Treating Multiple Recurrence in <i>C Difficile</i> Infection

Peter Salgo, MD: We’re hoping that we don’t get a recurrence. We’re hoping that if we do, it’s only 1 recurrence. But let’s discuss multiple recurrences in patients. These are difficult patients. We’ve already established that. What are the recommendations for these patients? How do you treat them?

Dale N. Gerding, MD: Those are really the most difficult patients we’re faced with trying to manage. There are several strategies out there. The guidelines recommend vancomycin tapering and pulse dosing as an approach to managing these patients. They also recommend fidaxomicin, as well as vancomycin followed by rifaximin, which is another drug. It is unapproved for treatment of Clostridium difficile (C. diff) but has less effect against the microbiome and is thought to enable the patient to recover their microbiome while they’re on therapy. And then the final recommendation that is completely new is the use of fecal microbiota transplantation.

Peter Salgo, MD: Right. I want to stop there for a second. Whether it’s doctors or lay people, they hear the term fecal transplant, and they stop. They go, “What are you talking about? I’ve got diarrhea, and you’re giving me stool? What on earth is the logic here?” How does it work?

Darrell S. Pardi, MD: Nothing tells you how much patients with C. diff suffer more than the fact that they will gladly accept a fecal transplant from a stranger to get over it. Very few patients will say, “No, I don’t want to have that.” So that tells you how much they suffer.

What is fecal transplant? Taking healthy bacteria from a normal, healthy person and transplanting it into a sick person—in this case, a patient with recurrent C. diff. The main pathophysiology for recurrent C. diff is that the normal flora is altered by previous antibiotic exposure. This restores the normal microbiome and so-called colonization resistance so that if a C. diff germinates, it has no place to infect.

Peter Salgo, MD: OK. From personal experience in watching this work, when it works, it’s almost miraculous. It’s tremendous.

Yoav Golan, MD: When it’s being done adequately, it almost always works. Obviously, it’s not the solution of choice. If you had C. diff, you would prefer not to get there. There are a few additional strategies for patients with recurrences. When we studied fidaxomicin in clinical trials, we didn’t study fidaxomicin in multiple recurrences. We did have a population of people who had their first recurrence (2 episodes within the past 3 months), and it was just as effective in this patient population as it was in those with initial C. diff. Their recurrence rate was higher than those who hadn’t had C. diff in the past 3 months. But it still cut the recurrence by half, compared with vancomycin. We now have an additional modality that we could use, called bezlotoxumab. It is a monoclonal antibody against toxin B and has an interesting story. The initial preparation to be evaluated actually had a monoclonal antibody against toxin A and toxin B, but the toxin A monoclonal antibody didn’t make any difference in terms of recurrence. And so we were left with the toxin B.

In clinical studies, it was shown that if you take someone with recurrences and infuse them, if you give them 1 infusion after a monoclonal antibody against toxin B, bezlotoxumab, it substantially reduced recurrence. Obviously, this is not for everyone who is having their first episode of C. diff, but when someone has a second or third episode, particularly if you think that they are at risk for getting into those multiple recurrences, that should be a step that you should consider, either in addition to or maybe before you actually get into the stool transplant.

Peter Salgo, MD: So you would actually try bezlotoxumab before a stool transplant? Is that what you’re saying?

Yoav Golan, MD: Yes. Stool transplant has its cost and has its inconveniences as well. While it’s very, very effective, you’d like to avoid using it on the large scale. I think that bezlotoxumab can be used to prevent people from getting into the situation of multi-multiple recurrences.

Peter Salgo, MD: It’s worth pointing out that we don’t just transplant stool. The patients have to be managed, and it’s got to be virus-free. It’s a very specific kind of procedure.

Darrell S. Pardi, MD: Yes, that’s really worth emphasizing. There are recommendations on the internet for home fecal transplant. We highly recommend against this because those donors are not screened. In a fecal transplant program, donors are highly screened multiple times per year for risk factors—behavioral risk factors and infections that would be asymptomatic. So if you’re going to do it, to minimize the risk-benefit ratio, you have to make sure the donors are carefully screened.

Peter Salgo, MD: Let’s go back to bezlotoxumab. You like it. Often you’d use it before you’d go ahead with a fecal transplant. How do you use it? What are the nuts and bolts here?

Yoav Golan, MD: I’ll use it in patients who I consider to be at high risk for C. diff. I’ll use it in patients who had prior C. diff. I would not use it in their initial episode of C. diff. I’ll try to use fidaxomicin in those patients to prevent the need for those types of strategies. In people who had 1 or 2 episodes of C. diff, who I think are going to be at high risk for C. diff, you can predict it. We talked about risk factors. You have people who have recurrent urinary tract infections and people with COPD [chronic obstructive pulmonary disease] who require antibiotics every once in a while. And you have people with cancer. You have people who are immunocompromised, who may not be able to mount immune response to the toxin, who actually require the toxin. We do know that there is some evidence that demonstrates that elderly people are less likely to mount an immune response. For those patients, it makes a lot of sense to use bezlotoxumab. You could say, “Why not give anyone an infusion, to reduce their risk of recurrence of C. diff? It’s a bad disease.” But it has its acquisition cost, as well, and you have to fit that in the context of….

Peter Salgo, MD: Right. This is a monoclonal antibody. In my experience, monoclonal antibodies cost a lot of money. All of them.

Yoav Golan, MD: Again, when you talk about the cost (whether it’s fidaxomicin or the monoclonal antibody or anything that’s branded and was just released to the market, that is better), there’s an investment. The question is, Is the investment worth doing? In a high-risk patient, I think it is.

Peter Salgo, MD: Help me out here. How does it work? You’ve talked about preventing recurrence. Yet it seems to be effective against the toxin and not against the bug itself. How does that translate into recurrence?

Dale N. Gerding, MD: This is an intravenous preparation, first of all. So you have to give this as an intravenous infusion. As a monoclonal antibody, it has a half-life of about 19 days. So it doesn’t last forever, although there are good data that say that it’s effective for as long as 6 months. The greatest efficacy is in patients with predefined high-risk factors—over age 65, being immunocompromised in any way, having had prior C. diff, or having had one of the high-risk organisms like the NAP1 organism. These patients got the greatest benefit from the use of bezlotoxumab.

Now, if a patient had more than one of these risk factors, that increased the likelihood that they would have a good response. It doesn’t reduce their recurrence rate to 0, but it significantly reduces recurrence. In the observation, the interesting thing was that if you didn’t have any risk factors for recurrence, you didn’t get any benefit from it. So there’s clearly a need to identify patients who are at risk for recurrence, if you’re going to give it. And the cost is substantial for a monoclonal antibody.

Peter Salgo, MD: We have 3 big studies. There’s MODIFY I, MODIFY II, and then there was a study in Clinical Infectious Diseases. That was a post hoc analysis. Did they all agree?

Darrell S. Pardi, MD: They all agree, and they all show benefit—particularly in these high-risk patients. Across the board, the overall reduction of recurrence went from 27% to 17%.

Peter Salgo, MD: That’s big.

Darrell S. Pardi, MD: Yes. If you look at the patients who really have risk factors, especially those who have multiple risk factors, you can identify groups that are really going to benefit from this.

Transcript edited for clarity.