Role of the Microbiome in Preventing Recurrent C difficile Infection

The most often overlooked part of treating Clostridioides difficile infection (CDI) is the restoration of a healthy gut microbiome. Colleen R. Kelly, MD, FACG,a gastroenterologist in Providence, Rhode Island, andan associate professor of medicineat Brown University, delivered a plenary talk at the Making a Difference in Infectious Disease (MAD-ID) 2022 annual meeting, held May 18-21, 2022, in Orlando, Florida, and touched on alternatives to antibiotic treatment for CDI, the role of the microbiome in keeping infection at bay, and the safety concerns that have come up in relation to fecal microbiota transplantation.

Kelly discussed her presentation with Contagion® in a video interview.

Transcript has been edited for length and clarity.

Contagion®: To start off, can you talk a bit about the role of the microbiome in general?

Kelly: Gastrointestinal microbiome is a very diverse and abundant species…We always think about bacteria, but also there’re a lot of other things, viruses and even fungi. This microbiome and all of these species are really integral to our health. The presence of a good, diverse healthy microbiome is really important to a baseline protection from pathogens, energy, and metabolism, vitamin production…so just really, really part of us.

Contagion®: What are the contributing factors to recurrence of CDI?

Kelly: Recurrent disease is a big problem, and it's really a great example of what can happen in the setting of dysbiosis and when your microbiome goes wrong. Antibiotics, which were used to treat C diff, they do a great job of killing C diff, but they really do nothing to restore that gut microbiome that's been damaged by antibiotics [so] that sort of sets people up to get C diff to begin with. You end up with a perpetual cycle where people get the vancomycin or fidaxomicin, it does a great job of controlling the C diff infection, but when that antibiotic is stopped, you still have that disrupted microbiome in place...that's going to allow C diff to again start to grow and produce toxin and make people sick again. So really restoration of a healthy microbiome is integral to stopping that cycle of recurrence.

Contagion®: I want to touch on some of the interventions that exist other than antibiotics for C diff. Let’s start with probiotics.

Kelly: This is my favorite…We just recently published the American College of Gastroenterology clinical guidelines and took a real deep dive into probiotics and whether they should have any role in C diff infection, because all these patients that come to see me with recurrent disease, they come in, they're on tons of probiotics, most of these aren't covered by insurance, so people are spending quite a bit of money. We want to really be able to give them, ‘what's the best evidence for probiotics in a setting?’ And what we came away with is that the evidence is very, very minimal and really not of a high enough quality or level of evidence that we should be recommending it as a treatment for our patients.

There're 2 situations—there's primary prevention where someone hasn't had C diff yet, but they are going to be getting antibiotics, you worry that they're at risk, and should you throw a probiotic in the mix in primary prevention studies? And there was a big Cochrane meta-analysis that sort of maybe showed that probiotics were a little helpful when you broke it all down. That was really driven by just a couple of studies that weren't of the greatest methodological quality and had some kind of funny things like very high baseline rates of C diff that we don't even really see in most populations. And so we decided that it wasn't really recommended for primary prevention.

Then you have the issue of secondary prevention [with] someone's already had C diff, they really don't want to have another recurrence. They're asking you, ‘if I if I take a probiotic now, will this keep the C diff from coming back?’ And the evidence for that is even less robust. There was a small, randomized, controlled trial [where it] did not seem to prevent recurrence in that population either. So, as a result, in the guidelines, we just pretty much said there's no evidence to use it in either setting.

Contagion®: What about fecal microbiota transplantation? Is this a viable treatment and where do we stand with it? There have been some safety alerts.

Kelly: Fecal microbiota transplant (FMT) has been around for a long time, but it really picked up around the turn of the century where we started seeing more of these recurrent infections and people who were just going on course after course of vancomycin, and not able to clear their C diff and it really gets at the root of the problem. You're restoring that disrupted gut microbiome, and it's highly effective. I don't believe that there's any intervention that I've ever been able to give a patient that's as effective as an FMT. I'm able to tell patients, with 1 FMT delivered vic colonoscopy, you’ve got about a 90 to 95% chance of breaking that cycle and you're not going to experience another recurrence.

There're other methods of administering it, certainly going through colonoscopy has its own procedural risks and costs so people have looked at administration rectally, have the FMT donor material in capsule form, and those also appear to be effective. The big issue is, where are we getting this donor stool from? For a good chunk of time, there were some stool banks that had stepped in and were providing donor stool at a very low cost to patients across the United States…Around COVID, a lot of that shutdown. There were some concerns just leading up to that about infection transmission.

In 2019, there was a safety report that came out of the FDA about patients who had contracted a multidrug-resistant organism (MDRO) after FMT and that, indeed, it had come from the donor. Interestingly, both those patients were enrolled in clinical trials looking at FMT for non-CDI or non CDF indications, but 1 of these patients actually died. As a result, they made recommendations that donor screening should be changed, that you should be screening for MDROs, you shouldn't use health care workers as donors because they might have a higher risk of carrying an MDR. There was also enteropathogenic E coli suspected transmission, and this was all pre-COVID. But then when COVID hit, we knew that people were shedding virus in the stool, and there was concern, obviously, could this be a method of transmission? All of the stool banks that were in operation and most of the FMT being done, along with a lot of other things, really were shut down and didn't happen for a while.

Unfortunately, we're in a bit of a period where we don't have immediate access to donor stool through banks for most patients. Hopefully, within the next year or so there's going to be some commercial sources of donor stool that are becoming available and will be FDA-approved for that purpose. But in the meantime, I'm again seeing patients who are traveling long distances to come see me for an FMT. Physicians are really struggling about where to source that donor stool from. The stool banks are still technically operational, they're just not sending out large amounts of doses like they were pre-COVID.

Contagion®: Any others you want to mention?

Kelly: Bezlotoxumab is an antitoxin antibody. The idea is some patients don't have as much of an immune response and this might contribute to the cycle of recurrence. So bezlotoxumab actually grows and latches onto toxin B and doesn't allow it to enter the cell. It's given as a 1-time infusion while the patient is still taking vancomycin or fidaxomicin and it lasts for about 30 days. The idea is, as the patient stops their antibiotic, you're maybe buying them some time for their microbiome to sort of naturally bounce back and kind of blocking the effects of C diff. It's a great idea.

Unfortunately, in reality, it's much less effective than an FMT. The number needed to treat to prevent 1 recurrence of C diff is about 10. And it's a pretty expensive medication and not always available to patients. We did put it in the guidelines as an option, but based on the studies of this drug, we thought that it should be limited to patients who are at the highest risk for recurrence so people who are older or immunocompromised or who had severe C diff infections, and not just used universally for everybody.