Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2024 Jul 1.
Published in final edited form as: Curr Opin Gastroenterol. 2023 May 15;39(4):257–262. doi: 10.1097/MOG.0000000000000949

Clostridium Difficile in Inflammatory Bowel Disease

Tamara Alhobayb 1, Matthew A Ciorba 1
PMCID: PMC10264153  NIHMSID: NIHMS1897950  PMID: 37265220

Abstract

Purpose of review:

The chronic inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, are associated with an increased risk of symptomatic Clostridium difficile infection (CDI). CDI may also masquerade as an IBD flare and complicate IBD management. This review provides a comprehensive overview of the epidemiology, diagnosis, and treatment of CDI in IBD patients.

Recent findings:

CDI remains common in IBD with complications including flares in disease activity, recurrent CDI episodes, and prolonged hospital stays. Newer IBD therapeutics including vedolizumab, ustekinumab, and tofacitinib are less likely to cause severe CDI. A high index of suspicion, rapid testing via a two-step method, and prompt treatment with vancomycin or fidaxomicin are paramount to managing CDI in IBD patients. Strategies to prevent recurrent CDI (rCDI) include the monoclonal antibody bezlotoxumab as well as fecal microbiota transplantation (FMT). FMT has a robust profile of safety and effectiveness in preventing rCDI in adults and children.

Summary:

Clinicians must remain vigilant in the prompt diagnosis and treatment of CDI in IBD patients. Corticosteroids, unnecessary antibiotics, and ongoing colonic inflammatory disease are modifiable risk factors. Improved infection control measures, newer IBD medications, and using effective CDI treatments will facilitate a reduced burden of severe CDI and complications for IBD patients.

Keywords: Inflammatory bowel disease, Clostridium difficile infection, Crohn’s disease, ulcerative colitis, fecal microbiota transplantation

Introduction

Patients with Inflammatory bowel disease are at increased risk of Clostridium difficile infection (CDI).1 Clostridium difficile is a gram positive, anaerobic, spore forming bacteria, which affects the large colon primarily upon disruption of the gut microbiota leading to colitis.2, 3 The prevalence of CDI in patients with pre-existing chronic conditions imposes a need for early detection, proper management, and prevention strategies to mitigate its impact on healthcare. The economic and clinical ramifications of CDI are considerable, with costs exceeding $1.2 billion annually in the US.4

The purpose of our review is to examine the latest research on CDI in the context of inflammatory bowel disease (IBD). We aim to emphasize important information regarding epidemiology, risk factors, and clinical outcomes. Additionally, we provide an overview of current diagnostic methods and highlight recent updates to treatment approaches based on international recommendations.

The evolving epidemiology of C. difficile infection in patients with IBD

During the early 2000s, a significant increase in the incidence of CDI was observed.5–8 CDI incidence increased not only in the general population but also in high-risk groups, including older individuals (aged >65 years), those with prolonged hospitalization, and those with multiple comorbidities, such as inflammatory bowel diseases (IBD)7–10. Multiple studies investigated the relationship between CDI and IBD and found that the increase in CDI occurrence among patients with IBD was great even than that in the general population7, 8, 11–13. A study conducted in Wisconsin demonstrated an increase in CDI case yearly incidence in the IBD population from a rate of 1.8% in 2004 up to 4.6% in 20057. Moreover, a large retrospective cohort study demonstrated that IBD patients had twice the risk of developing CDI than non-IBD patients, particularly those with UC8.

Compared to the general population, inflammatory bowel disease (IBD) patients who have CDI exhibit unique characteristics, such as being younger, without recent antibiotic exposure, and more likely to have acquired the infection in the community.7 The altered microbiome in IBD is thought to facilitate the proliferation of C. difficile by reducing the diversity of colonic microbiota. The underlying colitis likely mediates this effect, as demonstrated in earlier studies where UC patients had a significantly higher risk of CDI than CD patients with less extensive colonic disease.7, 8

Studies also investigated whether IBD medications increase the risk of CDI. Issa et al. found that patients on maintenance immunomodulators (6-MP, Azathioprine, or methotrexate) had an increased risk of CDI, whereas those on anti-TNFs did not.7 This lack of association between anti-TNFs and CDI was confirmed by Schneeweis et al.14 Bossuyt and colleagues further demonstrated that corticosteroids raised the risk of developing CDI threefold in a large Canadian study.1

The effects of newer IBD medications (anti-integrin, anti-IL-12/23, Jak inhibitors) on CDI incidence are not as well established. However, clinical trial and other studies indicate that these therapies are not associated with severe CDI in IBD patients. A retrospective study of 805 UC patients initiated on vedolizumab or anti-TNF therapy found 43 CDI cases and 11 severe CDI cases over 1436 patient-years of follow-up. It was also shown that the risk of severe CDI was lower in patients who were initiated on Vedolizumab.15 A safety analysis of ustekinumab trials demonstrated that similar rates of CDI through induction and at one year.16 Similarly, in the tofacitinib trials, Loftus et al reported CDI in UC patients receiving tofacitinib were infrequent, cases were mild-moderate in severity, and most resolved with treatment.17

Clinical presentation C. difficile infection in IBD patients

In practice, it can be challenging to differentiate between symptoms related to CDI and symptoms connected with an IBD flare. Patients typically encounter symptoms such as abdominal pain, weight loss, and bloody diarrhea during IBD flares. Meanwhile, CDI often results in symptoms like dehydration, abdominal cramps, watery diarrhea, loss of appetite, and weight loss, and in severe cases, rectal bleeding may also occur. The Infectious Disease Society of America (ISDA) and American College of Gastroenterology (ACG) recommend that patients who have three or more episodes of unformed stools in 24 hours with no clear explanation should undergo testing for CDI.18, 19 As a result, patients who experience a worsening of their inflammatory bowel disease (IBD) symptoms should undergo screening for the presence of C. difficile toxins.20–22

Diagnosis and testing

There are several types of tests available for detecting CDI; those include enzyme immunoassays (EIA) for toxin A and B, EIA for glutamate dehydrogenase (GDH), nucleic acid amplification tests (NAAT), toxigenic culture, and next-generation sequencing (NGS).23, 24 Unfortunately, there is no single perfect test for CDI as these tests vary in their sensitivity and specificity. The NAAT is a PCR test which tests for the presence of C. diff toxic genes. It has a high sensitivity but is limited in the inability to differentiate colonization from true infection.25 The other highly sensitive test in the GDH which is used as a screening test. The GDH test is used to detect the presence of the GDH enzyme which is expressed by both toxigenic and non-toxigenic strains of C diff. The toxin EIA is an excellent adjunct to the prior described tests as it detects the presence of C diff toxins A and/or B. It has a lower sensitivity and has up to 30% false negative rates. Therefore, it is used as a second step test after NAAT and GDH.26 Finally, toxigenic culture and next-generation sequencing (NGS) are advanced methods used for detecting the presence of C. difficile. However, due to their high cost and time-consuming nature, they are generally not used in routine clinical practice.27

The detection of C. difficile bacteria without any accompanying symptoms, known as colonization, is a frequent occurrence, especially among patients in hospitals and long-term care facilities.28 Therefore, diagnosing a C. difficile infection is not always a simple process. Relying solely on test results is not sufficient, and clinical evaluation of the patient should be considered when deciding whether to test for C. difficile. It is important to note that all testing modalities are not valid on formed stool. To overcome the limitations of C. difficile testing, it is recommended to implement a two-step testing approach instead of relying solely on a single test.29 Both the IDSA and ACG guidelines recommend using either NAAT or GDH testing as the initial step for diagnosing C. diff infection, followed by the second step of testing for the presence of toxins using toxin EIA. The ACG also suggests repeat testing in patients with negative results who have a high suspicion for CDI.

Performing a colonoscopy or a flexible sigmoidoscopy with biopsies can be beneficial in excluding other probable reasons for diarrhea like cytomegalovirus colitis, ischemic colitis or IBD flare. It is worth mentioning that in such a scenario, the mucosal appearance may not provide a clear distinction between CDI and IBD. This is especially true as the distinguishing feature of pseudomembranes, a commonly observed phenomenon in CDI patients in the general population, which are seldom present in individuals with pre-existing IBD.30

C. difficile infection worsens clinical outcomes in IBD patients

CDI worsens IBD outcomes with higher morbidity and mortality.7, 31 Navaneethan et al studied the impact of CDI on UC patients and found those with CDI had higher rates of emergency room visits (37.8% vs 4%) and colectomy (35.6% vs 9.9%). CDI infection and severe endoscopic disease were independent risk factors for colectomy. Moreover, approximately 55% of UC patients with CDI had escalated medical therapy compared to those without CDI.32

Anderson et al used propensity scoring to evaluate CDI’s long-term impact on patients with IBD, finding it was linked with increased steroid and antibiotic exposure, elevated C-reactive protein, reduced quality of life, and higher healthcare utilization and costs.33 In England, hospitalized patients with CDI and IBD had higher morbidity and mortality, emergency surgery and colectomy rates, and longer hospital stays compared to those with IBD alone.34.

Medical management of C. difficile infection in IBD patients

Prompt identification and management of CDI is crucial in IBD patients, but challenges exist, such as distinguishing symptoms from an IBD flare and a lack of prospective data on managing concurrent IBD and CDI.

Vancomycin or fidaxomicin are currently the recommended first line treatments for an initial episode of either non-severe or severe CDI.23 In two multinational trials, vancomycin was more effective than metronidazole in treating CDI.35 Another study found vancomycin superior for severe CDI treatment.36 As a result, metronidazole is not recommended as first-line treatment for CDI unless vancomycin or fidaxomicin are unavailable. Fidaxomicin and vancomycin have comparable CDI cure rates, but fidaxomicin has lower recurrence rates.37 However, fidaxomicin’s higher cost limits its use in clinical practice compared to vancomycin.

For an initial CDI episode, vancomycin is prescribed at 125 mg four times daily or fidaxomicin at 200 mg twice daily for 10 days. A Chicago based study found longer oral vancomycin duration (21–42 days) in IBD patients was linked to lower CDI recurrence (1.8% vs. 11.7% on 10–14 days therapy).38 This requires further validation.

For hospitalize fulminant C. difficile with signs of systemic illness, oral vancomycin (500 mg four times daily) should be combined with metronidazole 500 mg every eight hours. Rectal vancomycin is also indicated. Surgical intervention may be required for those unresponsive to therapy with fever or other signs of multi-organ failure.

Recurrent C. difficile infection in IBD patients

The recurrence of CDI (rCDI) is defined as the reappearance of symptoms accompanied by a positive stool test for C. difficile within eight weeks following the resolution of initial symptoms after completing the appropriate treatment. This could be attributed to either the relapse of the original strain or a new infection caused by a different strain of C. difficile. About 10%-35% of non IBD patients with CDI have recurrence. However, patients with IBD have a 33% higher likelihood of experiencing recurrence of CDI. In the IBD population, the risk factors that increase the likelihood of recurrent CDI are Crohn’s colitis and recent use of antibiotics, corticosteroids, 5-aminosalicylic acid (5-ASA) medications, or infliximab in relation to the initial CDI.

Post infection irritable bowel syndrome may masquerade at rCDI or unresolved CDI. Dual testing should confirm the lack of ongoing CDI and patients should be offered reassurance and may require additional therapies directed at the IBS. In our own practice, we have some patients who continue to have symptoms that are responsive to vancomycin even in the absence of positive testing. Why not evidence-based, we have maintained some of these patients on a single 125 mg dose of vancomycin long-term which has been successful for them.

Prevention of CDI recurrence

Several methods have been studied to prevent CDI and its recurrence. Typically, reducing the use of systemic antibiotics and avoiding unnecessary proton pump inhibitor therapy is advised.

Studies examining probiotics’ effect on CDI recurrence produced inconclusive results, with some showing a higher recurrence risk.39–41 The UK’s PLACIDE trial, which included 2,900 patients, found no evidence of probiotics’ effectiveness in preventing CDI and that probiotics hindered gut microbiome restoration after antibiotic use.39 Thus, probiotics are not recommended for CDI prophylaxis, and the ACG guideline recommends against their use.18

A human monoclonal antibody against Clostridium difficile toxin B, Bezlotoxumab was approved in 2016 for the prevention of C. difficile infection recurrence in adults who are at a high risk of developing rCDI. Two large RCT trials, MODIFY I and MODIFY II, provided evidence that bezlotoxumab significantly decreases rCDI in comparison to placebo.42 The rate of CDI recurrence was lower in patients treated with bezlotoxumab compared to placebo (17% vs. 28% in MODIFY I and 16% vs. 26% in MODIFY II) with a statistical significance of P < .001. In a post hoc analysis of those trials, Gerding et al identified patients with risk factors for recurrent CDI.43 They were able to show a great reduction in rCDI with bezlotoxumab in patients with more than 3 risk factors. Moreover, patient with 1–2 risk factor still benefited from the use of bezlotoxumab.

FMT for the treatment or prevention of CDI in IBD patients

Fecal microbiota transplantation has revolutionized the approach to treating recurrent CDI. As a result of numerous randomized trials comparing FMT to standard antibiotic treatment and placebo,44, 45 FMT is now a recommended therapy for recurrent CDI according to treatment guidelines.19 Unfortunately, most of these clinical trials do not involve patients with IBD. However, a retrospective cohort study by Kelly and colleagues found that immunosuppressed patients, including those with IBD, had an 89% success rate in treatment.46 The study also revealed that after undergoing FMT, 14% of patients experienced a worsening of IBD symptoms; however, the definition of what constitutes an IBD exacerbation was not defined. Multiple retrospective studies have shown that individuals with both IBD and recurrent CDI are at a higher risk of FMT treatment failure (25% - 30%).47, 48 A large retrospective study evaluated the outcomes of FMT for recurrent CDI in pediatric patients, with and without IBD. The study included 396 patients and found that the success rate of FMT was 75% in patients with IBD.49 Similarly, in large meta-analysis including 25 studies, the cure rate following FMT in IBD patients was 78%.50

In 2020, a prospective multicenter cohort study lead by Jessica Allegretti was published, which included 49 patients with recurrent CDI and IBD who underwent FMT.51 The study found that the failure rate of FMT was 10% by week 8. Additionally, all non-responders received a second FMT and achieved clinical response. The researchers conducted a secondary analysis of this cohort study to evaluate the outcomes of IBD in this population.52 In this analysis, it was found that the risk of de novo IBD flare after fecal microbiota transplantation (FMT) was minimal, with only one patient out of the 49 developing a de novo flare. Similar results were seen in a recent large prospective study evaluating clinical response and safety of FMT on adult IBD patients with rCDI.53 They found that FMT was safe in IBD patients including those who are on immunosuppressive medications. They also found that IBD flare after FMT was very rare.

The majority of research suggests that FMT is well-tolerated and severe adverse events are not reported in the literature. According to Fischer and colleagues’ large cohort study on IBD patients who received FMT for CDI, a small percentage of patients experienced an IBD flare after the procedure, and no severe adverse events that could be directly attributed to FMT were detected.54 In a prospective open-label trial, Goyal et al explored the safety and efficacy of FMT in pediatric IBD patients. They found that FMT-related adverse effects were mild to moderate and were self-limited.55

In practical terms, the source of FMT and its constitution are by variable by nature. The federal Food and Drug Agency recently approved Rebyota (trade name), a microbiome based, first-in-class therapeutic for the prevention of recurrence of C. difficile infection in adults. Registry and open label studies should provide insight into how this product may work for CDI in IBD and how it affects IBD disease activity.

Conclusion and Future Directions

CDI is a frequent complication among patients with IBD and can have detrimental consequences. Prompt identification and treatment are crucial in mitigating CDI-associated complications in IBD patients. However, a foolproof method for detecting CDI is currently unavailable, and therefore, a two-step algorithm has been proposed. The development of affordable and accurate testing options could revolutionize the diagnosis of CDI. More data on the incidence and clinical outcomes of CDI in patients receiving newer IBD therapeutic medications is needed, but available data are positive. Moreover, there is a need for more prospective studies to determine the best course of action in managing IBD and CDI concurrently. Evolving microbiome based therapies hold great promise for CDI and CDI in IBD patients.

Key points:

  • CDI occurrence is higher among patients with IBD than in the general population, particularly those with UC.

  • Patient with CDI and IBD have higher colectomy rates, and longer hospital stays compared to those with IBD alone.

  • Given the challenges of differentiating CDI symptoms from IBD flares, all patients who experience a worsening of their inflammatory bowel disease (IBD) symptoms should undergo screening for the presence of C. difficile toxins.

  • Vancomycin or fidaxomicin are currently the recommended first line treatments for an initial episode of either non-severe or severe CDI. A longer course may be required in IBD patients.

  • Bezlotoxumab and FMT can be used in patient with higher risk of recurrence to prevent CDI recurrence. Future microbiome base therapies hold great promise.

Funding:

P30DK052574, T32DK007130, R01AI167285, Lawrence C. Pakula, MD IBD Innovation and Education Fund, https://givinitallforguts.org/

Footnotes

Conflict of Interest Statement: The authors declare no conflicts of interest.

References

  • 1.Bossuyt P, Verhaegen J, Van Assche G, Rutgeerts P, Vermeire S. Increasing incidence of Clostridium difficile-associated diarrhea in inflammatory bowel disease. J Crohns Colitis 2009;3:4–7. [DOI] [PubMed] [Google Scholar]
  • 2.Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994;330:257–62. [DOI] [PubMed] [Google Scholar]
  • 3.Janezic S, Potocnik M, Zidaric V, Rupnik M. Highly Divergent Clostridium difficile Strains Isolated from the Environment. PLoS One 2016;11:e0167101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Kwon JH, Olsen MA, Dubberke ER. The morbidity, mortality, and costs associated with Clostridium difficile infection. Infect Dis Clin North Am 2015;29:123–34. [DOI] [PubMed] [Google Scholar]
  • 5.McDonald LC, Owings M, Jernigan DB. Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996–2003. Emerg Infect Dis 2006;12:409–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Morris AM, Jobe BA, Stoney M, Sheppard BC, Deveney CW, Deveney KE. Clostridium difficile Colitis: An Increasingly Aggressive Iatrogenic Disease? Archives of Surgery 2002;137:1096–100. [DOI] [PubMed] [Google Scholar]
  • 7.Issa M, Vijayapal A, Graham MB, Beaulieu DB, Otterson MF, Lundeen S, Skaros S, Weber LR, Komorowski RA, Knox JF, Emmons J, Bajaj JS, Binion DG. Impact of Clostridium difficile on inflammatory bowel disease. Clin Gastroenterol Hepatol 2007;5:345–51. [DOI] [PubMed] [Google Scholar]
  • 8.Rodemann JF, Dubberke ER, Reske KA, Seo DH, Stone CD. Incidence of Clostridium difficile infection in inflammatory bowel disease. Clin Gastroenterol Hepatol 2007;5:339–44. [DOI] [PubMed] [Google Scholar]
  • 9.Archibald LK, Banerjee SN, Jarvis WR. Secular trends in hospital-acquired Clostridium difficile disease in the United States, 1987–2001. J Infect Dis 2004;189:1585–9. [DOI] [PubMed] [Google Scholar]
  • 10.Kyne L, Sougioultzis S, McFarland LV, Kelly CP. Underlying disease severity as a major risk factor for nosocomial Clostridium difficile diarrhea. Infect Control Hosp Epidemiol 2002;23:653–9. [DOI] [PubMed] [Google Scholar]
  • 11.Bolton RP, Read AE. Clostridium difficile in toxic megacolon complicating acute inflammatory bowel disease. Br Med J (Clin Res Ed) 1982;285:475–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Regnault H, Bourrier A, Lalande V, Nion-Larmurier I, Sokol H, Seksik P, Barbut F, Cosnes J, Beaugerie L. Prevalence and risk factors of Clostridium difficile infection in patients hospitalized for flare of inflammatory bowel disease: a retrospective assessment. Dig Liver Dis 2014;46:1086–92. [DOI] [PubMed] [Google Scholar]
  • 13.Nguyen GC, Kaplan GG, Harris ML, Brant SR. A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients. Am J Gastroenterol 2008;103:1443–50. [DOI] [PubMed] [Google Scholar]
  • 14.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;30:253–64. [DOI] [PubMed] [Google Scholar]
  • 15.**.Dalal RS, Mitri J, Goodrick H, Allegretti JR. Risk of Gastrointestinal Infections After Initiating Vedolizumab and Anti-TNF-alpha Agents for Ulcerative Colitis. J Clin Gastroenterol 2022;37:336–43. [DOI] [PMC free article] [PubMed] [Google Scholar]; This is the first cohort study that assesses the risk of CDI in IBD patients using newer IBD medications including vedolizumab)
  • 16.Sandborn WJ, Feagan BG, Danese S, O’Brien CD, Ott E, Marano C, Baker T, Zhou Y, Volger S, Tikhonov I, Gasink C, Sands BE, Ghosh S. Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis of Results from Phase 2/3 Studies. Inflammatory Bowel Diseases 2020;27:994–1007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Loftus EV, Baumgart DC, Gecse K, Kinnucan JA, Connelly SB, Salese L, Su C, Kwok KK, Woolcott JC, Armuzzi A. Clostridium difficile Infection in Patients with Ulcerative Colitis Treated with Tofacitinib in the Ulcerative Colitis Program. Inflamm Bowel Dis 2022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Kelly CR, Fischer M, Allegretti JR, LaPlante K, Stewart DB, Limketkai BN, Stollman NH. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. Official journal of the American College of Gastroenterology | ACG 2021;116:1124–47. [DOI] [PubMed] [Google Scholar]
  • 19.McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Shaklee Sammons J, Sandora TJ, Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018;66:e1–e48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol 2019;114:384–413. [DOI] [PubMed] [Google Scholar]
  • 21.Bernstein CN, Fried M, Krabshuis JH, Cohen H, Eliakim R, Fedail S, Gearry R, Goh KL, Hamid S, Khan AG, LeMair AW, Malfertheiner, Ouyang Q, Rey JF, Sood A, Steinwurz F, Thomsen OO, Thomson A, Watermeyer G. World Gastroenterology Organization Practice Guidelines for the Diagnosis and Management of IBD in 2010. Inflammatory Bowel Diseases 2009;16:112–24. [DOI] [PubMed] [Google Scholar]
  • 22.Mowat C, Cole A, Windsor A, Ahmad T, Arnott I, Driscoll R, Mitton S, Orchard T, Rutter M, Younge L, Lees C, Ho G-t, Satsangi J, Bloom S. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571. [DOI] [PubMed] [Google Scholar]
  • 23.Khanna S, Shin A, Kelly CP. Management of Clostridium difficile Infection in Inflammatory Bowel Disease: Expert Review from the Clinical Practice Updates Committee of the AGA Institute. Clin Gastroenterol Hepatol 2017;15:166–74. [DOI] [PubMed] [Google Scholar]
  • 24.Crobach MJ, Dekkers OM, Wilcox MH, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): data review and recommendations for diagnosing Clostridium difficile-infection (CDI). Clin Microbiol Infect 2009;15:1053–66. [DOI] [PubMed] [Google Scholar]
  • 25.Polage CR, Gyorke CE, Kennedy MA, Leslie JL, Chin DL, Wang S, Nguyen HH, Huang B, Tang YW, Lee LW, Kim K, Taylor S, Romano PS, Panacek EA, Goodell PB, Solnick JV, Cohen SH. Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era. JAMA Intern Med 2015;175:1792–801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Gateau C, Couturier J, Coia J, Barbut F. How to: diagnose infection caused by Clostridium difficile. Clin Microbiol Infect 2018;24:463–8. [DOI] [PubMed] [Google Scholar]
  • 27.Senok AC, Aldosari KM, Alowaisheq RA, Abid OA, Alsuhaibani KA, Khan MA, Somily AM. Detection of clostridium difficile antigen and toxin in stool specimens: Comparison of the C. difficile quik chek complete enzyme immunoassay and GeneXpert C. difficile polymerase chain reaction assay. Saudi J Gastroenterol 2017;23:259–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Truong C, Schroeder LF, Gaur R, Anikst VE, Komo I, Watters C, McCalley E, Kulik C, Pickham D, Lee NJ, Banaei N. Clostridium difficile rates in asymptomatic and symptomatic hospitalized patients using nucleic acid testing. Diagn Microbiol Infect Dis 2017;87:365–70. [DOI] [PubMed] [Google Scholar]
  • 29.Qutub M, Govindan P, Vattappillil A. Effectiveness of a Two-Step Testing Algorithm for Reliable and Cost-Effective Detection of Clostridium difficile Infection in a Tertiary Care Hospital in Saudi Arabia. Med Sci (Basel) 2019;7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Sinh P, Barrett TA, Yun L. Clostridium difficile Infection and Inflammatory Bowel Disease: A Review. Gastroenterol Res Pract 2011;2011:136064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Zhang T, Lin Q-Y, Fei J-X, Zhang Y, Lin M-Y, Jiang S-H, Wang P, Chen Y. Clostridium Difficile Infection Worsen Outcome of Hospitalized Patients with Inflammatory Bowel Disease. Scientific Reports 2016;6:29791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Navaneethan U, Mukewar S, Venkatesh PG, Lopez R, Shen B. Clostridium difficile infection is associated with worse long term outcome in patients with ulcerative colitis. J Crohns Colitis 2012;6:330–6. [DOI] [PubMed] [Google Scholar]
  • 33.Anderson A, Click B, Ramos-Rivers C, Cheng D, Babichenko D, Koutroubakis IE, Hashash JG, Schwartz M, Swoger J, Barrie AM 3rd, Dunn MA, Regueiro M, Binion DG. Lasting Impact of Clostridium difficile Infection in Inflammatory Bowel Disease: A Propensity Score Matched Analysis. Inflamm Bowel Dis 2017;23:2180–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.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;33:1322–31. [DOI] [PubMed] [Google Scholar]
  • 35.Johnson S, Louie TJ, Gerding DN, Cornely OA, Chasan-Taber S, Fitts D, Gelone SP, Broom C, Davidson DM. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis 2014;59:345–54. [DOI] [PubMed] [Google Scholar]
  • 36.Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45:302–7. [DOI] [PubMed] [Google Scholar]
  • 37.Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue YK. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422–31. [DOI] [PubMed] [Google Scholar]
  • 38.Lei DK, Ollech JE, Andersen M, Weisshof R, Zmeter N, Sossenheimer P, Rubin DT. Long-Duration Oral Vancomycin to Treat Clostridioides difficile in Patients With Inflammatory Bowel Disease Is Associated With a Low Rate of Recurrence. Am J Gastroenterol 2019;114:1904–8. [DOI] [PubMed] [Google Scholar]
  • 39.Allen SJ, Wareham K, Wang D, Bradley C, Sewell B, Hutchings H, Harris W, Dhar A, Brown H, Foden A, Gravenor MB, Mack D, Phillips CJ. A high-dose preparation of lactobacilli and bifidobacteria in the prevention of antibiotic-associated and Clostridium difficile diarrhoea in older people admitted to hospital: a multicentre, randomised, double-blind, placebo-controlled, parallel arm trial (PLACIDE). Health Technol Assess 2013;17:1–140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Heil EL, Harris AD, Brown C, Seung H, Thom KA, von Rosenvinge E, Sorongon S, Pineles L, Goodman KE, Leekha S. A Multicenter Evaluation of Probiotic Use for the Primary Prevention of Clostridioides difficile Infection. Clin Infect Dis 2021;73:1330–7. [DOI] [PubMed] [Google Scholar]
  • 41.Barker AK, Duster M, Valentine S, Hess T, Archbald-Pannone L, Guerrant R, Safdar N. A randomized controlled trial of probiotics for Clostridium difficile infection in adults (PICO). J Antimicrob Chemother 2017;72:3177–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, Cornely OA, Rahav G, Bouza E, Lee C, Jenkin G, Jensen W, Kim Y-S, Yoshida J, Gabryelski L, Pedley A, Eves K, Tipping R, Guris D, Kartsonis N, Dorr M-B. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. New England Journal of Medicine 2017;376:305–17. [DOI] [PubMed] [Google Scholar]
  • 43.Gerding DN, Kelly CP, Rahav G, Lee C, Dubberke ER, Kumar PN, Yacyshyn B, Kao D, Eves K, Ellison MC, Hanson ME, Guris D, Dorr MB. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence. Clin Infect Dis 2018;67:649–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JFWM, Tijssen JGP, Speelman P, Dijkgraaf MGW, Keller JJ. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. New England Journal of Medicine 2013;368:407–15. [DOI] [PubMed] [Google Scholar]
  • 45.Cammarota G, Masucci L, Ianiro G, Bibbò S, Dinoi G, Costamagna G, Sanguinetti M, Gasbarrini A. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther 2015;41:835–43. [DOI] [PubMed] [Google Scholar]
  • 46.Kelly CR, Ihunnah C, Fischer M, Khoruts A, Surawicz C, Afzali A, Aroniadis O, Barto A, Borody T, Giovanelli A, Gordon S, Gluck M, Hohmann EL, Kao D, Kao JY, McQuillen DP, Mellow M, Rank KM, Rao K, Ray A, Schwartz MA, Singh N, Stollman N, Suskind DL, Vindigni SM, Youngster I, Brandt L. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol 2014;109:1065–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Khoruts A, Rank KM, Newman KM, Viskocil K, Vaughn BP, Hamilton MJ, Sadowsky MJ. Inflammatory Bowel Disease Affects the Outcome of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection. Clin Gastroenterol Hepatol 2016;14:1433–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Tariq R, Disbrow MB, Dibaise JK, Orenstein R, Saha S, Solanky D, Loftus EV, Pardi DS, Khanna S. Efficacy of Fecal Microbiota Transplantation for Recurrent C. Difficile Infection in Inflammatory Bowel Disease. Inflamm Bowel Dis 2020;26:1415–20. [DOI] [PubMed] [Google Scholar]
  • 49.*.Nicholson MR, Alexander E, Ballal S, Davidovics Z, Docktor M, Dole M, Gisser JM, Goyal A, Hourigan SK, Jensen MK, Kaplan JL, Kellermayer R, Kelsen JR, Kennedy MA, Khanna S, Knackstedt ED, Lentine J, Lewis JD, Michail S, Mitchell PD, Oliva-Hemker M, Patton T, Queliza K, Sidhu S, Solomon AB, Suskind DL, Weatherly M, Werlin S, de Zoeten EF, Kahn SA. Efficacy and Outcomes of Faecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection in Children with Inflammatory Bowel Disease. J Crohns Colitis 2022;16:768–77. [DOI] [PMC free article] [PubMed] [Google Scholar]; This large multicenter cohort study evaluated the efficacy of FMT for rCDI in children, comparing those with and without IBD, and found no significant difference in efficacy between the two groups.
  • 50.**.Tariq R, Syed T, Yadav D, Prokop LJ, Singh S, Loftus EV Jr., Pardi DS, Khanna S. Outcomes of Fecal Microbiota Transplantation for C. difficile Infection in Inflammatory Bowel Disease : A Systematic Review and Meta-analysis. J Clin Gastroenterol 2023;57:285–93. [DOI] [PubMed] [Google Scholar]; A recent meta-analysis of 25 studies demonstrated that FMT is an effective therapy for preventing rCDI in patients with IBD.
  • 51.Allegretti JR, Kelly CR, Grinspan A, Mullish BH, Kassam Z, Fischer M. Outcomes of Fecal Microbiota Transplantation in Patients With Inflammatory Bowel Diseases and Recurrent Clostridioides difficile Infection. Gastroenterology 2020;159:1982–4. [DOI] [PubMed] [Google Scholar]
  • 52.Allegretti JR, Kelly CR, Grinspan A, Mullish BH, Hurtado J, Carrellas M, Marcus J, Marchesi JR, McDonald JAK, Gerardin Y, Silverstein M, Pechlivanis A, Barker GF, Miguens Blanco J, Alexander JL, Gallagher KI, Pettee W, Phelps E, Nemes S, Sagi SV, Bohm M, Kassam Z, Fischer M. Inflammatory Bowel Disease Outcomes Following Fecal Microbiota Transplantation for Recurrent C. difficile Infection. Inflamm Bowel Dis 2021;27:1371–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.**.van Lingen EE, Baunwall S, Lieberknecht SSC, Benech NN, Ianiro GG, Sokol HH, Gasbarrini AA, Cammarota GG, Eriksen MMK, van der Meulen-de Jong AAE, Terveer EEM, Verspaget HHW, Vehreschild MM, Hvas CCL, Keller JJJ. Short- and long-term follow-up after fecal microbiota transplantation as treatment for recurrent Clostridioides difficile infection in patients with inflammatory bowel disease. Therap Adv Gastroenterol 2023;16:17562848231156285. [DOI] [PMC free article] [PubMed] [Google Scholar]; This recent large prospective study, with a long-term follow-up of up to three years, found that fecal microbiota transplantation (FMT) is a safe and effective treatment for recurrent Clostridioides difficile infection (rCDI) in patients with inflammatory bowel disease (IBD), and that exacerbation of IBD after FMT is not a common occurrence.
  • 54.Fischer M, Kao D, Kelly C, Kuchipudi A, Jafri SM, Blumenkehl M, Rex D, Mellow M, Kaur N, Sokol H, Cook G, Hamilton MJ, Phelps E, Sipe B, Xu H, Allegretti JR. Fecal Microbiota Transplantation is Safe and Efficacious for Recurrent or Refractory Clostridium difficile Infection in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis 2016;22:2402–9. [DOI] [PubMed] [Google Scholar]
  • 55.Goyal A, Yeh A, Bush BR, Firek BA, Siebold LM, Rogers MB, Kufen AD, Morowitz MJ. Safety, Clinical Response, and Microbiome Findings Following Fecal Microbiota Transplant in Children With Inflammatory Bowel Disease. Inflamm Bowel Dis 2018;24:410–21. [DOI] [PubMed] [Google Scholar]

RESOURCES