Pig Model Paves Way for C difficile Suppression

Ribaxamase, already shown to reduce Clostridium difficile (C. difficile), can control the emergence and spread of antibiotic resistance, as demonstrated in pig models in a report presented by Synthetic Biologics, Inc, a Maryland-based therapeutic development company.

Sheila Connelly, PhD, and colleagues from Synthetic Biologics, Inc, used a pig model of antibiotic-mediated gut dysbiosis—established with a cephalosporin, a penicillin, and a carbapenem—to demonstrate that ribaxamase would be able to protect the gut microbiome. The researchers explained that broad-spectrum, beta lactam antibiotics that are excreted in bile can damage the gut microbiome and lead to infections from pathogens such as C. difficile or vancomycin-resistant enterococci.

Rbaxamase, or SYN-004, is a clinical stage, oral beta-lactamase for use with parenteral beta lactam antibiotics, such as penicillins and cephalosporins—those intended to preserve the microbiome by breaking up the residual antibiotics in the intestinal tract. A previous Phase 2b study showed that ribaxamase significantly reduced C. difficile infections in patients receiving intravenous (IV) ceftriaxone (CRO). Connelly explained in a blog post that some might express concern that ribaxamase might reduce the overall efficacy of the antibiotics fighting the infection, but that should not be a worry because ribaxamase is designed to be released and stay in the gut. The antibiotic degradation purpose of the ribaxamase remains targeted in the specific area, Connelly continued.

There were 5 piglets, each weighing about 20 kg, in each cohort treated either with 50 mg/kg IV CRO once a day, 20 mg/kg oral amoxicillin twice a day, or 30 mg/kg IV ertapenem once a day for 7 consecutive days. One of the groups of 5 piglets received 75 mg oral ribaxamase 4 times a day in addition to CRO.

The research team then performed whole genome shotgun sequence analyses of the pig fecal DNA to determine what effect the antibiotics had on the gut microbacteria, if any. The researchers also wanted to quantify the antibiotic resistance genes as a way to measure antibiotic resistant bacteria within the fecal microbiome.

The investigators found that there was no significant difference within the CRO and ribaxamase combination cohort compared to the pretreatment. However, all 3 antibiotic courses caused significant changes to the gut microbiome, the study authors wrote. The researchers said they discovered a broad spectrum of resistance genes within 4 days of antibiotic treatment, including genes that conferred resistance to beta lactam and non-beta lactam antibiotics. The researchers were also surprised to learn that ribaxamase reduced the emergence of propagation of antibiotic resistant genes.

Connelly added in the blog that pig research is often directly translatable to humans. She continued that the results, termed “favorable,” indicate that the next step for the research team will be to conduct a study to determine whether a change in the ribaxamase delivery method would protect the gut microbiome when used with beta lactam antibiotics, such as amoxicillin.

The blog post is titled “From hog to human — How pigs can help fight superbugs” and published on Becker’s Infection Control & Clinical Quality.

The study is titled, “An Orally Delivered Beta-Lactamase Protects the Gut Microbiome from Antibiotic Mediated Damage and Mitigates the Propagation of Antibiotic-Resistance Genes in a Porcine Dysbiosis Model” and published in the journal Gastroenterology.

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