REVIEW
Fecal Microbiota Transplantation in the Treatment of Clostridium difficile Infections Matthew Austin, DO,a Mark Mellow, MD,b William M. Tierney, MDc a Department of Internal Medicine, University of Oklahoma Health Science Center, Oklahoma City; bDigestive Health Center, Integris Baptist Medical Center, Oklahoma City, Okla; cDepartment of Internal Medicine, Section of Digestive Diseases, University of Oklahoma Health Science Center, Oklahoma City.
ABSTRACT In recent years, Clostridium difficile infections have become more frequent, more severe, more refractory to standard treatment, and more likely to recur. Current antibiotic treatment regimens for Clostridium difficile infection alter the normal gut flora, which provide colonization resistance against Clostridium difficile. Over the past few years, there has been a marked increase in the knowledge of the gut microbiota and its role in health maintenance and disease causation. This has, fortuitously, coincided with the use of a unique microbial replacement therapy, fecal microbiota transplantation, in the treatment of patients with multiple recurrent Clostridium difficile infections. We briefly review current knowledge of the gut microbiota’s functions. We then review the indications for use of fecal microbiota transplantation in Clostridium difficile infection, the techniques employed, and results of treatment. Fecal microbiota transplantation has been shown to be efficacious for patients with multiply recurrent Clostridium difficile infections (reported cure rates of 90%), with an excellent short-term safety profile, and has been included in the American College of Gastroenterology treatment guidelines for this troublesome disease. Ó 2014 Elsevier Inc. All rights reserved. The American Journal of Medicine (2014) 127, 479-483 KEYWORDS: Clostridium difficile infections; Diarrhea; Fecal microbiota transplantation; Gut microbiota
Clostridium difficile is a ubiquitous, anaerobic, Grampositive, cytotoxin-producing bacillus first described by Hall and O’Toole in 1935 by isolating it from healthy neonates.1 Bartlett et al described the pathogenic role of Clostridium difficile in 1978.2 The spore-forming bacteria release toxins A and B that cause colon epithelial damage, inflammation, and pseudomembrane formation that manifests in diarrhea and colitis.2,3 Before the identification of Clostridium difficile as the causative agent, Tedesco reported in 1974 that patients receiving antibiotics were the
Funding: None. Conflicts of Interest: MM is on the speakers bureau for Optimer Pharmaceuticals (Dificid). The other authors have no potential conflicts of interest to report. Authorship: All authors had access to all data and editions of the manuscript as well as contributing to the ideas, planning, and writing of this article. Requests for reprints should be addressed to Matthew Austin, DO, Department of Internal Medicine, University of Oklahoma Health Science Center, Williams Pavillion 1130, P.O. Box 26901, Oklahoma City, OK 73190. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.02.017
group at highest risk of pseudomembranous colitis.4 This discovery fostered future research on the importance of the fecal microbiota in health and disease. It has become clear that commensal bacteria in the colon are an important defense mechanism against the proliferation of Clostridium difficile and may have complex immunoprotective effects.5 Clostridium difficile infections once were limited to nosocomial infections in the elderly but now are the cause of severe morbidity and mortality even in the healthy ambulatory patient with no recent antibiotic exposure.6 The rate of Clostridium difficile infections was level in the 1990s but nearly tripled from 1996 to 2005.3,6 A new strain of Clostridium difficile called NAP1/027 was identified that produces a binary toxin that has contributed to the increase in prevalence and virulence. This discovery came as a result of virulent Clostridium difficile infection outbreaks first identified in Quebec and 8 US sites.3,7 As a result, Clostridium difficile infections are now the leading cause of hospital-associated gastrointestinal illness.8-11 Once an infection occurs, it typically requires treatment with antimicrobials that target Clostridium difficile. While initial response rates are high, the recurrence rate for Clostridium difficile infections in the 1-8
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weeks after treatment can be as high as 35%, with subsequent much interest in recent years, including vaccine developrecurrences after retreatment occurring in 50%-65% of pament, intravenous immunoglobulin, and fecal microbiota tients.12,13 Multiple recurrences are associated with increasing transplantation.13 Most nonantibiotic treatments have yet to disability (diarrhea, weight loss, weakness) and the potential be proven efficacious. However, fecal microbiota transfor colectomy or death.12,13 The presence of Clostridium plantation has been shown to resolve recurrent Clostridium difficile infection in >90% of patients. Given its high cure difficile infections in hospitalized patients has an overall rate, fecal microbiota transplanmortality rate as high as 23% at 30 tation is now being used in some days.13 Clostridium difficile CLINICAL SIGNIFICANCE centers for Clostridium difficile infection management was estiinfection patients with refractory mated in 2010 to cost $1 billion Clostridium difficile infections can have disease, as well as for second rein the US.6 severe recurrent cases that are not currence if one or more of the effectively treated with current antibiinitial episodes was severe enough otic treatment. TREATMENT PARADIGMS to require hospitalization.11 The Antibiotics kill the bacteria but also goal of fecal microbiota transInitial therapy for Clostridium plantation is to break the cycle of difficile infection includes stopping destroy the gut microbiota that serves as imbalance of intestinal flora. By all antibiotic therapy if possible, a vital part of colon health, immunity, introducing donor feces, there is followed by the use of metroniand metabolic function. almost immediate restoration of dazole or vancomycin based on Fecal microbiota transplantation replaces bacterial diversity and Clostridium illness severity and comorbidthe altered gut flora to allow colonization difficile colonization resistance.6 ities.11 Metronidazole is the firstresistance. line agent in treatment for mild Transplantation of enteric flora to moderate Clostridium difficile for gastrointestinal disease began Transplantation has >90% efficacy in infection, although the failure rate in veterinary medicine in the 17th resolving recurrent Clostridium difficile appears to be increasing, with one century. It was termed transfauinfections. study indicating an increase in nation by the Italian anatomist failure rates from 2.5% to 18% Fabricius Acquapendente.12 The 3 after the year 2000. Vancomycin goal of the original human fecal transplant in 1958 was to “re-establish the balance of nature” is used initially for severe infections and also for recurrent when fecal enemas were used in 4 patients to successfully disease, sometimes in a pulsed or tapered therapy.11,14 treat fulminant, life-threatening pseudomembranous enteroVancomycin is active against all gram-positive aerobic and colitis.18,19 Fecal retention enemas were the administration anaerobic organisms. Vancomycin, along with other antimicrobials used for Clostridium difficile infection, suppresses technique for fecal microbiota transplantation for many the growth of Clostridium difficile, but also suppresses some years, but administration through duodenal tube began in normal bowel flora that provide colonization resistance.6,13 1991, via colonoscopy in 1998, and by self-administered enemas in 2010.6,12,20,21 A newly Food and Drug administration (FDA)-approved antibiotic, fidaxomicin, was compared with vancomycin in While there are no professional society guidelines rea multicenter randomized control trial. Cure rates were garding fecal microbiota transplantation, there are working equivalent to vancomycin, but fidaxomicin had a lower guidelines written by the Fecal Microbiota Transplantation recurrence rate (15% vs 25%).8,15 Despite these results, its Workgroup.6 In addition, multiple studies have described 16 use has been limited, as a 10-day course costs $2800. the technique using similar methodologies with some slight variations. In general, patients receive a course of antibiotics Clostridium difficile exists in both a vegetative form, the leading up to the transplant to decrease inflammation and toxin-producing replicative state, and a spore form. The Clostridium difficile spore burden. The antibiotics are stopped latter is particularly resistant to destruction even with anti2-3 days before the transplant. A bowel preparation is adseptics. This allows the organism to persist in the gut and ministered the day before transplant.6 Stool donor screening the environment. If the gut microbiota remains disturbed after Clostridium difficile infection therapy, the spores can varies somewhat among investigators, but should include, germinate to the vegetative form, resulting in recurrent at a minimum, ova and parasites, Salmonella, Shigella, disease. Campylobacter, and C. difficile toxin by polymerase chain Microbiota refers to the inhabitation of a particular region reaction. Serum studies include hepatitis A, B, and C, syphof the body by a community of microorganisms. The inilis, and human immunodeficiency virus. Many investigators testine commensal bacterial environment is termed the gut similarly screen the patient’s blood, so as to identify preexmicrobiota.17 In order to eradicate chronic Clostridium isting conditions that might manifest posttransplantation.10 difficile infection, most believe that the gut microbiota needs Once a donor is “cleared,” the transplantation procedure is to be restored to protect the intestinal lining and help scheduled. Fresh donor feces are then collected within a few eliminate or prevent residual spores from causing recurrent hours of the actual transplantation procedure. Stool is mixed disease.13 For this reason, nonantibiotic treatment has gained with water, preservative-free saline, or milk, and blended or
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hand mixed to a consistency of malted milk. The stool mixture is administered through nasogastric tube, upper endoscopy, colonoscopy, or enema. Total infused volume varies from 50 to 700 cc.6,10
THE GUT MICROBIOTA
Research on the gut microbiota is a rapidly expanding field due to technology using 16S ribosomal RNA, which allows the study of bacteria that cannot be cultured.19 The microbiota is complex and includes 100 trillion archaeal and bacterial cells and over 1000 species. Firmicutes and Bacteroidetes phyla make up more than 90% of the bacterial species.22 Many of the bacteria in the colon are considered pathogens in other contexts but are a normal component of the large intestine microbiota.23 These commensal organisms play an important role in digestion of complex carbohydrates, energy storage, maintaining the health of colonic enterocytes, enhancing immune function, and protecting against invasive pathogens.23,24 The role of the microbiota also has been implicated in diverse metabolic diseases including obesity, insulin resistance, and cardiovascular disease.25,26 Animal studies have demonstrated that the microbial inhabitants of the gut can alter the energy extraction from food contributing to these metabolic processes. In the obese, there is an altered composition of gut microbiota that responds to changes in body weight. This change in composition and function of gut microbiota can alter the metabolic function by promoting altered short-chain fatty acids absorption, changed cell signaling, and increased peripheral gluconeogenesis and lipogensis.22 Clostridium difficile infections cause limited disease unless the microbiota becomes substantially altered. If an alteration does occur, it can lead to a persistent dysbiosis (microbial imbalance).10 Chang et al27 performed 16S rRNA sequencing to map microbial communities in the stool of 10 people; 3 were normal subjects, 4 were experiencing their first episode of Clostridium difficile infection, and 3 had recurrent infections. The microbial communities were grouped according to phyla. The 3 controls and 4 patients with their initial occurrence of Clostridium difficile infection had phyla composed largely of Bacteroidetes and Firmicutes. The 3 patients with recurrent infection had decreased diversity and number of phyla, and lacked these two predominant phyla. One of the patients enrolled as a first episode of Clostridium difficile infection had phyla similar to the patients with recurrent infections. In fact, this patient developed a recurrence shortly thereafter. For the Clostridium difficile infection patients with no recurrence, Clostridium difficile represented 3.1% of the total sequences, but in recurrent disease patients it represented 31%.27-29 The theory behind fecal microbiota transplantation is that an altered microbiota can be manipulated to improve the diversity and proportion of phyla that promote colonic health.10 Khoruts et al28 described a patient with 8 months of recurrent Clostridium difficile infection despite multiple antibiotic regimens, referred for fecal microbiota
481 transplantation. Following transplantation, microbial diversity was restored. At both 14 and 33 days post transplant, the patient’s feces had a similar microbial fingerprint to the donors.28 Firmicutes and Bacteroidetes phyla are thought to play a large role in gut homeostasis. Bacteroides spp. are thought to inhibit Clostridium difficile proliferation. Firmicutes produce butyrate, an important short-chain fatty acid, which plays a critical role in maintaining the integrity of the colonic epithelium and regulating mucosal immune responses. Manipulating a patient’s fecal microbiota can be a microbiological therapy, but more investigation is needed to clarify the exact microbial and nonmicrobial components of the donor material that leads to Clostridium difficile eradication.28
METHODOLOGY This review of fecal microbiota transplantation was performed in June 2013 using MEDLINE search for “fecal microbiota transplantation,” “gut microbiota,” and “Clostridium difficile infection.” Three large landmark articles were identified in the midst of numerous case reports and case series. These 3 studies were noted to give the best strength for fecal transplantation. Further comprehensive background, FDA current policies, and future direction of Clostridium difficile infection treatment was obtained from this MEDLINE review, as well as from cross references obtained in the original search.
EFFICACY OF FECAL MICROBIOTA TRANSPLANTATION Fecal microbiota transplantation is a treatment option that is readily available, inexpensive, efficacious, and safe.6 Transplantation has demonstrated >90% clinical resolution of Clostridium difficile infections in the approximately 400 cases reported.10,12,14 Transplantation is safe based on current reports in the literature that have reported few adverse effects.10 Brandt et al12 describe the efficacy of colonoscopic fecal microbiota transplantation in a study of 77 patients from 5 centers across the US.12 All the patients had failed multiple treatment courses of antibiotic regimens. The patient population had an average age of 65 years, 73% were females, and 60% were living independently. Colonoscopyadministered fecal microbiota transplantation was used because it has been shown in a systematic review to be more effective than duodenal infusion.17 Sixty-eight percent had severe diarrhea consisting of >6 bowel movements/day before the procedure, and a majority had abdominal pain, weight loss, and fatigue. Primary cure was defined as resolution of diarrhea without recurrence within 90 days of transplantation. Secondary cure was defined as resolution of Clostridium difficile infections after one further course of vancomycin with or without repeat transplantation. Primary cure was achieved in 91% of patients and secondary cure was met in 76 of 77 patients. The one individual who was not cured was on hospice and died in a sub-acute rehabilitation facility. There were no adverse effects or
482 complications directly attributed to fecal microbiota transplantation. During a mean follow-up of 17 months after transplantation, no patient developed a recurrence of Clostridium difficile infections in the absence of antibiotic treatment for infections unrelated to Clostridium difficile.12 A randomized control study by van Nood et al29 of 43 patients from January 2008 through April 2010 was performed in the Netherlands. Thirty-five of the 43 had more than one recurrence of Clostridium difficile infections. Patients were randomly assigned to 3 groups. Group one received initial vancomycin regimen followed by bowel lavage and subsequent fecal microbiota transplant through nasoduodenal tube. The second group received a standard vancomycin regimen. The third group received a standard vancomycin regimen with bowel lavage. The primary end point measured was cessation of diarrhea associated with Clostridium difficile infection and no relapse after 10 weeks with 3 consecutive negative stool tests for Clostridium difficile toxin. There was an 81% resolution of Clostridium difficile infection-associated diarrhea following the first infusion and 94% following a second infusion in those unresponsive to the first treatment. The vancomycin group had 31% resolution, and the vancomycin and bowel lavage group had 23% resolution. The overall cure rate of fecal transplantation compared with the vancomycin alone was statistically superior (99.9% confidence interval, 1.08-290.05) and compared with vancomycin with bowel lavage (99.9% confidence interval, 1.21-290.12). The trial was stopped early due to the significant efficacy of fecal microbiota transplantation relative to controls. There was no significant difference in adverse events among the 3 groups except for belching, mild diarrhea, and abdominal cramping on the day of fecal microbiota transplantation in the infusion group. Recipients’ stool was found to be similar to their healthy donors based on amount of fecal bacterial diversity following transplantation.29 Mattila et al13 performed a retrospective review of 70 patients from 5 hospitals in Finland with the average age of 73 years.13 Patients underwent colonoscopic fecal microbiota transplantation and were followed for 12 weeks. All subjects had failed standard antibiotic therapy with an average of 4.5 courses of antibiotics before transplantation. Before fecal microbiota transplantation, all patients had stool testing for the specific strain of Clostridium difficile, and 51% had the NAP1/027 strain. There was 100% resolution of symptoms in all non-NAP1/027 strain patients. Of the patients with the virulent strain, 89% had recovery. The 4 patients with the NAP1/027 strain that did not respond had significant morbidity before fecal microbiota transplantation. All 4 died within 1.5-3 months, but none as a result of the procedure. Of the 66 responders, 4 relapsed in the first year following antibiotic treatment for unrelated conditions. Of these 4, 2 were treated successfully with a repeat transplantation, and 2 with antibiotics. There were no perforations or serious adverse reactions reported. Colonoscopic-administered transplantation allows diagnosis of, for example, inflammatory bowel disease and cancer that may be masked by Clostridium difficile infection.13
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CONTROVERSY SURROUNDING FECAL MICROBIOTA TRANSPLANTATION An FDA/National Institutes of Health consensus panel in May 2013 was convened to exchange knowledge and experience among experts regarding fecal microbiota transplantation. The FDA determined that feces used for transplantation are a biological agent that requires an investigational drug application.30 This decision was later reversed. Physicians may deliver fecal microbiota transplantation for Clostridium difficile infections provided informed consent is obtained from the patients. Consent should state that the procedure is investigational, its long-term effects are unknown, and it is currently contraindicated in pregnancy.31 The consensus panel discussed the need to perform more randomized clinical trials, establish clearer indications for fecal microbiota transplantation, standardize protocols of administration, and develop a large registry. Furthermore, donor screening guidelines need to be established. The FDA concluded that the use of fecal microbiota transplantation for all other disease entities remains investigational, and an investigational drug application is required.10
MICROBIAL TRANSPLANTATION—THE FUTURE Fecal microbiota transplantation consistently cures recurrent Clostridium difficile infections, with success rates >90%. No treatment to date has complete resolution rates this high. As of now, there is only one randomized control trial for fecal microbiota transplantation, which had several limitations, including a small sample size and nonblinding.14 Beyond the need for more randomized control trials, there is concern that the public has labeled fecal microbiota transplant aesthetically unappealing.19,32 However, in the Brandt et al12 study of 77 patients, 97% stated they would undergo another fecal microbiota transplantation for a recurrence of Clostridium difficile infections, and 53% stated they would choose it as their first-line treatment before antibiotics.12 The future of fecal microbiota transplantation will include research in using universal donors or a manufactured product. These sources would help eliminate the process of finding a suitable donor, but there could be drawbacks. A manufactured product would be expensive, as it would require extensive studies and regulatory clearance. A universal donor could lead to the spread of currently unknown pathogens to a large number of recipients. It is possible that the gut microbial population in a healthy person interacts with another human host more effectively than a manufactured bacteria.10 The long-term effects of all these products are unknown, as the microbial population performs extremely important metabolic and immunologic functions in the host.
CONCLUSION Clostridium difficile has emerged as a highly prevalent and morbid infection in both nosocomial and ambulatory
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settings.3 The increased morbidity has correlated with the development of virulent strains and has been associated with chronic refractory infections. Fecal microbiota transplantation has evolved from a medical oddity to an accepted method of treatment for refractory Clostridium difficile infection.11 Ongoing research will help to both underscore the critical components of the fecal microbiota that promote health, and further define the optimal methods and components of fecal microbiota transplantation.
References 1. Hall I, O’Toole E. Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, bacillus difficilis. Am J Dis Child. 1935;49(2):390-402. 2. Bartlett J, Chang T, Gurwith M, Gorbach S, Onderdonk A. Antibioticassociated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med. 1978;298(10):531-534. 3. Kelly C, LaMont JT. Clostridium difficile—more difficult than ever. N Engl J Med. 2008;359:1932-1940. 4. Tedesco F, Barton R, Alpers D. Clindamycin-associated colitis. Ann Intern Med. 1974;81(4):429-433. 5. Brandt L. American Journal of Gastroenterology Lecture: intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection. Am J Gastroenterol. 2013;108:177-185. 6. Bakken J, Borody T, Brandt L, et al. Treating clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011;9:1044-1049. 7. Bartlett J. Narrative review: the new epidemic of Clostridium difficileassociated enteric disease. Ann Intern Med. 2006;145:758-764. 8. Mullane K, Gorbach S. Fidaxomicin: first-in-class macrocyclic antibiotic. Expert Rev Anti Infect Ther. 2011;9(7):767-777. 9. Dolgin E. ‘Game changer’ antibiotic and others in works for superbug. Nat Med. 2011;17(1):10. 10. Brandt L, Kelly C. Public Workshop: Fecal Microbiota for Transplantation: Scientific and Regulatory Issues Center for Biologics, Evaluation, and Research for Biologics, Evaluation and Research (FDA) and the National Institute for Allergy and Infectious Diseasees (NIH). Bethesda, MD: Food and Drug Administration; 2013. 11. Surawicz C, Brandt L, Binion D, et al. Guidelines for diagnosis, treatment, and prevention of clostridium difficle infections. Am J Gastroenterol. 2013;108:478-498. 12. Brandt L, Aroniadis O, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent clostridium difficile infection. Am J Gastroenterol. 2012;107(7):1079-1087. 13. Mattila E, Uusitalo-Seppala R, Wuorela M, et al. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology. 2012;142:490-496. 14. Kassam Z, Lee C, Yuan Y, Hunt R. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108:500-508. 15. Louie T, Miller M, Mullane K. Fidaxomicin versus vancomycin for Clostridium difficle infection. N Engl J Med. 2011;364(5):422-431.
483 16. Grant E. Fidaxomicin: new therapy for Clostridium difficile-associated diarrhea. Formulary. 2011;46:297-308. 17. Gough E, Shaikh H, Manges A. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent clostridium difficile infection. Clin Infect Dis. 2011;53(10):994-1002. 18. Eiseman B, Silen W, Bascom G, Kauvar A. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44(5):854-859. 19. Kelly C. Fecal microbiota transplantationean old therapy comes of age. N Engl J Med. 2013;368(5):474-475. 20. Borody T, Campbell J. Fecal microbiota transplantation: techniques, applications, and issues. Gastroenterol Clin North Am. 2012;41(4): 781-803. 21. Flotterod O, Hopen G. Refractory clostridium difficile infection: untraditional treatment of antibiotic-induced colitis. Tidsskr Nor Laegeforen. 1991;111:1364-1365. 22. Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012;489:242-249. 23. UpToDate. Spatial organization of the intestinal microbiota in health and disease; 2013. Available at: http://www.uptodate.com/contents/ spatial-organization-of-intestinal-microbiotia-in-health-and-disease. Accessed June 4, 2013. 24. Yan F, Polk DB. Commensal bacteria in the gut: learning who our friends are. Curr Opin Gastroenterol. 2004;20(6):565-571. 25. Sokol H, Pignear B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105(43):16731-16736. 26. Sokol H, Seksik P, Rigottier-Gois L, et al. Specificities of the fecal microbiota in inflammatory bowel disease. Inflamm Bowel Dis. 2006; 12:106-111. 27. Chang JY, Antonopoulos D, Kalra A, et al. Decreased diversity of the fecal micriobiome in recurrent clostridium difficile-associated diarrhea. J Infect Dis. 2008;197:435-438. 28. Khoruts A, Dicksved J, Jansson J, Sadowsky M. Changes in the composition fo the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol. 2010;44:354-360. 29. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of the donor feces for recurrent clostridium difficile. N Engl J Med. 2013;368(5):407-415. 30. Midthun K. FDA Letter to the American Gastroenterological Association. Available at: http://highroadsolution.com/file_upload_2/ files/fdaþresponseþletterþtoþfmtþinquiry.pdf. Accessed March 18, 2014. 31. U.S. Food and Drug Administration. Important information about IND requirments for use of fecal micobiota to treat clostridium difficile infection not responsive to standard therapies. Available at: http:// www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetings Conferences/ucm357258.htm. Accessed March 18, 2014. 32. Hamblin J. Fecal transplantation: ‘we have an effective treatment, but its too gross’. The Atlantic. 2013. Available at: http://www.theatlantic. com/health/print/2013/01/fecal-transplantation-we-have-an-effectivetreatment-but-its-is-too-gross/267389/. Accessed June 4, 2013.
Fecal Microbiota Transplantation in the Treatment of Clostridium difficile Infections Matthew Austin, DO,a Mark Mellow, MD,b William M. Tierney, MDc a Department of Internal Medicine, University of Oklahoma Health Science Center, Oklahoma City; bDigestive Health Center, Integris Baptist Medical Center, Oklahoma City, Okla; cDepartment of Internal Medicine, Section of Digestive Diseases, University of Oklahoma Health Science Center, Oklahoma City.
ABSTRACT In recent years, Clostridium difficile infections have become more frequent, more severe, more refractory to standard treatment, and more likely to recur. Current antibiotic treatment regimens for Clostridium difficile infection alter the normal gut flora, which provide colonization resistance against Clostridium difficile. Over the past few years, there has been a marked increase in the knowledge of the gut microbiota and its role in health maintenance and disease causation. This has, fortuitously, coincided with the use of a unique microbial replacement therapy, fecal microbiota transplantation, in the treatment of patients with multiple recurrent Clostridium difficile infections. We briefly review current knowledge of the gut microbiota’s functions. We then review the indications for use of fecal microbiota transplantation in Clostridium difficile infection, the techniques employed, and results of treatment. Fecal microbiota transplantation has been shown to be efficacious for patients with multiply recurrent Clostridium difficile infections (reported cure rates of 90%), with an excellent short-term safety profile, and has been included in the American College of Gastroenterology treatment guidelines for this troublesome disease. Ó 2014 Elsevier Inc. All rights reserved. The American Journal of Medicine (2014) 127, 479-483 KEYWORDS: Clostridium difficile infections; Diarrhea; Fecal microbiota transplantation; Gut microbiota
Clostridium difficile is a ubiquitous, anaerobic, Grampositive, cytotoxin-producing bacillus first described by Hall and O’Toole in 1935 by isolating it from healthy neonates.1 Bartlett et al described the pathogenic role of Clostridium difficile in 1978.2 The spore-forming bacteria release toxins A and B that cause colon epithelial damage, inflammation, and pseudomembrane formation that manifests in diarrhea and colitis.2,3 Before the identification of Clostridium difficile as the causative agent, Tedesco reported in 1974 that patients receiving antibiotics were the
Funding: None. Conflicts of Interest: MM is on the speakers bureau for Optimer Pharmaceuticals (Dificid). The other authors have no potential conflicts of interest to report. Authorship: All authors had access to all data and editions of the manuscript as well as contributing to the ideas, planning, and writing of this article. Requests for reprints should be addressed to Matthew Austin, DO, Department of Internal Medicine, University of Oklahoma Health Science Center, Williams Pavillion 1130, P.O. Box 26901, Oklahoma City, OK 73190. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.02.017
group at highest risk of pseudomembranous colitis.4 This discovery fostered future research on the importance of the fecal microbiota in health and disease. It has become clear that commensal bacteria in the colon are an important defense mechanism against the proliferation of Clostridium difficile and may have complex immunoprotective effects.5 Clostridium difficile infections once were limited to nosocomial infections in the elderly but now are the cause of severe morbidity and mortality even in the healthy ambulatory patient with no recent antibiotic exposure.6 The rate of Clostridium difficile infections was level in the 1990s but nearly tripled from 1996 to 2005.3,6 A new strain of Clostridium difficile called NAP1/027 was identified that produces a binary toxin that has contributed to the increase in prevalence and virulence. This discovery came as a result of virulent Clostridium difficile infection outbreaks first identified in Quebec and 8 US sites.3,7 As a result, Clostridium difficile infections are now the leading cause of hospital-associated gastrointestinal illness.8-11 Once an infection occurs, it typically requires treatment with antimicrobials that target Clostridium difficile. While initial response rates are high, the recurrence rate for Clostridium difficile infections in the 1-8
480
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weeks after treatment can be as high as 35%, with subsequent much interest in recent years, including vaccine developrecurrences after retreatment occurring in 50%-65% of pament, intravenous immunoglobulin, and fecal microbiota tients.12,13 Multiple recurrences are associated with increasing transplantation.13 Most nonantibiotic treatments have yet to disability (diarrhea, weight loss, weakness) and the potential be proven efficacious. However, fecal microbiota transfor colectomy or death.12,13 The presence of Clostridium plantation has been shown to resolve recurrent Clostridium difficile infection in >90% of patients. Given its high cure difficile infections in hospitalized patients has an overall rate, fecal microbiota transplanmortality rate as high as 23% at 30 tation is now being used in some days.13 Clostridium difficile CLINICAL SIGNIFICANCE centers for Clostridium difficile infection management was estiinfection patients with refractory mated in 2010 to cost $1 billion Clostridium difficile infections can have disease, as well as for second rein the US.6 severe recurrent cases that are not currence if one or more of the effectively treated with current antibiinitial episodes was severe enough otic treatment. TREATMENT PARADIGMS to require hospitalization.11 The Antibiotics kill the bacteria but also goal of fecal microbiota transInitial therapy for Clostridium plantation is to break the cycle of difficile infection includes stopping destroy the gut microbiota that serves as imbalance of intestinal flora. By all antibiotic therapy if possible, a vital part of colon health, immunity, introducing donor feces, there is followed by the use of metroniand metabolic function. almost immediate restoration of dazole or vancomycin based on Fecal microbiota transplantation replaces bacterial diversity and Clostridium illness severity and comorbidthe altered gut flora to allow colonization difficile colonization resistance.6 ities.11 Metronidazole is the firstresistance. line agent in treatment for mild Transplantation of enteric flora to moderate Clostridium difficile for gastrointestinal disease began Transplantation has >90% efficacy in infection, although the failure rate in veterinary medicine in the 17th resolving recurrent Clostridium difficile appears to be increasing, with one century. It was termed transfauinfections. study indicating an increase in nation by the Italian anatomist failure rates from 2.5% to 18% Fabricius Acquapendente.12 The 3 after the year 2000. Vancomycin goal of the original human fecal transplant in 1958 was to “re-establish the balance of nature” is used initially for severe infections and also for recurrent when fecal enemas were used in 4 patients to successfully disease, sometimes in a pulsed or tapered therapy.11,14 treat fulminant, life-threatening pseudomembranous enteroVancomycin is active against all gram-positive aerobic and colitis.18,19 Fecal retention enemas were the administration anaerobic organisms. Vancomycin, along with other antimicrobials used for Clostridium difficile infection, suppresses technique for fecal microbiota transplantation for many the growth of Clostridium difficile, but also suppresses some years, but administration through duodenal tube began in normal bowel flora that provide colonization resistance.6,13 1991, via colonoscopy in 1998, and by self-administered enemas in 2010.6,12,20,21 A newly Food and Drug administration (FDA)-approved antibiotic, fidaxomicin, was compared with vancomycin in While there are no professional society guidelines rea multicenter randomized control trial. Cure rates were garding fecal microbiota transplantation, there are working equivalent to vancomycin, but fidaxomicin had a lower guidelines written by the Fecal Microbiota Transplantation recurrence rate (15% vs 25%).8,15 Despite these results, its Workgroup.6 In addition, multiple studies have described 16 use has been limited, as a 10-day course costs $2800. the technique using similar methodologies with some slight variations. In general, patients receive a course of antibiotics Clostridium difficile exists in both a vegetative form, the leading up to the transplant to decrease inflammation and toxin-producing replicative state, and a spore form. The Clostridium difficile spore burden. The antibiotics are stopped latter is particularly resistant to destruction even with anti2-3 days before the transplant. A bowel preparation is adseptics. This allows the organism to persist in the gut and ministered the day before transplant.6 Stool donor screening the environment. If the gut microbiota remains disturbed after Clostridium difficile infection therapy, the spores can varies somewhat among investigators, but should include, germinate to the vegetative form, resulting in recurrent at a minimum, ova and parasites, Salmonella, Shigella, disease. Campylobacter, and C. difficile toxin by polymerase chain Microbiota refers to the inhabitation of a particular region reaction. Serum studies include hepatitis A, B, and C, syphof the body by a community of microorganisms. The inilis, and human immunodeficiency virus. Many investigators testine commensal bacterial environment is termed the gut similarly screen the patient’s blood, so as to identify preexmicrobiota.17 In order to eradicate chronic Clostridium isting conditions that might manifest posttransplantation.10 difficile infection, most believe that the gut microbiota needs Once a donor is “cleared,” the transplantation procedure is to be restored to protect the intestinal lining and help scheduled. Fresh donor feces are then collected within a few eliminate or prevent residual spores from causing recurrent hours of the actual transplantation procedure. Stool is mixed disease.13 For this reason, nonantibiotic treatment has gained with water, preservative-free saline, or milk, and blended or
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hand mixed to a consistency of malted milk. The stool mixture is administered through nasogastric tube, upper endoscopy, colonoscopy, or enema. Total infused volume varies from 50 to 700 cc.6,10
THE GUT MICROBIOTA
Research on the gut microbiota is a rapidly expanding field due to technology using 16S ribosomal RNA, which allows the study of bacteria that cannot be cultured.19 The microbiota is complex and includes 100 trillion archaeal and bacterial cells and over 1000 species. Firmicutes and Bacteroidetes phyla make up more than 90% of the bacterial species.22 Many of the bacteria in the colon are considered pathogens in other contexts but are a normal component of the large intestine microbiota.23 These commensal organisms play an important role in digestion of complex carbohydrates, energy storage, maintaining the health of colonic enterocytes, enhancing immune function, and protecting against invasive pathogens.23,24 The role of the microbiota also has been implicated in diverse metabolic diseases including obesity, insulin resistance, and cardiovascular disease.25,26 Animal studies have demonstrated that the microbial inhabitants of the gut can alter the energy extraction from food contributing to these metabolic processes. In the obese, there is an altered composition of gut microbiota that responds to changes in body weight. This change in composition and function of gut microbiota can alter the metabolic function by promoting altered short-chain fatty acids absorption, changed cell signaling, and increased peripheral gluconeogenesis and lipogensis.22 Clostridium difficile infections cause limited disease unless the microbiota becomes substantially altered. If an alteration does occur, it can lead to a persistent dysbiosis (microbial imbalance).10 Chang et al27 performed 16S rRNA sequencing to map microbial communities in the stool of 10 people; 3 were normal subjects, 4 were experiencing their first episode of Clostridium difficile infection, and 3 had recurrent infections. The microbial communities were grouped according to phyla. The 3 controls and 4 patients with their initial occurrence of Clostridium difficile infection had phyla composed largely of Bacteroidetes and Firmicutes. The 3 patients with recurrent infection had decreased diversity and number of phyla, and lacked these two predominant phyla. One of the patients enrolled as a first episode of Clostridium difficile infection had phyla similar to the patients with recurrent infections. In fact, this patient developed a recurrence shortly thereafter. For the Clostridium difficile infection patients with no recurrence, Clostridium difficile represented 3.1% of the total sequences, but in recurrent disease patients it represented 31%.27-29 The theory behind fecal microbiota transplantation is that an altered microbiota can be manipulated to improve the diversity and proportion of phyla that promote colonic health.10 Khoruts et al28 described a patient with 8 months of recurrent Clostridium difficile infection despite multiple antibiotic regimens, referred for fecal microbiota
481 transplantation. Following transplantation, microbial diversity was restored. At both 14 and 33 days post transplant, the patient’s feces had a similar microbial fingerprint to the donors.28 Firmicutes and Bacteroidetes phyla are thought to play a large role in gut homeostasis. Bacteroides spp. are thought to inhibit Clostridium difficile proliferation. Firmicutes produce butyrate, an important short-chain fatty acid, which plays a critical role in maintaining the integrity of the colonic epithelium and regulating mucosal immune responses. Manipulating a patient’s fecal microbiota can be a microbiological therapy, but more investigation is needed to clarify the exact microbial and nonmicrobial components of the donor material that leads to Clostridium difficile eradication.28
METHODOLOGY This review of fecal microbiota transplantation was performed in June 2013 using MEDLINE search for “fecal microbiota transplantation,” “gut microbiota,” and “Clostridium difficile infection.” Three large landmark articles were identified in the midst of numerous case reports and case series. These 3 studies were noted to give the best strength for fecal transplantation. Further comprehensive background, FDA current policies, and future direction of Clostridium difficile infection treatment was obtained from this MEDLINE review, as well as from cross references obtained in the original search.
EFFICACY OF FECAL MICROBIOTA TRANSPLANTATION Fecal microbiota transplantation is a treatment option that is readily available, inexpensive, efficacious, and safe.6 Transplantation has demonstrated >90% clinical resolution of Clostridium difficile infections in the approximately 400 cases reported.10,12,14 Transplantation is safe based on current reports in the literature that have reported few adverse effects.10 Brandt et al12 describe the efficacy of colonoscopic fecal microbiota transplantation in a study of 77 patients from 5 centers across the US.12 All the patients had failed multiple treatment courses of antibiotic regimens. The patient population had an average age of 65 years, 73% were females, and 60% were living independently. Colonoscopyadministered fecal microbiota transplantation was used because it has been shown in a systematic review to be more effective than duodenal infusion.17 Sixty-eight percent had severe diarrhea consisting of >6 bowel movements/day before the procedure, and a majority had abdominal pain, weight loss, and fatigue. Primary cure was defined as resolution of diarrhea without recurrence within 90 days of transplantation. Secondary cure was defined as resolution of Clostridium difficile infections after one further course of vancomycin with or without repeat transplantation. Primary cure was achieved in 91% of patients and secondary cure was met in 76 of 77 patients. The one individual who was not cured was on hospice and died in a sub-acute rehabilitation facility. There were no adverse effects or
482 complications directly attributed to fecal microbiota transplantation. During a mean follow-up of 17 months after transplantation, no patient developed a recurrence of Clostridium difficile infections in the absence of antibiotic treatment for infections unrelated to Clostridium difficile.12 A randomized control study by van Nood et al29 of 43 patients from January 2008 through April 2010 was performed in the Netherlands. Thirty-five of the 43 had more than one recurrence of Clostridium difficile infections. Patients were randomly assigned to 3 groups. Group one received initial vancomycin regimen followed by bowel lavage and subsequent fecal microbiota transplant through nasoduodenal tube. The second group received a standard vancomycin regimen. The third group received a standard vancomycin regimen with bowel lavage. The primary end point measured was cessation of diarrhea associated with Clostridium difficile infection and no relapse after 10 weeks with 3 consecutive negative stool tests for Clostridium difficile toxin. There was an 81% resolution of Clostridium difficile infection-associated diarrhea following the first infusion and 94% following a second infusion in those unresponsive to the first treatment. The vancomycin group had 31% resolution, and the vancomycin and bowel lavage group had 23% resolution. The overall cure rate of fecal transplantation compared with the vancomycin alone was statistically superior (99.9% confidence interval, 1.08-290.05) and compared with vancomycin with bowel lavage (99.9% confidence interval, 1.21-290.12). The trial was stopped early due to the significant efficacy of fecal microbiota transplantation relative to controls. There was no significant difference in adverse events among the 3 groups except for belching, mild diarrhea, and abdominal cramping on the day of fecal microbiota transplantation in the infusion group. Recipients’ stool was found to be similar to their healthy donors based on amount of fecal bacterial diversity following transplantation.29 Mattila et al13 performed a retrospective review of 70 patients from 5 hospitals in Finland with the average age of 73 years.13 Patients underwent colonoscopic fecal microbiota transplantation and were followed for 12 weeks. All subjects had failed standard antibiotic therapy with an average of 4.5 courses of antibiotics before transplantation. Before fecal microbiota transplantation, all patients had stool testing for the specific strain of Clostridium difficile, and 51% had the NAP1/027 strain. There was 100% resolution of symptoms in all non-NAP1/027 strain patients. Of the patients with the virulent strain, 89% had recovery. The 4 patients with the NAP1/027 strain that did not respond had significant morbidity before fecal microbiota transplantation. All 4 died within 1.5-3 months, but none as a result of the procedure. Of the 66 responders, 4 relapsed in the first year following antibiotic treatment for unrelated conditions. Of these 4, 2 were treated successfully with a repeat transplantation, and 2 with antibiotics. There were no perforations or serious adverse reactions reported. Colonoscopic-administered transplantation allows diagnosis of, for example, inflammatory bowel disease and cancer that may be masked by Clostridium difficile infection.13
The American Journal of Medicine, Vol 127, No 6, June 2014
CONTROVERSY SURROUNDING FECAL MICROBIOTA TRANSPLANTATION An FDA/National Institutes of Health consensus panel in May 2013 was convened to exchange knowledge and experience among experts regarding fecal microbiota transplantation. The FDA determined that feces used for transplantation are a biological agent that requires an investigational drug application.30 This decision was later reversed. Physicians may deliver fecal microbiota transplantation for Clostridium difficile infections provided informed consent is obtained from the patients. Consent should state that the procedure is investigational, its long-term effects are unknown, and it is currently contraindicated in pregnancy.31 The consensus panel discussed the need to perform more randomized clinical trials, establish clearer indications for fecal microbiota transplantation, standardize protocols of administration, and develop a large registry. Furthermore, donor screening guidelines need to be established. The FDA concluded that the use of fecal microbiota transplantation for all other disease entities remains investigational, and an investigational drug application is required.10
MICROBIAL TRANSPLANTATION—THE FUTURE Fecal microbiota transplantation consistently cures recurrent Clostridium difficile infections, with success rates >90%. No treatment to date has complete resolution rates this high. As of now, there is only one randomized control trial for fecal microbiota transplantation, which had several limitations, including a small sample size and nonblinding.14 Beyond the need for more randomized control trials, there is concern that the public has labeled fecal microbiota transplant aesthetically unappealing.19,32 However, in the Brandt et al12 study of 77 patients, 97% stated they would undergo another fecal microbiota transplantation for a recurrence of Clostridium difficile infections, and 53% stated they would choose it as their first-line treatment before antibiotics.12 The future of fecal microbiota transplantation will include research in using universal donors or a manufactured product. These sources would help eliminate the process of finding a suitable donor, but there could be drawbacks. A manufactured product would be expensive, as it would require extensive studies and regulatory clearance. A universal donor could lead to the spread of currently unknown pathogens to a large number of recipients. It is possible that the gut microbial population in a healthy person interacts with another human host more effectively than a manufactured bacteria.10 The long-term effects of all these products are unknown, as the microbial population performs extremely important metabolic and immunologic functions in the host.
CONCLUSION Clostridium difficile has emerged as a highly prevalent and morbid infection in both nosocomial and ambulatory
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settings.3 The increased morbidity has correlated with the development of virulent strains and has been associated with chronic refractory infections. Fecal microbiota transplantation has evolved from a medical oddity to an accepted method of treatment for refractory Clostridium difficile infection.11 Ongoing research will help to both underscore the critical components of the fecal microbiota that promote health, and further define the optimal methods and components of fecal microbiota transplantation.
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483 16. Grant E. Fidaxomicin: new therapy for Clostridium difficile-associated diarrhea. Formulary. 2011;46:297-308. 17. Gough E, Shaikh H, Manges A. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent clostridium difficile infection. Clin Infect Dis. 2011;53(10):994-1002. 18. Eiseman B, Silen W, Bascom G, Kauvar A. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44(5):854-859. 19. Kelly C. Fecal microbiota transplantationean old therapy comes of age. N Engl J Med. 2013;368(5):474-475. 20. Borody T, Campbell J. Fecal microbiota transplantation: techniques, applications, and issues. Gastroenterol Clin North Am. 2012;41(4): 781-803. 21. Flotterod O, Hopen G. Refractory clostridium difficile infection: untraditional treatment of antibiotic-induced colitis. Tidsskr Nor Laegeforen. 1991;111:1364-1365. 22. Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012;489:242-249. 23. UpToDate. Spatial organization of the intestinal microbiota in health and disease; 2013. Available at: http://www.uptodate.com/contents/ spatial-organization-of-intestinal-microbiotia-in-health-and-disease. Accessed June 4, 2013. 24. Yan F, Polk DB. Commensal bacteria in the gut: learning who our friends are. Curr Opin Gastroenterol. 2004;20(6):565-571. 25. Sokol H, Pignear B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105(43):16731-16736. 26. Sokol H, Seksik P, Rigottier-Gois L, et al. Specificities of the fecal microbiota in inflammatory bowel disease. Inflamm Bowel Dis. 2006; 12:106-111. 27. Chang JY, Antonopoulos D, Kalra A, et al. Decreased diversity of the fecal micriobiome in recurrent clostridium difficile-associated diarrhea. J Infect Dis. 2008;197:435-438. 28. Khoruts A, Dicksved J, Jansson J, Sadowsky M. Changes in the composition fo the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol. 2010;44:354-360. 29. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of the donor feces for recurrent clostridium difficile. N Engl J Med. 2013;368(5):407-415. 30. Midthun K. FDA Letter to the American Gastroenterological Association. Available at: http://highroadsolution.com/file_upload_2/ files/fdaþresponseþletterþtoþfmtþinquiry.pdf. Accessed March 18, 2014. 31. U.S. Food and Drug Administration. Important information about IND requirments for use of fecal micobiota to treat clostridium difficile infection not responsive to standard therapies. Available at: http:// www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetings Conferences/ucm357258.htm. Accessed March 18, 2014. 32. Hamblin J. Fecal transplantation: ‘we have an effective treatment, but its too gross’. The Atlantic. 2013. Available at: http://www.theatlantic. com/health/print/2013/01/fecal-transplantation-we-have-an-effectivetreatment-but-its-is-too-gross/267389/. Accessed June 4, 2013.
