Editor’s Note: Managed care leaders are striving to make evidence-based decisions about new and emerging health technology. Managed Care and ECRI Institute have collaborated to disseminate bimonthly summaries of the Institute’s Emerging Technology Evidence Reports. ECRI Institute is an independent not-for-profit organization that researches the best approaches to improving patient care by analyzing the research literature on clinical procedures, medical devices, and drug therapies.

The bacterium Clostridium difficile (C. difficile) causes antibiotic-associated diarrhea, colitis, other serious intestinal conditions, and death in severe cases. C. difficile infection (CDI) occurs most often in individuals who have had one or more antibiotic courses, which can suppress normal colonic microbiota. This allows C. difficile to proliferate and release toxins that inflame and damage the gastrointestinal (GI) tract mucosa.

In the past decade, CDI incidence and severity have increased significantly in health care settings; more than 500,000 cases are reported each year. A 2012 Weekly Morbidity and Mortality Report from the U.S. Centers for Disease Control & Prevention reported that “the incidence, mortality, and medical care costs of CDIs have reached historic highs.”

When CDI is confirmed, physicians typically discontinue treatment with the inciting antibiotic and prescribe oral metronidazole for mild or moderate CDI, or oral vancomycin for severe CDI. Yet, up to 35% of patients have a CDI recurrence within two months after therapy.

The first recurrence is typically treated with the same regimen as the initial episode, or with a relatively new antibiotic, fidaxomicin (Dificid). To treat a second recurrence, physicians often use tapered or pulsed doses of vancomycin; however, up to 65% of patients develop a third recurrence after this therapy.

These recurrences are costly to treat and place patients at risk for serious morbidity and sometimes mortality.

Transplantation

Fecal microbiota transplantation (FMT) involves using one of several methods to introduce saline-diluted fecal matter from a healthy donor into the patient’s GI tract to recolonize the colon with healthy bacteria. Potential benefits of FMT include lower cost than several courses of antibiotics and hospitalization; faster treatment and resolution than achieved with several weeks of antibiotics; mild to no side effects; and reduced risk of antibiotic-associated resistance.

Gastroenterologists using this treatment typically recommend that donors be healthy family members or spouses/significant partners who have common genetic and/or environmental factors. To ensure a donor is healthy, clinicians prescreen them through interviews and laboratory testing before obtaining stool for transfer. Published reports describe different methods of preparing donated stool; however, the FMT Workgroup recently published a standard protocol for donor stool preparation.

The gastroenterologist can accomplish FMT using a nasogastric tube, a nasoduodenal/jejunal tube, an upper tract endoscope, a colonoscope, a retention enema, or combined upper and lower approaches. The procedure takes 5 to 25 minutes. The scarce reported cost data range from a few hundred to several thousand dollars per procedure, depending on the FMT preparation and administration method.

Treatment success is typically defined by symptom resolution without relapse within eight weeks of FMT. Regular checkups for CDI are required up to a year after FMT.

Key questions and findings

1. Does FMT for recurrent or relapsing CDI result in short-term and long-term CDI resolution?

Evidence from seven case series that reported short-term (≤3 month follow-up) data on 190 patients indicates that FMT results in high rates of CDI resolution (72.5% to 100%). There is evidence from three of these case series that suggests some patients not responding to FMT initially benefit from a second FMT.

Evidence from six case series that reported longer term data (>3 month follow-up) on 201 patients indicates that FMT results in high rates of CDI resolution (76.8% to 100%).

2. How does the efficacy of FMT compare to other treatments for recurrent and relapsing CDI (i.e., various vancomycin regimens, metronidazole, fidaxomicin, pooled intravenous immunoglobulin, monoclonal antibodies)?

One randomized controlled trial (RCT) (known as the FECAL trial) was halted early because of superior efficacy after an interim analysis found FMT to be significantly more effective than vancomycin alone or vancomycin plus bowel lavage. Most FMT patients (81.3%) had CDI resolution after a single FMT; 93.8% achieved resolution with a second FMT.

In contrast, only 30.8% of the vancomycin group and 23.1% of the vancomycin plus bowel lavage group had CDI resolution (p <0.001 for between group comparisons with FMT group).

3. What adverse events (AEs) have been reported in studies of FMT and how do AEs from FMT compare to AEs from antibiotic therapy?

In studies, FMT was generally well-tolerated. Eight of the nine FMT case series that assessed AEs reported that no AEs occurred among 290 study patients.

The remaining study (43 patients) found that about one-third of patients noted irregular bowel movements and excessive flatulence the first two weeks after the procedure.

In the RCT (FECAL trial), patients reported very short-term symptoms (resolved within three to 24 hours of FMT): diarrhea in most patients, abdominal cramps in about a third of patients, and belching in a few patients.

FMT diffusion has been tempered by the U.S. Food and Drug Administration’s (FDA) announcement in May 2013 that FMT must be treated as a drug or biologic requiring clinicians to submit an Investigational New Drug (IND) application to perform the procedure. ECRI Institute identified about 42 institutions in the United States, Europe, and Canada that offered the procedure as of January 2013, some as part of ongoing clinical trials and some on an exceptional case basis.

Physicians performing FMT have reported that patients with recurrent CDI are receptive to FMT because they are very ill with poor quality of life.

Health care facilities offering FMT would need to create dedicated laboratory facilities to test and safely process donor stool and facilitate safe administration to patients. Centers also should provide patient counseling.

Excerpted with permission from ECRI Institute’s database of Emerging Technology Evidence Reports. To download the full report, visit www.ecri.org/managedcare.

For inquiries about this report or membership in ECRI Institute’s Health Technology Assessment Information Service, e-mail htais@ecri.org.

State of Evidence Base

Quantity of evidence: Low

The evidence base consists of 10 retrospective pre-post treatment studies, one prospective pre-post treatment study, and one RCT. These studies reported on 406 patients with recurrent or relapsing CDI: 380 patients received FMT, and 26 control patients received vancomycin with or without bowel lavage. Given that more than 500,000 CDIs occur per year in the United States alone, it is reasonable to expect a larger evidence base on comparative effectiveness of FMT versus antibiotic therapy, including fidoxamicin (Dificid). Study of FMT as a first-line therapy is also warranted.

Quality of evidence: Moderate

CDI does not resolve without intervention; thus, case series with a pre-post treatment design can provide some informative data on the efficacy of CDI itself. Case series, however, cannot provide insight into the efficacy of FMT relative to other therapies for CDI. Only one RCT (the FECAL trial) has been published that directly compared FMT to a standard antibiotic therapy (vancomycin). Most of the published case series report single-center experiences that may not be generalizable to a broader population.

Consistency of evidence: High

The included studies reported consistent results regarding short- and longer-term efficacy and safety, and all studies reported FMT to be effective for resolving recurrent CDI in most patients (reported resolution rates were 72% to 100%).

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