TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION, VOL. 127, 2016
THE POWER OF POOP: FECAL MICROBIOTA TRANSPLANTATION FOR CLOSTRIDIUM DIFFICILE INFECTION MICHAEL B. EDMOND, MD, MPH, MPA IOWA CITY, IOWA
ABSTRACT The human gut is colonized with 200 to 1,000 bacterial species. Administration of antibiotics reduces the diversity of the intestinal microbiota, reduces colonization resistance, and can lead to infection with Clostridium difficile. These infections have become more prevalent and increasingly patients are experiencing multiple recurrences that are incurable with standard treatment. Although fecal microbiota transplantation (FMT) has been used for centuries in human and veterinary medicine, only recently has it be shown to be highly effective for recurrent C. difficile infection. The goal of FMT is to re-introduce a complete, stable community of gut microorganisms to repair or replace the disrupted native microbiota. FMT can be delivered via nasoenteric tube, colonoscopy, or enema. Despite a cure rate approximating 90%, many barriers to FMT have limited its availability to patients. The recent development of a not-for-profit stool bank has helped to make this therapy more accessible. Additional indications for FMT are currently under investigation.
INTRODUCTION During the past decade there has been a significant increase in the incidence of Clostridium difficile infection. Using populationbased surveillance, it is estimated that there are nearly half a million infections and 29,000 deaths in the United States annually (1). Approximately one-third of cases are not associated with inpatient hospitalization (i.e., community associated). The excess health care costs of C. difficile infection for acute care facilities alone approximate $5 billion yearly (2).
Correspondence and reprint requests: Michael B. Edmond, MD, MPH, MPA, C512 GH, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, Tel: 319-353-8352, Fax: 319-353-7043, E-mail: [email protected]. Potential Conflicts of Interest: Michael B. Edmond serves on the clinical advisory board of OpenBiome, a nonprofit stool bank, for which he receives no remuneration.
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The clinical manifestations of C. difficile infection are variable, ranging from asymptomatic carriage to self-limited diarrhea to pseudomembranous colitis, which in some cases may be accompanied by bowel perforation and/or septic shock followed by death. Approximately 20% of infected patients will have at least one recurrence (1), and some patients have multiple recurrences associated with cessation of treatment with oral vancomycin, typically occurring within 1−2 weeks after therapy is completed. Risk factors for recurrent infection include age ≥65 years, treatment with non−C. difficile antibiotics following infection, use of proton pump inhibitors, renal insufficiency, and prior treatment with fluoroquinolones (3).
FECAL MICROBIOTA TRANSPLANTATION: RATIONALE, HISTORY, AND INDICATIONS The human gut is colonized by as many as 100 trillion bacteria across 200 to 1,000 distinct species (4). This microbiota protects the host from pathogens through multiple mechanisms resulting in colonization resistance. Treatment with antibiotics disrupts the native microbiota, reduces colonization resistance, and allows C. difficile, if present, to germinate from spores, multiply, and produce toxins. Thus, the primary problem in C. difficile infection is the absence of healthy microbiota to keep the growth of C. difficile suppressed, and the rationale for fecal microbiota transplantation (FMT) is to re-introduce a complete, stable community of gut microorganisms (5). Patients with recurrent C. difficile infection have been found to have a loss of gastrointestinal bacterial diversity, which is reversed after engraftment of donor stool (6). Although FMT has been used for centuries in veterinary medicine, and there are reports of its use in humans in historical accounts, the first use of FMT in modern medicine occurred in 1957. Four patients in Denver with fulminant pseudomembranous colitis were treated with fecal retention enemas from a healthy donor. Improvement was noted within hours and all four were cured (7). Of note, C. difficile had yet to be discovered so the cause of pseudomembranous colitis was not known at that time. Subsequently, FMT was rarely performed as treatment of C. difficile infection with metronidazole and vancomycin was highly successful. However, in the last decade, an increasing proportion of patients with C. difficile infection have developed recurrent disease for which these agents are not effective, prompting the re-introduction of
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FMT, which is considered an investigational therapy by the US Food and Drug Administration (8). The currently accepted indications for FMT are (9): 1) Recurrent or relapsing C. difficile infection, defined as either ≥3 episodes with failure of a 6- to 8-week vancomycin taper, or ≥2 episodes of C. difficile infection resulting in hospitalization. 2) Moderate C. difficile infection not responding to vancomycin for at least 1 week. 3) Severe or fulminant C. difficile infection with no response to standard therapy after 48 hours. The most studied indication for FMT has been recurrent C. difficile infection. Three randomized open-label trials have demonstrated cure rates of 90% to 94% (10−12). Two of the three trials compared FMT with oral vancomycin (10,12) and demonstrated superiority of FMT. The third trial compared FMT delivered by the nasogastric route with delivery through colonoscopy (11), and demonstrated no difference in outcome based on delivery modality. In addition to data from randomized controlled trials, an analysis of 21 case series involving 453 patients found that the overall cure rate for FMT in recurrent C. difficile infection was 85% (13). DNA sequencing studies comparing populations of stool bacteria before and after FMT in patients with recurrent C. difficile infection and to donor stool demonstrate that engraftment occurs within the first 3 days after transplantation and is accompanied by resolution of symptoms (14).
FMT LOGISTICS Before the development of open stool banks, FMT required identification of a donor for each patient to be transplanted (i.e., directed donors). Donors were typically family members or friends. Typical donor exclusions included: infection or risk factors for infection with blood-borne pathogens (HIV, hepatitis B virus [HBV], hepatitis C virus [HCV]); risk for variant Creutzfeldt-Jakob disease; travel to areas with endemic infectious diarrheal illnesses within 6 months; antibiotic treatment within 3 months; gastrointestinal diseases; and treatment with immunosuppressants or chemotherapy (9). Donor testing typically includes serologic tests for HIV, hepatitis A, HBV, HCV, and syphilis, and stool testing for C. difficile, ova and parasites (including testing for Giardia and Cryptosporidium), and routine bacterial culture. This battery of tests can cost up to $1,500 and is not usually covered by insurance.
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On the day of FMT, the directed donor provides a fresh stool sample, which is mixed with water in a blender to produce a slurry. The slurry is then filtered before instillation. The filtrate can then be delivered via nasoenteric tube, colonoscopy, or retention enema. Preparation of the recipient for fecal transplantation depends on the delivery modality. For all modalities, patients are typically treated for several days with oral vancomycin to reduce the burden of C. difficile in the gut; this is discontinued 12−48 hours before FMT. When delivered via nasoenteric tube, a proton pump inhibitor is administered the evening before and morning of the transplantation procedure to prevent the patient’s gastric acid from killing the transplanted bacteria. When delivered via colonoscopy, the patient will require pre-treatment colonic lavage. Advantages of the nasoenteric route are the lack of need for pretreatment colonic lavage or sedation. Once the nasoenteric tube is placed, radiographic imaging is performed to demonstrate placement in the stomach or duodenum. Since gastric acid blockade has been performed before tube placement, tip placement in the stomach is acceptable. Fluoroscopic placement of the nasoenteric tube is rarely needed; one exception can be in patients with large hiatal hernias in whom the tube coils in the hernia. While the optimal dose of stool is unknown, the volume of stool solution administered is dependent on the route of delivery. For nasoenteric administration, a slurry created from 30 gm of stool and 70 mL of water, which is then filtered, is used to produce a dose volume of 25−30 mL (15). This is followed by flushing of the nasoenteric tube with 25 mL of water. The tube is then removed, and the patient can immediately resume a normal diet. With rectal/colonoscopic delivery the volume is typically 250 mL. More recently frozen stool capsules have become available. Preliminary evidence from three studies suggests that the efficacy is somewhat lower, which may be due to the smaller volume of stool solution delivered. Across the three studies (16−18), a cure rate of 67% was demonstrated with first treatment. Retreatment of non-responders resulted in an overall cure rate of 86%. Anonymous donor, frozen, banked stool offers a number of advantages over directed donation. Anonymous donor stool is likely to be safer than directed donor stool. For blood donors it has been shown that directed donors are 3-fold more likely to be infected with HIV, HBV, or HCV than non-directed donors (19). It also avoids the ethical problem of potential coercion to donate to a family member or friend, and also circumvents issues with confidentiality should the donor be found to have an excluding condition or screening test (20). The anonymous donor process can be highly
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selective and donor testing is typically more comprehensive than that used for directed donors. OpenBiome, a nonprofit stool bank that provides donor stool internationally, quarantines donated stool for 60 days, then repeats their testing battery before releasing product (21). This serves to detect donors who are in the seronegative window period for a blood-borne pathogen. Their donors continue to be tested every 60 days. In addition, serum and stool safety aliquots are archived should there need to be a look-back if a recipient develops an infection post-transplant. Because each stool bank donor provides numerous stool donations, the cost of donor testing is reduced as it is spread over multiple recipients. Another advantage of banked stool is that the patient is not required to identify a donor; some patients are uncomfortable asking a relative or friend to donate, and some patients are unable to identify a donor. Lastly, banked frozen stool can be stocked locally, available to be used on demand, and it reduces the time requirement for the treating physician. Overall, FMT appears to be generally safe, with few reported serious adverse effects. The most serious adverse effects appear to be related to the delivery mechanism rather than the FMT itself (e.g., aspiration related to colonoscopy sedation, colonic perforation during colonoscopy) (22). One case of bacteremia with E. coli following FMT via colonoscopy has been reported in a patient with recurrent C. difficile infection and Crohn’s disease (23). The author of this review has also observed a case of E. coli bacteremia and septic shock following FMT delivered via nasoenteric tube in a patient with cirrhosis and recurrent C. difficile infection (unpublished data). A case of fatal aspiration pneumonia following FMT via endoscopic delivery into the distal duodenum has been reported; however, it should be noted that the patient was sedated and the volume of stool solution was atypical for the upper gastrointestinal delivery route (100−150 mL in this case) (24). FMT has been accepted well by patients. In a study of 77 patients with recurrent C. difficile infection who were treated with FMT, 97% reported that would undergo another FMT for recurrent infection, and 53% reported that they would prefer FMT as the first treatment option as opposed to antimicrobial treatment (25).
FUTURE APPLICATIONS An emerging application for FMT is multidrug-resistant pathogen decolonization of the gastrointestinal tract. Two case reports demonstrate successful decolonization of multidrug-resistant gram-negative pathogens in humans (26,27). Decolonization of vancomycin-resistant
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enterococci has been demonstrated in mice (28), as well as a case report in a patient after heart and kidney transplantation (29). Other areas of investigation for the application of FMT to treat non-infectious diseases include obesity, non-alcoholic fatty liver disease, multiple sclerosis, insulin resistance, irritable bowel syndrome, and inflammatory bowel disease (30). In addition to expanding the indications for FMT, research into the production of synthetic stool is ongoing. Two studies investigated a synthetic stool product which consisted of 10 intestinal bacterial species, each grown in pure culture, then combined in sterile normal saline, and delivered via enema. In 14 patients with recurrent C. difficile infection treated with this product, cure was achieved in 86% (31,32). In another study, stool was obtained from a healthy donor and cultured (33). Of the 62 bacterial species isolated, 33 were chosen to be included in a synthetic product, which was delivered via colonoscopy to two patients with recurrent C. difficile. Both patients were cured. In summary, FMT has been shown to be highly effective for the treatment of recurrent C. difficile infection and well accepted by patients. It is relatively simple to perform in the ambulatory setting and access to the procedure has been improved with the ability to purchase carefully screened, frozen donor stool from an open stool bank.
REFERENCES 1. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015;372:825−34. 2. Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin Infect Dis 2012;55(suppl 2):S88−92. 3. Deshpande A, Pasupuleti V, Thota P, et al. Risk factors for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Infect Control Hosp Epidemiol 2015;36:452−60. 4. Wardell LH, Huttenhower C, Garrett WS. Current concepts of the intestinal microbiota and the pathogenesis of infection. Curr Infect Dis Rep 2011;13:28−34. 5. Borody TJ, Campbell J. Fecal microbiota transplantation: techniques, applications, and issues. Gastroenterol Clin N Am 2012;41:781−803. 6. Weingarden A, Gonzalez A, Vazquez-Baeza Y, et al. Dynamic changes in short- and long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection. Microbiome 2015;3:10. 7. Eiseman B, Silen W, Bascom GS, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958;44:854−9. 8. Moore T, Rodriguez A, Bakken JS. Fecal microbiota transplantation: a practical update for the infectious disease specialist. Clin Infect Dis 2014;58:541−5. 9. Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011;9:1044−9.
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10. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407−15. 11. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis 2014;58:1515−22. 12. Cammarota G, Masucci L, Ianiro G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther 2015;41:835−43. 13. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile infection: a systematic review. Ann Intern Med 2015;162:630−8. 14. Hamilton MJ, Weingarden AR, Unno T, et al. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes 2013;4:125−35. 15. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003;36:580−5. 16. Hirsch BE, Saraiya N, Poeth K et al. Effectiveness of fecal-derived microbiota transfer using orally administered capsules for recurrent Clostridium difficile infection. BMC Infect Dis 2015;15:191. 17. Stollman N, Smith M, Giovanelli A, et al. Frozen encapsulated stool in recurrent Clostridium difficile: exploring the role of pills in the treatment hierarchy of fecal microbiota transplant nonresponders. Am J Gastroenterol 2015;110:600−1. 18. Youngster I, Russell GH, Pindar C, et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014;312:1772−8. 19. Dorsey KA, Moritz ED, Steele WR, at al. A comparison of human immunodeficiency virus, hepatitis C virus, hepatitis B virus, and human T-lymphotropic virus marker rates for directed versus volunteer blood donations to the American Red Cross during 2005 to 2010. Transfusion 2013;53:1250−6. 20. Costello SP, Tucker EC, Brooy JL et al. Establishing a fecal microbiota transplant service for the treatment of Clostridium difficile infection. Clin Infect Dis 2015 (epub ahead of print). 21. OpenBiome. Available at: http://www.openbiome.org/. Accessed November 28, 2015. 22. Kelly CR, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol 2014;109:1065−71. 23. Quera R, Espinoza R, Estay C, et al. Bacteremia as an adverse event of fecal microbiota transplantation in a patient with Crohn’s disease and recurrent Clostridium difficile infection. J Crohns Colitis 2014;8:252−3. 24. Baxter N, Ahmad T, Colville A, et al. Fatal aspiration pneumonia as a complication of fecal microbiota transplant. Clin Infect Dis 2015;61:136−7. 25. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107:1079−87. 26. Singh R, van Nood E, Nieuwdorp M, et al. Donor feces infusion for eradication of extended spectrum beta-lactamase Escherichia coli in a patient with end stage renal disease. Clin Microbiol Infect 2014;20:O977−8. 27. Crum-Cianflone M, Sullivan E, Ballon-Landa G. Fecal microbiota transplantation and successful resolution of multidrug-resistant-organism colonization. J Clin Microbiol 2015;53:1986−9.
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28. Ubeda C, Bucci V, Caballero S, et al. Intestinal microbiota containing Barnesiella species cures vancomycin-resistant Enterococcus faecium colonization. Infect Immun 2013;81:965−73. 29. Stripling J, Kumar R, Baddley JW, et al. Loss of vancomycin-resistant Enterococcus fecal dominance in an organ transplant patient with Clostridium difficile colitis after fecal microbiota transplant. Open Forum Infect Dis 2015;2:ofv078. 30. Smits LP, Bouter KE, de Vos WM, et al. Therapeutic potential of fecal microbiota transplantation. Gastroenterology 2013;145:946−53. 31. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989;1:1156−60. 32. Emanuelsson F, Claesson BE, Ljungström L, et al. Faecal microbiota transplantation and bacteriotherapy for recurrent Clostridium difficile infection: a retrospective evaluation of 31 patients. Scand J Infect Dis. 2014;46:89−97. 33. Petrof EO, Gloor GB, Vanner SJ, et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut. Microbiome 2013;1:3.
DISCUSSION Carethers, Ann Arbor: Wonderful talk. I was wondering with the FDA regulations and needing certain regulations for doing the fecal microbiota transplantation (FMT) a couple of years ago—I was wondering how you consent your patients for a long-term effects of FMT because there are a lot of studies, largely from Jeff Gordon’s group, showing that we can modify heart disease, obesity, and those types of things with mouse and in twin studies. So I was wondering how you consent your patients. Edmond, Iowa City: We do a fairly careful informed consent process where we talk about those kinds of things but I have to say that when patients present for this therapy, none of that matters to them. They are not interested in the long-term effects. Often these are elderly patients. Their lives have been decimated by this infection and they want to be cured today. But you’re right, we don’t know what long-term issues that there may be. DuPont, Houston: Very nice review and description of process of this treatment. We have an active program in Houston and we are using lyophilized twice-filtered product that we give in enteric-coated capsules. Others are using capsules too, but I wanted to tell the group about my first experience with FMT. It was in 1970, I was a young assistant professor of infectious diseases at the University of Maryland. I had a very sick patient who was dying from antibiotic-associated colitis, developed renal failure. This was before IRBs, 8 years before C. difficile was identified. I went to the department chair and the hospital administrator to ask whether we could give stool to this patient to try to reverse this obviously fatal disease. They said fine. The chief of surgery at Maryland said, “I will get you stool from an elective surgical case.” He brought me the sample, we gave it to the patient, and the patient got miraculously well. I was going to publish it, so I went and reviewed a little bit about the donor and it was a typhoid carrier! I had infused eleven logs of Salmonella typhi into the rectum of my patient. Now there are three points about this: 1) I didn’t publish it; 2) you can give anybody’s stool to these patients and they do well; and 3) most importantly, you don’t get typhoid fever from the rectum. LeBlond, Billings: Just a query about the FDA’s position on this. The FDA regulates things that go interstate much more than things intrastate. For instance, in blood
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banking, if you have blood banking software and you don’t pass it across state lines, FDA doesn’t get involved with that. So what is the status of FDA regulation? Edmond, Iowa City: Human stool used for fecal transplantation is considered an investigational new drug. At this point in time, FDA requires that you get informed consent. You must disclose to the patient that it’s investigational and you can’t use it on pregnant women. There has been a proposal that was put forth by the FDA that would require that the donor know the recipient, or the treating physician must know the donor. So far, the FDA has not acted on that. Hook, Birmingham: I’ll second what you said. This is one of the most gratifying things I have ever been able to do for a patient and their thanks are really effusive. It’s remarkable. My question for you, however, has to do with the microbiome and fecal microbiota transplantation. Work at UAB suggests that all of us have different microbiomes—that our microbiomes are generated largely from our mothers, and that as we age our microbiomes begin to decay and are less substantive and resistant to infection. Our experience has shown that those parameters affect response to therapy—that, for instance, age of the donor and familial relationships may be related to the success of the fecal transplant. I was wondering about your thoughts regarding microbiome variation as far as the stool bank is concerned and whether in reality the better donor might be a closely related younger family member? Edmond, Iowa City: I think we just don’t know the answers to those questions. If you look at the OpenBiome [stool bank] website, they will tell you about their donor selection process. Their donors are typically young, very healthy people in their 20s with an average of BMI of 23. The BMI issue has come up because there has been some question about whether you can make people obese by using donor stool from obese patients. Del Rio, Atlanta: That was great, Mike. I think that going back to what Ned Hook was saying, as you know some people have talked about actually self-banking your stool so it could be used later. What would be your recommendations regarding that? Edmond, Iowa City: OpenBiome now offers that service. Autogolous fecal transplantation might be particularly useful for oncology patients. I should also add that OpenBiome is now offering frozen capsules for fecal transplantation, so we have an additional method of delivery. The downsides are that you have to take 30 capsules and the failure rate is higher than with delivery via nasogastric tube, enema, or colonoscopy. Del Rio, Atlanta: It may be worth getting people to bank their stool at age about 25, so that when you get to be 80 you can actually get your own stool bank. Edmond, Iowa City: Agree. May, Gainesville: Great talk. As an oncologist I am interested to know whether you have performed a fecal transplant on a neutropenic patient. Do you require a certain status for the immune system? Edmond, Iowa City: I have not done a fecal transplant on a neutropenic patient and with chemotherapy-induced neutropenia I try to wait until the patient’s white blood cell has recovered before I do it. I suppose in the situation where the patient was fairly ill and neutropenic, the oncologist and I would have a discussion about risk versus benefit and we may decide to try. Guarner, Atlanta: Some people object to the name fecal transplant, what do you have to say about that? Edmond, Iowa City: What is the objection? Guarner, Atlanta: They don’t like the name transplant itself. Edmond, Iowa City: Oh I see, I thought maybe it was the fecal part that they were uncomfortable with. I haven’t really thought through that. Maybe we should call it what the veterinarians call it, transfaunation.
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Barondess, New York City: I think you said that some of these patients respond with extraordinary rapidity to these transplants and I wonder if you’d speculate on the mechanism of the immediate responses to those within 24 hours or so. It seems awfully fast to change somebody’s colonic microbiome. Edmond, Iowa City: It does, but what is interesting is when the microbiome of these patients has been analyzed you can find that when engraftment occurs is when symptoms stop. So it appears that this occurs quite rapidly, usually within 24−48 hours from the time of transplant. Oates, Nashville: Could you tell us what progress is being made to identifying the organisms in these fecal transplants that are active agents? At the present time fecal organisms are available over the counter as probiotics at all the drug stores, and obviously they aren’t the right ones to bring about this cure. There clearly should be a future understanding of which organisms are effective and then developing them in a pharmaceutical method so you don’t have all these risks. Edmond, Iowa City: Exactly. What you point out is the goal of developing synthetic stool, which is the basically picking multiple strains of bacteria, growing them in pure culture, mixing them together, and then administering those. There have been two or three clinical trials that have looked at this. One used 10 different strains and another one used 33 strains of bacteria. These are very small studies but they were successful and that’s probably where all of this is headed ultimately—to be able to give a mixture of bacterial strains grown from pure cultures that doesn’t have all the other things that are found in stool.
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THE POWER OF POOP: FECAL MICROBIOTA TRANSPLANTATION FOR CLOSTRIDIUM DIFFICILE INFECTION MICHAEL B. EDMOND, MD, MPH, MPA IOWA CITY, IOWA
ABSTRACT The human gut is colonized with 200 to 1,000 bacterial species. Administration of antibiotics reduces the diversity of the intestinal microbiota, reduces colonization resistance, and can lead to infection with Clostridium difficile. These infections have become more prevalent and increasingly patients are experiencing multiple recurrences that are incurable with standard treatment. Although fecal microbiota transplantation (FMT) has been used for centuries in human and veterinary medicine, only recently has it be shown to be highly effective for recurrent C. difficile infection. The goal of FMT is to re-introduce a complete, stable community of gut microorganisms to repair or replace the disrupted native microbiota. FMT can be delivered via nasoenteric tube, colonoscopy, or enema. Despite a cure rate approximating 90%, many barriers to FMT have limited its availability to patients. The recent development of a not-for-profit stool bank has helped to make this therapy more accessible. Additional indications for FMT are currently under investigation.
INTRODUCTION During the past decade there has been a significant increase in the incidence of Clostridium difficile infection. Using populationbased surveillance, it is estimated that there are nearly half a million infections and 29,000 deaths in the United States annually (1). Approximately one-third of cases are not associated with inpatient hospitalization (i.e., community associated). The excess health care costs of C. difficile infection for acute care facilities alone approximate $5 billion yearly (2).
Correspondence and reprint requests: Michael B. Edmond, MD, MPH, MPA, C512 GH, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, Tel: 319-353-8352, Fax: 319-353-7043, E-mail: [email protected]. Potential Conflicts of Interest: Michael B. Edmond serves on the clinical advisory board of OpenBiome, a nonprofit stool bank, for which he receives no remuneration.
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The clinical manifestations of C. difficile infection are variable, ranging from asymptomatic carriage to self-limited diarrhea to pseudomembranous colitis, which in some cases may be accompanied by bowel perforation and/or septic shock followed by death. Approximately 20% of infected patients will have at least one recurrence (1), and some patients have multiple recurrences associated with cessation of treatment with oral vancomycin, typically occurring within 1−2 weeks after therapy is completed. Risk factors for recurrent infection include age ≥65 years, treatment with non−C. difficile antibiotics following infection, use of proton pump inhibitors, renal insufficiency, and prior treatment with fluoroquinolones (3).
FECAL MICROBIOTA TRANSPLANTATION: RATIONALE, HISTORY, AND INDICATIONS The human gut is colonized by as many as 100 trillion bacteria across 200 to 1,000 distinct species (4). This microbiota protects the host from pathogens through multiple mechanisms resulting in colonization resistance. Treatment with antibiotics disrupts the native microbiota, reduces colonization resistance, and allows C. difficile, if present, to germinate from spores, multiply, and produce toxins. Thus, the primary problem in C. difficile infection is the absence of healthy microbiota to keep the growth of C. difficile suppressed, and the rationale for fecal microbiota transplantation (FMT) is to re-introduce a complete, stable community of gut microorganisms (5). Patients with recurrent C. difficile infection have been found to have a loss of gastrointestinal bacterial diversity, which is reversed after engraftment of donor stool (6). Although FMT has been used for centuries in veterinary medicine, and there are reports of its use in humans in historical accounts, the first use of FMT in modern medicine occurred in 1957. Four patients in Denver with fulminant pseudomembranous colitis were treated with fecal retention enemas from a healthy donor. Improvement was noted within hours and all four were cured (7). Of note, C. difficile had yet to be discovered so the cause of pseudomembranous colitis was not known at that time. Subsequently, FMT was rarely performed as treatment of C. difficile infection with metronidazole and vancomycin was highly successful. However, in the last decade, an increasing proportion of patients with C. difficile infection have developed recurrent disease for which these agents are not effective, prompting the re-introduction of
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FMT, which is considered an investigational therapy by the US Food and Drug Administration (8). The currently accepted indications for FMT are (9): 1) Recurrent or relapsing C. difficile infection, defined as either ≥3 episodes with failure of a 6- to 8-week vancomycin taper, or ≥2 episodes of C. difficile infection resulting in hospitalization. 2) Moderate C. difficile infection not responding to vancomycin for at least 1 week. 3) Severe or fulminant C. difficile infection with no response to standard therapy after 48 hours. The most studied indication for FMT has been recurrent C. difficile infection. Three randomized open-label trials have demonstrated cure rates of 90% to 94% (10−12). Two of the three trials compared FMT with oral vancomycin (10,12) and demonstrated superiority of FMT. The third trial compared FMT delivered by the nasogastric route with delivery through colonoscopy (11), and demonstrated no difference in outcome based on delivery modality. In addition to data from randomized controlled trials, an analysis of 21 case series involving 453 patients found that the overall cure rate for FMT in recurrent C. difficile infection was 85% (13). DNA sequencing studies comparing populations of stool bacteria before and after FMT in patients with recurrent C. difficile infection and to donor stool demonstrate that engraftment occurs within the first 3 days after transplantation and is accompanied by resolution of symptoms (14).
FMT LOGISTICS Before the development of open stool banks, FMT required identification of a donor for each patient to be transplanted (i.e., directed donors). Donors were typically family members or friends. Typical donor exclusions included: infection or risk factors for infection with blood-borne pathogens (HIV, hepatitis B virus [HBV], hepatitis C virus [HCV]); risk for variant Creutzfeldt-Jakob disease; travel to areas with endemic infectious diarrheal illnesses within 6 months; antibiotic treatment within 3 months; gastrointestinal diseases; and treatment with immunosuppressants or chemotherapy (9). Donor testing typically includes serologic tests for HIV, hepatitis A, HBV, HCV, and syphilis, and stool testing for C. difficile, ova and parasites (including testing for Giardia and Cryptosporidium), and routine bacterial culture. This battery of tests can cost up to $1,500 and is not usually covered by insurance.
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On the day of FMT, the directed donor provides a fresh stool sample, which is mixed with water in a blender to produce a slurry. The slurry is then filtered before instillation. The filtrate can then be delivered via nasoenteric tube, colonoscopy, or retention enema. Preparation of the recipient for fecal transplantation depends on the delivery modality. For all modalities, patients are typically treated for several days with oral vancomycin to reduce the burden of C. difficile in the gut; this is discontinued 12−48 hours before FMT. When delivered via nasoenteric tube, a proton pump inhibitor is administered the evening before and morning of the transplantation procedure to prevent the patient’s gastric acid from killing the transplanted bacteria. When delivered via colonoscopy, the patient will require pre-treatment colonic lavage. Advantages of the nasoenteric route are the lack of need for pretreatment colonic lavage or sedation. Once the nasoenteric tube is placed, radiographic imaging is performed to demonstrate placement in the stomach or duodenum. Since gastric acid blockade has been performed before tube placement, tip placement in the stomach is acceptable. Fluoroscopic placement of the nasoenteric tube is rarely needed; one exception can be in patients with large hiatal hernias in whom the tube coils in the hernia. While the optimal dose of stool is unknown, the volume of stool solution administered is dependent on the route of delivery. For nasoenteric administration, a slurry created from 30 gm of stool and 70 mL of water, which is then filtered, is used to produce a dose volume of 25−30 mL (15). This is followed by flushing of the nasoenteric tube with 25 mL of water. The tube is then removed, and the patient can immediately resume a normal diet. With rectal/colonoscopic delivery the volume is typically 250 mL. More recently frozen stool capsules have become available. Preliminary evidence from three studies suggests that the efficacy is somewhat lower, which may be due to the smaller volume of stool solution delivered. Across the three studies (16−18), a cure rate of 67% was demonstrated with first treatment. Retreatment of non-responders resulted in an overall cure rate of 86%. Anonymous donor, frozen, banked stool offers a number of advantages over directed donation. Anonymous donor stool is likely to be safer than directed donor stool. For blood donors it has been shown that directed donors are 3-fold more likely to be infected with HIV, HBV, or HCV than non-directed donors (19). It also avoids the ethical problem of potential coercion to donate to a family member or friend, and also circumvents issues with confidentiality should the donor be found to have an excluding condition or screening test (20). The anonymous donor process can be highly
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selective and donor testing is typically more comprehensive than that used for directed donors. OpenBiome, a nonprofit stool bank that provides donor stool internationally, quarantines donated stool for 60 days, then repeats their testing battery before releasing product (21). This serves to detect donors who are in the seronegative window period for a blood-borne pathogen. Their donors continue to be tested every 60 days. In addition, serum and stool safety aliquots are archived should there need to be a look-back if a recipient develops an infection post-transplant. Because each stool bank donor provides numerous stool donations, the cost of donor testing is reduced as it is spread over multiple recipients. Another advantage of banked stool is that the patient is not required to identify a donor; some patients are uncomfortable asking a relative or friend to donate, and some patients are unable to identify a donor. Lastly, banked frozen stool can be stocked locally, available to be used on demand, and it reduces the time requirement for the treating physician. Overall, FMT appears to be generally safe, with few reported serious adverse effects. The most serious adverse effects appear to be related to the delivery mechanism rather than the FMT itself (e.g., aspiration related to colonoscopy sedation, colonic perforation during colonoscopy) (22). One case of bacteremia with E. coli following FMT via colonoscopy has been reported in a patient with recurrent C. difficile infection and Crohn’s disease (23). The author of this review has also observed a case of E. coli bacteremia and septic shock following FMT delivered via nasoenteric tube in a patient with cirrhosis and recurrent C. difficile infection (unpublished data). A case of fatal aspiration pneumonia following FMT via endoscopic delivery into the distal duodenum has been reported; however, it should be noted that the patient was sedated and the volume of stool solution was atypical for the upper gastrointestinal delivery route (100−150 mL in this case) (24). FMT has been accepted well by patients. In a study of 77 patients with recurrent C. difficile infection who were treated with FMT, 97% reported that would undergo another FMT for recurrent infection, and 53% reported that they would prefer FMT as the first treatment option as opposed to antimicrobial treatment (25).
FUTURE APPLICATIONS An emerging application for FMT is multidrug-resistant pathogen decolonization of the gastrointestinal tract. Two case reports demonstrate successful decolonization of multidrug-resistant gram-negative pathogens in humans (26,27). Decolonization of vancomycin-resistant
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enterococci has been demonstrated in mice (28), as well as a case report in a patient after heart and kidney transplantation (29). Other areas of investigation for the application of FMT to treat non-infectious diseases include obesity, non-alcoholic fatty liver disease, multiple sclerosis, insulin resistance, irritable bowel syndrome, and inflammatory bowel disease (30). In addition to expanding the indications for FMT, research into the production of synthetic stool is ongoing. Two studies investigated a synthetic stool product which consisted of 10 intestinal bacterial species, each grown in pure culture, then combined in sterile normal saline, and delivered via enema. In 14 patients with recurrent C. difficile infection treated with this product, cure was achieved in 86% (31,32). In another study, stool was obtained from a healthy donor and cultured (33). Of the 62 bacterial species isolated, 33 were chosen to be included in a synthetic product, which was delivered via colonoscopy to two patients with recurrent C. difficile. Both patients were cured. In summary, FMT has been shown to be highly effective for the treatment of recurrent C. difficile infection and well accepted by patients. It is relatively simple to perform in the ambulatory setting and access to the procedure has been improved with the ability to purchase carefully screened, frozen donor stool from an open stool bank.
REFERENCES 1. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015;372:825−34. 2. Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin Infect Dis 2012;55(suppl 2):S88−92. 3. Deshpande A, Pasupuleti V, Thota P, et al. Risk factors for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Infect Control Hosp Epidemiol 2015;36:452−60. 4. Wardell LH, Huttenhower C, Garrett WS. Current concepts of the intestinal microbiota and the pathogenesis of infection. Curr Infect Dis Rep 2011;13:28−34. 5. Borody TJ, Campbell J. Fecal microbiota transplantation: techniques, applications, and issues. Gastroenterol Clin N Am 2012;41:781−803. 6. Weingarden A, Gonzalez A, Vazquez-Baeza Y, et al. Dynamic changes in short- and long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection. Microbiome 2015;3:10. 7. Eiseman B, Silen W, Bascom GS, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958;44:854−9. 8. Moore T, Rodriguez A, Bakken JS. Fecal microbiota transplantation: a practical update for the infectious disease specialist. Clin Infect Dis 2014;58:541−5. 9. Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011;9:1044−9.
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10. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407−15. 11. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis 2014;58:1515−22. 12. Cammarota G, Masucci L, Ianiro G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther 2015;41:835−43. 13. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile infection: a systematic review. Ann Intern Med 2015;162:630−8. 14. Hamilton MJ, Weingarden AR, Unno T, et al. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes 2013;4:125−35. 15. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003;36:580−5. 16. Hirsch BE, Saraiya N, Poeth K et al. Effectiveness of fecal-derived microbiota transfer using orally administered capsules for recurrent Clostridium difficile infection. BMC Infect Dis 2015;15:191. 17. Stollman N, Smith M, Giovanelli A, et al. Frozen encapsulated stool in recurrent Clostridium difficile: exploring the role of pills in the treatment hierarchy of fecal microbiota transplant nonresponders. Am J Gastroenterol 2015;110:600−1. 18. Youngster I, Russell GH, Pindar C, et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014;312:1772−8. 19. Dorsey KA, Moritz ED, Steele WR, at al. A comparison of human immunodeficiency virus, hepatitis C virus, hepatitis B virus, and human T-lymphotropic virus marker rates for directed versus volunteer blood donations to the American Red Cross during 2005 to 2010. Transfusion 2013;53:1250−6. 20. Costello SP, Tucker EC, Brooy JL et al. Establishing a fecal microbiota transplant service for the treatment of Clostridium difficile infection. Clin Infect Dis 2015 (epub ahead of print). 21. OpenBiome. Available at: http://www.openbiome.org/. Accessed November 28, 2015. 22. Kelly CR, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol 2014;109:1065−71. 23. Quera R, Espinoza R, Estay C, et al. Bacteremia as an adverse event of fecal microbiota transplantation in a patient with Crohn’s disease and recurrent Clostridium difficile infection. J Crohns Colitis 2014;8:252−3. 24. Baxter N, Ahmad T, Colville A, et al. Fatal aspiration pneumonia as a complication of fecal microbiota transplant. Clin Infect Dis 2015;61:136−7. 25. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107:1079−87. 26. Singh R, van Nood E, Nieuwdorp M, et al. Donor feces infusion for eradication of extended spectrum beta-lactamase Escherichia coli in a patient with end stage renal disease. Clin Microbiol Infect 2014;20:O977−8. 27. Crum-Cianflone M, Sullivan E, Ballon-Landa G. Fecal microbiota transplantation and successful resolution of multidrug-resistant-organism colonization. J Clin Microbiol 2015;53:1986−9.
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28. Ubeda C, Bucci V, Caballero S, et al. Intestinal microbiota containing Barnesiella species cures vancomycin-resistant Enterococcus faecium colonization. Infect Immun 2013;81:965−73. 29. Stripling J, Kumar R, Baddley JW, et al. Loss of vancomycin-resistant Enterococcus fecal dominance in an organ transplant patient with Clostridium difficile colitis after fecal microbiota transplant. Open Forum Infect Dis 2015;2:ofv078. 30. Smits LP, Bouter KE, de Vos WM, et al. Therapeutic potential of fecal microbiota transplantation. Gastroenterology 2013;145:946−53. 31. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989;1:1156−60. 32. Emanuelsson F, Claesson BE, Ljungström L, et al. Faecal microbiota transplantation and bacteriotherapy for recurrent Clostridium difficile infection: a retrospective evaluation of 31 patients. Scand J Infect Dis. 2014;46:89−97. 33. Petrof EO, Gloor GB, Vanner SJ, et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut. Microbiome 2013;1:3.
DISCUSSION Carethers, Ann Arbor: Wonderful talk. I was wondering with the FDA regulations and needing certain regulations for doing the fecal microbiota transplantation (FMT) a couple of years ago—I was wondering how you consent your patients for a long-term effects of FMT because there are a lot of studies, largely from Jeff Gordon’s group, showing that we can modify heart disease, obesity, and those types of things with mouse and in twin studies. So I was wondering how you consent your patients. Edmond, Iowa City: We do a fairly careful informed consent process where we talk about those kinds of things but I have to say that when patients present for this therapy, none of that matters to them. They are not interested in the long-term effects. Often these are elderly patients. Their lives have been decimated by this infection and they want to be cured today. But you’re right, we don’t know what long-term issues that there may be. DuPont, Houston: Very nice review and description of process of this treatment. We have an active program in Houston and we are using lyophilized twice-filtered product that we give in enteric-coated capsules. Others are using capsules too, but I wanted to tell the group about my first experience with FMT. It was in 1970, I was a young assistant professor of infectious diseases at the University of Maryland. I had a very sick patient who was dying from antibiotic-associated colitis, developed renal failure. This was before IRBs, 8 years before C. difficile was identified. I went to the department chair and the hospital administrator to ask whether we could give stool to this patient to try to reverse this obviously fatal disease. They said fine. The chief of surgery at Maryland said, “I will get you stool from an elective surgical case.” He brought me the sample, we gave it to the patient, and the patient got miraculously well. I was going to publish it, so I went and reviewed a little bit about the donor and it was a typhoid carrier! I had infused eleven logs of Salmonella typhi into the rectum of my patient. Now there are three points about this: 1) I didn’t publish it; 2) you can give anybody’s stool to these patients and they do well; and 3) most importantly, you don’t get typhoid fever from the rectum. LeBlond, Billings: Just a query about the FDA’s position on this. The FDA regulates things that go interstate much more than things intrastate. For instance, in blood
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banking, if you have blood banking software and you don’t pass it across state lines, FDA doesn’t get involved with that. So what is the status of FDA regulation? Edmond, Iowa City: Human stool used for fecal transplantation is considered an investigational new drug. At this point in time, FDA requires that you get informed consent. You must disclose to the patient that it’s investigational and you can’t use it on pregnant women. There has been a proposal that was put forth by the FDA that would require that the donor know the recipient, or the treating physician must know the donor. So far, the FDA has not acted on that. Hook, Birmingham: I’ll second what you said. This is one of the most gratifying things I have ever been able to do for a patient and their thanks are really effusive. It’s remarkable. My question for you, however, has to do with the microbiome and fecal microbiota transplantation. Work at UAB suggests that all of us have different microbiomes—that our microbiomes are generated largely from our mothers, and that as we age our microbiomes begin to decay and are less substantive and resistant to infection. Our experience has shown that those parameters affect response to therapy—that, for instance, age of the donor and familial relationships may be related to the success of the fecal transplant. I was wondering about your thoughts regarding microbiome variation as far as the stool bank is concerned and whether in reality the better donor might be a closely related younger family member? Edmond, Iowa City: I think we just don’t know the answers to those questions. If you look at the OpenBiome [stool bank] website, they will tell you about their donor selection process. Their donors are typically young, very healthy people in their 20s with an average of BMI of 23. The BMI issue has come up because there has been some question about whether you can make people obese by using donor stool from obese patients. Del Rio, Atlanta: That was great, Mike. I think that going back to what Ned Hook was saying, as you know some people have talked about actually self-banking your stool so it could be used later. What would be your recommendations regarding that? Edmond, Iowa City: OpenBiome now offers that service. Autogolous fecal transplantation might be particularly useful for oncology patients. I should also add that OpenBiome is now offering frozen capsules for fecal transplantation, so we have an additional method of delivery. The downsides are that you have to take 30 capsules and the failure rate is higher than with delivery via nasogastric tube, enema, or colonoscopy. Del Rio, Atlanta: It may be worth getting people to bank their stool at age about 25, so that when you get to be 80 you can actually get your own stool bank. Edmond, Iowa City: Agree. May, Gainesville: Great talk. As an oncologist I am interested to know whether you have performed a fecal transplant on a neutropenic patient. Do you require a certain status for the immune system? Edmond, Iowa City: I have not done a fecal transplant on a neutropenic patient and with chemotherapy-induced neutropenia I try to wait until the patient’s white blood cell has recovered before I do it. I suppose in the situation where the patient was fairly ill and neutropenic, the oncologist and I would have a discussion about risk versus benefit and we may decide to try. Guarner, Atlanta: Some people object to the name fecal transplant, what do you have to say about that? Edmond, Iowa City: What is the objection? Guarner, Atlanta: They don’t like the name transplant itself. Edmond, Iowa City: Oh I see, I thought maybe it was the fecal part that they were uncomfortable with. I haven’t really thought through that. Maybe we should call it what the veterinarians call it, transfaunation.
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Barondess, New York City: I think you said that some of these patients respond with extraordinary rapidity to these transplants and I wonder if you’d speculate on the mechanism of the immediate responses to those within 24 hours or so. It seems awfully fast to change somebody’s colonic microbiome. Edmond, Iowa City: It does, but what is interesting is when the microbiome of these patients has been analyzed you can find that when engraftment occurs is when symptoms stop. So it appears that this occurs quite rapidly, usually within 24−48 hours from the time of transplant. Oates, Nashville: Could you tell us what progress is being made to identifying the organisms in these fecal transplants that are active agents? At the present time fecal organisms are available over the counter as probiotics at all the drug stores, and obviously they aren’t the right ones to bring about this cure. There clearly should be a future understanding of which organisms are effective and then developing them in a pharmaceutical method so you don’t have all these risks. Edmond, Iowa City: Exactly. What you point out is the goal of developing synthetic stool, which is the basically picking multiple strains of bacteria, growing them in pure culture, mixing them together, and then administering those. There have been two or three clinical trials that have looked at this. One used 10 different strains and another one used 33 strains of bacteria. These are very small studies but they were successful and that’s probably where all of this is headed ultimately—to be able to give a mixture of bacterial strains grown from pure cultures that doesn’t have all the other things that are found in stool.
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