Abstract
BACKGROUND: Exposure of the gut microbiota to antibiotics can alter the composition of the microbiome and lead to the emergence and spread of antibiotic resistance. SYN-004 (ribaxamase) is a clinical-stage β-lactamase intended to degrade certain IV β-lactam antibiotics in the GI tract to preserve the gut microbiome. In a phase 2b clinical study, ribaxamase significantly reduced C. difficile infection in patients treated with IV ceftriaxone. A new delayed-release ribaxamase formulation, SYN-007, intended for use with oral β-lactams, was evaluated in dogs that received oral amoxicillin plus the β-lactamase inhibitor, clavulanate (amox/clav). METHODS: SYN-007 was engineered for release in the lower small intestine, distal to the site of antibiotic absorption. Dogs received amox/clav (40 mg/kg amox/5.7 mg/kg clav, PO, TID) +/- SYN-007 (10 mg, PO, TID) for 16 doses. Amoxicillin serum levels were measured by LC/MS/MS after the first and last doses. DNA, isolated from feces collected before and after antibiotic treatment, was analyzed by whole-genome shotgun sequencing using CosmosID, Inc. metagenomics software. RESULTS: Serum amoxicillin levels were not significantly different +/- SYN-007 after the first and last doses of amox/clav. Microbiome analyses revealed that amox/clav disrupted the gut microbiome resulting in loss of some species and overgrowth of other taxa. SYN-007 attenuated changes to gut microbiome composition. Amox/clav exposure resulted in the emergence of many, mainly TEM β-lactamase genes that was reduced with SYN-007. CONCLUSION: Oral amox/clav disrupted the gut microbiome in dogs and resulted in the emergence of β-lactamase genes. SYN-007 diminished amox/clav-mediated microbiome disruption and attenuated emergence of β-lactamase genes. SYN-007 did not interfere with amox systemic absorption indicating that the β-lactamase was not released in the upper small intestine, the site of oral amoxicillin absorption. Antibiotic inactivation represents a potential new treatment paradigm for preservation of the gut microbiome and reduction of antibiotic resistance. SYN-007 has the potential to expand β-lactamase-mediated microbiome protection to oral as well as IV β-lactam antibiotics. DISCLOSURES: All authors: No reported disclosures.