Lawrence J. Brandt, MD
Lawrence J. Brandt, MD
Professor of Medicine, Division of Gastroenterology & Liver Diseases
Rising rates of Clostridium difficile (C. difficile) infection, combined with a limited number of effective antibiotics against this organism, have created a growing problem not only at Einstein/Montefiore but at hospitals and nursing homes throughout the country. Fecal bacteriotherapy (or, more properly, fecal microbiotic therapy), the controversial method of transplanting stool from a healthy individual to a diseased person, has shown to be highly effective in treating even the worst cases of this tenacious and highly resistant superbug.
Spores, Spores Everywhere
C. difficile is an anaerobic bacteria that exists in both vegetative (active) and spore (dormant) forms. The spores of this highly resistant, toxin-producing C. difficile organism can be found in food (beef, pork, and turkey are common carriers), in animals (horses, rabbits, hamsters, pigs, ostriches, and elephants), and on environmental surfaces (particularly in hospitals and medical care facilities) such as bed rails, floors, walls, doorknobs, or towel racks. These spores are resistant to antibacterial soaps and alcohol-based hand foams, and can survive for up to two years on inanimate surfaces. Proper handwashing is crucial to limiting their transmission. The bacteria are spread by contaminated hand-to-mouth contact, and, once ingested, the spores travel through the intestinal tract, replicate, and colonize in the large intestine (colon).
C. difficile produces two types of toxins, toxin A and toxin B, as well as a binary toxin that may accelerate and intensify their damage. The human gut is naturally protective, with diverse types of microorganisms known as intestinal microflora that provide "colonization resistance" against harmful bacteria like C. difficile. However, antibiotic exposure disturbs and largely diminishes this microflora, allowing C. difficile to proliferate and produce its toxins, causing diarrhea, fever, and abdominal pain, which are the main symptoms of C. difficile-associated disease (CDAD).
CDAD can sometimes cure itself if antibiotics are discontinued. More often, however, the disease can advance to pseudomembranous colitis, in which the toxins destroy the intestinal lining forming yellow plaques of inflamed and dead tissue on the walls of the colon; or to the life-threatening fulminant colitis, which can result in rapid deterioration necessitating surgical removal of the colon.
A Growing Healthcare Problem
The C. difficile organism is carried by a small percentage of healthy adults, and nearly a third of hospitalized patients (particularly those taking antimicrobials, and those in ICUs, or in the hospital for more than four weeks).
C. difficile is easily transmitted by healthcare workers, and historically most of those infected with C. difficile contracted it in the hospital. Recently, however, hospital-acquired infections have decreased and community-acquired infections have risen significantly (particularly those originating in nursing homes, assisted living facilities, and group homes). People at higher risk for C. difficile infection include those who are 65 and over; peripartum women; and patients with inflammatory bowel disease, cirrhosis, or immunosuppression; patients on proton pump inhibitors (to reduce gastric acid); or those who have had a nonsurgical gastrointestinal procedure. More recently, cases have begun to occur in younger people with no prior antibiotic exposure, making this disease a particular health concern. Around 500,000 cases and 15-20,000 deaths are reported each year in the United States costing more than three billion in healthcare dollars. New York City has the nation's highest occurrence of C. difficile.
To Treat, First Prevent
As with other infectious diseases, prevention is the most important part of treatment. Frequent handwashing with soap and water, appropriate antimicrobial use, and strict adherence to healthcare institution infection control policies are critical in limiting transmission of C. difficile. Alcohol-based hand sanitizers do not kill the spores, and if their use reduces handwashing this practice may be particularly dangerous. Healthcare staff, family members, and other visitors should be educated about the disease and its preventive measures.
The disease is most often diagnosed through a test for C. difficile toxin run on a sample of diarrheal or loose stool. Once the diagnosis is confirmed, physicians should stop the offending antibiotic if possible, and avoid the use of anti-motility drugs (like loperamide), which can worsen the disease.
Currently metronidazole and vancomycin are the most commonly prescribed antibiotics for C. difficile, although only vancomycin is FDA approved for this indication. While effective in treating the disease, these drugs have had limited success in treating recurring infections. Vancomycin is very expensive, costing as much as $240 a day, and a standard course of treatment is 10-14 days. For recurrent disease a tapering, pulsed regimen over a period of 2-3 months is often advised
Effective Treatment from an Unusual Source
The colonic bacteria in patients with recurrent C. difficile have decreased "phylogenetic richness" (microbial diversity). Restoring this phylogenetic richness may help the body regain its protective colonization factor which prevents C. difficile from becoming established in the colon. The NIH's Human Microbiome Project and the International Human Microbiome Consortium are examples of our increasing effort to understand how the human body's naturally occurring microbial communities (in this case, the phyla in the gastrointestinal tract) work to maintain health and cause disease. This information gained from these initiatives could improve our ability to prevent and treat diseases like C. difficile.
Fecal microbiotic therapy is one method of re-establishing the microbial integrity and normal diversity of the gut flora, while avoiding the use of prolonged, repeated courses of antibiotics. Veterinarians have historically harvested feces from healthy horses and infused it into horses with chronic diarrhea, curing the diarrhea; a similar technique, known as transfaunation, involves infusing rumen (stomach) content from healthy cows into cows with mastitis that are off feed.
The fecal microbiotic therapy procedure involves finding a donor (preferably an intimate partner or first-degree relative of the patient) and excluding individuals with recent antibiotic use, diarrhea, high-risk sexual behaviors, colorectal cancer, inflammatory bowel disease, and immunocompromise; stool and blood are tested for C. difficile, Giardia antigen, parasites, hepatitis B and C, HIV, and syphilis. Care should also be taken to ensure that before transplantation of stool, donors have not eaten anything to which recipients of fecal transplant are allergic.
Once the donor and his/her stool are cleared for transplantation, freshly passed stool is mixed with saline, filtered, and injected by nasogastric tube, upper endoscopy, colonoscopy or enema. While esthetically unpleasant and lacking reimbursement at present, fecal transplantation has shown to be rapidly effective (improvement can be seen in as little as two hours), with cure rates of more than 95% and close-to-zero relapse rates. The few relapses that have occurred have been cured by a second transplantation procedure.
The changes in recipients' fecal microbiomes following transplantation are currently being examined, and it is now known that recipient's stools resemble those of their donors for weeks after the procedure. Further research is warranted on proper and appropriate selection of donors, the best route for administering fecal microbiotic therapy, as well as proper safety measures for the transplantation procedure. Once the microbial agent is identified that is responsible for curing C. difficile disease, it is my hope that an artificial stool will be manufactured that can be administered in capsule form for treatment of CDAD.
Other conditions are also being evaluated for which fecal microbiotic therapy could be used, including severe first occurrences of CDAD, inflammatory bowel disease, and constipation. In a recent Swedish study, obese patients with diabetes improved their sensitivity to insulin after fecal transplant from healthy thin donors. Another study suggested that colonizing thin mice with the microbiota of obese mice resulted in weight gain; we are investigating the converse of this phenomenon--whether intestinal bacteria transplanted from a thin person will change the weight of an obese individual.