Editors from Contagion® spoke with Sahil Khanna, MBBS, associate professor of medicine and consultant in the Division of Gastroenterology and Hepatology, Department of Internal Medicine, at Mayo Clinic in Rochester, Minnesota, about the latest on the use of fecal microbiota transplant (FMT) for recurrent Clostridioides difficile infection (CDI).
Contagion®: Can you share your experience with the use of FMT in patients with recurrent CDI?
Khanna: In patients who have had 3 or more CDIs, the risk of recurrence is 60% or higher.1 The reason is because antibiotics that are used to traditionally treat CDI are broad spectrum, and so, although they kill C difficile, they also kill useful bacteria [in the gut microbiome]. When that happens, the patient does not have a diverse enough flora in the gut to fight against the C difficile, and the infection tends to recur. To combat this, stool is taken from an individual with healthy flora, processed, filtered, and then delivered into an [infected] recipient patient through multiple modalities, such as colonoscopy, enema, or oral capsule.2 (Also see Fecal Microbiota Transplant for the Treatment of Clostridioides difficile Infection: What’s New in 2020 and Beyond.) FMT has shown to be highly efficacious, with cure rates of 85% or higher after 1 or more fecal transplants.3
Is FMT used as a firstline treatment for CDI?
The first-line treatment for CDI is antibiotics, and sometimes immune-enhancing therapies such as bezlotoxumab are used in conjunction with antibiotics for first-line treatment in those patients who are at high risk of recurrence. Second-line treatment would be antibiotics again.2,4 When a patient has had 3 or more episodes of CDI, then FMT may be considered. The recommended course of action would be to first treat that patient with antibiotics for a period of 10 to 14 days, then hold off on antibiotics for about 24 to 72 hours. The goal of treating with antibiotics first, even at this stage, is to decrease the burden of the infection and the inflammation in the colon. For the most part, FMT would not be used to begin with and [certainly] not at the off-set when the patient is first having the infection.
Can you describe the successful outcomes associated with the use of FMT?
The first success refers to recurrence rates. Recurrence rates after FMT have been shown to be between 10% and 15%.3 This decrease in recurrence rates has also been shown to be associated with decreases in rates of hospitalization and decreases in health care resource utilization, demonstrated in cost-effectiveness modeling studies. [The results of 1] of these studies have shown that FMT is more cost-effective than antibiotic therapy for CDI,5 and other studies have shown improved quality of life in patients who have received FMT [for recurrent CDI] compared with [antibiotic therapy].6,7
From a clinical standpoint, FMT restores the gut microbiome, taking the recipient’s microbiome from a dysbiotic state to a healthy one, sometimes resembling that of the donor.2
Are your patients receptive to FMT?
Over the years, I have seen that few if any patients are not receptive to taking FMT. In patients who have had 3 or more CDIs, the disease has taken such a toll on their personal and work lives and their health that they are willing to try almost any kind of therapy available to them. I have not heard a lot of patients saying no because of the yuck factor that comes with it.
CDI is the most common infection in US hospitals,8 and still most patients have no idea what it is. The typical response from a patient when I mention FMT is “I had no idea what C difficile was, forget about the gut microbiome and FMT.” Oftentimes, patients have not been adequately counseled on the risk of CDI when they are prescribed an antibiotic [for an infection] because the overall risk of CDI is low in patients who have not had CDI previously. However, when patients have 2 or more CDIs, their primary care physician usually starts talking about FMT. That is likely because of the increased awareness because of the previous infection(s).
For all patients, we talk about the science behind FMT as well as the safety [of the treatment], the efficacy, and the risk factors. After an informed discussion, the patient’s receptivity increases.
Most patients [who know about FMT] are informed about the benefits. They have read about its efficacy. [These patients] are most concerned about unknown adverse events [AEs], especially in light of some infectious complications that have been reported with FMT. For example, in 2019, there were 2 cases of extended-spectrum β-lactamase— producing Escherichia coli bacteremia,9 and this year , a report came out about several cases of Shiga toxin—producing E coli transmission as a result of FMT.10 Currently, patients are worried about coronavirus disease 2019 [COVID-19] infection [as a result of FMT] because severe acute respiratory syndrome coronavirus 2, [the virus that causes COVID-19,] could be present in stool.11 Donors, on the other hand, are worried about uncovering unknown infections or agents that they may carry. Infectious risk is our biggest concern.
Are there other risks involved with the use of FMT?
Some risks are associations, whereas others are true cause and effect. In terms of associations, there was a published case of a patient who received FMT from an overweight individual and then eventually became overweight themselves.12 That case study brought a lot of media coverage, and people were concerned that they were going to become obese after undergoing FMT. [The results of a] follow- up study that analyzed data on multiple people who received FMT, larger studies with more individuals, showed no association of weight gain after FMT.13
The other risks that are associated with FMT refer to the modality of the procedure.14 [For example,] if FMT is performed with a nasogastric tube, there is a risk of vomiting and aspiration. With colonoscopy, there is a risk of perforation and other procedure-related risks. There are other unknowns, as well, such as the risk of postinfection irritable bowel syndrome [IBS].
Is there anything else that can be done to mitigate these risks?
Absolutely. Donors are screened via health questions and a history at every donation and periodically through lab tests for communicable diseases such as HIV, hepatitis [A, B, C] infections, syphilis, and human T-cell leukemia virus.4,15 These infections, which can be detected through a blood test, can also give an idea of a donor’s behavior, and those donors would be excluded. Donors are also periodically screened for infections in their stool through a stool pathogen panel [that screens for about 22 kinds of infections] and testing for parasites and multidrug-resistant infections. Starting in 2020, donors are also screened periodically for both respiratory and nonrespiratory symptoms [eg, fever, nausea, sore throat, cough, diarrhea] of COVID-19 infection16 and are tested through nasal swab and the presence of COVID-19 antibodies via a blood test.17 The donor stool is then kept under embargo until follow-up results are received.11
What are some of the operational challenges associated with the use of FMT?
The biggest operational challenge with the use of FMT is a lack of standardization on how to perform FMT. Patients can have different experiences based on which part of the world or even which part of the country they are in when they receive FMT. For example, the results of a systematic review published in Annals of Internal Medicine in 2017 on 85 published studies on the use of FMT found that methodological components— donor screening, donor testing, medications taking by donors, stool processing elements, and the training of people performing FMT—were not reported in the majority of the studies.18 This lack of standardization is one of the biggest challenges.
Another challenge is ensuring that FMT is being used in the right patient. The patient should truly have recurrent CDI and not postinfection IBS, which can be a confusing ailment in patients who have had CDI in the past.
How can clinicians make sure that a patient has recurrent CDI and not postinfection IBS?
To me, a 4-step process is required to make an accurate diagnosis of [recurrent] CDI. The first step is to ensure the patient has risk factors for [recurrent] CDI. Typically, these patients have had prior antibiotic use or recent CDI. The second and arguably most important step is to look for symptoms of CDI. In the vast majority of patients, these include the passing of mushy or watery stools 3 or more times a day for several days in a row. Patients should not experience days in between where there are no bowel movements or constipation. Symptoms of diarrhea should be independent of what the patient is eating, meaning it is not IBS but, rather, true diarrhea.4 It is important to take a detailed history from those patients to iron that out.
The third step is typically a stool test, and several modalities are available. There are PCR [polymerase chain reaction]— based stool assays, which should be done only in the presence of watery stools and the presence of the risk factors for CDI. PCR-based assays do not measure the toxin production, only the presence of the organism. A more accurate modality can be the 2-step glutamate dehydrogenase test in conjunction with an enzyme immunoassay test for the toxin itself, because this combination measures toxin production.4 The toxin production assay itself is not highly sensitive, and so results should be taken with a grain of salt.
The fourth step is to look at the patient’s prior responses to medication. If the patient has received a diagnosis of CDI 2 or more times in the past, prior treatment antibiotics— vancomycin; fidaxomicin; in some cases, metronidazole—should be reviewed and their responses assessed. If a patient states they had a previous CDI and were prescribed oral vancomycin or oral fidaxomicin and it almost seems as though they were taking a placebo [eg, no response to these medications], then it is unlikely that patient has a CDI. That patient could be colonized or have an alternate diagnosis. Primary nonresponse to CDI is extremely rare.17
Diagnosis of recurrent CDI is clinical and microbiological; it is not just a diagnosis based on a positive stool sample. Reviewed together, these 4 aspects should aid clinicians in making a clinical diagnosis of recurrent CDI with certainty.
The biggest take-home message that I would like to share with my colleagues on the use of FMT is to be judicious. Ensure that the patient truly has recurrent CDI and does not have postinfection iIBS.4,19 Ensure that you have an informed discussion with the patient about the risks, benefits, and alternative treatment options, especially in this time of COVID-19. The risk of transmission of COVID-19 should be mitigated as much as possible while doing FMT.
And then most importantly, after FMT is complete, it is important to follow up on those patients to see how they are doing and assess their symptoms and assess for AEs. If a patient is experiencing an AE, it should be promptly reported. I would also add that FMT is being studied for indications other than CDI, and it should be done only under research settings for indications other than CDI [at this time]. For example, if a patient asks for FMT for IBS, fatty liver disease, inflammatory bowel disease, or any such microbiome-associated illness, that patient should not undergo clinical FMT but, rather, they should undergo FMT under the guidance of a research setting.
Is this how you would like to see FMT evolve in the future?
There are clinical trials available all over the world for many of these diseases.20-26
That [is where] I am hoping to see FMT evolve. For the near foreseeable future, we are probably going to be able to do FMT in conjunction with a colonoscopy or via another modality with donor-directed stool. In the intermediate future, we will probably see 1 or more products approved by the FDA to be prescribed for use in the standardized setting, such as a capsule-based therapy or an enema-based therapy.
In the long term, we will see the defined microbic consortia for CDI, and we will see FMT or similar microbiome-based therapies being used to modulate psychiatric diseases, multidrug-resistant organism colonization, and more. FMT will not be the main treatment for multiple diseases but, rather, an adjunct to conventional therapies for multiple diseases outside of CDI. There are a lot of exciting advancements being studied in this field.
The field is advancing to the point that now we are seeing development of some standardized microbiome replacement therapies.27 Some are straight from-stool derivatives, whereas others are processed stool placed into capsules. There is also a product in development right now that is the synthetic microbial consortia, which has been grown in the lab and is not dependent upon procuring fresh donor stool.28
Do you think that FMT will evolve as we continue to map the human gut microbiome?
There have been studies mapping the human microbiome in healthy subjects, and there are now ongoing studies looking at dysbiosis.29 There are 3 aspects to it: whether or not dysbiosis is occurring, whether or not dysbiosis can be corrected, and then the effect of this correction on the disease [being studied]. For example, investigators on a randomized, placebo-controlled, pilot study, presented at Digestive Disease Week in 2019, studied the results of transferring [a sample of] the microbiome from a lean donor into obese recipients to see if the transfer would aid with weight loss [in the recipients].30 Study results indicated that although there was a change in dysbiosis in the recipients’ microbiomes, there was no change in weight after that change in dysbiosis happened. There is a lot to be learned from these different diseases as we understand them further.
Disclosures: Khanna has received research grants from Rebiotix Inc (a Ferring company) and consulting fees from Shire Plc; Premier, Inc; Facile therapeutics; and ProbioTech International Inc.
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14. Information pertaining to additional safety protections regarding use of fecal microbiota for transplantation — testing of stool donors for enteropathogenic Escherichia coli and Shiga-toxin-producing Escherichia coli. US Food and Drug Administration. April 6, 2020. Accessed September 30, 2020. www.fda.gov/vaccines-bloodbiologics/ safety-availability-biologics/ information-pertaining-additional-safety-protections-regarding-use-fecal-microbiota-transplantation-0
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21. Examining the efficacy of fecal microbiota transplantation (FMT) and dietary fiber in patients with ulcerative colitis (MINDFUL). Clinicaltrials.gov. Updated July 31, 2020. Accessed September 24, 2020. https://clinicaltrials.gov/ct2/ show/NCT03998488
22. Fecal microbiota transplant (FMT) capsule for improving the efficacy of anti- PD-1. Clinicaltrials.gov. Updated August 12, 2020. Accessed September 24, 2020. https://clinicaltrials.gov/ ct2/show/NCT04130763
23. Fecal microbiota transplantation (FMT) in metastatic melanoma patients who failed immunotherapy. Clinicaltrials. gov. Updated April 3, 2019. Accessed September 24, 2020. https://clinicaltrials. gov/ct2/show/NCT03353402
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28. Phase 2 study of VE303 for prevention of recurrent Clostridium difficile infection (CONSORTIUM). Clinicaltrials.gov. Updated March 19, 2020. Accessed September 28, 2020. https:// www.clinicaltrials.gov/ct2/show/ NCT03788434
29. NIH Human Microbiome Project. Human Microbiome Project Data Analysis and Coordination Center. Accessed September 24, 2020. www.hmpdacc.org/hmp/
30. Allegretti JR, Kassam Z, Mullish BH, et al. effects of fecal microbiota transplantation with oral capsules in obese patients. Clin Gastroenterol Hepatol. 2020;18(4):855-863.e2. doi:10.1016/j.cgh.2019.07.006 EXPERT INTERVIEW: SAHIL KHANNA, MBB