Clostridium difficile–associated diarrhea has become one of the most common healthcare-associated infections, with significant morbidity and mortality, especially among the elderly in the inpatient setting. Alarmingly, the incidence and severity of this condition have been increasing. Treatment of Clostridium difficile infection (CDI) is challenging due to the limited number of drugs that have proven to be effective, recurring disease, and concerns about antibiotic resistance.1
A procedure known as fecal microbiota transplantation (FMT; also termed fecal transplantation, fecal bacteriotherapy, stool transplant) has been used increasingly in recent years to treat recurrent and refractory CDI.2 The premise of FMT is to reintroduce a healthy diversity of bacteria into the patient's colon to reestablish colonization resistance against C difficile and prevent it from becoming a dominant organism in the recipient’s intestinal microflora, now referred to as the microbiome.3 The FMT procedure is noted to be quick, inexpensive, and effective at eradicating CDI, although more randomized controlled studies are needed.1,4 At present, FMT is neither routinely practiced nor widely available to patients, but has nevertheless reemerged as a practical therapeutic modality.2,5 With understanding and acceptance of the limitations of certain medication therapies, and with advocacy for the battle against antibiotic resistance, this article will provide an overview of FMT in the hope of raising awareness about this treatment modality.
Past, Present, and Future
Strikingly, there have been relatively few advances in the treatment of CDI since it was first identified as a cause of antibiotic-associated diarrhea (see Antibiotic-Associated CDI and Pseudomembranous Colitis) more than 30 years ago.1,6 The anaerobic, gram-positive pathogen that causes CDI manifests as serious intestinal conditions such as diarrhea and colitis and can cause many different symptoms, including watery diarrhea, fever, loss of appetite, nausea, and abdominal pain and tenderness.7,8 Metronidazole and vancomycin remain the mainstays of CDI treatment, and the recent approval of fidaxomicin provides a new alternative.1
The first successful use of FMT was reported in 1958, with a transplant done by enema; in the United States, the first case of FMT done by colonoscopy was reported in 2000.9 This approach has been used by veterinarians who treat horses that have diarrhea by infusing stool from healthy animals into the rectum of animals with illness; administration of rumen fluid to cows and alpacas, a procedure known as transfaunation, is also used to treat a variety of conditions.3
The most common indication for fecal transplantation in humans is recurrent CDI. This condition occurs most frequently in geriatric patients in hospitals and nursing homes, possibly owing to environmental contamination carried on the hands of healthcare providers and facility staff (e.g., from C difficile living on bathroom fixtures and medical equipment).4,10 Although half of all CDI cases occur in people < age 65 years, older adults are far more likely to have severe disease with associated complications and multiple recurrences.4 CDI in the community is on the rise; patients there are typically younger and have less severe infection than those with hospital-acquired CDI.4,11
For some individuals, the typical course of antibiotics targeted to treat the CDI does not eradicate the infection, but rather provides only short-term relief and a recurrence of the infection.4 CDI recurs in nearly one-third of patients who develop an initial infection.12 Approximately 600,000 cases of CDI occur each year in the U.S., with 15,000 of these patients having a recurrence.2 The incidence of CDI has risen sharply over the last 2 decades; the number of cases among hospitalized adults tripled between 1993 and 2005 and more than doubled between 2001 and 2005.4
The increasingly high incidence of CDI in developed countries has been attributed to the emergence of newer epidemic strains, a growing elderly population, extensive use of broad-spectrum antibiotics, and limited therapies for this diarrheal disease.8 Mortality rates have also increased, coincident with the emergence of the hypervirulent C difficile NAP1/BI/027 strain.4,13 New agents are urgently needed to address the challenges that exist owing to some drawbacks (e.g., cost, promotion of resistance, selectivity problems) of the treatment options currently available for CDI.8 Immunotherapy will likely play a greater role in the treatment of CDI in the future; immunotherapy with a vaccine and monoclonal antibodies is being studied in clinical trials.1 For a systematic review of sixty-four articles evaluating eight different treatment approaches, see Reference 12.
Exclusion Criteria, Donors, Risks
At the Mayo Clinic in Arizona, exclusion criteria include concurrent gastrointestinal illnesses and the inability to undergo colonoscopy; however, patients who are immunosuppressed and those who have undergone transplantation—with the exception of recent bone marrow transplants—may qualify.4 Concerns about the safety of banked stool as well as patient preference have so far limited donors to family members, such as a spouse; the premise is that the healthy person will have exposure to some of the same bacteria as the patient, living in the same environment, so their stool will be a good match.9 Donor stool must be thoroughly screened to avoid disease transmission; prior to FMT, the donor’s sample is screened for conditions including hepatitis, HIV infection, and syphilis.9 Collecting and banking donor stool for study and transplantation is underway. The use of standardized, frozen preparations of feces provides increased availability of feces for FMT and reduces the cost of screening individual donors.14 Among possible complications of FMT is colon perforation; long-term consequences of this treatment have yet to be determined.9,14
FMT Procedure and Randomized Controlled Study
FMT involves the transfer of “healthy” bacteria from a donor (i.e., through a processed mixture of stool) into the patient, referred to as the recipient.7 Fecal transplantation can be performed via nasogastric tube, nasojejunal tube, upper tract endoscopy, colonoscopy, and retention enema; a recently performed randomized, controlled study by van Nood et al assessed the success rate of FMT via a nasoduodenal tube.4,9,15 The study revealed that resolution of recurrent CDI was more effective with FMT than with vancomycin treatment alone. The researchers found that 81% of patients receiving FMT had resolution of recurrent CDI symptoms without relapse for 10 weeks, compared with 31% receiving vancomycin treatment.15 The CDI-resolution success rate in this study is similar to that of the systematic review and meta-analysis of uncontrolled cases which showed CDI resolution 92% of the time.16,17 Another group of researchers provides a description of the logistics by which the FMT procedure is performed and the factors that may affect quality, safety, and patient outcomes.2
According to the Cleveland Clinic, not all insurance companies cover FMT; costs include screening of the donor.7 While fecal transplants have been used successfully in some patients and been found to be highly efficacious in a single randomized trial, more randomized studies are needed.12 For those patients with an ongoing recurrent disease process, no longer being homebound after undergoing FMT can dramatically improve quality of life.
Summary
C difficile is a main cause of healthcare-associated infections and its incidence and severity are on the rise. Elderly persons are at an increased risk of morbidity and mortality from CDI, with management of recurrent disease presenting challenges for both patients and clinical healthcare providers. Although more randomized clinical trials are needed, FMT has reemerged as a successful treatment for recurrent CDI when primary treatment options have failed.14 It is expected that FMT can become the primary mode of therapy not only for recurrent CDI, but for inflammatory bowel disease and other nongastrointestinal conditions as well. However, more studies are needed to determine any potential unintended and long-term consequences of this treatment. Further, it is important for studies to teach us how the specifics of the gut microbiota can potentially provide colonization resistance against C difficile.
REFERENCES
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