (NC_017960.1) using Burrows-Wheeler Aligner (BWA) [10], and candidate variants were identified with The Genome Analysis Toolkit (GATK) [11]. Candidate variants were annotated using SnpEff [12].…”

Antibiotic advances: soil, sea and perverse disincentives

“…The bile acid sequestrant cholestyramine binds daptomycin. In mice, cholestyramine reduced faecal shedding of daptomycin‐resistant E. faecium up to 80‐fold 15 …”

Evolutionary medicine

“…How does resistance evolve in multiple drug treatment scenarios (McLeod and Gandon, 2021), and what are the interaction effects with co-occurring pathogens? What are the best practices for treating patients, given this knowledge (Morley et al, 2020)? What features of newly designed drugs are optimal in the face of these evolutionary processes?…”