By Johan S. Bakken, M.D., Ph.D.
Eight patients, each of whom experienced recurrent episodes of Clostridium difficile-associated diarrhea, were treated with staggered and tapered oral metronidazole or vancomycin combined with daily intake of kefir, an over-the-counter liquid probiotic dairy product. All eight successfully resolved their infection and did not experience any further diarrhea after completion of treatment. Further studies will be needed to determine whether gradual antibiotic withdrawal combined with kefir is a valuable treatment for recurrent C. difficile-associated diarrhea.
The incidence of Clostridium difficile-associated diarrhea (CDAD) has increased steadily during the last decade. Today, CDAD is the second most common nosocomial infection seen in hospitals in North America.1 Metronidazole is commonly used for initial treatment of CDAD,2 whereas vancomycin is recommended for more severe cases.3-5 Regardless of the antibiotic chosen for treatment, approximately 20% of patients develop relapsing CDAD (RCDAD) after completion of therapy.2,3,6
Individuals most likely to develop RCDAD are older and have comorbid illnesses, ongoing exposure to antibiotic agents, and hypoalbuminemia. Many have had prolonged stays in an intensive care unit.2,7
Treatment alternatives for RCDAD have not been well-defined,2 and empirical strategies to restore the normal bacterial microbiota in the colon and interrupt the relapsing pattern of infection have been proposed.7 Between 1990 and 2003, Aas et al. treated 18 patients with RCDAD at St. Mary’s Medical Center in Duluth with a liquid suspension of stool instilled into the proximal duodenum through a nasogastric tube. Fifteen of 16 evaluable patients (94%) saw their infection resolve and remained relapse free for 90 days after treatment.8 Although the success rate of this treatment has been relatively high,7-10 the aesthetic aspects associated with fecal bacteriotherapy (FBT) and the potential risk for transmission of contagious agents has limited its acceptance within the medical community. However, the rising incidence and mortality rates associated with CDAD11 as well as the incidence of recurrent disease and the emergence of the binary toxin-producing C. difficile strain NAP1 have generated increased interest in FBT.12
Fecal bacteriotherapy, however, has yet to gain acceptance among third-party payers, including Medicare, because of the limited cumulative experience with the procedure and the expense. The cost associated with screening donor blood and feces for contagious agents, the preparation of the donor fecal sample, and the placement of the appropriate catheter for instillation of the fecal suspension (nasogastric tube or retention enema tube) can surpass $2,500. Older patients who live on a fixed income may be unable to pay for the procedure out of pocket. Thus, even though FBT may successfully break the pattern of relapsing infection, the financial burden associated with this treatment may make it unattainable for those who need it most. Since 2005, we have offered an alternative treatment strategy at St. Luke’s Medical Center for patients with RCDAD who would be candidates for but cannot afford FBT. The treatment involves tapered withdrawal and staggered administration of metronidazole or vancomycin, combined with an oral probiotic agent (Table 1).
Testing the Protocol
The first patient in which we tested this treatment option was an 89-year-old woman who underwent hemicolectomy in February 2006 after being diagnosed with tubular adenomas of the sigmoid colon (Table 2). Oral neomycin and erythromycin prophylaxis was administered prior to surgery. Ten days after surgery, she developed diarrhea. The stool C. difficile toxin A/B immunoassay test was positive. She was treated with oral vancomycin, and the diarrhea resolved quickly. However, the diarrhea returned within a week after completion of vancomycin. During the next three months, she suffered several diarrhea relapses that responded only transiently to repeated treatment with metronidazole. The woman was then referred for FBT. At the time of evaluation, she was being treated with oral metronidazole 250 mg QID, and her stool pattern had become normal. The patient elected to continue metronidazole rather than proceed with FBT because of the associated costs. She was placed on a tapered metronidazole treatment course and was instructed to drink a 4-ounce glass of kefir with each meal. During the following eight weeks, metronidazole was gradually withdrawn following a staggered and tapered treatment routine. The patient was free of symptoms at her six-month follow-up exam.
Between April 2006 and July 2008, seven additional patients with RCDAD were subsequently referred for FBT. Each patient chose to continue treatment with the tapered and staggered antibiotic routine because of the out-of-pocket costs associated with FBT. The patients’ initial CDAD diagnosis and all subsequent relapses were confirmed by a positive stool toxin A/B immunoassay test (Meridian Immunocard, Cincinnati, Ohio). Each patient had experienced two or more clinical relapses after their initial episode of CDAD (mean relapse rate, 4.0), and all had failed multiple treatment attempts with metronidazole, vancomycin, or a combination of these antibiotics administered orally.
The patients in our study included six females and two males. Their average age was 69 years (SD:17). Five patients were immunocompromised; three had ulcerative colitis and had been treated with steroid enemas; two had received systemic prednisone for chronic obstructive pulmonary disease and idiopathic thrombocytopenia, respectively; four had been treated with an H2 blocker prior to developing CDAD. All eight patients successfully resolved their diarrhea without any subsequent recurrences. All eight continued to drink kefir with each meal for at least two months after completing their antibiotic treatment program. And all eight have remained relapse free for five months or longer (Table 2).
The Importance of Probiotic Bacteria
Bjørneklett has stated that all mammals need to continuously replenish the intestinal tract with bacteria from the outside world in order to maintain an intact ecosystem.13 However, the identities and the relative numbers of the bacterial species that are crucial for upholding the ecological balance in the colon are largely
During periods of health, bacterial flora suppresses growth of C. difficile in the colon. However, uncontrolled growth of C. difficile may occur once the healthy bacterial flora has been reduced or eliminated by antibiotic therapy. Furthermore, even though diarrhea improves transiently with antibiotic therapy, the disruption and decimation of the bacterial flora continues during metronidazole or vancomycin administration, and C. difficile remain in the colon as antibiotic-resistant spores. Once antibiotic therapy is discontinued, the spores germinate into vegetative forms and the diarrhea returns.
Successful and permanent resolution of CDAD, therefore, depends on restoring the bacterial ecosystem as quickly as possible in order to suppress growth of the remaining C. difficile. This is the philosophy behind the use of probiotic agents to complement antibiotic therapy (metronidazole or vancomycin) for patients with CDAD and, especially, with RCDAD.15
We elected to supplement the antibiotic treatment of our patients with Lifeway kefir, a fermented liquid dairy product with a diverse collection of probiotic bacterial species (Bifidobacterium breve, B. longum, Lactobacillus acidophilus, L. casei, L. acetylactis, L. lactis, L. plantarum, L. rhamnosus, Leuconostoc cremoris, and Saccharomyces florentinus) that comes in many palatable flavors. Kefir is inexpensive and can be purchased in most grocery stores in the United States. Our patients were instructed to drink a 4-ounce glass of kefir at least three times a day, and were encouraged to drink more if they liked the product. The infrequent antibiotic administration during a gradually tapered withdrawal period may enable metabolically inactive C. difficile spores to germinate into vegetative bacteria during periods when intraluminal concentrations of metronidazole or vancomycin in the colon were low or absent. Thus, it is possible that the number of C. difficile (both spores and vegetative forms) gradually decreased during the period of antibiotic withdrawal as a consequence of well-timed but infrequent antibiotic administration.
All of our patients successfully resolved their diarrheal illness after they had completed treatment with an intermittent antibiotic withdrawal program combined with daily ingestion of kefir, even when previous treatment attempts using the same antibiotic agent without kefir had failed. We hypothesize that the persistent administration of kefir enabled the ingested probiotic bacteria to survive in sufficient numbers during the period of metronidazole or vancomycin administration, thus exerting a suppressive or inhibitory effect on C. difficile, which allowed the relapsing diarrhea cycles to resolve. Further clinical studies of kefir and a gradual antibiotic withdrawal program will be needed to confirm our hypothesis. MM
Johan Bakken is a consultant in the section of infectious disease at St. Luke’s Medical Center in Duluth and an associate professor at the University of Minnesota Medical School Duluth’s Department of Family Medicine.
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