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Could fecal microbiota transplantation cure all Clostridium difficile infections? “Could fecal microbiota transplantation be the future therapy for all symptomatic Clostridium difficile infection subclasses? This is highly likely…” Thomas J Borody*1 Debra Peattie2 In its current form, fecal microbiota transplantation (FMT) is a novel medical therapy. Intriguingly, however, early Chi nese writings reveal that it was practiced centuries ago in its crudest form using ingested fecal material to treat gastro intestinal ailments such as food poisoning and severe diarrhea [1]. As we discuss here, this ancient medical practice may now be coming ‘full circle’. In 1958, Eiseman and colleagues documented the first modern report of FMT to treat pseudomembranous colitis due to suspected Clostridium difficile infection (CDI). The authors detailed an “immediate and dramatic response” following FMT and suggested that “this simple yet rational therapy method should be given more extensive clinical evalu ation” [2]. Although C. difficile was not described until 1978, the Eiseman et al. report and several others that followed [3,4] almost certainly described treatments for what we now know to be CDI colitis. Subsequently, recognizing the powerful therapeutic potential of normal gastroin testinal microbiota, Borody et al. reported on a case series of 55 patients treated with
Amit Kapur3 FMT at the Centre for Digestive Diseases (New South Wales, Australia) expanding into the areas of idiopathic colitis, irritable bowel syndrome and Crohn’s disease in addition to CDI cases [5]. At the time, CDI had not yet become a major clinical issue and went largely ‘under the radar’ until the emergence of epidemic strains in 2000 [6]. Since then, CDI incidence has increased exponentially, with higher morbidity and mortality than seen in previous years. Here, we examine the expanding role of FMT in the various presentations of CDI. Classification of CDI distinct from inflammatory bowel disease CDI can be characterized into several subdivisions based on its clinical behavior. Asymptomatic carriers aside, the largest sub group of CDI, numbering between 500,000 and 3 million new cases per year, is termed acute CDI (A-CDI). The majority of A-CDI patients can be cured by a short course of antibiotics such as metronidazole, vancomy cin or fidaxomicin. However, approximately 20–30% of A-CDI patients fail to be cured with an initial course of treatment, and
KEYWORDS
• Clostridium difficile • fecal microbiota • microbiome • microbiota • transplantation
“…Clostridium difficile infection incidence has increased exponentially, with higher morbidity and mortality than seen in previous years.”
Centre for Digestive Diseases, Level 1/229 Great North Road, Five Dock, New South Wales 2046, Australia Pleiades Advisors, 13 Oak Meadow Road, Lincoln, MA 01773, USA 3 Prince of Wales Hospital, Randwick, New South Wales 2031, Australia *Author for correspondence: Tel.: +61 2 9713 4011; Fax: +61 2 9713 1026;
[email protected] 1 2
10.2217/FMB.13.146 © 2014 Future Medicine Ltd
Future Microbiol. (2014) 9(1), 1–3
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Editorial Borody, Peattie & Kapur
“…timely fecal microbiota transplantation intervention is required to prevent progression to fulminant Clostridium difficile infection with its associated morbidity and mortality.”
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approximately 65% of these cases, termed relaps ing (R-CDI), will continue to relapse after further courses of antibiotics. A further small subgroup, termed severe CDI (S-CDI), may subsequently require hospitalization owing to severe diarrhea, weight loss, abdominal pain and leucocytosis. An even smaller subgroup, estimated at approximately 3–4% of patients, may progress to fulminant CDI (F-CDI), characterized by symptom progression beyond S-CDI and with poor response to treat ment, leading to surgery that is associated with poor outcomes and high mortality [7]. FMT is typically performed on R-CDI patients who continue to relapse despite antibiotic treat ment. The superior efficacy of FMT relative to antibiotic therapy has been summarized in a col lected case series [8] and in a randomized controlled trial by van Nood et al., which confirmed an effi cacy with FMT of approximately 94% compared with 31% with vancomycin [9]. Subsequently, the American College of Gastroenterology has rec ommended use of FMT for R-CDI [10]. Emerg ing data indicate that FMT is also effective in the various other subclasses of CDI, with the exception of A-CDI. A recent abstract on S-CDI summa rized collected ‘know-how’, demonstrating that S-CDI responds comparably to R-CDI without compromising safety and confirming previous reports [11]. Although there is a dearth of data supporting FMT use in F-CDI owing to ethical considerations, one report demonstrating success in F-CDI has been published [12]. Recent clini cal experience, where death resulted from delay, highlights the importance of using FMT early in the treatment paradigm of S-CDI. By the time a patient reaches the stage of F-CDI, intervention with FMT becomes more complicated due to fear of adverse events such as perforation; consequently, surgical intervention is often used at this late stage. Clearly, timely FMT intervention is required to prevent progression to F-CDI with its associated morbidity and mortality. There are no reports on the use of FMT in A-CDI; however, we now use FMT more frequently in these patients in our Sydney clinic to enhance efficacy, prevent further microbiota damage by antibiotics and arm such patients with a more complete set of gut microbiota for the future. It will be important to conduct a randomized controlled trial in this patient group.
is increasing in frequency and is associated with poor outcomes. In such coinfected patients, FMT treatment is being employed with greater fre quency, with rates of CDI eradication comparable with those of R-CDI [13]. Similarly, eradicating this infection can be safely achieved in immuno compromised CDI patients [14]. These case reports provide data supporting the use of FMT to treat CDI in IBD patients safely, even if they are on immunosuppressive therapy.
CDI complicating inflammatory bowel disease In patients with inflammatory bowel disease (IBD), coinfection with C. difficile (IBD–CDI)
Conclusion Could FMT be the future therapy for all symp tomatic CDI subclasses? This is highly likely; however, to keep pace with anticipated demand,
Future Microbiol. (2014) 9(1)
Adverse effects of FMT Only rarely have adverse effects of FMT been reported [8]. Reported acute adverse effects include bloating, borborygmi, consti pation, transient abdominal discomfort and anal discomfort. FMT continues to surprise us as its biological effects remain without significant adverse effects. Clearly, the vari ous methods of administration can lead to adverse effects; for example, colonoscopic perforation, anesthesia-associated aspiration and drug-associated effects. Nonetheless, two early reports of adverse effects have been pub lished. In two patients, norovirus diarrhea, subsequently shown to have been acquired after FMT, occurred around the time of when FMT was performed [15]. In a separate report, a 78‑year-old patient developed a flare up of pre-existing colitis after FMT, prompting the authors to report this as a complication [16]. Brandt et al. have reported medium-term adverse effects [17]. They noted subtle changes in bowel function and, in four patients, reported new diagnoses of rheumatoid arthri tis, Sjogren’s syndrome, idiopathic thrombo cytopenic purpura and peripheral neuropathy, although no clear causality was attributable to FMT. Long-term adverse effects of FMT have yet to be reported and require further study. However, considering that the FMT biologic originates from a donor and comparing this with, for example, daily-use antihypertensive drugs, it makes sense to note that the donor stool was collected from a 35‑year-old individ ual who has already undergone several decades of in vivo testing for adverse events, far exceed ing any US FDA requirement for prolonged testing of a biologic or drug in humans.
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Could fecal microbiota transplantation cure all Clostridium difficile infections? an FMT biologic will need to be available in powdered form for infusion as well as in encap sulated form for short- and long-term daily use [18]. An encapsulated FMT biologic will avoid using antibiotics in a condition largely caused by antibiotics and also will permit long-term usage in IBD–CDI to address both conditions. In 1958, Eiseman himself predicted that “enteric organisms in enteric coated capsules might be both more aesthetic and more effective” [2]. Clearly, we are coming ‘full circle’ toward a modified, ingested FMT predicated on that practiced as early the 4th century AD by Ge Hong in China [1]. References 1
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Zhang F, Luo W, Shi Y et al. Should we standardize the 1,700‑year old fecal microbiota transplantation? Am. J. Gastroenterol. 107(11), 1755–1756 (2012). Eiseman B, Silen W, Bascom GS et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 44(5), 854–859 (1958). Bowden TA, Mansberger AR, Lykins LE. Pseudomembranous enterocolitis: mechanism of restoring floral homeostasis. Am. Surg. 47, 178–183 (1981). Schwan A, Sjoln S, Trottestam U et al. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of normal faeces. Scand. J. Infect. Dis. 16, 211–215 (1984). Borody TJ, George L, Andrews P et al. Bowel-flora alteration: a potential cure for inflammatory bowel disease and irritable bowel syndrome? Med. J. Aust. 150, 604 (1989). McDonald LC, Owings M, Jernigan DB. Clostridium difficile infection in patients discharged from US short-stay hospitals. Emerg. Infect. Dis. 12, 409–415 (2006).
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Editorial
Financial & competing interests disclosure TJ Borody has a financial interest in the Centre for Digestive Diseases (New South Wales, Australia), where fecal microbiota transplantation is a treatment option. In addition, he has filed patent applications in this field. D Peattie has a financial interest in CIPAC Limited, a privately held company developing a therapeutic product for fecal microbiota transplantation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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Dupont HL. Diagnosis and management of Clostridium difficile infection. Clin. Gastroenterol. Hepatol. 11, 1216–1223 (2013).
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Borody TJ, Khoruts A. Fecal microbiota transplantation and emerging applications. Nat. Rev. Gastroenterol. Hepatol. 9, 88–96 (2011).
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van Nood E, Vrieze A, Nieuwdorp M et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368(5), 407–415 (2013).
10 Surawicz CM, Brandt LJ, Binion DG et al.
Guidelines for diagnosis, treatment and prevention of Clostridium difficile infections. Am. J. Gastroenterol. 108, 478–498 (2013). 11 Brandt LJ, Aroniadis OC. An overview of
fecal microbiota transplantation: techniques, indications, and outcomes. Gastrointest. Endosc. 78(2), 240–249 (2013). 12 You DM, Franzos MA, Holman RP.
Successful treatment of fulminant Clostridium difficile infection with fecal bacteriotherapy. Ann. Intern. Med. 148(8), 632–633 (2008). 13 Borody TJ, Wettstein A, Nowak A et al. Fecal
microbiota transplantation eradicates Clostridium difficile infection in inflammatory bowel disease. Presented at: 21st United
European Gastroenterology Week. Berlin, Germany, 12–16 October 2013. 14 Brandt L, Aroniadis O, Greenberg A et al.
Safety of fecal microbiota transplantation (FMT) in immunocompromised (IC) patients with inflammatory bowel disease (IBD). Am. J. Gastroenterol. 108(Suppl. 1), S556 (2013). 15 Schwartz M, Gluck M, Koon S. Norovirus
gastroenteritis after fecal microbiota transplantation for treatment of Clostridium difficile infection despite asymptomatic donors and lack of sick contacts. Am. J. Gastroenterol. 108, 1367 (2013). 16 De Leon LM, Watson JB, Kelly CR.
Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin. Gastroenterol. Hepatol. 11, 1036–1038 (2013). 17 Brandt LJ, Aroniadis O, Mellow M et al.
Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am. J. Gastroenterol. 107, 1079–1087 (2012). 18 Borody TJ, Peattie D, Campbell J.
Therapeutic potential of the human gastrointestinal microbiome. Drug Dev. Res. 74(6), 385–392 (2013).
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