Microbiome Treatments for Recurrent C. Difficile Infections
Roughly 29,000 Americans die of Clostridium difficile infections every year. This gram-positive bacterium produces severe intestinal disease, with fatality rates ranging from 6% to 30%. Because the spores are hard to kill and can remain viable for years, infections are easily passed to patients, especially in medical facilities. 1 While metronidazole and vancomycin are the treatments of choice, about 30% of patients will suffer at least one relapse.3
One low-tech alternative involves the transfer of stool from a healthy donor to the bowel of an ill recipient, known as a fecal microbiota transplant (FMT). This centuries-old treatment, recently rediscovered, is surprisingly effective for recurrent C. difficile infections, with a 90% cure rate. 6
“Our FMT patients have a life-threatening condition for which nothing else has worked,” said Michael Silverman, MD and chief of infectious diseases at Western University in London, Ontario, Canada. “These transplants help revert them to a healthy microbiome over a short time. The alternative is a lifetime of taking vancomycin.”
The microbiome, the population of microbes in and on our bodies, is a virtual organ that not only affects gut and skin health, but mood and mental health as well. In addition to C. difficile, the microbiome is being used to test treatments for cancer, inflammatory bowel disease (IBD), immunotherapy, cardiac and respiratory diseases, and even obesity. As many as 70 start-ups and research institutes are developing mixtures of cultured microbes to use as microbiome drugs. Instead of a stool sample, live cells or spores are packed into capsules and taken internally or applied topically to treat skin conditions such as acne and eczema.
Seres Therapeutics is testing an oral capsule for recurrent C. difficile infections. While initially promising, SER-109, which has breakthrough status and an orphan drug designation from the US Food and Drug Administration (FDA), failed phase 2 trials last year. Seres reviewed its data and incorporated learnings and feedback; SER-109 has now entered a phase 3 clinical trial. 4
Other companies with biotherapeutics in the pipeline include Azitra, with preclinical dermatological treatments; Finch Therapeutics, which is partnering with Takeda on a microbial mixture to treat IBD; and Vedanta Biosciences, which has a licensing deal with Johnson & Johnson to develop candidates to treat allergies, infections, and cancer.
Unlike new technologies being used to develop biologics such as antisense RNA and gene therapy, there aren’t huge technical hurdles to manufacture microbiome medications other than standardizing culturing techniques to ensure cell or spore viability. There is a concern among some industry experts, however, that regulatory agencies might not have the expertise to judge these treatments. 2
“The incidence of C. diff. and the percentage of people who have multiple relapses has been going up,” said Silverman, who was one of the first to use FMT to treat C. difficile in North America. In 2003, prior to regulation by Health Canada, he developed a self-administered enema procedure for patients. His clinic now treats two or three patients each month with FMT for recurrent C. difficile.
Stool samples are delivered to patients in one of three ways: enema; colonoscopy, which gets the microbes into the upper large colon; or via a nasogastric tube that delivers fecal matter to the small intestine. It is unknown which route is the most effective. Enemas are easier, although multiple FMTs are usually necessary if this approach is taken.
“A low-volume enema is the most practical procedure,” Silverman said. “It can be done by the patient and is the least expensive alternative.”
While the FDA considers fecal microbiota an investigational new drug, the agency issued an exception that allows physicians to perform FMT for recurrent C. difficile infections.5 In Canada, FMT is regulated as a new biologic drug, but can be used for infections that are refractory to standard treatments. In both countries stool samples must be screened for pathogens.
For a separate study investigating the effects of FMT on metabolic syndrome, Silverman had to screen 42 donors to find one that was suitable. Each required a physician consult, stool samples, and tests to ensure donors weren’t carrying multidrug-resistant microbes or other pathogens. It’s a huge amount of work.
“It would be better for everybody if we had a commercial product for C. diff. and we didn’t have to do fecal transplants,” said Silverman, who noted that his clinic will be part of the next Seres trial. “Beside the ‘ick’ factor, if we had a capsule free of pathogens, it would be easier and less expensive than having to do all this screening.”
- 1Buffie, C. G., et al. “Profound Alterations of Intestinal Microbiota following a Single Dose of Clindamycin Results in Sustained Susceptibility to Clostridium Difficile–Induced Colitis.” Infection and Immunity 80, no. 1 (January 2012): 62–73.
- 3Smith, Heidi, and Dan Smyth, MD. “C Diff Shows No Mercy!” Primary Care Reviews and Perspectives, June 2016. https://www.hippoed.com/pc/rap/episode/cdiffshowsno/clostridium
- 6Rohlke, Faith, and Neil Stollman. “Fecal Microbiota Transplantation in Relapsing Clostridium Difficile Infection.” Therapeutic Advances in Gastroenterology 5, no. 6 (November 2012): 403–420. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491681
- 4Seres Therapeutics. “Seres Therapeutics Initiates Phse 3 Study of SER-109.” Drug Discovery & Development, 14 June 2017. https://www.dddmag.com/news/2017/06/seres-therapeutics-initiates-phase-3-study-ser-109
- 2Fidler, Ben. “FDA Turmoil, Biology Mystery on List of Hurdles for Microbiome Drugs.” Xconomy.com, 14 February 2017. http://www.xconomy.com/newyork/2017/02/14/fda-turmoil-biology-mystery-on-listof-hurdles-for-microbiome-drugs
- 5US Food and Drug Administration. “Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium Difficile Infection Not Responsive to Standard Therapies.” March 2014. https://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/vaccines/ucm387023.htm