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[00:00:07] Angela: Hello, and welcome back to communicable the podcast brought to you by CMI communications estimates open access journal covering infectious diseases and clinical microbiology. My name is Angela Huttner. I'm an infectious disease doctor at the Geneva University hospital in Switzerland and editor in chief of CMI comps.

[00:00:26] Angela: I'm joined again by my co host. Mark Bonten, fellow editor at CMI comms, professor of molecular epidemiology of infectious diseases in Utrecht, Netherlands and CEO of ecraid.

[00:00:38] Marc: Hi, good to be here again.

Today, the topic is fecal microbiota transfer for Clostridioides difficile infection, C. diff. We have with us two expert guests, both clinician researchers.

[00:00:52] Angela: Professor Maria Wereschildt is the head of infectious diseases at Frankfurt University Hospital in Germany. Her clinical microbiome research group, begun in 2015, has focused on the development of microbiota based treatments against multidrug resistant bacteria. This includes FMT, live biotherapeutic products, and bacteriophages. To this aim, she also runs the Cologne Microbiota Bank, CMB, at Cologne University, in Germany, in addition to her appointment in Frankfurt.

[00:01:23] Angela: This CMP includes a functional GMP, Good Manufacturing Practices Laboratory, for the development of those FMT capsules. Maria is also one of the founders of EurFMT, E U R, FMT, an international network of academic FMT providers that aims to improve and provide data on FMT in practice.

[00:01:44] Angela: Maria, welcome to Communicable.

[00:01:46] Maria: Thank you for inviting me. It's really an honor to be here.

[00:01:50] Marc: Our second guest is Dimitri Drakonia, currently is the Section Chief for Infectious Diseases at the Minneapolis VA Health Care System and Associate Professor of Medicine at the University of Minnesota. He conducts clinical research on , C.

[00:02:04] Marc: diff infection, , but also on urinary tract infection and antimicrobial stewardship. He led the recently published multicenter RCT on FMT for C. diff infection, which we will certainly be talking about. And if you missed it, it was in CID in November. Dimitri welcome.

[00:02:21] Dimitri: Thank you.

[00:02:22] Dimitri: Pleasure to be here. we start each episode with a short get to know you question for our guests and our hosts.

[00:02:29] Marc: And, every one of in this discussion is calling in from a different country. And the question is what is a fun fact about the city that you're living in now. I'll start, let's say consider myself to live and work in Utrecht and that is a city of 375, 000 people in the center, exactly in the middle of the Netherlands, where all the train lines come together.

[00:02:51] Marc: this city claims to have the lowest unemployment average age of cities and villages in the Netherlands. So more than 40 percent of the population is under the age of 40. that is of course, because of the university here and other teaching institutes, it's a real, what we call a student city.

[00:03:10] Marc: Each day more, I start to see the joy of that. As an elderly person, biking to my work, I see all the students going to the university campus and I'm thinking of my time in Maastricht as a student. So that's the fun fact of my city. It's the youngest. place of the Netherlands.

[00:03:28] Angela: How about you, Angela?

For Geneva, I'm going to go along with this youth, thread. Something the city does, every summer for a little while organizes this, slide, right on the road that we live on.

Our street is. On a hill, . The firefighters would come out in the morning and block off traffic, so that all the kids in the city could just come and slide down, this huge slide. , all day long For one day in the summer, , they stopped it because of COVID everyone's kind of hoping they're going to restart it.

[00:03:57] Angela: So, maybe a subliminal message there. Anyway, so that's , something that you won't find, I guess, on the internet about Geneva. Maria, how about you in Frankfurt?

[00:04:07] Maria: So Frankfurt is also called Mhine-hattan in Germany. It's, nicknamed because it's located, on the bank of the Rhine River. And it's one of the very few places in Europe that actually has a skyline with a cluster of, skyscrapers.

[00:04:24] Maria: remotely resembling Manhattan, therefore Mine hattan. And, then we also have, a very specific type of sausages here. And, only if they are produced here, they are called Frankfurter sausage. And, , if they are produced somewhere else, they're called Wiener sausage. So it's a bit like with the champagne, but with sausages.

[00:04:47] Marc: Yeah. Fortunately, you can be from everywhere to enjoy, both, the Frankfurter and a Wiener.

[00:04:52] Marc: so, uh, Dimitri, what about you?

[00:04:54] Dimitri: well since this morning it was minus 20 Celsius. I'll just mention that this is the only metro area I know in the United States where you can both cross country and downhill ski in the winter inside the city.

[00:05:06] Dimitri: granted, our ski hill is not the Alps. the vertical drop is 53 meters, so you could even debate whether that's a hill. Maybe your slide wouldn't even consider that big enough to make it down, but we try to make do and our kids learn how to race on that.

[00:05:21] Angela: Very cool.

[00:05:22] Angela: So Dimitri in preparing for this talk microbiota transfer was not a few years or decades ago.

[00:05:30] Angela: It was in fourth century China, where. So called yellow soup was applied in cases of severe food poisoning and diarrhea. So can you give us a brief summary of the more recent history of FMT? When did this start being used in modern times?

[00:05:45] Dimitri: Yeah. so I've seen that same reference. I've, never been able to track it down and even if I could, I'm not sure I would be able to read it and verify it, but I've seen this reference to yellow soup.

the most recent one that I'm aware of is for a VA connection in 1958, there was this case report from a Colorado surgeon, Ben Iceman at the, Colorado VA, and he published a case series of four patients, and this is a study that, would never get done now. I think there was no IRB, and I'm not sure the subjects were consented for this.

frankly, a predated knowledge of C. difficile that was just known as antibiotic associated colitis, and he administered rectal enemas from donor stool from reading between the lines in the paper. It seems like his trainees were the source of the donor stool. I'm not sure how much choice they had in, that, and they administered this and three of the four improved, and from then on, if you go to PubMed and you search for fecal transplant, you will see a You know, less than five publications a year until about 2006, 2010, where things really exploded.

[00:06:53] Dimitri: And now, if you look in 2024, I think there was 1, 360 publications for fecal transplant. So there's just this tremendous growth And you kind of see this in the case reports, clinical trials, placebo controlled trials, meta analyses, it's really, you know, running the gamut now.

Yeah, I do recognize that. I think that one of the first papers came from Amsterdam where they experienced with patients with difficult to treat, I think it was recurrent CDI, , that was a, Very, very, positive result coming from that study and that, that was one of the first studies I remember.

[00:07:28] Marc: So Maria, can you give us a picture of, what actually is really happening at the cellular level when fecal microbiota are transferred? Who are the players in that game and, how does it work?

[00:07:39] Maria: That's a very good question. And, I may not be able to fully answer it, but I'll try. we do know that bacteria are definitely transferred because we can analyze the recipients and the donors before and after the microbiota transfer.

[00:07:57] Maria: And we see that a significant percentage of the bacteria of the donor do engraft. But we also know that, for example, bacteriophages are transferred, but we do not fully understand what their role in the clinical response really is. So that is something we really need to look into farther. And then we are also transferring a lot of metabolites that, our gut bacteria synthesize.

[00:08:26] Maria: And these metabolites also have a beneficial effect. the recurrent CDI situation. So, yes, all of this may play a role, but it's very hard to say which way the different factors actually carry.

[00:08:45] Angela: how Can we predict whether the transfer will actually take, or can we at all? What are the factors, if they're known, suggesting that a recipient's own microbiota might sort of withstand and resist these newcomers? being grafted onto them, wishing to be grafted on.

[00:09:04] Maria: So engraftment is a very interesting topic. you always have to imagine that if an ecosystem is already functioning and in an equilibrium, then its organisms are working together in synergy. They are consuming nutrients that they need and they are taking up space to exist.

[00:09:30] Maria: So if you send in new organisms into that ecosystem, They, will have a very hard time surviving in there or in grafting in our case. So, many studies are now showing that it's important to make space to create niches for these incoming bacteria so they can have space and nutrients, to live on and to actually stay in the gut of the recipient.

[00:09:58] Angela: you looking at [00:10:00] preparing the recipient with a course of antibiotics or some other anti microbial, to sort of prepare the terrain.

[00:10:07] Maria: Exactly. So, you can have a bowel lavage as a mechanic way of trying to create these niches, but, an antibiotic is far more efficacious in that.

[00:10:20] Maria: And, we usually use at least three days of vancomycin to prepare the gut for an FMT. But isn't really very structured evidence, to compare different methods. So think nobody can tell you whether three, four, five or 10 days would be better, or maybe a different antibiotic. This hasn't really been compared much.

[00:10:42] Marc: And then Maria from. analyzing the donor material, is there already evidence that you would be able to predict the success of your treatment based on composition of the donor material that you're going to use?

[00:10:57] Maria: So there are bioinformatic models that can predict which bacteria are likely to engraft, but for CDI, it's really not that important.

[00:11:08] Maria: If you choose a healthy donor, according to internationally, recognized, protocols and guidelines, then trials worldwide show the same response rates. even if no matching has taken place. So, it doesn't seem to be so difficult to be a suitable donor for recurrent C. diff infection, but for other diseases, this technique might become much more important.

[00:11:39] Marc: Good. and a question for both of you, and let's start with Dimitri mostly be talking about FMT for C. diff infection. Can you briefly tell us what other infections or indications are currently used for FMT?

[00:11:52] Dimitri: You know, currently here in the United States, the only approved indication if you were going by, trying to use an FDA product with an approval is, to prevent recurrence of C.

[00:12:02] Dimitri: difficile after the current episode has been successfully treated with a course of standard antimicrobial therapy. Now, when you go off to other things that people have tried, the world is your oyster. There is more things that have been tried, that I can. possibly enumerate. it's been certainly used for treatment of refractory C.

[00:12:20] Dimitri: difficile that's not responding to the treatment. it's been used for the prevention of recurrent urinary tract infections. It's been used for trying to colonization of multi drug resistant organisms. If you go to clinicaltrials. gov and search for Fecal microbiota transplant, or FMT, you will get page after page after page of studies, evaluating all sorts of conditions, some of which I, question where the, link is, but it's, interesting to see, and you will see conditions being studied such as Crohn's disease, ulcerative colitis, multiple sclerosis, anorexia.

[00:12:56] Dimitri: Autism, alcohol use disorder, graft versus host disease, melanoma in conjunction with chemotherapy, I mean, it is just, , things that I would never have foreseen being studied. Clearly, someone thinks there is something there, and we'll see where that science goes, but the, list of potential indications, again, the currently, the only one approved in the United States is for prevention of recurrent C.

[00:13:19] Dimitri: difficile, but people are looking. At almost anything they can imagine.

[00:13:24] Marc: Yes, and Maria, out of that long list of potential indications, where's your research focusing on?

[00:13:32] Maria: Yeah, so we are starting two trials on decolonization. One is a Personalized, approach, to remove, gram negative multidrug resistant bacteria from the gut.

[00:13:44] Maria: so here we do match the donors by use of an in vitro test to the bug that we want to get rid of. the other trial, will try to decolonize VRE in, patients who are receiving immunomodulatory cancer treatment. So there we are trying to kind of achieve two things to get rid of the VRE and also to improve the immunomodulatory effect of the cancer treatment.

[00:14:14] Maria: And then we, just got funding for a randomized control trial. to prevent recurrent urinary tract infections. And that's particularly exciting because we've been trying to get this for many years and, it was very difficult to convince someone that this actually makes sense and yeah, now we can do it.

[00:14:34] Maria: So we are very happy.

[00:14:35] Marc: Thank you, Maria. So I want to come back very briefly on the, application for the VRE, which stands for vancomycin resistant enterococci, what we consider a low grade pathogen, but potentially dangerous in patients with an immunocompromised status, and that's where you're going to use it for.

is vancomycin resistant, you're probably not going to use vancomycin as a pre exposure to clean the gut, of these patients. How do you hypothesize that fecal transplantation will work in such patients to, let's say, to clean the gut from the vancomycin resistant enterococci?

[00:15:08] Maria: Yeah, so you immediately identified the most difficult question in the trial design.

[00:15:15] Maria: so yes, here we cannot use an antibiotic induction treatment very well because we will just, amplify the VRE dominance that is already there. We don't want that. So, we are still discussing this a bit, but probably here we will actually just do the bowel lavage as a preparation because, these, patients are often already compromised in the composition of their microbiota.

[00:15:43] Maria: So we are quite optimistic that engraftment will take place even if we don't use a strong antibiotic induction treatment. And then, the idea is to re establish colonisation resistance by reestablishing the physiological diversity of the microbiota because what you see is that VRE starts to, be transmitted and in grafts, in patients, in situations when the microbiota is, verified, when it's depleted, and when you, manage to get a more diverse microbiota back, it can not survive any longer.

[00:16:24] Maria: Very well in the gut. we also have to say that it's probably hard to really get rid of it. There will still be very low level colonization, most likely. But our aim is to bring the patients below the standard, detection that would be performed using a swab and a chroma agar.

[00:16:45] Angela: Interesting, staying a little bit in the, general space, I'm just going to come back and give you both a question about sort of FMT in real life. Can you tell us in your respective countries, how easy is it for a lay person to undergo FMT for whatever they want?

[00:17:02] Angela: I'm talking about any FMT, not necessarily a GMP, regulated FMT. what's the reality of FMT?

[00:17:09] Maria: Yeah. So, In Germany, FMT is unfortunately not generally reimbursed by insurance companies . You can individually apply for reimbursement, but you also have to find a physician who will manufacture the FMT for you.

[00:17:26] Maria: we have a specific, clause in our drug law that allows physicians to do that. If they do it for a specific patient, they also administer it themselves. So they cannot send it to another physician who will then treat the patient. It all has to come from the same person. obviously not the donation, but the process of manufacturing it.

[00:17:50] Maria: So, I think that's quite a unique law. I've never heard of another country where this is possible. And this also gives us the opportunity to perform, FMTs, not only in recurrent CDI, but also in other cases where we feel that based on the declaration of Helsinki, we are, able to, perform an individualized treatment that is not registered.

[00:18:17] Marc: So Maria, is that in other countries, not what they call magistral of magistral, production, because it sounds very familiar to me. I'm It resembles the situation with bacteriophages.

[00:18:30] Maria: Yes, totally. but I have never heard, from another country where FMT is, let's say regulated in this way.

[00:18:39] Marc: No, no. That's correct. I have not examples of other countries, recognize this from the bacteriophage discussion where we exactly had that for the Netherlands and for other countries as well.

[00:18:50] Angela: And Dimitri in the U. S.? How accessible is FMT, I mean, on the internet, et cetera?

[00:18:56] Dimitri: Try describe accessibility in the U.

[00:18:59] Dimitri: S. healthcare system assumes that the U. S. has a coherent healthcare system. So that's a very difficult thing to answer, but I will say, amongst the hodgepodge of things that we have that resembles a system, it's highly variable. Certainly, if someone is enterprising, they can go online to YouTube and they will find people giving you a do it yourself at home.

[00:19:21] Dimitri: I do not endorse that. Certainly, their availability for testing would be quite minimal, but they will find recipes. You will also find You know, publications where they have described self administration of fecal transplant via enema with a kind of shopping list that you go to a grocery store and buy or a drugstore and buy an enema bottle and a blender that they recommend discarding after you use it.

[00:19:46] Dimitri: but getting more to the, sort of approved version. There now are two FDA approved, commercially available fecal derived products. my general practice is to use generic names versus trade names, but I just don't even know what the generic [00:20:00] names of these are. so I'll just say one is a Firmicute.

[00:20:02] Dimitri: You know, a, spore mixture that is, used to be series biotherapeutics, 109 was the study name, that was approved via large, phase 3 study that showed, significant. Improvement over placebo and prevention of recurrent C. diff. And is administered orally.

[00:20:19] Dimitri: There's another product. that's a proprietary mixture. That's administered rectally. both are available, within the veterans administration. We have pretty. Clear criteria, you have to, have recurrence after a trial of standard therapy. You have to try a course of bezelotoximab to prevent recurrence.

[00:20:37] Dimitri: And if you have recurrence after that, the VA will make either of those products available. In the non VA system, I honestly have no idea what our insurers do. I suspect it is a highly variable mixture of things, and I know that the cost is quite high. The orally administered product, I believe, retails around 20, 000 per course, whereas the rectally administered product is somewhere around 10, 000 per course.

[00:21:02] Dimitri: And again, I have no idea what insurance It's covering on that. That's one of the beauties of not being in the private sector on this. So highly variable from completely unregulated. Do it yourself to FDA approved products with high price tags.

[00:21:17] Angela: Wow.

[00:21:17] Marc: That's very interesting to hear.

[00:21:19] Marc: Dimitri, to stay with you, we want to change now to let's say the effectiveness and the clinical effectiveness, and I want to discuss your, study. But before we go into the details of the study, can you tell us a little bit about the context of the situation related to treatment of C. diff and, the place of FMT when you started to study?

[00:21:37] Dimitri: Yeah, and I would say that when we started the study, sort of analogous to where, Marie is right now with, Prevention of UTIs. There were promising, observational data at the time suggesting that FMT may have a large treatment effect, but there really was no RCT sort of the gold standard of how we evaluate interventions.

[00:21:57] Dimitri: this is the type of study that is needed and thrilled to hear. Marie is gonna be embarking on that for prevention of UTIs. you know, there were fairly, substantial observational studies, reasonable numbers, reporting significant effects. the tricky part with FMT is that there is a placebo effect in medicine.

[00:22:14] Dimitri: And when people are told that they are receiving something that, hey, this is, non approved, you need to sign a consent, this is something quite different. Outside of the ordinary, we are going to administer something that you may think is quite shocking, but it works nearly 100 percent of the time, especially when one of the outcomes is loose stools and, you know, sorry, there's no way to avoid being slightly gross when talking about C.

[00:22:37] Dimitri: difficile. Any of us who have run a marathon or done anything where you're nervous, you know that your mental state can impact your bowel motility. so when you are reassured that you're getting a highly effective treatment that will be better, you may change your bowel habits. And the first thing that you need to get a testing for C. difficile is a change in your bowel habits. So yeah. We thought that really it was important to have a true placebo controlled trial.

[00:23:01] Dimitri: There was one that we were aware of before when we were designing our trial, which was a study that, administered FMT or your own stool given back to you via colonoscope, done at two centers. Overall, it showed a benefit, but there was interesting findings where it seemed like the benefit was limited to one of the two clinical sites versus the other, which to us suggested that there is something that is being done.

[00:23:26] Dimitri: Outside of the product itself, some practice that's going on, and if truly FMT works, it should not work based on whether you do it in one site or the other. It should work all the time. And so we thought there really was a need and applied to the VA for funding for this, obtained it, went through the design process and a very long enrollment process.

[00:23:46] Dimitri: There's always a need. Thank you. you know, things that come up that you don't anticipate, one of which being a pandemic, and eventually came out with this study.

Great context. Thank you. Can you tell us now about the actual trial? For those who haven't read the article yet, which was published in November in CID, you should.

[00:24:03] Angela: And we'll put it in the show notes. So, Dimitri, us the whole, you know, from A to Z, we really want to hear about this trial.

[00:24:11] Dimitri: A to Z would be too long, but I'll give the brief summary is so when we first designed the trial, we proposed it as a trial, via Enema and then went through the design process and.

[00:24:21] Dimitri: Had various input from various experts, had a lovely executive team who helped steer this and came out saying that, no, really, if this is something that's going to be applicable and able to be done in non specialized centers, oral administration really was the way to go. So. Our goal was to find patients who had one or more recurrence of C.

[00:24:42] Dimitri: difficile and then administer either FMT via capsule or matching placebo. They were indistinguishable, and then follow them for the primary outcome, which was, quite a bit of discussion went into this, but the primary outcome was, Possible or definite recurrent C difficile or death occurring within 56 days.

[00:25:02] Dimitri: The 56 days is sort of a standard time period for the outcome. Safety data was gathered for 6 months. Definite C. difficile infection with signs of C. difficile plus a positive stool toxin test, possible C. difficile with signs of C.

[00:25:17] Dimitri: diff, so diarrhea, ileus, toxic megacolon with either a PCR test or no test or a test that was uninterpretable, but basically signs of diff, but without a positive stool toxin test.

[00:25:31] Marc: So, what were the results of the study?

[00:25:33] Dimitri: So, the results of the study, there were two planned interim analyses, when 50 percent of the, uh, Planned enrollment, had data collected and 75%.

[00:25:43] Dimitri: The study sponsor was very, focused on having a patient specific outcome with their argument being patients don't care whether their diarrhea is positive in the lab for something. They care does their diarrhea stop? Are they feeling better? Are they no longer having loose stools? So they really wanted us to focus on the possible or definite, recurrence. And at the first planned interim analysis, the primary outcome that occurred in 33% in the FMT arm and 30% in the placebo arm, which was clearly not statistically different. they then calculated a conditional power to detect a significant difference if the current trends held and if you went to full enrollment.

[00:26:20] Dimitri: So basically. If you keep going, what is the likelihood that a significant difference will be found? And that conditional power was less than 4%. So basically saying if you keep going, you have less than a 4 percent probability of having a significant difference between treatment arms. And that meant the pre specified criteria for stopping, the trial.

[00:26:38] Dimitri: So the study sponsor, the VA CSP recommended stopping, the Data Safety Monitoring Board concurred with that, and we stopped enrollment at that time.

[00:26:48] Angela: How did you feel about that, Dimitri? What would you have recommended if you were the sponsor,

[00:26:53] Dimitri: you know, ultimately you have the stopping rules and they are, put in for a reason. I think, given how the trends were going.

[00:27:00] Dimitri: It made sense. I remember where I was. . I was on vacation in Norway at the time. When you have an interim analysis and you get a call, you know that there's either 2 things.

[00:27:09] Dimitri: it was either so effective that it's unethical to continue enrollment, or that it's not effective and that you need to stop. And then the question is, well, why, why that result? I mean, we did the study thinking that well, there's promising data. It seems that this is a very effective, intervention.

[00:27:28] Dimitri: Why did it not work? And, you know, there's all sorts of possibilities. Perhaps we should have reserved this only for people who are having multiple recurrent episodes who have a higher chance of recurrence. And there was at least a suggestion in the numbers that there was, A hint of efficacy, but again, this was not statistically significant in those with greater than 1 versus with just 1 recurrence.

[00:27:52] Dimitri: Perhaps we should give more in the product. That is FDA approved for oral administration. The approved dose is taking it 3 days in a row and. You know, sometimes just amount matters. We all have a microbiota. That's made up of things. We ingest and maybe you just need a greater volume of going down to truly establish, Getting graph in there, perhaps we, despite choosing what we thought was a very well studied product that. There was some issue with the product. We are doing future studies looking at, engraftment data. We have stool samples from pre enrollment, and certain time periods after enrollment. And so we'll be able to see, was this an engraftment issue, or maybe it's just not as effective as we all think it is.

[00:28:34] Dimitri: I mean, the products that have received FDA approval in the United States, They certainly met criteria for getting in there, but they are not as promising as the earlier observational studies and people have pointed out that the randomized trial data is less, favorable than the observational data, which I think is similar to things we see in other things as you go to more rigorous studies.

[00:28:55] Dimitri: It generally is a little bit less effective. So who knows? would love input from others, including Maria, what she thinks of this. Thanks.

[00:29:02] Marc: Yes, let's go to Maria. Maria, you were not involved in the study, . what is your guess on why the futility that particular study for that indication?

[00:29:11] Maria: yes, So I did read the study results very carefully because I was very surprised by them. I actually, together with some other people, co authored a letter to the journal, pointing out what we thought was the main, let's say, challenge in, reaching the primary endpoint.

[00:29:29] Maria: So we saw that to be included into the trial, you needed to be, I think, 14 days without symptoms after having received treatment for CDI. And only then were you eligible for the, randomization. But most people who develop a recurrence develop it within the first two weeks after they stopped their treatment.

So, using this inclusion criterion, you were basically [00:30:00] ruling out all the people who were in most need, of the FMT. that is my opinion. And, you were pre selecting for the rare ones. who, eventually responded to antibiotics.

Yes. But the incidence of the primary outcome was about 30 percent in both groups, Maria, did you then expect that incident should have been higher if you would have had another, population, that you described that has recurrence within the first two weeks.

[00:30:29] Maria: But if you already exclude all the patients who would have profited from the intervention, you cannot expect to have a significant effect, the analysis.

[00:30:42] Marc: Dimitri, you want to respond?

[00:30:44] Dimitri: Yeah, thanks. So I'll just clarify. I think we, didn't do the best job of making that clear. So the enrollment could happen anywhere from 2 to 14 days. So the 14 day was the, outlier of how long you could be enrolled and you had to not recur at that point.

[00:31:00] Dimitri: But, anywhere, from 2 to 14 days, was the enrollment period, and on average, 6 days was when most people were enrolled. So 6 days had passed from the cessation of their antibiotics until administration of either the FMT or placebo, and there was a lot of, Discussion. Others have pointed out that if we give it too soon, there's the question of will your intervention still meet residual vancomycin or fidaxomycin or whatever they're being treated with, in the colon and perhaps, you know, you should wait longer.

[00:31:32] Dimitri: So there was some question of, like, how early should you go? How late should you go? The current FDA approved products are recommended to be given at 1 to 4 days. We did a post hoc analysis looking at among those who received the intervention less than 4 days from cessation of antibiotics versus greater than 4 days.

Did we see any benefit? And that's in 1 of our supplementary tables and there was no difference shown there. So there's no hint as of that, but I certainly agree that the optimal timing at this point really isn't known. I mean, I think you need to get the intervention in when you no longer have.

[00:32:07] Dimitri: antibiotic there to wipe out what you're trying to engraft. think the longer you wait, the more likely it is that someone will recur between antibiotic cessation and administration of the product. Now, if there's no sign of clinical recurrence at the time, I'm not aware of any data that says, like giving it at 3 days is better than 6 days if there's no.

[00:32:27] Dimitri: recurrence, but certainly the longer you wait, the more chance you you have of developing recurrence. And we certainly lost patients to that. So we would have people lined up for enrollment and we would get a call one or two days before saying that, sorry, , the diarrhea started and now I'm back on therapy.

[00:32:45] Dimitri: And so we would lose those to enrollment. So certainly some people didn't make it to be enrolled because it recurred. But among those who had not yet experienced recurrence, at least on the, data that we have it, we did not see any signal that getting them the intervention earlier versus later had any discernible difference.

[00:33:03] Maria: Ah, okay. That's very interesting. So it's not that clear anymore now to me.

[00:33:08] Dimitri: Very little is clear in this field.

[00:33:10] Maria: So what about the, microbiological, definition of the endpoint, which you already said it was a very clinical endpoint, not really a microbiological endpoint. Maybe that was also a problem.

[00:33:23] Dimitri: Yeah, that certainly was something, that we wondered As first designed, we anticipated a clear microbiological endpoint. there was a lot of debate amongst the executive committee, what should be the endpoint, as mentioned, they really pushed for a clinical endpoint, and as the funder, they, Carried considerable weight in that, when we looked at our subgroups of among those who had a confirmed, toxin test, there was no difference amongst the 2 groups.

[00:33:52] Dimitri: Again, though, that is a smaller breakdown of those. And those were, you know, in the subgroups who reported same thing with whether it's PCR testing or, any of the other components of the primary outcome, there did not seem to be a difference there, but certainly that is 1 of the possibilities.

[00:34:08] Dimitri: my guess, and this is purely speculation is that it's a combination of the. population that I suspect the patient who is most FMT may be someone who has multiple recurrences. And I think one thing that is very challenging in the field is differentiating someone who is having true C.

[00:34:29] Dimitri: difficile recurrence versus someone who is having bowel motility issues and happens to have some, um, Residual C. difficile present and nowadays with our testing, it is so sensitive and, certainly the PCR tests are, as we all know from covid and various other things, you can find residual DNA and have a positive C.

[00:34:51] Dimitri: Difficile test in the presence of someone having abnormal motility issues. even the toxin can be found in people who are having, motility issues who improve absent any therapy. So I think. Differentiating someone who is having true C. diff recurrence versus someone who is having post infectious bowel motility issues and happens to have a little bit of C.

[00:35:12] Dimitri: diff still present in their colon, is a real challenge and that's something that we struggle with clinically when someone calls up and says, Hey, I was told to let you know if I have recurrence of diarrhea and I had C. diff two months ago and now I had three loose stools. Sometimes it's pretty classic.

[00:35:30] Dimitri: They also have fevers. It turns out they have more than three loose stools, and they have all sorts of signs of infection, and you treat them. But sometimes it's pretty marginal. You ask them, did you feel like this when you had your prior C. diff? And they say, no. Is there any other reason you think you have diarrhea?

[00:35:45] Dimitri: Well, I went out and ate very spicy food last night, and I know that always does a number on my gut. And like, all right, well. I don't know what's going on in that case. So it's a pretty challenging situation, but I think finding the right person who you're confident has recurrent C. difficile and giving them a product that has good efficacy data.

[00:36:03] Dimitri: Right now, I think we at least have a couple that are FDA approved with, you know, trials that are demonstrating, , versus a placebo product that they have, benefit. That is where I, will be reaching.

[00:36:14] Marc: Yeah, Angela, I'm not sure what your gut feeling tells you, but

[00:36:17] Angela: Ha, ha, ha, Mark.

[00:36:19] Marc: Let's say, it's getting complicated. So, so Maria, what is the patient population that you are treating now after all the trials that have been done , for the C. diff infection indication?

[00:36:30] Maria: Yeah. So as I said, in Germany, when you, treat according to the declaration of Helsinki, you should have tried the registered products.

[00:36:38] Maria: So we say vancomycin and fidexomycin need to have been used. so minimum two episodes, And then, with the next recurrence after the treatment of that, I could actually, add the FMT, as a subsequent, treatment, but many patients only discovered that this exists after many recurrences. So, they are really multiple recurrent, like six or seven times.

[00:37:07] Maria: And most of them don't realize that this exists because not something that most physicians are aware of.

[00:37:15] Marc: is there information how many patients are treated per year Germany or in your institute with FMT for the recurrent CDI?

[00:37:23] Maria: Well it's really hard Yeah, , we have statistics for our hospital, and of course we know how many patients we treat with FMT per year, but those are not, necessarily patients of our hospital because as the person who manufactures the FMT has to administer it, the patients come to us from everywhere and then they go back home and home may be very far away.

[00:37:48] Maria: But there's no, obligatory registration, of FMTs. So if there's some physician somewhere that I'm not aware of, and he's doing this every day, I, I don't know. so this is why we first started a registry in Germany to at least Try to get an idea of what is going on. And now we've expanded this idea to the, European level.

[00:38:14] Maria: So that's one reason why we founded Euro FMT. one element of EurFMT is to have a European registry. or a unification of the different registries that already exist, so we can get a better sense of what's being done where, is it safe, is it efficacious, and also in Europe, we don't have any registered microbiota based drug.

[00:38:40] Maria: So we do definitely need FMT because otherwise there's nothing for these patients that we can still offer them.

[00:38:49] Marc: so far I trust your institute is a referral center for, Germany. You get patients from all over the place. How many did you treat last year? Do you have an idea? Is it in the tens? Is it in the one hundreds or even more?

[00:39:02] Maria: I would say it's around 40 and 60 per year.

[00:39:06] Marc: So one per week and it's not,

[00:39:08] Maria: it's not that much. So there are other countries where it's much more because it's reimbursed. and since it's not reimbursed, we are also not really, let's say, promoting this, because it's also something we do in our free time, and we can't really offer this to everybody under these circumstances.

[00:39:30] Marc: The registry across Europe is, I think, very important to quantify the use of this, practice.

[00:39:36] Maria: And

[00:39:37] Maria: we also have the new EU directive. This is really important to say also in this podcast. And, the new EU directive, categorizes FMT as a substance of human origin.

[00:39:48] Maria: up to now, the regulation was different in different European countries, and in Germany, it was a drug. But, with the new categorization, it will go more into the [00:40:00] direction of a transplant. maybe this will help us to get reimbursement for it. I'm really hoping that, because that would really, broaden patient access to.

[00:40:11] Maria: so much. It would be such a significant step forward.

[00:40:15] Marc: Yeah, Dimitri, you wanted to respond on this.

[00:40:17] Dimitri: was just going to make two points to those really good comments that Maria made. One of which is that, it highlights how difficult it is to do trials when here is a referral center in a very large country, Germany, getting 40 to 60.

[00:40:30] Dimitri: FMT cases a year, trying to do a study on this. So, you know, you generally only get small fraction of the people who are potentially eligible who will agree to enroll. Some people will say, no, I don't want to have a chance of receiving a placebo. And so if you're starting off with that small number, by the time you go through your various exclusion criteria, and then you say, are you willing to get a placebo?

[00:40:52] Dimitri: And are you willing to go through this study and have people contacting you? You shrink down to generally about 20 to 30 percent of people who are eligible who offer to enroll. And so you see that you start with a pretty small number. And by the time you go through those, you end up with a very small number.

[00:41:07] Dimitri: So these are challenging studies to do and get a good end out of it. And then the other thing I just wanted to point out is that. I've always found it really fascinating. to hear that is now in Europe as a whole is classified as a substance of human origin.

[00:41:21] Dimitri: I've always found it very challenging to sort of wrap my head around is this a drug or not? Because most drugs, you can look at a label and say, okay, this bottle of aspirin, the active ingredient is this compound, of which there is 99. 9 percent of it in there, and here are the fillers. And, you know, for every drug I can Pull up and, you know, read exactly what's in that tablet.

[00:41:42] Dimitri: What are the fillers? Is there gelatin? You know, what all gets put in? And this is something where I look at, like, they can't tell me what's in it. All they know is that, well, it's derived of these things. We can tell you that, well, it's at least this many of this family, but could be other stuff could be, you know, viruses honestly, it's one of the few interventions that you are given that, you read the label and you don't know.

[00:42:04] Dimitri: What's in it I'm sure the regulators really struggle with that. Like, how can we approve something where we don't actually know what exactly is in it? And does the composition change from lot to lot from donor to donor, even if we perfectly categorize it, you know, one time the donor goes and eats new products a month later, they come back and donate.

[00:42:24] Dimitri: It's slightly different, and how important is that, that it's slightly different? So it's a really challenging thing to classify, so clearly in the U. S., now they're FDA approved products. I honestly have to look if it's a drug versus a biologic, but it's a really difficult classification.

Maria, very naive question for me, it is now considered as a human substance, does this product now comes in the category of CAR T cells? And how are regulatory, persons now looking at the safety and the production, requirements? so you mentioned it's a good thing that it is now categorized as a human substance, but are we not shooting ourselves in the foot, as the Dutch say, by having it made a human substance.

[00:43:03] Maria: Concerning Germany, it can't get any worse than it is now. It's like impossible. Well, you always think that and then it gets worse. But I mean, classification as a drug is really tough. So I really doubt that it's going to get worse. And also what guides you in how something has to be processed, as a SOHO is the EDQM guide.

[00:43:27] Maria: And, I was also involved together with other people in writing the EDQM guide. So I can tell you that what is written in the new chapter on microbiota is feasible. So this is like rule book how you are supposed to do it. the EU directive refers to this EDQM guide as the, how to do it manual.

[00:43:54] Maria: So I'm pretty confident that this is an improvement. but every country has to implement this new directive until the end of 27. I'm sure that some countries Maybe Germany will be very creative in how to implement it without changing too many things because changing too many things will be a lot of work.

[00:44:18] Maria: I don't know exactly yet what's this will become in each individual country.

Well, that's very good information.

[00:44:26] Maria: I should probably point out that, Julesbert Keller and Christian Waes from Netherlands and Denmark, they were really, crucial. In getting this through, so, I would like to thank them again.

Excellent.

So fascinating discussion on Dimitri's trial on the difficulties of dealing with, a product, which is very dynamic. all the complexities that Mark talked about, and then the fact that you put it into somebody and

[00:44:54] Angela: it will behave differently from one recipient to another. We can't always predict, the behavior. Lots of complexities. so, overall, in light of Dimitri's trial, in light of other studies that we've seen, how should we use this tool? Who's the right patient for FMT? .

[00:45:12] Maria: think the guidelines worldwide are pretty uniform. They mostly say you must have had at least one recurrence and then you are eligible. And I fully agree with that.

[00:45:26] Angela: So you're saying Dimitri's, results, these interim results. They haven't, have they changed your approach? Honestly,

[00:45:35] Maria: not. have now treated probably, I don't know, at least over 400 people.

[00:45:43] Maria: And, this does not match my clinical experience. I know this is why we do trials. I know. still, I think. That, a recurrence in the patient who has had recurrences, they do know when they have one. That's my opinion. And I do trust, the results that, I can observe. in my patients. so I'm rather thinking what, sorry to say so Dimitri, but what went wrong in the trial that this result came out of the super efficacious method. So I'm rather trying to, wrap my head around that.

there are also other trials, um, there was a Cochrane analysis in 2023 and it was very clear. So this is why I'm also not so convinced that this data reflects reality because there were all these other trials that have been performed and published, in the meantime.

[00:46:43] Dimitri: , I think it's, you have to look at the totality. Some of those trials I will say were not placebo controlled. They were versus an active comparator. And I will say that like among the studies that, Got I believe it's the rectally administer product. it was a successful trial. but they're 95 percent confidence interval of showing benefit for prevention of recurrence. I think they overall said it, you know, that their product showed a 9 percent reduction. I could be a little bit off, but the 95 percent confidence interval range from as small as a 2 percent improvement or as large as a 21 percent improvement.

[00:47:20] Dimitri: And those numbers are, you know, they are better than than not getting it, but they are not as robust as prior non placebo controlled trial have. So I think there are other studies out there suggesting the benefit is not as large as prior. studies have shown. So I don't think we're a complete outlier in that case.

[00:47:38] Maria: But the Rebiota study is a great example because all trials on enemas have shown that enemas are less effective. So there's a great explanation for why Rebiota isn't. that efficacious because it's an enema. So that also for me, it's not in the same category as a colonoscopy or a capsule normally. so that doesn't count for me because I would never have performed an enema trial.

[00:48:06] Dimitri: it's one piece in the larger, Puzzle of data and I would also just point out that, you know, the, other product that is orally administered had a negative phase 2 trial and everyone wondered what was going on there. And so they increased the dose and they. Administered it 3 times versus 1 time and so I think there's lots of things, you know, it could be that if we had followed their lead, which was not available at the time of our study design and we administered it.

[00:48:32] Dimitri: Three times instead of once that a larger volume. So tripling the volume led to a difference. So there, may be quite good reasons it didn't work and why, it contrasts with the serious product that now is approved in the United States. But again, that product, you know, even with its 3 times, dosing.

[00:48:50] Dimitri: It's performance is still not as robust as the prior observational data, which I think is reflective of a lot of trials that observational data is generally better than trial data when you start enrolling the patients who, you know, have all the quirks that you have in a regular population that you have to treat in person versus a trial.

[00:49:09] Marc: So Angela, I think we're, completely out of scope here now because there's a naturally occurring pro con debate ongoing , this would be a great topic for, Esmit Global,

, all the discussion on the indication of the recurrence CDI. And. We're actually starting now also to see studies on, , recurrent UTI as an indication for this application.

, what's the current status there on the level of evidence or are we just getting the first, let's say, the first trials after the anecdotal findings? Where are we in that, context?

[00:49:43] Maria: Yeah, so there are some case series and, we also published, something there is, on clinicaltrials.

[00:49:50] Maria: gov, there's also a trial, but I have not seen, a published randomized controlled trial yet. but even if there was, I don't really think that [00:50:00] matters, because as you could just, witness, there can be so many ways to perform an FMT that even if we had 10 randomized controlled trials on, UTI, it would still be interesting with the 11th.

[00:50:13] Maria: So, I don't think these trials always have to be the only ones to have any meaning.

[00:50:19] Marc: Now, in the Netherlands, we know something of as selective digestive decontamination. It's not frequent transplantation, but it comes close in some respects. And after 40 trials, we still don't know, and we still don't agree.

[00:50:33] Marc: So Dimitri, what's your perspective on the recurrent UTI, indication for this,

[00:50:38] Dimitri: Promising. I would love to see further data. I'm thrilled to hear that there will be an RCT on this. think even when the first few come out, it'll be interesting to see how is it given which product I think one of the challenging things as we sort of heard with FMT is like calling.

[00:50:55] Dimitri: everything under one global label of FMT is perhaps too simplistic there really is like a what exactly do you mean by FMT which product which dose which frequency how are you administering it all of these things have to be answered and not just oh FMT works or FMT doesn't work it has to be how are you giving it and all those things need to be figured out.

[00:51:18] Angela: Yeah, that's a really good point. And I think, the way we do trials is, challenging, of course, for the traditional reasons, but also because, like you say, Dimitri, you kind of get one chance with the trial, right? You have to write down your protocol. You have to stick to it. But there are so many variations.

[00:51:35] Angela: In real life on how you can give things, how much of something you can give, what your patient should look like, , who gets whatever you want to give. When we spend all this money to do a trial and ask people to give their time for a trial, we worry about type one errors where you are concluding that there's a difference when there really wasn't a difference.

[00:51:54] Angela: But I think we Actually need to really worry about type two errors as well, where you walk away saying there was no difference, but maybe there was in real life that we missed a difference because we had one shot. We had one chance to get the right dose to get the right patient, the right population. , I like this idea that I think we all are agreeing with, that Maria says, you know, one RCT doesn't, , need to stand alone.

[00:52:21] Angela: There can be other ones. We can restructure, we can, have another hand at it.

[00:52:27] Dimitri: What I can say is that of the lessons learned, certainly if I had a time machine, I would go back and reconsider the dose.

[00:52:34] Dimitri: I would reconsider, whether or not we enroll those with one or multiple recurrences. And I would reconsider the travel because one thing we learned via COVID is that video conferencing and using digital, forms to obtain consent and shipping product worked just as well. Patients were much happier, with that.

Some did not like having A stranger coming to their home. Some wanted to meet at a restaurant. they very much preferred the option of doing a call now. digital divides do exist. Some people don't have the capability or the bandwidth to do such a thing, but it turns out that a, Digital enrollment and using shipping, which granted. Something is still showing up in an airplane, but at least that airplane was probably already flying. you know, that that was an option that in hindsight, we should have thought about long before.

[00:53:27] Marc: There's so much that we can learn and can improve too. actually make clinical trials more efficient and do clinical trials in a more efficient way.

[00:53:37] Angela: So as we come to a close, Maria and Dimitri, what are your key messages that you'd like to leave our listeners with?

[00:53:43] Dimitri: I would say, be as certain as you can that your patient has recurrency when you're considering FMT. where you are depends on what products you have available, but use the product that has the most robust data behind it that you can. Here in the United States, at this point, that is one of the commercially available FDA approved products.

[00:54:04] Dimitri: and then really try avoid antibiotics afterwards. One of the things I think is. Rather, futile is administering FMT to a patient who has a long track record of having 345 antibiotic courses in a year. why the newly administered, colonic flora will all of a sudden become resistant to those antibiotics is not clear to me.

[00:54:24] Dimitri: So, if a patient has a strong track record of using antibiotics, and we don't think that can be. Changed, I find moving to FMT probably futile. We're just going to eliminate it as soon as we spend all that time and effort to put it back in them.

[00:54:39] Angela: Thanks, Maria.

[00:54:40] Maria: So if you're curious about something or you feel that something could be helping your patient, but it hasn't been figured out yet, please stay on it, work on it.

[00:54:52] Maria: It's going to be very frustrating. but you will be getting somewhere. I think, about 10 years ago, I would never have thought that I would talk to a regulatory authority about how FMT should be performed and that I could make any difference at all. if you keep working on it, you can do it.

[00:55:13] Angela: That is very motivating. So, a huge thank you to both of our guests, Maria Wereschildt in Frankfurt, Germany, and Dimitri Draconia in Minneapolis, Minnesota, USA. And thank you for listening to Communicable, the CMI Comms This episode was hosted by Mark Bontan and Angela Huttner, editors at CMI Comms, Eskmit's open access journal.

[00:55:35] Angela: was edited by Dr. Katie Hostetler Oy and peer reviewed by Dr. Ariana Zaria of the Infectious Disease Department, Mother Teresa University Hospital Center in Tirana, Albania.

[00:55:46] Angela: The music was composed and conducted by Joseph McDade. This episode will be citable with a written summary referenced by a DOI in the next eight weeks, and any literature we've discussed today can be found in the show notes. You can subscribe to Communicable on Spotify, Apple, wherever you get your podcasts, or you can find it on ESCMID's website for the CMI Comms journal.

Thanks for listening and helping CMI Comms and ESCMID move the conversation in ID and clinical microbiology further along.