I. Disclaimer

This document is intended to be used as a reference for non-VA providers and not intended to replace clinical judgment when determining care pathways. These guidelines do not guarantee benefits or constitute medical advice. 

II. Clinical Determinations and Indications

1. Indications for Fecal Microbiota Products for Clostridioides difficile Infections   
2. Fecal microbiota products (stool-derived products) are indicated for the prevention of recurrence of Clostridioides difficile infection (CDI), following successful antibiotic treatment for recurrent CDI (rCDI). These products may be considered medically necessary/covered when ALL the following criteria are met: 
   • Clostridioides difficile infection is confirmed by a positive stool test for toxigenic Clostridioides difficile (C. difficile) and presence of greater than or equal to three unformed stools within 24 hours for at least 48 hours consecutively; ideally with a test detecting actual toxin, not just a polymerase chain reaction (PCR) test 
   • Veteran has experienced at least two recurrences of CDI within eight weeks of completion of standard antibiotic treatment 
     • (i.e., Fidaxomicin, Vancomycin) 
   • Veteran has been treated with standard antibiotics for the current episode of CDI with symptom resolution 
     • (e.g., clinical symptoms of C. difficile such as diarrhea have resolved with standard antibiotic treatment) 
   • At least one episode of CDI was treated with Fidaxomicin, unless not tolerated or contraindicated 
   • VA only approves the use of Food & Drug Administration (FDA) approved stool-derived products 
3. Note: This document is in alignment with the VA National Formulary. Please visit the VA Formulary Advisor to access VA Pharmacy Benefits Management Services’ resources and additional information on clinical criteria. 
   • Criteria for Use: REBYOTA and VOWST 

2. Limitations/Exclusions
3. VA only allows administration of FDA approved stool-derived products. All other stool-derived products for prevention of rCDI not listed in section II.a. are considered not medically necessary and not covered. 

REBYOTA is not indicated and therefore considered not medically necessary and not covered if any of the following are applicable: 

• History of severe allergic reactions to any components of REBYOTA 
  • e.g., polyethylene glycol in REBYOTA 
• History of severe food allergies 
• REBYOTA should be avoided in Veterans who are severely immunocompromised 
• Veteran is likely to require antibiotic therapy for a condition other than CDI   
• Veteran has planned surgery requiring perioperative antibiotics within eight weeks after treatment 

VOWST is not indicated and therefore considered not medically necessary and not covered if any of the following are applicable: 

• History of severe allergic reactions to any components of VOWST 
  • e.g., glycerol in VOWST 
• History of severe food allergies 
• VOWST should be avoided in Veterans with an absolute neutrophil count less than 500 cells/mm3 
• Veteran is likely to require antibiotic therapy for a condition other than CDI  
• Veteran has planned surgery requiring perioperative antibiotics within eight weeks after treatment

REBYOTA and VOWST are not indicated for the treatment of CDI. Use of fecal microbiota products for other conditions is considered investigational and experimental including but not limited to the following: 

• Asymptomatic C. difficile colonization 
• Ulcerative colitis 
• Crohn’s disease 
• Irritable bowel syndrome 
• Celiac disease 
• Cirrhosis 
• Obesity 
• Food allergies

For all other conditions or indications not listed in section II.a. of this document, fecal microbiota products such as REBYOTA and VOWST are considered not medically necessary and not covered due to insufficient evidence of efficacy and safety. 

3. Description of Treatment
4. The FDA approved the use of two stool-derived products, REBYOTA and VOWST for the prevention of rCDI. These stool-derived products should be considered after the patient has experienced at least two recurrences of CDI recurring within eight weeks of completion of standard antibiotic treatment which includes Fidaxomicin and/or Vancomycin. 

REBYOTA is a microbiome-based treatment used to prevent rCDI. It is administered 24-72 hours after the last dose of CDI-specific antibiotic therapy. REBYOTA is a single-dose treatment administered rectally. Before administration, patients should be asked to empty their bladder and bowels if possible. The patient should be positioned lying on their left side with right knee bent and arms resting comfortably. The lubricated administration tube is gently inserted approximately five inches into the rectum, aimed slightly toward the navel. The bag is slowly raised to allow REBYOTA to gradually flow with gravity. Once the entire bag has been delivered, the pinch clamp is closed and the tube is slowly withdrawn, keeping the patient in the left-sided position for 15 minutes. Once completed, patients can move freely with no restrictions on using the restroom. The most common adverse reactions reported were abdominal pain, diarrhea, abdominal distention, flatulence, and nausea. 

VOWST is also a microbiome-based treatment used to prevent rCDI. It is administered 48-96 hours after the last dose of CDI-specific antibiotic therapy. Eight hours prior to the first dose of VOWST, patients are instructed to drink 10 oz of magnesium citrate and not to eat or drink anything within the eight hours. In clinical studies, 250 mL of polyethylene glycol electrolyte solution was administered instead of the magnesium citrate for participants with impaired renal function. VOWST is administered orally as four capsules taken daily for three consecutive days. Each dose should be taken on an empty stomach, prior to the first meal of the day. The most common adverse reactions reported were abdominal distention, fatigue, constipation, chills, and diarrhea. 

III. Background and Supporting Information

The following information is for reference purposes only in accordance with the medical benefits package outlined in 38 C.F.R. § 17.38 (b). Each subsection supports VA’s determinations for medical necessity and alignment with generally accepted standards of medical practice. 

1. Background Information
   Clostridioides difficile Infection 

The human intestinal tract contains trillions of bacteria and microorganisms, commonly referred to as the normal “gut microbiota.” Clostridioides difficile (C. difficile) is a bacterium that can be found widely in the environment and transiently in the digestive system of about 2-5% of healthy adults. In some instances (e.g., while or after taking antibiotics to treat infections), the native microbiota is disrupted and the normal balance of the gut microbiota is altered, and if C. difficile is ingested or present in the gut it can multiply and dominate. Elevated amounts of C. difficile in the gut leads to the production of toxins, causing diarrhea, abdominal pain, and fevers. Severe cases can result in organ failure and even death. 

Certain antibiotics have greater risk for C. difficile infection (CDI), including Clindamycin, cephalosporins, and quinolones (e.g., Ciprofloxacin, Levofloxacin). Other risk factors for CDI include antibiotic use in the last 30 days, patients with a weakened immune system or a previous history of CDI, hospitalized patients, those living in a long-term care facility or nursing home, and patients over the age of 65 are at an increased risk of contracting C. difficile. 

Clostridioides difficile infection is suspected in at-risk patients with new and unexplained unformed or watery, and sometimes foul-smelling diarrhea, occurring more than three times per day. The diagnosis for CDI is confirmed through stool testing. Clostridioides difficile infections are highly contagious for susceptible patients who have had their gut microbiota compromised by antibiotics. Adequate hygiene practices and precautions help minimize bacterial spread, including hand washing with soap and water, use of personal protective equipment with proper disposal, and the use of cleaning agents specifically for C. difficile. 

Approximately 25% of people treated for CDI will have a recurrent infection. The reason may be that the first infection was resolved clinically but the C. difficile organism was never completely eradicated, or that the patient acquired a new CDI. The risk of further recurrence increases with each recurrent CDI (rCDI). After three or more recurrent infections the risk of another recurrence is greater than 50%. 

Management and Treatments 

Treatment regimens for CDI are based on their severity. Oral antibiotics such as Fidaxomicin or Vancomycin are considered appropriate treatment regimens to treat most CDIs. Severe complicated cases of CDI, also termed fulminant C. difficile infection, may also require surgical removal of the colon due to toxic mega colon. When patients experience two or more recurrences of CDI, stool-derived products, REBYOTA and VOWST, are administered after antibiotics have resolved the symptoms of the infection (e.g., diarrhea). 

REBYOTA 

REBYOTA was approved by the Food & Drug Administration (FDA) in November 2022 for the prevention of rCDIs. It is prepared from stool donated by qualified individuals. All donated stool is tested for a panel of transmissible pathogens. Because REBYOTA is made from human stool, it may contain food allergens. The potential for REBYOTA to cause an adverse food reaction is currently unknown. 

VOWST 

VOWST is the first orally administered fecal microbiota-based product approved by the FDA in 2023 for the prevention of rCDI. It is prepared from stool donated by qualified individuals and contains live bacterial spores from multiple species. All donated stool is tested for a panel of transmissible pathogens. Because VOWST is made from human stool it may contain food allergens. The potential for VOWST to cause an adverse food reaction is currently unknown. 

2. Research, Clinical Trials, and Evidence Summaries
   Randomized controlled trials (RCTs) have shown stool-derived products to be efficacious in preventing rCDI. The following outlines clinical research on available FDA-approved treatment options for the prevention of rCDI.

REBYOTA, a therapy developed by Ferring Pharmaceuticals, was the first FDA-approved, single-dose, microbiota-based live biotherapeutic product for the prevention of rCDI in adults. This approval was based on the study published by Khanna et al. (2022). This randomized, double-blind, placebo-controlled, phase III study evaluated the effects of RBX2660, trade name: REBYOTA, on treatment success or reducing recurrence of CDI. The study included patients from the phase II trial PUNCH CD2 in agreement with the FDA due to accrual issues. Patients with a positive stool assay for C. difficile and who were previously treated with standard-of-care antibiotics were randomly assigned to receive a subsequent blinded, single-dose enema of RBX2660 (n = 180) or placebo (n = 87). The study found CDI treatment success rates of 70.4% with RBX2660 versus 58.1% with placebo. Treatment success was defined as the absence of CDI diarrhea within eight weeks of study treatment. This study found that RBX2660 is a safe and effective treatment to treat rCDI following standard-of-care antibiotics, with a sustained response through six months. 

Lee et al. (2023) published an integrated safety analysis, providing cumulative safety data from five prospective clinical trials (three phase II trials and two phase III trials) evaluating REBYOTA for preventing rCDI in adults. Among the five trials, 978 study participants received at least one dose of REBYOTA and 83 participants received placebo only. Treatment-emergent adverse events (TEAEs), as defined by an adverse event occurring on or after the day of first treatment, coded using the Medical Dictionary for Regulatory Activities (MedDRA), were reported in 60.2% of placebo participants and 66.4% of REBYOTA participants. Most participants experienced mild or moderate TEAEs, including diarrhea, abdominal pain, and nausea, but were most frequently related to pre-existing conditions. Importantly, there were no reported infections for which the causative pathogen was traced to REBYOTA. This integrated safety analysis demonstrates that REBYOTA is a safe and well-tolerated treatment for patients with rCDI. 

Blount et al. (2025) reported results from a large phase III randomized, placebo-controlled trial evaluating REBYOTA (fecal microbiota, live-jslm) for preventing rCDI after antibiotic treatment. Patients received a single rectal dose of either REBYOTA or the placebo. Those treated with REBYOTA showed better outcomes, including healthier gut bacteria and improved bile acid balance which were key factors in reducing infection risk. These changes were stronger and lasted longer in the REBYOTA group compared to the placebo. The authors conclude that REBYOTA effectively restores gut health and lowers recurrence risk and recommend it as an FDA-approved, standardized therapy for this condition. 

VOWST, a treatment developed by the biotech company Seres Therapeutics, is an orally administered fecal microbiota product designated for the prevention of rCDI. VOWST received FDA approval based on a phase III development program, including the ECOSPOR III and ECOSPOR IV clinical trials. 

ECOSPOR III, published by Feuerstadt et al. (2022), was a multi-center, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of a CDI received either VOWST (n = 89) or placebo (n = 93) for three consecutive days after standard-of-care antibiotic treatment. The study found a statistically significant difference in reduction of rCDI at eight weeks, with 12% of VOWST participants experiencing a rCDI, compared to 40% in the placebo group. Further, at six months post-treatment, 79% of VOWST participants were recurrence-free, compared to 53% in the placebo group. Most adverse events were mild to moderate, with similar numbers between the two groups. The trial concluded that VOWST is superior to placebo in reducing the risk of rCDI. 

ECOSPOR IV, authored by Sims et al. (2023), was an open-label, multi-center, single-arm trial conducted to evaluate the safety and rate of rCDI after administration of VOWST through 24 weeks. The trial included 263 participants and found overall low rates of rCDI, consistent with the ECOSPOR III trial rates. Further, no TEAEs led to study withdrawal, as the majority were mild to moderate, including diarrhea, flatulence, and nausea, and resolved without sequelae. This clinical trial reinforced the notion that VOWST is well tolerated in a patient population with rCDI. 

Yu et al. (2025) conducted a comprehensive review of capsule-based fecal microbiota transplantation (cFMT) as a noninvasive alternative to traditional fecal microbiota transplantation for treating gut dysbiosis-related conditions. Clinical trials show cFMT is effective for rCDI, reducing recurrence rates from 31.6% to 12.5% at eight weeks and maintaining benefits for 24 weeks. Included studies also report improvements in gut microbial diversity and symptom relief. FDA approval of VOWST, the first oral microbiome therapy, underscores the growing acceptance of cFMT as a standardized treatment option. The authors conclude that cFMT offers comparable efficacy to colonoscopic fecal microbiota transplantation with better patient compliance and safety, recommending its use as a promising, scalable therapy while emphasizing the need for standardized protocols and long-term safety data. 

3. U.S. Food & Drug Administration Information
   REBYOTA and VOWST have received Biologics License Application (BLA) approval by the Food & Drug Administration (FDA) for the prevention of recurrence of Clostridioides difficile infection. 

To search for more FDA-approved and licensed biological products, including licensed biosimilar and interchangeable products, regulated by the Center for Drug Evaluation and Research (CDER), please visit the FDA-licensed (approved) Biological Products Database. 

4. Medicare Coverage Determinations
5. There are no available Medicare coverage determinations. VA and Medicare are governed by separate laws and regulations; thus, VA coverage determinations may be different.

5. Health Care Procedural Coding Information 
6. The following CPT^®/HCPCS codes listed in this section are provided for informational purposes only. Inclusion or exclusion of a code does not constitute or imply VA coverage or provider reimbursement. The list of codes may not be all-inclusive since the American Medical Association (AMA) and Centers for Medicare & Medicaid Services (CMS) code updates may occur more frequently than CDI updates. Please refer to section II.a. in this document to review indications and clinical criteria for medical necessity. 

The following CPT/HCPCS codes may be considered medically necessary/covered if the indications and clinical criteria outlined in section II.a. are met. Additional codes may also apply. 

CPT/HCPCS Code	Description
0780T	Instillation of fecal microbiota suspension via rectal enema into lower gastrointestinal tract
87493	Infectious agent detection by nucleic acid (DNA or RNA); Clostridioides difficile, toxin gene(s), amplified probe technique
J1440	Fecal microbiota, live- jslm, 1 ml

CPT copyright ^© 2026 American Medical Association. All rights reserved.

IV. Definitions

Term	Definition
Clostridioides difficile	A bacterium commonly found in the normal gut flora of the human intestine that may cause diarrhea and more serious intestinal conditions, such as colitis
Colitis	Inflammation of the large intestine (colon)
Colonoscopy	A procedure using a video camera called a colonoscope to view the colon and rectum
Distention	Enlarged or swollen from internal pressure
Dysbiosis	A clinical condition marked by altered gut microbiota and the disruption in the natural interaction of microorganisms resulting from external and internal host factors
Ileus (Paralytic ileus)	The inability of the intestine to contract normally and move contents to the intestinal tract
Microbiome	The microorganisms in a particular environment in the body or a part of the body
Sequelae	A condition which is the consequence of a previous disease or injury

V. References

Blount, K. F., Papazyan, R., Ferdyan, N., Srinivasan, K., Gonzalez, C., Shannon, W. D., & Fuchs, B. C. (2025). Microbiome and Metabolome Restoration After Administration of Fecal Microbiota, Live-jslm (REBYOTA) for Preventing Recurrent Clostridioides difficile Infection. The Journal of infectious diseases, 231(6), e1022–e1033.

Drekonja, D. M., Shaukat, A., Huang, Y., Zhang, J. H., Reinink, A. R., Nugent, S., Dominitz, J. A., Davis-Karim, A., Gerding, D. N., & Kyriakides, T. C. (2025). A Randomized Controlled Trial of Efficacy and Safety of Fecal Microbiota Transplant for Preventing Recurrent Clostridioides difficile Infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 80(1), 52–60.

Feuerstadt, P., Louie, T. J., Lashner, B., Wang, E. E. L., Diao, L., Bryant, J. A., Sims, M., Kraft, C. S., Cohen, S. H., Berenson, C. S., Korman, L. Y., Ford, C. B., Litcofsky, K. D., Lombardo, M. J., Wortman, J. R., Wu, H., Auniņš, J. G., McChalicher, C. W. J., Winkler, J. A., McGovern, B. H., Trucksis, M., Henn, M. R., & von Moltke, L. (2022). SER-109, an oral microbiome therapy for recurrent clostridioides difficile infection. The New England Journal of Medicine, 386(3), 220–229.

Johnson, S., Lavergne, V., Skinner, A. M., Gonzales-Luna, A. J., Garey, K. W., Kelly, C. P., & Wilcox, M. H. (2021). Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America, 73(5), e1029–e1044.

Kelly, C. R., Fischer, M., Allegretti, J. R., LaPlante, K., Stewart, D. B., Limketkai, B. N., & Stollman, N. H. (2021). ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. The American journal of gastroenterology, 116(6), 1124–1147.

Khanna, S., Assi, M., Lee, C., Yoho, D., Louie, T., Knapple, W., Aguilar, H., Garcia-Diaz, J., Wang, G. P., Berry, S. M., Marion, J., Su, X., Braun, T., Bancke, L., & Feuerstadt, P. (2022). Efficacy and safety of RBX2660 in PUNCH CD3, a phase III, randomized, double-blind, placebo-controlled trial with a bayesian primary analysis for the prevention of recurrent clostridioides difficile infection. Drugs, 82(15), 1527–1538.

Lee, C., Louie, T., Bancke, L., Guthmueller, B., Harvey, A., Feuerstadt, P., Khanna, S., Orenstein, R., & Dubberke, E. R. (2023). Safety of fecal microbiota, live-jslm (REBYOTA™) in individuals with recurrent Clostridioides difficile infection: data from five prospective clinical trials. Therapeutic Advances in Gastroenterology, 16.

Reed, C. (2020). AGA releases largest real-world report on safety and effectiveness of fecal microbiota transplantation (FMT). American Gastroenterological Association.

Shaukat, A., Drekonja, D. M., Huang, Y., Zhang, J. H., Davis-Karim, A., & Kyriakides, T. C. (2025). Efficacy and Safety of Fecal Microbiota Transplant for Prevention of Recurrent Clostridioides difficile Infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 81(3), e63–e65.

Sims, M. D., Khanna, S., Feuerstadt, P., Louie, T. J., Kelly, C. R., Huang, E. S., Hohmann, E. L., Wang, E. E. L., Oneto, C., Cohen, S. H., Berenson, C. S., Korman, L., Lee, C., Lashner, B., Kraft, C. S., Ramesh, M., Silverman, M., Pardi, D. S., De, A., Memisoglu, A., Lombardi, D. A., Hasson, B. R., McGovern, B. H., von Moltke, L., & ECOSPOR IV Investigators. (2023). Safety and tolerability of SER-109 as an investigational microbiome therapeutic in adults with recurrent clostridioides difficile infection: A phase 3, open-label, single-arm trial. JAMA Network Open, 6(2), e2255758.

U.S. Food & Drug Administration. (2023, April 26). FDA Approves First Orally Administered Fecal Microbiota Product for the Prevention of Recurrence of Clostridioides difficile Infection. U. S. Food & Drug Administration. Retrieved September 28, 2023.

U.S. Food & Drug Administration Purple Book Database of Licensed Biological Products. (n.d.). Retrieved July 1, 2023.

VA Formulary advisor. (n.d.).

Wang, J.-W., Kuo, C.-H., Kuo, F.-C., Wang, Y.-K., Hsu, W.-H., Yu, F.-J., Hu, H.-M., Hsu, P.-I., Wang, J.-Y., & Wu, D.-C. (2019). Fecal microbiota transplantation: Review and update. Journal of the Formosan Medical Association, 118(1), S23–S31.

Yu, H., Zhang, Y., Yang, D., Luo, H., & Zhou, Y. (2025). Advances in capsule-based fecal microbiota transplantation: clinical applications and innovations. Journal of translational medicine, 23(1), 1370.

VI. CDI History/Revision Information

Date	Summary of Updates
08/01/2026	Updated indications and clinical criteria for Fecal Microbiota Products for Clostridioides difficile Infections Removed the following clinical criteria “Received at least one trial of bezlotoxumab with or after standard C. difficile treatment, unless not tolerated, contraindicated or not practical due to setting” Updated limitations/exclusions criteria for Fecal Microbiota Products for Clostridioides difficile Infections Reorganized and categorized based on the two products, REBYOTA and VOWST Added additional exclusionary criteria for REBYOTA “Veteran is likely to require antibiotic therapy for a condition other than CDI” “Veteran has planned surgery requiring perioperative antibiotics within eight weeks after treatment” Added additional exclusionary criteria for VOWST “Veteran is likely to require antibiotic therapy for a condition other than CDI” “Veteran has planned surgery requiring perioperative antibiotics within eight weeks after treatment” Added “Health Care Procedural Coding Information” section Updated “Research, Clinical Trials, and Evidence Summaries” section Added evidence summaries by Blount et al., 2025, and Yu et al., 2025 Updated “Definitions” section Updated definition of colitis Added dysbiosis Updated “References” section Added Blount et al., 2025 and Yu et al., 2025
10/01/2024	New CDI created describing medically necessary indications / not medically necessary indications

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