May/June 2016

Frozen Fecal Microbiota Transplantation
By Christine Lee, MD, FRCPC, and Christiana Kim, BSc
Today's Geriatric Medicine
Vol. 9 No. 3 P. 10

Clostridium difficile infection (CDI) is the No. 1 cause of infectious diarrhea in health care facilities of developed countries, and its rates in the community are increasing.1-3 It is the most common health care–associated infection (HAI) in the United States.3,4 The infection is caused by Gram-positive, anaerobic, spore-forming bacillus, which can colonize the colon. It causes infection when its toxins are released in the large intestine of a person with microbial imbalance, known as dysbiosis of the digestive tract, commonly due to a recent antibiotic therapy. The infection can range from mild to severe illness.

Severe CDI is characterized by a white blood cell count greater than 15 X 109/L, acute kidney injury, and low albumin, which can also predict complications related to CDI such as requiring colectomy or death.5 The direct attributable mortality associated with CDI is 6%, and the treatment failure with standard antibiotic is increasing.6 Prevention of both primary episode and recurrent CDI is difficult, as the organism's spores are resistant to chemicals (the majority of environmental disinfectants), heat, and radiation.

Recurrence of CDI following antibiotic therapy is becoming increasingly common, especially in individuals over the age of 65, immunocompromised, and hospitalized patients.1,7 An estimated 20% to 30% of patients develop recurrence following the completion of treatment with metronidazole or oral vancomycin, and more than 60% experience further episodes of CDI after a recurrence of CDI.1,3,7-9 Treatment of CDI with antibiotic further propagates dysbiosis and subsequent recurrence of CDI.8,10

Fecal Microbiota Transplantation and How It Works
An alternative to antibiotic therapy is fecal microbiota transplantation (FMT). The concept of treating ailments such as food poisoning and severe diarrhea with FMT is not new; human feces were used to treat severe diarrhea in China in the 4th century.11 The first reported use of FMT to successfully treat antibiotic-associated pseudomembranous enterocolitis was in 1958.12 The first published report of using rectal infusion of feces specifically for CDI was in 1983.13 The use of FMT for management of recurrent CDI is based on the concept that patients with CDI lack protective and diverse colonic microbiota to defend against pathogens such as Clostridium difficile. Following a successful FMT, the microbiome of a patient with recurrent CDI resembles that of a healthy donor and remains as such over time.14-16

FMT is a procedure in which a stool is collected from a healthy screened donor and mixed with water or saline, and the supernatant component of the mixture is administered by nasogastric/jejunal tubes, colonoscopy, or retention enema. A donor must be healthy with no history of cancer, autoimmune disease, inflammatory bowel diseases, irritable bowel syndrome, obesity, or family history of colonic cancer. The donors' blood is routinely screened for human immunodeficiency viruses 1 and 2, hepatitis B and C, human T-cell lymphotrophic viruses I and II, and syphilis. The stool is tested for the presence of parasites, enteric pathogens, methicillin-resistant Staphylococcus aureus (known as MRSA), vancomycin-resistant Enterococcus, extended-spectrum beta-lactamase-producing organisms, carbapenem-resistant organisms, rotavirus, norovirus, and adenovirus.

A number of studies and systematic reviews have shown that the efficacy of FMT in curing recurrent CDI is more than 80%, which currently surpasses any other treatment modalities.17-20 Since 2010, there has been an explosion of research, publications, and media coverage related to FMT and its potential application in various medical conditions such as inflammatory bowel diseases (eg, ulcerative colitis [UC], Crohn's disease), irritable bowel syndrome, metabolic syndrome, and type 2 diabetes mellitus. A result from a randomized placebo-controlled trial of FMT in patients with active UC, which consisted of 75 patients (38 in FMT and 37 in placebo), showed that a statistically significant proportion of patients who received FMT achieved UC remission compared with the patients in the placebo group.21

Costs Associated With CDI
CDI is associated with high health care costs. A report released in 2012 by the Canadian Patient Safety Institute (CPSI) stated that the cost per case of hospital-acquired CDI ranged from CAN$2,265 to CAN$22,400.22 The cost estimate did not include the economic burden related to posthospital discharge, the societal cost of illness, the loss of mental or physical functional status, or the loss of occupational productivity due to CDI. The CPSI also calculated the cost estimate related to adverse events due to HAI in Canada to be approximately CAN$1.1 billion in 2010, and 36% of the cost incurred would have been preventable.22 A study from the United States reported that hospital-acquired CDI more than quadrupled the cost of hospitalizations, which increased the annual health care expenditures by $1.5 billion.6,23

Evidence for Use of Frozen FMT
A recent randomized clinical study, published in the Journal of the American Medical Association, studied 219 adult patients with history of recurrent or refractory CDI.24 Recurrent CDI was defined as "recurrence of CDI symptoms for 48 hours or longer within eight weeks following the completion of at least 10-day CDI antibiotic." Refractory CDI was defined as "persistent or worsening of diarrhea characteristic of CDI and at least one of the following: ongoing abdominal pain, temperature >38° C, or peripheral white blood cell counts greater than 15 X 109/L despite treatment with oral vancomycin at a dose of 500 mg four times daily for at least five days." Patients received FMT via retention enema.

The primary outcomes measured were clinical resolution of diarrhea without relapse at 13 weeks and adverse events in each group. The noninferiority margin was set at 15%. One hundred eight patients were randomized to receive frozen FMT, and 111 patients were allocated to receive fresh FMT. Of 219 patients, 178 were included in the per-protocol population. In the per-protocol population, the proportion of patients who achieved clinical resolution of diarrhea was 83.5% in the frozen FMT group and 85.1% in the fresh FMT group (difference, -1.6% [95% CI, -10.5% to ∞]). This met the noninferiority margin, and there were no observed differences in adverse events between the two treatment groups. There were also no significant adverse events directly related to FMT in either treatment group.

The strengths of this study were that more than 50% of patients were inpatients with multiple comorbidities, and also included patients with underlying inflammatory bowel disease and immunocompromised patients. In addition, the method of FMT preparation was simple and utilized inexpensive disposable items. Administration of FMT by enema is less invasive than via endoscopy or colonoscopy or nasojejunal/gastric administration and can be performed in any setting. To optimize rectal retention, a total of 50 cc volume was administered to each patient, which contributed to high tolerability and minimal discomfort to patients. Last, frozen FMT allows wide distribution of the product and minimizes the number and the laboratory costs associated with frequent donor screening compared with fresh FMT.

Conclusion
CDI is becoming increasingly common, especially in elderly patients, and recurrent CDI poses major challenges to patients and health care providers. Antibiotics have a minimal role in treatment of recurrent CDI, as antibiotic therapy promotes ongoing disturbance of microbiota in the colons of the affected patients. FMT is the most efficacious treatment in curing recurrent CDI as it restores the healthy microbiota, which are needed to combat pathogens such as Clostridium difficile. However, FMT is not readily available in many health care settings due to lack of donors, donor screening programs, and laboratory facilities to manufacture the product. It is reassuring that the frozen FMT delivered by enema is as efficacious as fresh FMT and can be delivered and administered widely.

— Christine Lee, MD, FRCPC, is a professor at McMaster University and a medical microbiologist at Hamilton Regional Laboratory Medicine in Hamilton, Ontario, Canada, and Island Health in Victoria, British Columbia, Canada.

— Christiana Kim, BSc, is a research analyst at St. Joseph's Healthcare Hamilton Research Institute.

References
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19. Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(4):500-508.

20. Lee CH, Belanger JE, Kassam Z, et al. The outcome and long-term follow-up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema. Eur J Clin Microbiol Infect Dis. 2014;33(8):1425-1438.

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24. Lee CH, Steiner T, Petrof EO, et al. Frozen vs fresh microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile infection: a randomized clinical trial. JAMA. 2016;315(2):142-149.