Thomas Lodise, PharmD, PhD

: If you could give one piece of advice to physicians caring for patients with C. difficile infection or recurrent C. difficile infection, Teena, what would that be?

For me, the big one is the follow-up of these patients with recurrent C. diff. We need to keep a close eye on these patients, because they can be really high risk for high morbidity and mortality given that some of them can be no compromised all the patients and recurrence can really take them downhill. We should be following up with them, giving them a good contact number, so they can reach out. While on therapy, are they taking their medications, or do they have access to their medications? It’s so important. A lot of times we prescribe them fidaxomicin, they are not able to fill it, and they are suffering from recurrence. For me, that is the most important thing.

: Bincy, what are your thoughts about the most important thing for management of either initial or recurrent C. difficile?

I will keep it simple to summarize everything. My main advice is to act early. Early for the diagnosis, and you have the suspicion. Once you know that, you start them on treatment, and assess them early after treatment to make sure they’re responding, so you don’t need to make adjustments immediately after that.

Paul, I know you’re asking about recurrent C. diff, but I must start with the good antibiotic stewardship. Only use antibiotics particularly in your high-risk patients. Having said that, we treat patients, and we talk to all about the emotional, physical, and all the different sequelae that’s associated with this disease. Unlike other domains and infectious diseases, we have drugs with superiority data. We need to be more aggressive. I think you did a good job highlighting the changes in the microbiota over time, particularly those with recurrent disease. For prompt treatment, I’m a very big advocate of fidaxomicin. I think we should be thinking about bezlotoxumab a bit earlier in the course. Then when we have these live biotherapeutics, and we have to prioritize their use. Again, there’s always issues, which is the right one to use. As more data become available, there will probably be certain circumstances where one may be preferred than the other. But the wait and see approach with this disease; you got a patient in front of you, number seated a 3 to 5 to 10, I’m unaware of this in any other domain. The data are compelling. We’re beginning to appreciate the underlying pathophysiology. Everything we’re doing makes sense. I think this is something that patients suffer with, and we actually have more options to reduce and extinguish that suffering. When I think about CDI [C. difficile infection], people need to think about that patient and all the sequelae otherwise, and really take a very proactive approach in terms of prioritizing somebody’s new treatments.

: We’ve had really important points here. We have treating earlier from Bincy. We have access from Teena. We have Tom, aggressive, which is appropriate. Not in the negative way, but aggressive treatment upfront to try to shut this down. What I’ll say is accurate or indicated treatments, phasing out metronidazole, considering fidaxomicin, considering bezlotoxumab, considering live biotherapeutic products, if and when they get approved, fecal transplant as it is now, so that these patients don’t go through all that suffering that they have gone through, going through recurrence after recurrence after occurrence. Now during this presentation, we’ve covered a lot of information. We spoke about the mechanics of C. difficile, when to refer patients with C. difficile, differential diagnoses, important educational initiatives. We spoke about a subset of patients with inflammatory bowel disease in C. diff that are kind of a special unique element and a unique group that we need to consider differently. We shifted gears. We spoke about the mechanisms of treatment of C. difficile, antimicrobials treating the vegetative phase, the microbiota eradicating the spore phase. We updated ourselves on the IDSA/SHEA [Infectious Diseases Society of America/Society for Healthcare Epidemiology of America guidelines from 2021. We then shifted gears, spoke about bezlotoxumab, fecal transplant, microbiota based live biotherapeutic products, the trials, the differences. And here we are, at the end of this presentation. I want to thank you for watching this 

. If you enjoy the content, please subscribe to the e-newsletters to receive upcoming peer exchanges and other great content right in your inbox. Thank you so much for all the panelists for being here tonight. It was such a pleasure working with you.

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Experts share advice for physicians taking care of patients with C. difficile infection (CDI).

Advice for Physicians to Manage C. Difficile Infection (CDI)

: As we shift gears to the last section, I think it’s important for all of us to have an opportunity to express what areas we think are most important; what unmet needs and prevention, diagnosis, treatment, and management are most important to you. Tom, why don’t you kick us off?

Well, it’s an exciting time. First and foremost, I think with FMT [fecal microbiota transplantation], with all the concerns, you read the reports about people getting ESBL [extended spectrum beta-lactamase] infections, the lack of standardization. These biotherapeutics are clearly a step forward. I was joking around calling them “next generation FMT,” but really, they’re standalone products and have very unique properties, many of which as Bincy indicated are proprietary. When I think about moving forward, we actually had this in the gram-negative space. Teena attested this. We went from co-listing to a bunch of agents. Now the question is, where do we place them? In a situation like this, I always say, “Well, who’s the patient?” We’re in the VA, we tend to be more conservative. We’ll look at people with 3 or more episodes, 2 recurrences, perhaps an individual with one recurrence that had a severe recurrence. In that population, Paul, there’s a lot of questions that remain. You mentioned the one thing is these biotherapeutics better prolonged extended taper doses of fidaxomicin. You talked about that one experience you saw that one site where people are getting at 40 plus days. Someone gets fidaxomicin, and then they get bezlotoxumab. Should we give one of these biotherapeutics in the individual? My thought is after the first recurrent to give bezlotoxumab guidelines supportive or thinking about at least our clinical trial data supports that. Then with 2 or more recurrences, we start thinking about these biotherapeutics. Even in that circumstance, head-to-head with these biotherapeutics versus fidaxomicin and bezlotoxumab preferably in an extended post dose type of regimen. We have new agents; they’ll be used they’ll be high priority. I always like to see what the publications bring forth and particularly the FDA labeling. They get a different dataset than what’s sometimes in the paper. That’s the patient population and we’re to consider them. At the same time, I don’t want to be that clinician that ask for another randomized clinical trial. We will prioritize their use. My thought is perhaps if you think about as bezlotoxumab a bit earlier in the course. Then those with 2 or more recurrences, 3 or more episodes, we’re going to start thinking about these new biotherapeutics that will hopefully soon be available.

: Bincy, do you have any thoughts on unmet needs and prevention, diagnosis, treatment, and management?

Yes. I know we talked a lot about science and data and new products, but I’m thinking from the patient’s perspective that we have to really control their symptoms early and improve their quality of life, got to get them on whichever treatment as early as possible, so that we can prevent the complications, the hospitalizations, and prevent this recurrence of their disease as well. But with new products coming out in the future, I think accessibility is going to be very important because we can have many of these FDA approved, but, if the patients can get to it or we can prescribe it or can be covered by insurance, what’s the point? I think accessibility is going to be very key for the future to get our patients healed up, treated, under control, in remission, as I would like to say, without having recurrence of the infections.

: Excellent. Teena, what are your thoughts?

Like everyone said, I think the most important thing is to have a consistent way of giving these live biotherapeutics. It is FDA approved; people can have easy access to it. I love the way Bincy pointed out the quality of life. I think it goes without saying how recurrent C. diff affects the patient’s quality of life; their emotional, mental, psychological abilities to perform day-to-day activities. It is majorly hindered. These products can really break that chain of the vicious cycle of dysbiosis, that’s what I’m most excited about.

: Excellent. We’re really seeing that we’re on the precipice of something special, which is hopefully an FDA approval of 1 of these live biotherapeutic products, which will be really a game changer, because the accessibility now is really a specialty centers. But hopefully, with an FDA approval, it will be much more available. People will be more comfortable using them, because there’s going to be hopefully phase 2, phase 3 data to support the usage in terms of consistent safety and efficacy profiles. Once you get that stamp, more people will be comfortable intervening, more people will understand better. Most importantly, our patients will feel a lot better; they will hopefully have that cycle broken earlier.

Bincy Abraham, MD, MS; Thomas Lodise, PharmD, PhD; Teena Chopra, MD, MPH; and Paul Feuerstadt, MD, share unmet needs, including access to therapies, in treatment of C. difficile infection (CDI).

Unmet Needs in Management of C. Difficile Infection (CDI)

: We've discussed the clinical trials, we've discussed the products, but it's important to realize that you can't compare the products next to each other because the trials were different. It's important to understand what levers can be pulled within the trials that might have an impact on results. One of those levers is the duration of the standard of care, antimicrobial. Tom, how can the duration of the standard of care antimicrobial prior to the intervention, potentially impact efficacy assessment of the product?

That's a very good question Paul. It could go either way. On the one hand, you want to make sure the patient receives adequate treatment. There's probably a minimal duration that you need to the treat to CDI [

], all vegetative forms of C. diff. But the other consideration, if you treat too long, you could create an environment of dysbiosis. In that environment, particularly if you use oral vancomycin, which is a broad-spectrum agent, it could be counterintuitive to what you're trying to achieve with treatment. We need to standardize this, at least 10 days, to make sure the patient achieved an initial cure. At the same time, we want to have at least some sort of washout period, 3-4 days. Because when we give one of these, I call them next generation FMTs [fecal microbiota transplantation], I know the FDA has their term, we want to make sure that we're not doing anything to kill some of those healthy bacteria that we're trying to replace. Paul, I'm curious on your thoughts, I anticipate you have thought a lot more about this than I do. The last thing I'll leave you with is: it's really a hard thing to assess. We're looking at trial data, we can do some post hoc analysis, and looked at how long patients were treated, but there could be some prescribing bias there, when someone's given a 10 – 21 day window. I imagine a lot of people see 14, because they like to split the difference, maybe some of those ones who got longer treatment, were not responding as well. I think we should peek at that but recognize there could be confounding by indication there. It's an important question, but I'll ask you that question, because I know you're very close to these data, and thought deeply into this.

: You bring up a lot of important points. It's like the sweet spot on a tennis racket or baseball bat; you don't want to hit it on the side, you want to get it in the right section. We haven't defined what that right section is, but we know what's too much [>40 days], and what's too little [<10 days]. There was a very nice foundational study that was interestingly designed they consider fecal transplant. I'm not going to get into the details, but the bottom line is, when they crunched the data across the 2 sites, 1 of the sites had a placebo intervention efficacy of 90%. How could a placebo intervention efficacy of a sustained clinical response be 90%? Well, it turns out at that site, the patients were getting months of vancomycin before they actually got the intervention due to delays in being able to see the provider. From that study, we largely learned that too much of a good thing, while it takes a long time to cure with vancomycin, a lot of those patients were getting cured most likely prior to the intervention. Finding that sweet spot is something that we still have to look into a little bit further. Now, other factors to consider comparing the trials or thinking about differences between the trials, are the number of episodes that patients were included. Bincy, how can the number of episodes impact how an intervention of a live biotherapeutic product can work?

 You bring up this question of will more episodes of C. diff infection lead to what Tom was alluding to, this dysbiosis? Will it lead to a more of a permanent dysbiosis for these patients? Will that make these LBPs [live biotherapeutic products] less effective? We don't know until we assess that. When we do more subanalysis of the data in patients that had less prior episodes to more prior episodes, we’ll see if this is actually going to be similar in efficacy or not. The other thought is that if it’s not as effective in those patients with prior episodes, do you think we’ll need more doses of these products rather than just a single dose for them? That’s something to consider for future studies.

: Excellent, yes. You’re right on target, but it’s important for all of us to realize when we interpret this data that different studies included different groups of patients. Some studies only included patients with 2 or more recurrences, some with 1 or more recurrence, some included patients with 1 or more recurrence later in the study. We must tease out what all that data looks like. As we gather more open label data, we’re going to get a better handle on what the efficacy might be. Of course, once we get into clinical practice, we’ll certainly get an idea, assuming one of these products gets an FDA approval. Now, diagnostics is complicated. It’s super important, and it also significantly impacts clinical trials. Teena, can you walk us through how that might affect whether the PCR [polymerase chain reaction] assay is used, or the enzyme-linked immunoassay, GDH [glutamate dehydrogenase] assay are used?

 Like we talked about earlier, PCR is very overtly sensitive. It may pick up colonization sometimes. If studies are using or relying on PCR alone, it can be problematic, because we might be enrolling patients who are colonized and giving them biotherapeutic products. That is one challenge. Again, the nuances of using the toxin alone when it can be falsely negative is another problem in the study. Thinking about that consistent approach, given that centers have different diagnostic tests available, and it is so difficult to enroll patients, we have to tease out those factors and consider them when we are looking at different studies.

: Excellent. The bottom line is, if one specific assay is used that is more accurate, you have to question, is that available to me? Is that not available to me? What is real world, or what is a clean study? A clean study isolates the patient population that we want best. That’s something that needs to be teased out but needs to be thought critically when we with clinician’s review some of this literature. Now, Tom alluded to before this “washout period.” A “washout period” is the time from the end of antimicrobial to the microbiota replacement therapy or the administration of the live biotherapeutic product. Why is that important? Frankly, if vancomycin is still in a patient’s system, it’s still within the colon and it hasn’t been released, the vancomycin is also going to impact what we’re administering as the supplementation. That’s why the amount of time between completion of therapy and intervention is important. Unfortunately, just like the sweet spot of timing of antimicrobials and length of time with antimicrobials, we’re not really sure what the sweet spot is for the washout period. It might just be that the patient needs to have 1 or 2 bowel movements between the time from antimicrobial to this intervention, but we are just not sure right now. Finally, Tom, can you tell us a little bit about bowel purges, and how that might impact the results?

 Paul, this is one I struggle with as well. It’s almost the same premise of having that washout period. Theoretically, you can think or remove some of the active CDI therapy still in place. But when we think about that patient and that host, the last thing you want to do is give them a bowel purge therapy. If there are concerns about residual antibiotic, perhaps having that waiting period, I know within the SER-109, they use the magnesium citrate to help facilitate this. Paul, I really don’t have a strong opinion on it. I can see some of the benefits, but at the same time in the setting of dysbiosis, do we really wanted to promote bowel purging? I would ask you to question as they did before. These are very gray areas for me. Clearly, we don’t have a randomized clinical trial to define best practices, but curious on your thoughts as well.

: I agree with you. We just don’t know. But it’s important that we critically think about it and say, “Well, wait a second. This was done here. This wasn’t done here. This is what we should do in clinical practice, assuming an FDA approval. This is what we don’t necessarily want to do, or this is something we might want to add to our clinical practice.” Now, all of these products RBX2660, SER-109, CP101, VE303, have proprietary doses. Bincy, can you explain to us what that means, if anything?

Actually, I don’t know if I can explain this to you. I alluded to this area earlier as well these studies are getting a single dose for their product, and certain patients that are more refractory; do they need more dosing? The other thing is, do they need a combination of these products where we’re getting multiple components of the better microbiome to treat them? It’s a great question that I don’t have an answer to. Hopefully, in the future, maybe they’ll all come together, and we’ll have a happy family LBP study.

: Agreed. You bring up a really important point, which is we don’t know what these doses mean. They’re proprietary. We didn’t have doses before when we were performing a fecal transplant in more rudimentary way. We said, “Look, this is what we have. We’re going to take a sample. We’re going to mix it with normal saline. We’ll spin it up in a blender, and we’ll give it.” It’s becoming more sophisticated. I don’t think there really is any way to compare them across trials, so yes, I completely concur.

Experts discuss differences in designs of clinical trials of 4 emerging microbiota-based live biotherapeutics - RBX2660, SER-109, CP101, VE303, for treatment of rCDI.

Differences Between Fecal Microbiota Transplantation Studies to Treat C. Difficile Infection (CDI)

 As we shift gears, we’re going to think about another product, called SER-109. This product differs from RBX2660 because it’s a capsule formulation, but it’s a narrow consortium. As opposed to RBX2660, which has spore- and non-spore-forming bacteria and a broader group of microorganisms, SER-109 is made up of firmicutes spores. It’s dosed as 4 capsules daily for 3 days, following the standard-of-care antimicrobial. Within this clinical trial, patients who had at least 2 recurrences of 

, and received fidaxomicin or vancomycin, had a brief washout period. They received a magnesium citrate bowel lavage, then were randomized to receive SER-109 or placebo.

They were followed for 8 weeks for occurrence, 24 weeks, or 6 months for safety. Overall efficacy within this treatment cohort was 88% for SER-109, vs 60% in the placebo arm, a statistically significant difference, and form fit function once again. Specifically, there were decreases in the proinflammatory 

 and increases in the firmicutes, specifically 

. Once again, we see that supplementation of the deficiencies helping the microbiota give that spore phase a specific knockout punch. RBX2660 and SER-109 have both finished phase 3 trials, but there are 2 products in phase 2 trials: CP101 and VE303. Bincy, can you walk us through those products and their data?

Sure. CP101 was a randomized, double blinded placebo-controlled trial. There’s going to be a phase 3 trial looking at CP101, which is a fecal matter transplant as a single oral dose, to look at prevention of recurrent 

 infection. The study is called PRISM4, so look out for that when you’re looking at abstracts in the future. They’re similar to all the other studies. This will be given after completing the standard-of-care antibiotics, after their most recent 

 recurrence. They’ll be randomized to get this vs placebo. The plan for the study is to evaluate 

 recurrence and safety up to week 8 as their primary end point. But we also want to look further out, to about week 24. That’s the goal of the study.

CP101 is an interesting product because it’s a broad consortium in a capsule form. It’s given as 10 capsules on a single day following the standard of care, vs VE303, which is a little different. VE303 is what we call a defined consortium, and it has 8 specific bacterial species. It also reported encouraging data at the major national conference in San Diego in May. That will also probably proceed to a phase 3 trial.

Drs Abraham and Feuerstadt share recent data with emerging live biotherapeutic products, SER-109, CP101, and VE303, for treatment of recurrent C difficile infection (rCDI).

Thomas Lodise, PharmD, PhD

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