Review question
We reviewed the evidence about the effect of stool transplant compared to currently used treatments such as antibiotics for the treatment of recurrent C difficile diarrhea in adults and children.
What is Clostridioides difficile infection and how is it treated?
Clostridioides difficile (C difficile) infection is a common bacterial illness that can cause life-threatening diarrhea (runny stools). Evidence suggests that an unhealthy mixture of gut bacteria called dysbiosis may increase the risk of repeated or multiple C difficile infections. Changing from an unhealthy to a healthier balance of gut bacteria through treatment may protect people from becoming sick with C difficile, or prevent repeated infections with this bacterium. Stool administration from healthy donors to people who have had multiple infections with C difficile, known as fecal microbiota transplantation (FMT), is an intervention that seeks to change an unhealthy mixture of gut microbes into a healthy balance of gut microbes.
What did we want to find out?
We wanted to discover whether using FMT in people with multiple C difficile infections leads to a higher percentage of resolution of the infection compared to commonly used therapies such as antibiotics and whether FMT may cause harm.
What did we do?
We searched medical databases for clinical trials looking at stool transplantation compared to currently used treatments such as antibiotics for the treatment of recurrent C difficile diarrhea in adults and children.
What did we find?
We found six clinical trials of 320 adults that met criteria for inclusion in this review that assessed the efficacy and safety of stool transplantation for the treatment of repeated C difficile infection. Two studies were conducted in Denmark, and one each in the Netherlands, Italy, Canada, and the US. The time of follow-up after the treatment with FMT ranged from eight weeks to 17 weeks. The amount of stool, route of administration, number of administrations, type of donor, and what type of treatment the comparison group received varied among the studies. Five studies excluded people who had weak immune systems (immunocompromised people); one study included people with weak immune systems and apparently normal immune systems (immunocompetent people).
Key results
Stool transplantation probably leads to a larger increase in resolution of repeated infections of C difficile than the other treatments studied. Other treatments included antibiotics such as vancomycin, which are commonly prescribed for this infection. These same studies looked at the rate of serious side effects and risk of death from FMT. Fecal microbiota transplantation likely leads to a small decrease in serious side effects; however, these effects were few. Fecal microbiota transplantation may decrease the risk of death in people with rCDI; however, there were few deaths in either group. Elimination of one study that included some immunocompromised people did not alter these conclusions, but, based on the low number of immunocompromised people enrolled in the included studies, conclusions could not be drawn about the benefits or harms of FMT for rCDI in the immunocompromised population at this time.
What are the limitations of the evidence?
We rated the overall certainty of the evidence using a set of criteria that takes into account the type of studies, potential flaws in how the studies were run, how similar or different reporting of the results was between studies, how studies measured the effect of the intervention, and mathematical confidence in the combined results. Based on these criteria, we judged the overall certainty of the evidence supporting stool transplants as more effective than other treatments for the resolution of repeated C difficile infection as moderate. The certainty of evidence for serious side effects was moderate and the certainty of evidence for deaths was low.
Study funding sources
None of the included studies was funded by a drug manufacturer or an agency that had a commercial interest in FMT.
How up to date is this evidence?
The evidence is current to 31 March 2022.
In immunocompetent adults with rCDI, FMT likely leads to a large increase in the resolution of recurrent Clostridioides difficile infection compared to alternative treatments such as antibiotics. There was no conclusive evidence regarding the safety of FMT for the treatment of rCDI as the number of events was small for serious adverse events and all-cause mortality. Additional data from large national registry databases might be required to assess any short-term or long-term risks with using FMT for the treatment of rCDI. Elimination of the single study that included some immunocompromised people did not alter these conclusions. Due to the low number of immunocompromised participants enrolled, conclusions cannot be drawn about the risks or benefits of FMT for rCDI in the immunocompromised population.
Clostridioides difficile (formerly known as Clostridium difficile) is a bacterium that can cause potentially life-threatening diarrheal illness in individuals with an unhealthy mixture of gut bacteria, known as dysbiosis, and can cause recurrent infections in nearly a third of infected individuals. The traditional treatment of recurrent C difficile infection (rCDI) includes antibiotics, which may further exacerbate dysbiosis. There is growing interest in correcting the underlying dysbiosis in rCDI using of fecal microbiota transplantation (FMT); and there is a need to establish the benefits and harms of FMT for the treatment of rCDI based on data from randomized controlled trials.
To evaluate the benefits and harms of donor-based fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile infection in immunocompetent people.
We used standard, extensive Cochrane search methods. The latest search date was 31 March 2022.
We considered randomized trials of adults or children with rCDI for inclusion. Eligible interventions must have met the definition of FMT, which is the administration of fecal material containing distal gut microbiota from a healthy donor to the gastrointestinal tract of a person with rCDI. The comparison group included participants who did not receive FMT and were given placebo, autologous FMT, no intervention, or antibiotics with activity against C difficile.
We used standard Cochrane methods. Our primary outcomes were 1. proportion of participants with resolution of rCDI and 2. serious adverse events. Our secondary outcomes were 3. treatment failure, 4. all-cause mortality, 5. withdrawal from study, 6. rate of new CDI infection after a successful FMT, 7. any adverse event, 8. quality of life, and 9. colectomy. We used the GRADE criteria to assess certainty of evidence for each outcome.
We included six studies with 320 participants. Two studies were conducted in Denmark, and one each in the Netherlands, Canada, Italy, and the US. Four were single-center and two were multicenter studies. All studies included only adults. Five studies excluded people who were severely immunocompromised, with only one study including 10 participants who were receiving immunosuppressive therapy out of the 64 enrolled; these were similarly distributed between the FMT arm (4/24 or 17%) and comparison arms (6/40 or 15%). The route of administration was the upper gastrointestinal tract via a nasoduodenal tube in one study, two studies used enema only, two used colonoscopic only delivery, and one used either nasojejunal or colonoscopic delivery, depending on a clinical determination of whether the recipient could tolerate a colonoscopy. Five studies had at least one comparison group that received vancomycin. The risk of bias (RoB 2) assessments did not find an overall high risk of bias for any outcome.
All six studies assessed the efficacy and safety of FMT for the treatment of rCDI.
Pooled results from six studies showed that the use of FMT in immunocompetent participants with rCDI likely leads to a large increase in resolution of rCDI in the FMT group compared to control (risk ratio (RR) 1.92, 95% confidence interval (CI) 1.36 to 2.71; P = 0.02, I2 = 63%; 6 studies, 320 participants; number needed to treat for an additional beneficial outcome (NNTB) 3; moderate-certainty evidence). Fecal microbiota transplantation probably results in a slight reduction in serious adverse events; however, the CIs around the summary estimate were wide (RR 0.73, 95% CI 0.38 to 1.41; P = 0.24, I² = 26%; 6 studies, 320 participants; NNTB 12; moderate-certainty evidence). Fecal microbiota transplantation may result in a reduction in all-cause mortality; however, the number of events was small, and the CIs of the summary estimate were wide (RR 0.57, 95% CI 0.22 to 1.45; P = 0.48, I2 = 0%; 6 studies, 320 participants; NNTB 20; low-certainty evidence). None of the included studies reported colectomy rates.