Executive Summary

Fecal microbiota transplantation (FMT) involves transplanting saline-diluted fecal matter from a healthy donor into the gastrointestinal tract of a patient with recurrent C. difficile infection (CDI) to try to reestablish healthy fecal composition and increase microbial diversity so that CDI resolves. FMT's potential benefits include more rapid symptom resolution than antibiotics, lower cost than several courses of antibiotics and hospitalization, and reduced risk of antibiotic-associated bacterial resistance. Since 2009, FMT has garnered interest due to the growing body of evidence suggesting its safety and effectiveness and payment penalties introduced in the United States for readmissions due to hospital-acquired infections.

 

Parameter Rating and Definition* Rationale

Reimbursement Status: 3

Expanding

Our searches of 11 representative, private, third-party payers that provide online medical coverage policies found 6 payers with a policy describing coverage with conditions, 2 payers denying coverage for this, and 5 payers without a specific policy.

Diffusion Status: 3

Middle

Adopted by 25% to <50% of healthcare providers and facilities expected to use this technology.

Clinicians have performed several thousand fecal microbiota transplantations (FMTs) worldwide, including more than 1,000 in the United States. According to one clinical expert, approximately half of U.S. hospital-based and academic practices and 15% to 25% of private/group practices offer FMT.

Effects on Staffing and Care Processes: 2

Low

Centers offering FMT need specific treatment protocols regarding patient counseling, donor stool testing, stool donation and storage, stool processing, and transplantation of processed material. Clinicians involved in implementing FMT will require minimal additional training.

Infrastructure Needs: 1

Negligible

FMT is a relatively simple procedure, but to offer it, facilities may need to create dedicated laboratory facilities to process and store the donor stool and facilitate administration to patients.

Technology Cost Impact on Providers: 1

Negligible

<$25,000 for acquisition and implementation.

Costs for providers may include those associated with staffing, training, testing donor material, and decontamination of equipment used for collection and administration.

Technology Cost Impact on Payers: 1

Negligible

<$5,000 per patient and/or negligible utilization driving negligible aggregate cost.

Estimated procedure charges range from $1,500 to $3,710. Costs include testing of donor stool, processing of stool, short-term storage of stool, and routine supplies to perform transplantation (e.g., colonoscope, nasogastric tube). Patients may need to pay for donor screening or a stool bank fee ($250) to acquire universal donor material if they do not have their own donor.

*Please see Appendix C for parameter definitions.

Who Should Read This

Evidence Summary of Selected Outcomes*

 

*Note: We grade strength of evidence based on the concepts and methods proposed by the GRADE working group using ratings of very low, low, moderate, and high. We list outcomes we deem of greatest importance to patients first. See Appendix A for details. See the Findings section for additional outcomes for which we did not assess SOE. The best-available evidence on this technology came from three randomized controlled trials, two nonrandomized, retrospective comparative studies, and 17 pre/post intervention studies, which served as the basis for the GRADE ratings we assigned. No studies compared fecal microbiota transplantation with any treatment other than vancomycin.

Adverse Events

Available evidence suggests that fecal microbiota transplantation (FMT) is generally safe to perform and well-tolerated. Commonly reported AEs are diarrhea, abdominal cramping, bloating, and belching; in most cases, these symptoms resolve within a few hours or days of FMT. One study patient, who developed appendicitis, fever, E Coli, and septicemia after infusion of a fixed mixture of commensal intestinal bacteria, recovered after treatment with antibiotics. No other infectious or serious complications were reported.

Overview

Related Names

Generic names: Autologous rehabilitation of gastrointestinal flora, bacterial biotherapy, colonoscopic fecal bacteriotherapy, donor stool transplant, fecal bacteriotherapy, gut flora rehabilitation, floral reconstitution, fecal bacteriotherapy, fecal donor instillation therapy, fecal enema, fecal flora reconstitution, fecal repopulation, fecal therapy, fecal transplantation, fecal repopulation, fecal transfusion, gut flora rehabilitation, gut rehabilitation, human probiotic transfusion, intestinal microbiota therapy, intestinal microbiota transplantation, microbiota ecosystems therapeutics, microbiota restoration therapy, rectal bacteriotherapy, stool transplant

In 2011, a Fecal Microbiota Transplantation (FMT) Workgroup, consisting of international experts in gastroenterology and infectious disease, agreed on "fecal microbiota transplantation" as the term for this procedure.1 According to the group, "Microbiota is now considered a more precise term than flora and microflora, and transplantation is deemed more accurate than reconstitution because the new species are donor derived, and thus are not reconstituted."2

Background/Disease

Clostridium difficile is a gram-positive, anaerobic, spore-forming bacillus responsible for the development of antibiotic-associated diarrhea, colitis, other serious intestinal conditions, and death in severe cases. The main causative factor is antibiotic use that suppresses the normal colonic flora, allowing proliferation of C. difficile and subsequent release of toxins that cause mucosal inflammation and damage.3,4C. difficile infection (CDI) typically affects older adults in hospitals or long-term care facilities where antibiotic use is high and the environment is contaminated by C. difficile spores.3,4 However, clinicians are also seeing community-acquired CDI in patients with no recent exposure to antibiotics or a healthcare facility and the emergence of CDI among younger healthy outpatients.5 This increased infection rate is likely due to the emergence of an epidemic strain of C. difficile (i.e., NAP1), which appears to be more virulent and more resistant to treatment than previous strains.6

Infection risk increases in patients with recent antibiotic exposure, gastrointestinal surgery/manipulation, inpatient stays in healthcare settings, a serious underlying illness, conditions that compromise immunity, advanced age (older than 60 years),4,6 and prescribed proton pump inhibitor therapy.7 Symptoms of CDI are watery diarrhea, fever, loss of appetite, nausea, malaise, and abdominal pain or tenderness.4,6 Physicians test patients presenting with symptoms for the presence of C. difficile using four general methods: stool culture, antigen testing, molecular methods (polymerase chain reaction), and toxin testing. These methods can be used alone or combined.

Treating CDI, especially recurrent or persistent CDI, is a challenge.8 Once CDI is confirmed in a symptomatic patient, physicians typically discontinue treatment with the inciting antibiotic8 and prescribe a 10- to 14-day course of oral metronidazole (i.e., Flagyl®) for mild or moderate CDI or oral vancomycin for severe CDI.8 However, after initial treatment, up to 35% of patients have a recurrence within two months.8,9 Physicians typically treat the first CDI recurrence with the same regimen as the initial episode.8,10 Another treatment option for CDI is a newer antibiotic (i.e., fidaxomicin [Dificid®]), which purportedly has a selected action on C. difficile and limited effect on microflora.11,12 To treat a second CDI recurrence, physicians often use tapered or pulsed doses of vancomycin, but up to 65% of patients develop further recurrence after stopping vancomycin therapy.1 Other possible treatments for recurrent severe CDI include vancomycin plus probiotics (i.e., Saccharomyces boulardii), vancomycin plus rifaximin, intravenous tigecycline plus oral vancomycin, pooled intravenous immunoglobulin, monoclonal antibodies, nonabsorbable antibiotics (e.g., oral bacitracin), and toxin binders (e.g., cholestyramine).2,12,13

A novel nonpharmacologic approach for treating multiple recurrences of CDI, known as fecal microbiota transplantation (FMT), is the focus of this report.14

Incidence and Prevalence

In healthcare settings, CDI is increasing in incidence and severity.15

United States

In the United States, the number of patients discharged from hospitals with CDI rose sharply between 2000 and 2009 from 139,000 to 336,600 cases.16 In 2010, the estimated yearly incidence of CDI was 500,000.1 Mortality attributed to CDI, based on multiple cause-of-death mortality data, increased from an estimated 3,000 deaths per year during 1999–2000 to 14,000 during 2006–2007.16 Most of these deaths (>90%) occurred in individuals ≥65 years of age.16 A 2012 morbidity and mortality report published by the U.S. Centers for Disease Control and Prevention reported that "the incidence, mortality, and medical care costs of CDIs have reached historic highs."16

Worldwide

According to a recent hospital-based survey, CDI incidence has also risen in Europe over the past 20 years.17 This survey of 97 hospitals in 34 European countries reported the CDI incidence in hospitalized patients was 41 per 100,000 patient-days.17

Technology Description

FMT involves introducing saline-diluted fecal matter (i.e., fecal suspension) from a healthy donor into the gastrointestinal tract of a patient with recurrent CDI9,18 with the intent of "reestablishing a more normal fecal composition and increased microbial diversity."19

Donor Selection and Screening

Commonly, gastroenterologists recommend that fecal donors be healthy family members (i.e., parents, siblings, adult children of older patients) or spouses/significant others who have common genetic and/or environmental factors.14,20-22 In these cases (i.e., directed donor model), the composition of the intestinal bacteria of the donor and patient is expected to be more closely related.20 Having comparable infectious risk factors minimizes the risk of transmitting an infectious agent between the donor and patient.1 However, some centers and stool banks use unrelated healthy individuals as donors (i.e., universal donor model).19,22 Recruiting universal donors may make the screening process more efficient because it eliminates having to find a different individual donor for each case.23

To ensure that the donor is healthy and that risk factors for diseases transmissible by stool can be identified, prospective donors undergo prescreening by interview.1 This interview is intended to identify "risks for diseases and conditions for which there are no laboratory tests, for which tests are not sensitive enough to detect infectious disease agents, and for which tests are unable to identify early-stage or window-period infections."1

Donor exclusion criteria may include the following:1,24,25

  • Known HIV or hepatitis B or C infection
  • Known exposure to HIV or viral hepatitis within the previous 12 months
  • High-risk sexual behaviors within the preceding three months
  • Use of illicit drugs
  • Tattoo or body piercing within previous six months
  • Incarceration or history of incarceration
  • Known current communicable disease
  • Risk factors for variant Creutzfeldt–Jakob disease
  • Travel within the past six months to areas of the world where diarrheal illnesses are endemic or risk of traveler's diarrhea is high
  • History of inflammatory bowel disease
  • History of irritable bowel syndrome, idiopathic chronic constipation, or chronic diarrhea
  • History of gastrointestinal malignancy or known polyposis
  • Antibiotic use within the preceding three months
  • Use of major immunosuppressive medications
  • Use of systemic antineoplastic agents
  • Recent ingestion of a potential allergen (e.g., nuts) to which recipient has a known allergy
  • History of major gastrointestinal surgery
  • Metabolic syndrome
  • Systemic autoimmunity (e.g., multiple sclerosis, connective tissue disease)
  • Atopic diseases (e.g., asthma, eczema, eosinophilic disorders of the gastrointestinal tract)
  • Chronic pain syndromes that may have an immunologic etiology (e.g., chronic fatigue syndrome, fibromyalgia)
  • History of malignant illness or ongoing oncologic therapy

Identified potential donors must then undergo extensive laboratory screening for contagious transmissible diseases before stool transfer.21 See Table 1 for a list of parasitology, microbiology, and virology tests commonly performed before FMT.1 Clinical experts concur that serum and stool testing should be performed within four weeks of donation.24

Table 1. Screening Tests for Fecal Donors
Infection Screen Stool Blood
Parasitology

Fecal Giardia antigen

Fecal Cryptosporidium antigen or acid-fast stain for Cryptosporidium if antigen testing is unavailable

Acid-fast stain for Cyclospora

Acid-fast stain for Isospora

Ova and parasites*

Not applicable
Microbiology

Routine culture for enteric pathogens*

C. difficile toxin B by polymerase chain reaction* or evaluation for toxins A and B by enzyme immunoassay

Helicobacter pylori fecal antigen

Rapid plasma regain*

Fluorescent treponemal antibody-absorption test

VirologyNot applicable

Serum hepatitis C virus antibody*

Serum hepatitis A virus immunoglobulin (Ig) M*

Serum hepatitis B surface antigen*

Serum hepatitis B core antibody (both IgG and IgM)

Serum Hepatitis B surface antibody

Serum HIV-EIA* types 1 and 2 antibody

*According to specialty society consensus24

Donor Instructions

Fecal donors may receive the following instructions:1

  • Take a gentle osmotic laxative the night before the procedure.
  • Avoid any foods to which the recipient might be allergic for five days before the procedure.
  • Notify the practitioner if symptoms of infection occur between screening and scheduled donation.

Stool Preparation

Although donated stool is relatively simple to prepare, published reports describe different preparation methods. The FMT Workgroup provided the following standard protocol for donor stool preparation:1

  • Dilute the stool sample using either preservative-free normal saline or whole milk to achieve the right consistency for the transplant.
  • Homogenize the mixture using a conventional household blender until it reaches a liquid slurry consistency.
  • Filter the mixture through gauze pads or a urine stone strainer to remove as much particulate matter as possible.
  • Use the prepared stool slurry immediately.

Published reports also describe various intervals between obtaining donor stool and administering it to the patient (e.g., 24 hours before, 6 hours before, immediately).22 The FMT Workgroup recommends preparing and using donor stool as soon as possible after passage, preferably within six hours.1

Recipient Pretreatment

Clinicians test FMT recipients for HIV types 1 and 2, hepatitis A, B, and C, and syphilis.25 Published reports describe different pretreatment regimens depending on administration route, which may include the following:

  • A 4-day course of vancomycin, which is discontinued 12 to 48 hours before the procedure22,26
  • A colonic lavage with a macrogol solution to remove the preexisting pathologic flora and C. difficile spores27
  • A large-volume bowel prep regardless of the administration (Illness severity may limit the patient's ability to perform this step.)1
  • Loperamide (i.e., Imodium®) to aid retention of transplanted material if FMT is delivered via enema or colonoscopy1
  • An oral proton pump inhibitor (i.e., omeprazole 20 mg) taken the evening before and the morning of the procedure to produce a favorable gastric pH if FMT is to delivered through a nasogastric tube1,26

Administration Routes

A gastroenterologist can instill the donor fecal suspension by a nasogastric tube, nasoduodenal/jejunal tube, an upper-tract endoscope, a colonoscope, retention enema, or a combination of upper and lower approaches.14,28 Clinicians at some centers have recently introduced oral capsulized FMT, which involves ingestion of several prepared capsules under direct supervision.29,30 No consensus exists on the preferred administration route, and no clear superiority of one method over another has been demonstrated.1,18 The delivery method may vary based on the needs and health status of individual patients.9 At many centers, clinicians perform FMT only via colonoscopic instillation.31 This method, which involves minimal training, allows direct simultaneous inspection of the mucosa and determination of preferential sites for infusing larger amounts of donor stool.28 According to a clinical reviewer of this report, "this FMT approach is not considered high risk, because the risk of perforating the affected colonic wall during the procedure is <1%."31 Some clinicians prefer using the nasogastric method because it provides more extensive exposure of the gastrointestinal tract to donor flora14,26 and is technically easier to perform.26 However, donor feces may be challenging to instill through a nasal tube in patients with diminished intestinal motility.27

The FMT Workgroup suggests using 25 to 50 mL of fecal solution for delivery via nasogastric and nasoduodenal tubes and 250 to 500 mL for delivery through a colonoscope or as a retention enema.1

Intended Benefits and Potential Disadvantages

Proponents have described the following benefits of using FMT to treat CDI recurrence:14

  • Less expensive than several courses of antibiotic treatments and hospitalization
  • More rapid symptom resolution than with several weeks of antibiotics
  • Reduced risk of antibiotic-associated bacterial resistance

FMT has a risk of disease transmission between the donor and recipient of diseases that are not screened for or that cannot be detected during the preparation of fecal material for transplantation. According to a clinical reviewer of this report, some adverse events could potentially not manifest for months or years depending on the agent transmitted."31 Also, the long-term effects of FMT on patients' immune system are unknown.

Service Provider

OpenBiome (Cambridge, MA, USA), a public stool bank operated by the Microbiome Health Research Institute dedicated to expanding access to FMT therapies, is providing screening services similar to those for blood products and organ transplant and sending prescreened, filtered, frozen fecal transplant material to U.S. hospitals.32 This organization does not sell feces products but is a service provider, charging for the screening, processing, and packaging services provided.33

OpenBiome collects stool from anonymous donors recruited from the Massachusetts Institute of Technology/Harvard academic community who are subjected to a rigorous screening protocol, including screening for general markers of health and immune status (i.e., complete blood count, C-reactive protein assay, hepatic function panel), to identify irregularities that might result from unspecified infections not detected in the targeted screens.33 Qualified donors can provide stool up to 60 days after the initial screening.33 Donor stool is immediately processed and stored at -80°C in frozen quarantine.33 OpenBiome releases material for clinical use only after the donor has successfully completed additional screening 60 days after the initial screening (i.e., the end of the collection period).33

Several other companies are developing FMT products (See Phase of Diffusion section below).

Regulatory Status

United States

FMT has been performed in many countries outside the United States for several years and in several U.S. institutions for a few years without any regulatory oversight because no requirements or guidance existed that pertained to donor screening, testing, and methods for preparing stool and performing the procedure. In December 2011, an international collaborative of clinicians from several institutions and professional societies formed the FMT Workgroup to develop guidelines regarding the rationale, methods, and use of FMT.1

As the procedure gained momentum, some clinicians and professional societies expressed concern about the lack of clear regulatory guidance for FMT, and several specialty societies (i.e., American Gastroenterological Association, American College of Gastroenterology, American Society for Gastrointestinal Endoscopy, North American Society for Pediatric Gastroenterology) contacted the U.S. Food and Drug Administration (FDA) for clarification of FMT regulation.34 FDA's Center for Biologics Evaluation and Research (CBER) recently determined that FMT falls within the center's definition of a biological product and a drug, a decision that FDA reaffirmed at a public workshop on FMT held in May 2013.35 CBER has not approved FMT for any therapeutic purpose and stated that an Investigational New Drug (IND) application is needed for FMT to treat any disease.35

Physicians and scientists have expressed concern that FMT is not appropriate for study under FDA's IND regulations and that applying these requirements will make FMT unavailable for individuals with CDI that is unresponsive to standard therapies.36 In response to these concerns, on June 17, 2013, FDA announced an intent "to exercise enforcement discretion regarding the IND requirements" if the treating physician obtains informed consent for FMT, including a statement that FMT to treat C. difficile is investigational and a discussion of potential risks.36 In July 2013, FDA issued guidance for industry that reflects this intention, titled, "Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies."37

Although not required, FDA encourages physicians who want to perform FMT to submit an IND application for FMT products. Recognizing that many academic physicians and investigators do not have regulatory expertise, Kelly et al. and Moore et al. recently published guidance on preparing and submitting IND applications to study FMT.38,39

In March 2014, FDA issued revised draft guidance for industry for comment purposes that includes additional information. FDA intends to exercise enforcement discretion, provided "the FMT product is obtained from a donor known to either the patient or the treating licensed health care provider and the stool donor and stool are qualified by screening and testing performed under the direction of the licensed health care provider for the purpose of providing the FMT product to treat his or her patient."40 FDA "does not intend to exercise enforcement for the use of an FMT product when the FMT product is manufactured from the stool of a donor who is not known by either the patient or the licensed health care provider treating the patient, or when the donor and donor stool are not qualified under the direction of the treating licensed health care provider." The comment period ended on March 31, 2014, and a recent news release indicated that critics are arguing that the proposed FDA guidance will actually make the procedure more risky and shut down stool banks."41

FDA plans to continue to evaluate its enforcement policy. When finalized, this guidance will supersede the July 2013 guidance document.

Other Countries

In April 2015, Health Canada issued a guidance document titled, Regulation of Fecal Microbiota Therapy for the Treatment of C. difficile Infections. This document states:42

Health Canada considers the fecal matter used in FMT to meet the definition of a drug under the Food and Drugs Act and, as a result, regulates FMT as a new biologic drug. The study of a new biologic drug requires a risk-benefit assessment focused on the quality, safety and efficacy of the drug as part of a Clinical Trial Application. Since no company or individual has sought market authorizations for materials used in FMT, the therapy is considered investigational, meaning that it can only be conducted in the context of an authorized clinical trial.

On an interim basis, Health Canada is exercising a risk-based, provisional interpretation regarding the Clinical Trial Application requirements for use of FMT to treat patients with CDI not responsive to conventional therapies. This approach is conditional upon provisions detailed in the guidance document. Health Canada plans "to establish a more appropriate long term regulatory approach for FMT."42

Reported Indications and Contraindications

Gastroenterologists may consult with infectious disease specialists to identify patients who may be good candidates for FMT.43 Generally, patients considered for FMT have a positive stool test for C. difficile toxin; diarrhea defined as 3 loose, watery bowel movements per day for 48 hours or >8 loose, watery bowel movements in 48 hours; and continued recurrence of symptoms despite antibiotic treatment.44

According to the FMT Workgroup, the procedure may be indicated for patients with any of the following:1

  • Recurrent or relapsing CDI, defined as at least three episodes of mild to moderate CDI and failure of a six- to eight-week taper with vancomycin with or without an alternative antibiotic or at least two episodes of severe CDI resulting in hospitalization and associated with significant morbidity
  • Moderate CDI not responding to standard therapy (i.e., vancomycin) for at least a week
  • Severe CDI with no response to standard therapy after 48 hours

Although current guidelines do not support FMT for this indication, according to a clinical reviewer of this report, "some clinicians are performing FMT as a first-line treatment for severe CDI."31

Clinical Guidelines and Standards

Guidelines

ECRI Institute searches identified the following six relevant guidelines.45-50

  • Stanford Division of Infectious Disease: Guidelines for Treatment of Clostridium difficile Infection. May 2014. This guidance lists FMT as an alternative treatment for patients with multiple recurrences of CDI. FMT requires both infectious disease and gastroenterology consults.50
  • U.K. National Institute for Health and Care Excellence (NICE): Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection. March 2014. This guidance recommends the following:49
  • Current evidence on the efficacy and safety of fecal microbiota transplant for recurrent Clostridium difficile infection is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.
  • This procedure should only be considered for patients with recurrent C. difficile infections that have failed to respond to antibiotics and other treatments.
  • Clinicians should ensure that a confidential record is kept of the donor and recipient of each faecal microbiota transplant.
  • NICE encourages further research into fecal microbiota transplant for C. difficile infection, specifically to investigate optimal dosage, mode of administration and choice of donor.
  • American College of Gastroenterology: Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infection. 2013. These guidelines state, "if there is a third recurrence after a pulsed vancomycin regimen, fecal microbiota transplant should be considered."45
  • European Society of Clinical Microbiology and Infectious Diseases: Treatment Guidance Document for Clostridium difficile Infection. 2013. This guideline states, "fecal transplantation following antibiotic treatment with an oral glycopeptide is reported to be highly effective in treating multiple recurrent CDI."46
  • Australasian Society for Infectious Diseases: Guidelines for the Diagnosis and Treatment of Clostridium difficile Infection. April 2011. These guidelines state the following:47

Fecal enemas (or preparations administered by nasogastric tube) to restore commensal flora ("stool transplant") have been used successfully in a number of refractory cases of recurrence, but significant logistical issues must be considered, including donor screening, the processing of the donor specimen and the route of administration.

  • National Health Service, Health Protection Agency, and the Department of Health: Clostridium difficile Infection: How to Deal with the Problem. 2009. This guidance lists donor stool transplant as a treatment consideration when all other options have been attempted and failed for patients with multiple CDI recurrences that result in malnutrition and wasting. The document states the following:48

Considering that disruption of the indigenous fecal flora is likely a major risk for infection with C. difficile and, particularly, for recurrent infection, instillation of stool from a healthy donor has been used with a high degree of success in several uncontrolled case series. The availability of this treatment is limited, however. If "fecal transplant" is considered, the donor should be screened for transmissible agents, and logistic issues need to be considered, including the timing, the collection and processing of the specimen from the donor, the preparation of the recipient, and the route and means of administration.

Consensus Statements

ECRI Institute searches identified the following four consensus statements.1,19,24,51

  • American Academy of Pediatrics: Clostridium difficile Infection in Infants and Children. 2013. This policy statement states that "fecal transplantation (enteric administration of donor stool flora) is used anecdotally" in children with recurrent CDI.51
  • Infectious Disease Society of America/American Society of Gastrointestinal Endoscopy/North American Society for Pediatric Gastroenterology, Hematology and Nutrition/American Gastroenterological Association/American College of Gastroenterology: Consensus Guidance on Donor Screening and Stool Testing for FMT. July 2013. This document provides recommendations for donor selection and screening, serum testing (to be performed within four weeks of donation), and stool testing (to be performed within four weeks of donation).24
  • Canadian Working Group: Fecal Microbial Therapy, Microbial Ecosystems Therapeutics. 2012. This consensus document summary states the following:19

Use of microbial ecosystem therapeutics to treat disease represents a paradigm shift in disease management. Several challenges lie ahead in pursuing this new treatment, including the need to comply with regulatory requirements that were developed for products that are not analogous to fecal material.

  • FMT Workgroup: Treating Clostridium difficile Infection with Fecal Microbiota Transplantation. December 2011. This consensus document discusses the rationale, methods, and use of FMT.1

Other Evidence Reports

ECRI Institute did not identify any other evidence reports that addressed FMT for treating recurrent CDI.

Considerations for Hospitals/Facilities

Staffing/Infrastructure Requirements

FMT is a relatively simple procedure, but to offer it, facilities may need to create dedicated laboratory facilities to process the donor stool and facilitate administration to patients. Centers offering FMT also need specific treatment protocols regarding patient counseling, donor testing, stool donation, stool processing, and transplantation of processed fecal material.52,53

Some clinicians request that patients mix donor stool with sterile water at home in a blender dedicated to this purpose and transport the sample to the center in an airtight container.54 Endoscopy technicians receive and prepare donated fecal samples for transplantation and should ensure that all necessary contact precautions are observed.14 Staff members who mix and/or handle fecal material must wear a fluid-resistant gown, gloves, and mask with goggles or eye shield.1 Also, because stool is a level-2 hazard, using a fume hood during stool preparation is recommended.1,9

Clinicians performing the procedure at Mayo Clinic (Phoenix, AZ, USA) identified an experienced gastroenterology nurse to serve as an FMT coordinator, whose role includes the following:52

  • Providing initial point of contact for interest in FMT
  • Creating standardized checklists for recipient and donor evaluation
  • Creating educational materials for recipients
  • Scheduling appointments and FMT procedures
  • Providing instructions and materials for proper sample collection
  • Counseling potential recipients and donors regarding the procedure
  • Serving as the liaison between endoscopy, gastroenterology, and infectious diseases
  • Coordinating donor screening evaluations and reviews with results with the physician to determine eligibility
  • Creating a patient and donor database
  • Serving as patient contact throughout process and follow-up
  • Monitoring outcomes (success, safety, and recurrence)
  • Working on process improvements and logistics 

Safety

Potential Risk of Disease Transmission

Early evidence suggests that FMT is safe and generally well-tolerated.55,56 (See Findings section for summary of adverse events [AEs] reported in published trials). However, because the procedure involves transplantation of fecal material, FMT has a risk of disease transmission between the donor and recipient of diseases that are not screened for or that cannot be detected during the preparation of fecal material for transplantation. According to a recent specialty society consensus document, the donor questionnaire should be similar to current protocols for screening blood donors.24

Patients on major immunosuppressive agents (e.g., high-dose corticosteroids, calcineurin inhibitors, mammalian target of rapamycin inhibitors, lymphocyte-depleting biological agents, antitumor necrosis factor agents, chemotherapeutic antineoplastic agents) could be at increased risk of AEs, although these rarely result in exclusion.1 In addition, patients with decompensated liver cirrhosis, advanced HIV/AIDS, recent bone marrow transplant, or other causes of severe immunodeficiency could be at increased risk of AEs.1

Colonoscopy Risks

Elderly patients and patients with renal impairment or congestive heart failure are at increased risk for complications before and during colonoscopy. Complications include electrolyte and fluid volume abnormalities from the required bowel preparation, colonic perforation, bleeding, and complications related to anesthesia.57,58 After therapeutic colonoscopy, colonic perforation has been reported in up to 5% of patients who are at an advanced age or have multiple comorbidities.59 However, according to a clinical reviewer for this report, "the risk of colon perforation during a colonoscopy for FMT is probably lower, because unlike other types of therapeutic colonoscopy (i.e., large polypectomy, decompression, stent placement), the FMT procedure does not include any high risk maneuvers."60

Safety Concerns: Publically Available Information on FMT

Readily available do-it-yourself FMT videos may contain misinformation that could harm a patient.60 Websites like http://thepowerofpoop.com promote the use of FMT for other chronic gastrointestinal conditions (e.g., irritable bowel syndrome, inflammatory bowel disease) for which limited safety and efficacy data exist.61 The Fecal Transplant Foundation estimates that patients perform more than 10,000 do-it-yourself FMTs a year.62

Potential Long-term Effects

Although FMT seems to be well-tolerated in the short-term, "little is known about the long-term impact of FMT on other illnesses and disorders (e.g., obesity, diabetes, [irritable bowel disease) or the transmission of drug-resistant organisms."52 FMT "likely triggers mucousal immune responses that, depending on the microbiota composition and the recipient's genotype, could range from pro- to anti-inflammatory."63 Because the long-term effects of FMT on the recipient's immune system are unpredictable, further studies are needed to understand individual variability in microbiota and whether FMT could potentially lead to disease.63-65 Furthermore, "follow-up of patients described in the literature has varied considerably and patient registries are needed."52

Training and Credentialing

Gastroenterologists who are experienced in upper and lower endoscopy techniques would require minimal training to perform FMT. Laboratory technicians would require minimal training to screen donor fecal material for pathogens and to prepare fecal material for transplantation.

The Credentialing Resource Center (CRC) drafted credentialing criteria in a clinical privilege white paper intended to serve as a starting point for institutions in developing a credentialing policy for FMT.43 CRC credentialing requirements for FMT include the following:43

  • Basic education: MD or DO
  • Successful completion of an Accreditation Council for Graduate Medical Education or American Osteopathic Association–accredited training program in gastroenterology and/or current certification or active participation in the examination process (with achievement of certification within [x] years) leading to certification by the appropriate board.
  • Practitioner must be privileged in the endoscopic procedure to be used when performing FMT.
  • If the practitioner holds an IND application, he or she must be able to show proof of IND.
  • Practitioner must understand and be able to explain to the patient that FMT uses investigational products and that the potential risks to the patient are not fully known.
  • Practitioner must know that mechanisms are in place at a given facility to track patient outcomes and document any untoward events and must be able to utilize those mechanisms.
  • Practitioner must understand and utilize measures in place to protect the identity of the fecal microbiota donor, if applicable.
  • Applicants must be able to demonstrate current competence and evidence of the successful performance of the endoscopic procedure to be used when performing FMT—that is, at least [n] colonoscopies or [n] retention enemas or [n] nasogastric tube procedures or [n] nasoduodenal tube procedures in the previous [x] months.

Competing and Complementary Technologies

As a treatment option for patients with recurrent CDI, FMT may compete with fidaxomicin (Dificid), vancomycin, vancomycin in tapered and pulsed doses, vancomycin plus probiotics (i.e., Saccharomyces boulardii), vancomycin plus rifaximin, intravenous tigecycline plus oral vancomycin, pooled intravenous immunoglobulin, monoclonal antibodies, nonabsorbable antibiotics (e.g., oral bacitracin), or toxin binders (e.g., cholestyramine).2,12,13

Possible side effects of taking oral vancomycin include bitter or unpleasant taste, mouth irritation, nausea or vomiting, skin rash, hives, scaling or welting of skin, and redness or other discoloration of skin. Patients with kidney disease or inflammatory bowel disease may have an increased chance of side effects. Also, using vancomycin for a prolonged period may result in the overgrowth of nonsusceptible organisms.66 People infected with drug-resistant bacteria are more likely to have longer, more costly hospital stays and may be more likely to die from an infection.21 Also, available probiotics "have limitations because they are generally not anaerobes, represent only a few strains, do not implant, and are not standardized."67

Phase of Diffusion

FMT is in an early phase of diffusion. The first FMT procedure was reported in 1958.68 For several decades after, clinicians performed only a few FMT procedures. However, since 2009, FMT has gained traction, perhaps because of increased incidence of recurrent CDI, the growing body of evidence that has garnered public attention, and payment penalties introduced in the United States regarding readmissions for hospital-acquired infections. Clinicians have performed several thousand FMTs worldwide,33,60 including more than 1,000 in the United States. The overall volume of FMT procedures performed annually is increasing,31 and the Fecal Transplant Foundation estimates that physicians will perform between 2,500 to 5,000 FMTs in the United States in 2015.62

According to a clinical expert who reviewed this report, "about half of hospital-based and academic practices and 15% to 25% of private/group practices now offer FMT."60 Providers offer FMT in most major population centers.33 However, many smaller cities and towns do not yet have providers offering FMT, requiring some patients to travel considerable distances to receive the treatment.33

As of February 2015, OpenBiome had provided more than 2,000 samples to 200 hospitals and clinics in the United States.69

Potential Challenges

Although rising CDI incidence, recurrence, and mortality rates and the emergence of the toxin-producing C. difficile strain NAP1 have generated increased interest in FMT, some challenges remain, including the following:14,70,71

  • Reimbursement issues
  • Challenging task of organizing and mobilizing donors
  • Concerns over transmission of contagious diseases
  • Sanitation issues with collecting, processing, and storing feces
  • Little funding for large-scale randomized controlled trials (RCTs)
  • Regulatory issues

Diffusion also depends on physician willingness to perform the procedure and patient acceptance.

Physician Acceptance of FMT

Our searches identified five studies that assessed physician attitudes toward FMT for treating recurrent CDI.72-76

Porter et al. (2015)73 surveyed hospital specialists in the United Kingdom to examine diffusion of FMT and identify barriers that might prevent use of the procedure to treat patients. Over 75% of those surveyed responded. Ninety-six percent of respondents believed that evidence supports FMT use, and 94% of respondents reported consulting on at least one patient a year for whom they would recommend FMT. However, only 22% of respondents reported FMT use in their institution in the last 10 years, and only 6% reported performing more than 10 FMTs in the last 10 years. Respondents expressed concerns about patient acceptance, donor selection, availability of screened fecal solution, procedure feasibility, and availability of local expertise. Authors concluded that, "a large gap exists in the United Kingdom between physicians desire to use FMT and the ability and facilities to provide it as a therapy at the bedside."73

Dennis et al. (2015)72 surveyed 253 Canadian internists, infectious disease specialists, gastroenterologists, and family physicians to assess attitudes and determine whether barriers to FMT adoption exist. Only 15% of those surveyed responded. A majority of respondents (60%) described themselves as being "not at all" or "somewhat" familiar with FMT, and most respondents (76%) had never referred a patient for the procedure, The most common reason for not referring patients for FMT was lack of awareness of where to access the treatment. No respondent believed that the procedure was too risky to consider, and the unappealing nature of FMT accounted for only 13% of reasons for not referring.

Zipursky et al. (2014)76 surveyed 139 physicians (i.e., internal medicine physicians, infectious disease specialists, gastroenterologists) to assess FMT experience with and attitudes toward the procedure. Of the 135 physicians who responded, 25 (20%) had treated a patient with FMT, 10 (8%) offered FMT to a patient, 9 (7%) referred a patient for FMT, and 83 (65%) had neither offered or referred a patient for FMT. The most common reasons for not offering or referring patients for FMT were not having the right clinical situation, the belief that patients would find it unappealing, and institutional or logistical barriers.

Bakkan et al. (2013)74 surveyed 1,212 members of the Emerging Infections Network, asking specific questions about treatment approaches for patients with CDI. Of these, 527 physicians responded when asked whether they would recommend FMT: 424/527 (80.5%) said they would consider FMT for recurrent disease, 125/527 (23.7%) would consider it for severe disease, and 47/527 (8.9%) indicated they would never recommend FMT.74 Of those surveyed, 532 physicians responded when asked whether FMT was available at their institution: 156/532 (29.3%) said FMT was available in their institution, 127/532 (23.9%) reported plans for implementing FMT, and 249/532 (46.8%) said FMT was not available.74 Reasons cited for the lack of an FMT program were difficulties with the logistics of the preparation and/or delivery of the fecal donor sample, the complexity and cost of donor screening, compensation/reimbursement issues, patient refusal, local legal issues and lack of Institutional Review Board approval, resistance to FMT by hospital administration, and conflicts of interest with local gastroenterology consultants.74

Sofi et al. (2013)75 sent a survey to 200 actively practicing gastroenterologists and infectious disease physicians to examine physician perceptions about FMT. Of the 118 physicians who responded, 102 (86.4%) were willing to use FMT, 11 (9.3%) were unwilling to use it, and 5 (4.2%) indicated they never thought of using it.75

Patient Attitudes

Physicians who perform the procedure report that patients with recurrent CDI are receptive to FMT because the patients have experienced several months of multiple diarrhea episodes daily.14 Our searches identified two reports that assessed patient attitudes about FMT.14,77 To assess how patients would perceive "gut rehabilitation" by any method in general, Medipex, Ltd. (Leeds, U.K.) prepared a report on the intervention, where it is being performed, its costs, and results of a survey it conducted of 22 patients in a hospital setting.14 (Medipex describes itself as "the NHS [National Health Service] Innovation Hub for the Yorkshire and Humber region in UK," providing "technology transfer services to the [NHS] in UK.") Most of the patients surveyed (64%) did not have a gastrointestinal condition. Patients completed the survey after a patient-led innovation exercise and forums in which patients discussed FMT, C. difficile, and ulcerative colitis. Almost all the patients surveyed (91%) indicated they would consider gut rehabilitation as a treatment option: 50% as a first-line treatment and 41% as a last-resort treatment.14 When given a choice of the administration route, an overwhelming majority (91%) of patients indicated a preference for oral administration in the form of a capsule over administration through a nasal feeding tube (4.5%) or a colonic feeding tube (4.5%).14

Zipursky et al. (2012) distributed a structured survey to assess patient perceptions of the aesthetics of FMT and their willingness to consider it as a treatment option for recurrent CDI. About half (192/400) of those surveyed returned completed response forms. The published study abstract states:77

When provided efficacy data only, 162 respondents (85%) chose to receive FMT, and 29 (15%) chose antibiotics alone. When aware of the fecal nature of FMT, 16 respondents changed their choice from FMT to antibiotics alone, but there was no significant change in the total number choosing FMT (154 [81%]; p = .15). More respondents chose FMT if offered as a pill (90%; p = .002) or if their physician recommended it (94%; p < .001). Respondents rated all aspects of FMT at least "somewhat unappealing," selecting "the need to handle stool" and "receiving FMT by nasogastric tube" as most unappealing. Women rated all aspects of FMT more unappealing; older respondents rated all aspects less unappealing. Most respondents preferred to receive FMT in the hospital (48%) or physician's office (39%); 77% were willing to pay out-of-pocket for FMT.

The authors concluded that "patients recognize the inherently unappealing nature of FMT, but they are nonetheless open to considering it as a treatment alternative for recurrent CDI, especially when recommended by a physician."77

Future Trends

Other Indications

FMT is under study to treat other conditions, including allergic diseases, autoimmune diseases, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, metabolic diseases, multiple sclerosis, neurodevelopmental disorders, pseudomembranous colitis (believed to be caused by C. difficile toxins), and pediatric ulcerative colitis.18,25,78-80 In February 2015, two physician members of the American Gastroenterological Association raised some concerns about expanding indications for FMT too quickly, calling for technique standardization, more rigorous recipient and donor selection criteria informed by full microbiota compositional analysis, and anaerobic processing of fecal samples. They expressed the following safety concerns:81

  • Risk of transmitting pathogens yet to be discovered
  • Risk of inducing bacterial translocation and sepsis in recipients with defective mucosal barrier function
  • Risk of transferring an undesirable phenotype with long-term consequences

Donor Material Processing

Facilities are looking for ways to make FMT simpler. North York General Hospital (Toronto, Ontario, Canada) has begun collecting and freezing stools of surgery patients upon admission. This hospital offers a processing and banking service that permits autologous FMT for patients who develop CDI postoperatively.82

Also, recognizing that donor identification and workup are associated with expense, possible treatment delay, and issues of sanitation and aesthetics, clinicians at the University of Minnesota Fairview Medical Center (St. Paul, MN, USA) recently introduced a standardized way to bank frozen processed fecal material that is ready to use when needed.83 Advanced preparation of donor material may increase the procedure's practicality.9,78

Fecal Microbiota Products in Development

Some clinicians believe that "FMT will only become widely available if the material becomes standardized, licensed, and ready to use."84 To that end, several groups are developing FMT products (e.g., oral capsules, synthetic stool that does not look or smell like stool, pre-made suspensions) that will likely be subject to FDA regulatory processes. In particular, "oral capsules are a source of intense interest to patients, physicians, and industry, because they obviate much of the complexity in FMT (i.e., donor identification, donor testing, sample preparation) and circumvent some of the uncomfortable social aspects of current FMT technology."60 Table 2 details FMT products in various stages of development and testing.

Table 2. Company/Researchers Developing Fecal Microbiota Products
Company Product Name Description Development Stage
Rebiotix, Inc.
(Roseville, MN, USA)85
RBX2660 microbiota suspensionReady-to-use microbiota suspension delivered via enema

Phase IIb RCT assessing safety and effectiveness

FDA orphan drug and fast-tracka designation

Pureflora, Inc.
(San Francisco, CA, USA)86
Unknown Single-use disposable device that maintains a completely closed system from donation to deliveryIn development
Monarch Laboratories (Irvine, CA, USA) and BTER (Biotherapeutics, Education and Research Foundation)87  

Not reported;

 

Medical MicrobiotaTM

Processing and banking service for autologous FMT;

FMT product screened for major pathogens and CGMP processed for allograft transplantation 

Not reported
CIPAC Limited (Australia with subsidiaries in California)88,89Full-Spectrum MicrobiotaTMLyophilized powder can be reconstituted for rectal infusion or encapsulated for short-term or long-term oral use. Developing a program for ongoing donation to support commercial manufacturing at the University of Minnesota
University of Guelph (Ontario, Canada)90,91

Microbial Ecosystem Therapeutics

RePOOPulate

Synthetic fecal mixture based on human gut flora isolated from a healthy donor administered through a colonoscope.

Does not look or smell like stool.

2 patients treated
Wellcome Trust Sanger Institute (Cambridge, UK)92Not reportedFMT capsulesPreclinical study
Seres Health
(Cambridge, MA, USA)93-95
SER-109 Microbial therapeuticPhase I/II trial, plans to advance to phase III trial
SER-262Oral microbiomePreclinical study

a The fast-track program is designed to facilitate the development and expedite the review of new drugs and vaccines that are intended to treat or prevent serious or life-threatening conditions and demonstrate the potential to address unmet medical needs.

CGMP:    Current Good Manufacturing Practices

FMT:      Fecal microbiota transplantation

RCT:       Randomized controlled trial

Vaccines in Development

Several vaccines targeting C. difficile are under development.96 Viropharma, Inc. (Exton, PA, USA) is developing an oral vaccine (VP 202621) that contains nontoxigenic C. difficile spores for preventing CDI recurrence.96 Merck Sharp & Dohme Corp. (Whitehouse Station, NJ, USA) is developing MK-3415A, a combination of two therapeutic antibodies targeting C. difficile toxins A and B.96 MK-3415A is being evaluated in phase III trials for preventing CDI recurrence.96 Sanofi Pasteur (Lyon, France) is developing a vaccine composed of inactivated C. difficile toxins A and B (i.e., ACAM-CDIFF) that is administered by intramuscular injection to prevent or treat CDI. In October 2010, FDA granted fast-track designation to this investigational C. difficile vaccine candidate.97 An ongoing phase III trial (NCT01887912) that plans to enroll 15,000 patients is evaluating the vaccine's efficacy to prevent primary symptomatic CDI in at-risk patients. Results of this RCT are expected in December 2017.

Drugs in Development

More effective treatment of initial infection may result in a decrease in CDI recurrence rates. Several new antibiotics are in phase III clinical development for treating CDI, including Ramoplanin™ (Nanotherapeutics, Inc., Alachua, FL, USA), surotomycin (Cubist Pharmaceuticals, Lexington, MA, USA), and oritavancin (The Medicines Co., Parsippany, NJ, USA)98

Targeted Therapies

Future therapies may include targeted probiotic administration or "targeted therapies that interfere with C. difficile spore germination, vegetative growth and toxin-mediated epithelial damage."99

Costs

Reported costs associated with basic screening of donor blood and stool for contagious agents, preparing the donor fecal sample, and placing a retention enema tube are estimated to be about $1,500.100,101 If the procedure is done by colonoscopy, the average cost of colonoscopy could add about $3,710 to the total cost of the procedure ($1,060 for patients with Medicare).101

For an upper route of administration, radiology fees may be incurred to rule out the presence of a large hiatal hernia and for placement of a nasoduodenal tube.84

Facility expenses vary depending on procedure duration and nursing staff requirements.84

OpenBiome

OpenBiome operates on a not-for-profit basis.32 The company charges hospitals and clinics a processing-and-shipping fee of $250 per specimen,32,33 and it aims to ultimately have screening and other operational costs of $3,000 per donor covered by the $250 fee. Collecting multiple samples from each qualified donor spreads screening costs over many treatments.33 According to OpenBiome, "the shortfall is covered by a charitable gift from a private family foundation."33

Reimbursement

ECRI Institute provides the following as reference and for information purposes only. Coding, coverage, and reimbursement information provided does not constitute legal advice and does not guarantee payment.

Coverage

The U.S. Centers for Medicare & Medicaid Services (CMS) has no national coverage determination for FMT, so coverage is left to the discretion of local Medicare carriers. How FDA's proposed regulation of FMT as a new biologic or drug will affect Medicare decision making is unknown.

Our searches of 11 representative private, third-party payers that provide online medical coverage policies (Aetna, Anthem, Blue Cross/Blue Shield [BC/BS] of Alabama, BC/BS of Massachusetts, CIGNA, HealthPartners, Humana, Medica, Regence, United Healthcare, Wellmark) found 6 payers with a policy describing coverage with conditions, 2 payers denying coverage for this, and 5 payers without a specific policy. See Table 3 for details.

Table 3. Third-party Payer Policies for Fecal Microbiota Transplantation
Payer Policy Name Date of Last Review Coverage Policy
Aetna102Fecal Bacteriotherapy12/22/2014"Aetna considers fecal bacteriotherapy medically necessary for persons with Clostridium difficile infection, with infection confirmed by a positive stool test for C. difficile toxin, that has recurred following at least one course of adequate antibiotic therapy (10 or more days of vancomycin at a dose of greater than or equal to 125 mg four times per day or 10 or more days of metronidazole at a dose of 500 mg three times per day)."
BC/BS Alabama103Fecal Microbiota Transplantation2/2015

"The use of fecal microbiota transplantation for treatment of patients with recurrent Clostridium difficile infection meets Blue Cross and Blue Shield of Alabama's medical criteria for treatment when:

• There have been at least three episodes of recurrent infection; AND

• Episodes are refractory to appropriate antibiotic regimens, including at least one regimen of pulsed vancomycin"

BC/BS Massachusetts104Fecal Microbiota Transplantation10/2014

"Fecal microbiota transplantation may be medically necessary for treatment of patients with recurrent Clostridium difficile infection under the following conditions:

There have been at least 3 episodes of recurrent infection; AND

Episodes are refractory to appropriate antibiotic regimens, including at least 1 regimen of pulsed vancomycin"

CIGNA105Complementary and Alternative Medicine7/15/2014"Cigna does not cover fecal bacteriotherapy because it is considered experimental, investigational, or unproven."
HealthPartners106Fecal Microbiota Transplant4/2015

"Fecal microbiota transplant is covered for current or relapsing Clostridium difficile infection defined as one of

the following:

  • At least 3 episodes of mild to moderate CDI and failure of a 6–8 week taper with vancomycin with or without an alternative antibiotic (e.g., rifaximin, nitazoxanide) -OR-
  • At least two episodes of severe CDI resulting in hospitalization and associated significant morbidity.

Fecal microbiota transplant is also covered for:

  • Moderate CDI not responding to standard therapy (vancomycin) for at least a week.
  • Severe fulminant C difficile colitis with no response to standard therapy after 48 hours."
Humana107

Fecal Microbiota Transplantation

 7/24/2014

"Humana members may be eligible under the Plan for fecal microbiota transplantation when the following criteria are met:

Minimum of three episodes of Clostridium difficile infection and associated diarrhea refractory to antibiotic therapy; AND

Physician documentation that patient has been informed of risks and benefits of procedure

All requests for repeat FMT for recurrence of initial diagnosis or a subsequent episode of CDI require review by a medical director."

Regence108New and Emerging Medical Technologies and Procedures12/2014Preparation of fecal microbiota for instillation, including assessment of donor specimen, is "considered investigational because the current scientific evidence is not yet sufficient to establish the impact of these technologies on health outcomes."
Wellmark109Fecal Bacteriotherapy (Fecal Transplant)2/2015

"Fecal microbiota transplantation/fecal bacteriotherapy may be considered medically necessary when

ALL of the following have been met:

  • Infection confirmed by a positive stool test for Clostridium difficile toxin
  • There have been at least 3 episodes of recurrent Clostridium difficile infection and associated diarrhea refractory to antibiotic therapy including at least one regimen of pulsed vancomycin.
  • Patient is not immunocompromised"

CDI:    Clostridium difficile infection

FMT:  Fecal microbiota transplantation

Coding  

In January 2013, the American Medical Association assigned a Current Procedural Terminology (CPT) code to describe preparation of fecal microbiota for instillation, which includes assessing the donor specimen.110 The new CPT coding descriptor instructs users to use an unlisted CPT code for fecal instillation by nasogastric tube of enema.110 CMS did not accept the proposed valuation recommendation for the new CPT code and subsequently developed a temporary Healthcare Common Procedure Coding System code with the same description (G0455) for interim billing purposes.111 The American Gastroenterological Association has issued specific coding guidance for submission of FMT claims to private payers and Medicare.112

Payment

For outpatient procedures performed in the United States, the technical component is reimbursed under an Ambulatory Payment Classification as part of Medicare's Hospital Outpatient Prospective Payment System, and the professional component is reimbursed according to Medicare's Physician Fee Schedule. See Table 4 for further details.

Table 4. Payment Information for Fecal Microbiota Transplantation
Procedure 2015 Medicare National Average OPPS Payment 2015 National Physician Fee Schedule
MD OfficeFacility
Preparation of microbiota for instillation including assessing the donor specimen (i.e., G0455)$131.75$76.52$131.93
Unlisted intestinal procedure$2,285.91Not valid for Medicare purposes.

OPPS:   Outpatient prospective payment system

In the inpatient setting, payment is linked to 1 of more than 500 Medicare Severity Diagnosis-Related Groups (MS‑DRGs) that are expected to have similar resource use across hospitals. Hospitals receive a predetermined lump sum for each Medicare discharge, regardless of cost. MS-DRG assignments are contingent on principal diagnosis, comorbid conditions, primary and secondary procedures performed, and complications. Payment for inpatient services is also adjusted depending upon the patient's geographic location and the type of hospital providing the services (i.e., teaching hospital, rural hospital).  

Possible MS-DRGs for BT include the following:

  • DRG 371 (Major gastrointestinal disorders and peritoneal infections with major complications and comorbidities), which has a 2015 Medicare national average payment of $10,048.45.113
  • DRG 372 (Major gastrointestinal disorders and peritoneal infections with complications and comorbidities), which has a 2015 Medicare national average payment of $6,116.66.113
  • DRG 373 (Major gastrointestinal disorders and peritoneal infections without complications and comorbidities/major complications and comorbidities), which has a 2015 Medicare national average payment of $4,321.38.113

Also, payers are not likely to cover the costs of donor screening;23 in many cases, patients have to contribute to the procedure's cost.14 "Medicare does not cover the costs of screening of the donor specimen, thus beneficiaries should be advised of the cost of screening, which they may be at risk of paying for out-of-pocket. This may require the physician to provide an Advanced Beneficiary Notice of Non-coverage Form to the donor and recipient beneficiary."112

Cost-effectiveness and Considerations

Costs of Treating Recurrent CDI

Initial screening and procedural costs to perform FMT may be offset by reducing the costs associated with treating CDI. CDI increases length of stay by a reported 2.6 to 4.5 days, and associated costs for inpatient care are about $2,500 to $3,500 per episode, excluding costs for surgical intervention.15 Treating recurrent CDI with intravenous immunoglobulin (400 mg/kg body weight) costs more than $10,000.14 Additional costs attributable to CDI treatment range from about $2,450 to almost $14,000 per hospitalization.16,114,115

FMT costs an estimated $4,000 to $5,000. Compared with repeated courses of antibiotic therapy with vancomycin or fidaxomicin, performing FMT to treat CDI recurrence may result in cost savings.14 However, if effective, retreating the first recurrence of CDI with metronidazole is considerably less costly than FMT. See Table 5 for details.

Table 5.  Costs Associated with Drugs for Treating Recurrent CDI
Possible Treatment Cost of a 10-day course45
Fidaxomicin 200 mg twice daily $2,800
Metronidazole 500 mg 3 times daily $22
Vancomycin 125 mg orally 4 times daily $680
Vancomycin 125 mg intravenous compounded for oral use $100 to $400

 

Cost-effectiveness Studies

Varier et al.116 constructed a decision-analytic computer simulation using inputs from the published literature that estimated the cost-effectiveness of FMT compared with tapered vancomycin as a therapeutic option for recurrent CDI. The effectiveness measure used was quality-adjusted life years (QALYs). Their analysis showed that "FMT was less expensive and more effective if cure rates for FMT and vancomycin were ≥70% and <91% and if FMT cost was <$3,206,"116 suggesting that FMT may be a cost-saving intervention to manage recurrent CDI.

Konijeti et al.117 constructed a decision-analytic model that compared the cost-effectiveness of four treatment strategies for first-line treatment of recurrent CDI: metronidazole, vancomycin, fidaxomicin, and FMT. Investigators used a willingness-to-pay threshold of $50,000 per QALY to define cost-effectiveness. Their analysis found that, "initial treatment of recurrent CDI using FMT colonoscopy was the most cost-effective strategy, with an incremental cost-effectiveness ratio of $17,016 relative to oral vancomycin."117 In settings where FMT is not available, the authors concluded that "the most cost-effective strategy was initial treatment with vancomycin."117

Evidence Review

We reviewed evidence to address the following five key questions:

Key Question 1: What is the effectiveness of FMT for treating recurrent CDI?
Key Question 2: How do the safety and effectiveness of FMT for treating recurrent CDI compare to those of other treatments for recurrent CDI?
Key Question 3: How do the safety and effectiveness of FMT from different donor sources compare?
Key Question 4: How do the safety and effectiveness of FMT by different routes of administration compare?
Key Question 5: What AEs have been reported in studies of FMT?

For Key Question 1, we assess CDI symptom resolution after FMT.

For Key Question 2, we examine how FMT compares with the following treatment options: vancomycin, metronidazole, vancomycin in tapered and pulsed doses, fidaxomicin, vancomycin plus probiotics, vancomycin plus rifaximin, pooled intravenous immunoglobulin, or monoclonal antibodies.

For Key Question 3, we examine comparisons between different donor sources, including those frozen from recipient for autologous FMT, fresh from related donor, fresh from unrelated donor, or frozen from unrelated donor.

For Key Question 4, we examine comparisons of FMT via different routes of administration, including colonoscopy, nasogastric tube, nasoduodenal/jejunal tube, upper tract endoscopy, retention enema, a combination of upper and lower approaches and oral capsules.

Our evidence review focuses on the following patient-oriented outcomes: resolution of CDI/symptoms (i.e., diarrhea, abdominal pain, fatigue) and AEs.

Methods

In April 2015, we searched MEDLINE, EMBASE, the Cochrane Library, Cinahl, and PubMed to identify relevant studies. See Search Strategy section for keywords and subject headings used in this search. We further retrieved relevant information via review of bibliographies/reference lists from peer-reviewed and from gray literature. Gray literature consists of reports, studies, articles, and monographs produced by government agencies, private organizations, educational facilities, consulting firms, and corporations.

Study Selection Criteria

ECRI Institute applied the following study-selection criteria to identify appropriate studies that could address the key questions:

  • Study must be published in English.
  • Study must be reported as a full-length article. We excluded abstracts and meeting presentations because they do not give complete results and sufficient detail about methodology to assess the risk of bias, and final results may differ from preliminary results.
  • To avoid double counting of patient outcomes, if more than one article has been published to describe the same study, the article must be the latest published report or have the most complete report of an outcome.
  • Comparative studies must assess at least 10 patients in each arm. Smaller studies are at greater risk of patient-selection bias and often are not statistically reliable.
  • To address Key Question 1, we include RCTs and nonrandomized comparative studies. We also include studies that enroll patients who had recurring symptoms despite multiple courses of standard treatment and reported CDI symptom resolution rates after FMT. We consider these studies a measure of the treatment's effectiveness compared with previous treatments and refer to them as pre-/post-treatment studies. We include pre-/post-treatment studies that assess at least 20 patients.
  • To address Key Question 2, we include RCTs and nonrandomized studies that compare FMT with other treatments for recurrent CDI.
  • To address Key Question 3, we include RCTs and nonrandomized studies that compare FMT using different donor sources.
  • To address Key Question 4, we include RCTs and nonrandomized studies that compare FMT by different administration routes.
  • To address the Key Question 5, we include any studies that assess at least 20 patients and report on AEs associated with FMT.

Included Studies

ECRI Institute's literature searches identified 22 studies that met our inclusion criteria and addressed at least 1 of our key questions. We provide details of the comparative studies in Table 6. For details on pre-/post-treatment studies that address Key Questions 1 and 5, see Table 7 in the Findings section below.

Table 6.  Fecal Microbiota Transplantation: Comparative Studies

Author

Clinical Site

Study Period

Study Design/Objective

Patient Population (n per group)

Key Outcomes Addresses Question # Notes

Cammarota et al. 2015118

Gemelli University Hospital in Rome from 7/2013 to 6/2014

RCT that randomly assigned patients with recurrent CDI to FMT (i.e., vancomycin for 3 days followed by 1 or more fecal infusions via colonoscopy) (n = 20) or tapered vancomycin (i.e., vancomycin for 10 days followed by vancomycin every 2 to 3 days for 3 weeks) (n = 19)a

CDI resolution

AEs

1,2, and 5Initially, patients with CDI recurrence after the first FMT were given a second 1 within a week. However, the protocol was changed after the first 2 patients had FMT and subsequent patients in the FMT study group with pseudomembranous colitis received repeated fecal infusions every 3 days until resolution of colitis.

van Nood et al. 2013119

Academic Medical Center (Amsterdam, The Netherlands) 1/2008 to 4/2010 FECAL trial

RCT that randomly assigned patients with recurrent CDI to 1 of 3 treatments: 500 mg oral vancomycin 4 times per day for 4 days, followed by bowel lavage and FMT through a nasoduodenal tube (n = 17); 500 mg of oral vancomycin 4 times per day for 14 days (n = 13); or 500 mg oral vancomycin 4 times per day for 14 days followed by bowel lavage (n = 13)b

CDI symptom resolution

AEs

1,2, and 5Study patients who developed recurrent CDI after the first FMT received a second FMT from a different donor. Patients in control groups were offered FMT off protocol if antibiotic therapy failed.

Youngster et al. 2014120

Massachusetts General Hospital (Boston, MA, USA)

12/2012 to 5/2013

RCT that randomly assigned patients with refractory or recurrent CDI to receive an FMT using a frozen inoculum from unrelated healthy donors via colonoscopy (n = 10) or nasogastric tube (n = 10).

CDI symptom resolution

AEs

1,4, and 5Investigators offered a second FMT if patients showed no improvement in CDI symptoms.

Satokari et al. 2015121

Helsinki University Hospital (Helsinki, Finland)

12/2007 to 2/2014

Retrospective comparative study that compared CDI recurrence rates of three groups of patients: those who received an infusion of previously prepared, freeze-stored feces (n = 23), those who received fresh feces from individual donors (n = 15), and those who received fresh feces from universal donors (n = 11).

CDI/symptom resolution

AEs

1, 3, and 5No notes

Hamilton et al. 201283

University of Minnesota Fairview Medical Center

(St. Paul, MN, USA)

Not reported

Retrospective comparative study that compared CDI recurrence rates in patients with underlying inflammatory bowel disease who received FMT using a patient-identified donor (n = 10) with those of patients who received FMT from a standard volunteer donor (n = 33).

CDI/symptom r

esolution

s

1, 3, and 5During this study, the donor identification and screening changed from using donors identified by the patient (i.e., family members, friends) to using universal unrelated volunteer donors. Preparation of the planned infusion moved from the endoscopy suite to a standardized process in the laboratory and then to banking ready-to-use frozen processed fecal material.

a Planned enrollment for the trial was 50 patients in each treatment group; however, the study was stopped after the planned 1-year interim analysis showed that FMT showed much higher efficacy than vancomycin.

b Planned enrollment for the FECAL trial was 120 patients (40 in each of 3 treatment groups); however, the data and safety monitoring board terminated the study early because an interim analyses found that most patients in both control groups had recurrent CDI and most patients in the FMT group had achieved resolution of symptoms with no recurrence.

AE:     Adverse events

CDI:    Clostridiumdifficile infection

FMT:  Fecal microbiota transplantation

RCT:   Randomized controlled trial

We identified 17 pre-/post-treatment studies29,53,122-136 that address Key Questions 1 and 5. These studies reported on 691 patients who received FMT to treat recurrent CDI. Study patients had recurring symptoms despite multiple courses of standard treatment with antibiotics. Fourteen of these studies29,53,122,124,126-133,135,136 reported single-center experience, and three studies123,125,134 reported on multicenter experience. These studies primarily assessed FMT among adult patients (ranging in age from 18 to 99 years); however, three of the case series29,125,130 included pediatric patients. Intimate partners, adult family members, or healthy volunteers served as stool donors. The FMT administration route in most studies was via colonoscopy,53,125,127,128,131,133-135 but some studies reported on FMT via rectal catheter,129 simultaneous jejunal enteroscopy and colonoscopy,122 nasogastric tube,124,130 percutaneous endoscopic gastrostomy tube,130 retention enema,123,126,132,133 gastroscopy,136 or oral capsule.29 In some case series, some patients received more than one FMT due to persistent symptoms after an initial FMT.26,29,53,123-126,129,130,132,133,136 Follow-up varied widely among studies. See Table 7 in the Findings section for details.

Strength-of-evidence Assessment

We graded strength of evidence for selected patient outcomes that potentially matter most to decision makers. Our grading approach is based on the concepts and methods proposed by the GRADE working group. We also incorporated the evidence assessment methods used by the Agency for Healthcare Research and Quality's Evidence-based Practice Centers. Our grading approach addressed risk of bias, consistency, directness, precision, magnitude of effect, dose-response gradient, and plausible confounders that would reduce a demonstrated effect. We assigned an evidence grade of "high," "moderate," "low," or "very low" for each selected outcome. The definitions of these evidence grades and more detailed description of the grading methods are provided in Appendix A.  

Findings

Key Question 1: What is the effectiveness of FMT for treating recurrent CDI?

Data from the FECAL RCT,119 1 RCT that compared FMT with tapered vancomycin,118 3 comparative studies that assessed different FMT methods (i.e., different donor sources, different administration routes),83,120,121 and 17 pre-/post-treatment studies29,53,122-136 indicate this treatment may be effective in resolving recurrent CDI in most cases after one FMT and in a small percentage of cases after repeat FMTs. See Table 7 for detailed results.

Table 7.  Effectiveness in Studies of Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection   

 

Author

Clinical Site

Study Period

Population

Definition of Successful Treatment

Reported Follow-up

(Range in Months)

Success after Initial FMT

#/total n (%)

Overall Success Rate

#/total n (%)*

Notes
Comparative Trials (FMT arms only)

Cammarota et al. 2015118

Gemelli University Hospital in Rome from 7/2013 to 6/2014

n = 20

Negative C difficile stool toxins10 weeks13/20 (65)18/20 (90)7 patients had pseudomembranous colitis caused by CDI: 6 of these patients received multiple fecal infusions.

van Nood et al. 2013119

Academic Medical Center (Amsterdam, The Netherlands) 1/2008 to 4/2010

n = 16

Resolution of CDI-associated diarrhea without relapse with 3 consecutive negative stool tests for CDI10 weeks13/16 (81.3) 15/16 (93.8)No notes

Youngster et al. 2014120

Massachusetts General Hospital (Boston, MA, USA)

12/2012 to 5/2013

n = 20

Clinical resolution of diarrhea without using antibiotics and without relapse for 8 weeks6 months14/20 (70)18/20 (90)No notes

Satokari et al. 2015121

Helinski University Hospital (Helinski, Finland)

12/2007 to 2/2014

n = 49

No recurrence of CDI symptoms3 months47/49 (95.9)48/49 (98)2 universal donors for frozen fecal preparations

Hamilton et al. 201283

University of Minnesota Fairview Medical Center

(St. Paul, MN, USA)

Not reported

n = 43

Complete symptom resolution: negative testing for C. difficile toxin B for 2 months 3 months37/43 (86)41/43 (95.3)No notes
Pre-/Post-treatment Studies

Lee et al. 2014126

McMaster University, St Joseph's Healthcare (Ontario, Canada)

1/2008 to 12/2012

n = 94

No recurrence of diarrhea at 6 months follow-up6 months45/94 (47.9)81/94 (86.2)

Patients had refractory CDI.

When patients took vancomycin between FMTs, the resolution rate increased to 86/94 (91.5%).

Kelly et al. 2014125

16 clinical centers

n = 80

No recurrence 12 weeks after FMTMean 11 months (3 to 46 months)62/80 (77.5)70/80 (87.5)Patient population was immunocompromised.

Tvede et al. 2014123

Multiple sites in Denmark

1/2000 to 12/2012

n = 55

Clinical cure defined as no diarrhea and no need for anti-clostridial treatment 1 month35/55 (63.6)38/55 (65.5)Infusion of a fixed mixture of commensal intestinal bacteria once daily for three days

Vigvari et al. 2014124

University of Pecs (Pecs, Hungary)

Not reported

n = 30

Symptom resolution without CDI recurrence within 6 weeks6 weeks27/30 (90)29/30 (96.7)

In 2 cases, FMT was preformed to treat an initial CDI.

In 20 cases, patients had severe infection at time of FMT.

Dutta et al. 2014122

Mt. Sinai Hospital (Baltimore, MD, USA)

12/2010 to 1/2013

n = 27

Marked reduction in stool frequency and negative stool C. difficile toxin 1 to 3 months after FMT

Mean 20.6 months

(9.7 to 34 months)

27/27 (100)27/27 (100)No notes

Emanuelsson et al. 2014129

Skaraborgs Hospital (Skovde, Sweden)

1994 to 2011

n = 23

Symptom resolution within 3 days and no signs of recurrence for 3 months

Median 18 months

(0 to 21 months)

15/23 (65.2)16/23 (69.6)During follow-up, 1 patient who initially responded developed diarrhea after receiving antibiotics for unrelated causes.

Allegretti et al. 201453

Brigham and Women's Hospital (Boston, MA, USA)

Not reported

n = 22

Resolution of CDIMean 3 months (2 weeks to 17 months)19/22 (86.4)21/22 (95.5)One non-responding patient refused a second FMT.

Youngster et al. 201429

Massachusetts General Hospital (Boston, MA, USA)

7/2013 to 1/2014

n = 20

Clinical resolution of diarrhea with no relapse at 8 weeks2 months14/20 (70)19/20 (95)

Frozen FMT capsules from unrelated donors

1 patient relapsed after second treatment.

Ray et al. 2014127

Ochsner Clinic Foundation (New Orleans, LA, USA)

8/2012 to 11/2013

n = 20

No recurrence of CDI Mean 3.2 months (0 to 10 months)20/20 (100)20/20 (100)No notes

Khan et al. 201412

8

University of Toledo Medical Center (Toledo, OH, USA)

7/2012 to 8/2013

n = 20

Resolution of diarrhea without recurrence within 3 months of FMT6 months18/20 (90)20/20 (100)No notes

Rubin et al. 2013130

Essentia Health Duluth Clinic (MN, USA)

1/2003 to 12/2010

n = 74

Symptom resolution without recurrence within 60 days2 months59/75 (78.7)59/75 (78.7)9/16 nonresponders responded to a subsequent course of treatment with vancomycin.

Patel et al. 2013131

Mayo Clinic
(Phoenix, AZ, USA)

1/1/2011 to 1/31/2013

n = 31

Symptom improvement or resolution

Mean 3 days

(1 to 18 days)

26/30 (86.6)

 

26/30 (86.6)No notes

Matilla et al. 2012134

5 hospitals in Finland

11/2007 to 11/2010

n = 70

Symptom resolution12 months66/70 (94.3)66/70 (94.3)

During the first year after FMT, 4 patients who initially responded had a relapse after receiving antibiotics for unrelated causes.

4 nonresponders had serious health conditions and died within 3 months of FMT.

Jorup-Rönström et al. 2012133

Stockholm South General Hospital (Stockholm, Sweden)

1/2004 to 12/2010

n = 32

No symptom relapse after single or repeated FMT

Median
26 months

(1 to 68)

15/32 (46.9)22/32 (68.8)Initial protocol involved FMT via rectal catheter. FMT by colonoscopy introduced late in the study resulted in higher success rate (4/5 [80%]).

Kassan 2012132

Site and time NR

n = 27

Symptom resolutionMean 14.2 months22/27 (81.5)25/27 (92.6)No notes

Kelly et al. 2012135

Women and Infants Hospital (Providence, RI, USA)

Unspecified 28-month period

n = 26

Free of significant diarrhea or CDI during follow-up

Mean
10.7 months

(2 to 30)

24/26 (92.3)24/26 (92.3)During follow-up, 3 patients developed symptoms and responded to over- the-counter fiber preparation, and 2 patients had CDI recurrence after treatment with antibiotics.

Garborg et al. 2010136

Serlandet Hospital HF (Kristiansand, Norway)

1/1994 to 12/2008

n = 40

No clinic contact due to symptom recurrence within 80 days2.7 months29/40 (72.5)33/40 (82.5)5 nonresponders had serious comorbid conditions and died within 2 months of FMT.

*Defined as success rate after initial FMT and repeat FMT (if performed in the study)

CDI:    C. difficile infection

FMT:  Fecal microbiota transplantation

NR:    Not reported

Key Question 2: How do the safety and effectiveness of FMT for treating recurrent CDI compare to those of other treatments for recurrent CDI?

The two RCTs118,119 that provide data to address this question were stopped before planned enrollment was accomplished after interim analyses showed increased effectiveness of FMT compared with standard treatments for recurrent CDI. Cammarota et al.118 reported that the FMT group had a higher overall cure rate than the vancomycin group (18/20 patients [90%] versus 5/19 patients [26.3%]; relative risk [RR] = 3.42; [95% CI: 1.59 to 7.36], p <0.0001). Immediately after FMT, 19/20 patients (95%) developed diarrhea and 12/20 patients (60%) had bloating and abdominal cramping. These symptoms resolved within 12 hours of FMT. No specific vancomycin-related AEs were reported.

In the FECAL trial interim analysis,119 van Nood et al. reported that the FMT group had a higher overall treatment success rate than the vancomycin group (15/16 [93.8%] patients) versus 4/13 [30.8%] patients; RR = 3.05 [95% CI: 1.34 to 6.95], p <0.001) or the vancomycin plus bowel lavage group (15/16 [93.8%] patients) versus 3/13 [23.1%] patients; RR = 4.06 [95% CI: 1.49 to 11.05], p <0.001). Reported AEs for each treatment arm were mild. On the day of the FMT,119 15/16 patients (93.8%) reported diarrhea, 5/16 patients (31.3%) reported abdominal cramps, 3/16 patients (18.8%) reported belching, 2/16 patients (12.5%) reported abdominal pain with cramping, 1/16 patients (6.3%) reported nausea, and 1/16 patients (6.3%) reported dizziness combined with diarrhea. All patients reported resolution of these symptoms within three hours. During follow-up, 2/16 patients (12.5%) received laxatives for constipation. In the vancomycin group, a few mild AEs were reported: 1/13 patients (7.7%) experienced dyspepsia, and 1/13 patients (7.7%) received laxatives for constipation. In the vancomycin plus lavage group, a few mild AEs were reported: 2/13 patients (15.4%) reported constipation, 1/13 patients (7.7%) received laxatives for constipation, 2/13 patients (15.4%) reported gastrointestinal distress (i.e., excess flatulence, persistent diarrhea), and 1/13 patients (7.7%) developed a urinary tract infection.

Key Question 3: How do the safety and effectiveness of FMT from different donor sources compare?

Two retrospective comparative studies83,121 provide data to address this question.

Satokari et al.121 reported similar symptom resolution rates 3 months after FMT for the study group that received previously frozen feces from a universal donor and the study group that received fresh feces from a universal donor (22/23 patients [95.7%] versus 11/11 patients [100%]; RR = 0.98 [95% CI: 0.84 to 1.14], p = 0.4) or fresh feces from an individual donor (22/23 patients [95.7%] versus 14/15 [93.3%]; RR = 1.02 [95% CI: 0.87 to 1.2], p = 0.8). At 1 year-follow-up, study investigators reported the same success rate in study groups that received fresh or frozen feces (22/25 patients [88%] versus 15/17 patients [88.0%]; RR = 1.0 [95% CI: 0.8 to 1.25], p = 0.98). 

Hamilton et al. reported similar initial CDI treatment success rates after FMT between donors identified by the patient (i.e., family members, friends) and universal unrelated volunteer donors: 70% (7/10) of patients in the patient-identified donor group and 90.9% (30/33) of patients in the universal donor group (RR = 0.77 [95% CI: 0.51 to 1.17], p = 0.10) achieved resolution of CDI.83 The study also reported similar treatment success rates between groups that received fresh or frozen universal donor material (91.7% [11/12 patients] versus 90.5% [19/21 patients]; RR = 1.01 [95% CI: 0.81 to 1.26], p = 0.91).83

Key Question 4: How do the safety and effectiveness of FMT by different routes of administration compare?

One RCT120 provides data to address this question. Youngster et al.120 reported no statistically significant difference in CDI treatment success rates between colonoscopy and nasogastric tube FMTs: 80% (8/10) of patients in the colonoscopy group and 60% (6/10) of patients in the nasogastric tube group achieved CDI resolution (RR = 1.33 [95% CI: 0.74 to 2.41], p = 0.628).120 One patient in the nasogastric tube group whose initial treatment failed refused a second FMT. Five remaining patients received a second FMT via nasogastric tube (their chosen administration route), and four had treatment success after the second FMT. The study reported no statistically significant difference in the overall treatment success rates after initial FMT and repeat FMT between 2 study groups: 100% (10/10) of patients in the colonoscopy group and 80% (8/10) of patients in the nasogastric tube group (RR = 1.24 [95% CI: 0.87 to 1.75], p = 0.53).120

Key Question 5: What AEs have been reported in studies of FMT?

Overall, available evidence suggests that FMT is generally safe and well-tolerated. One study patient, who developed appendicitis, fever, E Coli, and septicemia after infusion of a fixed mixture of commensal intestinal bacteria, recovered after treatment with antibiotics. No other infectious or serious complications were reported. Studies varied significantly in patient populations, FMT administration routes, and donor sources. Nine studies reported that no FMT-related AEs occurred in study patients.126,129-136 In the other studies, commonly reported AEs were diarrhea, abdominal cramping, bloating, and belching; in most cases, these symptoms resolved within a few hours or days of FMT. Table 8 provides details of other specific AEs reported in the studies of FMT.

Table 8.  Adverse Events: Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection
Study Adverse Event

Frequency

# events/n (%)

van Nood et al. 2013119Nausea resolved within 3 hours of FMT1/16 (6.3)
Constipation2/16 (12.5)
Youngster et al. 2014120Transient fever that resolved spontaneously1/20 (5)
Satokari et al. 2015121Mild transient fever 2/49 (4.1)
Tvede et al. 2014123 Appendicitis, fever, E Coli septicemia (patient was treated with antibiotics and recovered without CDI recurrence)1/46 (2.2)
Kelly et al. 2014125a Infectious complications directly attributable to FMT0/80 (0)
Death in patient with advanced cancer who aspirated during sedation for colonoscopy1/80 (1.3)
Self-limited abdominal pain/hospitalization after FMT1/80 (1.3)
Inflammatory bowel disease flare possibly related to FMT4/80 (5)
Ray et al. 2014127 Pain and nausea after colonoscopy that resolved quickly1/20 (5)
Continued diarrhea but negative for CDI1/20 (5)
Flatulence and nausea for 2 weeks post FMT1/20 (5)
Khan et al. 2014128 Mild diarrhea up to 3 months post FMT1/20 (5)
Fatigue up to 3 days after FMT13/20 (65)
Nausea up to 3 days after FMT2/20 (10)
Dutta et al. 2014122Low-grade fever that resolved spontaneously within 12 to 24 hours of FMT5/27 (18.5)

a Immunocompromised patients

For Key Question 5, we described the AEs reported in literature and did not draw a conclusion. Therefore, we did not assess the risk of bias of the studies or the overall strength of evidence for the safety outcome.

Ongoing Clinical Trials

ECRI Institute searches identified 15 relevant ongoing trials. See Table 9 for details on the seven ongoing RCTs.

Table 9. Ongoing Randomized Controlled Trials of Fecal Microbiota Transplantation

Study Name/Clinical Site

NCT Identifier

Planned Enrollment

Study Design and Objective

Primary Endpoints

Estimated Completion Date

Fecal Microbiota Transplantation for Relapsing CDI

Montefiore Medical Center
(Bronx, NY, USA) and
Miriam Hospital
(Providence, RI, USA)

NCT01703494

n = 53 adult outpatients referred after suffering a third documented CDI episode and who have been unable to maintain CDI cure after standard therapy with oral vancomycin

RCT determining whether FMT is an effective and safe treatment for a patient with relapsing CDI. Patients will receive FMT or sham FMT.

Primary endpoint: Resolution of diarrhea with maintenance of resolution for the 8-week follow-up period and no further requirements for anti-infective therapy for CDI.

September 2015

Ongoing but not recruiting patients

Fresh, Frozen or Lyophilized FMT for Multiple Recurrent C. difficile Associated Diarrhea

University of Texas Health Science Center (Houston, TX, USA)

NCT02318992 

n = 100 adults with a diagnosis of ≥3 recurrent C. difficile-associated diarrhea bouts in outpatients or    ≥2 bouts of C. difficile-associated diarrhea in an inpatient without other explanation for diarrhea and with ≥2 positive fecal tests for C. difficile toxin.

RCT investigating the efficacy of fresh, frozen, or lyophilized FMT via colonoscopy in patients with recurrent C. difficile-associated diarrhea

Primary endpoint: Clinical improvement is monitored by telephone/e-mail and/or e-mail during 90 days after FMT

September 2015

FMT Versus Standard Medical Therapy for Initial Treatment of Recurrent CDI

NorthShore University HealthSystem (Evanston, IL, USA)

NCT02255305

n = 60 adults with a diagnosis of active CDI and hospitalized patients presenting with first CDI relapse 

RCT comparing the safety and efficacy of FMT for treating the first recurrence of CDI and standard antibiotic therapy

Primary endpoint: Clinical resolution of diarrhea at 90 days

December 2015

A Prospective, Multi-center, Randomized Trial of FMT Delivered by Capsule vs Colonoscopy in the Management of Recurrent CDI

Edmonton, Alberta, Canada

NCT02254811

n = 200 adult patients with a diagnosis of at least 3 episodes of recurrent CDI, and CDI under symptomatic control with <3 loose/unformed bowel movements per 24 hour period for at least 2 consecutive days before procedure

RCT comparing the efficacy of FMT delivered by oral capsules and FMT delivered by colonoscopy

Primary endpoint: proportion of patients without recurrent CDI at 12 weeks

August 2016

Ongoing but not recruiting patients

A Randomized, Placebo-controlled Pilot Trial to Administer Fecal Microbial Therapy or Placebo in Children With Recurrent C. difficile Infection

Miller Children's Hospital and Children's Hospital of Los Angeles
(Los Angeles, CA, USA)

NCT01972334

n = 46 children (5 to 21 years) with recurrent CDI defined as the occurrence of more than 2 infections

RCT evaluating the safety and efficacy of FMT in children in preventing recurrent CDI. Study patients will receive FMT or sham FMT.

Primary endpoint: Time of recurrence of an infection up to 12 months

December 2016

Placebo Controlled Study of Fecal Microbiota Transplant for a Second Episode of C. difficile Infection in Adults Using a Frozen Encapsulated Inoculum

Massachusetts General Hospital (Boston, MA, USA)

NCT02343328

n = 50 adult patients with 2 episodes of CDI defined as having resolved symptoms after an initial microbiologically confirmed diagnosis of C. difficile, who have completed a course of antibiotics, and have a second positive test (toxin or polymerase chain reaction) obtained for a relapse of diarrhea symptoms by treating providers.

RCT assessing the safety and efficacy of oral fecal microbiota capsules. Patients will receive oral fecal microbiota or placebo capsules

Primary endpoint: Resolution of diarrhea/CDI symptoms and/or no relapse of C. difficile at 8 weeks

February 2017

A Phase 2B Prospective, Randomized, Double-blinded, Placebo-controlled Clinical Study Demonstrating the Efficacy and Safety of Rebiotix RBX2660 Microbiota Suspension for the Treatment of Recurrent Clostridium Difficile Infection

22 clinical sites in U.S. and Canada

NCT02299570

n = 117 adult patients with medical record documentation of recurrent CDI,  documented history that the CDI is controlled while on antibiotics, and a positive stool test for the presence of C. difficile within 60 days before enrollment.

RCT assessing the safety and efficacy of Rebiotix RBX2660 microbiota suspension enemas for treating recurrent CDI. Patients will receive Rebiotix RBX2660 or placebo enemas.

Primary endpoint: Efficacy of active treatment compared to placebo measured at 8–weeks post-treatment.

June 2017

CDI:    Clostridium difficile infection

FMT:  Fecal microbiota transplantation

RCT:   Randomized controlled trial

Discussion

The included studies have some limitations the reader should consider. Two of the comparative studies and 15 of the pre-post treatment studies are retrospective, which may be subject to patient selection bias and reporting bias and not necessarily account for patient or treatment variables that might affect outcomes. Furthermore, 19 of the 22 included studies reported on single-center experiences. Study populations varied and protocols differed for pretreatment, obtaining and processing FMT material, stool donors, stool preparation, administration route, adjunctive treatment, FMT frequency, definition of treatment success, and follow-up—factors that greatly limit generalizability to broader populations and interpretation of outcomes across studies.

Also, gaps in the evidence base exist. No study compares FMT with fidaxomicin, a newer antibiotic that purportedly has a selected action on C. difficile and limited effect on microflora. Also, the available evidence did not permit a conclusion regarding the optimal FMT administration route. Furthermore, data on FMT's long-term effects (e.g., on patient's immune system) were also lacking. Future studies, particularly well-designed RCTs comparing different FMT approaches, are needed to address these evidence gaps. Given FMT's high success rates reported in existing literature, some researchers argue that conducting RCTs in patients with recurrent CDI might not be ethical. However, our searches identified four ongoing RCTs comparing FMT with other treatments for recurrent CDI. Despite the ethical concern, the findings of these RCTs will enhance our understanding of FMT's comparative effectiveness for treating recurrent CDI. Patient registries and other research resources should be established to address concerns about possible disease transmission and long-term effects of FMT on patients' immune system.

Evidence Base Conclusions

This report aimed to address five key questions.

Key Question 1: What is the effectiveness of FMT for treating recurrent CDI?

FMT is effective in resolving CDI symptoms in most cases after one FMT and in a small percentage of cases after repeat FMTs. Strength of Evidence: Moderate. The evidence does not permit us to determine the optimal regimen because of wide variation in practices among different centers.

Key Question 2: How do the safety and effectiveness of FMT for treating recurrent CDI compare to those of other treatments for recurrent CDI?

FMT results in a higher overall cure rate than tapered vancomycin regimen, and adding FMT to an abbreviated course of vancomycin and bowel lavage is more effective than a standard vancomycin regimen or a standard vancomycin regimen and bowel lavage. Strength of Evidence: High. The two RCTs that addressed this question were stopped before planned enrollment was accomplished after interim analyses showed increased effectiveness of FMT compared with other treatments for recurrent CDI. Evidence does not permit us to determine how FMT compares with any other treatment because no evidence is available.

Key Question 3: How do the safety and effectiveness of FMT from different donor sources compare?

The evidence does not permit us to compare the safety and effectiveness of different donor sources. The studies that provided data assessed too few patients. Strength of Evidence: Very low.

Key Question 4: How do the safety and effectiveness of FMT by different routes of administration compare?

The evidence does not permit us to compare the safety and effectiveness of different routes of FMT administration (e.g., colonoscopy, nasogastric tube, upper-tract endoscope, retention enema, combination of upper and lower approaches, oral). The one comparative study that provided data assessed too few patients. Strength of Evidence: Very low.

Key Question 5: What AEs have been reported in studies of FMT?

Available evidence suggests that FMT is generally safe and well-tolerated. Commonly reported AEs are diarrhea, abdominal cramping, bloating, and belching; in most cases, these symptoms resolved within a few hours or days of FMT. One study patient, who developed appendicitis, fever, E. coli, and septicemia after infusion of a fixed mixture of commensal intestinal bacteria, recovered after treatment with antibiotics and had no CDI recurrence. No other infectious or serious complications were reported.

Glossary

Bibliography

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Resource List

Related Resources

Appendix A. Strength-of-evidence Assessment Methods

We grade strength of evidence (SOE) for selected patient outcomes in this report. Our grading approach is based on the concepts and methods proposed by the GRADE working group. Our approach also incorporates the evidence assessment methods adopted by the Agency for Healthcare Research and Quality's Evidence-based Practice Centers. Detailed descriptions of the GRADE and EPC methods are accessible using the links we provided above. To grade evidence in this report, we consider seven domains that may affect SOE: risk of bias, consistency, directness, precision, magnitude of effect, dose-response gradient, and plausible confounders that would reduce a demonstrated effect. For each selected outcome, we assign a grade of "high," "moderate," "low," or "very low." The definitions of the grades are provided in Table A-1.

Table A-1.  Strength-of-evidence Grade Definitions

Grade Definition  
HighWe have high confidence in the findings for this outcome. The body of evidence has few or no deficiencies. We believe that the findings are stable (i.e., another study would not change the conclusions).
ModerateWe have moderate confidence in the findings for this outcome. The body of evidence has some deficiencies. We believe that the findings are likely to be stable, but some doubt remains.
LowWe have limited confidence in the findings for this outcome. The body of evidence has major or numerous deficiencies. We believe that additional evidence is needed before concluding either that the findings are stable or that the estimate of effect is close to the true effect.
Very lowWe have no confidence in the findings for this outcome. No evidence is available or the body of evidence has unacceptable deficiencies.

 

We assessed each comparative study as having low, medium, or high risk of bias using the items in Table A-2.

Table A-2.  Items Used for Risk-of-bias Assessment

Item  Comment
Were patients randomly or pseudorandomly (e.g., using instrumental variable analysis) assigned to the study groups? Instrumental variable analysis can account for both measured and unmeasured confounders as long as the chosen variables have a strong association with treatment choice but no association with health outcomes. Studies using this method received a "yes" for this item. Studies using propensity scoring or multivariate regression received a "no."
Was there concealment of group allocation?
Were data analyzed based on the intention-to-treat-principle?
Were the patients blinded to the group assigned?
Were those who treated the patient blinded to the group to which the patients were assigned?
Were those who assessed the patient outcomes blinded to the group to which the patients were assigned?
Was the outcome measure of interest objective, and was it objectively measured?

CDI symptom resolution (C. diff toxin testing) was considered an objective outcome.

CDI symptom resolution (patient questionnaire) was considered a subjective outcome.

Was there a 15% or less difference in the length of follow-up for the 2 groups?
Did 85% or more of enrolled patients provide data at the time point of interest?
Was there fidelity to the protocol?

CDI:  Clostridium difficile infection

Appendix B. Results of Risk-of-bias and Strength-of-evidence Assessment

Table B-1.  Results of Risk-of-bias Assessment

Study Author/Year

Outcome(s) Q1. Were patients randomly assigned to
treatment groups?
Q2. Was there concealment of group
allocation?
Q3. Were data analyzed based on the
intention-to-treat-principle?
Q4. Were the patients blinded to the
group assigned?
Q5. Were those who treated the patient blinded to the group to which the
patients were assigned?
Q6. Were those who assessed the patient outcomes blinded to the group to which the patients were assigned? Q7. Was the outcome measure of interest objective, and was it objectively measured? Q8. Was there a 15% or less difference in the length of follow-up for the 2 groups? Q9. Did 85% or more of enrolled patients provide data at the time point of interest? Q10. Was there fidelity to protocol? Risk-of- bias Category (Rationale)
Cammarota et al. 2015 CDI symptom resolution Yes Yes Yes No No NR Yesa Yes Yes No High (protocol infidelity)
van Nood et al. 2013 CDI symptom resolution Yes NR Yes No No Yes Yesb Yes Yes Yes Medium (no blinding)
Satokari et al. 2015 CDI symptom resolution No NR Yes No No No Noc Yes Yes Yes High (no randomization)
Hamilton et al. 2012 CDI symptom resolution No NR Yes No No No Yesa Yes Yes Yes High (no randomization)
Youngster et al. 2014 CDI symptom resolution Yes NR Yes No No No Noc Yes Yes Yes Medium (subjective outcome with no blinding)

a Toxin stool test

b Structured interview, culture and toxin stool test

c  Questionnaire only

CDI:  Clostridium difficile infection

NR:  Not reported

We consider the pre-/post-treatment studies included in this report (Tvede et al. 2014; Allegretti et al. 2014; Vigvari et al. 2014; Youngster et al. 2014; Lee et al. 2014; Kelly et al. 2014; Ray et al. 2014; Khan et al. 2014; Dutta et al. 2014; Emanuelsson et al. 2014; Rubin et al. 2013; Patel et al. 2013; Kassam 2012; Jorup-Rönström et al.2012; Matilla et al. 2012; Kelly et al. 2012; Garborg et al. 2010) to have a high risk of bias.

Table B-2.  Results of Strength-of-evidence Assessment
Comparison/
Reference
Outcome Risk of Bias Consistency Directness Precision Magnitude of Effect Evidence Favors SOE Grade (Rationale)

FMT vs. Vancomycin

Cammarota et al. 2015

van Nood et al. 2013

CDI symptom resolutionMedium (-1)ConsistentDirectPreciseLargeb (+1)FMTHigh
Pre-/Post- Treatment StudiesaCDI symptom resolutionHigh (-2)ConsistentDirectPreciseLarge (+1)FMT

Moderate

(no randomization)

FMT with fresh vs. frozen universal donor material

Satokari et al. 2015

Hamilton et al. 2012

CDI symptom resolutionHigh (-2)ConsistentDirectImprecise (-1)Not largeNeither

Very Low

(large confidence interval)

FMT using individual donor vs. universal donor

Satokari et al. 2015

Hamilton et al. 2012

CDI symptom resolutionHigh (-2)ConsistentDirectImprecise (-1)Not largeNeither

Very Low

(large confidence interval)

Colonoscopy FMT vs. nasogastric tube FMT

Youngster et al. 2014

CDI symptom resolutionMedium (-1)Unknown (-1)DirectImprecise (-1)Not largeNeither

Very Low

(large confidence interval)

a Tvede et al. 2014; Allegretti et al. 2014; Vigvari et al. 2014; Youngster et al. 2014; Lee et al. 2014; Kelly et al. 2014; Ray et al. 2014; Khan et al. 2014; Dutta et al. 2014; Emanuelsson et al. 2014; Rubin et al. 2013; Patel et al. 2013; Kassam 2012; Jorup-Rönström et al.2012; Matilla et al. 2012; Kelly et al. 2012; Garborg et al. 2010

b Cammarota Study: RR = 3.42; van Nood Study: RR = 3.05

NA:     Not applicable

SOE:   Strength of evidence

Appendix C. Impact Ratings Definitions

Reimbursement Status

Definition: The extent to which third-party payer coverage and coding are in effect to enable insured patients' access to the intervention.

(4) Wide coverage: Medicare has a positive national coverage determination and/or ≥8 private payers provide coverage.

(3) Expanding coverage: Medicare has no national coverage determination; some local Medicare carriers provide coverage; four to seven major private payers provide coverage; others deny coverage, have no published policy in place, or decide coverage on a case-by-case basis.  

(2) Limited coverage: Medicare has no national coverage determination or provides coverage only in the context of a clinical trial (i.e., coverage with evidence development); one to three major private payers provide coverage.

(1) No coverage: Medicare has a national coverage determination that denies coverage. Most private third-party payers explicitly state that they do not cover the technology because they consider the technology or intervention to be "investigational" or "experimental" or consider the evidence insufficient.

Diffusion Status

Definition: The extent to which the technology or intervention has been adopted into clinical care at this time. Considerations include the proportion of clinicians or healthcare facilities that report or advertise using the technology or intervention.    

(4) Wide: Adopted by ≥50% of healthcare providers and facilities expected to use this technology.

(3) Middle: Adopted by >25% and up to 50% of healthcare providers and facilities expected to use this technology.

(2) Early: Adopted by about >10% and up to 25% of healthcare providers and facilities expected to use this technology.

(1) Innovative: use limited to clinical trials or adopted by <10% of healthcare providers and facilities that would be expected to use this technology after it is clinically and commercially available.

Effect on Staffing and Care Processes

Definition: The extent to which most providers need to change their staffing model and/or care processes if adopting this technology. Staffing impacts include need for additional staff or different model/team. Process impacts include shifts in amount of care delivered, care setting, and changes in patient volume and/or throughput.

(4) Substantial: Significant staffing changes and/or care process changes needed.

(3) Moderate: Some staffing changes and/or care process changes needed.

(2) Low: Limited staffing changes and/or care process changes needed.

(1) Negligible: Current staffing and/or care processes are probably sufficient.

Infrastructure Needs

Definition: The extent of new or expanded infrastructure that most providers will need if adopting the technology (e.g., new or expanded existing facilities, new capital equipment, supplies).

(4) Substantial: Significant additional infrastructure needed to adopt the technology.

(3) Moderate: Some additional infrastructure needed to adopt the technology.

(2) Small: Limited additional infrastructure needed to adopt the technology.

(1) Negligible: No additional infrastructure needed to adopt the technology.

Technology Cost Impact on Providers

Definition: The costs to implement and use the technology initially and ongoing; considers acquisition and maintenance, additional staff and training, additional infrastructure needed.

(4) Substantial costs associated with acquisition, implementation (estimated >$100,000).

(3) Moderate costs associated with acquisition, implementation (estimated >$50,000 up to <$100,000).

(2) Small costs associated with acquisition, implementation (estimated <$25,000 up to $50,000).

(1) Negligible costs associated with acquisition, implementation, and ongoing use. Resources and supplies required to use the technology are on hand at most healthcare facilities that would use the technology (estimated <$25,000).

Technology Cost Impact on Payers

Definition: The costs to payers (health plans and patients) for use of the new technology (drug, device, procedure). Considerations include cost per patient, size of the patient population expected to use it, and patient copay scenarios.

(4) Substantial per-patient costs (estimated >$50,000) and copays or substantial number of patients expected to use the technology.

(3) Moderate per-patient costs (>$25,000 to $50,000) and copays or moderate number of patients expected to use the technology

(2) Small per-patient costs ($5,000 to <$25,000) and copays or small number of patients expected to use the technology.

(1) Negligible per-patient costs (<$5,000) and copays or negligible number of patients expected to use the technology.

Topics and Metadata

Topics

Comparative Effectiveness; Treatment of Disease

Caresetting

Home Care; Hospital Inpatient; Hospital Outpatient; Physician Practice

Clinical Specialty

Gastroenterology; Clinical Laboratory; Geriatrics; Infectious Disease; Internal Medicine; Microbiology; Transplantation

Roles

Allied Health Personnel; Clinical Laboratory Personnel; Health Educator; Health Plan; Healthcare Executive; Nurse; Patient Safety Officer; Patient/Caregiver; Public Health Professional; Quality Assurance Manager; Regulator/Policy Maker; Risk Manager; Student; Utilization Management Professional

Information Type

Evidence Analysis

Phase of Diffusion

Middle Diffusion

Technology Class

Procedure

Clinical Category

Treatment--Therapeutic

UMDNS

SourceBase Supplier

Product Catalog

MeSH

Enterocolitis, Pseudomembranous; Clostridium Infections; Cross Infection; Recurrence; Colonoscopy; Colonoscopes

ICD9/ICD10

Intestinal infection due to clostridium difficile [008.45]

FDA SPN

COLONOSCOPE, GASTRO-UROLOGY [FDF]; COLONOSCOPE, GENERAL & PLASTIC SURGERY [FTJ]

SNOMED

Colonoscope [90412006]; Colonoscopy [73761001]; Clostridial infection [56688005]; Clostridium difficile infection [186431008]; Pseudomembranous enterocolitis [397683000]; Antibiotic induced pseudomembranous enterocolitis [397609004]; Cross infection [36406009]; Recurrence [246455001]

HCPCS

Disease/Condition

 

Publication History

DateActionComments
3/16/2012Published Initial publication
11/30/2012Revised/RepublishedComprehensive Update
1/25/2013Revised/RepublishedComprehensive Update; New RCT
5/16/2013 Updated Sections Regulatory Status (FDA regulation); Medicare Coverage; Summary
6/20/2013 Updated Sections Regulatory Status (FDA regulation); Summary
8/15/2014Comprehensive UpdateEntire report updated
6/30/2015Comprehensive UpdateNew Template/Grading of Evidence
7/21/2016Minor UpdateRevised format of Executive Summary Technology Impact Ratings, revised format of Evidence Summary of Selected Outcomes table, added circle graphics and footnote, Table B-1 (added Risk of Bias rationale), Table B-2 (added rationales and point upgrades and downgrades for Strength of Evidence grades)