Frozen vs Fresh Fecal Microbiota Transplantation (FMT) and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection (CDI) A Randomized Clinical Trial

Joseph Phan, Mercer University College of Pharmacy

According to the Centers for Disease Control and Prevention, C. difficile – was estimated to cause almost half a million infections in the United States in 2011, and 29,000 died within 30 days of the initial diagnosis. [1]  The Infectious Disease Society of America (IDSA) guidelines for the treatment of C. difficile states that the disruption of indigenous fecal flora is likely a major risk for C. difficile infection, and that instillation of stool from a healthy donor has been used with a high degree of success in several uncontrolled case series. [2]

A recently published noninferiority study sought to compare the effectiveness of transplantation of frozen versus fresh fecal micobiota in achieving clinical resolution of C. difficile associated diarrhea. [3]

Title: Frozen vs Fresh Fecal Microbiota Transplantation (FMT) and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection (CDI)
A Randomized Clinical Trial
Design Randomized, double-blind, noninferiority trial; N= 219
Objective To determine whether frozen-and-thawed (frozen, experimental) FMT is noninferior to fresh (standard) FMT in terms of clinical efficacy among patients with recurrent or refractory CDI and to assess the safety of both types of FMT
Study Groups Patients were randomly allocated to receive frozen (n= 114) or fresh (n= 118) FMT via enema.
Methods Patients are randomly assigned to frozen or fresh FMT.  All patients received suppressive antibiotics for their most recent episode of CDI, which was discontinued 24 to 48 hours prior to FMT.  On day one, patients received 50 mL of frozen or fresh FMT by enema.   Patients who showed no improvement of CDI symptoms by day four received an additional FMT with the same donor and allocation as the original FMT between days five and eight.  Patients not responding to two FMTs were offered repeat FMT or antibiotic therapy.

Fresh stool samples from healthy donors were transported to the processing laboratories within 5 hours of collection and stored at 5°C until frozen or used for FMT.  Approximately 100 g of stool sample was diluted with 300 mL of commercially bottled water and emulsified using a sterile wooden spatula.  Gauze was placed on top of an empty container to strain the solids, and the suspension in the container was aspirated into 60 mL syringes, which were also used to administer the enemas.  Patients randomized to receive fresh FMT received the suspension within 24 hours of collection; those randomized to receive the frozen FMT received the suspension within 24 hours of thawing.  Frozen suspensions were kept at −20°C for a maximum of 30 days and thawed overnight at 25°C; anaerobic bacteria counts have been found to remain stable for at least 30 days when stored at −20°C.

Duration July 2012 and September 2014
Primary Outcome Measure Clinical resolution of diarrhea without relapse at 13 weeks and adverse events.   Noninferiority margin was set at 15%.
Baseline Characteristics Patients in the modified intention-to-treat (mITT) arm who received frozen FMT were on average 73 years old, those that received fresh FMT were on average 72.5 years old.
Results A total of 219 patients (n = 108 in the frozen FMT group and n = 111 in the fresh FMT group) were included in the modified intention-to-treat (mITT) population and 178 (frozen FMT: n = 91, fresh FMT: n = 87) in the per-protocol population.  In the per-protocol population, the proportion of patients with clinical resolution was 83.5% for the frozen FMT group and 85.1% for the fresh FMT group (difference, −1.6% [95% CI, –10.5% to ∞]; p = .01 for noninferiority).  In the mITT population the clinical resolution was 75.0% for the frozen FMT group and 70.3% for the fresh FMT group (difference, 4.7% [95% CI, –5.2% to ∞]; p< .001 for noninferiority).  There were no differences in the proportion of adverse or serious adverse events between the treatment groups.
Adverse Events Common Adverse Events: transient diarrhea (70%), abdominal cramps (10%), or nausea (<5%) during the 24 hours following an FMT and constipation (20%) and excess flatulence (25%) during the follow-up period
Serious Adverse Events: Twelve patients (eight in the frozen FMT group and 4 in the fresh FMT group) required hospitalization because of illnesses unrelated to FMT following clinical resolution of CDI after FMT. A total of 19 patients (six in the frozen FMT group and 13 in the fresh FMT group) died during the 13-week study period.  Four patients (two in the frozen FMT group and two in the fresh FMT group) died with unresolved CDI: of these, one had received three FMTs, two had received two FMTs, and the other had received a single FMT.
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions Among adults with recurrent or refractory CDI, the use of frozen compared with fresh FMT did not result in worse proportion of clinical resolution of diarrhea.  Given the potential advantages of providing frozen FMT, its use is a reasonable option in this setting.

 

The results of this randomized double-blind trial shows that frozen fecal microbiota is not inferior to treatment with fresh fecal micobiota thus allowing for numerous advantages in preparation and safety.  The protocol used in this study utilizes disposable equipment and does not necessitate specialized, costly equipment. Furthermore, administration by enema is less invasive than colonoscopy or nasogastric administration.  Finally, frozen FMT reduces the number and frequency of donor screenings compared with fresh FMT.  Together, all of these advantages may potentially reduce cost with similar outcomes. [3]

References

  1. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372(9):825-34.
  1. Cohen, SH, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA). Infection Control and Hospital Epidemiology. 2010;31(5):431-455.
  1. 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. doi:10.1001/jama.2015.18098.
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