Ten-Year Follow-Up of Patients Treated with Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection from a Randomized Controlled Trial and Review of the Literature.

Fecal microbiota transplantation (FMT) has become a well-established treatment for recurrent Clostridioides difficile infection (rCDI). While short-term outcomes and adverse events relating to FMT have been well documented, there still is a paucity of data with regard to long-term safety. In this report, we describe the long-term follow-up of the prospective cohort of the first randomized controlled trial of FMT for rCDI, and review the existing literature. A total of 34 patients were treated with FMT for rCDI. Seven patients were still alive after a follow-up of more than 10 years and three patients were lost to follow-up. None of the 34 patients had experienced a new-onset autoimmune, gastrointestinal, or malignant disorder during follow-up. We did not find any deterioration or amelioration of pre-existing medical conditions. Furthermore, no deaths directly attributable to FMT could be identified. These findings are in accordance with the data in available literature. In conclusion, no long-term adverse events or complications directly attributable to FMT were found in our prospective cohort. Review of the available literature does not point to long-term risks associated with FMT in this elderly population, provided that carefully screened fecal suspensions are being used. No firm conclusion on the long-term safety of FMT in younger patients could be drawn.

Update of treatment algorithms for Clostridium difficile infection.

BACKGROUND: Clostridium difficile is the leading cause of antibiotic-associated diarrhoea, both in healthcare facilities and in the community. The recurrence rate of C. difficile infection (CDI) remains high, up to 20%. Since the publication of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidance document on CDI treatment in 2014, new therapeutic approaches have been developed and tested to achieve higher sustained clinical cure in CDI. AIM: To review novel treatments and approaches for CDI, except probiotics and vaccines. We focused on new antibiotics, antibiotic inactivators, monoclonal antibodies and gut microbiota modulating therapies. SOURCES: A literature review was performed for clinical trials published in PubMed, Embase or Cochrane Library between January 2013 and November 2017. CONTENT: We analysed 28 clinical trials and identified 14 novel agents. Completed phase 2 studies were found for cadazolid, LFF571, ridinilazole and nontoxigenic C. difficile strains. Four phase 3 active comparator studies comparing vancomycin with bezlotoxumab, surotomycin (n = 2) and rifaximin have been published. Seven clinical trials for treatment of multiple recurrent CDI with faecal microbiota transplantation were analysed, describing faecal microbiota transplantation by upper or lower gastrointestinal route (n = 5) or by capsules (n = 2). IMPLICATIONS: Metronidazole is mentioned in the ESCMID guideline as first-line therapy, but we propose that oral vancomycin will become the first choice when antibiotic treatment for CDI is necessary. Fidaxomicin is a good alternative, especially in patients at risk of relapse. Vancomycin combined with faecal microbiota transplantation remains the primary therapy for multiple recurrent CDI. We anticipate that new medication that protects the gut microbiota will be further developed and tested to prevent CDI during antibiotic therapy.

Host factors are more important in predicting recurrent Clostridium difficile infection than ribotype and use of antibiotics.

OBJECTIVE: A frequent complication of Clostridium difficile infection (CDI) is recurrent disease. The aim of this study was to determine whether early recurrence risk was higher after infection with ribotype 027 (outbreak strain) compared with infection with endemic strain types of C. difficile. METHODS: Consecutive patients diagnosed with CDI between May 2013 and March 2014 were included (outbreak strain, and non-outbreak strains). Patients who developed recurrent CDI within 30 days after completion of CDI treatment, were compared with patients without a recurrence. Medical charts were reviewed for demographic and clinical characteristics. General practitioners were contacted to complete data about the occurrence of recurrent CDI, and the use of medication after hospital discharge. RESULTS: In total, 135 patients were at risk for the development of recurrent CDI; 74 patients were infected by ribotype 027, and 61 patients by other ribotypes. Thirty-nine patients (29%) developed recurrent CDI within 30 days after completion of CDI treatment. In multivariable analysis, age ≥70 years (HR 3.05, 95% CI 1.54-6.03), and a duration of CDI treatment ≥11 days (HR 1.92, 95% CI 1.00-3.69) were clearly associated with recurrence; infection with ribotype 027 showed a HR of 1.72 (95% CI 0.88-3.33). CONCLUSION: During this outbreak of C. difficile in a tertiary care centre, age and a prolonged duration of CDI therapy (which is most likely a marker of underlying disease severity) were the main risk factors for recurrent CDI. This points to host factors as more important predictors for recurrent CDI than strain type or antibiotic use.

[Faecal microbiota transplantation: indications in perspective]. / Fecestransplantatie: wanneer wel en wanneer niet?

- As yet, with cure rates around 85%, recurrent Clostridium difficile infection is the only definite indication for faecal microbiota transplantation.- Faecal microbiota transplantation induces clinical remission and endoscopic improvements in 24-30% of patients with ulcerative colitis, compared to 5% (water) to 20% (autologous faeces) in placebo-treated patients. Current research focuses on the identification of 'super donors', and subgroups of patients in which faecal microbiota transplantation is effective.- In patients with metabolic syndrome, faecal microbiota transplantation may increase insulin sensitivity. Weight, body mass index, and energy metabolism are not affected by faecal microbiota transplantation in humans.- In addition to the aforementioned indications, faecal microbiota transplantation is an emerging treatment modality for patients with Crohn's disease, irritable bowel syndrome, graft-versus-host-disease, and carriage of multidrug-resistant micro-organisms. Randomized controlled trials, comparing faecal microbiota transplantation with placebo treatment, are required to determine the effectiveness of faecal microbiota transplantation in these patient groups.

How to: Establish and run a stool bank.

BACKGROUND: Since 2013, several stool banks have been developed following publications reporting on clinical success of 'faecal microbiota transplantation' (FMT) for recurrent Clostridium difficile infections (CDI). However, protocols for donor screening, faecal suspension preparation, and transfer of the faecal suspension differ between countries and institutions. Moreover, no European consensus exists regarding the legislative aspects of the faecal suspension product. Internationally standardized recommendations about the above mentioned aspects have not yet been established. OBJECTIVE: In 2015, the Netherlands Donor Feces Bank (NDFB) was founded with the primary aim of providing a standardized product for the treatment of patients with recurrent CDI in the Netherlands. Standard operation procedures for donor recruitment, donor selection, donor screening, and production, storage, and distribution of frozen faecal suspensions for FMT were formulated. RESULTS AND DISCUSSION: Our experience summarized in this review addresses current donor recruitment and screening, preparation of the faecal suspension, transfer of the faecal microbiota suspension, and the experiences and follow-up of the patients treated with donor faeces from the NDFB.

Cost analysis of an outbreak of Clostridium difficile infection ribotype 027 in a Dutch tertiary care centre.

BACKGROUND: The economic impact of Clostridium difficile infection (CDI) on the healthcare system is significant. From May 2013 to May 2014, an outbreak of C. difficile ribotype 027 occurred in a Dutch tertiary care hospital, involving 72 patients. The primary aim of this study was to provide insight into the financial burden that this CDI outbreak brought upon this hospital. METHODS: A retrospective analysis was performed to estimate the costs of a one-year-long C. difficile ribotype 027 outbreak. Medical charts were reviewed for patient data. In addition, all costs associated with the outbreak control measures were collected. FINDINGS: The attributable costs of the whole outbreak were estimated to be €1,222,376. The main contributing factor was missed revenue due to increased length of stay of CDI patients and closure of beds to enable contact isolation of CDI patients (36%). A second important cost component was extra surveillance and activities of the Department of Medical Microbiology and Infection Control (25%). CONCLUSION: To the authors' knowledge, this is the first study to provide insight into the attributable costs of CDI in an outbreak setting, and to delineate the major cost items. It is clear that the economic consequences of CDI are significant. The high costs associated with a CDI outbreak should help to justify the use of additional resources for CDI prevention and control.

[Fecal microbiota transplantation, a novel therapy for recurrent Clostridium difficile infection]. / Fecale microbiota transplantatie: een nieuwe behandeling voor recidiverende Clostridium difficile-infectie.

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.

Diagnostic yield of repeat sampling with immunoassay, real-time PCR, and toxigenic culture for the detection of toxigenic Clostridium difficile in an epidemic and a non-epidemic setting.

Current international guidelines lack definite conclusions regarding repeat stool sampling for the detection of toxigenic Clostridium difficile. We assessed the value of repeat sampling and compared the diagnostic yield in an epidemic to a non-epidemic setting. Consecutive fecal samples obtained during two time frames were analyzed using direct stool immunoassay toxin testing (enzyme immunoassay [EIA]), direct stool real-time PCR toxin gene testing, and toxigenic culture. Samples collected within 7 days of the initial sample were considered repeat tests. In the epidemic setting 989 patients were analyzed, and in the non-epidemic setting 1,015. In the epidemic setting 204 patients had two or more specimens included for analysis and in the non-epidemic setting 287 patients. In the epidemic setting 136 samples yielded a positive results, either by EIA or toxigenic culture; of these, 108 were positive according to EIA and 123 according to toxigenic culture. In the first test round 98 (90.7%, 95% CI 85.3 to 96.2), 114 (92.7%, 88.1 to 97.3), and 126 (92.6%, 88.3 to 97.0) positives were detected. Subsequent test rounds yielded 10 (9.3%, 3.8 to 14.7), 9 (7.3%, 2.7 to 11.9), and 10 (7.4%, 3.0 to 11.7) extra positives. In the non-epidemic setting EIA, toxigenic culture and PCR detected 33, 66, and 83 positives. The three tests combined 93 detected positives. In the first test round 30 (90.9%, 81.1 to 100.7), 63 (95.5%, 90.4 to 110.5), 76 (91.6%, 85.6 to 97.5), and 87 (93.5%, 88.6 to 98.5) positives were detected. Subsequent test rounds yielded 3 (9.1%, -0.7 to 18.9), 3 (4.5%, -0.5 to 9.6), 7 (8.4%, 2.5 to 14.4), and 6 (6.5%, 1.5 to 11.4) extra positives. In conclusion, repeat testing resulted in 4.5% to 9.3% extra positives. No significant difference between the settings studied could be demonstrated. Repeat sampling and multimodality testing may be chosen in an outbreak situation to detect all cases, effectively controlling nosocomial spread.