By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first live fecal microbiota product to prevent recurrence of Clostridioides difficile infection (CDI). The product is manufactured from human fecal matter sourced from qualified donors. The donors and stools are tested for a panel of transmissible pathogens, including SARS-CoV-2.1,2 The FDA granted fecal microbiota a fast-track priority review, a breakthrough therapy designation, and an orphan designation.2 It is distributed as Rebyota.
INDICATIONS
Rebyota can be prescribed to prevent recurring CDI for patients age 18 years and older who are following antibiotic treatment for recurring CDI.1
DOSAGE
Fecal microbiota is administered rectally as a single dose of 150 mL suspension.1 Administer 24-72 hours after the last dose of antibiotics for CDI. Each 150 mL of fecal microbiota contains between 1 × 108 and 5 × 1,010 colony-forming units (CFU) per mL of fecal microbes, including > 1 × 105 CFU/mL of Bacteroides in a solution of polyethylene glycol 3350 and saline.1 Fecal microbiota comes in a frozen carton (150 mL single dose). Thaw before administration.
POTENTIAL ADVANTAGES
Fecal microbiota transplantation (FMT) provides a new option to prevent recurring CDI.
POTENTIAL DISADVANTAGES
Reduction in CDI recurrence seems to be correlated with restorative microbiome changes.3 In a clinical trial, about 30% of subjects did not achieve treatment success.1,4 Comparing responders to non-responders, the latter showed no significant change in microbiome composition from baseline.3 The product may carry a risk of transmitting infectious agents and may contain food allergens.1,2 The most commonly reported (vs. placebo) adverse reactions were gastrointestinal in nature: abdominal pain (8.9% vs. 6.9%), diarrhea (7.2% vs. 3.4%), abdominal distention (3.9% vs. 2.3%), flatulence (3.3% vs. 0%), and nausea (3.3% vs. 1.1%).1
COMMENTS
FMT can restore “normal” microbiome function in patients with recurrent CDI (i.e., increase Bacteroidia and Clostridia-class bacteria and lower levels of Gammaproteobacteria and Bacilli).3 The effectiveness of fecal microbiota was evaluated using data from a randomized, double-blind, placebo-controlled, Phase III trial (study 1), as well as data from a previous Phase IIb trial (study 2).1,4 Because of recruitment challenges, the FDA allowed the use of one-dose fecal microbiota and placebo data from the Phase IIb trial and a Bayesian analytical model. Subjects presented with a confirmed diagnosis of recurring CDI, defined as one or more episodes (diarrhea three times or more or more loose stools within a 24-hour period for two consecutive days), and positive C. difficile toxin or toxigenic C. difficile, or at least two episodes of CDI resulting in hospitalization within the past year. Enrolled subjects had to complete 10 consecutive days of antibiotic therapy (mainly vancomycin) and control their CDI for a minimum of 24-72 hours (study 1) and 48 hours (study 2). Treatment groups included 177 patients in study 1 and 39 patients in study 2, along with 85 patients and 43 patients, respectively, in the placebo groups. Treatment success was defined as the absence of CDI diarrhea (defined three or more unformed/loose stools 24 hours or less for at least two consecutive days and a positive stool test for C. difficile toxin at the time of the diarrhea) within eight weeks of blinded treatment.1 Overall treatment success rates were 70.6% for fetal microbiota and 57.5% for placebo, and a 99.1% probability of superiority over placebo.
CLINICAL IMPLICATIONS
C. difficile is the leading cause of antibiotic-associated diarrhea (ADD), accounting for 15% to 25% of all episodes of ADD.5,6 Commonly implicated antibiotics include fluoroquinolone, third- or fourth-generation cephalosporins, clindamycin, and carbapenem.5 About 20% of CDI patients will resolve within two to three days after discontinuing suspected antibiotic. Treatments of choice are oral vancomycin or fidaxomicin.5,7,8 The Infectious Diseases Society of America recommends fidaxomicin for patients with recurrent CDI episodes, while vancomycin is an acceptable alternative.8 For multiple recurrences, vancomycin in a tapered and pulsed regimen, vancomycin followed by rifaximin, and FMT are options in addition to fidaxomicin.8 A Phase III trial (NCT03931941) is in progress, with an estimated enrollment of 750 subjects and allows for subjects to receive a second dose if they are protocol-specified treatment failures. The estimated completion date is September 2023. The cost for fetal microbiota is $9,000 per treatment.
REFERENCES
1. Ferring Pharmaceuticals. Rebyota prescribing information. November 2022.
2. U.S. Food & Drug Administration. FDA approves first fecal microbiota product. Nov. 30, 2022.
3. Orenstein R, Dubberke ER, Khanna S, et al. Durable reduction of Clostridioides difficile infection recurrence and microbiome restoration after treatment with RBX2660: Results from an open-label phase 2 clinical trial. BMC Infect Dis 2022;22:245.
4. Khanna S, Assi M, Lee C et al. 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 2022;82:1527-1538.
5. Centers for Disease Control and Prevention. FAQs for clinicians about C. diff.
6. Centers for Disease Control and Prevention. Clostridioides difficile infection (CDI) tracking.
7. Czepiel J, Drózdz M, Pituch H, et al. Clostridium difficile infection: Review. Eur J Clin Microbiol Infect Dis 2019;38:1211-1221.
Rebyota can be prescribed to prevent recurring Clostridioides difficile infection for patients age 18 years and older who are following antibiotic treatment for recurring episodes.
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