Medical Policy

Fecal Microbiota Transplant

Policy MP-062
Origination Date: 09/10/2020
Reviewed/Revised Date: 07/17/2024
Next Review Date: 07/17/2025
Current Effective Date: 07/17/2024

Disclaimer:
1. Policies are subject to change in accordance with State and Federal notice requirements.
2. Policies outline coverage determinations for U of U Health Plans Commercial, CHIP and
Healthy U (Medicaid) plans. Refer to the “Policy” section for more information.
3. Services requiring prior-authorization may not be covered, if prior-authorization is not
obtained.
4. This Medical Policy does not guarantee coverage or payment of the service. The service
must be a benefit in the member’s plan and the member must be eligible for coverage at
the time of service. Additional payment guidelines may be applied that are not included in
this policy.

Description:
Clostridium difficile infection (CDI), is a Gram-positive, spore-forming bacterium usually spread
by the fecal-oral route. Patients with recurrent CDI have been observed to have reduced
diversity of the intestinal microbiome and diminished numbers of bacteria relative to healthy
individuals that can cause disease asymptomatic carriage, mild diarrhea, colitis, or
pseudomembranous colitis.
According to the American Journal of Gastroenterology (AJG) Clostridium difficile infection is a
leading cause of hospital-associated gastrointestinal illness. Patients typically have extended
lengths-of-stay and CDI is a frequent cause of large hospital outbreaks of disease.
Fecal microbiota transplant (FMT) is the term used when stool is taken from a healthy
individual and instilled into a sick person with certain conditions, such as recurrent CDI. Studies
show that patients with recalcitrant CDI have abnormally proportioned colon microbiota and
that reintroduction of normal bacteria via donor feces corrects this imbalance and breaks the
cycle of CDI recurrence. The purpose of FMT treatment is based on the premise that an
imbalance in the community of microorganisms residing in the gastrointestinal (GI) tract is
associated with specific disease states, including susceptibility to infection. In its healthy state,
intestinal microbiota performs a variety of useful functions including aiding in the digestion of
carbohydrates, repressing the growth of pathogenic microbes, mediating the synthesis of
certain vitamins, and stimulating the lymphoid tissue to produce antibodies to pathogens.
FMT may be administered by oral capsules, colonoscopy, retention enema, or through a
nasojejunal (NJ)/nasoduodenal (ND) tube in the upper GI tract. The choice of the delivery route
depends in part on patient preferences, individual risk, cost, availability of resources and
expertise.

Policy Statement and Criteria

1. Commercial Plans/CHIP
U of U Health Plans considers fecal microbiota transplantation including capsulized,
frozen and suspension (via rectal enema), medically necessary for treatment of patients
with recurrent Clostridium difficile infection when the following criteria are met:
For Mild Disease:
A. At least 3 episodes of recurrent mild to moderate CDI* and failure of a 6-8 week
taper with vancomycin with or without an alternative antibiotic (e.g., rifaximin,
nitazoxanide, metronidazole, vancomycin); and
B. Persistent positive stool C. difficile toxin by testing

For Moderate to Severe Disease:

A. Persistent positive stool C. difficile toxin by testing and
B. At least one of the following:
i. Moderate CDI not responding to standard therapy (vancomycin) for at least a
10 days.
ii. At least two episodes of recurrent severe CDI# resulting in hospitalization and
associated significant morbidity, including renal failure.

For Fulminant Disease:

A. Severe fulminant C. difficile colitis with no response to standard therapy after 48
hours.

*Patients with moderate clinical disease have frequent loose, bloody stools (>4 per day), mild anemia not
requiring blood transfusions, and abdominal pain that is not severe. Patients have minimal signs of systemic
toxicity, including a low-grade fever. Adequate nutrition is usually maintained, and weight loss is not
associated with moderate clinical disease.
#
Patients with a severe clinical presentation typically have frequent loose, bloody stools (≥6 per day) with
severe cramps and evidence of systemic toxicity as demonstrated by a fever (temperature ≥37.5°C),
tachycardia (HR ≥90 beats/minute), anemia (hemoglobin <10.5 g/dL), or an elevated ESR (≥30 mm/hour).
Patients may have rapid weight loss.

U of U Health Plans considers fecal microbiota transplantation investigational/

experimental in all other circumstances.
 U of U Health Plans does NOT cover Rebyota™ suspension as current evidence is
insufficient to show superiority to standard fecal microbiota preparations.

2. Medicaid Plans
Coverage is determined by the State of Utah Medicaid program; if Utah State Medicaid
has no published coverage position and InterQual criteria are not available, the U of U
Health Plans Commercial criteria will apply. For the most up-to-date Medicaid policies
and coverage, please visit their website at: https://medicaid.utah.gov/utah-medicaid-
official-publications/ or the Utah Medicaid code Look-Up tool

CPT/HCPCS codes covered by Utah State Medicaid may still require further evaluation
to determine medical necessity for coverage.

Clinical Rationale
A 2017 systematic review (Quraishi et al) investigated the effect of FMT in patients with recurrent or
refractory CDI. In the pooled analysis, 92% of patients had a resolution of CDI (95% CI, 89% to 94%);
heterogeneity was classified as likely moderate (I 2=59%). Additionally, in the 7 trials that evaluated
FMT, the intervention overall was associated with an increase in the resolution of recurrent and
refractory CDI (relative risk, 0.23; 95% CI, 0.07 to 0.80). The 30 case series reported resolution rates for
CDI ranged from 68% to 100%. The reviewers considered the RCTs as having a low risk of bias for
adequate randomization with allocation concealment and intention-to-treat analysis. Nor did they
report an assessment of bias in terms of blinding, sample size adequacy, or possible differences in
baseline characteristics. However, they disputed that none of the trials demonstrated the efficacy of
FMT as being truly placebo-controlled, and the case series followed patients until resolution of CDI (10
weeks to 8 years), though some had an insufficient follow-up.
In another 2018 meta-analysis (Khan et al.) researched the literature of pooled data on the use of FMT
as a treatment option for recurrent CDI. Reviewers only selected randomized controlled trials that
compared FMT (fresh or frozen) with medical treatment. Among the selected studies, there was a non-
significant trend toward the resolution of diarrhea following a single fresh FMT infusion compared with
frozen FMT or medical treatment (odds ratio, 2.45; 95% CI, 0.78 to 7.71; p=0.12, I 2=69%), but different
forms and routes of FMT administration were shown to be equally efficacious. In conclusion, FMT is a
promising treatment modality for recurrent CDI. However, the authors found limited data for the
variability of FMT dose usages, small trial populations and time frames to assess the success or failure of
treatment.
In 2019, a third meta-analysis (Tariq et al) evaluated the efficacy of FMT as a treatment option for
recurrent CDI on the basis of results from open-label studies and placebo controlled clinical trials. The
authors wanted to investigate their observations on FMT cure rates for CDI being high in observational
studies (e.g., >90%) but then appear to be consistently lower in open-label studies and clinical trials.
Thirteen studies were included for evaluation, including six placebo-controlled RCTs and seven open-
label studies. Out of 610 patients receiving FMT, 439 patients achieved clinical cure (76.1%; 95%
confidence interval [CI]: 66.4% to 85.7%); study heterogeneity was significant (I 2 =91.35%). Cure rates
were found to be lower in randomized trials (139/216, 67.7%; 95% CI: 54.2% to 81.3%) vs open-label
studies (300/394, 82.7%; 95% CI: 71.1% to 94.3%; p < 0.001). Subgroup meta-analysis by FMT route of
administration indicated lower cure rates with enema than colonoscopy (66.3% vs 87.4%; p < 0.001).
However, no differences between colonoscopy and oral delivery were detected (87.4% to 81.4%; p=
0.17). Lower cure rates were observed for studies that included both recurrent and refractory CDI than
those that only included patients with recurrent CDI (63.9% vs 79%; p < 0.001). The authors concluded
that colonoscopy and oral route are more effective than enema for stool delivery and the efficacy seems
to be higher for recurrent than for refractory CDI.
A recent UpToDate (2020) review summarizes FMT as an effective treatment for recurrent (≥3
recurrences) CDI. The authors concluded that transplantation of stool microbiota from healthy
individuals to patients with recurrent CDI can break the cycle of CDI recurrence. In addition, the initial
results from the FMT National Registry published in Gastroenterology 2021 showed a 1 month cure rate
of over 90% in 200 patients who received just 1 FMT. At a 6 month follow-up, only 4% of patient had a
recurrence of CDI and less than 1% had a complication of treatment includes IBS or newly diagnosed
IBD. However, to minimize risk of infection, rigorous screening of potential healthy stool donors for
occult pathogens must be done. The optimal approach for administration is uncertain. If feasible oral
capsules should be tried first, then colonoscopy followed by enema retention and finally NJ or ND tube
for patients who cannot undergo FMT via the alternate routes.
In 2022, Hayes completed a health technology assessment of fecal microbiota transplantation for the
treatment of Crohn Disease (CD). The assessment determined that “A very low-quality body of evidence
is insufficient to draw conclusions regarding the efficacy of FMT to help patients with CD achieve or
maintain remission, but it does suggest that the procedure is safe in this population. A single
comparative study evaluated FMT versus placebo transplant, which found no statistically significant
benefit in efficacy with FMT. No other active- or sham-controlled trials were identified. The other 2
comparative studies in this evidence base lacked appropriate comparator or control groups and
evaluated variations in FMT administration approaches and timing of treatment. Pretest-posttest
studies found some improvements from baseline in efficacy outcomes. Substantial uncertainty remains
regarding the extent of the benefits, which patients might benefit from the treatment, optimal
treatment parameters, and whether there is long-term benefit.” In a 2024 annual review of abstracts for
this report, Hayes only found 1 newly published (2022) retrospective cohort study which met the
inclusion criteria. However, there was no new evidence with longer-term follow-up and no new
applications of the technology since publication of the2022 Health Technology Assessment
In 2016, the U.S. Food and Drug Administration (FDA) issued an updated draft guidance on enforcement
policy regarding investigational new drug requirements for use of FMT to treat CDI not responsive to
standard therapies. The draft guidance is similar to the 2013 guidance and states that the FDA is
continuing to consider how to regulate FMT and that, during this interim period, the agency will use
enforcement discretion regarding the use of fecal transplant to treat treatment-resistant CDI. The FDA
requires that physicians obtain adequate informed consent from patients or their legal representative
before performing the intervention. The document also stated that selective enforcement does not
apply to the use of fecal transplant for treating conditions other than treatment-resistant CDI.
In 2019, the FDA issued a safety regarding the use of FMT due to the potential risk of serious adverse
reactions or life-threatening infections caused by due to 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 beta-lactamase-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 (ESBL)-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:
 1) Donor screening that specifically addresses risk factors for colonization with MDROs and
exclusion of individuals at higher risk of colonization with MDROs such as 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.
2) MDRO testing of donor stool and exclusion of stool testing positive for MDROs. At the minimum,
tests should include: extended-spectrum beta-lactamase-producing enterobacteriaceae,
vancomycin-resistant enterococci, carbapenem-resistant enterobacteriaceae and methicillin-
resistant Staphylococcus aureus.
3) 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.
4) 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.
Lastly, the American College of Gastroenterology (2021) published guidelines on diagnosis, treatment,
and prevention of CDI. The guidelines addressed fecal microbiota transplant for treatment of three or
more CDI recurrences, as follows: "For the treatment of one to two CDI recurrences, the guidelines
recommend: tapering/pulsed-dose vancomycin for patients experiencing a first recurrence after an
initial course of fidaxomicin, vancomycin, or metronidazole (strong recommendation, very low quality of
evidence). In addition, Fidaxomicin for patients experiencing a first recurrence after an initial course of
vancomycin or metronidazole. FMT be considered for patients with severe and fulminant CDI refractory
to antibiotic therapy, in particular, when patients are deemed poor surgical candidates." In addition,
fecal transplant is now recommended to be an important treatment consideration for refractory
antibiotic resistant CDI for patients who have underlying ulcerative colitis (UC) given the risk of
exacerbation of the patient's underlying UC and the risk of complications from fulminant CDI in this
particular patient population.
The Infectious Diseases Society of America and Society for Healthcare Epidemiology of America updated
their clinical practice guidelines in 2018 for the diagnosis and treatment of CDI in children and adults.
For pediatric patients fecal microbiota transplantation may be used after multiple recurrences of CDI
following standard antibiotic treatments, this is considered a weak recommendation with very low
quality of evidence. In adult patients, fecal microbiota transplantation is strongly recommended for
patients with multiple recurrences of CDI who have failed appropriate antibiotic treatments as there is
moderate quality of evidence.
No recommendations were found from the U.S. Preventive Services Task Force.

Applicable Coding
CPT Codes
0780T Instillation of fecal microbiota suspension via rectal enema into lower
gastrointestinal tract
44705 Preparation of fecal microbiota for instillation, including assessment of donor
specimen
HCPCS Codes
G0455 Preparation with instillation of fecal microbiota by any method, including
assessment of donor specimen
Not covered:
J1440 Fecal microbiota, live - jslm, 1 ml

ICD-10 Codes
A04.7 Enterocolitis due to Clostridium difficile
A04.71 Enterocolitis due to Clostridium difficile, recurrent
A04.72 Enterocolitis due to Clostridium difficile, not specified as recurrent

References:
1. American Journal of Gastroenterology (AJG). (April, 2013). “Guidelines for Diagnosis, Treatment, and Prevention of
Clostridium difficile Infections” American Journal of Gastroenterology: April 2013 - Volume 108 - Issue 4 - p 478-498 doi:
10.1038/ajg.2013.4. Accessed September 18, 2020. Available at:
https://journals.lww.com/ajg/Fulltext/2013/04000/Guidelines_for_Diagnosis,_Treatment,_and.6.aspx#pdf-link
2. American Society of Colon and Rectal Surgeons (2015). Clinical Practice Guidelines. “Practice Parameters for the
Management of Clostridium difficile Infection”. Accessed September 18, 2020. Available at:
https://fascrs.org/ascrs/media/files/downloads/Clinical%20Practice%20Guidelines/practice_parameter_clostridium_difficile
_infection.pdf
3. Aroniadis, O.C., Brandt, L.J., Oneto, C., Feuerstadt, P., Sherman, A., Wolkoff, A.W., Kassam, Z., Sadovsky, R.G., Elliott, R.J.,
Budree, S. and Kim, M., 2019. Faecal microbiota transplantation for diarrhoea-predominant irritable bowel syndrome: a
double-blind, randomised, placebo-controlled trial. The lancet Gastroenterology & hepatology, 4(9), pp.675-685.
4. Costello SP, Hughes PA, Waters O et al. Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With
Ulcerative Colitis: A Randomized Clinical Trial. JAMA, 2019 Jan 16;321(2). PMID 30644982
5. El-Salhy M, Hausken T, Hatlebakk JG. Current status of fecal microbiota transplantation for irritable bowel syndrome.
Neurogastroenterology & Motility. 2021 Nov;33(11):e14157.
6. Feuerstadt P, Boules M, Stong L, Dahdal DN, Sacks NC, Lang K, Nelson WW. Clinical complications in patients with primary
and recurrent Clostridioides difficile infection: A real-world data analysis. SAGE Open Med. 2021 Jan
14;9:2050312120986733. doi: 10.1177/2050312120986733. PMID: 33505698; PMCID: PMC7812403.
7. Food and Drug Administration (FDA). (2016) Guidance for Industry: Enforcement Policy Regarding Investigational New Drug
Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to
Standard Therapies. Accessed September 10, 2020. Available at: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/enforcement-policy-regarding-investigational-new-drug-requirements-use-fecal-microbiota-0.
8. Food and Drug Administration (FDA). (2019) Fecal Microbiota Transplantation: Safety Communication - Risk of Serious
Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms. Accessed September 10, 2020 Available at:
https://www.fda.gov/safety/medical-product-safety-information/fecal-microbiota-transplantation-safety-communication-
risk-serious-adverse-reactions-due .
9. Hayes, Inc. Health Tech Assessment. “Fecal Microbiota Transplantation for the Treatment of Crohn Disease”. May 5, 2022.
Annual Review: May 13, 2024. Accessed: July 16, 2024. Available at: https://evidence.hayesinc.com/report/hta.fmt5234
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ay_rank=1

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