Zain Kassam

Fecal Microbiota Transplantation for Clostridium difficile Infection: Systematic Review and Meta-Analysis

OBJECTIVES: The clinical and economic burden of Clostridium difficile infection (CDI) is significant. Recurrent CDI management has emerged as a major challenge with suboptimal response to standard therapy. Fecal microbiota transplantation (FMT) has been used as a treatment to reconstitute the normal microbial homeostasis and break the cycle of antibiotic agents that may further disrupt the microbiome. Given the lack of randomized-controlled trials (RCTs) and limitations in previous systematic reviews, we aimed to conduct a systematic review with robust methods to determine the efficacy and safety profile of FMT in CDI.METHODS: An electronic search was conducted using MEDLINE (1946–March 2012), EMBASE (1974–March 2012) and Cochrane Central Register of Controlled Trials (2012). The search strategy was not limited by language. Abstract data were excluded and only completed studies that underwent the full, rigorous peer-review process were included. Studies that used FMT via any delivery modality for laboratory or endoscopically proven CDI with clinical resolution as primary outcome were included. A sample size of 10 or more patients was a further criterion. Elements of the Centre for Reviews and Dissemination checklist and the National Institute of Clinical Excellence quality assessment for case series checklist were employed to determine study quality. Eligibility assessment and data extraction were performed by two independent researchers. Both unweighted pooled resolution rates (UPR) and weighted pooled resolution rates (WPR) were calculated with corresponding 95% confidence intervals (CI) for overall studies, as well as predefined subgroups.RESULTS: Eleven studies with a total of 273 CDI patients treated with FMT were identified; no RCTs were found as none have been published. Two-hundred and forty-five out of 273 patients experienced clinical resolution (UPR 89.7%; WPR 89.1% (95% CI 84 to 93%)). There was no statistically significant heterogeneity between studies (Cochran Q test P=0.13, I2=33.7%). A priori subgroup analysis suggested that lower gastrointestinal FMT delivery (UPR 91.4%; WPR 91.2% (95% CI 86 to 95%)) led to a trend towards higher clinical resolution rates than the upper gastrointestinal route (UPR 82.3%; WPR 80.6% (95% CI 69–90%)) (proportion difference of WPR was 10.6% (95% CI −0.6 to 22%)). No difference in clinical outcomes was detected between anonymous vs. patient selected donors. There were no reported adverse events associated with FMT and follow-up was variable from weeks to years.CONCLUSIONS: FMT holds considerable promise as a therapy for recurrent CDI but well-designed, RCTs and long-term follow-up registries are still required. These are needed to identify the right patient, efficacy and safety profile of FMT before this approach can be widely advocated.

Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial

BACKGROUND & AIMS Ulcerative colitis (UC) is difficult to treat, and standard therapy does not always induce remission. Fecal microbiota transplantation (FMT) is an alternative approach that induced remission in small series of patients with active UC. We investigated its safety and efficacy in a placebo-controlled randomized trial. METHODS We performed a parallel study of patients with active UC without infectious diarrhea. Participants were examined by flexible sigmoidoscopy when the study began and then were randomly assigned to groups that received FMT (50 mL, via enema, from healthy anonymous donors; n = 38) or placebo (50 mL water enema; n = 37) once weekly for 6 weeks. Patients, clinicians, and investigators were blinded to the groups. The primary outcome was remission of UC, defined as a Mayo score ≤2 with an endoscopic Mayo score of 0, at week 7. Patients provided stool samples when the study began and during each week of FMT for microbiome analysis. The trial was stopped early for futility by the Data Monitoring and Safety Committee, but all patients already enrolled in the trial were allowed to complete the study. RESULTS Seventy patients completed the trial (3 dropped out from the placebo group and 2 from the FMT group). Nine patients who received FMT (24%) and 2 who received placebo (5%) were in remission at 7 weeks (a statistically significant difference in risk of 17%; 95% confidence interval, 2%-33%). There was no significant difference in adverse events between groups. Seven of the 9 patients in remission after FMT received fecal material from a single donor. Three of the 4 patients with UC ≤1 year entered remission, compared with 6 of 34 of those with UC >1 year (P = .04, Fishers exact test). Stool from patients receiving FMT had greater microbial diversity, compared with baseline, than that of patients given the placebo (P = .02, Mann-Whitney U test). CONCLUSIONS FMT induces remission in a significantly greater percentage of patients with active UC than placebo, with no difference in adverse events. Fecal donor and time of UC appear to affect outcomes. ClinicalTrials.gov Number: NCT01545908.

Fecal Transplant via Retention Enema for Refractory or Recurrent Clostridium difficile Infection

Published Online: November 28, 2011. doi:10.1001 /archinternmed.2011.548 AuthorAffiliations:DivisionofVascularSurgery(DrsSano, Unno, Yamamoto, and Tanaka), and Second Department of Surgery (Drs Sano, Unno, Yamamoto, Tanaka, and Konno),HamamatsuUniversitySchoolofMedicine,Hamamatsu, Japan. Correspondence: Dr Unno, Division of Vascular Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan (unno@hama-med.ac.jp). AuthorContributions:DrUnnohad full access toall of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Sano, Unno, and Yamamoto. Acquisition of data: Sano, Yamamoto, and Tanaka. Analysis and interpretationofdata:Sano,Unno,Yamamoto,Tanaka, andKonno. Drafting of the manuscript: Sano and Unno. Critical revision of themanuscript for important intellectualcontent:Unno,Yamamoto,Tanaka, andKonno. Statistical analysis: Sanoand Unno.Administrative, technical,andmaterial support:Unno, Yamamoto,andTanaka.Studysupervision:UnnoandKonno. Financial Disclosure: None reported. Funding/Support: We acknowledge the cooperation and support of the staff in the Second Department of Surgery, Hamamatsu University School of Medicine. They did not receive additional compensation for their contributions. Online-Only Material: The eTable is available at http: //www.archinternmed.com.

The adoptive transfer of behavioral phenotype via the intestinal microbiota: experimental evidence and clinical implications

There is growing interest in the ability of the intestinal microbiome to influence host function within and beyond the gastrointestinal tract. Here we review evidence of microbiome-brain interactions in mice and focus on the ability to transfer behavioral traits between mouse strains using fecal microbiota transplantation (FMT). Transplantation alters brain chemistry and behavior in recipient ex-germ free mice, raising the possibility of using FMT for disorders of the central nervous system, and prompting caution in the selection of FMT donors for conditions that may include refractory Clostridium difficile infection, diabetes and inflammatory bowel disease in humans.

Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial

Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally derived stool donor is safe in recurrent HE compared to SOC alone. An open‐label, randomized clinical trial with a 5‐month follow‐up in outpatient men with cirrhosis with recurrent HE on SOC was conducted with 1:1 randomization. FMT‐randomized patients received 5 days of broad‐spectrum antibiotic pretreatment, then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow‐up occurred on days 5, 6, 12, 35, and 150 postrandomization. The primary outcome was safety of FMT compared to SOC using FMT‐related serious adverse events (SAEs). Secondary outcomes were adverse events, cognition, microbiota, and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed until study end. FMT with antibiotic pretreatment was well tolerated. Eight (80%) SOC participants had a total of 11 SAEs compared to 2 (20%) FMT participants with SAEs (both FMT unrelated; P = 0.02). Five SOC and no FMT participants developed further HE (P = 0.03). Cognition improved in the FMT, but not the SOC, group. Model for End‐Stage Liver Disease (MELD) score transiently worsened postantibiotics, but reverted to baseline post‐FMT. Postantibiotics, beneficial taxa, and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout. Conclusion: FMT from a rationally selected donor reduced hospitalizations, improved cognition, and dysbiosis in cirrhosis with recurrent HE. (Hepatology 2017;66:1727–1738)

Fecal microbiota transplant in severe and severe-complicated Clostridium difficile: A promising treatment approach

ABSTRACT Severe and severe-complicated Clostridium difficile infection (CDI) is associated with high morbidity and mortality. Colectomy is standard of care; however, post-surgical mortality rates approach 50%. Case reports suggest fecal microbiota transplant (FMT) is a promising treatment of severe and severe-complicated disease but there is a paucity of data. Here, we present a single center experience with a novel sequential FMT protocol for patients refractory to maximal medical therapy. This approach consists of at least one FMT delivered via colonoscopy with criteria for repeat FMT and continued vancomycin therapy based on clinical response and pseudomembranes. Our cohort included 57 consecutive inpatients diagnosed with severe or severe-complicated CDI and treated with FMT. Overall, 91% (52/57) experienced clinical cure at 1 month with a 100% cure rate among severe CDI (n = 19) patients and an 87% cure rate for severe-complicated CDI (n = 33) patients. For the cohort, the survival rate was 94.7% at 1 month and 78.6% at 3 months. There were no serious adverse events related to FMT including no procedure-related complications or perforation. There was no difference in outcome between fresh or frozen fecal material. Sequential FMT for inpatients with severe or severe-complicated CDI is promising and may be preferred over colectomy in certain patients.

Review of the Emerging Treatment of Clostridium difficile Infection with Fecal Microbiota Transplantation and Insights into Future Challenges

Clostridium difficile infection (CDI) is one of the most common health care-associated infections in the United States. Currently, there are no standardized methods to prepare or deliver the fecal microbiota transplantation (FMT). Various methods are used to prepare the FMT, which is usually administered via nasogastric tube, colonoscopy, or by enema. Several clinical trials are underway to assess the true efficacy and safety of FMT for CDI. These trials include CDI studies assessing FMT via colonoscopy and frozen encapsulation, fresh versus frozen-and-thawed FMT by enema, FMT compared with a vancomycin taper, and FMT in the pediatric population.

OpenBiome remains open to serve the medical community

867 Nonetheless, we do appreciate the need to collect additional data on the safety profile of this emerging treatment. Toward this end, we are working with the FDA to initiate a long-term safety study under an IND that we hope will inform both policy discussions and clinical research. Until further data are available, we believe that the standing policy does an enormous service to public health by enabling access to lifesaving care for patients with CDI who have few other treatment options. We have been deeply impressed by the sensitivity, responsiveness and care taken by the FDA to balance the needs for appropriate oversight and immediate care. We feel that existing policy could be improved by instituting mandatory minimum screening requirements for all FMT donors to mitigate the risk of disease transmission. These screening guidelines could create a foundation around which to build rigorous, permanent standards for screening and processing human stool as a tissue product. We look forward to continued collaborative engagement with our partners at the FDA, the relevant medical societies and patient advocacy groups to ensure continued safe access to FMT.

Clostridium difficile associated risk of death score (CARDS): a novel severity score to predict mortality among hospitalised patients with C. difficile infection

Clostridium difficile infection (CDI) is a public health threat and associated with significant mortality. However, there is a paucity of objectively derived CDI severity scoring systems to predict mortality.

Systematic Review and Meta-analysis: Fecal Microbiota Transplantation for Treatment of Active Ulcerative Colitis

BACKGROUND Changes in the colonic microbiota may play a role in the pathogenesis of ulcerative colitis (UC) and restoration of healthy gut microbiota may ameliorate disease. A systematic review and meta-analysis was conducted to assess fecal microbiota transplantation (FMT) as a treatment for active UC. METHODS A literature search was conducted to identify high-quality studies of FMT as a treatment for patients with UC. The primary outcome was combined clinical remission and endoscopic remission or response. Secondary outcomes included clinical remission, endoscopic remission, and serious adverse events. Odds ratios with 95% confidence intervals (CIs) are reported. RESULTS Overall, 4 studies with 277 participants were eligible for inclusion. Among 4 randomized controlled trials, FMT was associated with higher combined clinical and endoscopic remission compared with placebo (risk ratio UC not in remission was 0.80; 95% CI: 0.71-0.89) with a number needed to treat of 5 (95% CI: 4-10). There was no statistically significant increase in serious adverse events with FMT compared with controls (risk ratio adverse event was 1.4; 95% CI: 0.55-3.58). CONCLUSIONS Among randomized controlled trials, short-term use of FMT shows promise as a treatment to induce remission in active UC based on the efficacy and safety observed. However, there remain many unanswered questions that require further research before FMT can be considered for use in clinical practice.Background: Changes in the colonic microbiota may play a role in the pathogenesis of ulcerative colitis (UC) and restoration of healthy gut microbiota may ameliorate disease. A systematic review and meta-analysis was conducted to assess fecal microbiota transplantation (FMT) as a treatment for active UC. Methods: A literature search was conducted to identify high-quality studies of FMT as a treatment for patients with UC. The primary outcome was combined clinical remission and endoscopic remission or response. Secondary outcomes included clinical remission, endoscopic remission, and serious adverse events. Odds ratios with 95% confidence intervals (CIs) are reported. Results: Overall, 4 studies with 277 participants were eligible for inclusion. Among 4 randomized controlled trials, FMT was associated with higher combined clinical and endoscopic remission compared with placebo (risk ratio UC not in remission was 0.80; 95% CI: 0.71–0.89) with a number needed to treat of 5 (95% CI: 4–10). There was no statistically significant increase in serious adverse events with FMT compared with controls (risk ratio adverse event was 1.4; 95% CI: 0.55–3.58). Conclusions: Among randomized controlled trials, short-term use of FMT shows promise as a treatment to induce remission in active UC based on the efficacy and safety observed. However, there remain many unanswered questions that require further research before FMT can be considered for use in clinical practice.