Export file:

Format

  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text

Content

  • Citation Only
  • Citation and Abstract

Low dose oral beta-lactamase protects the gut microbiome from oral beta-lactam-mediated damage in dogs

1 Synthetic Biologics, Inc., Rockville, MD, United States
2 CosmosID, Inc., Rockville, MD, United States
3 University of Maryland Institute for Advanced Computer Studies, College Park, MD, United States

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.
  Figure/Table
  Supplementary
  Article Metrics

References

1. Blaser MJ (2014) The microbiome revolution. J Clin Invest 124: 4162–4165.    

2. Kaleko M, Bristol JA, Hubert S, et al. (2016) Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection. Anaerobe 41: 58–67.    

3. Kokai-Kun JF, Roberts T, Coughlin O, et al. (2017) The oral β-lactamase SYN-004 (ribaxamase) degrades ceftriaxone excreted into the intestine in phase 2a clinical studies. Antimicrob. Agents Chemother 61: e02197–16.

4. Kokai-Kun J, Connelly S (2019) Ribaxamase, an Orally Administered -lactamase, Protects the Gut Microbiome in Patients Treated with Ceftriaxone. J Transl Sci 6: 1–9.

5. Clinicaltrials.gov (2018) A study of SYN-004 for the prevention of C. diff in patients with a LRTI. NCT02563106, September 29, 2015 ed. Available from: https://clinicaltrials.gov/ct2/show/NCT02563106?term=NCT02563106&recrs=e&draw=2&rank=1.

6. Kokai-Kun JF, Roberts T, Coughlin O, et al. (2019) Use of ribaxamase (SYN-004), a beta-lactamase, to prevent Clostridium difficile infection in beta-lactam-treated patients: a double-blind, phase 2b, randomised placebo-controlled trial. Lancet Infect Dis 19: 487–496.    

7. Connelly S, Fanelli B, Hasan NA, et al. (2019) Oral Beta-Lactamase Protects the Canine Gut Microbiome from Oral Amoxicillin-Mediated Damage. Microorg 7: 150.    

8. Philip AK, Philip B (2010) Colon targeted drug delivery systems: a review on primary and novel approaches. Oman Med J 25: 79–87.    

9. Connelly S, Fanelli B, Hasan NA, et al. (2019) Oral beta-lactamase protects the gut microbiome from damage caused by oral amoxicillin/clavulanate without interfering with amoxicillin systemic absorption in dogs. Unpublished data [In press].

10. Roberts T, Kokai-Kun JF, Coughlin O, et al. (2016) Tolerability and Pharmacokinetics of SYN-004, an Orally Administered beta-Lactamase for the Prevention of Clostridium difficile-Associated Disease and Antibiotic-Associated Diarrhea, in Two Phase 1 Studies. Clin Drug Investig 36: 725–734.    

11. Bristol A, Hubert S, Hofmann F, et al. (2017) Formulation development of SYN-004 (ribaxamase) oral solid dosage form, a beta-lactamase to prevent intravenous antibiotic- associated dysbiosis of the colon. Int J Pharm 534: 25–34.    

12. Shannon CE (1948) A mathematical theory of communication. Bell Syst Tech J 27: 379–423.    

13. Gaujoux R, Seoighe C (2010) A flexible R package for nonnegative matrix factorization. BMC Bioinf 11: 367.    

14. Daughton CG, Ruhoy IS (2013) Lower-dose prescribing: minimizing "side effects" of pharmaceuticals on society and the environment. Sci Total Environ 443: 324–337.    

15. Coelho LP, Kultima JR, Costea PI, et al. (2018) Similarity of the dog and human gut microbiomes in gene content and response to diet. Microbiome 6: 72.    

16. Warda AK, Rea K, Fitzgerald P, et al. (2019) Heat-killed lactobacilli alter both microbiota composition and behaviour. Behav Brain Res 362: 213–223.    

17. Gronvold AM, L'Abee-Lund TM, Sorum H, et al. (2010) Changes in fecal microbiota of healthy dogs administered amoxicillin. FEMS Microbiol Ecol 71: 313–326.    

18. Allaker RP (2012) Non-sporing anaerobes. In: Greenword D, Slack R, Barer M, et al. editor. Medical Microbiology,18Eds., Churchill Livingston, 359–364.

19. Schroeder PJ, Jenkins DG (2018) How robust are popular beta diversity indices to sampling error? Ecosphere 9: e02100.    

© 2019 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Article outline

Show full outline
Copyright © AIMS Press All Rights Reserved