Monitoring for Treatment Response in Clostridium Difficile

Peter L. Salgo, MD: What are the markers you’re looking for in terms of response? And if I hear you correctly, it’s not necessarily the diarrhea and it’s not necessarily epiphenomenon—because they’re direct—it’s other things other than the diarrhea.

Erik Dubberke, MD: It’s the whole patient.

Peter L. Salgo, MD: You’re looking at the entire clinical picture?

Erik Dubberke, MD: Yes.

Peter L. Salgo, MD: But the patient’s sitting there losing volume, is sick, and you’re giving vancomycin. And the diarrhea is not going away. Isn’t there temptation to do something else?

Erik Dubberke, MD: It is something. Actually, people are scared to give antidiarrheals in the setting of Clostridium difficile. But if they’re on effective doses of vancomycin and everything else is getting better, I give antidiarrheals. I don’t hesitate.

Peter L. Salgo, MD: Do you guys buy into that? I was always taught never to do that because you don’t stop the transudation of fluid, the gut gets bigger, and maybe you’re going to even predispose to more gut…

Yoav Golan, MD, MS: I think this remains controversial. While there isn’t good evidence that antimotility drugs will make the Clostridium difficile much worse, we have a rule in infectious disease that you don’t treat infectious diarrhea with antimotility drugs.

There have been cases. I must say that many of the patients who are diagnosed with Clostridium difficile nowadays don’t really have Clostridium difficile. That’s because they are diagnosed with tests that are oversensitive and do not differentiate between colonization and infection. And so, our experience is somewhat mixed in this regard. But I want to say that, in terms of therapy, the clinical trials are very stringent in their definition of who responds and who does not. Very often, you think the patient is doing better by the criteria—the patient failed therapy; results showed that vancomycin is effective in 90% of patients. And, if you take our experience, I would think that it’s probably effective in more than 90% of patients.

But one of the problems that we still have with Clostridium difficile appropriate therapy is with those patients who appear very, very sick and will remain very, very sick despite therapy; this is a challenging group. It may not be a problematic group in the community because those patients end up in the ICU most commonly. But this is still a group that we struggle with. And a lot of what we do in this group is not completely evidence-based.

Peter L. Salgo, MD: What are you looking for? You’re looking for white count, fever, toxicity. Clearly, diarrhea matters in terms of fluid balance?

Erik Dubberke, MD: The patient that I was talking about—it’s those patients where everything is getting better, but they have, sometimes, persistent diarrhea, sometimes, persistent abdominal pain, or sometimes both. But everything else is getting better. They’re not having such severe diarrhea where they are losing fluid or where they still need intravenous fluids. So, that’s a different subset of patients. Those are the patients that have the most severe colitis. Those are the ones with toxic megacolon, where, sometimes, you need to proceed with surgery for their Clostridium difficile if they’re that sick.

Lawrence J. Brandt, MD: We’ll come to surgery and fecal transplant later, but the point about the diarrhea is it’s a very valuable thing to look at. I think you can expect an improvement in somewhere between 3 and 5 days. Certain people take a little longer to respond. The older patient or the patient with renal disease may take longer to respond. But sometimes in a patient who is cured, the diarrhea never resolves. And these patients probably have a postinfectious irritable bowel syndrome—that can occur in about 20% to 25% of patients.

Peter L. Salgo, MD: Wait, 20% to 25%? That’s huge.

Lawrence J. Brandt, MD: It’s huge.

Peter L. Salgo, MD: About a quarter of the people that you’re going to treat will get better, technically, from their Clostridium difficile. But they’ll have persistent diarrhea. They’re not going to be very happy about this.

Lawrence J. Brandt, MD: They’re not very happy about that, that’s correct.

Peter L. Salgo, MD: So, how long do you treat “all-comers” Clostridium difficile before you say, “Okay, we’re done,” if, in fact, you’re not getting any diarrheal response?

Lawrence J. Brandt, MD: So, you’re asking me about a patient who came in, I diagnosed Clostridium difficile, I treated them, and their diarrhea didn’t get better?

Peter L. Salgo, MD: I’m asking everybody. Let me be more clear, perhaps. Here’s somebody with Clostridium difficile. We’ve established the diagnosis. You start one of your drugs, metronidazole or vancomycin. You’re going to treat to some endpoint, and if diarrhea isn’t necessarily the endpoint and it won’t be in a quarter of your patients, what is your endpoint?

Lawrence J. Brandt, MD: Well, it’s not my endpoint—not in a full quarter of patients because, in many of those patients, there is a dramatic improvement in the diarrhea, but they never return to normal. So, it’s not that the diarrhea doesn’t respond; it does respond. They’re not as sick as they were, but they’re still not having normal bowel movements, and that’s important. You have to establish a baseline for these patients that is different than their baseline before their infection.

Peter L. Salgo, MD: What’s a typical length of treatment in terms of time you’re on antibiotics?

Dale N. Gerding, MD: Studies usually report 10 days, but it’s well known that if you’re treating with metronidazole that you frequently have to extend to 14 or even 21 days of treatment. We did a trial in which we were limiting people to 14 days of treatment, and we were losing patients in our trial because everyone was treating them with metronidazole for longer than 14 days. Again, that’s one of the issues with metronidazole—it seems to be slower-acting than vancomycin as well. But, generally, 10 to 14 days is normal.

Peter L. Salgo, MD: So, you’ve treated somebody, the diarrhea has backed down, white count is better, fever is better, and electrolytes are okay. For all intents and purposes, they’re better. You’ve stopped your antibiotic therapy. Now, how do you follow up with them? What is your typical call-back period? How often do you see them? What do you do?

Dale N. Gerding, MD: Well, you’ve got to warn them that the recurrence rate with Clostridium difficile is going to be around 25%. In other words, they’re going to get their diarrhea back again (in about a quarter of patients), and they have to be prepared for that. And so you tell them, “Call me if your diarrhea comes back and we’ll get you in and evaluate you.”

Peter L. Salgo, MD: This disease just sounds worse and worse and worse because there’s about 25% who never get back to baseline. They have some diarrhea following their acute attack. Then there’s, I’m guessing, although there is probably some overlap, another 25%.

Dale N. Gerding, MD: Part of them will be the same 25%.

Peter L. Salgo, MD: Right. But somewhere between 15% and 25% are never, well, not never, but are going to have more symptoms as you go along. What kind of follow-up do you do, typically?

Dale N. Gerding, MD: Basically, you just have to inform patients of the possibility that this is going to happen and also caution them about taking any more antibiotics if they can absolutely avoid them.

Peter L. Salgo, MD: A lot of my patients come in and say, “Don’t give me antibiotics, because my doctor said I had Clostridium difficile and I shouldn’t have any.

Transcript edited for clarity.