IMT for C. difficile Infection

There is actually no such thing — the term, also commonly referred to as ‘stool transplant’ is an unfortunate shorthand for ‘Fecal Microbiota Transplant’.  The less than desirable fecal transplant imagery prompted the Microbiota Therapeutics Program to update the terminology to Intestinal Microbiota Transplantation (IMT). The word ‘microbiota’ refers to all the microbes that live in the intestine and are part of your digestive system. It is these microbes that get transferred from a healthy individual into a patient who lost their normal microbes, typically because of antibiotic treatments.

The microbiota is an important part of your digestive system and normally helps to digest dietary fiber. In addition, healthy microbiota is integral to maintain proper body metabolism,  immune function, and nervous system activity. Microbiota gets damaged whenever antibiotics are used. The intestine then becomes vulnerable to infection by pathogens like Clostridium difficile (“C. diff ”), a bacterium that makes toxins, which injure the intestine and lead to colitis and diarrhea. While several antibiotics can kill C. diff, they also further the damage to the normal bacteria. This can lead to cycles of infections and re-infections in some patients leading to a condition called recurrent C. difficile infection. Intestinal microbiota transplant repairs the healthy composition of gut microbes and restores the body’s defenses against C. diff.

The University of Minnesota Microbiota Therapeutics Program manufactures microbiota products at its FDA-approved facility in accordance with Good Manufacturing Practices. All donors have to qualify as blood donors first, but also be in perfect overall health, i.e., require no medications for any indication (obviously, including antibiotics), have a lean body, and even have no allergies. Over 95% of individuals who apply to be a donor in our program do not qualify. The health of the donors is ensured with rigorous history and physical examinations and laboratory tests for blood-borne and intestinal infectious diseases, metabolic health, and markers of autoimmunity. The donor individuals participating in this program are volunteers. The stool donations are done in a supervised bathroom at the University. The raw material is transferred into the laboratory facility, where the microbiota is separated away and prepared either as a frozen liquid suspension for colonoscopic administration or as freeze-dried microbiota in capsules that can be taken orally. Importantly, some of the donor tests have to be repeated several weeks after the preparation before material release to ensure safety per the FDA-approved protocol.

There are two possible routes of administration in our program. The liquid suspension of microbes is administered via a colonoscopy. Alternatively, the microbiota can be taken as an oral preparation of capsules. The dose of microbes is the same. The oral preparation is generally contained in 3-5 capsules and is taken once on an empty stomach. Importantly, the treatment is always given after a course of antibiotics. IMT is not currently a treatment by itself without antibiotics first. The patient needs to take antibiotics for at least 10 days to kill the C. difficile bacteria in the colon. After that there is a short period to clear the antibiotics from the body; this period is somewhat different for colonoscopic versus oral capsule IMT. Clearance of residual antibiotics is an important step to prevent killing of the new microbes.

The success rate in breaking the cycle of recurrence of C. diff infection in the published literature is ~ 70-90%. A number of randomized, placebo-controlled trials comparing vancomycin or fidaxomicin alone versus IMT showed superiority of IMT. In our own program we performed over 800 IMTs. In the absence of underlying inflammatory bowel disease the success rate with colonoscopic IMT is ~ 92% (that means that 1 out of 10 fail with one treatment) and oral capsule IMT is ~ 80% (2 out of 10 fail). If one treatment fails, we can repeat the treatment. Ultimately, the procedure is up to 98% effective.

There is no clinical laboratory test that can prove that C. difficile is gone. The clinical laboratory tests for presence of C. difficile toxin gene in stool. Production of toxin requires presence of active C. difficile bacteria. It is still possible to have C. difficile spores, which can be undetected by the clinical test. Therefore, testing stool in absence of symptoms is not recommended. Most failures occur ~ 2-3 weeks after stopping antibiotics for C. difficile (the earliest is 1 week). If your diarrheal symptoms return, we need to re-test for the infection. If no relapse has occurred within 2 months following IMT, late relapse is very unlikely going forward. Exceptions are relapses with future antibiotic exposures or underlying inflammatory bowel diseases (see below). It is also important to appreciate that there are many potential infectious and non-infectious causes of diarrhea. Please contact our clinic if you develop new diarrheal symptoms or have any other questions.

Serious adverse events with IMT are extremely rare and few of these have even been clearly linked to IMT. We are quite comfortable that no known pathogens are being transmitted with this treatment given our rigorous protocol of donor screening and testing. However, it is important to appreciate that there are unknowns, just as in any donor-derived biological material. There could be potential pathogens we have not yet recognized, for example. It is somewhat reassuring that the donors are all completely healthy and in a way their microbiome has already been tested in them. However, that is not a guarantee of safety because their microbes may behave differently in a new recipient. It is also important to recognize that the gut microbiota is an organ itself within the human body. This is why we take extreme measures to recruit only the healthiest people as donors. However, once again, we can’t know at this time how this “healthy” microbiota may function in a new host.

It is also very important to understand that full recovery from C. difficile infection may take some time. Many patients develop a post-infectious irritable bowel syndrome, which is characterized by abdominal cramps, increased bowel movement frequency, fecal urgency (a need to rush to the bathroom), and abdominal bloating and gas. Some of these symptoms are very similar to C. difficile infection. Therefore, it is critical that we don’t just assume that diarrheal symptoms mean that C. diff is back, but test and make the proper diagnosis with all the information put together.

In our experience and in the published literature the chance of C. diff relapse following IMT is high – approximately 25% (1 in 4). We would like to be notified whenever an antibiotic is prescribed for IMT recipients. We have specific recommendations on a number of common indications and considerations for additional measures for when antibiotics are being used.

There are many nuances in management of C. diff in patients with inflammatory bowel disease (Crohn’s and Ulcerative Colitis). First, the diagnosis can be difficult. Some IBD patients may be merely colonized with C. diff. In other words, their symptoms are caused by IBD itself and not C. diff. The issue of colonization versus true infection is important in all patients, but the distinction is much easier in patients without IBD. C. diff often causes flares of IBD, and even when C. diff disappears, IBD flare can continue and progress. Intestinal microbiota transplant in patients with IBD is associated with (1) lower success rates of clearing C. diff (~75-80% compared to 90-98% in patients without IBD), (2) possibility of IBD flare or progression even if C. diff is cleared, (3) much greater chance of late (> 2 months) relapse of C. diff. Overall, we believe there is still a role for the treatment in IBD care, but this is clearly a complex situation and we are increasingly focusing more research efforts in this area. We suspect that the protocols for how the treatment is administered will need to be modified as more research is done.

The capsule option is newer, introduced in 2015. So far we learned that normalization of the gut microbiome is somewhat delayed with the capsule treatment relative to colonoscopic. Nevertheless, the capsule preparation still has a fairly good success rate of ~ 80%, and it is certainly simpler. Patients with swallowing problems obviously are not eligible for the capsule IMT. Colonoscopic route is also the only option in most patients with underlying inflammatory bowel disease. If there is uncertainty about the causes of diarrhea, we will likely recommend the colonoscopic route. In addition, we typically prefer the colonoscopic route whenever there is a standing indication for a screening, surveillance, or diagnostic colonoscopy. This is because the colon purgative can disrupt the new microbes and increase the risk of C. diff relapse – so, it makes little sense to do capsule IMT and then do a colonoscopy a month later.

At this time, there are no formally FDA-approved commercial MIT products. The FDA allows the use of IMT for treatment of C. difficile infections that cannot be cured with antibiotics alone (currently the standard therapy). IMT is also endorsed as a last resort rescue treatment of C. difficile infections by all major professional societies in Gastroenterology and Infectious Disease Medicine. Our IMT products are manufactured in accordance with an FDA approved protocol in an FDA-approved facility in accordance with Good Manufacturing Practices (GMP). Technically, all IMT products are currently considered to be investigational.

Importantly, there is an ongoing debate as to whether IMT should be treated as a drug or tissue transplant. The FDA has decided to regulate it as a drug. However, most investigators and regulators in some other countries (e.g., France, Italy) consider IMT to be a tissue transplant. We feel that the drug paradigm has serious limitations and may not be optimal for innovation or access to treatment. We anticipate the debate will continue for some time. We feel that the one perspective that is missing the most is that of patients! We welcome your involvement.

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