CLINICAL REVIEW ARTICLE
The Use and Efficacy of Fecal Microbiota Transplantation for Refractory Clostridium difficile in Patients with Inflammatory Bowel Disease Robert J. Gianotti, MD and Alan C. Moss, MD
Abstract: Clostridium difficile (CD) is an anaerobic, spore-forming bacillus that is responsible for a spectrum of gastrointestinal illness ranging from asymptomatic carriage to toxic megacolon and death. The prevalence of CD infection is increasing in both hospitalized and community-based inflammatory bowel disease populations. Standard antibiotic therapy fails to cure or prevent recurrence in more than 50% of patients, thus increasing the need for alternative therapies. Recently, fecal microbiota transplantation has received renewed attention as a therapy for refractory or recurrent CD infection. A high success rate combined with a favorable safety profile makes this therapy an attractive option for patients who have failed standard antibiotic therapy. Increasingly, this therapy is used in patients with CD infection and inflammatory bowel disease, as the combination of active inflammation and toxin-producing CD provides a challenging mix for clinicians. (Inflamm Bowel Dis 2016;22:2704–2710) Key Words: microbiology of IBD, basic science areas, fecal transplant in IBD, Clostridium difficile in IBD
THE PROBLEM OF CLOSTRIDIUM DIFFICILE IN INFLAMMATORY BOWEL DISEASE Clostridium difficile infection (CDI) has a significant impact on patients with inflammatory bowel disease (IBD). The majority of patients with IBD develop CDI in the outpatient setting.1 In a national survey of nearly 1000 patients with community-acquired CDI (no overnight hospital stay within 12 weeks of diagnosis), approximately 11% were known to have IBD, and 9% of all patients were receiving immunosuppression. Household contacts with CDI, PPI use, and exposure to young infants ,1 year were associated with an increased risk of community-acquired CDI.2 A 2011 systematic review of CDI and IBD revealed that CDI is more common in IBD, especially ulcerative colitis (UC). Additional risk factors for acquisition include the use of immunosuppresants and antibiotics, although the risk related to antibiotics was lower than in control cases. There are no controlled trials on the efficacy of antibiotics in treating CDI in patients with IBD.3 Over the past 2 decades CDI rates have been increasing in patients hospitalized with IBD,4 and patients with CDI-IBD appear to fare worse than their non-IBD counterparts.1,4–8 Several population-based studies suggest an increased mortality from CDI Received for publication August 9, 2016; Accepted August 24, 2016. From the Beth Israel Deaconess Medical Center, Harvard Medical School, Boston Massachusetts. The authors have no conflict of interest to disclose. Address correspondence to: Alan C. Moss, MD, 330 Brookline Avenue, Boston, MA 02215 (e-mail: [email protected]). Copyright © 2016 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000950 Published online 12 October 2016.
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in IBD patients. In IBD patients hospitalized for infection-related complications, CDI was found to be associated with excess inpatient mortality (odds ratio, 3.2, 95% confidence interval, 2.6–4.0).5 Odds of colectomy in CDI-IBD patients, particularly those with UC-CDI compared with UC or Crohn’s disease (CD) alone, increased significantly between the years 1998 and 2007.4 Ricciardi et al8 showed that the mortality risk from routine intestinal surgery in IBD increased from 2% to 18% with CDI and was nearly 26% in the UC-CDI subgroup. Risk factors for both colectomy and mortality include serum albumin ,3g/dL, hemoglobin ,9 g/dL, and serum creatinine .1.5 mg/dL in hospitalized patients with CDI-IBD.9 CDI is a major factor in relapsing diarrhea in patients with IBD formerly in clinical remission, found in 5% to 20% of patients.10,11 Risk factors for CDI in hospitalized IBD patients include an increased prevalence in those with UC, recent antibiotic use, proton pump inhibitors, and low albumin of ,3 g/dL. The use of immunosuppresants in IBD appears to increase the risk for CDI. A retrospective analysis of risk factors for the development of CDI-IBD showed that immunomodulator use, including 6-mercaptopurine, azathioprine, and methotrexate, may increase the risk of CDI (74% versus 56%; P ¼ 0.02), whereas biologics did not.1 In contrast, another single-center data reported that the risk of CDI was not influenced by immunosuppressant or anti–tumor necrosis factor (TNF) therapy, highlighting the need to avoid making generalizations about causality for immunosuppression and CDI based on nonrandomized, single-center data.12 One reason why patients with IBD may be at higher risk of CDI is genetics. In an exploratory analysis, Ananthakrishnan et al,13 identified 6 risk loci associated with increased rates of CDI in a cohort of UC patients and identified 2 loci that were Inflamm Bowel Dis Volume 22, Number 11, November 2016
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protective. Risk alleles defining pathways involving TNF and nuclear factor-kB may be associated with the increased risk for CDI. The relative risk for CDI was increased in female patients and those with pancolitis in this study. Interestingly, there was an increased exposure to biologic therapy in the patients free of CDI, suggested by the authors to be possibly related to increased rates of mucosal healing.13 IBD patients with ileal pouch anal anastomosis and ileostomy may also be at a risk for CDI. CDI may be found in up to 10% of patients with ileal pouch anal anastomosis and chronic diarrhea,14 and nearly 60% of these patients will have a recurrent CDI after an initial therapy with vancomycin. This high recurrence rate makes these patients likely to be referred for fecal microbiota transplantation (FMT). CDI has also been reported in patients with ileostomy, and infection may cause a sever enteritis. Colonic metaplasia and microbial population shifts may increase the risk of CDI in these patients.15
TREATMENT EFFICACY IN CDI AND IBD The mainstay of treatment for CDI is the antibiotics metronidazole and vancomycin. In general, metronidazole is reserved for the treatment of mild-to-moderate, uncomplicated disease. Guidelines from the American College of Gastroenterology suggest the following classification of disease severity16 (Table 1). Metronidazole therapy is recommended in mild-tomoderate disease, although many practitioners often start therapy in any hospitalized patient with vancomycin due to the relatively high rates of treatment failure (22%) and early recurrence (28%) with metronidazole.17 We do not routinely recommend the use of metronidazole in patients with IBD. Vancomycin therapy with 125 mg 4 times per day should be the initial therapy for all patients with severe disease. Dose escalation to 500 mg 4 times per day and the addition of intravenous metronidazole or vancomycin delivered through retention enema can be considered for severe and complicated cases.16,18 Treatment of recurrent CDI is
TABLE 1. Clostridium difficile Infection (CDI) Severity Severity Mild Moderate
Clinical and Laboratory Parameters
CDI + diarrhea CDI + diarrhea + additional symptoms not listed under severe disease Severe CDI + albumin ,3 g/dL and either WBC $15,000 cells/ mm3 or abdominal pain without complications Complicated CDI + admission to intensive care unit; hypotension; fever $38.58C; ileus; impaired mental status; WBC $35,000 or #2000 cells/mm3; lactate .2.2 mmol/L; end organ failure Recurrent CDI reoccurrence within 8 weeks of therapy WBC, white blood cell.
Use and Efficacy of Fecal Microbiota
often with a repeat course of the initial therapy, a prolonged vancomycin pulsed and taper19 or with fidaxomicin.20 There is a paucity of data looking at the treatment of CDI specifically in IBD populations because many studies exclude patients with IBD or immunosuppression (Table 2). The American College of Gastroenterology guidelines suggest a test-and-treat strategy for all hospitalized patients with IBD in a flare and outpatients with diarrhea previously in.16 Recurrence rates of CDI in adults are reported to range between 15% and 30%19 and are likely higher in patients with IBD with some centers reporting rates as high as 60%.39 A single-center pediatric cohort showed the rate of recurrence in IBD to be 34% versus 7.5% in non-IBD control subjects. More than 75% of the patients had CD, with a greater proportion of CDI patients having colonic involvement (95% versus 67%) as is often seen in pediatric populations.40 Many IBD patients will require combined immunosuppressant therapy to treat the underlying disease, in addition to antibiotic therapy against CDI. Corticosteroid treatment, which is often a mainstay of the initial management for severe UC, increases the risk for CDI approximately 3-fold16 and concomitant glucocorticoids with CDI approximately double the 30-day mortality.41 As mentioned previously, combined immunomodulators and antibiotics have a worse prognosis than antibiotics used alone in the management of IBD-CDI.42 A conditional recommendation in the American College of Gastroenterology practice guidelines support the ongoing use of immunosuppression in CDI but suggest holding dose escalation or addition of anti-TNF until therapy for CDI has been ongoing for up to 72 hours,16 although this is a conditional recommendation based on no quality evidence. In severe cases, early surgical evaluation is suggested. Unfortunately, many patients go on to relapse with multiple infections, requiring repeated courses of antibiotics. Patients with a first recurrence have high relapse rates ranging from 30% to 60%.39 Fecal microbiota therapy has emerged to fill an important role in the treatment of recurrent CDI.
FMT FOR RECURRENT CDI IN IBD FMT is the transfer of healthy donor stool for the purpose of reestablishing an appropriate balance of microbiota. Recently, FMT use has increased for the treatment of recurrent CDI, and there is a growing body of literature examining the effectiveness of FMT for the primary treatment of IBD. Disruptions of the endogenous flora, particularly a loss in diversity, plays a major role in gastrointestinal disease states, including CDI43 and IBD.44 FMT has been used for the treatment of human gastrointestinal disease for more than 1000 years.45 The first reported use in the treatment of pseudomembranous colitis caused by Staphylococcus was in 1958.46 FMT was first used for CDI in 1983 in a 65-year-old woman with recurrent CDI who was refractory to multiple course of vancomycin through fecal retention enema.47 Sporadic use of FMT persisted until recently when epidemic strains of CDI emerged with increasing rates of recurrence,48 in www.ibdjournal.org |
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TABLE 2. Efficacy of FMT in CDI with and Without IBD Author
Population
Result
17 patients with severe and or complicated CDI 146 patients .65 years old with recurrent, severe, or complicated CDI
94.1% overall cure, resolution of symptoms at 90 days 95.9% overall cure, primary resolution of symptoms without recurrence at 12 wk or after second FMT
Zainah et al23
14 hospitalized patients with severe CDI 13 through NGT
Kronman et al24
10 pediatric patients, $3 recurrences of CDI All by means of NGT 39 patients randomly assigned to FMT versus vancomycin pulse, $1 recurrence of CDI 20 patients with recurrent CDI treated with FMT capsules 10 pediatric patients with recurrent CDI treated with FMT by means of NGT (2) or colonoscopy (8)
79% cure (11/14), , 3 loose stools for 2 consecutive days without need for CDI therapy after day 7 90% cure (9 of 10), resolution of diarrhea
Aroniadis et al21 Agrawal et al22
Cammarota et al25 Youngster et al26 Russell et al27
Lee et al28
94 patients treated with retention enema for recurrent or refractory CDI
Kelly et al29
80 immunocompromised patients treated with FMT for recurrent, refractory, and/or severe CDI
Van Nood 201430
43 patients with recurrent CDI randomized to FMT by means of nasoduodenal route, vancomycin, or vancomycin + lavage 70 patients with recurrent CDI treated with FMT by means of colonoscopy
Mattila et al31 Kelly et al32
26 patients treated for recurrent CDI by means of colonoscopy
Kassam et al33
27 patients treated for recurrent CDI with retention enema 12 patients with recurrent CDI treated by means of colonoscopy 40 patients treated with FMT by means of either duodenal infusion or colonoscopy for recurrent CDI 19 patients treated with FMT by means of colonoscopy for recurrent CDI 15 patients treated with FMT by means of nasogastric tube for recurrent CDI 18 patients treated with FMT by means of nasogastric tube for recurrent CDI
Yoon et al34 Garborg et al35
Rohlke et al36 MacConnachie et al37 Aas et al38
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90% cure, resolution of diarrhea at 10 wk
Result of IBD No IBD patients reported 3 patients with CD 2 patients with UC Outcome not specifically reported No IBD patients reported
30% with IBD (3 of 10), all on either AZA, MTX, TNF or combo 100% cure (3 of 3), no complications No IBD patients reported
70% primary and 90% overall cure rate
No IBD patients reported
90% primary cure rate
3 patients with IBD 1 IBD unclassified—toxin free at 4 mo 1 CD—symptoms persisted, EIA toxin positive recurrence 8 wk after FMT 1 UC on adalimumab—resolution of CDI, colectomy for severe IBD 3 patients with IBD 100% cure
84% overall cure without recurrence at 6 mo treated with 4 or more enema FMT Overall cure rate of 89%, no infectious complications, 1 death related to procedural sedation before FMT
Overall cure 94%
100% of non-O27 strains cured at 12 wk 89% of O27 strains cured at 12 wk 92% cured without symptoms at a mean of 12 mo 93% with clinical resolution of symptoms 100% with a durable clinical response Overall, 83% with clinical resolution of symptoms at 80 days after FMT Overall, 95% cure with a single FMT 73% of patients had resolution of symptoms with a single treatment 94% of patients had resolution of symptoms
36 patients with IBD on immunosuppressants Overall cure 94% 3 of 36 experienced IBD flare following FMT No IBD patients reported
No IBD detected by colonoscopy 2 patients with evidence of chronic colitis on colonoscopy, 100% response to FMT No IBD patients reported 1 patient with IBD excluded 2 of 7 nonresponders were diagnosed with “immunologic colitis” and were successfully treated with steroids No IBD patients reported No IBD reported No IBD reported
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particular, the BI/NAP-1 strain with increased levels of toxin production, fluoroquinolone resistance, and higher associated mortality.49,50
EFFICACY IN PATIENTS WITH CDI ALONE A recent randomized trial of FMT30 by means of nasoduodenal infusion of donor feces following a lead in with oral vancomycin compared with vancomycin with and without bowel lavage demonstrated significantly higher rates of resolution of CDI-related diarrhea (81.3% versus 30.8%; P ¼ 0.008) (Table 2). Cure rates without relapse increased to 93.8% after 3 patients were re-treated with FMT.30 In a multicenter follow-up study of elderly patients, FMT was both safe and effective in recurrent, severe, and complicated CDI. The primary and secondary cure rates were 82.9% and 95.9%, respectively.51 The mean age was 70.6 years, and 5 of 146 patients included in the study had a preexisting diagnosis of IBD; there were no serious adverse events in these patients. FMT is safe and effective in patients with severe or complicated CDI. A recent cohort of 17 patients with severe or complicated disease treated with FMT showed primary and secondary cure rates of 88.2% and 94.1%, respectively. There were no reported adverse events related to FMT.52 In a recent, small, open-label, randomized study of FMT given by colonoscopy compared with vancomycin therapy, FMT was superior, with overall cure rates of 90% and 25%, respectively. The study was stopped at 1 year because preliminary analysis demonstrated the clear superiority of FMT. Interestingly, 7 of the 20 patients who received FMT required multiple infusions as a result of the presence of pseudomembranous colitis. Adverse events in FMT included postprocedure diarrhea, bloating, and cramping, which resolved within 24 hours. The authors excluded patients with prolonged use of steroids, and it was not reported if any of the patients had concomitant IBD.25
EFFICACY IN PATIENTS WITH IBD AND CDI The largest cohort to report on patients with IBD receiving FMT for recurrent or refractory CDI was by Kelly et al29 in 2014 (Table 2). This retrospective descriptive study was of 80 patients classified as immunocompromised for various reasons, including HIV/AIDS, malignancy, solid organ transplant, and IBD (n ¼ 36). The overall cure rate for FMT was 89%. Of those patients, 30 patients were receiving steroids, 19 patients were receiving immunomodulators (azathioprine, 6-mercaptopurine, methotrexate), 16 were on anti-TNF therapy (infliximab, adalimumab, certolizumab), and 2 were receiving an alpha-4 integrin inhibitor. The overall cure rate in IBD was 94% with 86% cure after a single FMT. Four IBD patients were hospitalized for IBD flare within 12 weeks of FMT; this was classified as possibly related to the FMT. Three of these patients required steroids, and 1 underwent colectomy within 1 month of FMT. Three patients underwent colectomy within 100 days of FMT, but none were directly attributed to CDI or complications of FMT.
Use and Efficacy of Fecal Microbiota
Importantly, the rate of SAE and AE were not significantly different for patient with immunocompromise related to IBD versus non-IBD (14% versus 16% for AE; P # 0.3224).29 The one death that was related to FMT occurred as a result of aspiration during sedation for the second FMT by means of colonoscopy; this was a solid organ transplant patient with advanced esophageal cancer. The authors were unable to conclude whether FMT was the exacerbating factor in the patients who received FMT. Unfortunately, data were not collected on the natural history of IBD or endoscopic severity. The authors point out that it is difficult to clearly separate diarrhea related to CDI and that associated with underlying mucosal inflammation. A cohort of 10 pediatric patients who received FMT by means of nasointestinal tube for recurrent CDI (defined as 3 or more recurrences) demonstrated a 90% cure rate with a single FMT and 100% following a second infusion in a single patient; 30% of the patients had comorbid IBD on immunomodulators or anti-TNF therapy. All IBD patients had a resolution of symptoms with a single FMT.24 An associated editorial cautions the use of adult donors for pediatric patients with unknown effects on host-immune interactions and the possibility of accelerated “immune aging.”53 Another single-center study of 10 pediatric IBD patients included 3 with IBD. All 3 patients required additional immunosuppression after FMT and 1 patient required colectomy. Two of 3 patients progressed, despite negative stool toxin by EIA after FMT.27 A single-center study of 94 patients treated with FMT by means of enema demonstrated an overall cure rate of 86.2%, with a small subset of patients requiring 4 or more FMT treatments. Three IBD patients were included in this cohort, and all were cured of CDI without reference to disease severity, immunosuppression regimen, or the number of FMTs required.28 A recent report by Youngster et al26 demonstrated effectiveness of a frozen, encapsulated form of FMT for treating recurrent CDI. Overall, 18 of 20 patients (90%) met the primary endpoint of diarrhea resolution by 8 weeks. Two patients with IBD were included in this study, one of whom was a pediatric patient on low-dose steroid therapy who required a repeat capsule FMT for symptom resolution. The other patient was an adult with IBD on no immunosuppression who has a prompt clinical response to a single capsule FMT.26
FECAL MICROBIOTA THERAPY IN IBD WITHOUT CDI Recent research has started to explore the question of whether FMT is useful as a primary therapy for IBD without CDI. Two randomized controlled trials of FMT in patients with active UC were published for the first time in 2015. Rossen et al54 studied 50 patients in a double-blind, randomized trial of FMT by means of nasoduodenal tube (TURN: Transplantation of Feces in Ulcerative Colitis; Returning Nature’s Homeostasis). The placebo arm was an infusion of autologous stool. The www.ibdjournal.org |
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patients received an infusion at study entry and at week 3. The primary endpoint was a composite of clinical remission defined as simple colitis activity index #2 and a $1-point decrease in the Mayo endoscopic score. There was no significant difference in the primary endpoint between patients who received donor stool or autologous stool (30.4% versus 20%, ITT; P ¼ 0.51). There were no major adverse events related to FMT, although 1 patient was found to have small bowel CD and was admitted with a small bowel perforation 5 weeks after FMT. Additional reported AEs included increased stools frequency and increased bowel sounds. There were no infectious complications, although 2 patients in the donor group had a transient fever.54 This study also included an analysis of the microbial populations of patients and donors. UC patients had decreased abundance of Clostridium cluster IV, XIVa, and XVIII and higher abundance in Bacteroidetes, Bacilli, Proteobacteria, and Clostridium clusters IX and XI when compared with donors.54 Diversity was significantly increased at week 12 in responders of both groups when compared with nonresponders, and responders in the donor group were more likely to have a similar microbiota to their donor at week 12. In the second trial, Moayyedi et al55 compared the efficacy of 6-weekly fecal enema to placebo enema in a group of 75 patients with moderately active UC. The primary endpoint was remission based on clinical Mayo score ,3 and endoscopic Mayo score ¼ 0. This study highlighted the important and unique finding of a “super donor.” The responders in this trial were more likely to have received stool from a specific donor B than other donors (39% versus 10%; P ¼ 0.06); in fact, the DSMB stopped the trial early for futility but allowed enrolled patients to complete the trial, and at that time, donor B came back into the pool and the remaining patients all received stool from this “super donor.”55 FMT is still in its early stages. The procedure can be cumbersome for patients and donors requiring demanding screening, bowel preparation and associated procedural risks, and the inherent distasteful nature of stool transfer. A goal of therapy will be the eventual replacement of whole donor stool transfer by an orally available pill composed of specific bacterial populations. One area of active research is the use of nontoxigenic strains of CD to prevent recurrence. One recent safety study evaluated the use of CD strain M3. There were no significant differences in adverse events between patients receiving spores versus placebo. In fact, the rate of recurrence for CDI in patients receiving the highest dose (107 spores) was 5% compared with 30% in the placebo group.56 These strainspecific therapies will likely become a mainstay of treatment in the coming years. Our current method for treating recurrent CDI with and without IBD is the same. We counsel patients about the risk of flare to underlying IBD, but this risk has not been confirmed in population-based studies. Our recent study evaluating the safety of FMT in active CD57 did not show an increased risk of disease flare after a standard colonoscopic delivery of FMT. Our own
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institutional experience with FMT for CDI does not show an increased risk of flare in patients with concomitant IBD.
REGULATORY STATUS OF FMT IN IBD PATIENTS The growing popularity of stool banking has gained attention with practitioners and the Food and Drug Administration (FDA) alike. Currently, the most recent iteration of the FDA draft guidance (March 2016) proposes to enact enforcement discretion and not require clinicians to submit an investigational new drug (IND) application to use FMT material for recurrent CDI. The IND is a time- and resource-intensive FDA application for the study of new drugs that is cumbersome for individual clinicians to apply with limited time. The current guidance states that the donor must be known and screened by the clinician. The enforcement discretion will not extend to stool banking citing safety concerns of centralized processing, transmission of infectious agents, and other potential unidentified risks. Stool banks would need to submit an IND. Fortunately, it appears that in the current form, clinicians receiving stool material from a bank with an IND would be exempt from IND obligations. All other uses of FMT, including as primary therapy for IBD, continue to require investigators to submit an IND. Our current methods employ the use of the Openbiome, a nonprofit stool bank in the greater Boston area. The rigorous testing standards increase the safety profile of the donor samples, streamline the process for both patients and practitioners, and overall reduce costs associated with screening and testing potential donors. Samples arrive and are stored at 2208C until the procedure. We use 250-mL aliquots delivered after thawing in 1 bolus to the cecum during a prepped colonoscopy. In certain patients at the risk for enhanced intestinal transit and rapid expulsion of the FMT, we use loperamide before and after the procedure to slow motility, and we use smaller aliquots of stool available in 50 mL. The use of stool bank samples saves valuable time and screening costs, and we can often accommodate patients using banked material within hours to days as opposed to the extended period required to find and screen a suitable donor.
CONCLUSIONS Overall, FMT for CDI in patients with IBD appears to be safe and effective at preventing recurrent infection. Despite the excellent efficacy and safety, many questions remain unanswered. What particular species are required for successful FMT and what proportion of the transplanted organisms persist in recipients? What role do metabolic products of the transplanted organisms play in C. difficile eradication? We also question whether IBD patients with C. difficile colonization should receive prophylactic FMT or cholestyramine to prevent symptoms. Future directions include narrowing the spectrum of organisms needed to achieve eradication, an oral delivery system, and explorations of methods to prevent CDI in our high-risk IBD patients.
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1. Issa M, Vijayapal A, Graham MB, et al. Impact of Clostridium difficile on inflammatory bowel disease. Clin Gastroenter Hepatol. 2007;5: 345–351. 2. Chitnis AS, Holzbauer SM, Belflower RM, et al. Epidemiology of community-associated Clostridium difficile infection, 2009 through 2011. JAMA Intern Med. 2013;173:1359–1367. 3. Goodhand JR, Alazawi W, Rampton DS. Systematic review: Clostridium difficile and inflammatory bowel disease. Aliment Pharmacol Ther. 2011; 33:428–441. 4. Ananthakrishnan AN, McGinley EL, Saeian K, et al. Temporal trends in disease outcomes related to Clostridium difficile infection in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2011;17:976–983. 5. Ananthakrishnan AN, McGinley EL. Infection-related hospitalizations are associated with increased mortality in patients with inflammatory bowel diseases. J Crohn’s Colitis. 2013;7:107–112. 6. Ananthakrishnan AN, McGinley EL, Binion DG. Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease. Gut. 2008;57:205–210. 7. Nguyen GC, Kaplan GG, Harris ML, et al. A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients. Am J Gastroenterol. 2008;103: 1443–1450. 8. Ricciardi R, Ogilvie JW Jr, Roberts PL, et al. Epidemiology of Clostridium difficile colitis in hospitalized patients with inflammatory bowel diseases. Dis Colon Rectum. 2009;52:40–45. 9. Ananthakrishnan AN, Guzman-Perez R, Gainer V, et al. Predictors of severe outcomes associated with Clostridium difficile infection in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2012;35: 789–795. 10. Mylonaki M, Langmead L, Pantes A, et al. Enteric infection in relapse of inflammatory bowel disease: importance of microbiological examination of stool. Eur J Gastroenterol Hepatol. 2004;16:775–778. 11. Meyer AM, Ramzan NN, Loftus EV Jr, et al. The diagnostic yield of stool pathogen studies during relapses of inflammatory bowel disease. J Clin Gastroenterol. 2004;38:772–775. 12. Stoica O, Trifan A, Cojocariu C, et al. Incidence and risk factors of Clostridium difficile infection in patients with inflammatory bowel disease. Rev Med Chir Soc Med Nat Iasi. 2015;119:81–86. 13. Ananthakrishnan AN, Oxford EC, Nguyen DD, et al. Genetic risk factors for Clostridium difficile infection in ulcerative colitis. Aliment Pharmacol Ther. 2013;38:522–530. 14. Seril DN, Ashburn JH, Lian L, et al. Risk factors and management of refractory or recurrent clostridium difficile infection in ileal pouch patients. Inflamm Bowel Dis. 2014;20:2226–2233. 15. Peacock O, Speake W, Shaw A, et al. Clostridium difficile enteritis in a patient after total proctocolectomy. BMJ Case Rep. 2009;2009. bcr10. 2008.1165. 16. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478–498. quiz 99. 17. Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis. 2005;40:1586–1590. 18. Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA. 2015;313:398–408. 19. Maroo S, Lamont JT. Recurrent clostridium difficile. Gastroenterology. 2006;130:1311–1316. 20. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364:422–431. 21. Aroniadis OC, Brandt LJ, Greenberg A, et al. Long-term follow-up study of fecal microbiota transplantation for severe and/or complicated Clostridium difficile infection: a multicenter experience. J Clin Gastroenterol. 2016;50:398–402. 22. Agrawal M, Aroniadis OC, Brandt LJ, et al. The long-term efficacy and safety of fecal microbiota transplant for recurrent, severe, and complicated Clostridium difficile infection in 146 elderly individuals. J Clin Gastroenterol. 2016;50:403–407. 23. Zainah H, Hassan M, Shiekh-Sroujieh L, et al. Intestinal microbiota transplantation, a simple and effective treatment for severe and refractory Clostridium difficile infection. Dig Dis Sci. 2015;60:181–185.
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24. Kronman MP, Nielson HJ, Adler AL, et al. Fecal microbiota transplantation via nasogastric tube for recurrent clostridium difficile infection in pediatric patients. J Pediatr Gastroenterol Nutr. 2015; 60:23–26. 25. 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;41:835–843. 26. Youngster I, Russell GH, Pindar C, et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. J Am Med Assoc. 2014;312:1772–1778. 27. Russell GH, Kaplan JL, Youngster I, et al. Fecal transplant for recurrent Clostridium difficile infection in children with and without inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2014;58:588–592. 28. Lee CH, Belanger JE, Kassam Z, et al. The outcome and long-term follow-up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema. Eur J Clin Microbiol Infect Dis. 2014;33: 1425–1428. 29. Kelly CR, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014;109:1065–1071. 30. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368: 407–415. 31. 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. 32. Kelly CR, de Leon L, Jasutkar N. Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results. J Clin Gastroenterol. 2012;46:145–149. 33. Kassam Z, Hundal R, Marshall JK, et al. Fecal transplant via retention enema for refractory or recurrent Clostridium difficile infection. Arch Intern Med. 2012;172:191–193. 34. Yoon SS, Brandt LJ. Treatment of refractory/recurrent C. difficileassociated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol. 2010;44:562–566. 35. Garborg K, Waagsbo B, Stallemo A, et al. Results of faecal donor instillation therapy for recurrent Clostridium difficile-associated diarrhoea. Scand J Infect Dis. 2010;42:857–861. 36. Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution for recurrent Clostridium difficile infection: results and methodology. J Clin Gastroenterol. 2010;44:567–570. 37. MacConnachie AA, Fox R, Kennedy DR, et al. Faecal transplant for recurrent Clostridium difficile-associated diarrhoea: a UK case series. QJM. 2009;102:781–784. 38. 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;36:580–585. 39. Issa M, Ananthakrishnan AN, Binion DG. Clostridium difficile and inflammatory bowel disease. Inflamm Bowel Dis. 2008;14:1432–1442. 40. Kelsen JR, Kim J, Latta D, et al. Recurrence rate of clostridium difficile infection in hospitalized pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2011;17:50–55. 41. Das R, Feuerstadt P, Brandt LJ. Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with clostridium difficile-associated disease. Am J Gastroenterol. 2010;105: 2040–2049. 42. Ben-Horin S, Margalit M, Bossuyt P, et al. Combination immunomodulator and antibiotic treatment in patients with inflammatory bowel disease and clostridium difficile infection. Clin Gastroenterol Hepatol. 2009;7: 981–987. 43. Britton RA, Young VB. Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology. 2014;146: 1547–1553. 44. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146: 1489–1499. 45. Zhang F, Luo W, Shi Y, et al. Should we standardize the 1,700-year-old fecal microbiota transplantation? Am J Gastroenterol. 2012;107:1755. author reply p -6. www.ibdjournal.org |
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46. Eiseman B, Silen W, Bascom GS, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44: 854–859. 47. Abedin MZ, Narins SC, Park EH, et al. Lovastatin alters biliary lipid composition and dissolves gallstones: a long-term study in prairie dogs. Dig Dis Sci. 2002;47:2192–2210. 48. Petrella LA, Sambol SP, Cheknis A, et al. Decreased cure and increased recurrence rates for Clostridium difficile infection caused by the epidemic C. difficile BI strain. Clin Infect Dis. 2012;55:351–357. 49. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;372:1539–1548. 50. McFarland LV, Surawicz CM, Rubin M, et al. Recurrent Clostridium difficile disease: epidemiology and clinical characteristics. Infect Control Hosp Epidemiol. 1999;20:43–50. 51. Agrawal M, Aroniadis OC, Brandt LJ, et al. The long-term efficacy and safety of fecal microbiota transplant for recurrent, severe, and complicated Clostridium difficile infection in 146 elderly individuals. J Clin Gastroenterol. 2015.
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52. Aroniadis OC, Brandt LJ, Greenberg A, et al. Long-term follow-up study of fecal microbiota transplantation for severe and/or complicated Clostridium difficile infection: a multicenter experience. J Clin Gastroenterol. 2015. 53. Lynch SV. Fecal microbiota transplantation for recurrent Clostridium difficile infection in pediatric patients: encouragement wrapped in caution. J Pediatr Gastroenterol Nutr. 2015;60:1–3. 54. Rossen NG, Fuentes S, van der Spek MJ, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology. 2015;149:110–118. e4. 55. Moayyedi P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. 2015;149:102–109. e6. 56. Gerding DN, Meyer T, Lee C, et al. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. JAMA. 2015;313:1719–1727. 57. Vaughn BP, Gevers D, Ting A, et al. Mo1228 fecal microbiota transplantation induces early improvement in symptoms in patients with active Crohn’s disease. Gastroenterology. 2014;146:S-591–S-592.
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The Use and Efficacy of Fecal Microbiota Transplantation for Refractory Clostridium difficile in Patients with Inflammatory Bowel Disease Robert J. Gianotti, MD and Alan C. Moss, MD
Abstract: Clostridium difficile (CD) is an anaerobic, spore-forming bacillus that is responsible for a spectrum of gastrointestinal illness ranging from asymptomatic carriage to toxic megacolon and death. The prevalence of CD infection is increasing in both hospitalized and community-based inflammatory bowel disease populations. Standard antibiotic therapy fails to cure or prevent recurrence in more than 50% of patients, thus increasing the need for alternative therapies. Recently, fecal microbiota transplantation has received renewed attention as a therapy for refractory or recurrent CD infection. A high success rate combined with a favorable safety profile makes this therapy an attractive option for patients who have failed standard antibiotic therapy. Increasingly, this therapy is used in patients with CD infection and inflammatory bowel disease, as the combination of active inflammation and toxin-producing CD provides a challenging mix for clinicians. (Inflamm Bowel Dis 2016;22:2704–2710) Key Words: microbiology of IBD, basic science areas, fecal transplant in IBD, Clostridium difficile in IBD
THE PROBLEM OF CLOSTRIDIUM DIFFICILE IN INFLAMMATORY BOWEL DISEASE Clostridium difficile infection (CDI) has a significant impact on patients with inflammatory bowel disease (IBD). The majority of patients with IBD develop CDI in the outpatient setting.1 In a national survey of nearly 1000 patients with community-acquired CDI (no overnight hospital stay within 12 weeks of diagnosis), approximately 11% were known to have IBD, and 9% of all patients were receiving immunosuppression. Household contacts with CDI, PPI use, and exposure to young infants ,1 year were associated with an increased risk of community-acquired CDI.2 A 2011 systematic review of CDI and IBD revealed that CDI is more common in IBD, especially ulcerative colitis (UC). Additional risk factors for acquisition include the use of immunosuppresants and antibiotics, although the risk related to antibiotics was lower than in control cases. There are no controlled trials on the efficacy of antibiotics in treating CDI in patients with IBD.3 Over the past 2 decades CDI rates have been increasing in patients hospitalized with IBD,4 and patients with CDI-IBD appear to fare worse than their non-IBD counterparts.1,4–8 Several population-based studies suggest an increased mortality from CDI Received for publication August 9, 2016; Accepted August 24, 2016. From the Beth Israel Deaconess Medical Center, Harvard Medical School, Boston Massachusetts. The authors have no conflict of interest to disclose. Address correspondence to: Alan C. Moss, MD, 330 Brookline Avenue, Boston, MA 02215 (e-mail: [email protected]). Copyright © 2016 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000950 Published online 12 October 2016.
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in IBD patients. In IBD patients hospitalized for infection-related complications, CDI was found to be associated with excess inpatient mortality (odds ratio, 3.2, 95% confidence interval, 2.6–4.0).5 Odds of colectomy in CDI-IBD patients, particularly those with UC-CDI compared with UC or Crohn’s disease (CD) alone, increased significantly between the years 1998 and 2007.4 Ricciardi et al8 showed that the mortality risk from routine intestinal surgery in IBD increased from 2% to 18% with CDI and was nearly 26% in the UC-CDI subgroup. Risk factors for both colectomy and mortality include serum albumin ,3g/dL, hemoglobin ,9 g/dL, and serum creatinine .1.5 mg/dL in hospitalized patients with CDI-IBD.9 CDI is a major factor in relapsing diarrhea in patients with IBD formerly in clinical remission, found in 5% to 20% of patients.10,11 Risk factors for CDI in hospitalized IBD patients include an increased prevalence in those with UC, recent antibiotic use, proton pump inhibitors, and low albumin of ,3 g/dL. The use of immunosuppresants in IBD appears to increase the risk for CDI. A retrospective analysis of risk factors for the development of CDI-IBD showed that immunomodulator use, including 6-mercaptopurine, azathioprine, and methotrexate, may increase the risk of CDI (74% versus 56%; P ¼ 0.02), whereas biologics did not.1 In contrast, another single-center data reported that the risk of CDI was not influenced by immunosuppressant or anti–tumor necrosis factor (TNF) therapy, highlighting the need to avoid making generalizations about causality for immunosuppression and CDI based on nonrandomized, single-center data.12 One reason why patients with IBD may be at higher risk of CDI is genetics. In an exploratory analysis, Ananthakrishnan et al,13 identified 6 risk loci associated with increased rates of CDI in a cohort of UC patients and identified 2 loci that were Inflamm Bowel Dis Volume 22, Number 11, November 2016
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protective. Risk alleles defining pathways involving TNF and nuclear factor-kB may be associated with the increased risk for CDI. The relative risk for CDI was increased in female patients and those with pancolitis in this study. Interestingly, there was an increased exposure to biologic therapy in the patients free of CDI, suggested by the authors to be possibly related to increased rates of mucosal healing.13 IBD patients with ileal pouch anal anastomosis and ileostomy may also be at a risk for CDI. CDI may be found in up to 10% of patients with ileal pouch anal anastomosis and chronic diarrhea,14 and nearly 60% of these patients will have a recurrent CDI after an initial therapy with vancomycin. This high recurrence rate makes these patients likely to be referred for fecal microbiota transplantation (FMT). CDI has also been reported in patients with ileostomy, and infection may cause a sever enteritis. Colonic metaplasia and microbial population shifts may increase the risk of CDI in these patients.15
TREATMENT EFFICACY IN CDI AND IBD The mainstay of treatment for CDI is the antibiotics metronidazole and vancomycin. In general, metronidazole is reserved for the treatment of mild-to-moderate, uncomplicated disease. Guidelines from the American College of Gastroenterology suggest the following classification of disease severity16 (Table 1). Metronidazole therapy is recommended in mild-tomoderate disease, although many practitioners often start therapy in any hospitalized patient with vancomycin due to the relatively high rates of treatment failure (22%) and early recurrence (28%) with metronidazole.17 We do not routinely recommend the use of metronidazole in patients with IBD. Vancomycin therapy with 125 mg 4 times per day should be the initial therapy for all patients with severe disease. Dose escalation to 500 mg 4 times per day and the addition of intravenous metronidazole or vancomycin delivered through retention enema can be considered for severe and complicated cases.16,18 Treatment of recurrent CDI is
TABLE 1. Clostridium difficile Infection (CDI) Severity Severity Mild Moderate
Clinical and Laboratory Parameters
CDI + diarrhea CDI + diarrhea + additional symptoms not listed under severe disease Severe CDI + albumin ,3 g/dL and either WBC $15,000 cells/ mm3 or abdominal pain without complications Complicated CDI + admission to intensive care unit; hypotension; fever $38.58C; ileus; impaired mental status; WBC $35,000 or #2000 cells/mm3; lactate .2.2 mmol/L; end organ failure Recurrent CDI reoccurrence within 8 weeks of therapy WBC, white blood cell.
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often with a repeat course of the initial therapy, a prolonged vancomycin pulsed and taper19 or with fidaxomicin.20 There is a paucity of data looking at the treatment of CDI specifically in IBD populations because many studies exclude patients with IBD or immunosuppression (Table 2). The American College of Gastroenterology guidelines suggest a test-and-treat strategy for all hospitalized patients with IBD in a flare and outpatients with diarrhea previously in.16 Recurrence rates of CDI in adults are reported to range between 15% and 30%19 and are likely higher in patients with IBD with some centers reporting rates as high as 60%.39 A single-center pediatric cohort showed the rate of recurrence in IBD to be 34% versus 7.5% in non-IBD control subjects. More than 75% of the patients had CD, with a greater proportion of CDI patients having colonic involvement (95% versus 67%) as is often seen in pediatric populations.40 Many IBD patients will require combined immunosuppressant therapy to treat the underlying disease, in addition to antibiotic therapy against CDI. Corticosteroid treatment, which is often a mainstay of the initial management for severe UC, increases the risk for CDI approximately 3-fold16 and concomitant glucocorticoids with CDI approximately double the 30-day mortality.41 As mentioned previously, combined immunomodulators and antibiotics have a worse prognosis than antibiotics used alone in the management of IBD-CDI.42 A conditional recommendation in the American College of Gastroenterology practice guidelines support the ongoing use of immunosuppression in CDI but suggest holding dose escalation or addition of anti-TNF until therapy for CDI has been ongoing for up to 72 hours,16 although this is a conditional recommendation based on no quality evidence. In severe cases, early surgical evaluation is suggested. Unfortunately, many patients go on to relapse with multiple infections, requiring repeated courses of antibiotics. Patients with a first recurrence have high relapse rates ranging from 30% to 60%.39 Fecal microbiota therapy has emerged to fill an important role in the treatment of recurrent CDI.
FMT FOR RECURRENT CDI IN IBD FMT is the transfer of healthy donor stool for the purpose of reestablishing an appropriate balance of microbiota. Recently, FMT use has increased for the treatment of recurrent CDI, and there is a growing body of literature examining the effectiveness of FMT for the primary treatment of IBD. Disruptions of the endogenous flora, particularly a loss in diversity, plays a major role in gastrointestinal disease states, including CDI43 and IBD.44 FMT has been used for the treatment of human gastrointestinal disease for more than 1000 years.45 The first reported use in the treatment of pseudomembranous colitis caused by Staphylococcus was in 1958.46 FMT was first used for CDI in 1983 in a 65-year-old woman with recurrent CDI who was refractory to multiple course of vancomycin through fecal retention enema.47 Sporadic use of FMT persisted until recently when epidemic strains of CDI emerged with increasing rates of recurrence,48 in www.ibdjournal.org |
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TABLE 2. Efficacy of FMT in CDI with and Without IBD Author
Population
Result
17 patients with severe and or complicated CDI 146 patients .65 years old with recurrent, severe, or complicated CDI
94.1% overall cure, resolution of symptoms at 90 days 95.9% overall cure, primary resolution of symptoms without recurrence at 12 wk or after second FMT
Zainah et al23
14 hospitalized patients with severe CDI 13 through NGT
Kronman et al24
10 pediatric patients, $3 recurrences of CDI All by means of NGT 39 patients randomly assigned to FMT versus vancomycin pulse, $1 recurrence of CDI 20 patients with recurrent CDI treated with FMT capsules 10 pediatric patients with recurrent CDI treated with FMT by means of NGT (2) or colonoscopy (8)
79% cure (11/14), , 3 loose stools for 2 consecutive days without need for CDI therapy after day 7 90% cure (9 of 10), resolution of diarrhea
Aroniadis et al21 Agrawal et al22
Cammarota et al25 Youngster et al26 Russell et al27
Lee et al28
94 patients treated with retention enema for recurrent or refractory CDI
Kelly et al29
80 immunocompromised patients treated with FMT for recurrent, refractory, and/or severe CDI
Van Nood 201430
43 patients with recurrent CDI randomized to FMT by means of nasoduodenal route, vancomycin, or vancomycin + lavage 70 patients with recurrent CDI treated with FMT by means of colonoscopy
Mattila et al31 Kelly et al32
26 patients treated for recurrent CDI by means of colonoscopy
Kassam et al33
27 patients treated for recurrent CDI with retention enema 12 patients with recurrent CDI treated by means of colonoscopy 40 patients treated with FMT by means of either duodenal infusion or colonoscopy for recurrent CDI 19 patients treated with FMT by means of colonoscopy for recurrent CDI 15 patients treated with FMT by means of nasogastric tube for recurrent CDI 18 patients treated with FMT by means of nasogastric tube for recurrent CDI
Yoon et al34 Garborg et al35
Rohlke et al36 MacConnachie et al37 Aas et al38
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90% cure, resolution of diarrhea at 10 wk
Result of IBD No IBD patients reported 3 patients with CD 2 patients with UC Outcome not specifically reported No IBD patients reported
30% with IBD (3 of 10), all on either AZA, MTX, TNF or combo 100% cure (3 of 3), no complications No IBD patients reported
70% primary and 90% overall cure rate
No IBD patients reported
90% primary cure rate
3 patients with IBD 1 IBD unclassified—toxin free at 4 mo 1 CD—symptoms persisted, EIA toxin positive recurrence 8 wk after FMT 1 UC on adalimumab—resolution of CDI, colectomy for severe IBD 3 patients with IBD 100% cure
84% overall cure without recurrence at 6 mo treated with 4 or more enema FMT Overall cure rate of 89%, no infectious complications, 1 death related to procedural sedation before FMT
Overall cure 94%
100% of non-O27 strains cured at 12 wk 89% of O27 strains cured at 12 wk 92% cured without symptoms at a mean of 12 mo 93% with clinical resolution of symptoms 100% with a durable clinical response Overall, 83% with clinical resolution of symptoms at 80 days after FMT Overall, 95% cure with a single FMT 73% of patients had resolution of symptoms with a single treatment 94% of patients had resolution of symptoms
36 patients with IBD on immunosuppressants Overall cure 94% 3 of 36 experienced IBD flare following FMT No IBD patients reported
No IBD detected by colonoscopy 2 patients with evidence of chronic colitis on colonoscopy, 100% response to FMT No IBD patients reported 1 patient with IBD excluded 2 of 7 nonresponders were diagnosed with “immunologic colitis” and were successfully treated with steroids No IBD patients reported No IBD reported No IBD reported
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particular, the BI/NAP-1 strain with increased levels of toxin production, fluoroquinolone resistance, and higher associated mortality.49,50
EFFICACY IN PATIENTS WITH CDI ALONE A recent randomized trial of FMT30 by means of nasoduodenal infusion of donor feces following a lead in with oral vancomycin compared with vancomycin with and without bowel lavage demonstrated significantly higher rates of resolution of CDI-related diarrhea (81.3% versus 30.8%; P ¼ 0.008) (Table 2). Cure rates without relapse increased to 93.8% after 3 patients were re-treated with FMT.30 In a multicenter follow-up study of elderly patients, FMT was both safe and effective in recurrent, severe, and complicated CDI. The primary and secondary cure rates were 82.9% and 95.9%, respectively.51 The mean age was 70.6 years, and 5 of 146 patients included in the study had a preexisting diagnosis of IBD; there were no serious adverse events in these patients. FMT is safe and effective in patients with severe or complicated CDI. A recent cohort of 17 patients with severe or complicated disease treated with FMT showed primary and secondary cure rates of 88.2% and 94.1%, respectively. There were no reported adverse events related to FMT.52 In a recent, small, open-label, randomized study of FMT given by colonoscopy compared with vancomycin therapy, FMT was superior, with overall cure rates of 90% and 25%, respectively. The study was stopped at 1 year because preliminary analysis demonstrated the clear superiority of FMT. Interestingly, 7 of the 20 patients who received FMT required multiple infusions as a result of the presence of pseudomembranous colitis. Adverse events in FMT included postprocedure diarrhea, bloating, and cramping, which resolved within 24 hours. The authors excluded patients with prolonged use of steroids, and it was not reported if any of the patients had concomitant IBD.25
EFFICACY IN PATIENTS WITH IBD AND CDI The largest cohort to report on patients with IBD receiving FMT for recurrent or refractory CDI was by Kelly et al29 in 2014 (Table 2). This retrospective descriptive study was of 80 patients classified as immunocompromised for various reasons, including HIV/AIDS, malignancy, solid organ transplant, and IBD (n ¼ 36). The overall cure rate for FMT was 89%. Of those patients, 30 patients were receiving steroids, 19 patients were receiving immunomodulators (azathioprine, 6-mercaptopurine, methotrexate), 16 were on anti-TNF therapy (infliximab, adalimumab, certolizumab), and 2 were receiving an alpha-4 integrin inhibitor. The overall cure rate in IBD was 94% with 86% cure after a single FMT. Four IBD patients were hospitalized for IBD flare within 12 weeks of FMT; this was classified as possibly related to the FMT. Three of these patients required steroids, and 1 underwent colectomy within 1 month of FMT. Three patients underwent colectomy within 100 days of FMT, but none were directly attributed to CDI or complications of FMT.
Use and Efficacy of Fecal Microbiota
Importantly, the rate of SAE and AE were not significantly different for patient with immunocompromise related to IBD versus non-IBD (14% versus 16% for AE; P # 0.3224).29 The one death that was related to FMT occurred as a result of aspiration during sedation for the second FMT by means of colonoscopy; this was a solid organ transplant patient with advanced esophageal cancer. The authors were unable to conclude whether FMT was the exacerbating factor in the patients who received FMT. Unfortunately, data were not collected on the natural history of IBD or endoscopic severity. The authors point out that it is difficult to clearly separate diarrhea related to CDI and that associated with underlying mucosal inflammation. A cohort of 10 pediatric patients who received FMT by means of nasointestinal tube for recurrent CDI (defined as 3 or more recurrences) demonstrated a 90% cure rate with a single FMT and 100% following a second infusion in a single patient; 30% of the patients had comorbid IBD on immunomodulators or anti-TNF therapy. All IBD patients had a resolution of symptoms with a single FMT.24 An associated editorial cautions the use of adult donors for pediatric patients with unknown effects on host-immune interactions and the possibility of accelerated “immune aging.”53 Another single-center study of 10 pediatric IBD patients included 3 with IBD. All 3 patients required additional immunosuppression after FMT and 1 patient required colectomy. Two of 3 patients progressed, despite negative stool toxin by EIA after FMT.27 A single-center study of 94 patients treated with FMT by means of enema demonstrated an overall cure rate of 86.2%, with a small subset of patients requiring 4 or more FMT treatments. Three IBD patients were included in this cohort, and all were cured of CDI without reference to disease severity, immunosuppression regimen, or the number of FMTs required.28 A recent report by Youngster et al26 demonstrated effectiveness of a frozen, encapsulated form of FMT for treating recurrent CDI. Overall, 18 of 20 patients (90%) met the primary endpoint of diarrhea resolution by 8 weeks. Two patients with IBD were included in this study, one of whom was a pediatric patient on low-dose steroid therapy who required a repeat capsule FMT for symptom resolution. The other patient was an adult with IBD on no immunosuppression who has a prompt clinical response to a single capsule FMT.26
FECAL MICROBIOTA THERAPY IN IBD WITHOUT CDI Recent research has started to explore the question of whether FMT is useful as a primary therapy for IBD without CDI. Two randomized controlled trials of FMT in patients with active UC were published for the first time in 2015. Rossen et al54 studied 50 patients in a double-blind, randomized trial of FMT by means of nasoduodenal tube (TURN: Transplantation of Feces in Ulcerative Colitis; Returning Nature’s Homeostasis). The placebo arm was an infusion of autologous stool. The www.ibdjournal.org |
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patients received an infusion at study entry and at week 3. The primary endpoint was a composite of clinical remission defined as simple colitis activity index #2 and a $1-point decrease in the Mayo endoscopic score. There was no significant difference in the primary endpoint between patients who received donor stool or autologous stool (30.4% versus 20%, ITT; P ¼ 0.51). There were no major adverse events related to FMT, although 1 patient was found to have small bowel CD and was admitted with a small bowel perforation 5 weeks after FMT. Additional reported AEs included increased stools frequency and increased bowel sounds. There were no infectious complications, although 2 patients in the donor group had a transient fever.54 This study also included an analysis of the microbial populations of patients and donors. UC patients had decreased abundance of Clostridium cluster IV, XIVa, and XVIII and higher abundance in Bacteroidetes, Bacilli, Proteobacteria, and Clostridium clusters IX and XI when compared with donors.54 Diversity was significantly increased at week 12 in responders of both groups when compared with nonresponders, and responders in the donor group were more likely to have a similar microbiota to their donor at week 12. In the second trial, Moayyedi et al55 compared the efficacy of 6-weekly fecal enema to placebo enema in a group of 75 patients with moderately active UC. The primary endpoint was remission based on clinical Mayo score ,3 and endoscopic Mayo score ¼ 0. This study highlighted the important and unique finding of a “super donor.” The responders in this trial were more likely to have received stool from a specific donor B than other donors (39% versus 10%; P ¼ 0.06); in fact, the DSMB stopped the trial early for futility but allowed enrolled patients to complete the trial, and at that time, donor B came back into the pool and the remaining patients all received stool from this “super donor.”55 FMT is still in its early stages. The procedure can be cumbersome for patients and donors requiring demanding screening, bowel preparation and associated procedural risks, and the inherent distasteful nature of stool transfer. A goal of therapy will be the eventual replacement of whole donor stool transfer by an orally available pill composed of specific bacterial populations. One area of active research is the use of nontoxigenic strains of CD to prevent recurrence. One recent safety study evaluated the use of CD strain M3. There were no significant differences in adverse events between patients receiving spores versus placebo. In fact, the rate of recurrence for CDI in patients receiving the highest dose (107 spores) was 5% compared with 30% in the placebo group.56 These strainspecific therapies will likely become a mainstay of treatment in the coming years. Our current method for treating recurrent CDI with and without IBD is the same. We counsel patients about the risk of flare to underlying IBD, but this risk has not been confirmed in population-based studies. Our recent study evaluating the safety of FMT in active CD57 did not show an increased risk of disease flare after a standard colonoscopic delivery of FMT. Our own
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institutional experience with FMT for CDI does not show an increased risk of flare in patients with concomitant IBD.
REGULATORY STATUS OF FMT IN IBD PATIENTS The growing popularity of stool banking has gained attention with practitioners and the Food and Drug Administration (FDA) alike. Currently, the most recent iteration of the FDA draft guidance (March 2016) proposes to enact enforcement discretion and not require clinicians to submit an investigational new drug (IND) application to use FMT material for recurrent CDI. The IND is a time- and resource-intensive FDA application for the study of new drugs that is cumbersome for individual clinicians to apply with limited time. The current guidance states that the donor must be known and screened by the clinician. The enforcement discretion will not extend to stool banking citing safety concerns of centralized processing, transmission of infectious agents, and other potential unidentified risks. Stool banks would need to submit an IND. Fortunately, it appears that in the current form, clinicians receiving stool material from a bank with an IND would be exempt from IND obligations. All other uses of FMT, including as primary therapy for IBD, continue to require investigators to submit an IND. Our current methods employ the use of the Openbiome, a nonprofit stool bank in the greater Boston area. The rigorous testing standards increase the safety profile of the donor samples, streamline the process for both patients and practitioners, and overall reduce costs associated with screening and testing potential donors. Samples arrive and are stored at 2208C until the procedure. We use 250-mL aliquots delivered after thawing in 1 bolus to the cecum during a prepped colonoscopy. In certain patients at the risk for enhanced intestinal transit and rapid expulsion of the FMT, we use loperamide before and after the procedure to slow motility, and we use smaller aliquots of stool available in 50 mL. The use of stool bank samples saves valuable time and screening costs, and we can often accommodate patients using banked material within hours to days as opposed to the extended period required to find and screen a suitable donor.
CONCLUSIONS Overall, FMT for CDI in patients with IBD appears to be safe and effective at preventing recurrent infection. Despite the excellent efficacy and safety, many questions remain unanswered. What particular species are required for successful FMT and what proportion of the transplanted organisms persist in recipients? What role do metabolic products of the transplanted organisms play in C. difficile eradication? We also question whether IBD patients with C. difficile colonization should receive prophylactic FMT or cholestyramine to prevent symptoms. Future directions include narrowing the spectrum of organisms needed to achieve eradication, an oral delivery system, and explorations of methods to prevent CDI in our high-risk IBD patients.
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Inflamm Bowel Dis Volume 22, Number 11, November 2016
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