Restorative proctocolectomy with ileal pouch anal anastomosis. Clostridium difficile Infection in Patients With Ileal Pouch Anal Anastomosis

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6: Clostridium difficile Infection in Patients With Ileal Pouch Anal Anastomosis BO SHEN,* ZHI DONG JIANG, VICTOR W. FAZIO, FEZA H. REMZI, LILIANA RODRIGUEZ, ANA E. BENNETT, ROCIO LOPEZ,* ELAINE QUEENER,* and HERBERT L. DUPONT,, ** *Center for Inflammatory Bowel Disease, Department of Gastroenterology/Hepatology, Department of Colorectal Surgery, and Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio; Center for Infectious Disease, University of Texas School of Public Health, Houston, Texas; Baylor College of Medicine, Houston, Texas; and **St Luke s Episcopal Hospital, Houston, Texas Background & Aims: There has been an increase in the incidence and severity of Clostridium difficile associated diarrhea in the U.S. The importance of C difficile infection in patients with ileal pouch anal anastomosis (IPAA) is unknown. This study was designed to determine risk of acquiring C difficile infection in pouch disorders. Methods: Consecutive ulcerative colitis patients (n 115) with IPAA undergoing pouch endoscopy were enrolled from May 2005 March Fecal specimens of pouch aspirate were collected during pouch endoscopy and analyzed for C difficile toxin A and B by enzyme-linked immunosorbent assay. Nineteen clinical, endoscopic, and histologic variables were assessed with stepwise selection methods. Two multivariate logistic regression models were constructed. Results: Twenty-one patients (18.3%) were positive for C difficile infection. Adjusting for other factors in the model, men were 5.12 (95% confidence interval, ) times more likely to have C difficile infection than women. Compared with patients with pancolitis, those with preoperative leftsided colitis were 8.4 (95% confidence interval, ) times more likely to have C difficile infection. Six of 6 patients with C difficile infection (3 with refractory pouchitis, 2 with Crohn s disease, and 1 with irritable pouch syndrome) with repeat clinical, endoscopic, and laboratory evaluation after anti C difficile therapy experienced clinical remission and disappearance of C difficile toxin from stools, with 4 showing decreased mucosal inflammation. Conclusions: C difficile infection involving IPAA is common, characteristically occurring with or without previous receipt of antibiotics. Treatment of C difficile infection in patients with IPAA might improve the clinical outcome. Restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) is the surgical treatment of choice for patients with UC with medically refractory disease, dysplasia, or cancer and for the majority of patients with familial adenomatous polyposis (FAP). 1,2 The etiology and pathophysiology of pouchitis are not understood. The fact that pouchitis occurs almost exclusively in patients with underlying UC, is rarely seen in patients with FAP, and generally responds to antibiotic therapy suggests an infectious or inflammatory etiology in genetically susceptible persons with IBD. The bulk of evidence points toward an abnormal mucosal innate or adaptive immune response and to altered microflora in the pouch leading to acute and/or chronic inflammation. 2 4 Altered flora might contribute to the development of pouchitis by increase in concentration or by presence of virulent organisms. 4 6 Pouchitis develops after ileostomy is taken down, and the pouch mucosa is first exposed to a fecal stream. Manipulation of microflora with antibiotic or probiotic therapy in patients with pouchitis provides additional evidence of involvement of microflora in the pathogenesis of pouchitis. There have been no consistent pathogens found responsible for this disease process. Pouchitis likely represents a disease spectrum ranging from an acute antibiotic-responsive entity to a chronic antibioticrefractory disorder. 7 Chronic refractory pouchitis is a common cause of pouch failure. 8 Patients with this condition typically do not respond to antibiotic therapy. It is important to investigate why these patients do not respond to conventional antibiotic therapy. Possible causes of pouchitis in a subset of patients include NSAID use, 9,10 cytomegalovirus infection, 11,12 celiac disease, cuffitis, and active Crohn s disease. 10 Case reports have suggested that concurrent C difficile infection (CDI) might contribute to a refractory course of pouchitis. 13,14 In addition, the incidence and prevalence of CDI in IBD and non-ibd populations appear to be increasing, particularly in hospitalized patients. 15 This prompted our current investigation to test the hypothesis that CDI might be associated with chronic inflammatory conditions of the pouch. The aims of the study were to study various pouch disorders for CDI, to determine risk factors for CDI, and to see whether anti-cdi therapy led to improvement in pouchitis symptoms. Methods Patients The Cleveland Clinic Institutional Review Board approved this study, and informed consent was obtained from all patients. From our Pouchitis Clinic from May 2005 March 2006, we enrolled 115 consecutive IPAA patients with underlying UC who underwent routine diagnostic or surveillance pouch endoscopy. To minimize selection bias, we conducted the study on all consecutive patients who met inclusion criteria. Abbreviations used in this paper: CDI, Clostridium difficile infection; FAP, familial adenomatous polyposis; IPAA, ileal pouch anal anastomosis; PDAI, Pouchitis Disease Activity Index by the AGA Institute /08/$34.00 doi: /j.cgh

2 July 2008 CLOSTRIDIUM DIFFICILE IN ILEAL POUCHES 783 Inclusion and Exclusion Criteria Inclusion criteria were IPAA patients (1) with underlying UC and (2) undergoing diagnostic pouch endoscopy for their symptoms or surveillance pouch endoscopy for dysplasia. Exclusion criterion was IPAA patients with underlying FAP. Study Design The patients demographic, clinical, endoscopic, radiographic, and histologic data were entered into our prospectively maintained database. At time of fecal specimen collection, all patients underwent outpatient pouch endoscopy with biopsy. Segmental evaluation and biopsy of the afferent limb, pouch, and rectal columnar cuff were performed during pouch endoscopy. The endoscopic features of acute inflammation for each segment were documented. The Pouchitis Disease Activity Index (PDAI) 16 endoscopy scores, from 0 6, were measured to grade inflammation of the afferent limb, pouch, and cuff, respectively. On approximately half of the subjects, we studied biopsy material for chronic inflammatory changes including crypt distortion, lamina propria mononuclear infiltration, and villous atrophy. We also studied the afferent limb histology in as many of these subjects as possible. Not part of this study, all subjects were managed with 1 or more antibacterial agents by the treating physician. The treatments given typically included 1 or more of the following drugs: ciprofloxacin, rifaximin, and tinidazole. A subset of study subjects returned for evaluation 2 4 weeks after initial therapy, at which time they were restudied clinically by pouch endoscopy and for presence of C difficile toxins in the pouch aspirate. In general, subjects returned for restudy if they were clinically not improved, or if they lived in or near the Cleveland area. Fecal specimens of pouch aspirate collected during pouch endoscopy were temporarily stored and then shipped overnight on ice (4 C) via overnight courier to Houston (Center for Infectious Diseases, University of Texas Houston School of Public Health) for C difficile toxin A and B assay by enzymelinked immunosorbent assay with Cytoclone ELISA kit (Cambridge Biotech Corp, Cambridge, MA). 17 In addition, the samples were studied in Houston by standard enteric microbiology methods for Shigella, Salmonella, Campylobacter, Aeromonas, Plesiomonas, Giardia, Entamoeba histolytica, and Cryptosporidium. 18 Diagnostic Criteria Diagnosis of pouch disorders was based on clinical, endoscopic, radiographic, and histologic assessments. For the diagnosis of active pouchitis we used the Modified PDAI, consisting of symptoms (range, 0 6) and endoscopy findings (range, 0 6) with composite score 5 points. 16,19 Diagnosis of normal pouch, Crohn s disease of the pouch, cuffitis, and irritable pouch syndrome was based on criteria previously published by our group. 7,20,21 In addition, inflammation at the afferent limb, pouch, and cuff was quantified by using the PDAI endoscopy score (range, 0 6). 16 The diagnostic criterion for CDI was the presence of toxin A and/or toxin B in pouch aspirate. Per study protocol, routine clinical treatment plan for each patient was not dependent on the results of the C difficile test. Clinical Variables and Their Definitions A total of 19 demographic and clinical variables were studied including (1) demographics: age, gender, clinical setting (outpatient vs inpatient status); (2) clinical and epidemiologic findings: family history of IBD, extent of UC (left-sided colitis or proctitis versus pancolitis), duration of UC, duration of IPAA, pouch configuration and stage, indication for proctocolectomy (refractory disease versus dysplasia or cancer), PDAI symptom score, PDAI endoscopic score, Modified PDAI scores, afferent limb endoscopic score, cuff endoscopic score, extraintestinal manifestations including arthralgias or primary sclerosing cholangitis; and (3) other potential risk factors: current or past smoking habit, daily alcohol use, use of proton pump inhibitors, 5-aminosalicylates, corticosteroids, immunomodulators, NSAIDs, antidepressants, antianxiety agents, or narcotic analgesics, and use of antibiotics within the past 4 weeks or for longer than the 4 weeks before enrollment. Outcome Measurement The primary outcome of the study was prevalence of CDI in the population and the identification of risk factors associated with CDI in patients with IPAA. Statistical Analysis Descriptive statistics were computed for all variables. These included medians, 25th and 75th percentiles for continuous factors, and frequencies for categorical factors. To study several possible causes and consequences of CDI, univariate comparisons were made with Wilcoxon rank sum tests, 2, and Fisher s exact tests, as appropriate. Two multivariable logistic regression models were constructed, one to study the possible causes of CDI and a second to study the possible consequences of the infection. Factors of interest were considered for an initial logistic regression model, and the final models were chosen by using a stepwise selection method. A significance level of.05 was used for all analyses. All analyses were performed with SAS 9.1 software, SAS Institute, Cary, NC. Results Non C difficile enteric pathogens were not detected in pouch aspirates. Of 115 patients with UC who had IPAA, 21 (18.3%) tested positive for C difficile toxin. On the basis of a univariable analysis (Tables 1 3), only gender was significantly associated with having CDI (P.024). Compared with women, men were 3.58 (95% confidence interval, ) times more likely to have CDI. No other factors were found to be significantly associated with CDI. Specifically, stage of IPAA, UC duration, pouch type, colectomy indication, extraintestinal manifestations, daily alcohol consumption, prior use of antibiotics, corticosteroids, proton pump inhibitors, NSAIDs, antidiarrheals, antidepressants, antianxiety agents, or narcotics were not found to be associated with development of CDI in pouchitis patients (P.05). Risk Factors for Clostridium Difficile Infection In Table 4 the results of the logistic regression analysis regarding risk factors for CDI are presented, with a focus on male gender, having left-sided colitis, prior use of antibiotics, proton pump inhibitors, immunomodulators, or cortiscosteroids. Adjusting for all other factors in the model, men were 5.12 (95% confidence interval, ) times more likely to have CDI than women. Also, compared with subjects with

3 784 SHEN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 7 Table 1. Demographic and Clinical Characteristics in Patients With IPAA in the Present Study C difficile positive C difficile negative Factor N Median (P25, P75) N Median (P25, P75) P value Age (y) (36.0, 52.0) (34.0, 52.0).9 IPAA duration (y) (2.0, 8.0) (3.0, 11.0).29 Duration of UC (y) (6.0, 19.0) (8.0, 20.0).57 Factor N Positive (%) N Negative (%) P value Gender.024 Male Female Extent UC.16F Pancolitis Left-sided colitis Family history of IBD.053 No Yes Pouch type.99f J Other Stage IPAA.63F Colectomy indication.30f Refactory Dysplasia Extraintestinal manifestation.98 None Arthralgia F, Fisher s Exact test; P25, 25th percentile; P75, 75th percentile. pancolitis, those with left-sided colitis were 8.4 (95% confidence interval, ) times more likely to have CDI. Not shown in the table, duration of the pouch was not a risk factor for CDI, with pouch duration for C difficile-positive versus C difficilenegative subjects of versus years, respectively (P.422). In a subgroup of 51 subjects from the 115 enrolled in the study, we examined the mucosal biopsies for chronic changes and for mucosal adaptive colon-like changes of pouch mucosa to determine differences in CDI-positive versus CDI-negative cases. All 51 subjects exhibited at least some chronic changes, of whom 8 (15.4%) were positive for C difficile. We studied afferent limb histology in 43 patients, of whom 6 (14%) were positive for C difficile. There was no evidence to suggest that the presence of C difficile was associated with villous atrophy, crypt architectural distortion, or lamina propria lymphoplasmacytic expansion in either afferent limb or pouch biopsy specimens (P.05). Consequences of Clostridium Difficile Infection Symptom and endoscopy scores in subjects with and without CDI are given in Table 3. There was no apparent difference in either score in the 2 patient groups. The various pouchitis diagnoses also did not predict patients more frequently positive for CDI. Pouch endoscopy was performed as an indication for active symptoms in 20 (95.1%) subjects in the CDI-positive group and in 74 (78.7%) in the CDI-negative group with pouchitis (P.077). The mean PDAI symptom scores for the 2 groups were and (P.259), respectively. The Modified PDAI score was found to be highly correlated with both symptom score ( 0.84; P.0001) and endoscopy score ( 0.71; P.0001) and thus was excluded from the model. Diagnosis of pouch disease status, PDAI symptom scores, PDAI endoscopy scores, afferent limb and cuff endoscopy scores were kept in the final model because of clinical importance. In Table 5, results of the logistic regression analysis regarding the possible clinical associations with CDI are presented. Clinical diagnosis and inflammatory responses were similar in the subjects with and without CDI. Clinical Symptoms, Endoscopy, and Persistence of Clostridium Difficile Toxin After Evaluation Twenty-six of the patients returned for clinical and endoscopic evaluation and C difficile toxin testing 2 4 weeks after initial evaluation and therapy. Six of 26 were later shown to have CDI, and 20 were found to be CDI-negative. The 6 patients with CDI (3 with refractory pouchitis, 2 with Crohn s disease of the pouch, 1 with irritable pouch syndrome) all exhibited clinical improvement compared with baseline PDAI symptom scores after initial treatment with drugs expected to have anti C difficile activity (rifaximin or tinidazole). Four of 6

4 July 2008 CLOSTRIDIUM DIFFICILE IN ILEAL POUCHES 785 Table 2. Possible Risk Factors for CDI in Study Patients with IPAA Factor N C difficile Positive (%) N C difficile Negative (%) P value Smoking.82 Never Current Ex-smoker Daily alcohol use.56f No Yes Clinical setting.46f Outpatient Inpatient Proton pump inhibitor use.99f No Yes Aminosalicylate use.21f No Yes Corticosteroid use.99f No Yes Antibiotic use.88 None weeks weeks Immunomodulator use.74f No Yes NSAID use.99f No Yes Antidepressant use.99f No Yes Antianxiety agents.99f No Yes Narcotic analgesics.99f No Yes F, Fisher s Exact test. CDI patients had improvement in mucosal acute inflammation (PDAI endoscopy score). All 6 subjects with CDI had negative stool tests for C difficile toxins at follow-up visit. Thirteen of 20 (65%) subjects (8 with refractory pouchitis, 9 with Crohn s disease of the pouch, and 3 cuffitis) negative for CDI receiving similar treatment as the CDI-positive subjects as part of routine clinical care exhibited clinical improvement, and 8 of 20 (40%) exhibited a reduction in PDAI endoscopy scores. Follow-up data of the 15 subjects with CDI and 74 subjects negative for CDI were not available. Discussion The prevalence and incidence of CDI have appeared to be increasing in recent years, particularly in institutionalized patients In addition, recent studies have also shown that concurrent CDI is prevalent in patients with IBD. 15,25 Purported risk factors for C difficile-associated colitis or diarrhea are maintenance immunomodulator use, 15 colonic involvement of IBD, and a diagnosis of UC. 25 In IBD, CDI might be associated with disease activation and refractoriness. 26 Whether the current C difficile epidemic has affected disease course in patients with IPAA is unknown. We speculated that the patient population in the setting of our Pouchitis Clinic was susceptible to CDI, because many of the patients with a variety of pouch disorders were on intermittentcourse or long-term antibiotic therapy, and some of the patients were treated with 5-aminosalicylates or corticosteroids. In the current study, the prevalence of CDI was 18.3% in 115 consecutive patients with healthy or diseased pouches. The risk factors for CDI were male gender and preoperative left-sided colitis versus pancolitis. To our surprise, CDI was not associated with other factors, including the clinical form of pouchitis, presence of Crohn s disease of the pouch, or prior use of antibiotics, proton pump inhibitors, or corticosteroids. Nonetheless, the eradication of C difficile with antibiotic therapy in the 6 patients with chronic pouchitis, Crohn s disease of the pouch, or irritable pouch syndrome was associated with improvement in their clinical illness. In a genetic study of the innate immune receptor, NOD2/ CARD15, a polymorphism was found in 18% of patients with pouchitis versus 8% in those without this complication. 27 Our group has identified a host polymorphism in the interleukin-8 gene that predicted increased risk of CDI in hospitalized patients 28 and was associated with a defective immune response to C difficile toxin A in patients with CDI. 29 Additional study of host genetics in patients with IPAA with and without CDI is needed to better understand the role of heritable factors in susceptibility to pouchitis. The pathogenesis of pouchitis, Crohn s disease of the pouch, and cuffitis is not clear. No single pathogen has been identified to be the responsible agent for all cases. Development of pouchitis is likely to be influenced by presence of heavier than normal mucosa-associated or luminal flora or to presence of flora with virulence properties. 4 6,30 With the presence of stasis in the pouch, exposure to fecal contents and the increased microbial load could be the initiating event that allowed for the onset of inflammatory changes. 31 Sulfateproducing bacteria have been detected in pouches of UC patients but found to be absent in pouches of FAP patients. 5 During episodes of pouchitis, this group demonstrated that the total anaerobes, Clostridium perfringens and hemolytic strains of Escherichia coli were increased, whereas total aerobes were decreased. Antibiotic therapy decreased total anaerobic and aerobic bacterial concentrations and selectively inhibited Bacteroides, Enterococcus, Bactobacillus, and Bifidobacterium, which corresponded to the resolution of pouch inflammation. 30 Although pouch mucosal inflammatory changes are important in pouchitis, the extent of mucosal inflammation fails to predict severity of the clinical illness. 32 Whereas in some pouchitis cases, C difficile might just be an innocent bystander, in other patients, the organism might be associated with exacerbation or refractoriness of symptoms or pouch inflammation, as illustrated by the 6 cases showing improvement in symptoms and pouch inflammation with eradication of the bacteria. The notion is also supported by previous case reports from our group 14 and others. 13 In these reports, stool samples from patients with metronidazole-refractory pouchitis remained positive for C difficile. We recommend the rou-

5 786 SHEN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 7 Table 3. Consequences of CDI in Study Subjects With IPAA C difficile positive C difficile negative Clinical & anatomy N Median (P25, P75) N Median (P25, P75) P value PDAI symptom score (2.0, 4.0) (1.0, 4.0).27 Pouch endoscopy score (0.0, 2.0) (0.0, 2.0).25 Modified PDAI score (2.0, 6.0) (2.0, 5.0).75 Afferent limb endoscopic score (0.0, 1.0) (0.0, 1.0).57 Cuff endoscopic score (0.0, 3.0) (0.0, 2.0).43 Pouchitis category N Positive (%) N Negative (%) P value Diagnosis.64F Normal pouch Irritable pouch syndrome Pouchitis Cuffitis Crohn s disease F, Fisher s Exact test. tine study of stools for C difficile toxins in patients with chronic refractory pouchitis, with treatment of those with a positive test by using agents with known activity against the organism, including oral vancomycin 22,33,34 or rifaximin. 35 It is difficult to explain why CDI occurs so commonly in patients with IPAA, yet interestingly, the high prevalence might not always relate to conventional risk factors such as antibiotic use and disease state of the pouch. In addition to a possible role of C difficile in the pathogenesis of selected patients with pouchitis, other explanations for our findings include (1) C difficile might be an innocent bystander in these cases and might not be associated with the cause and course of pouchitis, or (2) falsepositive results of the C difficile toxin assays might be seen in setting of IBD. The spectrum of CDI ranges from asymptomatic carriage to fulminant colitis. C difficile is a common nosocomial pathogen responsible for most cases of pseudomembranous colitis and up to 20% of cases of antibiotic-associated diarrhea. The organism is prone to colonize the colonic mucosa, but it might colonize the mucosa of the small bowel and might contribute to the development of postcolectomy enteritis. 36 The location of colonization of C difficile in patients with IPAA could be the small bowel, ileal pouch with or without colonic metaplasia, or retained rectal columnar cuff. We suggest that the ileal pouch might be susceptible to CDI. Previous studies have shown that the small bowel might be a site of CDI in humans Of possible importance of pathogenesis of CDI in pouchitis patients, the fecal stream with stasis of the pouch might lead to Table 4. Logistic Regression Analysis for Risk Factors of CDI in Study Subjects With IPAA Factor Reference OR (95% CI) P value Gender Male vs female 5.12 ( ).015 Clinical setting Inpatient vs outpatient 2.80 ( ).45 Extent of UC Left-sided colitis vs pancolitis 8.39 ( ).029 Proton pump inhibitor use Yes vs no 1.23 ( ).45 Immunomodulator use No vs yes 1.19 ( ).46 Corticosteroid use No vs yes 1.24 ( ).78 Antibiotic use 4 weeks vs none 2.03 ( ).84 Antibiotic use 4 weeks vs none 1.52 ( ).87 OR, odds ratio: CI, confidence interval. Table 5. Logistic Regression Analysis for Clinical Associations With CDI in Study Subjects With IPAA Factor Reference OR (95% CI) P value Diagnosis Crohn s disease vs normal 1.39 ( ).81 Diagnosis Cuffitis vs normal 0.79 ( ).87 Diagnosis Irritable pouch syndrome vs normal 3.44 ( ).34 Diagnosis Pouchitis vs normal 1.19 ( ).89 Symptom score 1 unit increase 1.25 ( ).26 Endoscopy score 1 unit decrease 1.09 ( ).66 Afferent limb score 1 unit decrease 1.10 ( ).73 Cuff score 1 unit decrease 1.04 ( ).84 OR, odds ratio; CI, confidence interval.

6 July 2008 CLOSTRIDIUM DIFFICILE IN ILEAL POUCHES 787 changes of mucosa resembling those seen in the colon. 40 Colonic metaplasia, as evidenced by the presence of villous blunting, crypt cell hyperplasia, expression of colon epithelium-specific antigens such as human tropomyosin-5, and alterations of mucin glycoproteins, increases the risk for pouchitis. 41,42 The natural history of pouch mucosa in patients with UC after restorative proctocolectomy includes in some patients the development of inflammation, colonic metaplasia, villous atrophy, and malignant transformation. 3 These changes might predispose to CDI, although they were not found in the present study. There are a number of limitations to our study. First, the study was conducted in a tertiary care subspecialty clinic setting, which might have been subjective to selection bias. In addition, we did not isolate C difficile by stool culture followed by polymerase chain reaction identification of toxin types to detect binary toxin genes (cdta and cdtb) and partial deletions of the tcdc gene found in the current epidemic and hypervirulent strain. 24 The most important limitation is the size of the study sample. To draw firm conclusions about the role of CDI in patients with pouchitis, additional studies are needed. In conclusion, CDI occurred commonly in patients with IPAA, with the association occurring most frequently in men. A preoperative left-sided colitis was found to be a risk factor for CDI. CDI in this population had no apparent association with previous receipt of antibiotics. Importantly, treatment of CDI in our patients with pouchitis improved their clinical appearance, although the presence of CDI was not shown in the study to be associated with inflammatory changes in the ileal pouches. References 1. Fazio VW, Ziv Y, Church JM, et al. 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7 788 SHEN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 7 comparison of metronidazole and ciprofloxacin in the treatment of pouchitis. Dis Colon Rectum 2004;47: Chaussade S, Denizot Y, Valleur P, et al. Presence of PAF-acether in stool of patients with pouch ileoanal anastomosis and pouchitis. Gastroenterology 1991;100: Shen B, Achkar JP, Lashner BA, et al. Endoscopic and histologic evaluation together with symptom assessment are required to diagnose pouchitis. Gastroenterology 2001;121: Pepin J, Routhier S, Gagnon S, et al. Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada. Clin Infect Dis 2006;42: Zar FA, Bakkanagari SR, Moorthi KM, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45: Johnson S, Schriever C, Galang M, et al. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis 2007;44: Lundeen SJ, Otterson MF, Binion DG, et al. Clostridium difficile enteritis: an early postoperative complication in inflammatory bowel disease patients after colectomy. J Gastrointest Surg 2007;11: Taylor RH, Borriello SP, Taylor AJ. Isolation of Clostridium difficile from the small bowel. Br Med J (Clin Res Ed) 1981;283: Testore GP, Nardi F, Babudieri S, et al. Isolation of Clostridium difficile from human jejunum: identification of a reservoir for disease? J Clin Pathol 1986;39: Vesoulis Z, Williams G, Matthews B. Pseudomembranous enteritis after proctocolectomy: report of a case. Dis Colon Rectum 2000;43: Shepherd NA, Healey CJ, Warren BF, et al. Distribution of mucosal pathology and an assessment of colonic phenotypic change in the pelvic ileal reservoir. Gut 1993;34: Biancone L, Palmieri G, Lombardi A, et al. Tropomyosin expression in the ileal pouch: a relationship with the development of pouchitis in ulcerative colitis. Am J Gastroenterol 2003;98: Tysk C, Riedesel H, Lindberg E, et al. Colonic glycoproteins in monozygotic twins with inflammatory bowel disease. Gastroenterology 1991;100: Address requests for reprints to: Herbert L. DuPont, MD, 1200 Herman Pressler, RAS E-733, Houston, TX hdupont@sleh.com; ; fax: Dr DuPont has received honoraria for speaking for the following companies: Salix Pharmaceuticals, Merck Vaccine Division, McNeil Consumer Healthcare, Romark Institute for Medical Research, Merck Vaccine Division, and IOMAI Corporation and has received grants through the University of Texas to support research from Salix Pharmaceuticals, Romark Institute for Medical Research, IOMAI Corporation, and Optimer Pharmaceuticals. Dr Shen has received honoraria and research grants from Salix Pharmaceuticals. Dr Jiang has received honoraria for speaking for Salix Pharmaceuticals and has received grants through the University of Texas to support research from Salix Pharmaceuticals.