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The question of which patients respond best to a fecal transplant who have a history of recurrent 

] is an important one, and there have been a number of case series that have looked into this. This question was tackled at a major infectious disease conference in October of 2020. They looked retrospectively at a cohort of patients who received a fecal transplant within their health care system. The fecal transplant material was supplied by a stool bank. They looked overall at 81 patients and found that 89% responded to the fecal transplant and had suppression of their 

 infection and clinical cure. Right on target with what all or most of the other retrospective studies that have looked at this have shown. But they also showed that 36% of individuals also had transient loose stools and persistent loose stools after the fecal transplant. Now, this is a known effect. Fecal transplants have been shown to be associated with several subtle or less subtle adverse events, one of them being persistent loose stools, or transient loose stools, another being gas and bloating, another being constipation, and finally, mild abdominal discomfort. These [adverse] effects usually last several months, maybe 3 or 4 of them.

 will get a post-infection IBS [irritable bowel syndrome]. Of the group that have more refractory symptoms, or more recurrences, they’re more likely to get post-infection IBS, and that is probably why there was a higher percentage seen here. Who is at greatest risk for getting a post-infection IBS? Patients who had IBS in the first place is what they showed here. Who are more likely to respond to the fecal transplant? Patients who received longer antimicrobial courses before the transplant, and patients with a higher body mass index. It’s unclear why patients with a higher body mass index will be more likely to respond to a fecal transplant, but it’s clear why patients who received more antimicrobials prior to the transplant are more likely to respond. They’re probably treated completely prior to the transplant, and the transplant is a reenforcing factor.

As we discussed previously, in patients who have recurrent 

, we want to treat both the bacteria, but also the microbiota. The antimicrobials, when patients have received prolonged antimicrobials courses, that has probably done the trick, and supplementing the colonization resistance with the microbiota gives it that knockout punch. The longer the antimicrobials, the more likely to get rid of the bacteria, reenforcing the colonization resistance with the fecal transplant.

When we approach patients with recurrent and multiply recurrent 

, thinking about the body mass index, thinking about the length of time that they’ve received vancomycin is essential to understanding who might respond, according to this study. But also understanding that patients might get transient or persistent loose stools afterward as a result of a post-infection IBS is also essential for all of us practitioners to consider when we use this treatment for our patients.

It is an exciting time in the world of therapeutics for 

 infection, and recurrent and multiply recurrent infection, but 2021 is framing up to be a pivotal year in the management of recurrent 

 infection. Why is that? That is because we have a number prospective randomized controlled trials of pharmaceutically produced fecal microbiota transplantation material that is possibly going to gain FDA approval in 2021.

The 3 products are from Rebiotix/Ferring [Pharmaceuticals], RBX2660, an enema formulation of fecal transplant, just completed a phase 3 prospective randomized controlled trial with positive topline results, showing a beneficial effect compared with placebo. SER-109 [from Seres Therapeutics, Inc], an oral capsule formulation of 

 spores, a form of fecal transplant that also had positive, topline phase 3 prospective randomized-controlled trial results. And finally, CP101, from Finch Therapeutics, they completed a phase 2 prospective randomized controlled trial, and hopefully will be launching a phase 3 trial in 2021 for data analysis perhaps in 2022. We can see that more codified and less heterogenous forms of fecal microbiota transplant with potentially FDA approval are coming in 2021. With less heterogeneity of these products, we have more stable efficacy and safety data, and as clinicians we should be excited for more predictability of usage of these materials and better outcomes for our patients, with more widespread availability of such products.

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Fecal Microbiota Transplant Outcomes and Therapy Advances 

: The question of refractory versus recurrent 

 is typically defined by patients who have classic 

 diagnosed with stool assay, treated, and will recur in a fixed period with similar symptoms to when they presented originally. The issue arises with the timing for recurrence; some studies use 4 weeks, some studies use 8 weeks, some studies use 12 weeks, other studies use 24 weeks. The Centers for Disease Control and Prevention have landed on an 8-week follow-up, and most prospective randomized controlled trials use that 8-week marker.

Recurrent disease is fairly codified; however, refractory disease is not. Refractory disease is any patient who doesn’t seem to be responding to therapy but might not necessarily have that classic feeling better on antimicrobials and standard of care therapy, and then getting the symptoms again in the future.

A nice abstract was put forward at ID [Infectious Diseases] Week in October of 2020. Within that abstract they looked at the University of Virginia Health System for individuals who received fecal microbiota transplant for either recurrent infection or refractory infection. Within that abstract, they didn’t give clear definitions for recurrent and refractory infection, but what they put forward was that in the recurrent group, 5 out of 6 patients responded to a fecal transplant. Overall efficacy was 83%, whereas in the refractory group, 4 out of 7 patients responded, tabulating to about 57%.

What do we derive from this? What they derived from this is in a recurrent group of inpatients with 

 fecal transplants seem to work, and those numbers are on par with other studies. In the refractory group, they said you can give a fecal transplant, and it might work about 57% of the time. One of the most important pearls of understanding patients with 

 is understanding that if a patient is not responding to vancomycin or fidaxomicin, they probably don’t have 

 infection. Some 99.5% of the time, patients should have some response, at least halving the frequently of their bowels, and their stools should become somewhat formed.

One of the reasons I’ve enjoyed treating patients with 

, beyond curing them, is that a lot of individuals come to my office saying, “I have refractory 

.” And I sit down in the office with them and I say, “Well, what have you been treated with so far?” And they’ll tell me, “Well, I’ve received vancomycin.” And I’ll say, “Well, how many bowel movements were you having a day with the 

 before the vancomycin?” And they say, “7 or 8.” And I’d say, “Well, once you received the vancomycin, how many bowel movements were you having?” And they’d say, “7 to 8.” And I’d say, “Well, you probably don’t have 

. It’s my responsibility to try to figure out what that is, what your diagnosis is, and how we can get you better.”

What can be a diagnosis that we see in patients with 

 in the past? Post-infection irritable bowel syndrome [IBS] is common. It’s estimated that about 25% of patients who get 

 will end up with post-infection IBS. How do we differentiate them? With a history similar to what I provided recently; we ask the patient about the frequency of their bowel habits. Typically, with a post-infection IBS, patients’ bowel habits will be about half or less of what they presented with initially with 

. You can ask the patients about the odor of their stool. Believe it or not, patients will say, “Oh no, it smells like 

 right now,” or, “No, it smells like my previous odor.” If it smells like 

. If it doesn’t, most likely not. And of course, the definition of irritable bowel syndrome; what is the definition of irritable bowel syndrome? An association of abdominal discomfort with bowel movements, either a relief or worsening of that discomfort.

As a gastroenterologist, I have the ability to also do a flexible sigmoidoscopy or a colonoscopy if the diagnoses is in question. Take some biopsies, we can look for a diagnosis like microscopic colitis. Of course, it’s also important to review the patient’s medication lists. A lot of these patients have multiple medical comorbidities. Perhaps they had a medication that was added recently that caused loose stools and softening of the stools, increased frequency. As a clinician, when it comes to recurrent 

, and when it comes to this “refractory 

,” unfortunately, we have to put on our thinking caps, go through a differential diagnosis and figure out what’s going on, to help those patients feel better.Sometimes it’s a simple recurrence, we can tease that out through history; sometimes it’s not, and we can tease that out through some of the tools we have available to us. But a clinical history is essential in differentiating those who have a true recurrence versus those who have a “refractory disease” that might be a result of another diagnosis.

Fecal Microbiota Transplant for Recurrent vs Refractory CDI

 There was one other significant update to the IDSA/SHEA [Infectious Diseases Society of America/Society for Healthcare Epidemiology of America] guidelines that was put forward at ID [Infectious Diseases] Week in 2020. That was a recommendation stating that bezlotoxumab should be considered in any individual with at least 1 risk factor for recurrence of 

] infection. Why is that? What are the data behind this?

The data behind this comes from 2 prospective, randomized controlled trials entitled MODIFY I and MODIFY II. These were published a couple of years ago. In these trials, 386 people were randomized to receive bezlotoxumab in MODIFY I, and 395 patients to receive bezlotoxumab in MODIFY II.

What is bezlotoxumab? Bezlotoxumab is a fully humanized monoclonal antibody designed to bind toxin B in a specific manner. By binding toxin B it theoretically decreases rates of recurrence, and it does that in prospective randomized controlled trials. Within the original MODIFY I and MODIFY II trials, there were other groups. If you’ve read the literature or you’re aware of the literature, one of those groups was actoxumab, a fully humanized monoclonal antibody to toxin A, and a combination of bezlotoxumab and actoxumab. Actoxumab wasn’t as efficacious as was expected, so this product didn’t come to market. And we’re going to limit our discussion on that today and focus solely on the placebo arms and the bezlotoxumab arms.

Within those prospective randomized control trials, the groups that received placebo in MODIFY I had a recurrence rate of 27% versus 16% in the group that received bezlotoxumab. In MODIFY II, recurrence rates with the placebo arm were 25%, and with bezlotoxumab, 15%. It’s essential to understand that bezlotoxumab is a one-time infusion given in addition to a standard of care antimicrobial, and that’s how it was administered within these studies.

Now, within these studies they also looked at risk factors for recurrence: age over 65, any history of 

 infection, any immune compromised state for the patients, the hypervirulent strain, NAP1/B1/027 strain, or severe infection. Overall, there were trends for decreased rates of recurrence across the board; however, in the age over 65 group, both studies achieved statistical significance in the subgroup analysis, with the number needed to treat to reduce recurrence in 1 patient, of 6. That’s truly remarkable. That became the foundation for these recommendations that I just put forward of using bezlotoxumab.

Where did they come up with that 1 risk factor for recurrence? They did a subgroup analysis, published by Dale Girding, MD, et al, that looked at these original phase 3 prospective randomized controlled trials and put them together. When they looked at patients who had 1 risk factor for recurrence from the list that I just put forward, the group that received placebo recurred 31.3%, the group that received bezlotoxumab, 17.1%. When patients had 2 risk factors for recurrence, recurrence rates in placebo were 41.1% versus 26.9%. Three or more risk factors for recurrence, 46.1% with placebo, versus 21.2% with bezlotoxumab. The more risk factors you have, the more effective the bezlotoxumab is. But we see that even with 1 risk factor for recurrence, bezlotoxumab nearly cuts in half the recurrence rates.

At ID Week in October of 2020, a nice abstract was put forward looking at the real-world practical usage of bezlotoxumab. Within this analysis, they looked at 120 individuals. They compared a group of individuals who received either standard of care antimicrobials alone between January of 2015 and December of 2017, or standard of care antimicrobials plus bezlotoxumab, the fully humanized monoclonal antibody one-time infusion, given in addition to that standard of care antimicrobial. That group was assessed from September of 2017 to September of 2019. Overall, 47 individuals received standard of care antimicrobial plus bezlotoxumab, and 73 individuals received standard of care antimicrobial alone. They then looked at the 90-day recurrence rates, and overall, bezlotoxumab made a significant difference. The group that received bezlotoxumab recurred 12.8% of the time, versus 42.5% in the group that received standard of care antimicrobials alone. A statistically significant difference, but a practical real-world data support for the IDSA/SHEA guideline update for individuals who have 

 infection that have 1 risk factor for recurrence, which was the group that was studied in this analysis, showing a remarkable difference from 12.8% to 42.5% for rates of 90-day recurrence. Following this provisional update to the IDSA/SHEA guideline, we should strongly consider using bezlotoxumab in a cohort of patients who have 

IDSA/SHEA Guidelines Update and ID Week: Bezlotoxumab

: At ID [Infectious Diseases] Week in October of 2020, we had a major update to the IDSA/SHEA [Infectious Diseases Society of America/Society for Healthcare Epidemiology of America] guidelines. This update took a provisional format that’s still being reviewed, but was being presented publicly as a precursor to a publication that should come in late 2020 or early 2021. These recommendations built upon the IDSA/SHEA guidelines from 2018. They initially took on the question of initial treatment of 

 infection or primary infection. And when they did a PICO [patient/population, intervention, comparison, outcomes] analysis with updated data, they decided that fidaxomicin, 200 mg twice daily for 10 days, should be used preferentially in front of vancomycin, 125 mg 4 times daily.

How did we get to that recommendation? Let’s look back at some of the literature that built on fidaxomicin. And what is fidaxomicin? Fidaxomicin is a narrow spectrum antimicrobial, meaning it targets 

 and has a minimal effect on the surrounding colonization resistance, or the surrounding microbiota. By doing that, you treat the 

 but you also minimize the collateral damage to the colonization resistance, minimizing risks of recurrence in the future. That’s theoretical, but that has been borne out in several studies, and let’s talk about them.

There were 2 phase 3 prospective randomized controlled trials published in 2011 that compared vancomycin with fidaxomicin head-to-head. Across those trials, 542 patients received fidaxomicin, 200 mg twice daily for 10 days, and 563 patients received vancomycin, 125 mg 4 times daily for 10 days, and then they were followed for 28 days thereafter for recurrence. They initially looked at initial treatment response. And initial treatment response was powered for noninferiority, and fidaxomicin achieved that, with a response rate of 88.2% versus 85.8% with the vancomycin. But what I described before is that fidaxomicin has that narrow spectrum, so it should have decreased rates of recurrence. And in the modified intention to treat analysis, that was achieved with statistical significance. Recurrence rates with vancomycin were 25.3%, whereas recurrence rates with fidaxomicin were 15.4%, a statistically significant difference favoring fidaxomicin.

Many of us practice in the real world and not as part of a prospective randomized controlled trial. The question of how well fidaxomicin performs in the real world came up in a study that was put forward by Simon Goldenberg, MD, et al. This is a study that was based out of the United Kingdom, looking at several medical facilities and health care systems that used fidaxomicin in a variety of ways.

Let’s first focus on using it for initial treatment. They used historical controls for their recurrence rates, and then prospective data for usage of fidaxomicin for initial infection, and in the 2 health care systems that I’m going to quote right now, for all infections. The historical data in health care system A within that study had a recurrence rate of 10.6%. Once fidaxomicin was added, 3.1%, a statistically significant difference. In health care system B, which also used fidaxomicin universally, the historical recurrence rate was 16.3%, versus 3.1% once fidaxomicin was being used. We can see a real significant delta and improvement, or lessening, of recurrence rates when fidaxomicin is being used.

 infection. And with this 2020 ID Week update to the IDSA/SHEA guidelines, they recommended using fidaxomicin in front of vancomycin for recurrence as well. Where did that come from? Let’s go back to the study that we were just discussing by Goldenberg, et al. In a group that received fidaxomicin for first recurrence, the historical controls had recurrence rates of 21.1%, versus 12.5% in the prospective group that received fidaxomicin. What we see is, even if fidaxomicin wasn’t used initially but was used for recurrence, recurrence rates decreased.

Now, that’s the real-world application, but there are also prospective randomized controlled data that looked into this, and that was a subgroup analysis of 28% of all the individuals in the pivotal phase 3 trials comparing vancomycin with fidaxomicin. In that group, 28% of the individuals had had 

 within the prior 3 months. When they looked at the rates of recurrence of the group that then received vancomycin, recurrence rates were 35.5%; the group that received fidaxomicin, 19.7%, a statistically significant reduction in rates of recurrence.

In addition, there’s a more modern study that was published a couple of years ago out of Europe. They looked at 364 individuals hospitalized with 

 infection and randomized them to either receive vancomycin, 125 mg 4 times daily for 10 days, or a unique application of fidaxomicin, giving it twice daily for 5 days, and then every other day for days 7 through 25, almost a taper of sorts. Overall, initial treatment response in the vancomycin arm was 82.1% versus 80% with fidaxomicin. Noninferior, so they were similar; however, rates of recurrence in the fidaxomicin arm were remarkably lower. Rates of recurrence with vancomycin were 19% versus 6.2% in the fidaxomicin arm, a statistically significant difference. Within this update to the 2018 guidelines, it is now recommended that fidaxomicin be used in front of vancomycin for first recurrence, with consideration either for 1 tablet twice daily for 10 days, or 1 tablet twice daily for 5 days, and then every other day for days 7 through 25.

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