Fecal microbiota transplantation (FMT) appears effective and relatively safe for recurrent Clostridium difficile infection (CDI), but there is too little evidence to draw reliable conclusions about use of the procedure for refractory or initial CDI, a new systematic review suggests.
Dimitri Drekonja, MD, from the Minneapolis Veterans Affairs Health Care System, Minnesota, and colleagues published the results of their review in the May 5 issue of the Annals of Internal Medicine. Despite the overall low quality of the studies, the authors emphasize the importance of the large positive effect of FMT in the RCTs and in the case-series studies. FMT was successful in 85% of recurrent CDI and 55% of refractory CDI compared with 30% to 80% success rates for medical therapies.
In an accompanying editorial, Christina, M. Surawicz, MD, professor of medicine, University of Washington School of Medicine, Seattle, writes, "The excitement about FMT is justified given its high efficacy in treating recurrent CDI, relative availability and simplicity, and favorable cost profile compared with other therapies."
CDI recurs in 15% to 30% of patients after an initial infection, and recurrence risk rises after every subsequent episode. The authors note, "In 2013, the Centers for Disease Control and Prevention placed C. difficile into the top threat category ('urgent') in its threat report on antimicrobial resistance."
Dr Surawicz comments, "Recurrent CDI is difficult to treat, even with pulsed antibiotic regimens and probiotics. Patients who have several recurrences become debilitated and discouraged, and some believe that they may never get rid of the infection."
Few Randomized Trials
In the last several years, FMT has emerged as a near-mainstream treatment for CDI, but much of the data have come from relatively small trials. In addition, the guidelines that address its use are not consistent.
Therefore, to clarify its value in patient care, Dr Drekonja and colleagues searched the literature for relevant trials. They identified two small RCTs on use of FMT for patients with recurrent CDI. Both RCTs tested FMT in patients with recurrent CDI and were unblinded and judged to have moderate risk of bias.
The first trial enrolled 43 patients and compared FMT administered via nasoduodenal tube after 4 to 5 days of oral vancomycin with 14 days of continued vancomycin and with 14 days of vancomycin plus bowel lavage. Symptoms resolved within 3 months in 81% of patients receiving FMT, 31% of patients receiving vancomycin, and 23% of patients receiving vancomycin plus bowel lavage. The study was terminated early because of the low response rates in the comparator groups.
The second unblinded RCT compared FMT given via nasogastric tube with FMT given via colonoscopy in 20 patients. Symptoms resolved completely for 70% of patients overall; outcomes were similar for the two methods.
Dr Drekonja and colleagues write, "Overall, recurrent CDI treated in the setting of an RCT resulted in 27 of 36 patients (75%) having resolution of symptoms without recurrence."
The authors also reviewed data from 21 case-series studies of FMT for recurrent CDI. Comparison of these studies was complicated by the fact that outcome reporting was variable, sometimes combining resolution of symptoms and recurrence. In most cases, FMT was administered to largely asymptomatic patients after antimicrobial treatment. Overall, FMT-treated patients remained without recurrence in 85% of episodes, and the authors suggest that FMT might have contributed to symptom resolution, recurrence prevention, or both.
In antibiotic-refractory CDI, the benefits of FMT were less certain. The reviewers identified seven studies in refractory CDI, none of which compared FMT with standard therapy. Symptom resolution ranged from 0% to 100%, with an overall resolution rate of 55%.
In initial CDI, the reviewers found seven cases of up-front FMT use, all from case-series studies, with insufficient data to reach conclusions about efficacy.
FMT Safe in Trials, Regulatory Questions Remain
The safety analysis largely confirmed the safety of FMT. Adverse events in the 2 RCTs included diarrhea, cramping, belching, nausea, abdominal pain, bloating, transient fever, and dizziness, all of which were mild. No serious adverse events were associated with FMT. Similarly, the case-series studies reported few FMT-related adverse events.
When the reviewers examined data on the acceptability of the treatment, they found that only 8 of 43 patients agreed to enroll in an FMT RCT after a first recurrence, but 97% of those who had received FMT were willing to have it again in the future.
Dr Drekonja and colleagues conclude, "In summary, low-strength evidence supports FMT as having a substantial effect and few short-term adverse events for adults with recurrent CDI. There is insufficient evidence about FMT for patients with refractory CDI or for initial treatment of CDI. Evidence is insufficient about whether treatment effects vary by FMT donor, preparation, or delivery method."
The authors note that in many cases, FMT seemed to be given with the intent of preventing recurrence after most CDI symptoms had been resolved by antimicrobial treatment. They advised that future FMT studies should be designed with careful attention to whether the primary outcome should be symptom resolution or recurrence prevention.
A key unmet need is for a large, blinded RCT that would compare FMT with placebo in patients randomized after standard antimicrobial therapy. Other unanswered questions include the best source and processing methods for donor stool and the best timing for FMT after antimicrobial use.
Regulatory questions also remain. Dr Drekonja and colleagues note that the US Food and Drug Administration currently requires an investigational new drug application for clinical studies, but not for FMT use by individual clinicians treating CDI. Dr Surawicz adds, "There must be regulatory oversight because there are risks for infection and possible microbiome-related conditions, such as the metabolic syndrome. Regulations should standardize screening, preparation of material, and long-term follow-up."
The study was funded by the US Department of Veterans Affairs. Dr Drekonja received personal fees from Rebiotix during the conduct of the study. The other authors and Dr Surawicz have disclosed no relevant financial relationships.
Ann Intern Med. 2015;162:662-663, 630-638. Article abstract, Editorial extract
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Cite this: Fecal Transplant Effective for Recurrent C diff, Review Shows - Medscape - May 06, 2015.
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