#126 – What’s the Microbiome Gut to Do with It

Hello antimicrobial audiophiles, and welcome to Breakpoints, the Society of Infectious Diseases Pharmacist Podcast. My name is Julianne Justo, and I'm a clinical pharmacist lead in infectious diseases at Dartmouth Hitchcock Medical Center, and an adjunct clinical associate professor in medical education at the Dartmouth College Geisel School of Medicine. Today, we're back to talk about the big beautiful group of microorganisms that live in us and on us, the microbiome.

Quite a bit has changed since the last time we reviewed this topic in twenty twenty two via episode number sixty two on novel therapeutics. Yep, pun intended. While the microbiota based therapies are more familiar to clinicians at this point, their real world implementation remains a bit tricky in practice.

So we're bringing in the experts to discuss the latest in microbiome research overall and more specifically what's happening with microbiota-based therapies for the management of Clostroduites difficile infection in the This podcast series was supported by an educational sponsorship from Nestle Health Science. We thank them for their support of unrestricted high quality educational content from SIDP.

So our first guest today is Dr. Krista Gens. Krista is the System Antimicrobial Stewardship Program Manager at Alina Health in Minneapolis, Minnesota. She has over a decade of experience in infectious diseases pharmacy and has been a key leader in advancing antimicrobial stewardship across the continuum of care. Krista has helped launch the FECO Microbrata Transplant or FMT program At ALANA Health for patients with recurrent C. difficile infections.

In fact, from twenty eighteen to twenty twenty three, more than two hundred patients received FMT through this initiative. That's incredible. Kudos to you guys, Krista. Of course, she has a strong interest in CDI, the microbiome, and One Health. Her first review article on FMT and emerging CDI treatments was actually published way back in twenty thirteen, and she has continued to contribute through multiple publications and presentations in the years since.

She is a like mind when it comes to maintaining our good bugs. So welcome, Krista. We're excited to have you. Thank you. It's an honor to be here. Thanks for inviting me. Wonderful. And our second guest today is Dr. Javier Viafuerte Galvez. who is a gastroenterologist at Beth Israel Deaconist Medical Center and instructor in medicine at Harvard Medical School with clinical expertise in immune-mediated digestive disorders, particularly Clostrodies Diffecle Infection, or CDS.

He leads an NIH funded research program, or K twenty three, investigating immune, metabolic, and microbial predictors of CDI outcomes. His work has identified novel biomarkers, including stool interleukin 1 beta and toxin concentrations that differentiate CDI from asymptomatic carriage and predict adverse outcomes. He is also part of the Celiacs Center at BIDMC and has investigated long-term adherence to a gluten-free diet and ethnoracial factors in celiac disease diagnosis.

He's currently pursuing a master's degree in biomedical informatics to apply computational approaches to redefine the C. difficile colonization to infection continuum. God bless you for doing that work. So welcome, Javier. We're excited to learn from you today. Thank you so much. Uh hi everyone. We're so excited to have you guys from different walks of life and to hear your perspectives. And like we said, we've talked about the microbiome before, but obviously the science has been advanced.

So I'd like to start with the following. What is the latest in our understanding of the role that the microbiome plays in human health? How does that inform our understanding of the pathophysiology of C. difficile infection specifically? Wow, that's uh you know, such a huge question. Well, actually two questions. I guess you know, the first one Our latest understanding uh in the role of the microbiome in human health. Uh, I think we are discovering important correlations.

between microbial composition function in multiple diseases uh from you know digestive diseases, neurological diseases, and endocrinologic diseases, but really the whole spectrum of human health. just like we interact with the environment through our skin or respiratory tract, we interact with the environment through our uh GI tract. So these bugs are really our interest

of the world. There is more that w the that we are learning every day that we can actually integrate into our clinical practice rapidly. And I think that's one of the biggest challenges. Now, uh narrowing things to to C de Facile, I think this is one of the model designs.

where uh we've learned about the importance of the microbiome. I think uh we can try to summarize things as a dysfunctional uh composition and functional of the gut microbe population is what predisposes us to getting C. diff infection and That imbalance is uh sometimes provoked by a course of antibiotics or some chemotherapy, or sometimes some underlying disease like inflammatory bowel disease.

And uh We are learning little by little what species and what functions those species of microbes that go missing have and how these lead to infection or colonization, which is really a continuum. So little by little we're trying to pinpoint which ones, but I think we're really early. There's some work we recently did trying to identify, for instance, species that could help prevent colonization. Through bioinformatic pipeline.

And I think that's you know the subtext of this. All this data that we now have, we're only able to interpret it thanks to computational advances. You know, us uh clinicians are having a lot of difficulty interpreting. So that's really why, you know, I I I got into the masters that you mentioned earlier. To speak the language and be able to understand a little more these uh these techniques that lead to the knowledge that we're getting.

I noticed some of the preprints that you have on like bioarchive already. You're working with colleagues and it seems like your whole research team is trying to figure out are there certain bacteria that are characteristically lost that would set the environment up for development of C. difficile colonization and then infection. There was a lot of

technical terms in that paper, but hopefully I'm understanding that correctly. I think yeah, I think you said it best. So which bacterial species But also, you know, it it goes deeper and deeper, you know, it's like the Russian doll because now now we're talking about strains too. Because uh for instance with uh fake alibacterium proxy, we know that it's it it's strains that actually can favor colonization resistance.

And it's not like any of these uh bacteria. Uh and who knows, m maybe we'll go beyond strains. So it is very it's the Russian doll metaphor is becoming very clear, right? It's getting more complicated the more we look. Yeah. Well, thank you for setting that stage for us. We're excited to see more come from your group. Good luck with your masters. I can't wait to see what you come up with. And also to see what else is coming out in the field.

For us as clinicians, within the last year or so, there have been significant shifts in the availability of C. difficile therapeutics. So can you guys help us review the microbiome based therapies that are on the market in the United States to manage C. difficile infection? Krista, let's start with you. Yeah, so uh there are kind of three products that we can talk about today and I guess I'll start with the traditional fecal microbiota transplant, which I'll talk or refer to as FMT from now on.

And a lot of us ha are familiar with this and I mentioned or as was mentioned this was what we used to administer at my health system. a donor stool and it currently requires an IND and that's where I'll kind of take a sidestep here and talk a little bit about open biome. Open Biome was a non-for-profit organization that was the largest supplier of FMT products.

For a very long time. Unfortunately, this has changed recently as you alluded to because of the FDA's recent decision to end enforcement discretion on that I so it can be a little confusing when you're talking about it'cause it's FMT I technically always required an I and D, but the F D A essentially announced in July of twenty two thirteen, and I remember when this came out, they essentially announced that they wouldn't enforce it.

Um but now that has changed and so large stool donor banks like Open Biome unfortunately are unable to supply FM I will say though that Open Biome has transitioned their webpage a little bit and they do have directions on there on how to start an FMT program. And it's like a turnkey model for building your own hospital based FMT program. So they're still around but they've definitely pivoted their business.

So if you do want to go the FMT route, it can be really challenging to find somewhere that will So I'm lucky to be in Minnesota and we do have the University of Minnesota nearby. that is able to offer that to patients. But depending upon what's available in your area, it can be done via different routes and protocols can vary. Which is you know, offers a an interesting challenge.

of in itself. Uh the cost is also super variable and really depends on the the mode of administration, but I can at least say, like on the University of Minnesota website, it states that it can offer it free of cost to the patient. So it really is gonna be pretty variable and kinda difficult And that leads us though to the newer products that have been recently approved, and that includes the Fecal Microbiota Recal Enema product.

AKA Rebiota and then the Fecal Microbiota Spores, otherwise known as VAust. So if we talk about the fecal enema product right now, it is a ready to use Mycobriota, form and an enema. You have to give it within 24 to 72 hours from your last dose of antibiotics. Both of these are gonna be coming from a specialty pharmacy, so that adds an another kind of challenge sometimes.

But the NMO product is frozen. It has to be thawed under refrigeration for at least twenty four hours. So that can sometimes be a minor logistical hurdle. And then once you do thaw, it has to be used within five days. So there's definitely some planning involved. If you look at the spores product, you at least don't have to have that freezing and thawing cycle. But similarly you have to start it within two to four days of your completed therapy.

Interestingly, the spores require a bowel prep, so magnesium citrate one day prior. And then eight hours prior and then you have to do the four capsules once daily for three days. So is that enema? At least you can do oral capsules. But this also has to come from a spot. The cost is definitely probably the biggest difference between these products.

with the fecal enema being uh around ten thousand dollars and then the oral spores being close to eighteen thousand dollars and that's cash price so insurance coverage. So those are kinda the I would say like the big three options we have. Very good. So just to summarize, there's three microbiome based therapies that we would think of and clinical use for patients. The first one being the traditional FECO microbrata transplant.

The biggest supplier in the US open biome unfortunately is no more as of the beginning of this year, but donor derived FMT is available through local institutions through the pursuit of that IND or investigational new drug application. So we will, by the way, make that wonderful open biome webpage link that uh Krista mentioned. We'll make that available for our listeners in the show notes in case you're interested in getting some support.

for starting or potentially restarting a donor derived FMT program locally. The other two options being those live biotherapeutic products or LBPs with varying formulations, right? So the rectal enema versus the spore capsules, and they have varying costs and logistics. So very good. And just for the sake of reference here, we'll verbally refer to the Fecomacabrata rectal enema product, but that technically the generic name of the package insert has that suffix of live dash. J S L M.

And then the fecal microbiota spores, that's what we'll refer to them verbally, but the again, the name within the prescribing information has that suffix of live dash BRPK. That's a mouthful, so we're not gonna say those suffixes every time. But it's also interesting that the fecal microbials

in particular, require within the package insert that bowel prep prior to administration. I know a lot of folks have looked at that and they're like, Huh, why is that in there? Aside from that's how the trials were designed, that's a protocol that they followed.

We were able to find that the American Gastroenerological Association or AGA in their guidelines suggest it in part has to do with flushing out any residual antibiotics from the GI tract that were being used to treat the C. difficile infection. ahead of SPORE administration to make sure you have the optimal effectiveness for these agents. So we'll make sure to again put those links in the show notes as well.

And it does say that if a bowel purge is given, FMT can be given one day after stopping antibiotics. However, if no bowel purge is given, then three days off of antibiotics is recommended to allow for clearance of oral antibiotics. So I thought that was a cool little pearl that we would throw in there because It's a lot of our listeners that end up being the ones trying to operationalize the order of these different events for these patients.

And then I think one more piece, Krista, can you help us understand like what's the language for the specific indication, particularly for these LBPs? Yeah, that's a really good point that these are not treatment. This is purely for prevention. of recurrent CDI. And I think that is something to really that also I guess differentiates it from FMT, which FMT can be used for the treatment of something like fulminant CDI.

Excellent. Thank you for clarifying that. So now that we have a sense of what is available within the US market, how and when do national clinical guidelines recommend that these therapies be considered for use? So, you know, the AGA guidelines are the most recent and and and thorough attempt to summarize the evidence around the use of these microbial therapeutics.

They make recommendations for CDI and also they recommend against routine use of these for other diseases like gastroenterological DC more commonly like alsofcolitis, Crohn's disease, pouchitis, and IBS. They break down CDI indications into first recurrent CDI and second refractory severe or false.

So let's start with a with a ladder, the severe refractory severe or fulminant. So they define severe disease as per the IDSA infection Society of America criteria of leukocytosis more than fifteen or creanin more than one point five. They defined fulminant disease through shock ilias or megacolon.

And recommend consideration of FMT, so the conventional FMT with donor stool, in patients who have not responded for over 24 hours to standard of care and type by I. One thing I really like is that they recommend a multi subdisciplinary evaluation with gastroenterology, infectious diseases, and colorectal surgery. The therapy they recommend is conventional FMT from screen donor stool administered intracolonically either by a flexible sigmoidoscopy or colonoscopy without colonic lavage.

Why no colonic lavage in uh in this case? Because there may be Ilias or megacolons, so it's just impractical or dangerous. And the second thing is it's time. Right. Th this is a an urgent emergent procedure. When we used to do it it would be something that had a twenty four hour clock to be done. Now, let's go to the other indication, which is uh recurrent CDI. So they further break down their recommendations by the degree of immunosuppression.

Uh I mean this is a cautious approach based on the limited data on the safety of these FDA approved microbiotherapies for immunosuppressed patients. However, the breakdown it is itself based on anecdotal evidence of harm with live therapeutics in immunocompromised patients.

Y you probably r uh will remember this the older story of uh Esbulardi fungimin in in some severely immunocompromised patients uh who uh were given probiotics. So they recommend uh considering microbiotherapies for prevention. uh further recurrences after completing a course of standard of care antibiotics in a second recurrence, meaning a third episode of that cycle. These uh therapeutics, uh the FD approved ones include the Spor capsules or VOS.

the stable enema preparation that I uh usually refer to as RBT, and the conventional FMT. So let's go by the degree of immunosuppression. So mild and moderately immunocompromised patients. They recommend only conventional FMT as really good evidence for its safety exists. In severely immunocompromised patients, the guideline recommends against all microbiota therapy. This is an era where I honestly disagree because the degrees of immunocompromise are rarely objectively

One of uh my uh colleagues uh in infectious disease, Doctor Carolyn Alonso has actually been working on defining this. And, you know, looking through literature, the definition of the degree is really, really not clear. Clinical behavior of patients may may differ independently of the mechanism or of immunosuppression or lab parameters like like uh neutrophil counts or C D four counts.

So the other point is that since uh conventional FMP is not realistically available in most of the US anymore, we're left with recommendations that don't really reflect reality, right? Uh if you have someone who's mildly or moderately immunosuppressed, which is for instance, all my I B D patients Am I not gonna give them uh an LBP? And finally the recommendation against uh a therapeutic I think it should be nuanced by shared decision making, you know.

If uh granted that patients are not necessarily in the their best moment to make a uh shared decision making. uh but uh perhaps with their family members and with local expertise. Uh for instance, uh there there is expertise of FMT in profoundly neutropenic patients. in many institutions, uh especially since this has been trialed as a prevention for uh grap versus host disease. So I think that's one of the areas where I feel like the guideline uh should give clinicians a little more leeway.

Thank you for that. That's a wonderful overview. Um, and and I definitely appreciate, and that's part of why we have these podcasts, you know, to kind of walk through where's the current totality of the evidence, what are national guidelines. And it really does come to specialists like you in those difficult cases.

where they be, you know, an attempt to prevent recurrent CDI in someone who is severely immune compromised and is really suffering significant morbidity and potentially mortality risk for the potential of subsequent CDI episodes.

And then it's difficult difficult these days with the loss of US easy access to conventional FMT via open biome. So I definitely hear where you're coming from and That is heartening actually to hear that, you know, you're having a lot of these discussions about situations that might be beyond what the AGA guidelines for fecom microbiota therapies are recommending.

that mimics at least what I'm seeing here at Dartmouth, where we are still considering some of these options for some of these patients. And it usually is Shared decision making with a patient, with a primary team, as you said, a multidisciplinary approach.

So I definitely can see that debate reflected in our own practice locally. But Krista I also want to hear from you. So would you agree that the AGA guidelines in this particular situation, might be too cautious or conservative when it comes to their wrecks for the severely immune compromised patients in particular?

Yeah, thanks Julie. That's it you know, it is a tough question, but you know, I do agree. I think in many cases, especially with what we know about FMT it's clinically reasonable to think the benefits could outweight the risks of LBPs for immunocompromised patients, even if those risks haven't been fully explored in the literature.

So, you know, well I think the guidelines give us and they state in there that they're conditional recommendations, right? And they're based on low, very low certainty of evidence. I think there's definitely room for clinical judgement there and especially when we're trying to balance the safety and the risk benefit scale. for individual patients like Javier was mentioning and the fact that it's really challenging to get FMT these days, I think that's a reasonable consideration.

But I think, you know, I also kinda exercise a degree of caution here too, obviously. Like I think anyone would you know, I I'm I'm cautiously enthusiastic about L B Ps But you know, I m I think it's also fair to say they don't have the same level of biodiversity as traditional FMT and we don't know yet how they

to each other so there's a lot of excitement here but a lot of a known but I think that's where like when we have experts like Javier and we're doing shared decision making, I think that's very reasonable. Yeah, I definitely appreciate that perspective uh from both of you, kind of where understanding where the data are, where the data end. And actually as you guys are talking, I I just hear a call for additional research.

All of these are research questions in large part due to lack of data either for these specific indications, these specific patient subpopulations that we have. So I think it makes a lot of sense and I would encourage again our audience, because we know the demand is there. We know the need is there for our patients to have these therapies. you know, it probably is ripe for a local investigational trial that's assessing because there is

to a certain extent clinical equipoise on a case by case basis. Are either of you kind of working on some of those or are you familiar with colleagues that might be working on those currently? I know like the University of Minnesota But yeah, not nothing uh uh uh locally other than that. So I I agree, like definite need. I think there are some subgroup analysis of the of the tribe.

uh th both the capsule formulation and the uh enema formulations. So there are some subgroup analysis from the enema formulation. suggesting that there may be a you know, some safety signal for uh immunocompromise. But that I think that's really you know, subgroup I I I rarely go, you know, I I'm like a little reassured, but I'm not like I feel like I can do this without a very in depth discussion with a patient if I had to go for these. Definitely requires specialist care at that point.

My rule of thumb though is that, you know, these products are vastly m more screened and controlled than a regular donor stool. So and regular donor stool seems to be exceedingly safe. So if if I had to have a guess, they're probably safe, but just don't want to know. I think that makes a lot of sense. And hence at at the point where I think the AGA guidelines are is very appropriate understanding where the actual data are.

So moving on in addition to these microbiota based therapies, there have been even more changes when it comes to available CDI therapies in particular the adjunctive therapy of bezlotoximab. So can you guys update us w what happened with bezlotoximab this year? Uh sadly it's it's off the mark. Merck has not provided much detail directly, however, based on multiple sources it appears that it it was not profitable. Beslo was, you know, really the first FD approved advanced therapy we had in.

So it it it was really a big change for us. Uh it reduced uh absolute risk of recurrence by about fifteen percent. Which compared to FMT may be modest. However, if we combine this with uh judicious antibiotic stewardship and small iterations uh in in care to manage post infectious GI symptoms, It helped many patients who are now baffled by the loss of this option.

In our experience it it it really worked well in Massachusetts, you know, it was both in the Medicaid and Medicare and Mass Health formulary. So basically if we had a patient over the age of sixty five we didn't need to get prior authorization and and it was basically guaranteed that we could get them into our an infusion center.

And our fission center found a way to schedule them before the end of anti of the antibiotic course. So we had a well-oiled system for patients with recurrent CDI uh with uh with bezil. So this uh change comes uh w the one of the worst possible times with, you know, open biome and and and thus conventional FMT being gone and in addition multiple barriers to access more narrow spectrum antibiotics such as Fidaxomy.

I I wanted to point out that there are some subgroup analysis of the Echo Sport trials for VOS that would suggest that the effect is uh robust to repeat antibiotic use. But bezotoximas is really the workforce for these patients who had a substantial risk of repeat antibiotic exposure. Such is common situations, patients with recurrent UTIs due to kidney stones, urinary stents, or uh recurrent respiratory infections from CF, bronchictasia.

So patients we see all the time and that I feel like ID docs see even more frequently than us in gastroenterology. Then the other population that had a great benefit were the patients with C V I D uh common variable immunodeficiency, or the patients with

substantial uh B cell depleting therapies. So for instance people who had a lymphoma and were after a RCHOP uh for with retamab or patients with multiple myeloma patients with multiple sclerosis uh receiving these therapies who really are missing humoral immunity and may not have as much, you know, microbial dysfunction driving cycle but but really a deficiency in the humeral immunity. So uh it's it's a big loss.

Yeah. No, I feel for you and for all of our patients, to be quite honest. It's it's sad to see Besla go the way of other antimicrobials whose business use cases just didn't work out. I think it's it's all the more reason to kind of discuss the latest available therapies which also come with hefty average wholesale prices as kinda Krista alluded to before to see if w if and when they can be optimally utilized.

It's hard enough to get a new antimicrobial or infectious disease therapeutic to the market. So to have another one that kind of falls off the market is is very sad. So let's all have like a moment of silence for Beslo Toxima. Yeah. R R I Peslo. R. P. Beslow.

talk a little bit more about which of these microbiome based therapies that are still available for CDI, whether it be the traditional donor derived fecal microbiota transplant or FMT, the fecal microbiota rectal enema. also known as Rebiota and or the Fico Microburata Spore Capsules, also known as Vaust. Um, which one of these products are you currently offering locally, if any?

Uh well I can talk about what we're doing in start off with another kind of big sigh about where I really mourn the loss of the open biome product. you know, once that F D A landscape shifted, as we discussed, we had to abruptly stop offering FMT at our health system. And obviously pains my heart'cause the the program that I worked so hard to build disappeared, um, almost overnight when we were informed that Open Biome could no longer send us products.

So, unfortunately l us, like many institutions, just weren't equipped to take on the labor intensive process of individual I and Ds and daughter screening. Uh I've already alluded to this. I mean, uh one of the benefits of I about being in Minnesota is having the University of Minnesota nearby. So we still have that option for those rare cases where FMT is truly needed, like fulminant C DI.

If we do have those cases, then we will transfer them to the University of Minnesota. But now as we're discussing today, there is excitement surrounding L So we we haven't protocolized yet and neither is uh uh neither product is on our hospital formulary related to some of the costs that we've already discussed, but However, we have seen operational success in the outpatient space, and this is really

I think what's exciting is the role of specialty pharmacy in this area. We are really fortunate to have, for example, an ID pharmacist on our Alina special pharmacy. and she's been navigating some of the prior os processes and been doing so successfully. So it's been giving us a little bit more experience on that side of things. And we've had patients

receive L B Ps with like a zero copay. So it's it's one of those things where we're still learning and trying to figure this out, but I think I'll just put in a plug for a specialty pharmacy'cause that's really kinda having a moment right now and it feels this particular space feels like it's another area where specialty is really gonna come in clutch.

So a quick shout out to Henry Ford. They recently had a poster at At MAD ID specifically looking at this and they did a QI initiative. So a lot of cool research and Yeah, th they had a really nice piece in uh Contagion Live that we can link into the show notes as well talking about that Henry Ford experience. Um, I do think, you know, a lot of our audience, y you guys are the folks that implement uh these changes as the landscape is changing, I think

Breakpoints is putting the call out there. Uh get her done. You know, let's make sure whether it's having specialty pharmacy available, Dartmouth Health also has a fantastic specialty pharmacy group. And we've been able to get um patients these L B Ps as well. But we're like you, Krista, very much at the front end. I think we're gonna talk about guidelines for C Dive treatment this week as of the time of this recording. So it's all kinda happening now.

Javier, what about you? What are you guys doing at B I D M C? So we have mostly been using VOS, the the spore capsule preparation for our patients with uh recurrent CDI. W while there are no head-to-head trials, VOS seems to have some superior efficacy compared to RBT, to the NMF preparation, uh as compared to placebo and the prevention of recurrence of CDI.

Um just gonna quote you know some numbers from uh from the AGA guideline. These are relative risks of recurrence. So a relative risk of recurrence after conventional FMT Is decreased by one one point ninety seven with a ninety five percent confidence interval of one point thirty six to two point eighty six. The spore preparation or VOS is an RR of one point forty six. with a confidence interval from one point twenty one t uh to one point seventy five. And then the live anima preparation

has an RR of 1.17 with a ninety-five percent confidence interval of point ninety nine to one point thirty nine. So this is really where we're from where I'm drawing uh This you know, superior efficacy argument. Now, we did consider offering a R B T but uh dedicating a procedure room and staff to administer the NMA was really

not easy to justify to our division because you know that room is competing for colonoscopies and endoscopies. So hard to make an argument to to the administrative team about that. It is my understanding that the company now offers uh at home administration services but no patient uh has chosen this option over capsules to date and I have uh um you know offered it as an option so I I have not had uh much buy-in yet.

I can imagine, you know, if if you're able to swallow capsules, enema does not seem very uh, you know, charming as a as an option. I have yet to find a patient who w is unable or unwilling to take the bowel prep. And I know that this has been brought up. It may be just a selection bias, because if you're seeing a gastroenterologist

I guess you're you know you're more likely to know that uh gastroenterologists send people to bowel preps. But the bowel prep for for the spore preparation is really uh you know less than what we use for video capsule endoscopy. So it's very tolerable. It's you know, very, very minor. Uh so says the GI doc. Yeah. It's basically the equivalent of a medium dose of polylenglycol for concentration. So it's considering it a lavage is is Fair enough.

But anyway, I have had a a few patients who could not take the capsules due to m neuromuscular disease. You know, they have a a peg tube and uh there was really no way to open up uh those capsules. Uh we did ask. Uh the people uh at Nestle and they were like, Mm, no. So we ended up doing a uh long tapers of liquid vancomycin, followed by crushed and dissolved Rhafaxamin Chaser.

Of course some good education and antibiotics thort trip and it did the trick, but you know, those those patients were really uh tricky ones. Uh to manage. Without an advance there. Oh my gosh, there's like so many really good pearls like all loaded in there. Thank you. Um and yeah, it sounds like even you're still seeing these patients that still need customized care plans based on what's happening. I think it's also

As a pharmacist, I love to know when I can and cannot uh open capsules. I'll be honest I might not have even asked the question if it was this particular fecal microbiota product. just because of some of the perceptions that kinda come along with that. But it's helpful to know that you reached out to the manufacturer and just based on their data, it's not recommended at this time. Also the something that I was learning as we were going through'cause we have

talked to these manufacturers over the year. I don't know about you guys. I I tend to find that they're open to to feedback as we've been going through. And I remember asking about an at home option for the rectal enema product many years ago. And I'm not saying that it was as a result of my individual question, but I do think that the various makers of these LBPs have tried to be responsive.

in both offering as an example the home administration program, which by the way, does have home health nurses, so they're not just mailing this frozen rectal enema product to the patient's home and saying good luck. Um it's it's coming along with some some wraparound care to assist with that. I personally have not had any patient pursue that option yet. Krista, I'm not sure if you have. No, not to my knowledge anyway.

Yeah, but I just know that we have an audience that deals with a variety of different patient needs and so if that's something that you wanted to investigate, I think that's worth looking into. As we're on a train talking about clinical pearls, I want to know what other clinical pearls have you guys learned as you've implemented these therapies into your practice. Krista, can I start with you?

Yeah, absolutely. I think I might just touch on Some of the operational side of things'cause I think we've talked about You know, the outpatient administration and insurance coverage and that kind of thing, but I think one of the biggest things we've learned is that it can take a while for the prior authorization process to go through. and then it can take a while to get the product from the specialty pharmacy. So you really do have to plan ahead. It's not something that

you know, in day nine or ten of their oral vango or phadoximycin you're suddenly thinking about, oh, maybe we should look at this product. It's something that you really should prescribe on the same day that they're starting

C div in order to get it on time. So I think that's something that people need to keep in mind. It's not something Uh you know, thinking like on the inpatient side too, where if we have non formulary products we're used to being able to like oh we'll just order it in and get it the next day and that's not the case.

Like this. And I I wanted to add one other thing too, which um we've kind of semi touched on, but I one thing I've really learned from patients over the years is that even with whatever product you're looking at, whether it's traditional F M T or erectal enema or spore capsules. There really isn't a yuck factor for these products. You know, most patients are so desperate to never have C diff again that

F M Ts or L B Ps are no issue. There's no question for them. And I had one patient case that really stuck with me because We were both around the same age, were otherwise healthy, we had young kids and she described to me the pain she experienced. I mean, she described it as someone wrapping barbed wire around her intestine pulling. Oh, God. And yeah, I mean and she had a pretty severe case, but this is the kind of patient that we'd be looking at.

And I cut asked her at the time this was actually before L V Ps were available, but I asked her like, Well what do you think of FMT and she was basically like, Where do I sign up? She's like, There is no yuck factor for me right now. So Right. Yeah, it you know, with for most patients with C D I it's not gonna take much convincing, I guess, as far as like trying to navigate how potentially yucky these sound. I mean, I think the li to me, the logistical and the economical issues are the biggest

That's fascinating. Yeah, Javier, what what are the pearls that you've seen? Are they in line with what Krista's describing? Oh absolutely, absolutely. And you know, going to the to the yuck factor, you know, I have patients that, you know, will just show requesting FMT. Just to just to have the you know, the disappointment of learning that it's no longer available.

I've had patients who come and tell me, Well, I've tried uh FMT, you know, I I got m you know, uh the material from my uh n nephew a couple weeks ago, tried twice, it doesn't seem like it worked. But the fact that it's regulated against doesn't mean it's not happening in the community, which I think is a is a really good argument to get it back, you know, in in in the community.

But yeah, definitely there is a lot of uh motivated people and and that that just highlights how the experience of of recurrent C diff is. It's really it one of the worst things I

describe. Absolutely. Um I agree also with uh what Chris just said. The the ideal moment to just prescribe an L B P is when you start the antibiotics. Otherwise you're not gonna get them. Right? And and sometimes we also we actually have to just uh Do a a a long uh long tape or just to get it uh just to get uh to the LBP.

Because really ev in someone who's recurred two or three times, just time off of the antibiotic is every day is the risk of recurrence, right? Sometimes Oh the Yeah the capsules didn't make it for two days. So I was actually gonna ask you that question, Javier, considering the sequencing of timing from the end of CDI treatment um and having a very specific space before the LBPs are administered with whichever method.

I was about to ask if you do in fact find yourself sometimes extending the CDI therapy in order to coordinate that. It sounds like you do have to do that sometimes. Absolutely. Yeah. And sometimes it's even, you know, extending until they get to see me in the office and I can you know, order it because it it I I cannot really, you know, prescribe it without knowing that it's truly recurrent CDI because it's it's not rare that people, you know, are colonized and have post infectious IBS.

That could be a whole episode on its own. Certainly. Um but it's I think um w we've already kind of alluded to the fact that there are some tapers and some kind of pulse regimens and stuff like that. I've also seen that employed in practice too to help patients kind of get through to to that timing. I think

By the time you get to a third episode of CDI, a lot of the regimens are going to be very customized, right? With hopefully specialists across multiple teams involved. So that makes a lot of sense. So really quick, I d I think our audience is very interested in this, but I'm just curious, just to be super clear, have either of you used specifically LBPs on the inpatient side at your institutions to date?

No, we have not. The case for use in patient is is not that frequent, right? Uh they're not indicated in fulminant. C DI and we don't have any data to s you know, any good data to suggest that that it they would be Useful there. So it you know, giving it in patient for prevention of recurrence it often patients are still on antibiotics, you know, before discharge. So there's really I don't think there's a good uh rationale to to use the current

Yeah, I think that makes a lot of sense. So I I agree with you, the use case for inpatient utilization of the LBPs, particularly for their unlevel indication of prevention of recurrent CDI, is gonna be rare that you would have that timing line up while uh a patient is hospitalized. So I think that's helpful for the audience that is kind of

Delving into this area, getting back up to speed. Um this area, it sounds like from what both of you are describing, is ripe for again, many in our audience, especially our trainees, to get involved in QI projects that improve our health systems overall and increase that timely access to these therapies. So like what Henry Ford is doing and what I know a few others are doing as well.

So we're turning our attention to much the same thing here at Dartmouth where like I said we've managed to do LBPs in the outpatient setting thus far in a handful of patients, but We really need to partner with specialty pharmacy and these GI Clinic, multidisciplinary ID clinic as well to operationalize the sequence of events moving forward. Especially I think it's hard if the patient

starts in the hospital setting and then you're trying to transition them to the outpatient and time everything. I think that it's a it's a tall order. But you know, folks in this audience are smart and we can do it. So kudos to those of you that have already worked that out and I encourage you to to publish on your experience so that everybody can learn from it.

All right, so we've talked a lot about kind of current state for these microbiota based therapies. Do either of you have plans to expand these therapies, either the number of products or process of care or otherwise, you kind of have alluded to a little bit, but kind of what the burning thing, if anything, that you want to do next in this space.

Yeah, well we're we're basically in the discussion phase of including LPPs in our clinical pathways and obvious That's one of the things I like about my job as a And I'm a Corbial Stewardship Program Manager for the system is that I'm over both inpatient and outpatient. And this is a great example where we're gonna need a lot of

collaboration between inpatient and outpatient and it's obviously as we already mentioned a great opportunity to partner with our colleagues in specialty pharmacy as you mentioned. So We aren't there yet, but we're definitely discussing on how we would do this so we could get the timing right for all these I think we were in a similar situation. Our health system, so mm b B I D M C is now part of BILH, so there's a new guideline in process of being approved.

I've been to some of those meetings. However, uh the practical clinical pathways are not really yet part of this effort because These are very dissimilar hospitals and and and community practices. So implementing these uh you know, these guidelines uh at different sites it may pose various challenges.

But within B I D M C Monica Mahoney, one of our ID pharmacists, uh she spearheaded this this uh effort and together with a specialty pharmacy, there's really a very streamlined process to obtain uh VOS, the the And we also, you know, were able to provide feedback to Nestle about the assistance programs uh to which they were very receptive because

Once we had a patient that you know realized that they needed like oh two or three denials, it's like, well, two or three denials that will be two or three recurrences later. So they they were like, Oh yeah, that you're right, that makes sense. The wording needs to So they they've been helpful too.

Absolutely. I think that's that's an excellent point that you bring up. I think for the LBPs that are coming online, I think they're aware that average wholesale price for, you know, a course of therapy is significant and requires foresight and a little bit of preparation on the part of the clinical team. I've been pleasantly surprised uh, you know, across the products that they seem to have relatively robust uh financial support systems.

So I would encourage whether you're a physician or a nurse or a pharmacist or other allied healthcare professional who is charged locally with kind of getting a patient from A to Z in terms of um that assessment for financial coverage that you're making use of the websites for the manufacturers and seeing what support that they have and and as you're seeing things that are barriers that you're reaching out to them kind of across the board.

And also shout out to Monica. Yeah, S IDP member, OPAC Queen, Master Friendship Bracelet Maker. So I'm glad to hear that you are working with ID pharmacists even locally at your institution, Javier. All right. So turning back to some of the tougher cases though. Um Oh no, absolutely. Without the ID pharmacist we'd be lost. Oh I d I did not make him say that. That's very sweet. And and we're always glad to hear it. Um it's definitely a team sport to kind of put all these pieces together.

Speaking of things that require team sport though. I wanna turn back our attention to some of the tougher cases. You both have alluded to potentially limited options for Fulminant CDI cases or another important subpopulation is pediatric patients. So my question to you is is pretty clear. I just want you to summarize for us. Are you able to operationalize donor derived FMT right now at either of your institutions or other products?

for such cases. So just summarize what were your current status is for those. Yeah, so unfortunately we do not have an to operationalize donor-drived FMT. And so we do transfer those patients. And I guess I think we're should be very thankful that we're fortunate to have a local option that we can transfer to. Um but we yeah, we aren't able to operationalized donor drive F and T for ourselves. At least at this time.

Yeah, i in our case uh the the situation is uh similar that we're not able to operationalize this. Uh we we unfortunately do not have a Byron Vaughn across the street to transfer to to U Minnesota. So we have to try to deal with the best we can. Many uh of our patients will still respond to maximum medical therapy with oral and or rectal vancomycin plus intravenous metronidazoles, and we give them twenty four hours to respond.

We are also fortunate to to have a top notch uh colorectal surgery group at B I D M C who, you know, if needed will be able to perform collectomies in the safest possible manner. It's very different, you know, that uh someone who usually does hernia's and gallbladders goes and takes out a colon that's falling apart versus someone who takes out colons that are falling apart for a living. So there's a huge difference in outcomes there. But it we are in a in a very uh sad situation.

Because um the regulatory changes last year have left us without a a therapy that is very well known to be safe and efficacious. In simple words, it you know, FMT prevents death and collective. Our colorectal surgeons were the first ones to be to be, you know, really disappointed because uh this is not the colectomy they want to be doing, right? If if it's preventive. It was also something that was pioneered in North America. You know, all these studies are usually uh done in the US and Canada.

But now, you know, we see our colleagues in Europe and Asia expanding its use and we're no longer too uh able to provide it to our sickest and most in need patients. So I'm hopeful that with time the FDA will reverse this decision and Uh however the longer the situation persists, the fewer physicians are trained and credentialed in both you know recommending and performing this colonoscopy delivered FMT. So there is a time. I couldn't agree with both of you more. It's it it is Kind of a sad

state in terms of like the therapeutics that we're able to offer our patients. I do know there's a couple of centers across the US. I think IU Health in Indiana being one where they are still able to do

donor derived FMT at a pretty common clip. Um and I think they're part of the group that um there there's a couple of groups that are working with Open Biome to help give the advice to local institutions. So hopefully I mean n there there's only so many hours in the day and everybody's already strapped but I'm hopeful that, you know, in hearing some of this need and kind of where the data are that we can help inspire folks and and link them up with the resources that they might need to pursue.

donor derived FMT uh locally at their institution via an IND. I think especially for those that are not as familiar with IND, there is a

A protocol IND that can be done at the institutional level such that you're not doing it for a single patient every single time. You can kind of do some of the work ahead of time, which Of the centers that are doing donor drive FMT to date, that's the the process that they typically pursue because to do all the paperwork in an urgent setting is is very difficult.

So again, I'm putting another call out to folks if if this is your jam on the inpatient side and you're seeing these patients'cause we still do, or if you're like me are working at um, you know, a joint uh hospital that also has an adjoining children's hospital. Um, I think there's a lot of research questions that remain either for fighting for FMT or expanding uh our our experience for L B Ps potentially into pediatric patients under clinical research protocol.

So Javier, you mentioned something really interesting though, in terms of how the global landscape for availability of FMT is changing. This is, I'll be honest, an area that I'm not as well versed in. Can you provide me with a quick recap of the status of, in particular, traditional FMT internationally? Does does it remain available?

Yes, uh absolutely. You know, after many of the studies that that were done in North America, uh European colleagues of course saw the data, made their own studies and During the last uh two GI meetings I I've been to uh I've met uh you know colleagues from Germany, from France.

That actually contacted me to see w how we're doing with FMT and then and I had to tell them, Well no, we're you know, we're not doing it anymore. And they are expanding stool banks, uh very well regulated. They they have framewor n like national frameworks. or of stool banks too. And they're using these for recurrent C diff or for fulminant C diff and for research purposes too.

That's uh from in Europe uh there's also a very large public funded uh stool bank in China that's also shipping uh internationally uh it uh to to many parts of Asia. And there's actually some interest uh you know, when I recently gave a couple talks w one one in Lima, one in Bogota, uh of like oh maybe we uh you know, now that we cannot get open biome, maybe we could get it from the Chinese bank.

So there is a lot of interest. These therapeutics, you know, the FDA proof therapeutics are not available in the developing world. uh which is you know another equity gap. And uh FMT is also not easily available uh in the developing world except for you know large countries with with large research centers like uh like in India or or Pakistan.

Yeah. Thank you for that summary. I think that is really fascinating. Um and I hope that that work with traditional FMT will will continue globally and we'll still get to learn from that. Switching gears a little bit, now that we have these therapeutic options, I want to talk about the emerging data. So what are the most interesting questions currently being investigated regarding the microbiome research and its impact on patient health that you guys are jazzed about?

Uh it's really the spring of the live biotherapeutics. There's never been more in the pipeline and it's never been as exciting as now. Uh now. At the same time You you don't only need a good product for a good indication. You need those products to succeed in the market. And that's a lot more complex. Case in point with bezlatoxima, right? It it's not even a new class, but it's a good drug with a good indication. And uh it it couldn't be sustainable.

I would go as far as saying that it occupied a critical niche. So CDI is a perfect model to show the promise of uh LBPs, but uh LBPs will need to move beyond CDI and consolidate as a class. Moving to standardized bacteria or bacteria consortia that are culturable and thus can be scaled at lower costs will be the rate limiting factor.

And we're already seeing some efforts uh in that direction, the VE three oh three is a bacterial consortium from uh Vedanta pharmaceuticals that has had a very promising face two trial uh published for R C D I in JAMA last year.

that that it's going uh in in that direction. Uh there's also been some, you know, less successful attempts. It's not all the success. You know, it's a series, uh the uh the same people who develop VOS, the the spore um capsules for for s R C DI, uh tried uh uh a ul an all-sort of colliders product that that did not succeed. Uh so there's also like a huge cost uh in developing these products that, you know, are not always gonna be success.

Yeah, I totally agree, Javier, and I I just find the whole microbiome research arena just so fascinating and One of my absolute favorite topics to talk about is the research happening around quorum sensing and its impact on the human gut Food, microbiomes. And for those that are unfamiliar, quorum sensing is a communication system used by microorganisms to essentially coordinate group behaviors based upon population, density.

And anyway, it's it's it's very interesting and I what it's exciting is that quorum sensing may become a target for future therapeutics. And they even looked at and there's emerging research on how diet can influence quorum sensing, especially in gut organisms like and bacteroides and it's just this really cool intersection of microbiology, nutrition and this clinical potential. So I just I just think it's so fascinating.

Not to be corny, but it reminds me of not only that adage, you are what you eat, but you are what your bacteria sense to each other with corn molecules. Like we're headed in that direction. Very much. Like it's all part of the same overall ecosystem that makes up the human body. Just in those answers alone, you guys are definitely like nerdy enough to practice in the infectious disease andor go microbiome space.

And you know what's coming, those of you that are loyal listeners to breakpoints, I'm still gonna do our favorite segment of the pod, which is I feel nerdy. So Krista and Javier, I feel nerdy is a safe space to nerd out over your favorite IDE topics, quirks, and fun facts.

So for today's I feel nerdy, I want to know what is your favorite fact about the microbiome? And Krista, you can't say quorum sensing because you just said that for a different question. So no fact is too weird or too nerdy. Who wants to go first? I can just qu quickly give a fun fact that I learned recently and that Bacterial cells may actually outnumber human cells, so we actually may be more bacteria than human when it comes to our cell coat.

And then one thing I think too as as we're just understanding, right, how complex these things are, but there are actually studies showing that bacteria are responsible for making up to ninety-five percent of the body's serotonin. So there's a a happy fact for you. Oh wow. I didn't know that. That's pretty cool. Javier, what about you?

I didn't know that one uh either. Uh you know, uh over the years I I've often shared with uh patients, colleagues, some interesting factors about the gut microbiome, you know, such as You know, gut microbiota cells outnumber somatic cells ten to one or there's a functional redundancy in the gut microbiome. However, every time I say one in in particular what when I tell the fellows, because you know, they they go really fact check me.

It ends up being debunked very soon. I'll just give you one example. Like the the number of cells in the in the gut microbiome has been recalculated. Uh this estimation of ten to one was in the seventies. And the figure apparently is closer to one to one. Uh and however, this is based on samples of urban western high income subjects, so there's reason to believe that may vary quite a bit around the world.

But if you think about it, you know, an error of ten exponent one in the calculation fifty years ago is not terrible. So uh you know, whoever did this uh in the seventies uh Did not uh stray too far from the truth. So yeah, uh there's so many uh things about this uh that are so interesting and and I I love that we keep, you know, proving ourselves wrong and and and right again all the time.

I agree. One order of magnitude off is n is not too bad considering the technology and and knowledge that was available at the time. So I'm with you. Um all right, any last minute pearls or thoughts on microbiome-based therapeutics? Anything burning that you wanna get off your chest before we wrap up the pod?

Yeah, I think we especially those of us that work with C diff patients we know how terrible it can be but I you know I can't overstate the financial burden that recurrent C diff places on our health systems and I just recently saw a study at a community hospital and they found that just over twenty nine patients over a four year period actually cost their health system about two point two million dollars. So it's it's so expensive and such a great burden on our health system and our society.

And we're only just beginning to understand the complexity of the human microbiome and just really exciting to see where we're gonna be in the next five to ten years. Yeah, I I echo uh Chris's thoughts on the financial burden. That's that's so much for, you know, a a small relatively small number of people. I I wanna take this further, you know.

We we all have had patients lose uh their life or their colons to C. diff. But more frequently than that, what we observe are are people who go from a generally healthy life to a cycle of recurrences. that's often worsened by post infectious yeah symptoms. and uh carries these food avoidances, fear of going out, social isolation, sometimes, you know, losing their jobs or just retiring early.

I think the last five years in my practice uh have opened my eyes to the plight of patients with R C DI and and the impact on their families and communities. And I think there's still too few clinicians at the intersection of uh of gastroenterology and infectious diseases who can help these patients to access appropriate treatment. whether microbiome based or not, and educate them in order to guide them back to recover.

It's an exciting time for discovery, no doubt about it, but we still have a lot to do to implement the technology we actually currently have. So I think that's uh we we need to take this with a lot of sobriety and uh uh and and and humility. Well, and I wanna thank both of you for all the work that you continue to do to both research in this space and get the word out in terms of the availability of current therapeutics and where we need to go from here. So

Thank you both for sharing all your wisdom that you have with regards to microbiome-based therapies. And also thank you all for joining me today, our loyal audience, for listening to Breakpoints, the Society of Infectious Diseases Pharmacists Podcast. I've been your host, Julian Gesto, and our featured speakers have been doctors Christigens and Javier Villa Fuerte Galvez.

Breakpoints was created by Julianne Justo, Aaron McCreary, and Jason Pogue. The episode was produced by Megan Clatt and Lacey Warden. It was edited by Besma Hassani, peer reviewed by Ashley Selby and Joey Cohn. Transcribed by Kimberly Askren and Beth Addington. The executive producer of Breakpoints is Lisa Dumco. Our theme song was recorded by SIDP member Steve Smoke. This podcast series was supported by an educational sponsorship from Nestle Health Science.

You can subscribe to Breakpoints on Apple Podcasts, Spotify, or wherever you get your podcast. If you'd like to support us further, please, please consider writing a review on your favorite podcast platform and share this episode with a friend. It really helps. Thank you for your ongoing support of our little pod and for helping SEDEP achieve our vision of safe and effective antimicrobials for now and the future.