Josbert J. Keller

Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile

BACKGROUND Recurrent Clostridium difficile infection is difficult to treat, and failure rates for antibiotic therapy are high. We studied the effect of duodenal infusion of donor feces in patients with recurrent C. difficile infection. METHODS We randomly assigned patients to receive one of three therapies: an initial vancomycin regimen (500 mg orally four times per day for 4 days), followed by bowel lavage and subsequent infusion of a solution of donor feces through a nasoduodenal tube; a standard vancomycin regimen (500 mg orally four times per day for 14 days); or a standard vancomycin regimen with bowel lavage. The primary end point was the resolution of diarrhea associated with C. difficile infection without relapse after 10 weeks. RESULTS The study was stopped after an interim analysis. Of 16 patients in the infusion group, 13 (81%) had resolution of C. difficile-associated diarrhea after the first infusion. The 3 remaining patients received a second infusion with feces from a different donor, with resolution in 2 patients. Resolution of C. difficile infection occurred in 4 of 13 patients (31%) receiving vancomycin alone and in 3 of 13 patients (23%) receiving vancomycin with bowel lavage (P<0.001 for both comparisons with the infusion group). No significant differences in adverse events among the three study groups were observed except for mild diarrhea and abdominal cramping in the infusion group on the infusion day. After donor-feces infusion, patients showed increased fecal bacterial diversity, similar to that in healthy donors, with an increase in Bacteroidetes species and clostridium clusters IV and XIVa and a decrease in Proteobacteria species. CONCLUSIONS The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin. (Funded by the Netherlands Organization for Health Research and Development and the Netherlands Organization for Scientific Research; Netherlands Trial Register number, NTR1177.).

Reset of a critically disturbed microbial ecosystem: faecal transplant in recurrent Clostridium difficile infection

Recurrent Clostridium difficile infection (CDI) can be effectively treated by infusion of a healthy donor faeces suspension. However, it is unclear what factors determine treatment efficacy. By using a phylogenetic microarray platform, we assessed composition, diversity and dynamics of faecal microbiota before, after and during follow-up of the transplantation from a healthy donor to different patients, to elucidate the mechanism of action of faecal infusion. Global composition and network analysis of the microbiota was performed in faecal samples from nine patients with recurrent CDI. Analyses were performed before and after duodenal donor faeces infusion, and during a follow-up of 10 weeks. The microbiota data were compared with that of the healthy donors. All patients successfully recovered. Their intestinal microbiota changed from a low-diversity diseased state, dominated by Proteobacteria and Bacilli, to a more diverse ecosystem resembling that of healthy donors, dominated by Bacteroidetes and Clostridium groups, including butyrate-producing bacteria. We identified specific multi-species networks and signature microbial groups that were either depleted or restored as a result of the treatment. The changes persisted over time. Comprehensive and deep analyses of the microbiota of patients before and after treatment exposed a therapeutic reset from a diseased state towards a healthy profile. The identification of microbial groups that constitute a niche for C. difficile overgrowth, as well as those driving the reinstallation of a healthy intestinal microbiota, could contribute to the development of biomarkers predicting recurrence and treatment outcome, identifying an optimal microbiota composition that could lead to targeted treatment strategies.

Fecal microbiota transplantation: facts and controversies.

Purpose of review To review the current evidence on fecal microbiota transplantations (FMTs) for recurrent Clostridium difficile infections (CDIs), metabolic syndrome and inflammatory bowel disease. Recent findings Recently, a randomized trial confirmed the efficacy of this treatment strategy in patients with recurrent CDI. For other disorders, evidence is still limited. To date, studies have been performed to try and influence the course of metabolic syndrome and inflammatory bowel disease. Summary There is increasing interest in the role of altered microbiota in the development of a myriad of diseases. Together with new insights comes an interest in influencing this altered microbiota as a potential target for therapy. FMTs are effective against recurrent CDI, a disorder caused by disruption of the normal microbiota. Restoration of intestinal flora and thereby restoration of colonization resistance is thought to be the mechanism responsible for cure. With the developments in FMT and the extension of this treatment modality to both intestinal and extra-intestinal diseases, a new field of targeted therapy awaits. The ultimate goal is the development of powerful probiotic regimens that can replace FMT. Currently, FMT should only be given in a strict experimental setting for other conditions than CDI.

Consensus report: faecal microbiota transfer – clinical applications and procedures

Faecal microbiota transplantation or transfer (FMT) aims at replacing or reinforcing the gut microbiota of a patient with the microbiota from a healthy donor. Not many controlled or randomised studies have been published evaluating the use of FMT for other diseases than Clostridium difficile infection, making it difficult for clinicians to decide on a suitable indication.

Treatment of recurrent and severe Clostridium difficile infection.

Clostridium difficile infection (CDI) is a serious complication of hospitalization and antibiotic use with a high mortality and very high costs. Despite appropriate treatment, a subset of patients develop chronic recurrent CDI. Some other patients develop severe and life-threatening colitis. The risk factors, pathogenesis, and treatment of recurrent CDI and severe CDI are discussed in this review. In particular, fecal microbiota transplantation (FMT) as a treatment strategy is outlined and a treatment algorithm incorporating FMT is described.

Complications, effectiveness, and long term follow-up of fecal microbiota transfer by nasoduodenal tube for treatment of recurrent Clostridium difficile infection

Background Fecal microbiota transfer (FMT) is an effective treatment for recurrent Clostridium difficile infection (CDI), but data on procedure-related complications and long-term outcome are scarce. Methods All patients treated with FMT for recurrent CDI at the Academic Medical Center between July 2010 and January 2016 were included. FMT was performed according to the FECAL trial protocol: administration of fresh donor feces (related or unrelated donor) through a duodenal tube after pre-treatment with vancomycin and bowel lavage. We collected information on FMT-related complications, recurrent CDI, and short- and long-term adverse events by telephone interviews using a structured questionnaire at three months after FMT, and at the time of data collection of this study. Results In total, 39 patients were treated with FMT. The primary cure rate (no recurrence ≤8 weeks after one infusion with donor feces) was 82% (32 of 39 patients). Of the seven patients with recurrent CDI after FMT, four were cured by antibiotic therapy alone (fidaxomicin in three patients, metronidazole in one patient) and three by repeat FMT. Peri-procedural complications occurred in five patients, comprising fecal regurgitation or vomiting. One patient died one week post-FMT due to pneumonia; a causal relation with FMT could not be excluded. The follow-up period ranged between 3 and 68 months. No long-term side effects were reported. Conclusions Our data underline the efficacy of FMT as treatment for recurrent CDI. Importantly, it is possible to cure post-FMT recurrences with antibiotic therapy alone. Peri-procedural complications do occur and should be closely monitored to help identify high-risk patients. To minimize the risk of complications, all FMT candidates should be evaluated to assess the most ideal delivery method.

Fecal Microbiota Transfer for Multidrug-Resistant Gram-Negatives: A Clinical Success Combined With Microbiological Failure.

Abstract Combined fecal microbiota transfer and antibiotic treatment prevented recurrences of urinary tract infections with multidrug-resistant (MDR) Pseudomonas aeruginosa, but it failed to eradicate intestinal colonization with MDR Escherichia coli. Based on microbiota analysis, failure was not associated with distinct diminished microbiota diversity.

Faecal microbiota transplantation in clinical practice

Dear Sir, We would like to add some remarks to the report of a consensus meeting about faecal microbiota transplantation (FMT) by Cammarota et al. 1 Already, donor faeces banks exist at an institutional or national level in Germany, UK and The Netherlands, to support treatment of patients with recurrent Clostridium difficile infection (CDI).2 Unfortunately, these centres were not consulted for advice, and it is felt that some conclusions of the report need clarification and adjustments. First, the statement about expert centres is inaccurate. The critical steps for safe and effective FMT are (1) patient selection, (2) donor (stool) selection and screening, and (3) biobanking of faeces suspensions. We agree that donor screening should be performed …

Is the Lower Gastrointestinal Route Really Preferred Over the Upper Gastrointestinal Route for Fecal Microbiota Transfer

To the Editor: Furuya-Kanamori et al1 recently published a paper entitled “Upper Versus Lower Gastrointestinal Delivery for Transplantation of Fecal Microbiota in Recurrent or Refractory Clostridium difficile Infection: A Collaborative Analysis of Individual Patient Data From 14 Studies” in the Journal of Clinical Gastroenterology. We question if the authors’ conclusion that the lower gastrointestinal (LGI) route is preferred over the upper gastrointestinal (UGI) route in treatment of recurrent Clostridium difficile infection, is a correct interpretation of the literature analyzed. First, the patient groups differ in baseline characteristics. Substantially more children have been included in the UGI group (12%) than in the LGI group (3%). Fecal microbiota transfer (FMT) has not been well studied in the pediatric population, and its efficacy needs to be established before pooling data with adults. No adjustment has been made for possible confounders other than age and sex (such as comorbidity, antibiotic use after FMT, and number of FMT treatments), which can influence the relapse rate significantly. Second, the article does not describe a thorough quality assessment of the studies included in the metaanalysis. For instance, the authors did not address the fact that more than half of the patients received less than the recommended 50 g of donor feces, as Gough et al,2 demonstrated a 4 times greater relapse rate when <50g of stool was used. In contrast, data of the first published randomized controlled trial of FMT by van Nood et al,3 is not included in this meta-analysis. Third, the treatment effect of the LGI and UGI route only diverges from 30 days onwards, and not directly after 30 days as suggested in the article. The median follow-up period was 80 days in the UGI and 354 days in the LGItreated patients. Therefore, the difference between the groups at 90 days follow-up is based on a very small sample of patients. As there is no biological plausibility for the superiority of the LGI route, and the temporality of the observed effect opposes a direct treatment effect, we suppose that this outcome may have been a result of bias. Since 2008, we have treated several dozens of patients in the Netherlands with FMT via a nasoduodenal tube. We have not noticed any recurrences 30 days after FMT, with a median follow-up time of 21 months (van Beurden et al, manuscript submitted). We prefer the UGI route because it is generally well tolerated by patients, and less invasive compared with colonoscopy, especially in an inflamed bowel as with severe Clostridium difficile infection. We agree with the authors that a randomized controlled trial with a sufficient sample size is required to determine the optimal route for administration of FMT.

[Fecal microbiota transplantation, a novel therapy for recurrent Clostridium difficile infection].

Clostridium difficile infection is caused by a disturbance of the gut microbiota, often resulting from the use of antibiotics. Among a sub group of patients with this disorder, treatment with antibiotics is not effective. They develop a chronic, recurrent infection. Such patients can be treated with a fecal microbiota transplantation (FMT), or fecal transplantation. The crucial steps for safe application of fecal transplantation are central donor selection and screening. To optimise safety and to guarantee the availability of donor feces for fecal transplantation, the Nederlandse Donor Feces Bank (Dutch Donor Feces Bank) was established. At this facility, ready-to-use, screened donor feces can be ordered for patients with (recurrent) Clostridium difficile infections, who can then be treated at their own hospital.