“The road to health is paved with good intestines."
- Sherry A. Rogers, M.D., allergist and immunolgist
“This is a new frontier in medicine. We are just at the beginning of learning how microbes affect health and disease, and approval of this therapy will help us study microbiome-based therapies beyond C. difficile.”
- Sahil Khanna, M.B.B.S., M.S., gastroenterologist, Mayo Clinic
Clostridioides difficile—commonly referred to as “C. diff”—kills between 15,000 and 30,000 Americans a year. On November 30, 2022, the U.S. Food and Drug Administration (FDA) approved the drug Rebyota –the first fecal microbiota product—for the prevention of recurrent bowel infection caused by C. diff. Commenting on the FDA’s approval of Rebyota, Peter Marks, M.D., Ph.D., the director of the FDA’s Center for Biologics Evaluation and Research, said “[T]oday’s action represents an important milestone.” In this Germ Gem’s post, I explain why the FDA’s approval of the first fecal microbiota product is a landmark decision.
What is C. diff? In 1935, Ivan C. Hall and Elizabeth O’Toole first isolated the Gram-positive bacterium Clostridium difficile from the stool of a healthy infant. In 2016, taxonomists changed its genus name to Clostridioides. While the species name, difficile, was chosen to reflect the difficulty with culturing and isolating this bacterium, it could just as well capture the striking “differences” of this bacterium from all others that cause diarrheal disease.
What makes C. diff different? C. diff has a higher morbidity and mortality rate than other types of bacteria that cause gastroenteritis. The infection it precipitates, pseudomembranous colitis, makes people very sick (morbidity) and is the most lethal (mortality) of all. In severe cases of pseudomembranous colitis, called “toxic megacolon,” colectomy (surgical removal of the colon) is required as a life-saving measure.
In addition, no other bacterium poses as big a threat to hospitalized patients as C. diff. In the U.S., it is the most common cause of hospital-acquired infection. In the hospital setting, C. diff is estimated to result in almost 500,000 cases per year, with close to 30,000 associated deaths. (Although it was initially recognized exclusively as a cause of hospital-acquired infection, in recent years the proportion of cases of community-acquired C. diff is mounting.)
Also, its pathogenesis differs markedly from that of other bacteria. A critical feature of C. diff’s pathogenesis is that it produces toxins that damage the colon. (Up to 5% of healthy people are colonized with non-toxin producing C. diff that causes no trouble at all.) But perhaps the most distinguishing feature of C. diff’s pathogenesis is that it is an iatrogenic infection, that is, it is caused by healthcare providers (doctors and other professionals) who prescribe antibiotics to treat other bacterial infections (and sometimes, mistakenly viral infections).
The crux of this aspect of its pathogenesis is that antibiotics indiscriminately kill friendly bacteria colonizing the gut called commensals or mutualists that provide protection against pathogens, like C. diff. Once those protective bacteria are removed by antibiotics, the ground is prepared for the establishment of C. diff.
How is C. diff transmitted? The main vehicles for the transmission of C. diff from person to person are the contaminated hands of healthcare providers. But, a recent study reported in MedPage Today, “That’s Not Just Gum on the Soles of Your Shoes,” also suggests that the soles of shoes are frequently contaminated with C. diff that could also play a role in its transmission.
Treatment of C. diff. Another unique feature of C. diff is that it’s the only bacterial infection, or for that matter, the only human ailment, for which the FDA has approved fecal microbiota transplantation (FMT)—transplanting the feces from a healthy donor into a C. diff patient.
At first blush, the thought of using bacteria from the feces of healthy donors to treat C. diff colitis, seems incredible, that is, until you understand C. diff’s pathogenesis. In fact, the use of friendly bacteria to rid the bowel of pathogens might be considered a legitimate form of germ warfare.
Three years ago in my Germ Gems post “The Latest Poop on Fecal Microbiota Transplantation,” I discussed the ancient and modern day roots of FMT. The pressing need for effective treatments of C. diff hasn’t changed since that December 3, 2019 Germ Gems post. Nonetheless, over the past several years the nature of the transplanted material has become increasingly refined, as is witnessed by the FDA approval of Rebyota.
Developed by the Swiss company Ferring Pharmaceuticals, Rebyota is derived from donated human stool that is screened for all known pathogens. It is administered as a single-dose treatment through the rectum, and it is FDA approved only for treatment of recurrent C. diff colitis. (First episodes of C. diff are still treated with an antibiotic, although fidaxomicin is now recommended rather than vancomycin.) At greatest risk of recurrent infections are older adults and those with a compromised immune system.
The good news is that while Rebyota is the first microbiota-based treatment of C. diff, it won’t be the last. Developed and funded by the American company Seres Therapeutics, the microbiome-based agent SER-109 is already waiting in the wings. It’s an oral microbiome therapeutic composed of purified spores from bacteria in the phylum Firmicutes. In January 2022, the New England Journal of Medicine reported that SER-109 outperformed a placebo in patients with recurrent C. diff.
According to an October 2022 report in Journal American Medical Association, “Extended Follow-up of Microbiome Therapeutic SER-109 Through 24 Weeks for Recurrent Clostridioides difficile Infection in a Randomized Clinical Trial,” the promising results of SER-109 are holding up. Based on its route of administration (an oral capsule versus rectal infusion for Rebyota), if SER-109 gains FDA approval, all other things being equal, it seems likely to win out.
What you need to know? If you are one of the unlucky recipients of an antibiotic, in or out of the hospital, who develops diarrhea, you should contact your healthcare provider. If C. diff is detected in a stool sample, they are likely to confer with a gastroenterologist regarding the treatment plan.
Future prospects for repairing the human gut microbiome. The excitement following FDA approval for Rebyota goes beyond treatment of recurrent C. diff. The scientific and technological underpinnings of this approach to treatment of a gut infection are proof of principle for other diseases in which an altered gut microbiome is implicated, e.g., inflammatory bowel disease, irritable bowel syndrome, allergies, asthma, diabetes, autism, and obesity. These conditions should all be seriously considered as candidates for development of gut microbiome-related treatments aligned with the their respective altered microbiomes.