Clostridium difficile infection (CDI) caused approximately 453,000 healthcare-associated infections in the United States in 2011, resulting in 29,000 deaths within 30 days of initial diagnosis. CDI causes severe diarrhea, most often in older adults who are taking antibiotics for other illnesses (Lessa, 2015).
Antibiotics play a significant and important role in saving lives by destroying the harmful bacteria that cause primary infection. Unfortunately, antibiotics can be indiscriminate and also destroy the good bacteria that lives in the GI tract, removing a crucial element in protecting the body from infections. C. difficile spores are prevalent in the environment, so in patients that have depleted levels of healthy bacteria because of antibiotic treatment, C. difficile infection (CDI) quickly grows out of control (Mayo Clinic, 2016). Protection of the population of microbes living in the GI tract, known as the ‘gut microbiome,’ from the unwanted effects of antibiotics may hold the key to preventing CDI, thus avoiding thousands of deaths every year.
The gut microbiome is the collection of microbes (composed of bacteria, bacteriophage, fungi, protozoa and viruses) that live inside the stomach and intestines of the human body (Yang, 2012). When β-lactam antibiotics are administered intravenously, a significant portion of them can be excreted in the bile into the intestine, leading to disruption of the balance of the gut microbiome and loss of colonization resistance. This loss of colonization resistance allows C. difficile spores to germinate, grow and cause CDI (Gough et al, 2011). Current approved strategies for treating CDI are limited, and can be further damaging to an already fragile gut microbiome. Excretion of β-lactam antibiotics into the GI tract can also lead to the emergence of antimicrobial resistance (AMR) in the gut. There is a large and growing unmet medical need to protect the gut microbiome from the deleterious effects of residual and still viable IV β-lactam antibiotics excreted into the intestine, thus providing protection from a significant risk factor for development of CDI.
An ambitious biotech company in Rockville, MD, thinks they may have an answer. A group of researchers are applying cutting-edge microbiome science designed to effectively deliver therapeutic outcomes. The team at Synthetic Biologics is developing an intervention designed to protect the gut microbiome from the harmful effects of certain IV β-lactam antibiotics, while allowing the antibiotic to fight the primary infection unimpeded.
SYN-004 (ribaxamase) is an orally-administered, β-lactamase that is designed to be co-administered during, and for a short time after, administration of IV β-lactam antibiotics. Results from their Phase 2b proof-of-concept trial demonstrated a significant relative risk reduction for CDI by more than 71% in patients that received ribaxamase as compared with a placebo, while also significantly reducing new colonization of VRE, a microorganism resistant to the antibiotic vancomycin (Kokai-Kun et al, 2017). These results are consistent with ribaxamase’s mechanism of action in not only preventing CDI, but also potentially reducing the emergence of AMR in the gut microbiome.
We are pushing the boundaries of
In previously completed clinical trials, ribaxamase appeared to be safe and well tolerated and has the potential to fill the critical, unmet need to prevent CDI in patients being treated with IV β-lactam antibiotics, with the added benefit of potentially reducing the emergence of AMR microorganisms in the gut (Connelly et al, 2017). According to Dr. Ray Stapleton, Senior VP Manufacturing, “saving and improving lives of patients is why biotechnology companies exist. We are pushing the boundaries of current knowledge with our programs in an attempt to open new avenues of treatment.”
Two core elements to stop the cycle of antibiotic resistance are to avoid infections in the first place and change the way antibiotics are used. An infection prevented is one that doesn’t need treatment. Protection of the gut microbiome from antibiotic exposure through inactivation of the antibiotic in the upper GI tract before it can damage the gut microbiome is intended to prevent opportunistic infections, such as C. difficile, from occurring, and may also reduce the emergence of antibiotic resistance (Kokai-Kun et al, 2017).
Science is always changing and expanding into new frontiers, especially in human health. The CEO of Synthetic Biologics, Jeff Riley, considers it a privilege and a never-ending adventure to leverage the minds of brilliant scientists to develop new therapeutic solutions. He says, “Helping to improve the human condition is a calling and not simply a job.”
SYN-004 was granted a Breakthrough Therapy Designation by the FDA and is currently preparing for Phase 3 of development.
- C. difficile infection. (2016, June 18). Retrieved August 30, 2017, from http://www.mayoclinic.org/diseases-conditions/c-difficile/symptoms-causes/dxc-20202389
- Connelly, S., Bristol, J. A., Hubert, S., Subramanian, P., Hasan, N. A., Colwell, R. R., & Kaleko, M. (2017). SYN‐004 (ribaxamase), an oral beta‐lactamase, mitigates antibiotic‐mediated dysbiosis in a porcine gut microbiome model. Journal of Applied Microbiology.
- Gough, E., Shaikh, H., & Manges, A. R. (2011). Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clinical infectious diseases, 53(10), 994-1002.
- Gut Microbiota Info. (n.d.). Retrieved August 30, 2017, from http://www.gutmicrobiotaforhealth.com/en/about-gut-microbiota-info/
- Healthcare-associated Infections. (2016, March 01). Retrieved August 30, 2017, from https://www.cdc.gov/hai/organisms/cdiff/cdiff_infect.html
- Kokai-Kun, J. F., Roberts, T., Coughlin, O., Sicard, E., Rufiange, M., Fedorak, R., & Sliman, J. (2017). The oral β-lactamase SYN-004 (ribaxamase) degrades ceftriaxone excreted into the intestine in phase 2a clinical studies. Antimicrobial agents and chemotherapy, 61(3), e02197-16.
- Lessa, Fernando, Yi Mu, Wendy Bamberg, et al. Burden of Clostridium difficile Infection in the United States — NEJM. (2015, February 26). Retrieved August 30, 2017, from http://www.nejm.org/doi/full/10.1056/NEJMoa1408913#t=abstract
- SYN-004 (ribaxamase): Synthetic Biologics, Inc. (SYN). (n.d.). Retrieved August 30, 2017, from http://www.syntheticbiologics.com/product-pipeline/syn-004-ribaxamase
- Yang, Joy. The Human Microbiome Project: Extending the definition of what constitutes a human. (2012, July 16). Retrieved August 30, 2017, from https://www.genome.gov/27549400/the-human-microbiome-project-extending-the-definition-of-what-constitutes-a-human/