IDWeek 2018: Beyond Fecal Transplants for Modifying the Microbiome

My presentation was on microbiome therapeutics for infectious diseases. That term encompasses, I think, a lot of different items: probiotics, symbiotics, defined consortia. Some people would also put fecal transplants in that rubric.

I think one of the main takeaways is that we're not there yet in terms of safety or efficacy for really taking these studies and making concrete recommendations for our patients. One reason is that, in terms of safety, there are a lot of concerning issues in the kinds of populations that we might want to use this in. For example, we've seen endocarditis and bacteremia happen from probiotics in patients and they've done the studies to look and make sure that the probiotic strain is indeed the one that matched the clinical isolate in those cases. Those were patients that had immunocompromising conditions or central lines—many of the ones that are at high risk for some of the things we're trying to prevent with these therapeutics.

Another not so serious complication, but one I think is good advice for clinicians who do see patients taking these is that a lot of patients feel worse after this. I've had patients with Clostridium difficile infection who on their own started taking probiotics often without telling me and that actually made their symptoms worse—they've gotten diarrhea, bloating, and they've felt a lot worse. They come to me and tell me about it, and I tell them to stop it. It never occurred to them to even stop it, and that it might be linked to the probiotic and they get better.

On the flip side, in terms of evidence moving away from safety, there is a signal. In my talk, I discussed some of the meta-analyses which are showing some benefits in C. difficile infection in particular. There's been some real amazing success stories outside of C. difficile and other infections. Neonatal sepsis is a good one, where these investigators in India showed a 40% decrease in incident neonatal sepsis in the babies that were given the probiotic and that course costs a dollar per course, and the number needed to treat there was 27. So for $27, you're saving a life and there aren't many public health interventions that can be that effective—maybe seatbelts and vaccines may be the exception.

However, in other domains, the evidence is much more shaky. I think one of the main problems is that we have lots of heterogeneity in patients that are going into these studies, lots of different strains and diseases being studied, and all of those little details make a difference. I would advise clinicians reviewing the evidence to make this substitution: everytime you see the word "probiotic" use the word "drug." That's about as specific as you can get when it comes to probiotics. They're all over the place. Even a particular species can have very many different strains that have different effects.

I think the final message is that we really need better research and that research should be guided by mechanistic first principles. In the last few years, we are in a situation at least with C. difficile for example, where people are doing those mechanistic studies to really try to from first principles going by certain mechanisms that we know work in C. difficile infection, design probiotics that fit those mechanisms, testing them in their cell culture bioreactor and mouse models and then finally making it into clinical practice. But we're a few years away from being able to say here's a specific probiotic that will treat this specific condition.

What are your current thoughts on the efficacy of fecal transplant?

We kind of got lucky when it comes to C. diff. and stool transplant. A lot of the case reports in early uncontrolled studies and even some control studies, they vary widely in terms of the dose that's given, the route that's given, how you prepare and formulate it, exactly what the timing is. It seems to work in most of those settings fairly well.

However, in the last year, we've had a couple of studies. That one was Colleen Kelly's study where they did a placebo control state was the first placebo-controlled study for C. difficile infection, and it was efficacious in the whole cohort, but it had two sites. And if you looked at one of the sites—the site in New York—those patients actually got well, just as well in the placebo group compared to the intervention group. The placebo was taking the patient's own stool, preparing it and giving it back to them.

Why might that be? That's very curious right? If you look closely, those patients all were waiting sometimes six months or more before having their stool transplant, unlike the other group, and while they were waiting they were on Vancomycin that whole time or at least a majority of that time. So one has to wonder what if you just stopped their Vancomycin might they have even needed a stool transplant. So, on the one hand this is saying that really waiting a long time if you're just on Vancomycin, maybe there's not an additional benefit to doing stool transplant.

On the other end, what if you did it right away? A group led by Susan Putin in Canada looked at patients who got Vancomycin for two weeks and we're randomized either to a Vancomycin taper extending over the course of the next month and a half, or immediate fecal transplant. They actually stopped that study early for futility. They thought it was unethical to continue offering stool transplant to these patients because that's how badly they were compared to the Vancomycin taper.

Now why might that be? It could be because the timing might not be appropriate—it might be that we shouldn't be using stool transplant early in the disease course. It might be that they used enemas and there are some data suggesting that maybe enema is not the most optimal route to infuse stool for a fecal transplant. We don't know. That's another wrench sort of in this Paradigm that we have about fecal transplant being effective for C. diff.

And the last one I'll point out is a study where they used fecal filtrates. Now, this wasn't a randomized control trial—it was a case series of about six patient that all got better with these sterile fecal filtrates. These investigators did go through the pains of trying to culture from them and making sure that there weren't any live cultural bacteria in there. Now, that calls into question the very Paradigm of do we even need to transport microbes? There are things other than microbes in stool—there's bile acids and metabolites and inflammatory mediators, and things like viruses and other microbes that are small enough that will pass through the filter. So what component of this tool is even the most important, I don't think we have fully figured out even for C. difficile infection.

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