Peter L. Salgo, MD: Now let’s talk about managing Clostridium difficile. If we can define who gets it, who do you test? How do you figure out that this is really Clostridium difficile? Who has moderate or severe disease? We’re left with the obvious question: What do you do about it? We have guidelines. What do the guidelines say about what factors impact the treatment of Clostridium difficile?
Daniel E. Freedberg, MD, MS: The things that are going to impact the response to treatment for Clostridium difficile—whatever agent you’re using—are a lot of the same factors that we’ve been talking about as risk factors for getting Clostridium difficile to begin with. So, age—people are going to be more likely to get Clostridium difficile and do worse on whatever treatment they’re started on. Lack of normal immunity—patients who are immunosuppressed because they’ve gotten a solid organ transplant because they have inflammatory bowel disease or other reasons like that; or other factors that just compromise their normal ability to resist Clostridium difficile infection. These are the things that are going to suggest to you that a patient is going to not do as well in response to treatment for Clostridium difficile.
Peter L. Salgo, MD: So, patients who are at higher risk, patients who are sicker to begin with, jump on earlier and more aggressively?
Daniel E. Freedberg, MD, MS: And certainly follow more closely for response.
Peter L. Salgo, MD: This is whether they’re in the hospital or outpatients, as well?
Daniel E. Freedberg, MD, MS: Yes, absolutely.
Peter L. Salgo, MD: What is the standard of care for Clostridium difficile? Vancomycin, metronidazole—we talked about that. Why don’t we start by talking about these standard treatments for mild to moderate infection? How do you use them? How effective are they? How safe are they?
Lawrence J. Brandt, MD: Well, I think that for mild disease, at first episode, most physicians will recommend following the guidelines. We start with metronidazole—500 mg, 4 times a day, for 10 to 14 days. That’s mild disease. And, for the most part, this will be effective. But, I have to tell you that I’m starting to move away from that.
Peter L. Salgo, MD: Why is that?
Lawrence J. Brandt, MD: Because, metronidazole is a difficult drug to take. It tastes terrible. It causes an upset stomach. You can’t drink alcohol with it, so that’s an important point. I think that the recurrence rates, which are a very real problem with Clostridium difficile, are greater with metronidazole than they are with vancomycin. So, I’m interested in how the infectious disease, and other gastroenterologists, doctors will agree or disagree with me. I’m not using metronidazole as much now as I was before.
Daniel E. Freedberg, MD, MS: I agree, although the guidelines do suggest that metronidazole is still a valid first-line treatment for mild disease now—for patients with just diarrhea and no systemic signs. But, really, there are 2 reasons why you would probably use metronidazole instead of vancomycin. One is cost. So, a metronidazole 10-day course costs about $10 instead of hundreds of dollars, which is the cost for vancomycin.
Peter L. Salgo, MD: Vancomycin is really that much more expensive?
Daniel E. Freedberg, MD, MS: Yes. It’s at least a couple hundred dollars more expensive.
Peter L. Salgo, MD: Really? It’s been out a long time.
Dale N. Gerding, MD: It’s actually about $1200 versus about $10.
Lawrence J. Brandt, MD: But, it would be important to note that although it’s $1200 for the capsules, you can take the liquid intravenous form of the disease by mouth, as well as can get a pharmacist to make it up for you. You can do that for anywhere from $75 to $100.
Yoav Golan, MD, MS: There are a few additions. I must say that we, too, have switched from metronidazole to mostly vancomycin. And I certainly haven’t used metronidazole for any of my patients for quite a few years now. A few other reasons for that, besides the fact that metronidazole can also be toxic and can be associated with neuropathies (sometimes those are irreversible), is that the guidelines have not been updated in some time and will be updated soon. I think that there may be some changes.
But, we have to be conscious about the fact that over the period of time since the last guidelines, there have been emerging data, that we always knew, that metronidazole might not be as good as vancomycin for severe disease. But, now there is emerging data that it’s also not as good for mild and moderate disease. And also, you have to remember that vancomycin is more elegant because it’s topical therapy for topical disease—a disease that’s contained within the colon. Metronidazole is systemic therapy. You get less and less metronidazole in the gut as you have less inflammation and less diarrhea. So, for all those reasons, I think that vancomycin has become the drug of choice for many patients.
Dale N. Gerding, MD: We have, now, the largest comparative, blinded, randomized trial of vancomycin versus metronidazole. The study included over 250 patients in each arm, and the results show that for all patients, vancomycin was about 10% more effective than metronidazole and was statistically very significant.
Peter L. Salgo, MD: Well, 10% is a lot.
Dale N. Gerding, MD: Right. If you were to take metronidazole today, which does not have an FDA indication for treating Clostridium difficile, and you were to subject it to a phase 3 trial and it lost by 10%, the FDA would never approve it. So, this is all information that’s come out since the 2010 guidelines.
Peter L. Salgo, MD: If you say to me (somebody who’s not looking at this data as an infectious disease or gastroenterologist, but somebody who treats), “I treat an awful lot of Clostridium difficile,” you’re telling me that metronidazole isn’t as effective and is occasionally associated with irreversible neurologic issues?
Daniel E. Freedberg, MD, MS: The only other reason I’ve heard cited for using metronidazole instead of oral vancomycin is a fear of causing more vancomycin resistance and maybe increasing VRE (vancomycin-resistant enterococci) colonization. But, Dale, did you do a study looking at that? I believe metronidazole, as well, increases rates of VRE colonization?
Dale N. Gerding, MD: Actually, Dr. Curtis Donskey, did the trial. It showed that metronidazole results in VRE colonization.
Yoav Golan, MD, MS: In fact, some studies show that metronidazole was the strongest risk factor. As we talk about vancomycin, I think it’s also important that we talk about the dose. We talk about the cost of care and we talk about the fact that cost sometimes shifts people from vancomycin to metronidazole. It is important that the recommended dose for people with the first episode of Clostridium difficile is 125 mg, 4 times a day. This will produce plenty of concentration in the gut, and many doctors use higher doses without data that supports that.
Peter L. Salgo, MD: This is vancomycin we’re talking about?
Yoav Golan, MD, MS: Vancomycin. And so, as vancomycin becomes the main stage of therapy, it is important to remember the 125 mg dose.
Erik Dubberke, MD: There was actually one small study done in the 1980s comparing 500 mg, 4 times a day, to 125 mg, 4 times a day. And there’s no difference in response. So, if you’re giving a 250 mg dose, you’re doubling the cost. If you’re giving a 500 mg dose, you’re quadrupling the cost versus 125 mg.
Lawrence J. Brandt, MD: I’ve seen, in my hospital—and I think it’s pretty common in all hospitals—that if a patient is sick and is not responding to the lower dose, they always go to the higher dose.
Erik Dubberke, MD: It doesn’t make sense. Again, pathophysiologically, with that 125 mg, 4 times a day dose, you’ve got levels of vancomycin at least 500 times higher than you need to kill Clostridium difficile. So, why 10,000 times more? It’s not going to kill more Clostridium difficile.
Peter L. Salgo, MD: Are you saying that if you’re giving vancomycin and it’s not working, no matter what the dose, it isn’t going to work?
Erik Dubberke, MD: I think some of it is these people have had so much damage to their colons, due to the Clostridium difficile toxins, that it just takes a while for them to resolve. What I typically do is just continue them on the same vancomycin dose, and, as long as all other parameters are getting better, the white count is coming down, the fever has gone away, and the condition is becoming more stable, I just stay the course.