Systematic Review
Copyright ©The Author(s) 2017.
World J Gastroenterol. Jul 21, 2017; 23(27): 4986-5003
Published online Jul 21, 2017. doi: 10.3748/wjg.v23.i27.4986
Table 1 Epidemiology of Clostridium difficile infection in inflammatory bowel disease
Ref.Patient populationSampling time frameDiagnosis methodDisease activityConclusions
Keighley[92] (1983)IBD adult inpatients1978-1980Stool culture on selective medium + cytotoxicity assayActiveCDI incidence (%) IBD: 5.7; UC 4.7; CD 6.3
Gurian et al[93] (1983)IBD adult inpatients and outpatients1980-1981Stool culture on selective medium + cytotoxicity assayActiveCDI incidence (%) IBD: 0
Rolny et al[26] (1983)IBD adult inpatients1980-1981Stool culture on selective medium + cytotoxicity assayActiveCDI incidence (%) UC: 5; CD: 7.7
Greenfield et al[21] (1983)IBD adult inpatients and outpatients1980-1981Stool culture on selective medium + cytotoxicity assayMixedCDI incidence (%) UC: 13.7; CD: 13.2
Burke et al[94] (1987)IBD adult outpatients1984-1986Stool culture on selective medium + cytotoxicity assayActiveCDI incidence (%) IBD 3.2
Gryboski[95] (1991)IBD pediatric inpatients and outpatients1986-1990Stool culture on selective medium + cytotoxicity assayActiveCDI incidence (%) IBD 16; UC: 18; CD 14
Meyer et al[22] (2004)IBD adult inpatients and outpatients2000-2001Immunoassay for Toxin A until 2001 then EIA for Toxin A/BActiveCDI incidence (%) IBD: 16.7; UC: 12.5; CD: 23.8; IC: 11.1
Mylonaki et al[23] (2004)IBD adult inpatients and outpatients1997-2001ELISA for Toxins A/BActiveCDI incidence (%) IBD: 5.5; CD: 13.2
Issa et al[24] (2007)IBD adult inpatients and outpatients2005ELISA for Toxins A/BActiveCDI incidence (%) UC: 6.1; CD: 4.1
IBD patients accounted for 4% of the total CDI patient cohort in 2003, 7% in 2004, and 16% in 2005
Rodemann et al[16] (2007)IBD pediatric and adult inpatients (United States)1998-2004Cell cytotoxic cultureActiveCDI incidence (%) UC: 3.9; CD: 1.6
2002 onwards C. difficile Toxin A/B immunoassayCDI incidence increase: UC > CD > non-IBD
Non-IBD population: 8.5 to 15.9/1000 admissions
CD: 9.5 to 22.3/1000 admissions
UC: 18.4 to 57.6/1000 admissions
Shen et al[33] (2008)UC adult outpatients with IPAA2005-2006ELISA for Toxin A/BMixedCDI incidence (%) UC: 18.3
Bossuyt et al[20] (2009)IBD and non-IBD CDI adult inpatients2000-2008EIA for Toxin A until 2005, then EIA for Toxins A/BActiveAll patients: 3.75-fold increase in CDI between 2000-2003 and 2004-2008
Balamurugan et al[96] (2008)UC adult outpatients2004-2005PCR for C. difficileMixedCDI incidence (%) UC: 92
Ananthakrishnan et al[18] (2008)IBD and non-IBD CDI adult inpatients1998-2004N/RN/RCDI incidence increase: UC: 24 to 39/1000 discharge ; CD: 8 to 12/1000 discharges
Nguyen et al[17] (2008)IBD and non-IBD adult inpatients1998-2004N/RN/RCDI incidence increase: UC: 26.6 to 51.2/1000 discharges
Pascarella et al[35] (2009)IBD pediatric inpatients2005-2007Enzyme immunoassay for toxins A/BMixedCDI incidence (%) UC: 21.3; CD: 35
Ricciardi et al[27] (2009)IBD adult inpatients1993-2003N/RActiveCDI incidence (%) UC: 2.8; CD: 1.0
CDI incidence increase: IBD: 12.2 to 21/1000 discharges; CD + colonic involvement: 12.2 to 23.1/1000 discharges
Wultańska et al[36] (2010)IBD pediatric outpatients2005-2007EIA for Toxins A/BMixedCDI incidence (%) IBD: 60; UC: 61; CD: 59
or PCR
Ananthakrishnan et al[58] (2011)IBD adult inpatients1998, 2004, 2007N/RN/RCDI incidence increase: CD: 0.8 to 1.5% of hospitalizations; UC: 2.4 to 5.3% of hospitalizations
Absolute mortality increase in CDI + IBD (5.9% to 7.2%)
Kaneko et al[46] (2011)UC pediatric and adult inpatients and outpatients2006-2009ELISA for Toxin AActiveCDI incidence (%) UC inpatient: 36.6; UC outpatient: 41.7
Mezoff et al[37] (2011)IBD pediatric patients2007-2008EIA for Toxins A and BMixedCDI incidence (%) UC: 5.8; CD: 7.8; IC: 11.1
Ott et al[28] (2011)IBD adult inpatients2001-2008ELISA for Toxins A/B or characteristic histologyActiveCDI incidence (%) IBD: 4.0; CD: 13.2; UC: 4.7
Banaszkiewicz et al[38] (2012)IBD pediatric inpatients2007-2010EIA for Toxins A and BMixedCDI incidence (%) IBD: 47
Antonelli et al[29] (2012)IBD adult inpatients2007-2010N/RActiveCDI incidence (%) UC: 11.1; CD: 1.7
Murthy et al[31] (2012)UC adult inpatients2002-2008N/RActiveCDI incidence (%) UC: 9.0
Lamousé-Smith et al[97] (2013)IBD pediatric inpatients and outpatients (United States)2006-2012PCR for Toxin B +/- ELISA for Toxin A/BMixedCDI incidence (%) UC: 18.4; CD: 11.6
Masclee et al[47] (2013)IBD adult outpatients2009-2010PCR for C. difficile and Toxin A/BActiveCDI incidence (%) IBD: 4.9; UC: 3.4; CD: 5.9
Mir et al[39] (2013)IBD pediatric patients2010-2012EIA or PCR for Toxin A/BN/RCDI incidence (%) IBD: 8.1; UC: 5.6; CD: 9.3 ; IBDU: 11.1
No significant variation in IBD incidence over 3 yr
Pant et al[98] (2013)IBD pediatric inpatients2000, 2003, 2006, 2009N/RN/RCDI incidence increase: IBD: 21.7 to 28 cases/1000 IBD cases per year; UC: 28.1 to 42.2/1000 cases per year; CD: 18.3 to 20.3/1000 cases per year
Li et al[34] (2013)IBD adult outpatients with IPAA2010-2011PCR for Toxin B geneActiveCDI incidence (%) IBD: 10.7; UC: 10.4; CD: 0; IC: 25.0
Martinelli et al[40] (2014)IBD pediatric inpatients and outpatients2010-2011EIA for Toxins A/BMixedCDI incidence (%): IBD: 10.0; UC: 7.5; CD: 11.9
Regnault et al[30] (2014)IBD adult inpatients2008-2010Stool culture on selective medium + cytotoxicity assay +/- toxigenic cultureActiveCDI incidence (% hospitalizations): IBD: 7.0; UC: 6.8; CD: 7.2
Negrón et al[32] (2014)UC adult inpatients2000-2009EIA for Toxins A/BActiveCDI incidence (%) UC: 6.1
Hourigan et al[99] (2014)IBD and non-IBD pediatric and adult inpatients1993-2012N/RN/RCDI incidence increase: IBD: 19.9 to 67/1000 admissions
Rate of increase in CDI not significantly different between patients with or without IBD
Krishnarao et al[25] (2015)IBD adult inpatients and outpatients2008-2011EIA and PCRMixedCDI incidence (%) IBD: 5.1
Sandberg et al[19] (2015)IBD pediatric inpatients1997-2011N/RN/RHospitalization rate increase: CDI + IBD: 2.8 to 14.4 per million population per year
Rate of increase for UC + CDI = CD + CDI
Simian et al[100] (2016)IBD adult and pediatric inpatients and outpatients2014-2015PCRN/RCDI incidence (%) UC: 5.0; CD: 5.0
Roy et al[101] (2016)CD adult outpatients on chronic antibiotic therapy > 6 mo1992-2015N/RN/RCDI incidence (%) CD: 2.0
Table 2 Risk factors for Clostridium difficile infection in inflammatory bowel disease
Ref.Sampling time frameSettingDiagnosis methodIdentified risk factors
Razik et al[44] (2016)2010-2013InpatientPCRNon-ileal CDHospitalisation for CDI; recent antibiotic use; biologic therapy; 5-ASA; Steroids
McCurdy et al[54] (2016)2005-2011Inpatient and outpatientPCRCMV infectionN/A
Seril et al[45] (2014)2010-2013Inpatient and outpatientPCR for Toxin BPost-surgery mechanical intestinal complications; low serum immunoglobulin levelNone identified
Regnault et al[30] (2014)2008-2010InpatientStool culture on selective medium + cytotoxicity assay +/- toxigenic cultureNone identifiedNSAIDs
Connelly et al[52] (2014)N/RN/RPCR for Toxin A geneIL-4 gene associated SNP rs2243250Not studied
Ananthakrishnan et al[102] (2014)1998-2010InpatientN/RLow vitamin D concentrationNot studied
Ananthakrishnan et al[56] (2013)N/RInpatient and outpatientELISA for Toxin A/BFemale sex; pancolitis; IBD-related SNPsProtective : Anti-TNF therapy
Monaghan et al[53] (2013)2009-2012N/RToxigenic cultureImpaired ability to generate: toxin-specific antibody, memory B-cell responsesNot studied
Li et al[34] (2013)2010-2011OutpatientPCR for Toxin BNone identifiedRecent hospitalization
Masclee et al[47] (2013)2009-2010OutpatientPCR for C. difficile and Toxins A/BNone identifiedNone identified
Kaneko et al[46] (2011)2006-2009Inpatient and outpatientELISA for Toxin ANone identifiedNone identified
Kariv et al[43] (2011)2000-2006Inpatient and outpatientEIA for Toxin A/BRecent surgeryRecent antibiotic use; recent hospitalization
Ricciardi et al[27] (2009)1993-2003InpatientN/RColonic involvementNot studied
Schneeweiss et al[49] (2009)2001-2006Inpatient and outpatientN/RNot studiedCorticosteroid initiation
Nguyen et al[17] (2008)1998-2004InpatientN/RColonic involvementNot studied
Issa et al[24] (2007)2005InpatientELISA for Toxin A/BColonic involvementMaintenance immunomodulator use
Rodemann et al[16] (2007)1998-2004InpatientCell cytotoxic cultureAgeNot studied
2002 onwards C. difficile Toxin A/B immunoassayComorbidity
Mylonaki et al[23] (2004)1997-2001InpatientELISA for Toxin A/BNone identifiedRecent antibiotic use
Table 3 Outcomes of inflammatory bowel disease patients with Clostridium difficile infection
Ref.Patient populationSampling time frameStudy designnOutcomes
Razik et al[44] (2016)Adult CDI2010-2013Retrospective, single-center, cohort study503Incidence of rCDI
IBD + CDIIBD > non-IBD [2.04/100 person-months (95%CI: 1.55-2.64) vs 1.25 episodes per 100 person-months (95%CI: 1.05-1.48)]
IBD > non-IBD (6.4% vs 0.3%)
Skowron et al[61] (2016)Adult IBD + IPAA2000-2010Retrospective, observational, single-center cohort study417CDI pre-colectomy associated with post-reconstruction pouch failure (HR = 3.02 95%CI: 1.23-7.44)
Inpatient (United States)
McCurdy et al[54] (2016)Adult IBD2005-2011Retrospective, case-control, single-center, study248Colectomy-free survival at 1 yr
IBD + CMVIBD + CDI > IBD + CMV + CDI (71.5% vs 30%)
IBD + CMV + CDIIBD + CMV controls > IBD + CMV + CDI (57.1% vs 30%)
Inpatient and outpatient (United States)
Negrón et al[32] (2014)Adult UC2000-2009Retrospective, case-control, multi-center, database study481Emergent surgery
Inpatient (Canada)CDI + UC > UC alone [OR = 3.39 (95%CI: 1.02-11.23)]
Development of new infectious postoperative complication
CDI + UC > UC alone (OR = 4.76, 95%CI: 1.10-20.63)
Horton et al[70] (2014)Adult IBD2006-2010Retrospective, observational, single-center study114Readmission:
Inpatient (United States)UC + CDI > CD + CDI (24% vs 10%, P = 0.04)
IBD + steroids > no-steroids (29% vs 8%, P < 0.01)
UC + CDI > CD + CDI, index admission (27.4% vs 0%, P < 0.01)
IBD + steroids > no-steroids (32% vs 6%, P < 0.01)
Pant et al[98] (2013)Pediatric IBD2000, 2003, 2006, 2009Retrospective, nested case-control, nationwide database study12610LOS:
Inpatient (United States)CDI + IBD > IBD (8.0 vs 6.0, aRC = 2.1 d, 95%CI: 1.4-2.8)
Hospitalization cost:
CDI + IBD > IBD alone ($45126 vs $34703, aRC = $11506, 95%CI: 6192-16829)
Parenteral nutrition:
CDI + IBD > IBD alone (15.9% vs 12.1% aOR = 1.5, 95%CI: 1.1-2.0)
Blood transfusions:
CDI + IBD > IBD alone (17.7% vs 9.8%, aOR = 1.8, 95%CI: 1.4-2.4).
Li et al[34] (2013)Adult IBD + IPAA2010-2011Prospective, single-center, cohort study19642.9% cured by single course of Vancomycin
Outpatient (United States)57.1% recurrent/refractory CDI
Chu et al[103] (2013)Adult UC + CDI2002-2012Retrospective, single-center, observational study23Morbidity and mortality after colectomy:
Inpatient (United States)UC + CDI + full antibiotic course pre-op = UC + CDI + incomplete antibiotic course pre-op
Ananthakrishnan et al[55] (2013)Adult IBD2007Retrospective, nested case-control, nationwide database study67221 hospitalizationsMortality:
Inpatient (United States)CDI + IBD vs IBD alone (OR = 3.23, 95%CI: 2.55-4.03).
Murthy et al[31] (2012)Adult UC2002-2008Retrospective, database, cohort study2016Mortality:
Inpatient (Canada)CDI + UC > UC alone, 5-yr risk (aHR = 2.40, 95%CI: 1.37-4.20)
CDI + UC > UC alone, index hospitalization (aHR = 8.90, 95%CI: 2.80-28.3)
CDI + UC > UC alone, 5 years post-discharge (aHR = 2.41, 95%CI: 1.37-4.22)
Navaneethan et al[60] (2012)Adult UC2002-2007Retrospective, single-center, cohort study146UC-related ER visits:
Inpatient and outpatient (United States)CDI + UC vs UC alone, 1 yr post index infection (37.8% vs 4%, P < 0.001)
CDI + UC vs UC alone, 1 yr post index infection (35.6% vs 9.9%, P < 0.001)
CDI associated with colectomy within 1 yr (OR = 10, 95%CI: 2.7-36.3)
Escalation in therapy:
CDI + UC year after CDI admission vs year prior (55.8% vs 12.9%, P < 0.0001)
Jen et al[57] (2011)Adult IBD2002-2008Retrospective, nested case-control, nationwide database study241478 hospitalizationsMortality:
Inpatient (England)IBD + CDI (defined as hospital-acquired > IBD alone (aOR = 6.32, 95%CI: 5.67-7.04)
IBD + CDI > IBD alone (27.9 d longer)
GI surgery:
IBD + CDI > IBD alone (aOR = 1.87, 95%CI: 0.60-5.85)
Kariv et al[43] (2011)Adult UC2000-2006Single-center78Colectomy within 3 mo not associated with CDI
Inpatient and outpatient (United States)No UC or CDI associated mortality identified
Ananthakrishnan et al[58] (2011)Adult IBD1998, 2004, 2007Retrospective, nested case-control, nationwide database study-Mortality:
Inpatient (United States)IBD + CDI > IBD alone, from 1998 to 2007 (OR = 2.38, 95%CI: 1.52-3.72 to OR = 3.38, 95%CI: 2.66-4.29).
Kelsen et al[62] (2011)Pediatric IBD1997-2007Retrospective, nested case-control, single-center study315rCDI:
Inpatient (United States)CDI + IBD > CDI-alone (34% vs 7.5%, P < 0.0001)
Escalation in therapy:
IBD + CDI > IBD alone (67% vs 30%, P < 0.001)
Jodorkovsky et al[59] (2010)Adult UC2004-2005Retrospective, single-center, case-control study99UC-related hospitalizations:
Inpatient (United States)CDI + IBD > IBD alone, over 1 yr
CDI at index admission predictor for colectomy within 1 yr (OR = 2.38, 95%CI: 1.01-5.6)
CDI status not a significant predictor for requirement for emergent colectomy at index admission
CDI + IBD = IBD alone
Ben-Horin et al[64] (2010)Adult IBD + CDI2000-2008Retrospective, multi-center, cohort study93Morbidity and mortality:
Inpatient (Europe/Israel)IBD + CDI patients + pseudomembranes on endoscopy = IBD + CDI without pseudomembranes
Nguyen et al[17] (2008)IBD and non-IBD controls1998-2004Retrospective, nested case-control, nationwide database study116842 hospitalizationsMortality:
Inpatient (United States)UC + CDI > CDI alone (OR = 3.79, 95%CI: 2.84-5.06)
CD + CDI > CDI alone
Hospitalization cost:
UC + CDI > CDI alone
Table 4 Treatment of clostridium difficile infection in inflammatory bowel disease[3,4]
First episode
Stop all non-CDI related antibiotic therapy if possible
Mild to moderate diseaseDiarrhea and symptoms not meeting criteria for severe diseaseMetronidazole 500 mg by mouth 3 times per day for 10 d to 14 dIn hospitalized patients with UC and nonsevere CDI, treatment with a vancomycin-containing regimen vs metronidazole alone resulted in fewer readmissions and shorter LOS[70]
Vancomycin 125 mg by mouth 4 times per day for 10 to 14 d
Severe diseaseSerum albumin < 3 g/dL AND one of the following:Vancomycin 125 mg by mouth 4 times per day for 10 to 14 d
WBC ≥ 15000 cells/mm3
Abdominal tenderness
Creatinine ≥ 133 μmol/L
Severe, complicated diseaseAdmission to intensive care unitVancomycin 500 mg by mouth or nasogastric tube 4 times per dayConsider early surgical consultation
Hypotension ± vasopressor requirementand
Fever ≥ 38.5 °CMetronidazole 500 mg IV every 8 h
Ileusand, if ileus,
Mental status changesVancomycin 500 mg in 500 mL saline as enema 4 times per day
WBC ≥ 35000 cells/mm3 or ≤ 2000 cells/mm3
Serum lactate ≥ 2.2 mmol/L
End organ failure
Recurrent CDI
First recurrenceMetronidazole 500 mg by mouth 3 times per day for 10 to 14 d
Vancomycin 125 mg by mouth 4 times per day for 10 to 14 d
Fidaxomicin 200 mg by mouth 2 times per day for 10 d
Second recurrence-Tapered and pulsed vancomycin
Fidaxomicin 200 mg by mouth 2 times per day for 10 d
Subsequent recurrence-Fecal microbiota transplant
Table 5 Case reports of corticosteroid initiation in Clostridium difficile infection
Reference (year of publication)Patient data
Treatment regimenOutcome
DemographicsClinical presentation
Cavagnaro et al[104] (2003)5MBloody diarrhea (> 10 loose stools/d), tenesmus, abdominal tenderness, feverOral vancomycin (40 mg/kg per day divided in 6-hourly doses) and IV metronidazole (20 mg/kg per day divided in 8-hourly doses) × 14 dResolution of diarrhea within 24 h of steroid initiation
WBC 19000 cells/mm3, albumin 21 g/LResolution of endoscopic changes at 6 wk
Positive C. difficile toxinIV methyldrnisolone (2 mg/kg per day in two divided doses) on day 14 × 3 d
Pseudomembranous colitis on flexible sigmoidoscopy on day 14Prednisone 2 mg/kg per day tapered over one month
Sykes et al[105] (2012)54FModerate CDI that resolved with 10-d course antibioticsOral metronidazole × 10 d with resolution of symptoms (doses not specified)Decreased stool frequency, normalization of vital signs, reduction in CRP to 132 within 48 h of steroid initiation
Recurrent diarrhea and abdominal pain 10 d after completion of antibiotics withResolution of diarrhea, further reduction in CRP to 15 after 9 d of steroid therapy
left colonic thickening on CT and positive C. difficile toxinOral vancomycin and metronidazole upon admission (doses not specified) × 4 dResolution of endosocopic changes at 1 mo
Fever, tachycardia on day 4Sustained clinical response at 5 mo
with pseudomembranous colitis on flexible sigmoidoscopyOral vancomycin 125 mg every 6 h × 9 d
CRP increased from 149 on admission to 236 on day 4IV hydrocortisone 100 mg every 6 h × 9 d
Prednisolone 30 mg daily with tapering regimen
73FModerate-severe CDI that resolved with 10-d course antibioticsMetronidazole 400 mg every 8 h × 10 d with resolution of symptomsResolution of diarrhea, normalization of vital signs, reduction in CRP to 7 within 48 h of steroid initiation
Recurrent moderate CDI 1 wk after completion of antibiotics that resolved with another 10-d course of antibioticsComplete clinical response at 14 d with no further relapses
Recurrent CDI 10 d after completion of antibiotics with fever, tachycardia, increased CRP 87Oral vancomycin 125 mg every 6 h × 10 d with resolution of symptoms
Slow response to antibiotics with flexible sigmoidoscopy on day 8 with pseudomembranous colitis
Oral vancomycin 125 mg every 6 h × 8 d with tapering regimen over 14 d
Prednisolone 30 mg daily × 7 d followed by tapering regimen
91FModerate CDI with persistent diarrhea despite courses of metronidazole and vancomycinOral metronidazole 400 mg every 8 h × 10 d without resolution of symptomsResolution of diarrhea and normalization of CRP within 72 h of steroid initiation
CRP 11No further relapses
Flexible sigmoidoscopy with pseudomembranous colitisOral vancomycin 125 mg every 6 h for prolonged course without resolution of symptoms
Prednisolone 30 mg daily × 14 d with continued vancomycin tapering regimen over 4 wk