Fidaxomicin in the Treatment of Clostridium Difficile Infections

Peter L. Salgo, MD: We’ve been talking about metronidazole and vancomycin. There’s another drug out there. There’s fidaxomicin. Why is it here? How is it different? How does it work? What is it?

Yoav Golan, MD, MS: Fidaxomicin represents the new thinking, or the new approach, to Clostridium difficile. Our approach to Clostridium difficile is just as strange as the bacteria is. You know that from the package insert of many antibiotics, there’s a warning: this use of this antibiotic will increase your patient’s risk of Clostridium difficile. And we know that even antibiotics that are used to treat Clostridium difficile, as we heard, increase your risk of Clostridium difficile. Hence, we treat Clostridium difficile with an antibiotic.

We treat the disease with its risk factor, which there’s really no other condition in medicine that I know of where the risk factor is actually being used for therapy. So, there’s something that we don’t do right and, particularly if you look at vancomycin or metronidazole, for sure, that’s an antibiotic designed to decimate the gut flora. The last thing you want to do in someone who had Clostridium difficile is to further decimate the gut flora. But we also know that vancomycin, which is typically a gram-positive type of antibiotic, will decimate many of the gram negatives that the concentrations are achieving. So, we’re saying, “Well, there is something that we do wrong, and we see this very high recurrence rate.” In fact, as Dale mentioned earlier, there was always a question of whether Clostridium difficile was born to have such a high recurrence rate or if there is something that we do that facilitates this recurrence rate.

I think this Genzyme study that ended up failing, that Dale had mentioned earlier, actually showed that if you take a “no antibiotic” approach, you may actually have much lower recurrence. So, the problem is that when you have someone sick with Clostridium difficile, you have to treat their symptoms. You have to make them feel better. And for the foreseeable future, and I guess people will agree here, we are going to use antibiotics. So, then the question is, how can we make the antibiotics more targeted?

Fidaxomicin represents this new approach. What we’re trying to do with fidaxomicin is design an antibiotic that’s narrow-spectrum, that’s targeting Clostridium difficile and perhaps a few other bacteria, but will leave the rest of the gut flora alone. So, at the time that you treat Clostridium difficile, you don’t deplete the gut flora with the belief of the understanding that by the end of therapy, which is the vulnerable period of time, the gut flora is going to be robust enough to prevent recurrence.

Now, fidaxomicin works in a different mechanism of action compared to some of the other antibiotics. Without getting into the specifics of the mechanism, I think it’s important to mention that its cidal for Clostridium difficile. It kills Clostridium difficile very well versus some of the other antibiotics, and it does that in concentrations that are lower than the concentrations required for vancomycin or metronidazole.

Peter L. Salgo, MD: You can’t leave me hanging though. You can’t tell me, “We know the mechanism, but I’m not going to share it with you.” Tell me a little bit about how it works.

Yoav Golan, MD, MS: So, fidaxomicin is an RNA polymerase inhibitor. Basically, it interferes with the ability of the bacteria to transcreate and replicate their DNA. So, it’s an RNA toxin in a sense, and without the RNA, there’s no protein synthesis. Without protein synthesis, in the case of fidaxomicin and Clostridium difficile combination, this results in cidal activity.

Peter L. Salgo, MD: How do they get it specific for Clostridium difficile, as opposed to all-comers?

Yoav Golan, MD, MS: That’s interesting. It actually makes fidaxomicin an unattractive antibiotic if you think about that. All antibiotics approved in the past 15, 20 years were just bigger, more broad spectrum, and more active. And now we have an antibiotic whose claim to fame is actually what it doesn’t do—not what it does do.

Fidaxomicin is actually a natural product. It’s produced by bacteria that exists in nature, and it tends to only affect gram-positive bacteria (and only some gram-positive bacteria). It’s not completely specific to Clostridium difficile. We know it can affect enterococcus. If you monitor the gut flora over time and look at patients who received fidaxomicin for 10 days, as opposed to metronidazole (Flagyl), you see that the effect on the gut flora is much more limited.

Peter L. Salgo, MD: Okay. So, it’s more focused.

Erik Dubberke, MD: What’s been demonstrated is that, as I mentioned before, there are certain bacteria populations, communities, that appear to be protective against Clostridium difficile-causing infection. And fidaxomicin tends not to kill those bacteria. It actually allows them to come back while on therapy.

Peter L. Salgo, MD: It kills the bad guys and lets the good guys, who protect you from the bad guys, repopulate.

Erik Dubberke, MD: Exactly.

Peter L. Salgo, MD: Well, that’s not bad. There must be, then, head-to-head studies of fidaxomicin versus vancomycin in terms of the risk for recurrence, for example. What does that show?

Yoav Golan, MD, MS: There have been studies. There actually have been several studies. There have been 2 large, phase III studies. First, they looked at cure rates and they showed that fidaxomicin was very similar to vancomycin in producing cure in about 90% of patients. And as I mentioned earlier, in the real world, it’s probably a bit higher for both antibiotics. But the most important thing is the second part of the study: when you stopped therapy and actually followed those patients for recurrence, in the case of fidaxomicin, the recurrence rate was lower. One of 4 patients, on average, developed a recurrence if they were treated with vancomycin. One in 8 patients (half the recurrence rate more or less) developed recurrence with fidaxomicin—about 13% of patients.

Peter L. Salgo, MD: That’s a dramatic difference.

Transcript edited for clarity.