Curr Gastroenterol Rep (2014) 16:393 DOI 10.1007/s11894-014-0393-1
INFLAMMATORY BOWEL DISEASE (S HANAUER, SECTION EDITOR)
Managing Clostridium difficile in Inflammatory Bowel Disease (IBD) Jana G. Hashash & David G. Binion
# Springer Science+Business Media New York 2014
Abstract Clostridium difficile (C. difficile) infection has emerged as a significant clinical challenge for patients suffering from inflammatory bowel disease (IBD). C. difficile can both precipitate and worsen flares of IBD, contributing to emergent colectomies and mortality. Advances in the management of C. difficile infection in IBD include recommendations for testing for this infection in the setting of clinical flare and hospitalization, improved diagnostic testing, identification of high rates of carriage and infection in pediatric IBD, and new data associating patterns of IBD genetic risk alleles with the development of this infection. Therapeutically, oral vancomycin has emerged as a superior treatment for IBD patients with moderate to severe disease compared with metronidazole. Although highly effective in the general population, fecal microbiome transplantation for recurrent C. difficile infection in IBD patients has been associated with colitis flare in the majority of patients who have received this treatment. Keywords C. difficile infection . Inflammatory bowel disease . IBD . Metronidazole . Vancomycin . Fecal microbiome transplant
Introduction Clostridium difficile (C. difficile), a spore forming gram positive anaerobic bacillus, has emerged as the major nosocomial infection complicating hospitalized patients in the USA, with This article is part of the Topical Collection on Inflammatory Bowel Disease J. G. Hashash : D. G. Binion (*) Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, Mezzanine Level C Wing PUH, Pittsburgh, PA 15213, USA e-mail: [email protected]
a spectrum of illness ranging from loose bowel movements and mild diarrhea to fulminant colitis, sepsis, and death. At the present time in the USA, mortality associated with C. difficile infection outnumbers deaths attributed to the human immunodeficiency virus. Following its initial association with human disease in the late 1970s and early 1980s, subgroups of patients who appeared to be highly susceptible to C. difficile infection were identified. These high-risk groups included solid organ transplant recipients, oncology patients in the midst of chemotherapy, and the elderly, including residents of long-term care facilities and nursing homes. The rise in C. difficile associated morbidity and mortality has been attributed to a more than doubling of cases in the USA as well as the emergence of the BI/NAP1 epidemic strain of C. difficile, which produces excess toxin B, directly contributing to tissue injury and clinical severity [1]. Although initial reports did not find an association between C. difficile infection and patients suffering from inflammatory bowel disease (IBD), studies from Milwaukee, Wisconsin and St. Louis, Missouri published in 2007 demonstrated that IBD patients were at a higher risk for contracting this infection [2, 3]. Confirmatory studies using the Nationwide Inpatient Sample demonstrated that there was a dramatic rise in C. difficile infections amongst IBD patients with a subsequent increase in morbidity and mortality [4]. IBD patients have now been recognized as a subgroup of patients who are high risk for contracting this infection, with serious clinical consequences (Table 1). The two major forms of IBD, Crohn’s disease and ulcerative colitis, are lifelong chronic inflammatory disorders of the gastrointestinal tract. IBD is felt to result from an inappropriate immune reaction to commensal bacteria in genetically susceptible individuals. At present, IBD is an incurable illness lacking definitive treatment, and medical therapy has relied on chronic immunosuppression to decrease the inflammatory response in individuals and maintain clinical remission. Flares
393, Page 2 of 6 Table 1 Predictors, diagnosis, and treatment of C. difficile Predictors of C. difficile Recent antibiotic exposure Recent hospitalization Immunosuppressed state (IBD, solid organ transplant recipient, and chemotherapy) Elderly patients Residents of nursing homes and long-term facilities Diagnosis of C. difficile Enzyme-linked immunosorbent assays (ELISA) Polymerase chain reaction (PCR) Treatment of C. difficile Oral metronidazole Oral vancomycin Oral vancomycin and intravenous metronidazole Surgical resection Fecal microbiome transplant (for recurrent disease)
Curr Gastroenterol Rep (2014) 16:393
The impact of C. difficile on hospital admissions for IBD patients was characterized by Nguyen and colleagues in Ontario, Canada, where they found that 9 % of ulcerative colitis patients admitted to the hospital were found to have a concomitant C. difficile infection during that hospital stay. More importantly, these authors found that C. difficile infection significantly increased short- and long-term mortality (5 years after infection) in their regional cohort of patients. Colectomy risk was increased during the index hospitalization but not during the 5-year follow-up suggesting that other mechanisms were contributing to the increased mortality [7•]. Authors from the Netherlands attempted to quantify the impact of C. difficile on rates of hospitalization for IBD patients. In contrast to the majority of the studies, these authors did not find that C. difficile was contributing to a significant percentage of IBD flares leading to hospitalization [8]. Pediatric IBD and C. difficile
of IBD, particularly colitis, have been treated with bursts of steroid therapy. Thus, the cornerstones of IBD treatment are agents which may both increase the risk of developing C. difficile infection and worsen its clinical course. The overlap in symptoms between both IBD flare and C. difficile infection has likely played a role in the severity of this infection, as identifying the infection in the setting of a patient who is experiencing a synergistic disease flare is critical for achieving optimal outcomes. There has been a substantial progress in our understanding of C. difficile infection, particularly in the clinical course of IBD. This review will specifically focus on four areas: (1) further defining IBD patients at risk for infection, clinical factors associated with severe infection, and new data associating genetic markers with developing of C. difficile infection in IBD; (2) progress in C. difficile diagnostics; (3) advances in initial antibiotic treatment options for IBD patients with C. difficile infection; and (4) the use of fecal microbiome transplant for IBD patients who are suffering from recurrent C. difficile infection.
Burden of C. difficile in IBD Worldwide Increase in C. difficile Infections in IBD Patients The rise in C. difficile infections seen in North American centers during the 2000–2010 time period has been paralleled by a rising incidence in European and Asian centers [5]. Reports from the European Crohn’s and Colitis Organization (i.e., Belgium, France, Israel, and the United Kingdom) have documented increased overlap between C. difficile infections and patients with IBD [6].
The rise in C. difficile infections in IBD patients, originally identified in adult patients, has recently been described in the pediatric IBD patient population. New evidence has confirmed that pediatric populations are at risk for C. difficile infection. Hourigan and colleagues prospectively evaluated 85 pediatric IBD patients and 78 controls, finding C. difficile carriage in 17 % of the IBD patients and 3 % of controls (p=0.012) [9]. The prevalence of C. difficile in pediatric IBD at the time of diagnosis was assessed by Mir and Kellermeyer. These authors found that 8.1 % of their pediatric IBD patients at diagnosis had C. difficile infection, which was significantly higher than the rate of C. difficile infection in the general population [10•]. Predicting Severe C. difficile Infection in IBD Patients There have been studies on the effect of IBD therapy on the risk of developing C. difficile and its clinical course. Corticosteroids, immunomodulators (i.e., azathioprine, six mercaptopurine, and methotrexate), and anti-tumor necrosis factor drugs suppress the immune system, placing IBD patients at a higher risk for opportunistic infections [11]. The natural history of contracting C. difficile infection appears to be correlated with the use of corticosteroid compounds. Work from Schneeweiss, using a British Columbia provincial healthcare database, demonstrated a threefold increased risk of developing a C. difficile infection in individuals who were exposed to any amount and any duration of corticosteroid therapy [12•]. From the Nationwide Inpatient Sample, Ananthakrishnan and McGinley showed that 27.5 % of IBD hospitalizations were related to infections [13]. These infectionrelated hospitalizations demonstrated a fourfold increase
Curr Gastroenterol Rep (2014) 16:393
in mortality compared to the IBD hospitalizations which were not associated with infection. Amongst all of the infections which were assessed, pneumonia, sepsis, and C. difficile were associated with the greatest excess mortality risk. Antibiotic exposure is the classic risk factor for developing C. difficile infection, and antibiotic treatment has been a routine component of IBD therapy, particularly patients with J-pouch ileoanal reconstruction. Although ulcerative colitis patients who have undergone colectomy are no longer at risk for C. difficile colitis, infection of the reconstructed ileal pouch which functions as a “neo-colon” is now well recognized. Inflammation of the ileoanal pouch is mechanistically felt to originate from the high bacterial concentrations in the ileal mucosa, and treatment of pouchitis has relied on either episodic or chronic antibiotic therapy. C. difficile infection of the ileal pouch is now well recognized, and physicians should be suspicious of this in patients with increased stool frequency, recent hospitalization, or those who develop weight loss [14]. IBD Genetic Loci are Associated with Development of C. difficile Infection There has been substantial success in efforts to define the genetic loci which are linked to the pathogenesis of IBD, with the identification of 163 genetic risk loci [15]. New investigation is attempting to translate these genetic discoveries into the clinic, to specifically determine whether specific patterns of genetic mutations will predispose individuals to develop infection with C. difficile. Ananthakrishnan and colleagues were able to model patterns of genetic risk in a prospective cohort of 319 wellcharacterized ulcerative colitis patients, of who 29 developed a C. difficile infection (9 %) [16•]. These authors found that female gender and pancolitis were risk factors, and the use of anti-tumor necrosis factor medications was protective against C. difficile infection. Six genetic polymorphisms including the TNFRSF14 were associated with increased C. difficile infection risk, and two loci were protective. This study showed that clusters of IBD risk alleles were associated with higher rates of developing C. difficile infection. Presence of at least one high-risk locus in an IBD patient was associated with an increase in risk for C. difficile infection (20 vs. 1 %). The precise biologic explanation for this genetic association with C. difficile infection has yet to be elucidated.
Diagnostic Strategies—C. difficile and IBD Over the past 5 years, there has been an evolution in clinical tests for diagnosing C. difficile infection, where
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polymerase chain reaction (PCR)-based molecular approaches has replaced enzyme linked immunosorbent assays (i.e., ELISA). PCR-based techniques for C. difficile detection in stool specimens are more sensitive, with reported diagnostic accuracy in excess of 80 %. In two reviews from the Cleveland clinic, investigators compared the diagnostic accuracy of ELISA and PCR-based strategies in hospitalized patients from 2006–2011 to 2009– 2011 [17, 18]. In the study by Wang and colleagues, 5.9 % of 222 IBD patients tested by ELISA were positive compared with 13.5 % of 103 IBD patients tested by PCR [18]. There was no significant difference in clinical outcomes between these two groups. Recommendations for a single stool specimen being sufficient to diagnose C. difficile infection in IBD patients were formally evaluated in a study by Deshpande and colleagues [17]. Performing a second ELISA test in the IBD patients increased diagnostic yield and appeared to be an important improvement in care [17]. As the PCR-based approaches for diagnosing C. difficile infection have become the dominant strategy in the USA, additional insight into the limitations of this approach has been investigated. Specifically, the impact of treatment on the sensitivity and performance characteristics of the PCR diagnostic test was formally evaluated in a prospective study by Sunkesula and colleagues [19•]. Although this was not specifically carried out in the IBD patient population, these authors followed a series of patients diagnosed with C. difficile infection undergoing treatment to determine the performance characteristics of stool C. difficile PCR testing on each day that the patients were receiving antibiotic therapy [19•]. Initiation of antibiotic therapy with oral vancomycin, metronidazole, or both agents resulted in a rapid decrease in the diagnostic accuracy of the C. difficile PCR testing, where half of the tests became negative by 3 days of therapy and all tests became negative by 5 days of therapy. This paper highlights an important concept, which is the initiation of medical therapy, either in the setting of a confirmed infection or empiric therapy for a suspected infection, will effectively negate the diagnostic accuracy of stool testing after 3–5 days of C. difficile antibiotic treatment. This implies no role to document clearance of C. difficile at the completion of treatment, as the PCR assays will routinely become negative. Furthermore, the rapid decline in diagnostic accuracy of the C. difficile PCR testing within 3 days of treatment implies that initiation of empiric therapy should be followed by the full therapeutic course (10–14 days) in responding patients as subsequent stool analysis in the midst of treatment is no longer helpful. Given that the criteria for C. difficile treatment are a high clinical index of suspicion and not a positive stool assay, the paper by Sunkesula reinforces the need to commit to therapy for a full therapeutic course in patients who are felt to be clinically at risk.
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Treatment of C. difficile in IBD—Antibiotic Therapy The American College of Gastroenterology (ACG) guidelines for the diagnosis, management, and prevention of C. difficile infection were published in early 2013, and this document provided a new emphasis on detecting and treating C. difficile infection in high-risk populations, specifically IBD [20]. The ACG guidelines specifically included five scenarios involving IBD patients: (1) All patients with IBD hospitalized with a disease flare should undergo testing for C. difficile infection (strong recommendation and high-quality evidence). (2) Ambulatory patients with IBD who develop diarrhea in the setting of previously quiescent disease or in the presence of risk factors such as recent hospitalization or antibiotic use should be tested for C. difficile infection (strong recommendation and moderate-quality evidence). (3) In patients who have IBD with severe colitis, simultaneous initiation of empiric therapy directed against C. difficile infection, and treatment of an IBD flare may be required while awaiting results of C. difficile testing (conditional recommendation and low-quality evidence). (4) In patients with IBD, ongoing immunosuppression medications can be maintained in patients with C. difficile infection. Escalation of immunosuppression medications should be avoided in the setting of untreated C. difficile infection (conditional recommendation and low-quality evidence). (5) Patients with IBD who have a surgically created pouch after colectomy may develop C. difficile infection and should be tested if they have symptoms (strong recommendation and moderate-quality evidence). The ACG guidelines also provided a novel structure for categorizing disease severity during C. difficile infection and matching this parameter with medical and surgical treatment options [20]. The ACG guidelines provided a working definition for the severity of infection, mild to moderate, severe, and severe complicated, which can be extrapolated to the IBD patient population [21•]. Mild to moderate patients warrant initial therapy with metronidazole. Severe patients should receive treatment with oral vancomycin. Severe complicated patients (i.e., hospitalized individuals) should be treated with oral vancomycin in combination with intravenous metronidazole and surgical consultation should be obtained. In the setting of recurrent C. difficile infection, prolonged therapy (multiple weeks/months) with oral vancomycin 125 mg orally four times daily is the preferred approach, given the cumulative toxicity associated with metronidazole. This is an important consideration, as clinical recurrence is identified in one quarter of C. difficile infections in the general population and up to 39 % of IBD patients [22]. The ACG guidelines recognized that fidaxomicin, a new macrocyclic antibiotic agent approved by the FDA in 2011 for the treatment of C. difficile infection, is an additional therapeutic modality which can be considered. Fidaxomicin has similar efficacy and toxicity with oral vancomycin, but may
Curr Gastroenterol Rep (2014) 16:393
offer the benefit of reduced C. difficile recurrence within 4 weeks of the initial treatment course (clinical recurrence seen in 25.3 % of vancomycin treated and 15.4 % of fidaxomicin treated subjects). However, the high cost of this agent has frequently relegated its use in patients who have experienced recurrent disease after initial treatment with less costly agents (i.e., metronidazole and oral vancomycin). Thus, fidaxomicin is often being used in patients with recurrent C. difficile infection, which is a more challenging clinical problem, and a clinical application which was not addressed in the pivotal trials. Information regarding the use of fidaxomicin in IBD is extremely limited at this time, as an IBD diagnosis was an exclusion criteria for participation in the registry trials.
Treatment—Fecal Microbiome Transplant (FMT) Recurrence of infection with C. difficile is a significant problem as approximately one quarter of patients initially treated with metronidazole or oral vancomycin will experience clinical relapse within the next 1–3 months. As mentioned previously, this may be improved with the initial use of fidaxomicin, but was not specifically investigated in the IBD patient population [23•]. The ACG guidelines for C. difficile treatment recommend consideration of FMT after the second documented recurrence. This data were based on success of the approach in a randomized trial using universal donors and duodenal infusion [24•]. This study by van Nood and colleagues in Amsterdam did not specifically include patients with IBD. Specific data regarding the performance of FMT for the treatment of recurrent C. difficile infection in the IBD patient population is emerging with both success and what may be FMT-related disease flare [25]. Although success rates of C. difficile infection treatment with FMT are promising, caution should be used in IBD patients as there has been a report of transient flare ups of disease activity after FMT [26•]. Enthusiasm for the use of FMT in IBD patients for the specific treatment of C. difficile infection should also be tempered by the fact that pilot studies investigating the safety and efficacy of FMT in patients with Crohn’s disease and ulcerative colitis as a primary form of therapy were complicated by transient deterioration in the majority of the subjects [27, 28]. Compliance with Ethics Guidelines Conflict of Interest nothing to disclose.
Jana G. Hashash and David G. Binion have
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Curr Gastroenterol Rep (2014) 16:393
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References
14.
Papers of particular interest, published recently, have been highlighted as
15.
• Of importance
1.
2.
3.
4.
5. 6.
7.•
8.
9.
10.•
11.
12.•
13.
Kelly CP, LaMont JT. Clostridium difficile—more difficult than ever. N Engl J Med. 2008;359(18):1932–40. Erratum in: N Engl J Med. 2010 Oct 14;363(16):1585. Rodemann JF, Dubberke ER, Reske KA, da Seo H, Stone CD. Incidence of Clostridium difficile infection in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5(3):339–44. Issa M, Vijayapal A, Graham MB, Beaulieu DB, Otterson MF, Lundeen S, et al. Impact of Clostridium difficile on inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5(3): 345–51. Ananthakrishnan AN, McGinley EL, Binion DG. Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease. Gut. 2008;57(2): 205–10. Burke KE, Lamont JT. Clostridium difficile inection: a worldwide disease. Gut Liver. 2014;8(1):1–6. Jen MH, Saxena S, Bottle A, Aylin P, Pollok RC. Increased health burden associated with Clostridium difficile diarrhoea in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2011;33(12):1322–31. Murthy SK, Steinhart AH, Tinmouth J, Austin PC, Daneman N, Nguyen GC. Impact of Clostridium difficile colitis on 5-year health outcomes in patients with ulcerative colitis. Aliment Pharmacol Ther. 2012;36(11–12):1032–9. Approximately 9% of hospitalized ulcerative colitis patients have C. difficile infection in this study from Ontario, Canada. Masclee GM, Penders J, Jonkers DM, Wolffs PF, Pierik MJ. Is Clostridium difficile associated with relapse of inflammatory bowel disease? Results from a retrospective and prospective cohort study in the Netherlands. Inflamm Bowel Dis. 2013;19(10):2125–31. Hourigan SK, Chirumamilla SR, Ross T, Golub JE, Rabizadeh S, Saeed SA, et al. Clostridium difficile carriage and serum antitoxin responses in children with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(13):2744–52. Mir SA, Kellermayer R. Clostridium difficile infection in newly diagnosed pediatric inflammatory bowel disease in the midsouthern United States. J Pediatr Gastroenterol Nutr. 2013;57(4): 487–8. Approximately 8% of newly diagnosed pediatric IBD patients have C . difficile infection, which supports the practice of testing of all newly diagnosed IBD patients. Dave M, Purohit T, Razonable R, Loftus Jr EV. Opportunistic infections due to inflammatory bowel disease therapy. Inflamm Bowel Dis. 2014;20(1):196–212. Schneeweiss S, Korzenik J, Solomon DH, Canning C, Lee J, Bressler B. Infliximab and other immunomodulating drugs in patients with inflammatory bowel disease and the risk of serious bacterial infections. Aliment Pharmacol Ther. 2009;30(3):253–64. Corticosteroid exposure tripled risk of IBD patients developing C. difficile infection in this study from British Columbia, Canada. AntiTNF agents were not associated with developoing C. difficile in IBD. Ananthakrishnan AN, McGinley EL. Infection-related hospitalizations are associated with increased mortality in patients with inflammatory bowel diseases. J Crohn’s Colitis. 2013;7(2):107–12.
16.•
17.
18.
19.•
20.
21.•
22.
23.•
24.•
Li Y, Qian J, Queener E, Shen B. Risk factors and outcome of PCRdetected Clostridium difficile infection in ileal pouch patients. Inflamm Bowel Dis. 2013;19(2):397–403. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422): 119–24. Ananthakrishnan AN, Oxford EC, Nguyen DD, Sauk J, Yajnik V, Xavier RJ. Genetic risk factors for Clostridium difficile infection in ulcerative colitis. Aliment Pharmacol Ther. 2013;38(5):522–30. Female gender, pancolitis, and anti-TNF therapy were protective against developing C. difficile infection in this analysis of a small number of ulcerative colitis patients. Increasing number of IBD risk alleles were associated with increased risk of developing C. difficile infection in ulcerative colitis. Deshpande A, Pasupuleti V, Patel P, Pant C, Pagadala M, Hall G, et al. Repeat stool testing for Clostridium difficile using enzyme immunoassay in patients with inflammatory bowel disease increases diagnostic yield. Curr Med Res Opin. 2012;28(9):1553–60. Wang Y, Atreja A, Wu X, Lashner BA, Brzezinski A, Shen B. Similar outcomes of IBD in patients with Clostridium difficile infection detected by ELISA or PCR assay. Dig Dis Sci. 2013;58(8):2308–13. Sunkesula VC, Kundrapu S, Muganda C, Sethi AK, Donskey CJ. Does empirical Clostridium difficile infection (CDI) therapy result in false-negative CDI diagnostic test results? Clin Infect Dis. 2013;57(4):494–500. Analysis of the performance characteristics of stool PCR testing for C. difficile following initiation of antibiotic therapy against the infection in patients with documented disease. PCR tests turned negative at a rapid rate, with 50% of patients testing negative 3 days into therapy and essentially all patients becoming negative 5 days into treatment. This study demonstrates no role for repeat stool testing as the PCR assay will turn negative prior to completing a therapeutic course of antibiotic therapy for C. difficile infection. It also highlights the importance of completing an empiric course of therapy once initiated, as testing is no longer accurate 3–5 days into treatment. Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108(4):478–98. quiz 499. Review. Ananthakrishnan AN, Guzman-Perez R, Gainer V, Cai T, Churchill S, Kohane I, et al. Predictors of severe outcomes associated with Clostridium difficile infection in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2012;35(7):789–95. Observational clinical trial demonstrating clinical factors which correlate with poor outcome in IBD patients suffering from C. difficile infection. Libot A, Issa M, Zadvornova Y, Stein DJ, Venu N, Perera LP, et al. Initial vancomycin monotherapy is associated with higher rates of subsequent Clostridium difficile infection in inflammatory bowel disease population. Gastroenterology. 2011;140:S-159. abstract #992. Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5): 422–31. Pivotal trial demonstrating safety and efficacy of fidaxomicin in the treatment of initial C. difficile infection and potential superiority with reduction in short term recurrence. IBD patients were excluded from this trial. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–15. Pivotal trial establishing the efficacy and superiority of FMT in the treatment of recurrent C. difficile infection.
393, Page 6 of 6 25.
Anderson JL, Edney RJ, Whelan K. Systematic review: Faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther. 2012;36(6):503–16. 26.• De Leon LM, Watson JB, Kelly CR. Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol. 2013;11(8):1036–8. First publication demonstrating problems of FMT for treatment of recurrent C difficile infection in IBD.
Curr Gastroenterol Rep (2014) 16:393 27.
28.
Vermeire S, Joossens M, Verbeke K, et al. Pilot study on the safety and effi cacy of faecal microbiota transplantation in refractory Crohn’s disease. Gastroenterology. 2012;142:S360. Angelberger S, Reinisch W, Makristathis A, Lichtenberger C, Dejaco C, Papay P, et al. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. Am J Gastroenterol. 2013;108(10): 1620–30.
INFLAMMATORY BOWEL DISEASE (S HANAUER, SECTION EDITOR)
Managing Clostridium difficile in Inflammatory Bowel Disease (IBD) Jana G. Hashash & David G. Binion
# Springer Science+Business Media New York 2014
Abstract Clostridium difficile (C. difficile) infection has emerged as a significant clinical challenge for patients suffering from inflammatory bowel disease (IBD). C. difficile can both precipitate and worsen flares of IBD, contributing to emergent colectomies and mortality. Advances in the management of C. difficile infection in IBD include recommendations for testing for this infection in the setting of clinical flare and hospitalization, improved diagnostic testing, identification of high rates of carriage and infection in pediatric IBD, and new data associating patterns of IBD genetic risk alleles with the development of this infection. Therapeutically, oral vancomycin has emerged as a superior treatment for IBD patients with moderate to severe disease compared with metronidazole. Although highly effective in the general population, fecal microbiome transplantation for recurrent C. difficile infection in IBD patients has been associated with colitis flare in the majority of patients who have received this treatment. Keywords C. difficile infection . Inflammatory bowel disease . IBD . Metronidazole . Vancomycin . Fecal microbiome transplant
Introduction Clostridium difficile (C. difficile), a spore forming gram positive anaerobic bacillus, has emerged as the major nosocomial infection complicating hospitalized patients in the USA, with This article is part of the Topical Collection on Inflammatory Bowel Disease J. G. Hashash : D. G. Binion (*) Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, Mezzanine Level C Wing PUH, Pittsburgh, PA 15213, USA e-mail: [email protected]
a spectrum of illness ranging from loose bowel movements and mild diarrhea to fulminant colitis, sepsis, and death. At the present time in the USA, mortality associated with C. difficile infection outnumbers deaths attributed to the human immunodeficiency virus. Following its initial association with human disease in the late 1970s and early 1980s, subgroups of patients who appeared to be highly susceptible to C. difficile infection were identified. These high-risk groups included solid organ transplant recipients, oncology patients in the midst of chemotherapy, and the elderly, including residents of long-term care facilities and nursing homes. The rise in C. difficile associated morbidity and mortality has been attributed to a more than doubling of cases in the USA as well as the emergence of the BI/NAP1 epidemic strain of C. difficile, which produces excess toxin B, directly contributing to tissue injury and clinical severity [1]. Although initial reports did not find an association between C. difficile infection and patients suffering from inflammatory bowel disease (IBD), studies from Milwaukee, Wisconsin and St. Louis, Missouri published in 2007 demonstrated that IBD patients were at a higher risk for contracting this infection [2, 3]. Confirmatory studies using the Nationwide Inpatient Sample demonstrated that there was a dramatic rise in C. difficile infections amongst IBD patients with a subsequent increase in morbidity and mortality [4]. IBD patients have now been recognized as a subgroup of patients who are high risk for contracting this infection, with serious clinical consequences (Table 1). The two major forms of IBD, Crohn’s disease and ulcerative colitis, are lifelong chronic inflammatory disorders of the gastrointestinal tract. IBD is felt to result from an inappropriate immune reaction to commensal bacteria in genetically susceptible individuals. At present, IBD is an incurable illness lacking definitive treatment, and medical therapy has relied on chronic immunosuppression to decrease the inflammatory response in individuals and maintain clinical remission. Flares
393, Page 2 of 6 Table 1 Predictors, diagnosis, and treatment of C. difficile Predictors of C. difficile Recent antibiotic exposure Recent hospitalization Immunosuppressed state (IBD, solid organ transplant recipient, and chemotherapy) Elderly patients Residents of nursing homes and long-term facilities Diagnosis of C. difficile Enzyme-linked immunosorbent assays (ELISA) Polymerase chain reaction (PCR) Treatment of C. difficile Oral metronidazole Oral vancomycin Oral vancomycin and intravenous metronidazole Surgical resection Fecal microbiome transplant (for recurrent disease)
Curr Gastroenterol Rep (2014) 16:393
The impact of C. difficile on hospital admissions for IBD patients was characterized by Nguyen and colleagues in Ontario, Canada, where they found that 9 % of ulcerative colitis patients admitted to the hospital were found to have a concomitant C. difficile infection during that hospital stay. More importantly, these authors found that C. difficile infection significantly increased short- and long-term mortality (5 years after infection) in their regional cohort of patients. Colectomy risk was increased during the index hospitalization but not during the 5-year follow-up suggesting that other mechanisms were contributing to the increased mortality [7•]. Authors from the Netherlands attempted to quantify the impact of C. difficile on rates of hospitalization for IBD patients. In contrast to the majority of the studies, these authors did not find that C. difficile was contributing to a significant percentage of IBD flares leading to hospitalization [8]. Pediatric IBD and C. difficile
of IBD, particularly colitis, have been treated with bursts of steroid therapy. Thus, the cornerstones of IBD treatment are agents which may both increase the risk of developing C. difficile infection and worsen its clinical course. The overlap in symptoms between both IBD flare and C. difficile infection has likely played a role in the severity of this infection, as identifying the infection in the setting of a patient who is experiencing a synergistic disease flare is critical for achieving optimal outcomes. There has been a substantial progress in our understanding of C. difficile infection, particularly in the clinical course of IBD. This review will specifically focus on four areas: (1) further defining IBD patients at risk for infection, clinical factors associated with severe infection, and new data associating genetic markers with developing of C. difficile infection in IBD; (2) progress in C. difficile diagnostics; (3) advances in initial antibiotic treatment options for IBD patients with C. difficile infection; and (4) the use of fecal microbiome transplant for IBD patients who are suffering from recurrent C. difficile infection.
Burden of C. difficile in IBD Worldwide Increase in C. difficile Infections in IBD Patients The rise in C. difficile infections seen in North American centers during the 2000–2010 time period has been paralleled by a rising incidence in European and Asian centers [5]. Reports from the European Crohn’s and Colitis Organization (i.e., Belgium, France, Israel, and the United Kingdom) have documented increased overlap between C. difficile infections and patients with IBD [6].
The rise in C. difficile infections in IBD patients, originally identified in adult patients, has recently been described in the pediatric IBD patient population. New evidence has confirmed that pediatric populations are at risk for C. difficile infection. Hourigan and colleagues prospectively evaluated 85 pediatric IBD patients and 78 controls, finding C. difficile carriage in 17 % of the IBD patients and 3 % of controls (p=0.012) [9]. The prevalence of C. difficile in pediatric IBD at the time of diagnosis was assessed by Mir and Kellermeyer. These authors found that 8.1 % of their pediatric IBD patients at diagnosis had C. difficile infection, which was significantly higher than the rate of C. difficile infection in the general population [10•]. Predicting Severe C. difficile Infection in IBD Patients There have been studies on the effect of IBD therapy on the risk of developing C. difficile and its clinical course. Corticosteroids, immunomodulators (i.e., azathioprine, six mercaptopurine, and methotrexate), and anti-tumor necrosis factor drugs suppress the immune system, placing IBD patients at a higher risk for opportunistic infections [11]. The natural history of contracting C. difficile infection appears to be correlated with the use of corticosteroid compounds. Work from Schneeweiss, using a British Columbia provincial healthcare database, demonstrated a threefold increased risk of developing a C. difficile infection in individuals who were exposed to any amount and any duration of corticosteroid therapy [12•]. From the Nationwide Inpatient Sample, Ananthakrishnan and McGinley showed that 27.5 % of IBD hospitalizations were related to infections [13]. These infectionrelated hospitalizations demonstrated a fourfold increase
Curr Gastroenterol Rep (2014) 16:393
in mortality compared to the IBD hospitalizations which were not associated with infection. Amongst all of the infections which were assessed, pneumonia, sepsis, and C. difficile were associated with the greatest excess mortality risk. Antibiotic exposure is the classic risk factor for developing C. difficile infection, and antibiotic treatment has been a routine component of IBD therapy, particularly patients with J-pouch ileoanal reconstruction. Although ulcerative colitis patients who have undergone colectomy are no longer at risk for C. difficile colitis, infection of the reconstructed ileal pouch which functions as a “neo-colon” is now well recognized. Inflammation of the ileoanal pouch is mechanistically felt to originate from the high bacterial concentrations in the ileal mucosa, and treatment of pouchitis has relied on either episodic or chronic antibiotic therapy. C. difficile infection of the ileal pouch is now well recognized, and physicians should be suspicious of this in patients with increased stool frequency, recent hospitalization, or those who develop weight loss [14]. IBD Genetic Loci are Associated with Development of C. difficile Infection There has been substantial success in efforts to define the genetic loci which are linked to the pathogenesis of IBD, with the identification of 163 genetic risk loci [15]. New investigation is attempting to translate these genetic discoveries into the clinic, to specifically determine whether specific patterns of genetic mutations will predispose individuals to develop infection with C. difficile. Ananthakrishnan and colleagues were able to model patterns of genetic risk in a prospective cohort of 319 wellcharacterized ulcerative colitis patients, of who 29 developed a C. difficile infection (9 %) [16•]. These authors found that female gender and pancolitis were risk factors, and the use of anti-tumor necrosis factor medications was protective against C. difficile infection. Six genetic polymorphisms including the TNFRSF14 were associated with increased C. difficile infection risk, and two loci were protective. This study showed that clusters of IBD risk alleles were associated with higher rates of developing C. difficile infection. Presence of at least one high-risk locus in an IBD patient was associated with an increase in risk for C. difficile infection (20 vs. 1 %). The precise biologic explanation for this genetic association with C. difficile infection has yet to be elucidated.
Diagnostic Strategies—C. difficile and IBD Over the past 5 years, there has been an evolution in clinical tests for diagnosing C. difficile infection, where
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polymerase chain reaction (PCR)-based molecular approaches has replaced enzyme linked immunosorbent assays (i.e., ELISA). PCR-based techniques for C. difficile detection in stool specimens are more sensitive, with reported diagnostic accuracy in excess of 80 %. In two reviews from the Cleveland clinic, investigators compared the diagnostic accuracy of ELISA and PCR-based strategies in hospitalized patients from 2006–2011 to 2009– 2011 [17, 18]. In the study by Wang and colleagues, 5.9 % of 222 IBD patients tested by ELISA were positive compared with 13.5 % of 103 IBD patients tested by PCR [18]. There was no significant difference in clinical outcomes between these two groups. Recommendations for a single stool specimen being sufficient to diagnose C. difficile infection in IBD patients were formally evaluated in a study by Deshpande and colleagues [17]. Performing a second ELISA test in the IBD patients increased diagnostic yield and appeared to be an important improvement in care [17]. As the PCR-based approaches for diagnosing C. difficile infection have become the dominant strategy in the USA, additional insight into the limitations of this approach has been investigated. Specifically, the impact of treatment on the sensitivity and performance characteristics of the PCR diagnostic test was formally evaluated in a prospective study by Sunkesula and colleagues [19•]. Although this was not specifically carried out in the IBD patient population, these authors followed a series of patients diagnosed with C. difficile infection undergoing treatment to determine the performance characteristics of stool C. difficile PCR testing on each day that the patients were receiving antibiotic therapy [19•]. Initiation of antibiotic therapy with oral vancomycin, metronidazole, or both agents resulted in a rapid decrease in the diagnostic accuracy of the C. difficile PCR testing, where half of the tests became negative by 3 days of therapy and all tests became negative by 5 days of therapy. This paper highlights an important concept, which is the initiation of medical therapy, either in the setting of a confirmed infection or empiric therapy for a suspected infection, will effectively negate the diagnostic accuracy of stool testing after 3–5 days of C. difficile antibiotic treatment. This implies no role to document clearance of C. difficile at the completion of treatment, as the PCR assays will routinely become negative. Furthermore, the rapid decline in diagnostic accuracy of the C. difficile PCR testing within 3 days of treatment implies that initiation of empiric therapy should be followed by the full therapeutic course (10–14 days) in responding patients as subsequent stool analysis in the midst of treatment is no longer helpful. Given that the criteria for C. difficile treatment are a high clinical index of suspicion and not a positive stool assay, the paper by Sunkesula reinforces the need to commit to therapy for a full therapeutic course in patients who are felt to be clinically at risk.
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Treatment of C. difficile in IBD—Antibiotic Therapy The American College of Gastroenterology (ACG) guidelines for the diagnosis, management, and prevention of C. difficile infection were published in early 2013, and this document provided a new emphasis on detecting and treating C. difficile infection in high-risk populations, specifically IBD [20]. The ACG guidelines specifically included five scenarios involving IBD patients: (1) All patients with IBD hospitalized with a disease flare should undergo testing for C. difficile infection (strong recommendation and high-quality evidence). (2) Ambulatory patients with IBD who develop diarrhea in the setting of previously quiescent disease or in the presence of risk factors such as recent hospitalization or antibiotic use should be tested for C. difficile infection (strong recommendation and moderate-quality evidence). (3) In patients who have IBD with severe colitis, simultaneous initiation of empiric therapy directed against C. difficile infection, and treatment of an IBD flare may be required while awaiting results of C. difficile testing (conditional recommendation and low-quality evidence). (4) In patients with IBD, ongoing immunosuppression medications can be maintained in patients with C. difficile infection. Escalation of immunosuppression medications should be avoided in the setting of untreated C. difficile infection (conditional recommendation and low-quality evidence). (5) Patients with IBD who have a surgically created pouch after colectomy may develop C. difficile infection and should be tested if they have symptoms (strong recommendation and moderate-quality evidence). The ACG guidelines also provided a novel structure for categorizing disease severity during C. difficile infection and matching this parameter with medical and surgical treatment options [20]. The ACG guidelines provided a working definition for the severity of infection, mild to moderate, severe, and severe complicated, which can be extrapolated to the IBD patient population [21•]. Mild to moderate patients warrant initial therapy with metronidazole. Severe patients should receive treatment with oral vancomycin. Severe complicated patients (i.e., hospitalized individuals) should be treated with oral vancomycin in combination with intravenous metronidazole and surgical consultation should be obtained. In the setting of recurrent C. difficile infection, prolonged therapy (multiple weeks/months) with oral vancomycin 125 mg orally four times daily is the preferred approach, given the cumulative toxicity associated with metronidazole. This is an important consideration, as clinical recurrence is identified in one quarter of C. difficile infections in the general population and up to 39 % of IBD patients [22]. The ACG guidelines recognized that fidaxomicin, a new macrocyclic antibiotic agent approved by the FDA in 2011 for the treatment of C. difficile infection, is an additional therapeutic modality which can be considered. Fidaxomicin has similar efficacy and toxicity with oral vancomycin, but may
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offer the benefit of reduced C. difficile recurrence within 4 weeks of the initial treatment course (clinical recurrence seen in 25.3 % of vancomycin treated and 15.4 % of fidaxomicin treated subjects). However, the high cost of this agent has frequently relegated its use in patients who have experienced recurrent disease after initial treatment with less costly agents (i.e., metronidazole and oral vancomycin). Thus, fidaxomicin is often being used in patients with recurrent C. difficile infection, which is a more challenging clinical problem, and a clinical application which was not addressed in the pivotal trials. Information regarding the use of fidaxomicin in IBD is extremely limited at this time, as an IBD diagnosis was an exclusion criteria for participation in the registry trials.
Treatment—Fecal Microbiome Transplant (FMT) Recurrence of infection with C. difficile is a significant problem as approximately one quarter of patients initially treated with metronidazole or oral vancomycin will experience clinical relapse within the next 1–3 months. As mentioned previously, this may be improved with the initial use of fidaxomicin, but was not specifically investigated in the IBD patient population [23•]. The ACG guidelines for C. difficile treatment recommend consideration of FMT after the second documented recurrence. This data were based on success of the approach in a randomized trial using universal donors and duodenal infusion [24•]. This study by van Nood and colleagues in Amsterdam did not specifically include patients with IBD. Specific data regarding the performance of FMT for the treatment of recurrent C. difficile infection in the IBD patient population is emerging with both success and what may be FMT-related disease flare [25]. Although success rates of C. difficile infection treatment with FMT are promising, caution should be used in IBD patients as there has been a report of transient flare ups of disease activity after FMT [26•]. Enthusiasm for the use of FMT in IBD patients for the specific treatment of C. difficile infection should also be tempered by the fact that pilot studies investigating the safety and efficacy of FMT in patients with Crohn’s disease and ulcerative colitis as a primary form of therapy were complicated by transient deterioration in the majority of the subjects [27, 28]. Compliance with Ethics Guidelines Conflict of Interest nothing to disclose.
Jana G. Hashash and David G. Binion have
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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References
14.
Papers of particular interest, published recently, have been highlighted as
15.
• Of importance
1.
2.
3.
4.
5. 6.
7.•
8.
9.
10.•
11.
12.•
13.
Kelly CP, LaMont JT. Clostridium difficile—more difficult than ever. N Engl J Med. 2008;359(18):1932–40. Erratum in: N Engl J Med. 2010 Oct 14;363(16):1585. Rodemann JF, Dubberke ER, Reske KA, da Seo H, Stone CD. Incidence of Clostridium difficile infection in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5(3):339–44. Issa M, Vijayapal A, Graham MB, Beaulieu DB, Otterson MF, Lundeen S, et al. Impact of Clostridium difficile on inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5(3): 345–51. Ananthakrishnan AN, McGinley EL, Binion DG. Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease. Gut. 2008;57(2): 205–10. Burke KE, Lamont JT. Clostridium difficile inection: a worldwide disease. Gut Liver. 2014;8(1):1–6. Jen MH, Saxena S, Bottle A, Aylin P, Pollok RC. Increased health burden associated with Clostridium difficile diarrhoea in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2011;33(12):1322–31. Murthy SK, Steinhart AH, Tinmouth J, Austin PC, Daneman N, Nguyen GC. Impact of Clostridium difficile colitis on 5-year health outcomes in patients with ulcerative colitis. Aliment Pharmacol Ther. 2012;36(11–12):1032–9. Approximately 9% of hospitalized ulcerative colitis patients have C. difficile infection in this study from Ontario, Canada. Masclee GM, Penders J, Jonkers DM, Wolffs PF, Pierik MJ. Is Clostridium difficile associated with relapse of inflammatory bowel disease? Results from a retrospective and prospective cohort study in the Netherlands. Inflamm Bowel Dis. 2013;19(10):2125–31. Hourigan SK, Chirumamilla SR, Ross T, Golub JE, Rabizadeh S, Saeed SA, et al. Clostridium difficile carriage and serum antitoxin responses in children with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(13):2744–52. Mir SA, Kellermayer R. Clostridium difficile infection in newly diagnosed pediatric inflammatory bowel disease in the midsouthern United States. J Pediatr Gastroenterol Nutr. 2013;57(4): 487–8. Approximately 8% of newly diagnosed pediatric IBD patients have C . difficile infection, which supports the practice of testing of all newly diagnosed IBD patients. Dave M, Purohit T, Razonable R, Loftus Jr EV. Opportunistic infections due to inflammatory bowel disease therapy. Inflamm Bowel Dis. 2014;20(1):196–212. Schneeweiss S, Korzenik J, Solomon DH, Canning C, Lee J, Bressler B. Infliximab and other immunomodulating drugs in patients with inflammatory bowel disease and the risk of serious bacterial infections. Aliment Pharmacol Ther. 2009;30(3):253–64. Corticosteroid exposure tripled risk of IBD patients developing C. difficile infection in this study from British Columbia, Canada. AntiTNF agents were not associated with developoing C. difficile in IBD. Ananthakrishnan AN, McGinley EL. Infection-related hospitalizations are associated with increased mortality in patients with inflammatory bowel diseases. J Crohn’s Colitis. 2013;7(2):107–12.
16.•
17.
18.
19.•
20.
21.•
22.
23.•
24.•
Li Y, Qian J, Queener E, Shen B. Risk factors and outcome of PCRdetected Clostridium difficile infection in ileal pouch patients. Inflamm Bowel Dis. 2013;19(2):397–403. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422): 119–24. Ananthakrishnan AN, Oxford EC, Nguyen DD, Sauk J, Yajnik V, Xavier RJ. Genetic risk factors for Clostridium difficile infection in ulcerative colitis. Aliment Pharmacol Ther. 2013;38(5):522–30. Female gender, pancolitis, and anti-TNF therapy were protective against developing C. difficile infection in this analysis of a small number of ulcerative colitis patients. Increasing number of IBD risk alleles were associated with increased risk of developing C. difficile infection in ulcerative colitis. Deshpande A, Pasupuleti V, Patel P, Pant C, Pagadala M, Hall G, et al. Repeat stool testing for Clostridium difficile using enzyme immunoassay in patients with inflammatory bowel disease increases diagnostic yield. Curr Med Res Opin. 2012;28(9):1553–60. Wang Y, Atreja A, Wu X, Lashner BA, Brzezinski A, Shen B. Similar outcomes of IBD in patients with Clostridium difficile infection detected by ELISA or PCR assay. Dig Dis Sci. 2013;58(8):2308–13. Sunkesula VC, Kundrapu S, Muganda C, Sethi AK, Donskey CJ. Does empirical Clostridium difficile infection (CDI) therapy result in false-negative CDI diagnostic test results? Clin Infect Dis. 2013;57(4):494–500. Analysis of the performance characteristics of stool PCR testing for C. difficile following initiation of antibiotic therapy against the infection in patients with documented disease. PCR tests turned negative at a rapid rate, with 50% of patients testing negative 3 days into therapy and essentially all patients becoming negative 5 days into treatment. This study demonstrates no role for repeat stool testing as the PCR assay will turn negative prior to completing a therapeutic course of antibiotic therapy for C. difficile infection. It also highlights the importance of completing an empiric course of therapy once initiated, as testing is no longer accurate 3–5 days into treatment. Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108(4):478–98. quiz 499. Review. Ananthakrishnan AN, Guzman-Perez R, Gainer V, Cai T, Churchill S, Kohane I, et al. Predictors of severe outcomes associated with Clostridium difficile infection in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2012;35(7):789–95. Observational clinical trial demonstrating clinical factors which correlate with poor outcome in IBD patients suffering from C. difficile infection. Libot A, Issa M, Zadvornova Y, Stein DJ, Venu N, Perera LP, et al. Initial vancomycin monotherapy is associated with higher rates of subsequent Clostridium difficile infection in inflammatory bowel disease population. Gastroenterology. 2011;140:S-159. abstract #992. Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5): 422–31. Pivotal trial demonstrating safety and efficacy of fidaxomicin in the treatment of initial C. difficile infection and potential superiority with reduction in short term recurrence. IBD patients were excluded from this trial. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–15. Pivotal trial establishing the efficacy and superiority of FMT in the treatment of recurrent C. difficile infection.
393, Page 6 of 6 25.
Anderson JL, Edney RJ, Whelan K. Systematic review: Faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther. 2012;36(6):503–16. 26.• De Leon LM, Watson JB, Kelly CR. Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol. 2013;11(8):1036–8. First publication demonstrating problems of FMT for treatment of recurrent C difficile infection in IBD.
Curr Gastroenterol Rep (2014) 16:393 27.
28.
Vermeire S, Joossens M, Verbeke K, et al. Pilot study on the safety and effi cacy of faecal microbiota transplantation in refractory Crohn’s disease. Gastroenterology. 2012;142:S360. Angelberger S, Reinisch W, Makristathis A, Lichtenberger C, Dejaco C, Papay P, et al. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. Am J Gastroenterol. 2013;108(10): 1620–30.
