A Systematic Review: Fecal Microbiota Transplantation for Clostridium difficile Infection
Clostridium difficile (C. difficile) has become an increasingly important pathogen. Initially, C. difficile infection (CDI), and accompanying diarrheal illness, was largely confined to patients with healthcare exposure; however, it is now also affecting those with no or limited contact with a healthcare system. In 2013, the Centers for Disease Control and Prevention placed C. difficile in its top (urgent) threat category in its first threat report on antimicrobial resistance. A major challenge in treating CDI is the high rate of recurrent disease. Symptomatic recurrence occurs in 15-30% of patients, and among those with a single episode of recurrence, the risk of further recurrence increases. Fecal microbiota transplantation (FMT) – the instillation into the gastrointestinal tract of stool from a "non-infected stool donor" – is increasingly used to treat patients with recurrent CDI, based on the idea that restoring the organisms that comprise the normal colonic flora, by importing the colonic microbiome of a healthy person, can resolve diarrheal symptoms.
The VA Evidence-Based Synthesis Program located in Minneapolis, MN conducted a systematic review of the published literature to examine the effectiveness of FMT for treatment of CDI, in part to help guide policymakers within the VA healthcare system in determining whether or not the evidence supporting FMT is sufficient to implement FMT programs in their facilities, and if so, how and in which patients. Investigators reviewed the literature for articles published from 1980 through May 2014. After applying inclusion/exclusion criteria, 31 articles were used in their review, including 2 randomized controlled trials (RCTs), 25 case series, and 4 case reports. Their analyses of the data from these articles were used to provide the Summary, which is followed by more detailed information.
There was low strength of evidence from small randomized controlled trials (RCTs) and case series that FMT may have a substantial effect and few short-term adverse events for adults with recurrent CDI. One small moderate-quality RCT study found that FMT reduced symptom recurrence compared to standard CDI therapy that included the antibiotic vancomycin, and one very small moderate-quality RCT found FMT resulted in a high symptom resolution rate that did not differ by delivery routes (nasogastric tube vs. colonoscopy). There is insufficient evidence on FMT for patients with refractory CDI, and only a single case report on the initial treatment of CDI. Evidence is insufficient as to whether treatment effects vary by FMT donor, preparation, or delivery method.
FMT for Recurrent CDI Compared to Standard Therapy
Two small moderate risk of bias RCTs and 19 case series (range 2 to 74 participants; total n=480 receiving FMT) reported on the use of FMT for patients with recurrent CDI. Findings show:
- A high proportion of patients treated with FMT had resolution of symptoms. However, authors commonly reported that antimicrobials for CDI were given prior to FMT to ensure that patients were asymptomatic or had a "reduction in symptoms" at the time of FMT. Thus, in most cases FMT was administered when patients were asymptomatic or symptoms were resolving, with the FMT possibly contributing to further symptom resolution, prevention, or both.
- In the RCT that compared FMT via nasoduodenal tube to two control groups (n=43), 81% of patients in the FMT group achieved resolution of symptoms within the first three months. These results were significantly different from the vancomycin (31%) or vancomycin plus bowel lavage (23%) control groups.
- In the RCT that compared two FMT treatment approaches (n=20), a high proportion of patients in each group had resolution of symptoms. The difference between treatment approaches was not significant (60% in the nasogastric tube group and 80% in the colonoscopy group).
- Across all studies of patients with recurrent CDI, including FMT via an upper gastrointestinal (GI) (k=6), colonoscopy (k=10, including the RCT with both upper GI and colonoscopy groups), enema (k=5), or combination approach (k=1), resolution of symptoms was observed in 83%. Although comparisons across studies should be interpreted with considerable caution, FMT involving colonoscopy resulted in the highest overall symptom resolution rates, followed by upper GI tract and enema.
FMT for Refractory CDI
Five case series enrolled patients with refractory CDI (117 participants; 112 treated via enema and 5 via colonoscopy). The reported resolution of symptoms ranged widely (0% to 100%, mean=53%).
FMT for Initial CDI
One small case study included one patient treated with FMT for initial CDI. The patient's symptoms resolved following FMT via enema.
FMT and Adverse Events
Few serious adverse events were reported, and no clear link between FMT and serious adverse events could be established. In one series of immuno-compromised patients, serious adverse events and adverse events were each observed in 15% of patients, with approximately one-third considered related to FMT. Long-term safety data regarding FMT are lacking.
FMT and Acceptability
No study systematically assessed acceptability to patients with prior or current episodes of CDI. However, anecdotal findings suggest that the procedure was an acceptable alternative for patients with recurrent CDI.
Additional data from randomized controlled trials, non-randomized controlled studies, or higher-quality cohort studies would be of value to address the comparative effectiveness of FMT vs. optimal medical management. Future research is needed to clarify important elements of FMT including: the number of CDI episodes after which FMT provides the greatest relative benefit (should it exist); optimal medical management (i.e., antibiotic type, dose, delivery and duration); and the preferred methods for fecal material and patient preparation, preferred donor selection, and optimal delivery and timing of FMT.
Drekonja D, Reich J, Gezahegn S, Greer N, Shaukat A, MacDonald R, Rutks I, and Wilt TJ. Fecal Microbiota Transplantation for Clostridium Difficile Infection: A Systematic Review of the Evidence. VA ESP Project #09-009; 2014.
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