Fecal Transplantation in Clostridium Difficile

Peter L. Salgo, MD: I want to talk about surgery. When is that indicated? Then, we’ll go on to fecal transplants.

Lawrence J. Brandt, MD: Well, it’s interesting that we go from the most expensive to the least expensive. Bezlotoxumab, the most expensive perhaps, fecal transplant, the least expensive because we all have the drug and we deposit it in the toilet every day.

I’d like to start with fecal transplant. I did my first fecal transplant in 1990, and now it’s sort of caught on as almost a wonder drug. And what’s interesting about it is the cure rates for patients with recurrent disease. That’s when we can use it. It is not an FDA-approved drug, but the FDA will allow you to use it for patients who are having their third recurrence of disease or a recurrence that is particularly severe and wound up necessitating a hospitalization or in a patient who is very severely, almost deathly ill, in their index episode. We’ve treated several patients in the latter group.

Let me explain how it works, first. One of the things that we’ve been talking about in recurrent disease is the reason the disease is probably recurrent is because that patient with recurrent disease doesn’t have the normally rich, diverse communities of bacteria that normal patients have (patients without recurrent Clostridium difficile). And with fecal transplant, you can immediately restore the normality of the community and, therefore, re-give the patient that colonization resistance—their ability to prevent the Clostridium difficile colonies from establishing themselves again.

Having said that, it becomes even more complicated because there recently was a publication that showed that you don’t have to have the live bacteria there. You can sterile-filter the stool so that now it’s culture-negative. Now we don’t get all the bugs when we culture stool; we only get about 5% to 20% of the bugs. But, essentially, it’s a sterile mixture now. That still worked. So, that brings us back to the point that Erik made, which is maybe it’s not the bugs themselves. Maybe it’s the metabolic products of the bugs? Maybe it’s the way that they metabolize bile salts and raise the concentration of secondary bile salts that inhibit the growth of the Clostridium difficile?

But mechanism aside, when do we use it? We use it for recurrence or when patients are severely ill. What kind or results can we expect? If you infuse the stool into the cecum colonoscopically, you’ll get about a 91% to 93% cure rate. If you do it endoscopically and put a smaller volume, higher concentration into the duodenum, you’ll get about an 84% rate. If you only put it in by enema (a short distance), you’ll get about an 84% rate. You could give patients fecal capsules. These are made by a stool banking company, and they’re stool capsules. They’re frozen. They’re then shipped to you frozen. You defrost them and you give them to patients. The dose is 25 capsules taken over whatever period of time you need to take them—a half hour, to 2 hours, 3 hours, or 4 hours. And that will give you somewhere around perhaps a 75% cure rate. If you took them 2 days in a row (25 capsules), you can bump that up to about 79% or perhaps 80%.

Yoav Golan, MD, MS: We may see some differences between infectious disease on the panel and as gastroenterologists. Stool transplants work very, very well in a very select group of patients. There’s no question about that. But one of the problems with stool transplants is it’s not scalable and it’s potentially problematic. We think the world is in a biome. The biome can be associated with inflammatory bowel disease, or many things, and we never know what we really transferred to our patient. I also want to say that while it’s an attractive approach to identify those bacteria that matter and put them in capsules, the 2 companies that are most advanced with that and have just completed their phase II trials completely failed. So, while this may be a futuristic approach to preventing multiple recurrences, I think that we are not there. To complement or to complete the infectious disease physician’s approach, stool transplants may work very well when desperate. What we are trying to do is we’re trying to improve our practice so that we don’t get into a multiple recurrence state so that fewer patients will actually get to a state in which they have multiple recurrences.

Daniel E. Freedberg, MD, MS: So, my experience has been very similar to yours: that with well-selected patients with multiple recurrences, FMT (fecal microbiota transplantation) works tremendously well. But my experience for inpatients has been a little bit different. And when I’ve been called to be involved with a critically ill patient to do a FMT, I haven’t had as much success. Now, I don’t know if I’m being called too late in the game, and I wonder if you could tell me about your experience there? What has it been like?

Lawrence J. Brandt, MD: Now we’re sort of flirting with a patient. Do we call the surgeon to take out the colon, or part of the colon, or whatever surgical approach we want to use for this? Sometimes you don’t have to take out the colon; you can just do an ostomy, an ileostomy, and do a prograde lavage with vancomycin and save the colon. But in that terribly sick patient with severe disease, toxic megacolon, one can do fecal transplant. I’ve done about half a dozen, myself, in patients with toxic megacolon and they’ve all gotten better. Sometimes you can see the improvement within an hour. I have seen patients with terribly high fevers, a big belly, white counts in the 50-100,000 range, and leukemoid reaction. And 3 hours after the fecal transplant, their belly is already down, they’re less tender, they’re now more awake, and their white count is dropping. It’s only a couple of cases that have done that.

Erik Dubberke, MD: My own anecdotal experience with IVIG is very similar, where there was very rapid improvement with a single high dose. I go with the 500-mg/kg dose. If there’s someone I’m seeing that I think might need surgery, I try to do that first. And again, in my mind, every patient that I’ve been able to do that quickly enough to, I think I’ve been able to avoid a colectomy.

Daniel E. Freedberg, MD, MS: Actually, one very great overall point to make here is that in that kind of very sick patient that we’re talking about, this is really a multidisciplinary patient. Early on, you should get your infectious disease specialist, your gastroenterologist, or your colorectal surgeon involved—not when it’s too late. You should consider these options—IVIG, fecal transplant, loop ileostomy—that have pretty good success rates. If you consider them early, you’re going to have a better time persuading your surgeon to do that if that’s what’s needed.

Dale N. Gerding, MD: There was a paper by Giovanni Camarotta, MD, an Italian paper, in which they were administering fecal transplants by colonoscopy, and 2 patients had pseudomembrane seen at colonoscopy. They did the fecal transplants. Neither one of them did well, and, in fact, both of them died. They were put on vancomycin.

Daniel E. Freedberg, MD, MS: Thank you. You made me feel better about my own personal experience with Clostridium difficile in the ICU.

Dale N. Gerding, MD: After that, whenever they saw pseudomembrane at colonoscopy, they went back 3 days later and did another fecal transplant. They repeated it until the patient got better. Is that something you’re seeing? Have you seen pseudomembrane?

Lawrence J. Brandt, MD: Yes. So, what you’re saying now is you’re speaking about a change in the technique? Rather than do 1 fecal transplant, do several? Let’s think of it in terms of a 3-day approach, not going in very far—because for these patients, to do a colonoscopy on them can be frightfully dangerous—but to go in as far as you feel comfortable going in, maybe only a foot or a foot-and-a-half, and put in a volume of stool and come out. And then the next day, do the same thing. And the next day, do the same thing. And during that time, also give the vancomycin. So, I think that in the United States, we’re starting to evolve toward that kind of an approach.

Transcript edited for clarity.