Coverage Policy Manual
Policy #: 2013017
Category: Medicine
Initiated: April 2013
Last Review: October 2018
  Fecal Microbiota Transplantation for the Treatment of Clostridium Difficile

Description:
Fecal microbiota transplantation (FMT) involves the infusion of intestinal microorganisms via transfer of stool from a healthy individual into a diseased individual, with the intent of restoring normal intestinal flora. Fecal transplant is proposed for the treatment of treatment-refractory Clostridium difficile infection (CDI), as well as for other conditions including inflammatory bowel disease (IBD).
 
Background
FMT, also called donor feces infusion, intestinal microbiota transplantation, and fecal bacteriotherapy, involves the infusion of intestinal microorganisms via transfer of stool from a healthy individual into a diseased individual to restore normal intestinal flora. The stool can be infused as a liquid suspension into a patient’s upper gastrointestinal tract though a nasogastric tube or gastroscopy, or into the colon through a colonoscope or rectal catheter.
 
The goal of FMT is to replace damaged and/or disordered native microbiota with a stable community of donor microorganisms. The treatment is based on the premise that an imbalance in the community of microorganisms residing in the gastrointestinal tract (ie, dysbiosis) is associated with specific disease states, including susceptibility to infection.
 
The human microbiota, defined as the aggregate of microorganisms (bacteria, fungi, archaea) on and in the human body, is believed to consist of approximately 10-100 trillion cells, approximately 10 times the number of human cells. Most human microbes reside in the intestinal tract and most of these are bacteria. In its healthy state, intestinal microbiota perform a variety of useful functions including aiding in the digestion of carbohydrates, mediating the synthesis of certain vitamins, repressing growth of pathogenic microbes, and stimulating the lymphoid tissue to produce antibodies to pathogens.
 
To date, the major potential clinical application of fecal microbiota transplantation is treatment of CDI. Infection of the colon with C difficile is a major cause of colitis and can cause life-threatening conditions including colonic perforation and toxic megacolon. C difficile occurs naturally in intestinal flora. The incidence of CDI in North America has increased substantially in the past decade. For example, according to hospital discharge diagnosis data, there were more than 300,000 cases of CDI in 2006, compared with fewer than 150,000 cases in 2000. Moreover, CDI causes an estimated 15,000 to 20,000 deaths per year in U.S. hospitals (Kachrimanidou, 2011; Nelson, 2011).
 
It is unclear what causes C difficile overgrowth, but disruption of the normal colonic flora in conjunction with colonization by C difficile are major components. Disruption of the normal colonic flora occurs most commonly following administration of oral, parenteral or topical antibiotics. Standard treatment for CDI is antibiotic therapy. However, symptoms recur in up to 35% of patients and up to 65% of patients with recurrences develop a chronic recurrent pattern of CDI (Gough, 2011).  
 
Other potential uses of fecal microbiota transplant include treatment of conditions in which altered colonic flora may play a role. These include IBD, irritable bowel syndrome, idiopathic constipation and nongastrointestinal disease such as multiple sclerosis, obesity, autism and chronic fatigue syndrome. However, for these conditions, the contribution of alterations in colonic flora to the disorder is uncertain or controversial.
 
There is interest in alternatives to human feces that might have the same beneficial effects on intestinal microbiota without the risks of disease transmission. A proof of principle study was published in 2013 that evaluated a synthetic stool product in 2 patients with recurrent CDI (Petrof, 2013). The product is made from 33 bacterial isolates that were developed from culturing stool from a healthy donor.
 
Regulatory Status
In July 2013, the U.S. Food and Drug Administration (FDA) issued guidance regarding investigational new drug requirements for use of fecal microbiota transplant to treat CDI not responsive to medication therapy (FDA, 2013). The document states that FDA is continuing to consider how to regulate fecal microbiota transplant and that, during this interim period, the agency will use enforcement discretion regarding use of fecal transplant to treat treatment-resistant CDI infections. FDA requires that physicians obtain adequate informed consent from patients or their legal representative before performing the intervention. The document also states that selective enforcement does not apply to use of fecal transplant for treating conditions other than treatment-resistant CDI.
  
Coding
Effective January 1, 2013, there is a new CPT code 44705 for FMT which represents the physician work and practice expense of the backbench work to obtain and prepare a fecal microbiota specimen.  The actual instillation of the specimen by nasogastric tube or enema would be reported using CPT code 44799.  
 
The Centers for Medicare and Medicaid Services (CMS) established a HCPCS “G” code (also effective January 1, 2013) - G0455 - Preparation with instillation of fecal microbiota by any method, including assessment of donor specimen.
 

Policy/
Coverage:
Effective January 2017
 
Fecal microbiota transplantation meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of patients with recurrent C.difficile following at least one course of adequate antibiotic therapy.
 
Fecal microbiota transplantation does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for all other indications.
 
For members with contracts without primary coverage criteria, fecal microbiota transplantation is considered investigational for all other indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to January 2017
    
Fecal microbiota transplantation meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of patients 18 years of age and older with recurrent C.difficile following at least one course of adequate antibiotic therapy.
 
Fecal microbiota transplantation does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for all other indications.
 
For members with contracts without primary coverage criteria, fecal microbiota transplantation is considered investigational for all other indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
    
 

Rationale:
Recurrent Clostridium difficile infection (CDI)
The available literature consists of 2 randomized controlled trial (RCTs) and numerous case series or case reports. Other than a few case reports of patients with acute Clostridium difficile (CDI), studies treated patients with recurrent infection.
 
RCTs The first RCT that evaluated fecal microbiota transplantation was published in 2013 (van Nood, 2013). This nonblinded study, by van Nood et al in the Netherlands, included 43 patients 18 years and older with at least 1 recurrence of CDI. Exclusion criteria included prolonged compromised immunity, admission to an intensive care unit, and need for vasopressor medication.
 
Patients were randomized to 1 of 3 treatment groups: 1) fecal microbiota transplantation (FMT ,here called donor feces infusion) (n=17); 2) antibiotic therapy (n=13); or 3) antibiotics and bowel lavage (n=13). The FMT intervention involved collecting feces from healthy screened donors on the day of infusion, diluting the feces with 500 mL of sterile saline and infusing the solution (mean=141g) through a nasoduodenal tube. Patients assigned to the FMT group also received a modified course of vancomycin (500 mg orally 4 times a day for 4-5 days) and bowel lavage before infusion. A second infusion was given to patients in the FMT group who had a relapse after the first treatment. Potential donors underwent an evaluation process that included completing a questionnaire on potential risk factors for transmissible diseases, screening feces for parasites, and screening blood for antibodies for viruses. The study was initially designed to include 120 patients (40 per group), but, because of the high relapse rate in the control groups, the data and safety monitoring group recommended early termination of the trial. The primary efficacy outcome was cure without relapse within 10 weeks of initiating treatment. Cure was defined as absence of diarrhea that could not be explained by other causes and 3 consecutive negative tests for CDI toxin. Relapse was defined as diarrhea with a positive stool test for CDI toxin during this 10-week period. For the 3 patients who received a second infusion, follow-up was extended to 10 weeks after the second treatment. Patients were questioned about symptoms of diarrhea, and stool tests were performed on days 14, 21, 35, and 70 and when diarrhea was reported. One patient in the FMT group was excluded from analysis.
 
A total of 15 of 16 patients (94%) of analyzed patients in the FMT group were cured: 13 after a single infusion and another 2 after a second infusion from a different donor. In contrast, only 4 of 13 patients (31%) in the antibiotics-only group and 3 of 13 patients (23%) in the antibiotics and bowel lavage group were cured. The overall cure rate was significantly higher in the FMT group compared with the other 2 groups (p<0.001). Most patients in the FMT group experienced short-term adverse events (ie, diarrhea in 94%, cramping in 31%, belching in 19%) that resolved within 3 hours.
 
Data on the diversity of fecal microbiota were available for 9 patients in the FMT group. Diversity was measured on a scale ranging from 1 to 250, with higher values indicating more diversity. Before infusion, mean microbiota diversity was low (mean=57, standard deviation [SD]=26). Within 2 weeks of infusion, diversity increased to a mean of 179 (SD=42), a level similar to the diversity levels in the donors (mean=172, SD=54).
 
A second RCT, published by Youngster et al in 2014, compared infusion of donor stools by colonoscopy or nasogastric tube (Youngster, 2014).  A total of 20 patients with relapsing and recurrent CDI were included. Patients needed to have a relapse of CDI following at least 3 episodes of mild-to-moderate CDI and failure of a course of vancomycin or at least 2 episodes of severe CDI that resulted in hospitalization and was associated with significant morbidity. All patients underwent FMT and were randomized to 1 of 2 infusion routes, colonoscopy or a nasogastric tube. Both groups had 90cc thawed inoculum. Stool donors were healthy nonrelatives who successfully completed an extensive screening process. Stool was frozen up to 156 days before use. Patients could receive a second FMT if symptoms did not resolve following the initial transplant.
 
The primary efficacy outcome was clinical cure, defined as resolution of diarrhea (ie, <3 bowel movements per 24 hours) while off antibiotics for CDI, without relapse for 8 weeks. Fourteen patients were cured after the first FMT, 8 in the colonoscopy group and 6 in the nasogastric tube group; the difference between groups was not statistically significant (p=0.628). Of the remaining 6 patients, 1 refused additional treatment and the other 5 underwent a second transplant. According to the study protocol, patients could choose the route of administration for the second procedure, and all of them chose the nasogastric tube. Four additional patients were cured after the second transplant, for an overall cure rate of 18 of 20 (90%). This study did not find that either route of administration of donor feces was superior to the other, but patients preferred use of a nasogastric tube.
 
Uncontrolled studies
Several systematic reviews of uncontrolled studies on fecal microbiota transplantation for treating CDI have been published (Gough, 2011; Guo, 2012; Sofi, 2013). Of these, only Sofi et al conducted a pooled data analysis. (10) The investigators searched the literature through April 2012. The authors did not identify any RCTs that evaluated FMT (their literature search was conducted before publication of a 2013 RCT, discussed next). A total of 25 observational studies (10 case reports, 15 case series) provided data on 239 adult patients treated with fecal microbiota transplants for CDI. All of the case series were retrospective, and sample sizes ranged from 4 to 70 patients; only 4 studies included more than 25 patients. Most studies included recurrent CDI, but several case reports treated patients who were severely ill due to acute CDI. Fecal transplants were performed by the gastroduodenal route in 91 patients (32%) and by the colonic route in 198 (68%) patients. Treatment success was defined as resolution of CDI symptoms at follow-up. Mean follow-up post-transplant ranged from 10 days to 65 months. In a pooled analysis of individual patient data, the overall treatment success rate was 91.2%. Subanalyses revealed a significantly higher treatment failure rate in patients treated by the colonic versus the duodenal route and patients with symptoms for at least 60 days versus less than 60 days.
 
A 2014 retrospective case series included 94 patients with refractory or recurrent CDI who underwent 1 or more FMT via retention enema (Lee, 2014). Cure was defined as no recurrence of diarrhea in the 6 months after treatment. A total of 45 of 94 patients (48%) were cured following a single FMT. When 4 or more FMTs were administered, the cure rate was 86.2%, and this increased further to 91.5% when antibiotics were administered between FMTs.
 
Section Summary
One small RCT, which enrolled patients who had failed at least 1 course of antibiotic treatment, reported a large increase in resolution of C difficile with FMT plus antibiotics compared with antibiotics alone with or without bowel lavage. A second RCT compared different modes of administration and did not find a significant difference in fecal transplantation via colonoscopy or nasogastric tube. This study also reported a high overall CDI cure rate, but did not have a medical treatment control group. Case reports and case series report a high rate of resolution of CDI following treatment with FMT. Further studies are needed to determine the optimal patient selection criteria and treatment protocol for this therapy.
 
Inflammatory Bowel Disease
In 2012, Anderson et al published a systematic review of the available literature on fecal microbiota transplant for treatment of inflammatory bowel disease (IBD) (Anderson, 2012). The investigators searched for published studies and conference abstracts in any language reporting on patients with IBD treated with fecal transplants for IBD symptoms or infectious diarrhea. A total of 17 studies with 41 patients met the review’s inclusion criteria. None of the studies were controlled; all were case reports or case series. Nine articles reported on 26 patients (18 with ulcerative colitis, 6 with Crohn disease, and 2 with undefined IBD) who received fecal microbiota transplants because their IBD was resistant to standard management. The other 8 articles included 15 patients (9 with ulcerative colitis and 6 with Crohn disease) whose primary indication for fecal transplant was recurrent CDI.
 
Outcome data were reported for 17 of the 26 patients being treated for IBD. Thirteen of 17 (76%) patients stopped IBD medications within 6 weeks. Data on IBD symptoms before and after the procedure were available for 16 patients. All of these reported a reduction or resolution of IBD symptoms within 4 months of receiving fecal transplants, and 15 reported complete resolution of symptoms within a year. Three of 13 patients reported no disease recurrence at long-term follow-up (which was 3-6 months in 15 patients and 1-13 years in 12 patients).
 
Section summary
Data are available on only a small number of patients with IBD treated with fecal microbiota transplant and there is a lack of controlled studies. Improvements in IBD symptoms have been reported, but further controlled studies in larger numbers of patients are needed to establish efficacy,
 
Ongoing clinical trials
A search of online clinicaltrials.gov database in March 2014 found a number of ongoing RCTS evaluating fecal microbiota transplant. These trials can be grouped into several categories, as follows:
 
Evaluating fecal microbiota transplant as a treatment for recurrent CDI:
Stool Transplant in Pediatric Patients With Recurring C Difficile Infection (NCT01972334): Double-blind RCT comparing fecal transplant to a placebo procedure in children (age 8-18 years) with recurrent CDI. Estimated enrollment is 46 patients.
 
Oral Vancomycin Followed by Fecal Transplant Versus Tapering Oral Vancomycin (NCT01226992): Nonblinded RCT to compare 2 weeks of oral vancomycin treatment followed by single-dose fecal transplant via rectal enema with 2 weeks of oral vancomycin treatment followed by tapering of vancomycin. Estimated enrollment is 146 patients.
 
Evaluating fecal microbiota transplant as a treatment for other conditions:
Fecal Biotherapy for the Induction of Remission in Active Ulcerative Colitis (NCT01545908): Double-blind RCT to compare 6 weekly fecal transplant enemas with placebo enemas in patients with ulcerative colitis.
Estimated enrollment is 130 patients.
 
Standardized Fecal Microbiota Transplantation for Crohn Diseases (NCT01793831): Nonblinded RCT to compare a single fecal transplant procedure with standard medical care in patients with ulcerative colitis or Crohn disease. Estimated enrollment is 30 patients.
 
Evaluating technical aspects of the transplant procedure:
Multi-Centre Trial of Fresh vs. Frozen-and-Thawed HB T(Fecal Transplant)for Recurrent CDI (NCT01398969): Double-blind RCT to compare an enema of fresh human fecal bacteriotherapy and frozen-and-thawed fecal bacteriotherapy. The study includes patients with recurrent CDI. Estimated enrollment is 136 patients.
 
Practice Guidelines and Position Statements
In April 2013, the American College of Gastroenterology published a guideline on diagnosis, treatment, and prevention of CDIs (ACG, 2014). The guideline addressed fecal microbiota transplant for treatment of 3 or more CDI recurrences, as follows:
 
“If there is a third recurrence after a pulsed vancomycin regimen, fecal microbiota transplant (FMT) should be considered. (Conditional recommendation, moderate-quality evidence)”
 
For treatment of 1 to 2 CDI recurrences, the guideline recommended:
“The first recurrence of CDI can be treated with the same regimen that was used for the initial episode. If severe, however, vancomycin should be used. The second recurrence should be treated with a pulsed vancomycin regimen. (Conditional recommendation, low-quality evidence)”
 
2016 Update
A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2014 systematic review by Sha  and colleagues identified published reports on 644 patients with CDI worldwide who were treated with FMT (Sha. 2014). There was 1 RCT and the rest of the studies were uncontrolled. The overall success rate of FMT for treating CDI was 90.7%. Only 5 of the patients with CDI were children, and 4 out of 5 of these (80%) experienced clinical resolution following treatment. A 2015 series by Kronman and colleagues found that 9 of 10 (90%) children with recurrent CDI had resolution of symptoms after FMT and remained asymptomatic during the follow-up period (median: 44 days) (Kronman, 2015).
 
The 2014 Sha and colleagues systematic review, described above, also included literature on FMT for treatment of IBD (Sha, 2014). The authors identified reports of 111 IBD patients worldwide who received fecal transplants for IBD. All of the studies were case series. Treatment was successful in achieving remission of IBD 87 of 111 (77.8%) patients, including all 3 of the children.
 
In 2015, Drekonja and colleagues systematically reviewed the literature on FMT for treating CDI (Drekonja, 2014). In addition to the 2 RCTs previously described, the authors identified 28 case series and 5 case reports Twenty one case series included patients with recurrent CDI and, in these studies, 85% of patients treated with FMT remained free of symptoms without additional recurrences (the number of patients successfully treated was not reported). Seven case series included patients with refractory CDI, defined as an episode of CDI that did not respond to antimicrobial treatment. Resolution of symptoms in the studies on refractory CDI ranged widely, from 0% to 100%, with an overall resolution rate of 55%. There were reports of only 7 patients treated with FMT for initial CDI. The case series reported few adverse effects of treatment with FMT.
 
Inflammatory Bowel Disease
Randomized Controlled Trials
In 2015, 2 double-blind placebo-controlled RCTs were published that evaluated fecal microbiota transplantation for treatment of ulcerative colitis (UC). Both trials were discontinued due to futility but 1 of them ultimately had positive findings. The 2 RCTs varied in their control conditions, outcomes measures, and intervention lengths.
 
Moayyedi and colleagues (2015) enrolled 75 patients aged 18 and older with active UC (Mayo Clinic score ≥4 and endoscopic Mayo Clinic score ≥1) and without C. difficile infection. (Moayyedi, 2015). Patients were randomized to FMT (n=38) or placebo (n=37). The intervention consisted of 6 weekly treatments with donor stool solution or placebo, given as a retention enema. Donors were screened prospectively for pathogens and rescreened every 6 months. Patients underwent clinical and endoscopic examination at week 7 (±3 days). The primary outcome was UC remission at week 7, defined as a full Mayo score <3 and a flexible sigmoidoscopy finding of complete healing of the mucosa (endoscopic Mayo score=0).
 
The investigators initially aimed to recruit 130 patients. After 50% of the participants were enrolled, the Data Monitoring and Safety Committee (DMSC) recommended that the trial be discontinued for futility, and that the enrolled patients complete the study. At the 7-week follow-up, 9 of 38 patients in the FMT group (24%) and 2 of 37 patients in the placebo group (5%) achieved UC remission. The different between groups was statistically significant, p=0.03. There was not a significant difference between groups in the adverse event rate.
 
Roosen and colleagues (2015a) included 50 patients with mild to moderately active UC (Roosen, 2015). To participate, patients needed to have a patient-reported Simple Clinical Colitis Activity Index (SCCAI) between 4 and 11, an endoscopic Mayo score of ≥1 and stable medication use. Patients were randomized to 2 treatments with FMT, 3 weeks apart or a placebo intervention (autologous FMT). FMT was done via a nasoduodenal tube using 500 mL fecal suspension. Patients underwent clinical and endoscopic examination at baseline, 6 weeks and 12 weeks. The primary endpoint was clinical remission at 12 weeks, defined as a SCCAI score ≤2 and at least a 1-point improvement o the combined Mayo endoscopic score of the sigmoid and rectum.
 
The investigators initially calculated that a sample size of 42 patients was need for the primary outcome analysis. The sample size calculated assumed a response rate of 70% in the treatment group and 22.5% in the control group. At the first interim analysis, after 20 patients had completed 12 weeks of follow-up, a lower response rate was observed and an increase in the sample size was recommended. At the second interim analysis, the DSMC recommended terminating the trial for futility. At the time of study termination, 50 patients had been randomized. Two patients had been excluded from the study post-randomization, leaving 48 patients in the intention to treat analysis. A total of 37 patients had completed the study. In the ITT analysis of the primary outcome measure, 7 of 23 patients in the active FMT group (30.4%) and 8 of 25 patients in the control group (32%) met criteria for clinical remission. The difference between groups was not statistically significant, p=1.0. Four patients, 2 in each group, experienced a serious adverse event. Other than 1 case of abdominal pain, the serious adverse events were not considered to be treatment-related. The majority of patients experienced mild adverse events during or shortly after treatment, the most common of which was transient borborygmus and increase in stool frequency.
 
Two small RCTs on FMT for treatment of UC have been published. Both trials were discontinued for futility, and data from already-enrolled patients were analyzed. One trial found a statistically significantly higher remission rate after active FMT compared to a control intervention, but this finding is limited by the low numbers of patients with remission (n=11 total remissions) and short follow-up (7 weeks). The other trial reported no difference in remission rates. This evidence is not sufficient to allow conclusions on the efficacy of FMT for UC. In addition, questions remain about the optimal route of administration, donor characteristics and number of transplants. Data on a small number of patients with CD are available and there are no controlled studies of FMT in this population.
 
A systematic review by Rossen and colleagues of studies on FMT identified 1 case series on constipation (n=3), 1 on pouchitis (n=8) and 1 on irritable bowel syndrome (n=13) (Roosen, 2015b). There was also 1 small RCT (n=18) on FMT for treatment of metabolic syndrome. The RCT, by Vrieze and colleagues (Vrieze, 2012). compared donor
 
The evidence for FMT in patients who have recurrent CDI refractory to antibiotic therapy includes 2 RCTs and observational studies. Relevant outcomes are symptoms, change in disease status and treatment related morbidity. Case reports and case series report a high rate of resolution of recurrent CDI following treatment with FMT. Few treatment related adverse events have been reported. The evidence is sufficient to determine qualitatively that the treatment results in meaningful improvements in the net health outcome.
 
The evidence for FMT in patients who have inflammatory bowel disease includes 2 RCTs in patents with UC and observational studies. Relevant outcomes are symptoms, change in disease status and treatment-related morbidity. Two small RCTs on FMT for treatment of UC have been published. Both trials were discontinued for futility, and data from already-enrolled patients were analyzed. One trial found a statistically significantly higher remission rate after active FMT compared to a control intervention, but this finding is limited by the low numbers of patients with remission (n=11 total remissions) and short follow-up (7 weeks). The other trial reported no difference in remission rates. Data on a small number of patients with CD are available and there are no controlled studies of FMT in this population. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
The evidence for FMT in patients who have other conditions potentially treatable with fecal microbiota transplantation eg, acute Clostridium difficile infection, pouchitis, irritable bowel syndrome, constipation and metabolic syndrome includes a small number of case series and/or case reports Relevant outcomes are symptoms, change in disease status and treatment-related morbidity. Data are available on only small numbers of patients and there is a lack of comparative studies. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Ongoing Clinical Trials
Some currently unpublished trials that might influence this policy are listed below:
Ongoing
 
(NCT 01896635) Fecal Microbiota Transplantation in Ulcerative Colitis (FOCUS); planned enrollment 80; completion date September 2016.
 
(NCT01793831) Standardized Fecal Microbiota Transplantation for Crohn Diseases; planned enrollment 30; completion date June 2015.
 
2018 Update
A literature search was conducted through September 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Quraishi et al published a systematic review and meta-analysis of 7 RCTs comparing FMT with standard antibiotic regimen in 1973 patients with recurrent and refractory CDI (follow-up, 10-13 weeks), and 30 case series (sample sizes ≥10 patients) describing the effect of FMT in 1545 patients with recurrent and refractory CDI (Quraishi, 2017). Reviewers deemed the 7 RCTs as having a low risk of bias (including adequate randomization with allocation concealment and intention-to-treat analysis). Reviewers did not report an assessment of bias in terms of blinding, sample size adequacy, or possible differences in baseline characteristics. They argued that none of trials examining the efficacy of FMT were truly placebo controlled, and the 30 case series followed patients until resolution of CDI (range, 10 weeks to 8 years), though some had incomplete follow-up. In the pooled analysis, 92% of patients had a resolution of CDI (95% confidence interval [CI], 89% to 94%); heterogeneity were classified as likely moderate (I2=59%). Additionally, in the 7 trials that evaluated FMT, the intervention overall was associated with an increase in the resolution of recurrent and refractory CDI (relative risk [RR], 0.23; 95% CI, 0.07 to 0.80). The 30 case series reported resolution rates for CDI from 68% to 100%.
 
The Quraishi review found FMT to be effective in the treatment of recurrent and refractory CDI, and no serious adverse events from FMT were reported in the RCTs through the follow-up period. Most adverse effects in the case series were minor (bloating, belching, abdominal cramps, pain or discomfort, nausea, vomiting, excess flatulence, constipation, transient fever, urinary tract infections, self-limiting diarrhea, irregular bowel movement). However, reviewers noted several limitations. Based on variability in the definitions of CDI resolution used across the studies, reviewers could not distinguish between recurrent and refractory CDI. There were also variations across studies in terms of recipient preparations, number of infusions, time to resolution, follow-up, overall response, dosing, concurrent use of medications, and other non-specified biases. Heterogeneity between most studies was considerable.

CPT/HCPCS:
44705Preparation of fecal microbiota for instillation, including assessment of donor specimen
44799Unlisted procedure, small intestine
G0455Preparation with instillation of fecal microbiota by any method, including assessment of donor specimen

References: American College of Gastroenterology (ACG). Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Available online at: http://gi.org/guideline/diagnosis-andmanagement- of-c-difficile-associated-diarrhea-and-colitis/. Last accessed March, 2014.

Brandt LJ.(2013) American journal of gastroenterology lecture: intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection. Am J Gastroenterol. 2013 Feb;108(2):177-85.

Cohen SH, Gerding DN, Johnson S et al.;(2010) Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31(5):431-55.

Drekonja D, Reich J, Gezahegn S, et al.(2015) Fecal microbiota transplantation for Clostridium difficile infection: a systematic review. Ann Intern Med. May 5 2015;162(9):630-638. PMID 25938992

Food and Drug Administration (FDA). Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies. July 2013. Available online at: http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform ation/Guidances/Vaccines/UCM361393.pdf. Last accessed March, 2014.

Gough E, Shaikh H, Manges AR.(2011) Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011; 53(10):994-1002.

Guo B, Harstall C, Louie T et al.(2012) Systematic review: faecal transplantation for the treatment of Clostridium difficile-associated disease. Aliment Pharmacol Ther 2012; 35(8):865-75.

Kachrimanidou M, Malisiovas N.(2011) Clostridium difficile infection: a comprehensive review. Crit Rev Microbiol 2011; 37(3):178-87.

Kassam Z, Lee CH, Yuan Y, Hunt RH.(2013) Fecal microbiota transplantation for clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013 Apr;108(4):500-8.

Kelly CP.(2013) Fecal microbiota transplantation- an old therapy comes of age. N Engl J Med. 2013 Jan 31;368(5):474-5.

Kronman MP, Nielson HJ, Adler AL, et al.(2015) Fecal microbiota transplantation via nasogastric tube for recurrent clostridium difficile infection in pediatric patients. J Pediatr Gastroenterol Nutr. Jan 2015;60(1):23-26. PMID 25162365

Lee CH, Belanger JE, Kassam Z et al.(2014) The outcome and long-term follow-up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema. Eur J Clin Microbiol Infect Dis 2014.

Moayyedi P, Surette MG, Kim PT, et al.(2015) Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. Jul 2015;149(1):102-109 e106. PMID 25857665

Nelson RL, Kelsey P, Leeman H et al.(2011) Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database Syst Rev 2011, (9):CD004610.

Petrof EO, Gloor GB, Vanner SJ et al.(2013) Stool substitute transplant therapy for the eradication of Clostridium difficile infection: 'RePOOPulating' the gut. Microbiome 2013; 1(1):3.

Rossen NG, Fuentes S, van der Spek MJ, et al.(2015) Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. (2015a) Gastroenterology. Jul 2015;149(1):110-118 e114. PMID 25836986

Rossen NG, MacDonald JK, de Vries EM, et al.(2015) Fecal microbiota transplantation as novel therapy in gastroenterology: A systematic review. (2015b) World J Gastroenterol. May 7 2015;21(17):5359-5371. PMID 25954111

Sha S, Liang J, Chen M, et al.(2014) Systematic review: faecal microbiota transplantation therapy for digestive and non-digestive disorders in adults and children. Aliment Pharmacol Ther. May 2014;39(10):1003-1032. PMID 24641570

Sofi AA, Silverman AL, Khuder S et al.(2013) Relationship of symptom duration and fecal bacteriotherapy in Clostridium difficile infection-pooled data analysis and a systematic review. Scand J Gastroenterol 2013; 48(3):266-73.

van Nood E, Vrieze A, Nieuwdorp M, et al.(2013) Duodenal infusion of donor feces for recurrent clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407-15.

Vrieze A, Van Nood E, Holleman F, et al.(2012) Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. Oct 2012;143(4):913-916 e917. PMID 22728514

Youngster I, Sauk J, Pindar C et al.(2014) Fecal Microbiota Transplant for Relapsing Clostridium difficile Infection Using a Frozen Inoculum From Unrelated Donors: A Randomized, Open-Label, Controlled Pilot Study. Clin Infect Dis 2014.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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