Frozen Fecal Microbiota Transplantation
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
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
Evidence for Use of Frozen FMT
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.
— 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.
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16. Weingarden AR, Chen C, Bobr A, et al. Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection. Am J Physiol Gastrointest Liver Physiol. 2014;306(4):G310-G319.
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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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