Dataset Information

Oral Beta-Lactamase Protects the Canine Gut Microbiome from Oral Amoxicillin-Mediated Damage.

ABSTRACT: Antibiotics damage the gut microbiome, which can result in overgrowth of pathogenic microorganisms and emergence of antibiotic resistance. Inactivation of antibiotics in the small intestine represents a novel strategy to protect the colonic microbiota. SYN-004 (ribaxamase) is a beta-lactamase formulated for oral delivery intended to degrade intravenously administered beta-lactam antibiotics in the gastrointestinal (GI) tract. The enteric coating of ribaxamase protects the enzyme from stomach acid and mediates pH-dependent release in the upper small intestine, the site of antibiotic biliary excretion. Clinical benefit was established in animal and human studies in which ribaxamase was shown to degrade ceftriaxone in the GI tract, thereby preserving the gut microbiome, significantly reducing Clostridioides difficile disease, and attenuating antibiotic resistance. To expand ribaxamase utility to oral beta-lactams, delayed release formulations of ribaxamase, SYN-007, were engineered to allow enzyme release in the lower small intestine, distal to the site of oral antibiotic absorption. Based on in vitro dissolution profiles, three SYN-007 formulations were selected for evaluation in a canine model of antibiotic-mediated gut dysbiosis. Dogs received amoxicillin (40 mg/kg, PO, TID) +/- SYN-007 (10 mg, PO, TID) for five days. Serum amoxicillin levels were measured after the first and last antibiotic doses and gut microbiomes were evaluated using whole genome shotgun sequence metagenomics analyses of fecal DNA prior to and after antibiotic treatment. Serum amoxicillin levels did not significantly differ +/- SYN-007 after the first dose for all SYN-007 formulations, while only one SYN-007 formulation did not significantly reduce systemic antibiotic concentrations after the last dose. Gut microbiomes of animals receiving amoxicillin alone displayed significant loss of diversity and emergence of antibiotic resistance genes. In contrast, for animals receiving amoxicillin + SYN-007, microbiome diversities were not altered significantly and the presence of antibiotic resistance genes was reduced. These data demonstrate that SYN-007 diminishes amoxicillin-mediated microbiome disruption and mitigates emergence and propagation of antibiotic resistance genes without interfering with antibiotic systemic absorption. Thus, SYN-007 has the potential to protect the gut microbiome by inactivation of beta-lactam antibiotics when administered by both oral and parenteral routes and to reduce emergence of antibiotic-resistant pathogens.

SUBMITTER: Connelly S

PROVIDER: S-EPMC6560916 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Oral Beta-Lactamase Protects the Canine Gut Microbiome from Oral Amoxicillin-Mediated Damage.

Connelly Sheila S Fanelli Brian B Hasan Nur A NA Colwell Rita R RR Kaleko Michael M

Microorganisms 20190527 5

Antibiotics damage the gut microbiome, which can result in overgrowth of pathogenic microorganisms and emergence of antibiotic resistance. Inactivation of antibiotics in the small intestine represents a novel strategy to protect the colonic microbiota. SYN-004 (ribaxamase) is a beta-lactamase formulated for oral delivery intended to degrade intravenously administered beta-lactam antibiotics in the gastrointestinal (GI) tract. The enteric coating of ribaxamase protects the enzyme from stomach aci ...[more]

PMID: 31137766

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Project description:Antibiotics, while lifesaving, damage the gut microbiome and can precipitate proliferation of pathobionts. A strategy to preserve gut microbiome integrity is to eliminate biologically active antimicrobials excreted into the gastrointestinal tract (GI) without negatively affecting antibiotic therapeutic efficacy. Clinical proof of concept was achieved with SYN-004 (ribaxamase), a beta-lactamase enzyme formulated for oral delivery with intravenous penicillins and cephalosporins. Ribaxamase inactivated intestinal ceftriaxone, protected the gut microbiome, and significantly reduced the incidence of Clostridioides difficile disease. For use with oral beta-lactam antibiotics, a delayed release formulation of ribaxamase, SYN-007, was engineered for dissolution in the lower small intestine distal to the site of oral antibiotic absorption. In dogs that received oral amoxicillin, SYN-007 reduced microbiome disruption without interfering with amoxicillin systemic absorption. Here, a study to determine the lowest effective dose of SYN-007 was performed. Dogs received amoxicillin (40 mg/kg, PO, TID) +/- SYN-007 (PO, TID) at three doses, 10 mg, 3 mg, or 1 mg for five days. Serum amoxicillin levels, measured after the first and last antibiotic doses, were not significantly different +/-SYN-007 at all dose levels indicating that SYN-007 did not interfere with amoxicillin systemic absorption. Microbiome analyses demonstrated that amoxicillin significantly reduced bacteria richness and microbiome diversity resulting in altered microbiome composition. However, with all doses of SYN-007, microbiome richness and diversity were not significantly different from pretreatment and changes in microbiome composition were attenuated. These data demonstrate that effective SYN-007 doses can be reduced at least 10-fold while maintaining gut microbiome preservation. The potential to employ low SYN-007 doses to protect the gut microbiota has important implications for enhancing therapeutic outcomes for patients receiving oral beta-lactam antibiotics while simultaneously reducing cost per dose and ultimately, healthcare expenses.

Project description:Beta-lactamases, enzymes produced by bacteria to degrade beta-lactam antibiotics, have been harnessed as therapeutics to protect the gut microbiome from damage caused by antibiotics. Proof-of-concept of this approach using SYN-004 (ribaxamase), a beta-lactamase formulated for oral delivery with intravenous (IV) penicillins and cephalosporins, was demonstrated with animal models and in humans. Ribaxamase degraded ceftriaxone in the gastrointestinal tract, protected the gut microbiome, significantly reduced the incidence of Clostridioidesdifficile disease and attenuated emergence of antibiotic resistant organisms. SYN-007 is a delayed release formulation of ribaxamase intended for use with oral beta-lactams. In dogs treated with oral amoxicillin, SYN-007 diminished antibiotic-mediated microbiome disruption and reduced the emergence of antibiotic resistance without altering amoxicillin systemic absorption. Here, SYN-007 function in the presence of clavulanate, a beta-lactamase inhibitor, was investigated. Dogs received amoxicillin (40 mg/kg, orally (PO), three times a day (TID)) or the combined antibiotic/beta-lactamase inhibitor, amoxicillin/clavulanate (40 mg/kg amoxicillin, 5.7 mg/kg clavulanate, PO, TID) +/- SYN-007 (10 mg, PO, TID) for five days. Serum amoxicillin levels were not significantly different +/- SYN-007 compared to amoxicillin alone or amoxicillin/clavulanate alone as controls for both first and last doses, indicating SYN-007 did not interfere with systemic absorption of the antibiotic. Whole genome shotgun metagenomics analyses of the fecal microbiomes demonstrated both amoxicillin and amoxicillin/clavulanate significantly reduced diversity and increased the frequency of antibiotic resistance genes. Microbiome damage appeared more severe with amoxicillin/clavulanate. In contrast, with SYN-007, microbiome diversity was not significantly altered, and frequency of antibiotic resistance genes did not increase. Importantly, SYN-007 functioned in the presence of clavulanate to protect the gut microbiome indicating that SYN-007 activity was not inhibited by clavulanate in the dog gastrointestinal tract. SYN-007 has the potential to expand microbiome protection to beta-lactam/beta-lactamase inhibitor combinations delivered orally or systemically.

Project description:Antibiotics seize an effect on bacterial composition and diversity and have been demonstrated to induce disruptions on gut microbiomes. This may have implications for human health and wellbeing, and an increasing number of studies suggest a link between the gut microbiome and several diseases. Hence, reducing antibiotic treatments may be beneficial for human health status. Further, antimicrobial resistance (AMR) is an increasing global problem that can be counteracted by limiting the usage of antibiotics. Longer antibiotic treatments have been demonstrated to increase the development of AMR. Therefore, shortening of antibiotic treatment durations, provided it is safe for patients, may be one measure to reduce AMR. In this study, the objective was to investigate effects of standard and reduced antibiotic treatment lengths on gut microbiomes using a murine model. Changes in the murine gut microbiome was assessed after using three different treatment durations of amoxicillin (3, 7 or 14 days) as well as a control group not receiving amoxicillin. Fecal samples were collected before and during the whole experiment, until three weeks past end of treatment. These were further subject for 16S rRNA Illumina MiSeq sequencing. Our results demonstrated significant changes in bacterial diversity, richness and evenness during amoxicillin treatment, followed by a reversion in terms of alpha-diversity and abundance of major phyla, after end of treatment. However, a longer restitution time was indicated for mice receiving amoxicillin for 14 days, and phylum Patescibacteria did not fully recover. In addition, an effect on the composition of Firmicutes was indicated to last for at least three weeks in mice treated with amoxicillin for 14 days. Despite an apparently reversion to a close to original state in overall bacterial diversity and richness, the results suggested more durable changes in lower taxonomical levels. We detected several families, genera and ASVs with significantly altered abundance three weeks after exposure to amoxicillin, as well as bacterial taxa that appeared significantly affected by amoxicillin treatment length. This may strengthen the argument for shorter antibiotic treatment regimens to both limit the emergence of antibiotic resistance and risk of gut microbiome disturbance.

Dataset Information

Oral Beta-Lactamase Protects the Canine Gut Microbiome from Oral Amoxicillin-Mediated Damage.

Publications

Oral Beta-Lactamase Protects the Canine Gut Microbiome from Oral Amoxicillin-Mediated Damage.

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