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

Abstract

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 βlactam 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 preantibiotic 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.

Colonization dynamics of extended-spectrum beta-lactamase-producing Enterobacterales in the gut of Malawian adults

“…Defining the contribution of antimicrobial selection versus new ESBL-E acquisition events following antimicrobial exposure will guide prevention efforts and should be a priority for future studies—as should understanding the way in which antimicrobials may act to reduce colonization resistance and aid transmission. Healthcare-associated transmission could be reduced by infection prevention and control procedures but antimicrobial selection pressure amplifying minority ESBL-E carried before hospital admission would need new strategies to protect the microbiota against selection for ESBL-E, such as antimicrobial binding compounds 25 or oral beta-lactamases 26 .…”

“…Sensitivity analysis varying the SNP threshold from 0 to 10 did not materially alter the conclusions (Supplementary Figs. [24][25][26].…”

Clostridioides difficile infection in the allogeneic hematopoietic cell transplant recipient

“…It acts by degrading betalactam antibiotics in the lower gastrointestinal tract. 80 Ribaxamase has been tested in a double-blind, phase 2b, randomized placebocontrolled trial on 433 patients receiving intravenous cephalosporins.…”

“…Ribaxamase is an oral enteric‐coated beta‐lactamase pellet that is intended to be used with intravenous penicillins and cephalosporins to prevent the disruption of the microbiome. It acts by degrading beta‐lactam antibiotics in the lower gastrointestinal tract 80 . Ribaxamase has been tested in a double‐blind, phase 2b, randomized placebo‐controlled trial on 433 patients receiving intravenous cephalosporins.…”

Dynamics of gut mucosal colonisation with extended spectrum beta-lactamase producing Enterobacterales in Malawi

“…Defining the contribution of antimicrobial selection versus novel acquisition events in driving ESBL-E prevalence following antimicrobial exposure across high and low-income settings will guide prevention efforts and should be a priority for future studies. Healthcare associated transmission could be reduced by infection prevention and control procedures, but antimicrobial selection pressure would need novel strategies to protect the microbiota against selection for resistant bacteria such as antimicrobial binding compounds 26 or oral beta lactamases 27 .…”