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, 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 Peer Exchange. 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.

Videos

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, 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).

SER-109, CP101, VE303 for Treatment of Recurrent C. difficile Infection (rCDI)

We know that FMT [fecal microbiota transplant] works. We know that there’s a delta in the efficacy, and the delta is largely from open-label studies which had north of 90% efficacies for the most part, vs randomized controlled trials, which have closer to 70% efficacy. Teena, can you walk us through some of the challenges we have with treatments of 

 You and Tom alluded to this earlier. When you were talking about dysbiosis, you were talking about this vicious cycle of dysbiosis that our recurrent patients enter. When we talk about the treatment of 

 we’re giving, it’s almost counterintuitive. We’re giving antibiotics, and antibiotics are the biggest risk factors for 

. Then we treat these patients with antibiotics and causing dysbiosis. These antibiotics, particularly vancomycin, are very broad acting and not microbiome sparing. Both metronidazole and vancomycin will destroy our microbiome. Fidaxomicin, on the other hand, is more microbiome sparing, yet these antibiotics are going to destroy our microbiome. We aren’t addressing the underlying cause of dysbiosis. In my opinion, this is the biggest challenge we have in treatment of recurrent 

. Hence the need for these newer biotherapeutics that can address the dysbiosis. Hence the importance of fecal transplant, as Tom mentioned.

Excellent. We’ve had a hearty discussion on fecal microbiota transplantation, which is the method we’ve used for the better part of 10-plus years to supplement the microbiota, to supplement that deficiency, and to decrease recurrences. But there were limitations of those trials. They were usually relatively small and weren’t multicentered. Some were retrospective—very few were prospective—and there was heterogeneity with what was being used. A transplant being given in San Diego [California] might be different from Portland, Oregon; Houston, Texas; Miami, Florida; and New Haven, Connecticut. Contextualizing this, we’re driving toward more codified formulations, more predictable safety and efficacy profiles, and products that have been taken through more rigid clinical trials.

What I’m introducing is something called microbiota-based live biotherapeutic products. That’s a mouthful. That’s the FDA term. The short term is LBPs. There are 4 products that have gone through either phase 3 and phase 2, or phase 2 trials. Those are RBX2660, SER-109, CP101, and VE303. We’re going to dig a little deeper into these products over the next couple of sections. Before we do, we have to understand what the clinical trials look like.

There were certain similarities between all these clinical trials. First, across all these clinical trials, patients enrolled had recurrent 

, all the trials were multicentered, all the trials had a randomization, and all the trials had a placebo control group. Also, all the trials included an antimicrobial prior to intervention. This is a very important concept. When we consider microbiota replacement therapy or microbiota supplementation, it’s essential for us to realize that’s this isn’t done in a silo. It’s done after an antimicrobial used to minimize that vegetative phase, the microbiota replacement therapy that supplements the microbiota deficiencies.

Drs Chopra and Feuerstadt summarize challenges with current treatments and discuss live biotherapeutic products that are being studied for recurrent C difficile infection (rCDI).

Challenges with Current Treatments and Emerging Treatments for C. difficile Infection (CDI)

We know that fecal transplant is effective at reducing recurrence of 

, so it’s effective at eradicating that spore phase. We’ve spoken already about the mechanism of action. We spoke about the safety. It’s safe; it works. We spoke about monitoring. Tom, can you walk us through some of the foundational trials that have shown us efficacy for fecal microbiota transplantation?

As you’re aware, we started with a lot of case series and observational studies, and the results are rather impressive. When FMT [fecal microbiota transplantation] was administered to the proximal small bowel, we saw success rates of 75% to 94%, and it was even higher with installation of FMT into the colon. Then we start getting into randomized clinical trials. Everybody is aware of the first 1, by [Els] van Nood and colleagues [in 2013]. It was a small study, but they showed remarkable benefit with the use of FMT relative to vancomycin in an open-label trial. The results were so impressive that the trial was stopped early. There are a lot of data to support it.

Since then, there have been several randomized clinical trials, and the results are somewhat mixed. They were probably summarized best by [Raseen] Terik and colleagues. This was a meta-analysis, and they looked at 13 recently completed trials as they worked their way down their inclusion-exclusion algorithm. They found a lower success rate. This was in randomized and open-labor trials, but there was considerable heterogeneity, which reflected the heterogeneity within our patients with CDI [

 infection]. A couple of things we took from this was that they only looked at FMT, and higher cure rates with colonoscopy relative to enema, but no difference in colonoscopy relative to oral administration.

In another study, when they looked at people getting multiple FMTs, there seemed to be some benefit. We think about the disease, especially in those with a friable colon, who may need multiple FMTs. In that circumstance, with multiple FMTs, we see success rates that within the observational trials closer to 90% or above 90%. When we think about oral, there appears to be some benefit to delivering it to the colon. There are all these concerns with gastric acid breaking down FMT, so that’s preferred with direct colonic installation.

One other thing I’ll say is that when we think about use of FMT, it seems to be a bit better for recurrent vs refractory CDI, so it’s combined. There’s a lot of heterogeneity in these trials. They have different definitions of response. We talked about all the issues with diagnostic testing. Some probably have a lot of false positives. That may drive down that cure rate, and it’s a clinical diagnosis. There are a few take-aways. It’s very good for recurrent disease. There appears to be some benefit with direct colonic installation. If we’re going to use oral, it must at least get to the duodenum. But further studies are needed to find their place in therapy and find that optimal patient.

Dr Lodise summarizes foundational trials that led to the use of fecal microbiota transplant for the treatment of rCDI.

Foundational Trials for Fecal Microbiota Transplantation for C. difficile Infection

, what approach do you have or what approach do you suggest for monitoring patients and how long should they be monitored for?

That’s a great question, Paul. As you know, 1 of 6 people end up getting recurrent 

 within 2 to 8 weeks of their initial episode. What’s important is that when we’re treating patients with 

, we guide them when to contact their physicians because these patients can be colonized. Any install to their microbiome can get recurrent 

. Even after antibiotics are stopped within the first couple of months, they’re at very high risk of getting recurrent 

. I usually follow these patients for at least 3 months after their initial episode and sometimes up to 6 months. If the patient is at high risk, like an older patient or a patient who’s immunocompromised and on steroids, transplant patients in particular can get recurrent 

 even within the first year. Keep in mind that in addition to also guiding them on what infection prevention precautions to take at home, washing their hands with soap and water to prevent the spread and getting reinfected is so important.

Excellent. Teena, you bring up a really important point, which is that there’s no correct answer. Some believe it’s 8 weeks, some believe it’s 4 weeks, some believe it’s 90 days, 6 months, or 1 year. The key concepts are what you said, which is that the highest risk for occurrence is about 8 weeks. A lot of us go 90 days, or 12 weeks—6 months in those who have multiple risk factors, 1 year if they have quite a few risk factors. My question is, do you test to confirm eradication?

No. I wouldn’t confirm eradication because the test can be positive for a long period of time. It depends on your clinical judgment. As a physician, what are you seeing? As a clinician, how is your patient doing? What is the frequency of their diarrhea? [Are you helping them] maintain a stool diary, guiding them on their diet—all the things Tom [mentioned]—to get back to that state of eubiosis and get out of dysbiosis. [We have to] guide them on a high-fiber diet, full of vegetables and fruits, including diverse foods, so they can have that good microbiome.

Excellent. I don’t check either to confirm eradication because what’s essentially happening is the microbiota are in the process of eradicating, so the patients will probably be colonized at that point because our bodies are working things out.

Dr Teena Chopra shares her approach to monitoring patients with C difficile infection (CDI).

Monitoring Patients with C. difficile Infection (CDI) and rCDI

Let’s shift gears, we spoke about antimicrobials, which treat the vegetative phase. We spoke about bezlotoxumab, which essentially binds toxin B and decreases the inflammatory response. But we have that black box, that dysbiotic state, that second piece that we need to be healthy to reduce future recurrence. Tom, can you walk us through fecal microbiota transplant in detail? Its mechanism of action, and which patients may benefit from it?

As the name suggests, it’s the delivery of human donor stool to a person via a colonoscopy, an enema, a nasal gastric tube, or a nasoduodenal tube, or a capsule popularly known as the poop pill. It’s prescribed for patients with debilitating GI infections, like 

, and that’s why we’re here today. The thought is you restore a balance in the microbiome. You want to get a better proportion of healthy vs unhealthy bacteria. We’re trying to go back from a dysbiotic state to eubiosis.

Essentially, we’re taking those deficiencies—the firmicutes and 

and we’re replenishing them with a full complement. What that does metabolically is alter the bile salt milieu. The bile salt milieu, we believe, has switches that turn 

 on or off. In the appropriate complement of bacterial phyla, we can shift 

 off and allow the microbiome to the opportunity to eradicate 

Bincy, we’ve seen fecal transplant. It’s been around for centuries but largely in clinical medicine over the last 10-plus years. Are there any safety signals we need to be concerned about with fecal microbiota transplantation?

 Good question. Patients have asked us this as well. The bottom line is that FMT [fecal microbiota transplantation] seems to be safe in the long term. Our biggest concern was the risk of infections. We’re bringing in stool, which has tons of bacteria, but we’ve looked at that by the donors, going through a vigorous testing to rule out any infections specific from the donor. In fact, there’s very low risk of transmission of infections with FMT when appropriately done.

On review of literature, looking at other potential long-term safety [concerns], some cities suggest a risk of report weight gain. That was unrelated to the donor BMI. Even the skinny donors contributed to weight gain in these patients. That happened in up to 10% of patients. This brings up the question: is it a direct effect? Or could it be that patients lost weight or weren’t gaining weight because of recurrency of infections and being unhealthy in general? There were also some reports of GI diseases, such as chronic diarrhea or irritable bowel syndrome, in about 13%. We need to keep that in mind, but no mortality was found looking at long-term safety of FMT.

It seems very safe. There are a couple of reports from the FDA that looked at transcription of various bacteria that weren’t properly screened for. You alluded to this, but whenever we consider fecal microbiota transplant, or FMT, it’s important to think about where we’re gaining the source stool, what process they’re going through, and how comprehensive their process is.

Drs Tom Lodise and Bincy Abraham provide an overview of fecal microbiota transplantation and long-term safety of FMT use.

Thomas Lodise, PharmD, PhD

Articles