Expert Perspectives on Advances in the Management of C. Difficile - Episode 15
Peter L. Salgo, MD: I think it’s been the mantra for years that if you strip the microbiome, you’re going to get C diff [Clostridioides difficile] or you make it highly likely. You see in TV, if you just eat enough yogurt, because yogurt’s great, you will never get C diff but that’s not where we’re going here. I remember the first time I heard about fecal transplants. My response was, “Yeah, right, this can’t possibly work,” until I saw it work once; a heart transplant patient who was dying not of rejection, not of heart failure, but of diarrhea. This person got and had C diff. This person got a fecal transplant and within 24 hours it was gone.
Teena Chopra, MD, MPH: You are so right.
Peter L. Salgo, MD: It’s ridiculous.
Teena Chopra, MD, MPH: I think of a similar experience. When I did my first fecal transplant a few years ago, I went back to check on my patient the next day after the transplant because I was really nervous. She was a young grandmother who had stopped working and she had had her eighth or ninth episode of C diff, and I still remember her. I went back to check how she was doing the next day and she wasn’t there. The first thing I asked was, “My patient, did she die?” But no, she was discharged.
Peter L. Salgo, MD: We always go there. Let’s go have a look, the bed is empty and it’s like, “Oh my gosh!”
Paul Feuerstadt, MD, FACG, AGAF: Uh-oh.
Peter L. Salgo, MD: Not so much here though. It worked.
Teena Chopra, MD, MPH: No, yeah.
Peter L. Salgo, MD: By the way, everybody’s had the same experience. This is ridiculously interesting. What does fecal microbiota transplantation really entail? You want to start us off on that, Teena Chopra, MD, MPH?
Teena Chopra, MD, MPH: Sure. It is basically replacing your gut microbiome with a healthy microbiome which is more diverse, and it can help with colonization resistance and prevent the increased multiplication of C diff. It keeps the C diff suppressed. That’s what it is. We have traditionally done fecal transplant in different ways, and now there are companies that are manufacturing and screening commercially available healthy stool that can easily be transplanted. We just completed publishing our data on fecal transplant we did for the last 2 years in about 55 patients, and we saw the first transplant was successful in 85% of our patients. For the second transplant, the results were as high as 92%; 17% of my patients were immunocompromised. It was very interesting and like you said, very gratifying to see the success rates in these patients with recurrent C diff.
Peter L. Salgo, MD: Explain to me the mechanism here. It’s one thing to say we’re going to replace the microbiome; we’re going to get all these good bugs that’s going to make the C diff go away. Now I come back with the nasty question, how? How does it work?
Teena Chopra, MD, MPH: For the process of transplant, most of the times we do it through the rectal route. These patients, like you said, are very sick, are having recurrent episodes, and their life has become really debilitating. I have done fecal transplants using a rectal enema using a piston syringe and transplanting about 250 mL [milliliters] of healthy donor stool that is commercially available through various companies. They provide you with prescreened stool which has been screened for different types of parasites and various blood infections. Then you put the patient in a left ..... position and you transplant healthy stool.
Peter L. Salgo, MD: You’re giving me a mechanical answer.
Teena Chopra, MD, MPH: Yes.
Peter L. Salgo, MD: I want a philosophical answer. I’m going to try Paul Feuerstadt, MD, FACG, AGAF out of the blue. I know that Teena has told us how to give it. When you do it, why does it work?
Paul Feuerstadt, MD, FACG, AGAF: Going back to the original trial that looked into this by Cheng in 2008, probably gives us the best insight. It was a simple study. They looked at 10 individuals, 3 of them had no C diff, they were over 65, they did not have an oncologic diagnosis: those are your controls. Four of them had initial infection, 3 of them had recurrent C diff. They very simply compared the diversity of the microbiota and the constituency, how variable it was and what was there. When they compared no infection with initial infection, there were no statistically significant differences. The microbiota or colonization resistance was bent but it wasn’t broke. When they compared initial infection with recurrent infection, that’s where the microbiota was broke. Specifically, the diversity went down and there was a significant depletion of the Bacteroidetes and the Firmicutes.
To directly answer your question, we believe, and it’s been shown in multiple trials now, that replenishing the Bacteroidetes and the Firmicutes is most essential to preventing future recurrence. There’s another element here though which is when they compared no infection with initial infection; the microbiota was bent but not broke. What do I mean and what is the clinical application of that?
The clinical application of that is that when we treat C difficile originally, we don’t necessarily need to restore the microbiota or have the patient restore their own microbiota without a transplant; we just need to target the bacteria. This is where the updated 2020 Provisional IDSA/SHEA [Infectious Diseases Society of America/Society for Healthcare Epidemiology of America] guidelines play a significant role. If you use fidaxomicin, which is a targeted therapy, it has minimal effect on that surrounding colonization resistance, therefore preserving what’s there. Patients are much less likely to recur and much more likely to be successful. That’s how I believe this all kind of fits together.
Teena Chopra, MD, MPH: To add to that, in order to be more specific to your question, if you look at the diversity index of a transplanted patient who has had a fecal transplant, you will see that the diversity goes up. It’s the diversity of the healthy bacteria, the Bacteroidetes and Firmicutes, that are going to help with the colonization resistance.
Peter L. Salgo, MD: Is it like Pacman? Is Bacteroidetes in there chewing away these spores? What is Bacteroidetes actually doing? I’m just curious. Does anybody know?
Paul Feuerstadt, MD, FACG, AGAF: To answer your question a little further, I think Teena Chopra, MD, MPH did a really nice job and talked about probably the most important point, which is the least understood point, and that’s something called the metabolome. She mentioned that with regards to this. What we’re looking at here are individual factors: diversity, various living organisms, bacteria, archaea, fungi, viruses, protozoa. Honestly, we care about that but what we really care about is what does that group of things produce and how does it interact with our body?
It’s like anything else in medicine. I like to say the more you ask the worse it gets. You asked, so let’s go a little bit deeper. One of the factors that we’ve studied quite extensively are the bile salts. There are 2 sets of bile salts that can play an important role in activating C difficile to convert from the spore phase to the vegetative phase and also inhibiting the vegetative stage. Bile salts emanate from cholesterol, where they form primary bile salts, cholate and chenodeoxycholate, and those get degraded or converted to secondary bile salts. It turns out, the thing that converts them is 7-dehydroxylase from something called C scindens [Clostridium scindens].
Importantly though, in patients that have active C difficile, cholate is increased and the secondary bile salts are depleted. You set up a milieu that favors conversion from the spore phase to the vegetative phase, and the bile salts that normally inhibit the vegetative phase are weakened; you’re creating an entire environment that is supportive of C difficile proliferating. It’s a complicated answer to a relatively simple question. Going back to the metabolome, C scindens is part of our microbiota. When that’s been removed, you don’t convert to the secondary bile salts, therefore you don’t inhibit the vegetative phase and it proliferates.
Peter L. Salgo, MD: Which of the specific patients would benefit best from an FMT, a fecal microbiota transplant, Teena Chopra, MD, MPH?
Teena Chopra, MD, MPH: These are the same patients that we’ve talked about: older patients over 65 years of age who have had recurrent disease or patients who we know that they are going to continue to get recurrent disease and they have this stage of dysbiosis that they cannot recover from. They have had so many episodes and they have this continued insult to their microbiome, either in the form of antibiotics or in the form of immunosuppressive drugs or steroids. These are the patients that I have done transplants on and I’ve seen that they have responded to fecal microbiome. Sometimes it takes the first transplant in 85% of the patients, and sometimes it takes 2 transplants for them to respond.
Peter L. Salgo, MD: Are there specific guidelines, let’s say from the 2018 IDSA and the SHEA guidelines, as to when a patient is eligible for an FMT?
Teena Chopra, MD, MPH: Yes. Based on the guidelines, during their second recurrence, most of the physicians will offer them the option of doing a fecal transplant.
Peter L. Salgo, MD: If you enjoyed this content, you should subscribe. We have an e-newsletter, and you can receive upcoming Peer Exchanges and other great content in your inbox—that’s right, electronically. I’ll see you next time. I’m Dr. Peter Salgo. Thanks again for watching.
Transcript Edited for Clarity