Medical Policy: 08.01.23
Original Effective Date: February 2015
Reviewed: January 2021
Revised: January 2021
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Fecal Bacteriotherapy, also called fecal microbiota transplantation (FMT) involves the infusion of intestinal microorganisms via transfer of stool from a healthy individual into a diseased individual, with the intent of restoring normal intestinal flora. Fecal transplant is proposed for the treatment of treatment-refractory Clostridioides (previously Clostridium) difficile infection (CDI).
The US Food and Drug Administration (FDA) has classified human stool as a biological agent and determined that its use in fecal microbiota transplantation (FMT) therapy and other research should be regulated to ensure patient safety.
Fecal transplantation is usually performed by colonoscopy and less commonly by nasoduodenal tube. During colonoscopy the colonoscope is advanced through the entire colon. As the colonoscope is withdrawn, the donor stool is delivered through the colonoscopy into the colon.
Current guidelines state that the preferred route of administration of FMT is colonoscopy due to risk for aspiration and long-term bacterial overgrowth in the small intestine following NG or enteroscopy administration.
The goal of FMT is to replace damaged and/or disordered native microbiota with a stable community of donor microorganisms. The treatment is based on the premise that an imbalance in the community of microorganisms residing in the gastrointestinal tract (i.e., dysbiosis) is associated with specific disease states, including susceptibility to infection.
OpenBiome has collaborated with Finch Therapeutics to develop CP101, a freeze-dried oral FMT capsule.
Practice Guidelines and Position Statements
The American College of Gastroenterology
The American College of Gastroenterology recommends that FMT should be considered second-line therapy for a third recurrence of CDI.
American Gastroenterological Association (AGA)
AGA Clinical Practice Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis
In patients with mild–moderate ulcerative colitis (UC) without Clostridium difficile infection, the AGA recommends fecal microbiota transplantation be performed only in the context of a clinical trial.
Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)
In 2018, IDSA and SHEA updated the 2010 clinical practice guidelines for the diagnosis and treatment of clostridium difficile infection in adults and children. The Societies recommended pharmacotherapy using vancomycin, fidaxomicin, and/or metronidazole depending on the episode and the severity of the C difficile.
The guidelines strongly recommended fecal microbiota transplantation (FMT) as a treatment option for adults following an initial treatment of CDI and two recurrences (i.e. after three treated CDI episodes) that have been non-responsive to at least two regimens of antibiotics (i.e., various combinations of vancomycin, fidaxomicin, and/or metronidazole). Similar recommendations are made for children but the strength of the recommendations is low and the quality of evidence is low for pharmacotherapy and very low for FMT.
The Societies recommendations for the treatment of C. difficile included the following:
- Initial episodes, non-severe: oral vancomycin (VAN) 125 mg four times a day for ten days; OR oral fidaxomicin (FDX) 200 mg twice a day for ten days; OR if neither VAN or FDX are available, oral metronidazole 500 mg three times a day for ten days.
- Initial episode, severe: oral VAN 125 mg, four time a day for ten days; OR FDX 200 mg twice a day for ten days
- Initial episode, fulminant; 500 mg VAN oral or via NG tube four times a day. If ileus is present consider rectal instillation of VAN. Intravenous metronidazole, 500 mg every eight hours, with VAN if ileus is present.
- First recurrence: VAN 125 mg four times a day for ten days if metronidazole was used for initial episode; OR prolonged tapered and pulsed VAN regimen if a standard VAN regimen was used initially; OR FDX 200 mg twice a day for ten days if VAN was used for the initial episode.
- Second or subsequent recurrence: VAN in tapered and pulsed regimen; OR oral VAN 125 mg four times a day for ten days followed by rifaximin 400 mg three times a day for 20 days; OR FDX 200mg twice a day for 10 days; OR fecal microbiota transplantation (IDSA, 2018).
While the previous guidelines recommended metronidazole as the first-line therapy for initial cases of mild-to-moderate CDI and vancomycin for more severe cases, the new guidelines recommend either vancomycin or fidaxomicin (FDX) as the drug of choice for all initial episodes.
Currently, the use of fecal capsules (oral administration) has been shown to be inferior to upper or lower gastrointestinal infusion (e.g., endoscopy, nasogastric tube, enema, colonoscopy).
Food and Drug Administration (FDA)
In 2019, the FDA issued a safety alert regarding the use of FMT due to the potential risk of serious or life-threatening infections caused by the transmission of multi-drug resistant organisms (MDROs). Two immunocompromised individuals received investigational FMT and developed invasive infections caused by the transmission of extended-spectrum betalactamase-producing Escherichia coli. One of the affected individuals died. The donor stool used in each patient's FMT procedures had not been tested for extended-spectrum beta-lactamase-producing gram-negative organisms prior to use. Follow-up testing verified donor stool was positive for MDROs identical to the organisms isolated from the two patients. Due to these events, the FDA has determined that the following additional protections are required for any investigational use of FMT:
- Donor screening that specifically addresses risk factors for colonization with MDROs and exclusion of individuals at higher risk of colonization with MDROs (eg, health care workers, persons who have recently been hospitalized or discharged from long-term care facilities, persons who regularly attend outpatient medical or surgical clinics, and persons who have recently engaged in medical tourism).
- MDRO testing of donor stool and exclusion of stool testing positive for MDROs. At a minimum, tests should include:
- extended-spectrum beta-lactamase-producing Enterobacteriaceae
- vancomycin-resistant enterococci
- carbapenem-resistant Enterobacteriaceae
- methicillin-resistant Staphylococcus aureus
- All FMT products currently in storage for future use must be quarantined until donor MDRO carriage risk can be assessed and FMT products are tested and found negative for MDROs.
- The informed consent process for FMT treatment subjects should describe the risk of MDRO transmission and infection and the measures being implemented for donor screening and stool testing.
Fecal microbiota transplantation/fecal bacteriotherapy may be considered medically necessary in patients when ALL of the following have been met:
- Infection confirmed by a positive stool test for Clostridioides (previously Clostridium) difficile infection
- Treatmet is administered by upper or lower gastrointestinal infusion
- There have been at least 3 episodes of recurrent Clostridioides difficile infection and associated diarrhea refractory to antibiotic therapy including at least one of the following regimens:
- tapered and pulsed vancomycin (VAN) or
- vancomycin (VAN) 125mg four times a day for 10 days followed by rifaximin 400 mg three times a day for 20 days or
- fidaxomicin (FDX) 200mg twice a day for 10 days
- Patient is not immunocompromised, including:
- Patients on major immunosuppressive agents including high-dose corticosteroids, calcineurin inhibitors, mammalian target of rapamycin (mTOR) inhibitors, lymphocyte-depleting biological agents, anti-tumor necrosis factor agents, and others; chemotherapeutic antineoplastic agents.
- Patients with decompensated liver cirrhosis, advanced HIV/acquired immune deficiency syndrome, recent bone marrow transplant, or other cause of severe immunodeficiency
The current studies fail to address and show success with repeated fecal transplants. Therefore, the use of repeat fecal transplant for any indication is considered not medically necessary.
Fecal bacteriotherapy is considered not medically necessary for the first or second episode of clostridium difficile.
Fecal microbiota transplantation/fecal bacteriotherapy is considered investigational for, but not limited to, the following conditions:
- Alopecia Areata
- Autism Spectrum DIsorder
- Constipation/Slow transit constipation
- Crohn’s disease
- Colon Cancer
- D-lactic acidosis
- Diarrhea not associated with Clostridioides difficil
- Graft versus Host Disease or prevention of graft vs host disease
- Insulin resistance
- Irritable Bowel Syndrome
- Inflammatory Bowel Disease
- Mental Health Disorders (e.g. anziety, OCD, autism)
- Metabolic Syndrome
- Multiple Sclerosis
- Neurologic disorders
- Other Autoimmunie Disorders
- Prophylactically for CDI
- Ulcerative Colitis
Recurrent Clostridioides (formerly Clostridium) difficile infection (CDI) is defined by complete abatement of CDI symptoms while on appropriate therapy, followed by reappearance of symptoms within two to eight weeks after treatment has been stopped.
Procedure Codes and Billing Guidelines:
To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
- 44705 Preparation of fecal microbiota for instillation, including assessment of donor specimen.
- G0455 Preparation with instillation of fecal microbiota by any method, including assessment of donor specimen.
- 44799 Unlisted procedure, small intestine
- American College of Gastroenterology (ACG). Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections
- Food and Drug Administration (FDA). Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile infection Not Responsive to Standard Therapies. July 2013
- Van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ (2013). Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. N Engl J Med 20 Jan 16.
- NICE guideline: Faecal microbiota transplant for recurrent clostridium difficile infection March 2014
- ECRI Institute, emerging technology reports. Fecal microbiota transplantation for treating recurrent clostridium difficile infection. Updated Aug 2014
- Austin M, Mellow M, Tierney WM. Fecal microbiota transplantation in the treatment of clostridium difficile infections. Am J Med. 2014 Jun;127(6):479-83. doi: 10.1016/j.amjmed.2014.02.017. Epub 2014 Feb 26
- Kelly CR, de Leon L, Jasutkar N. Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results. J Clin Gastroenterol. 2012;46:145–149
- Kelly CP. Fecal microbiota transplantation--an old therapy comes of age. N Engl J Med. 2013;368:474–475
- Vyas D, L’esperance HE, Vyas A. Stool therapy may become a preferred treatment of recurrent Clostridium difficile? World J Gastroenterol. 2013;19:4635–4637
- Brandt LJ, Aroniadis OC. An overview of fecal microbiota transplantation: techniques, indications, and outcomes. Gastrointest Endosc. 2013;78:240–249
- Moore T, Rodriquez A, Bakken JS. Fecal microbiota transplantation: a practical update for the infectious disease specialist. Clin Infect. Dis. 2014:58(4):541-545
- Surawicz CM1, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, McFarland LV, Mellow M, Zuckerbraun BS. Guidelines for diagnosis, treatment, and prevention of clostridium difficile infections. Am J Gastroenterolo. 2013 Apr;108(4):478-98; doi: 10.1038/ajg.2013.4
- Borody TJ, Leis S, Pang G, et al. Fecal microbiota transplantation in the treatment of recurrent clostridium difficile infection
- Brandt LJ, Aroniadis OC, Mellow M, et al.: Long-Term Follow-Up of Colonoscopic Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection. Am J Gastroenterol 2012; 107: 1079–87
- Mattila E, Uusitalo-Seppala R, Wuorela M, et al.: Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology 2012; 142: 490–6
- Allen-Vercoe E, Reid G, Viner N, Gloor GB, Hota S, Kim P, Lee C, O’Doherty K, Vanner SJ, Weese JS, et al. A Canadian Working Group report on fecal microbial therapy: microbial ecosystems therapeutics. Can J Gastroenterol. 2012;26:457–462.
- Kelly CR, et al. Update on fecal microbiota transplantation 2015: indications, methodologies, mechanisms and outlook. Gastroenterol 2015 May 15 [Epub ahead of print].
- Kelly CR, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol 2014 Jul;109(7):1065-71.
- Aroniadis OC, Brandt LJ, Greenberg A et al. Long-term Follow-up Study of Fecal Microbiota Transplantation for Severe and/or Complicated Clostridium difficile Infection: A Multicenter Experience. J Clin Gastroenterol. 2015 Jun 23.
- Borody TJ, Leis S, Pang G, Wettstein AR. Fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. UptoDate Inc., Waltham, MA
- Varier RU, et al. Cost-effectiveness analysis of fecal microbiota transplantation for recurrent Clostridium difficile infection. Infect Control Hosp Epidemiol 2015 Apr;36(4):438-44.
- Rossen NG, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterol 2015 Mar 30 [Epub ahead of print].
- Drekonja D, et al. Fecal microbiota transplantation for Clostridium difficile infection: A systematic review. Ann Intern Med 2015 May 5;162(9):630-8.
- Malani PN, Rao K. Expanded evidence for frozen fecal microbiota transplantation for clostridium difficile infection: A fresh take. JAMA. 2016;315(2):137-138.
- Almeida R, Gerbaba T, Petrof EO, et al. Recurrent Clostridium difficile infection and the microbiome. J Gastroenterol. 2016;51(1):1-10.
- Lee CH, Steiner T, Petrof EO, et al. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent clostridium difficile infection: A randomized clinical trial. JAMA. 2016;315(2):142-149.
- Kakihana K, Fujioka Y, Suda W, et al. Fecal microbiota transplantation for patients with steroid-resistant/dependent acute graft-versus-host disease of the gut. Blood. 2016 Jul 26 [Epub ahead of print]
- Fecal Microbiota Transplantation, FDA Emerging Clinical Issues (2016).
- Quraishi MN, Widlak M, Bhala N, et al. Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection. Aliment Pharmacol Ther. Sep 2017;46(5):479-493. PMID 28707337
- McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018; 66:e1
- Infectious Disease Society of America (ISDA). Fecal microbiota transplantation. Investigational new drug protocol. 2016. Accessed Jul 16, 2018.
- Infectious Disease Society of America (ISDA). Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Feb. 2018. Accessed Jul 16,2018.
- Mizuno, S, Masaoka, T, Naganuma, M, Kishimoto, T, Kitazawa, M, Kurokawa, S, Nakashima, M, Takeshita, K, et al. Bifidobacterium-Rich Fecal Donor May Be a Positive Predictor for Successful Fecal Microbiota Transplantation in Patients with Irritable Bowel Syndrome. Digestion. 2017;96(1):29-38. PubMed: 28628918 [PMID].
- Johnsen, PH, Hilpusch, F, Cavanagh, JP, Leikanger, IS, Kolstad, C, Valle, PC, and Goll, R. Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet Gastroenterol Hepatol. 2018;3(1):17-24. PubMed: 29100842 [PMID]
- ECRI Institute, Fecal Microbiota Transplantation for Treating Irritable Bowel Syndrome (Health Technology Assessment Information: Hotline Response) Aug. 2018.
- Kao, D., Roach, R., Silva, M., et al. Effect of oral capsule vs colonoscopy delivered fecal microbiota transplantation on recurrent clostridium difficile infection: A randomized clinical trial. JAMA. 2017;318(20):1985-1993. doi:10.1001/jama.2017.17077.
- Biehl LM, Cruz Aguilar R, Farowski F, et al. Fecal microbiota transplantation in a kidney transplant recipient with recurrent urinary tract infection. Infection. 2018 Aug 14
- Kang Y, Cai Y. Altered gut microbiota in HIV infection: Future perspective of fecal microbiota transplantation therapy. AIDS Res Hum Retroviruses. 2018 Jul 9
- Bulik-Sullivan EC, Roy S, Elliott RJ, et al. Intestinal microbial and metabolic alterations following successful fecal microbiota transplant for D-lactic acidosis. J Pediatr Gastroenterol Nutr. 2018 Jun 12
- Philips CA, Phadke N, Ganesan K, et al. Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis. Indian J Gastroenterol. 2018 Jun 21
- Ding C, Fan W, Gu L, et al. Outcomes and prognostic factors of fecal microbiota transplantation in patients with slow transit constipation: Results from a prospective study with long-term follow-up. Gastroenterol Rep (Oxf). 2018;6(2):101-107.
- Maharshak N, Ringel Y, Katibian D, et al. Fecal and mucosa-associated intestinal microbiota in patients with diarrhea-predominant irritable bowel syndrome. Dig Dis Sci. 2018;63(7):1890-1899.
- Nusbaum DJ, Sun F, Ren J, et al. Gut microbial and metabolomic profiles after fecal microbiota transplantation in pediatric ulcerative colitis patients. FEMS Microbiol Ecol. 2018;94(9).
- Xu D, Chen VL, Steiner CA, et al. Efficacy of fecal microbiota transplantation in irritable bowel syndrome: A systematic review and meta-analysis. Am J Gastroenterol. 2019;114(7):1043-1050.
- Ianiro G, Eusebi LH, Black CJ, et al. Systematic review with meta-analysis: efficacy of faecal microbiota transplantation for the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2019;50(3):240-248.
- Gutin L, Piceno Y, Fadrosh D, et al. Fecal microbiota transplant for Crohn disease: A study evaluating safety, efficacy, and microbiome profile. United European Gastroenterol J. 2019;7(6):807-814.
- Sun J, Xu J, Ling Y, et al. Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice. Transl Psychiatry. 2019;9(1):189.
- Huang H, Xu H, Luo Q, et al. Fecal microbiota transplantation to treat Parkinson's disease with constipation: A case report. Medicine (Baltimore). 2019;98(26):e16163.
- Kaako A, Al-Amer M, Abdeen Y. Bezlotoxumab use as adjunctive therapy with the third fecal microbiota transplant in refractory recurrent Clostridium difficile colitis; a case report and concise literature review. Anaerobe. 2019 ;55:112-116.
- Singh S, et al. AGA technical review on the management of mild-to-moderate ulcerative colitis. Gastroenterology 2019 Feb;156(3):769-808.e29.
- Aldrich AM, Argo T, Koehler TJ, et al. Analysis of treatment outcomes for recurrent Clostridium difficile infections and fecal microbiota transplantation in a pediatric hospital. Pediatr Infect Dis J. 2019;38(1):32-36
- Canadian Agency for Drugs and Technologies in Health. Lyophilized Versus Frozen Fecal Microbiota Transplant for Recurrent Clostridium Difficile Infection, Inflammatory Bowel Disease, and Irritable Bowel Syndrome: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines. 2019.
- ECRI Institute. Fecal Microbiota Transplantation for Treating Irritable Bowel Syndrome. Plymouth Meeting (PA): ECRI Institute; 2020 Jul 01. (Custom Rapid Responses).
- Food and Drug Administration (FDA). Fecal Microbiota Transplantation: Safety Communication - Risk of Serious Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms. 2019;
- Tariq R, Pardi DS, Bartlett MG et al. Low Cure Rates in Controlled Trials of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection: A Systematic Review and Metaanalysis. Clin. Infect. Dis., 2019 Apr 9;68(8). PMID 30957161
- Lee CH, Chai J, Hammond K et al. Long-term durability and safety of fecal microbiota transplantation for recurrent or refractory Clostridioides difficile infection with or without antibiotic exposure. Eur. J. Clin. Microbiol. Infect. Dis., 2019 Jun 6;38(9). PMID 31165961
- Zhou HY, Guo B, Lufumpa E, et al. Comparative of the Effectiveness and Safety of Biological Agents, Tofacitinib, and Fecal Microbiota Transplantation in Ulcerative Colitis: Systematic Review and Network Meta-Analysis. Immunol Invest. Feb 02 2020: 1-15. PMID 32009472
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