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Can Ursodeoxycholic Acid Play a Role in C diff Prevention?

In a session at 6th International C diff Awareness Conference and Health EXPO, Norman Javitt, MD, PhD, research professor of medicine and pediatrics, NYU School of Medicine, in New York, New York, gave a presentation on the potential of ursodeoxycholic acid to prevent and treat Clostridium difficile infection.

Interview transcript: (modified slightly for readability)

Contagion®: What is ursodeoxycholic acid bridge therapy and how does it work?

Javitt: A few years ago, a single study was published that [reported] ursodeoxycholic acid was used to treat someone with recurrent C diff with a spectacularly good effect that cured the patient long term. Now why did that happen? It goes back to research that's been done not that long ago— maybe 5 to 10 years ago—that while everyone knew that the occurrence of C diff infection was mostly related to having taken antibiotics, [the question was] what do antibiotics do to make you prone to get C difficile?

It turns out that those individuals who develop antibiotics were walking around with C diff spores in their colon, but [the spores] were not bothering them. You can find those spores in infants and newborn children, where they are, in a sense, dormant. Why do they suddenly become activated?

What develops is that, normally, the liver makes bile acids that are excreted in the bile and go in your intestines with every meal. They are called primary bile acids because they are made in the liver. As those bile acids normally go through your intestines—particularly when it gets into your colon—you have billions of bacteria that are converted and metabolized to what are called secondary bile acids. [The] secondary bile acids have the normal function of keeping those spores in the dormant state. The major secondary bile acid that has that effect is deoxycholic acid.

Certain antibiotics are notorious for wiping out the normal bacteria that account for the conversion of the primary bile acids to secondary bile acids. Because of the antibiotics, you lose your secondary bile acids and, even worse, the primary bile acids stimulate the growth of those spores. Antibiotic-associated C difficile infection occurs because you lose your normal gut microbiome that normally makes the secondary bile acids. It turns out that ursodeoxycholic acid, which is to a small extent normally in people's bile, is a surrogate for deoxycholic acid; it has the same effect on keeping those spores dormant.

When I read that paper, it seemed to me that this would be a great medication to extend its therapeutic benefits from the diseases for which it's already been used, to the treatment of C diff.

The ursodeoxycholic acid [would] bridge you over from the normal microbiome you had before you took the antibiotics, to the normal microbiome you should get back after you stopped taking the antibiotics. The ursodeoxycholic acid acts as a bridge, suppressing these spores so that you don't develop the inflammation.

Contagion®: Have any additional studies examined the use of ursodeoxycholic acid in the C diff field?

[The paper] was a single publication on a case study. What's surprising is how long it takes for the word to get out. You can read something and you think instantly that it should go viral, but, it's never gone viral. I think it will [go viral] this year because now a 16 patient study been published showing that ursodeoxycholic acid was 93.7% effective for just that purpose. Eventually, when it goes viral, it's going to become an important medication for the management of [C difficile infection]. I'm not talking about cure or prevention or throw everything else away; it's an adjunct to every form of therapy.

If you want to use [fecal microbiota transplantation] (FMT), give ursodeoxycholic acid with it. If you want to use the new compounds that are developing, give ursodeoxycholic acid with it. All you want to achieve is that the patient never gets another episode. This is what you can call ‘adjunctive therapy’ and because of the high safety profile, the patient is at very little risk. With every medication, you always have to speak with the patient and tell them the risks and benefits. And now the patient needs to decide if that benefit-risk ratio is worth taking. With ursodeoxycholic acid, because the risk is so low, [even] if it may only be 93% beneficial, that is still pretty good.

Let me add an addendum. Relatively few patients have been treated [with ursodeoxycholic acid] and so I cannot say, overall, how much this is going to impact the whole field. You have to treat thousands of patients before you can get reliable statistical data, but from a logical point of view, it should be effective. If you have taken an antibiotic and lowered your microbiome but you have enough of it left to come back, then it should be effective. If your microbiome is out, and you need a new microbiome, then it’s not going to work.

Contagion®: What are the next steps for using ursodeoxycholic acid in C diff patients?

I would predict—and this is very speculative—that if you look 10 years down the road, if your physician says ‘You have pneumonia, and I have to give you clindamycin, which has a 30% chance of causing C diff infection if you have those spores,’ [the physician will add], ‘just to keep you from getting C diff, I'm going to give you a course of ursodeoxycholic acid with the antibiotic to try and bridge you over.’

The next step is to get the word out and get people to try it in clinical trials. It is at a disadvantage because the drug is a generic drug and no drug company will sponsor a trial like that; it's not proprietary. [Therefore,] it is very hard to get a funding agency to fund ursodeoxycholic acid studies to see how effective it will be in a large population.

Contagion®: What are the clinical implications?

The clinical implication is that there will be a lot less primary occurrence of C diff infection, and [ursodeoxycholic acid] should be more effective in reducing current episodes of C diff infection. But, it could turn out that ursodeoxycholic acid might not be effective in certain situations and we have to define when it will be useful, and when not.
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