Lawrence J. Brandt

Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.

Clostridium difficile infection (CDI) is a leading cause of hospital-associated gastrointestinal illness and places a high burden on our health-care system. Patients with CDI typically have extended lengths-of-stay in hospitals, and CDI is a frequent cause of large hospital outbreaks of disease. This guideline provides recommendations for the diagnosis and management of patients with CDI as well as for the prevention and control of outbreaks while supplementing previously published guidelines. New molecular diagnostic stool tests will likely replace current enzyme immunoassay tests. We suggest treatment of patients be stratified depending on whether they have mild-to-moderate, severe, or complicated disease. Therapy with metronidazole remains the choice for mild-to-moderate disease but may not be adequate for patients with severe or complicated disease. We propose a classification of disease severity to guide therapy that is useful for clinicians. We review current treatment options for patients with recurrent CDI and recommendations for the control and prevention of outbreaks of CDI.

An Evidence-Based Position Statement on the Management of Irritable Bowel Syndrome

IBS is characterized by abdominal discomfort associated with altered bowel function; structural and biochemical abnormalities are absent. e pathophysiology of IBS is multifactorial and of intense recent interest, largely because of the possibility of developing targeted therapies. As IBS is one of the most common disorders managed by gastroenterologists and primary care physicians, this monograph was developed to educate physicians about its epidemiology, diagnostic approach, and treatments. e American College of Gastroenterology (ACG) IBS Task Force updated the 2002 monograph because new evidence has emerged on the bene* t and risks of drugs used for IBS. Furthermore, new drugs also have been developed and the evidence for e+ cacy of these drugs needed to be assessed. To critically evaluate the rapidly expanding research about IBS, a series of systematic reviews were performed. Standard criteria for systematic reviews were met, including comprehensive literature searching, use of prespeci* ed study selection criteria, and use of a standardized and transparent process to extract and analyze data from studies. Evidence-based statements were developed from these data by the entire ACG IBS Task Force. Recommendations were graded using a formalized system that quanti* es the strength of evidence. Each recommendation was classi* ed as strong (grade 1) or weak (grade 2) and the strength of evidence classi* ed as strong (level A), moderate (level B), or weak (level C). Recommendations in this position statement may be crossreferenced with the supporting evidence in the accompanying article, “ An Evidenced Based Review on the Management of Irritable Bowel Syndrome ” .

Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent clostridium difficile infection

OBJECTIVES:Clostridium difficile infection (CDI) has increased to epidemic proportions over the past 15 years, and recurrence rates of 30–65% with failure to respond to multiple courses of antimicrobials are common. The aim of this study was to report the efficacy of fecal microbiota transplantation (FMT) in patients with recurrent CDI in five geographically disparate medical centers across the United States.METHODS:A multicenter long-term follow-up study was performed on the use of FMT for recurrent CDI. We were able to contact 77 of 94 eligible patients who had colonoscopic FMT for recurrent CDI ≥ 3 months before. Respondents completed a 36-item questionnaire via mail and/or phone that solicited pre-FMT, post-FMT, and donor data. Study outcomes included primary cure rate (resolution of symptoms without recurrence within 90 days of FMT) and secondary cure rate (resolution of symptoms after one further course of vancomycin with or without repeat FMT).RESULTS:Seventy-three percent of patients were women and the average age was 65 years. The long-term follow-up period ranged from 3 to 68 months between FMT and data collection (mean: 17 months). The majority of patients were living independently at the time of FMT; however, 40% were ill enough to be hospitalized, homebound, or living in a skilled nursing facility. Spouses and partners accounted for 60% of donors and 27% were either first-degree relatives or otherwise related to the patient. The average symptom duration before FMT was 11 months and patients had failed an average of five conventional antimicrobial regimens; nonetheless, 74% of patients had resolution of their diarrhea in ≤ 3 days. Diarrhea resolved in 82% and improved in 17% of patients within an average of 5 days after FMT. The primary cure rate was 91%. Seven patients either failed to respond or experienced early CDI recurrence (≤ 90 days) after FMT. Four of these patients were successfully treated with vancomycin with or without probiotics; two patients were treated unsuccessfully with vancomycin, but subsequent FMT was successful; one patient was not treated and died in hospice care of unclear cause. The secondary cure rate was 98%. All late recurrences of CDI occurred in the setting of antimicrobial therapy for treatment of infections unrelated to C. difficile. In all, 53% of patients stated they would have FMT as their preferred first treatment option if CDI were to recur. While no definite adverse effects of FMT were noted, two patients had improvement in a pre-existing medical condition and four patients developed diseases of potential interest after FMT.CONCLUSIONS:FMT is a rational, durable, safe, and acceptable treatment option for patients with recurrent CDI.

Fecal Microbiota Transplant for Treatment of Clostridium difficile Infection in Immunocompromised Patients

OBJECTIVES:Patients who are immunocompromised (IC) are at increased risk of Clostridium difficile infection (CDI), which has increased to epidemic proportions over the past decade. Fecal microbiota transplantation (FMT) appears effective for the treatment of CDI, although there is concern that IC patients may be at increased risk of having adverse events (AEs) related to FMT. This study describes the multicenter experience of FMT in IC patients.METHODS:A multicenter retrospective series was performed on the use of FMT in IC patients with CDI that was recurrent, refractory, or severe. We aimed to describe rates of CDI cure after FMT as well as AEs experienced by IC patients after FMT. A 32-item questionnaire soliciting demographic and pre- and post-FMT data was completed for 99 patients at 16 centers, of whom 80 were eligible for inclusion. Outcomes included (i) rates of CDI cure after FMT, (ii) serious adverse events (SAEs) such as death or hospitalization within 12 weeks of FMT, (iii) infection within 12 weeks of FMT, and (iv) AEs (related and unrelated) to FMT.RESULTS:Cases included adult (75) and pediatric (5) patients treated with FMT for recurrent (55%), refractory (11%), and severe and/or overlap of recurrent/refractory and severe CDI (34%). In all, 79% were outpatients at the time of FMT. The mean follow-up period between FMT and data collection was 11 months (range 3–46 months). Reasons for IC included: HIV/AIDS (3), solid organ transplant (19), oncologic condition (7), immunosuppressive therapy for inflammatory bowel disease (IBD; 36), and other medical conditions/medications (15). The CDI cure rate after a single FMT was 78%, with 62 patients suffering no recurrence at least 12 weeks post FMT. Twelve patients underwent repeat FMT, of whom eight had no further CDI. Thus, the overall cure rate was 89%. Twelve (15%) had any SAE within 12 weeks post FMT, of which 10 were hospitalizations. Two deaths occurred within 12 weeks of FMT, one of which was the result of aspiration during sedation for FMT administered via colonoscopy; the other was unrelated to FMT. None suffered infections definitely related to FMT, but two patients developed unrelated infections and five had self-limited diarrheal illness in which no causal organism was identified. One patient had a superficial mucosal tear caused by the colonoscopy performed for the FMT, and three patients reported mild, self-limited abdominal discomfort post FMT. Five (14% of IBD patients) experienced disease flare post FMT. Three ulcerative colitis (UC) patients underwent colectomy related to course of UC >100 days after FMT.CONCLUSIONS:This series demonstrates the effective use of FMT for CDI in IC patients with few SAEs or related AEs. Importantly, there were no related infectious complications in these high-risk patients.

Efficacy of 5-HT 3 Antagonists and 5-HT 4 Agonists in Irritable Bowel Syndrome: Systematic Review and Meta-Analysis

OBJECTIVES:Irritable bowel syndrome (IBS) is a chronic functional disorder. 5-Hydroxytryptamine (5-HT) is a key modulator of gastrointestinal sensorimotor function. Many patients have IBS that can be difficult to treat, which has led to the development of newer agents, such as 5-HT3 antagonists and 5-HT4 agonists. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to estimate the efficacy of all available 5-HT agents in IBS.METHODS:MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to June 2008). Trials recruiting adults with IBS in primary, secondary, or tertiary care comparing 5-HT3 antagonists or 5-HT4 agonists with placebo were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference.RESULTS:The strategic search identified 1,593 citations. A total of 29 RCTs were eligible for inclusion; placebo was compared with 5-HT3 antagonists in 11 RCTs, with tegaserod in 11, and with mixed 5-HT3 antagonists/5-HT4 agonists in 7. The study quality was generally high. The RR of IBS symptoms persisting with 5-HT3 antagonists vs. placebo was 0.78 (95% CI: 0.71–0.86), with a similar benefit for both alosetron and cilansetron. Tegaserod was also superior to placebo (RR=0.85; 95% CI: 0.80–0.90). Renzapride and cisapride had no benefit in IBS.CONCLUSIONS:Alosetron, cilansetron, and tegaserod are all effective in the treatment of IBS. Serious adverse events were rare in the eligible RCTs included in this systematic review.

Recommendations for Probiotic Use—2011 Update

This study describes the consensus opinion of the participants of the third Yale Workshop on probiotic use. There were 10 experts participating. The recommendations update those of the first 2 meetings that were published in 2005 and 2008. The workshop presentations and papers in this supplement relate to the involvement of normal microbiota involved in intestinal microecology, how the microbes interact with the intestine to affect our immunologic responses, the stability and natural history of probiotic organisms, and the role of the intestinal microbatome with regard to affecting cardiac risk factors and obesity. Recommendations for the use of probiotics in necrotizing enterocolitis, childhood diarrhea, inflammatory bowel disease, irritable bowel syndrome, and Clostridium difficile diarrhea are reviewed. As in previous publications, the recommendations are given as A, B, or C ratings. The recent positive experiences with bacteriotherapy (fecal microbiome transplant) are also discussed in detail and a positive recommendation is made for use in severe resistant C. difficile diarrhea.

Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial

Clostridium difficile infection (CDI) is the most common health careassociated infection in U.S. hospitals, with approximately 453000 infections and 29000 deaths in 2011 (1). Antibiotics are frequently ineffective (2, 3), with recurrence rates of 15% to 35% after a first episode and up to 65% after treatment of a second recurrence (4, 5). Recurrences are clinically challenging and are typically treated with prolonged courses of antibiotics, which maintain and exacerbate intestinal dysbiosis (6). Fecal microbiota transplantation (FMT) restores the normal composition of gut microbiota and is recommended when antibiotics fail to clear the infection (3). However, the evidence for FMT rests largely on case series and several open-label clinical trials that have suggested cure rates of 81% to 100% in recurrent CDI (712). To date, there has not been an adequately controlled and blinded trial of FMT for CDI treatment. Furthermore, the optimal method for administering FMT has not been determined. Evidence suggests that colonoscopic delivery has advantages in terms of efficacy (9), safety (13), and patient acceptance and tolerability (14) compared with administration via the nasoenteric route. We therefore performed a double-blind, randomized, controlled study of colonoscopic FMT for treatment of recurrent CDI. Cure rates and adverse events (AEs) were compared between donor FMT and autologous FMT (given as a placebo) in patients who had at least 3 CDI recurrences. Methods Design Overview This prospective, dual-center, double-blind, randomized, controlled trial compared FMT using donor stool or the patients own stool administered by colonoscopy. Patients treated with autologous FMT whose CDI relapsed during the 8-week follow-up were offered FMT using donor stool. Those who underwent donor FMT and had relapse were offered repeated FMT using stool from a different donor. Patients were enrolled between 15 November 2012 and 10 March 2015 at 2 academic hospitals: Montefiore Medical Center in the Bronx, New York (NY), and The Miriam Hospital in Providence, Rhode Island (RI). Microbiome analyses on donor and patient fecal specimens were performed at the University of Minnesota in Minneapolis. The institutional review board at each center approved the study protocol (Supplement). A data and safety monitoring board monitored the trial using halting rules for serious, unexpected, and related adverse safety outcomes, and all authors performed data analysis. Supplement. Supplemental Information Study Population The study population comprised adult outpatients who had 3 or more documented CDI recurrences (defined as 3 unformed stools over 24 hours for 2 consecutive days and either a positive stool test result for C difficile or pseudomembranes on colonoscopy) and who did not maintain cure after a course of tapered or pulsed vancomycin or were unable to taper or discontinue vancomycin (or an alternative antibiotic with activity against CDI) without recurrent diarrhea requiring anti-CDI treatment. All patients had completed at least 10 days of vancomycin therapy for the most recent CDI and continued therapy until 2 to 3 days before the procedure. Major exclusion criteria included age 75 years or older; inflammatory bowel disease, irritable bowel syndrome (IBS), or chronic diarrheal disorder; any immunocompromised state or immunodeficiency; anaphylactic food allergy; previous FMT; untreated, in situ colorectal cancer; and inability to undergo colonoscopy. Donor Identification and Screening Patients were permitted to identify a donor or choose to be treated with stool from healthy volunteers who were recruited at each site. All prospective donors underwent a medical interview and physical examination and were excluded if they had a known communicable disease, features of the metabolic syndrome, a diarrheal disorder, an autoimmune or atopic disease, a tumor, a neurologic disorder, or chronic pain syndrome or if they had used antibiotics for any indication within 3 months. Potential donors also completed a modified AABB full-length donor history questionnaire, and those with risk factors for infectious agents were excluded (Supplement). Testing for HIV-1 and HIV-2 was performed within 2 weeks before donation for FMT. Other serologic and stool testing was performed within 1 month before FMT and included testing for hepatitis A, B, and C viruses; testing for Treponema pallidum; polymerase chain reaction (PCR) testing for detection of C difficile toxin; culture for enteric pathogens (Escherichia coli, Salmonella, Shigella, Yersinia, Campylobacter, Listeria monocytogenes, Vibrio parahaemolyticus, and V cholerae); testing for fecal Giardia and Cryptosporidium antigens; acid-fast stain for detection of Cyclospora and Isospora; ova and parasite testing; and enzyme immunoassay for detection of Rotavirus. Patients also had baseline testing for HIV-1 and HIV-2; hepatitis A, B, and C viruses; and T pallidum. Randomization and Interventions Donors took an osmotic laxative (magnesium hydroxide) the evening before and provided fresh stool the day of FMT. All donor specimens were transported on ice and processed within 6 hours of collection. Patients were given a standard bowel purge (sodium sulfate, potassium sulfate, and magnesium sulfate oral solution) the evening before the procedure. For patient convenience, sodium sulfate, potassium sulfate, and magnesium sulfate oral solution was substituted for the polyethylene glycol (PEG) bowel purge described in the study protocol. After initiating the preparation, patients were required to collect the first stool passed (for possible use in autologous FMT), transfer it to a clean container, and keep it either refrigerated or on ice. Within 1 hour before the scheduled FMT procedure, the nonblinded research assistant took possession of the stool specimens from both the donor and the patient. Patients were equally allocated to the donor and autologous FMT groups via block randomization by C difficile positivity at baseline, with stratification by study site. The protocol specified a dose of 100 g of stool diluted in 500 mL of nonbacteriostatic 0.9% normal saline immediately before the procedure, but the study relied on fresh stool, which has unpredictable weight and volume, and most provided specimens were less than 100 g. Because patients had discontinued use of vancomycin, had completed bowel lavage, and had been randomly assigned, we elected to use the lesser amount of fecal material. In those circumstances, available stool was weighed and suspended in a proportionately reduced volume of saline. A mean stool dose of 64 g (SD, 25 g; range, 20 to 100 g) was infused for donor FMT. Colonoscopies were performed within the endoscopy units of the study centers. Endoscopic findings and the depth of insertion were recorded. The study physician administered 300 mL of the fecal suspension through the instruments working channel into the furthest point reached (terminal ileum or cecum). After FMT, patients were transferred to the recovery area and encouraged to retain the stool for at least 1 hour. If they were unable to do so, the time of the first postprocedure bowel movement was recorded. Follow-up Patients were instructed to contact the clinical team if they had recurrence of diarrhea and were provided with a thermometer for daily oral temperature readings and a diary card to record solicited AEs for 7 days and unsolicited AEs for 30 days after transplantation. They were contacted by telephone 2 and 7 days after FMT and then biweekly for 8 weeks and questioned about stool form and frequency. All patients were seen in the clinic for follow-up 2 and 8 weeks after treatment, where they were assessed for infectious and gastrointestinal symptoms and underwent physical examination. They submitted stool specimens at baseline and at each post-FMT visit for C difficile PCR testing and microbiome analysis. All patients were contacted by telephone by a study representative 6 months after the last treatment to record any serious AEs (SAEs), new medical conditions or diagnoses, or changes in medical conditions or medications since the last study contact. End Points The primary efficacy end point was the rate of clinical cure in the intention-to-treat (ITT) population 8 weeks after FMT or at the time of early withdrawal. Clinical cure was defined as lack of CDI recurrence with maintenance of resolution (that is, <3 unformed stools per day) for 8 weeks without requirement for further antibiotics (metronidazole, vancomycin, or fidaxomicin). Because nucleic acid testing does not distinguish colonized patients from those with symptomatic disease (15), it cannot test for cure (2, 16); therefore, patients meeting the definition of clinical cure were considered to be cured regardless of the results of follow-up PCR testing of stool for C difficile. Safety end points were evaluated by review of SAEs, AEs, new medical conditions or diagnoses, or changes in medical conditions at the 6-month follow-up. Analysis of Fecal Microbiota Fecal microbiota was analyzed from patients at least 5 days before and 2 and 8 weeks after FMT, as well as from donor samples. DNA extraction, 16S ribosomal RNA gene amplification, and sequencing were performed by the University of Minnesota Genomics Center. Processing details are described in the Supplement, and data are archived in the Sequence Read Archive at the National Center for Biotechnology Information under BioProject accession number SRP066964. Taxonomic assignments were made against the Ribosomal Database Project using mothur software, version 1.34.0 (17). Alpha and beta diversity of bacterial communities were evaluated using the same software. Shannon indices and abundance-based coverage estimate parameters were calculated to assess alpha diversity. Differences in beta diversity and abundances of genera were performed using analysis of similarity and KruskalWallis analysis, respectively (18). Statis

Vascular ectasias of the right colon in the elderly: A distinct pathologic entity

Vascular ectasias (angiodysplasias, arteriovenous malformations) of the cecum and ascending colon are a frequent cause of lower intestinal bleeding in the elderly that has been overlooked by clinicians and pathologists. Their nature and etiology have been poorly understood until recently. This article reviews the previous literature and presents a complete and detailed description of these lesions based on the examination of 87 areas showing vascular ectasia from 26 colons. Their morphology spans a spectrum from small focal early lesions to multiple large late lesions. The early lesions are characterized by markedly dilated, large, tortuous submucosal veins with minimal dilatation of their tributaries in the mucosa. The late lesions showed further dilatation of submucosal veins and venules and extensive replacement of the overlying mucosa by racemose collections of dilated and thin walled venules and capillaries, three of which demonstrated rupture into the colonic lumen. The pathology of these lesions is considered to be specific enough to establish vascular ectasias of the colon as a distinct entity.

Long-term Follow-up Study of Fecal Microbiota Transplantation for Severe and/or Complicated Clostridium difficile Infection: A Multicenter Experience.

Goal:Our aim was to investigate fecal microbiota transplantation (FMT) efficacy in patients with severe and/or complicated Clostridium difficile infection (CDI). Background:FMT is successful for recurrent CDI, although its benefit in severe or complicated CDI has not specifically been evaluated. Study Methods:A multicenter long-term follow-up study was performed in patients who received FMT for severe and/or complicated CDI (diagnosed using standard criteria). Pre-FMT and post-FMT questionnaires were completed. Study outcomes included cure rates and time to resolution of symptoms. Results:A total of 17 patients (82% inpatients, 18% outpatients) were included (76.4% women; mean age, 66.4 y; mean follow-up, 11.4 mo). Patients had severe and complicated (76.4%) or either severe or complicated (23.6%) CDI. Sixteen patients (94.1%) had diarrhea, which resolved in 12 (75%; mean time to resolution, 5.7 d) and improved in 4 (25%) after FMT. Eleven patients (64.7%) had abdominal pain, which resolved in 8 (72.7%; mean time to resolution, 9.6 d) and improved in 3 (27.3%) after FMT. Two of 17 patients experienced early CDI recurrence (⩽90 d) after FMT (primary cure rate, 88.2%); and in 1 patient, a second FMT resulted in cure (secondary cure rate, 94.1%). Late CDI recurrence (≥90 d) was seen in 1 of 17 patients (5.9%) in association with antibiotics and was successfully treated with a repeat FMT. No adverse effects directly related to FMT occurred. Conclusions:FMT was successful and safe in this cohort of patients with severe or complicated CDI. Primary and secondary cure rates were 88.2% and 94.1%, respectively.

Disseminated Intravascular Coagulation in Nonocclusive Mesenteric Ischemia: The Lack of Specificity of Fibrin Thrombi in Intestinal Infarction

The significance and frequency of fibrin thrombi (FT), the pathological hallmark of disseminated intravascular coagulation (DIC), in ischemic intestine were analyzed in a retrospective study of the infarcted bowel of patients with occlusive mesenteric ischemia (OMI) and nonocclusive mesenteric ischemia (NOMI). Representative intestinal sections were studied from 10 patients with NOMI of the small and/or large bowel and 12 patients, with OMI of varied etiology. Three patients with inflammatory bowel disease and 1 patient with DIC and bowel necrosis were also studied. Routine hematoxylin and eosin stains for fibrin were prepared for each specimen. The number of FT was quantitated. FT were identified in each of the 10 cases of NOMI; however in only 2 were they prominent. FT were identified in 6 of the 12 cases of OMI and in 4 of these 6 they were a prominent feature. Rare FT were present in the cases of inflammatory bowel disease and did not correlate with the inflammatory process. No FT were present in the intestinal sections of the DIC case. FT are a nonspecific feature of necrosis and can be identified in both occlusive and nonocclusive ischemic bowel disease. Their presence in the intestine of NOMI therefore cannot be used to implicate DIC as the primary cause of this entity.