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

Authors Kokai-Kun JF, Le C, Trout K, Cope JL, Ajami NJ, Degar AJ, Connelly S

Received 28 April 2020

Accepted for publication 5 July 2020

Published 22 July 2020 Volume 2020:13 Pages 2521—2535

DOI https://doi.org/10.2147/IDR.S260258

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Suresh Antony


John F Kokai-Kun,1 Chenxiong Le,1 Kenneth Trout,1 Julia L Cope,2 Nadim J Ajami,2 Andrew J Degar,2 Sheila Connelly1

1Synthetic Biologics, Inc., Rockville, MD, USA; 2Diversigen, Inc., Houston, TX, USA

Correspondence: Sheila Connelly Email sconnelly@syntheticbiologics.com

Introduction: Intravenous (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 Clostridium difficile infection (CDI) and can promote antimicrobial resistance by selecting resistant organisms and eliminating competition by non-resistant organisms. Ribaxamase is an orally administered β-lactamase for use with IV β-lactam antibiotics (penicillins and cephalosporins) and is intended to degrade excess antibiotics in the upper GI before they can disrupt the gut microbiome and alter the resistome.
Methods: Longitudinal 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.
Results: Database 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.

Keywords: oral β-lactamase, ceftriaxone, gut resistome, whole-genome shotgun sequencing, clinical study, antimicrobial resistance

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