Colleen R. Kelly

Treating clostridium difficile infection with fecal microbiota transplantation

Clostridium difficile infection is increasing in incidence, severity, and mortality. Treatment options are limited and appear to be losing efficacy. Recurrent disease is especially challenging; extended treatment with oral vancomycin is becoming increasingly common but is expensive. Fecal microbiota transplantation is safe, inexpensive, and effective; according to case and small series reports, about 90% of patients are cured. We discuss the rationale, methods, and use of fecal microbiota transplantation.

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.

Weight Gain After Fecal Microbiota Transplantation

Fecal microbiota transplantation (FMT) is a promising treatment for recurrent Clostridium difficile infection. We report a case of a woman successfully treated with FMT who developed new-onset obesity after receiving stool from a healthy but overweight donor. This case may stimulate further studies on the mechanisms of the nutritional-neural-microbiota axis and reports of outcomes in patients who have used nonideal donors for FMT.

Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results.

Goals: We aim to present a data detailing our success with fecal microbiota transplantation (FMT) and to provide a simple treatment protocol. Background: Relapse is a common problem in patients treated for Clostridium difficile infection, often requiring prolonged courses of oral vancomycin with limited alternative treatment options. Administration of the entire fecal flora from a healthy individual to restore beneficial physiological species is referred to as FMT (also termed fecal bacteriotherapy or stool transplant). Although introduced over 50 years ago with high cure rates in published case series, FMT is neither routine practice nor widely available to patients. Study: Twenty-six patients with relapsing C. difficile infection underwent FMT over a 28-month period. FMT was performed during colonoscopy by direct infusion of minimally processed donor stool. Results: Twenty-four female and 2 male patients underwent FMT. The mean duration of CDI was 12.6 months (range, 4 to 84 mo) before FMT. These patients have been followed for a mean duration of 10.7 months (range, 2 to 30 mo). Twenty-four patients have remained free of significant diarrhea or CDI. One experienced loose stool and resumed vancomycin despite remaining C. difficile negative; she developed CDI recurrence 11 months post-FMT after taking cephalexin. Another had diarrhea 2 months post-FMT. Stool was not tested for C. difficile; she received 1 week of vancomycin and CDI did not recur after this. Conclusions: FMT through colonoscopy was simple, safe, and 92% effective in preventing further diarrhea or CDI relapse in this group of 26 patients with recurrent CDI.

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

A Novel Microbiome Therapeutic Increases Gut Microbial Diversity and Prevents Recurrent Clostridium difficile Infection

BACKGROUND Patients with recurrent Clostridium difficile infection (CDI) have a ≥60% risk of relapse, as conventional therapies do not address the underlying gastrointestinal dysbiosis. This exploratory study evaluated the safety and efficacy of bacterial spores for preventing recurrent CDI. METHODS Stool specimens from healthy donors were treated with ethanol to eliminate pathogens. The resulting spores were fractionated and encapsulated for oral delivery as SER-109. Following their response to standard-of-care antibiotics, patients in cohort 1 were treated with SER-109 on 2 consecutive days (geometric mean dose, 1.7 × 10(9) spores), and those in cohort 2 were treated on 1 day (geometric mean dose, 1.1 × 10(8) spores). The primary efficacy end point was absence of C. difficile-positive diarrhea during an 8-week follow-up period. Microbiome alterations were assessed. RESULTS Thirty patients (median age, 66.5 years; 67% female) were enrolled, and 26 (86.7%) met the primary efficacy end point. Three patients with early, self-limiting C. difficile-positive diarrhea did not require antibiotics and tested negative for C. difficile at 8 weeks; thus, 96.7% (29 of 30) achieved clinical resolution. In parallel, gut microbiota rapidly diversified, with durable engraftment of spores and no outgrowth of non-spore-forming bacteria found after SER-109 treatment. Adverse events included mild diarrhea, abdominal pain, and nausea. CONCLUSIONS SER-109 successfully prevented CDI and had a favorable safety profile, supporting a novel microbiome-based intervention as a potential therapy for recurrent CDI.

The Long-term Efficacy and Safety of Fecal Microbiota Transplant for Recurrent, Severe, and Complicated Clostridium difficile Infection in 146 Elderly Individuals.

Objectives:Clostridium difficile infection (CDI) in the elderly has a higher prevalence, greater morbidity and mortality, and lower response to conventional treatment than the general population. Fecal microbiota transplant (FMT) is highly effective therapy for CDI but has not been studied specifically in the elderly. This study aims to determine the long-term efficacy and safety of FMT for recurrent (RCDI), severe (SCDI), and complicated (CCDI) CDI in elderly patients. Methods:A multicenter, long-term follow-up study was performed with demographic, pre-FMT, and post-FMT data collected from elderly patients with RCDI, SCDI, and CCDI, through a 47-item questionnaire. Outcome measures included primary and secondary cure rates, early (<12 wk) and late (≥12 wk) recurrence rates, and adverse events (AEs), including post-FMT diagnoses. Results:Of 168 eligible patients, 146 patients met the inclusion criteria. Of these, 68.5% were women. The mean (range) age was 78.6 (65 to 97) years and the follow-up period was 12.3 (1 to 48) months. FMT was performed for RCDI in 89 (61%), SCDI in 45 (30.8%), and CCDI in 12 (8.2%) patients. The primary and secondary cure rates were 82.9% and 95.9%, respectively. Early and late recurrences occurred in 25 and 6 patients, respectively. AEs included CDI-negative diarrhea in 7 (4.8%) and constipation in 4 (2.7%) patients. Serious AEs, recorded in 6 patients, were hospital admissions for CDI-related diarrhea, one of which culminated in death. New diagnoses post-FMT included microscopic colitis (2), Sjogren syndrome (1), follicular lymphoma (1), contact dermatitis and idiopathic Bence-Jones proteinuria (1), and laryngeal carcinoma (1)—all, however, were associated with predisposing factors. Conclusions:FMT is a safe and effective treatment option for RCDI, SCDI, and CCDI in elderly patients.

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.

Fecal Microbiota Transplantation is Safe and Efficacious for Recurrent or Refractory Clostridium difficile Infection in Patients with Inflammatory Bowel Disease

Background:New treatments are needed as Clostridium difficile infection (CDI) is becoming increasingly formidable. Fecal microbiota transplantation (FMT) has a 90% success rate in the treatment of recurrent CDI. However, evidence regarding its safety, efficacy, and effect on disease activity in patients with inflammatory bowel disease (IBD) is lacking. Methods:This cohort study used data from 8 national and international academic centers. Patients with established IBD who underwent FMT for recurrent CDI were followed for a minimum of 3 months. The primary outcome was CDI recurrence at 3 months after FMT. The secondary outcomes were (1) IBD activity and severity at 3 months based on the judgment of the treating physician, endoscopic findings, and clinical disease activity scores; and (2) safety. Results:Sixty-seven patients were included in the analysis. Thirty-five (52%) had Crohns disease, 31 (46%) ulcerative colitis, and one indeterminate colitis with 43 (64%) patients on an immunosuppressive agent at the time of FMT. The initial FMT was successful in 53 (79%) patients. After the FMT, IBD disease activity was reported as improved in 25 (37%), no change in 20 (30%), and worse in 9 (13%) patients. Serious adverse events included colectomy (1.4%), hospitalization for CDI (2.9%), hospitalization for IBD flare (2.9%), small bowel obstruction (1.4%), CMV colitis (1.4%), and pancreatitis (1.4%). Discussion:The overall CDI cure rates were high, with a large percentage of patients experiencing clinical improvement of their IBD after FMT. A minority of patients developed an IBD flare. No severe adverse events directly attributable to FMT were found in this largest reported series of recurrent or refractory CDI patients with concurrent IBD.