C difficile: New Therapy for a Dangerous Disease?

David A. Johnson, MD


April 07, 2011

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Hello. I'm Dr. David Johnson, Professor of Medicine and Chief of Gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia. Today is April 6, and the US Food and Drug Administration (FDA) advisory panel has recommended to the formal FDA unanimous approval of a new drug in a new drug class specifically for treatment of Clostridium difficile colitis. Because this is going to achieve much news coverage over the next several weeks, I thought it would be helpful for you to review what led to this unanimous recommendation and review the literature on this particular drug, and how it might apply to our clinical practice.

Let's start with C difficile; we see this pathogen all the time in clinical practice. It is recognized as the number 1 cause of hospitalization for diarrheal illness in the United States and Europe. Moreover, we recognize an increasingly virulent strain, which accounts for about one third of C difficile cases, and which is associated with a significant risk for not only morbidity, but mortality. It's a North

American pulsed-field type 1 (NAP1), restriction endonuclease analysis (REA) type BI, or polymerase chain reaction ribotype 027 strain, a strain that we recognize as a significant subset of C difficile. However, this strain is potentially more virulent and poses a more formidable treatment problem.

The primary treatment of C difficile has traditionally been metronidazole or vancomycin. Metronidazole is absorbed very well and excreted primarily through the bile, from where it is delivered to the colon, so it's not as effective in patients who have a significant ileus or in patients who potentially have serious systemic disease. Vancomycin is administered orally. It's not absorbed and is a very good drug, but it potentially has other side effects such as selection of resistant organisms. We've seen vancomycin-resistant enterococcus, among other microbes, in hospitalized patients.

This new class of medication is focused on a very narrow window of treatment. They are macrocyclic antibiotics and RNA polymerase inhibitors. The idea in developing this drug was to focus just on C difficile and gram-positive organisms across the board. These drugs allow the concomitant flourishing of other normal colonic bacteria, such as bacteroides. Fidaxomicin is a bacteriocidal drug, whereas vancomycin is a bacteriostatic drug. This may potentially have advantages with respect to the development of resistant organisms over time and may potentially change the relapse rate.

The data emerging from phase 3 trials that have been published most recently in the New England Journal of Medicine [1]looked at fidaxomicin in comparison with vancomycin. This was a multicenter study, involving 52 sites in the United States and 15 in Canada, with a total of 642 patients randomly assigned to receive either fidaxomicin/placebo, or vancomycin/placebo. Fidaxomicin was given at a dosage of 200 mg twice a day and vancomycin was given at 125 mg 4 times daily. Analysis was done by intention-to-treat and per protocol.

The primary objective was noninferiority to vancomycin. The secondary outcome was the relapse rate. Vancomycin and metronidazole relapse rates are generally 20%-30%, and this typically occurs within the first 2 weeks. The study window was 4 weeks, during which relapse rates were assessed, but not beyond that. This is something we will need to follow. Relapse rates for the 2 drugs were different, by approximately 10% in favor of the fidaxomicin group, with a number-needed-to-treat (NNT) of 10.

When looking at subgroups of more virulent strains, the NNT was amplified, because in the virulent strains, there was still no difference between the drugs. In the nonvirulent strains, which accounted for about 66% of the strains in this study, the NNT emerged with an absolute risk reduction difference of 17 with a NNT of approximately 6. This becomes a very formidable drug with respect to the significant potential to prevent C difficile infection. If we knew the patient's virulence, it wouldn't make a difference. If we are talking about prevention in less virulent strains, however, it would make a significant difference because the NNT here is 6, whereas across the board, the NNT is 10.

No differences were noted between the 2 drugs in side effects or toxicities. These drugs are very safe and effective. The comparison with vancomycin is the gold standard.

How do I put this into perspective for clinical practice? With fidaxomicin, we have a drug that is able to kill, rather than just inhibit C difficile, as seen with vancomycin. It is a twice-daily drug, so that facilitates compliance, which I think is important, and it has a very significant effect, especially in the less virulent strains of C difficile but not so much in the more virulent strains.

The limitations here, however, are not knowing what effect this drug has on the relapse rate beyond 4 weeks. I will have to wait and see the effectiveness of fidaxomicin over a longer period of time before I'm ready to use the drug uniformly. I would raise the question first, what is it going to cost? Vancomycin is very expensive.

Be aware that you can actually compound vancomycin in a very cost-effective way. Ask your compounding pharmacist to take the intravenous vancomycin formulation and encapsulate it, and you'll find that it's about $1 a day for treatment. This is a miraculous cost-effective measure for patients who need the vancomycin dosing. Metronidazole remains the drug of choice in my practice for patients with mild disease. There are side effects, such as nausea, and some neuropathic changes that have significant consequences if you don't stop the drug immediately. In general, metronidazole is a very inexpensive drug. Vancomycin can be very inexpensive, and it must be remembered that it can raise the risk for drug-resistant bacteria.

Fidaxomicin seems to have a niche for potentially decreasing the risk for serious bacterial infections. Time will tell how this plays out beyond 4 weeks and ultimately, what it costs as we take a look at numbers needed to treat across the board. For relapse of the less virulent strains, which accounts for about two thirds of the patients we see, NNT closer to 6 becomes a cost-effective analysis and time will tell as to how well that will play out with data analysis of extended follow-up.

I want to set the stage for this new drug, and new drug class, which have multiple potential reasons to be better drugs. Many questions must still be answered. Look for this, analyze it carefully, and wait for more information, and hopefully a new class of therapy will emerge. The more we understand, the better we can treat C difficile. I look forward to discussing this topic and others (that are important to your clinical practice) with you in the near future. I'm Dr. David Johnson. Thanks for listening.


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