Ribaxamase, an Orally Administered β-Lactamase, Diminishes Changes to Acquired Antimicrobial Resistance of the Gut Resistome in Patients Treated with Ceftriaxone.

introductionIntravenous (IV) β-lactam antibiotics, excreted through bile into the gastrointestinal (GI) tract, may disrupt the gut microbiome by eliminating the colonization resistance from beneficial bacteria. This increases the risk for

methodsLongitudinal fecal samples (349) were collected from patients who participated in a previous Phase 2b clinical study with ribaxamase for prevention of CDI. In that previous study, patients were treated with ceftriaxone for a lower respiratory tract infection and received concurrent ribaxamase or placebo. Extracted fecal DNA from the samples was subjected to whole-genome shotgun sequencing and analyzed for the presence of antimicrobial resistance (AMR) genes by alignment of sequences against the Comprehensive Antibiotic Resistance Database. A qPCR assay was also used to confirm some of the results.

resultsDatabase alignment identified ~1300 acquired AMR genes and gene variants, including those encoding β-lactamases and vancomycin resistance which were significantly increased in placebo vs ribaxamase-treated patients following antibiotic exposure. qPCR corroborated the presence of these genes and supported both new acquisition and expansion of existing gene pools based on no detectable copy number or a low copy number in pre-antibiotic samples which increased post-antibiotics. Additional statistical analyses demonstrated significant correlations between changes in the gut resistome and clinical study parameters including study drug assignment and β-lactamase and vancomycin resistance gene frequency. DISCUSSION: These findings demonstrated that ribaxamase reduced changes to the gut resistome subsequent to ceftriaxone administration and may help limit the emergence of AMR.