By Richard R. Watkins, MD, MS, FACP, FIDSA
Associate Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General Medical Center, Akron, OH
Dr. Watkins reports that he has received grant/research support from Allergan.
SYNOPSIS: In a small randomized, controlled trial that compared fecal microbiota transplant (FMT) administered by enema to a six-week oral vancomycin taper, FMT was not more effective for patients with recurrent Clostridium difficile infection.
SOURCE: Hota SS, Sales V, Thomlinson G, et al. Oral vancomycin followed by fecal transplantation versus tapering oral vancomycin treatment for recurrent Clostridium difficile infection: An open-label, randomized controlled trial. Clin Infect Dis. First published online Nov. 9, 2016.
The management of recurrent Clostridium difficle infection (CDI) is challenging. The most common therapy for the past several years has been a prolonged course of oral vancomycin, frequently prescribed as a taper. Recently, fecal microbiota transplant (FMT) has become more widely available and utilized, especially in recalcitrant cases. Hota and colleagues sought to determine which of these two treatments was more effective for cases of recurrent CDI.
The study was a randomized, controlled trial from Canada that compared a 14-day course of oral vancomycin followed by an FMT vs. a six-week vancomycin taper. The inclusion criteria were patients 18 years of age and older with at least two episodes of CDI who had received at least one 10-day or more course of oral vancomycin. There were numerous exclusion criteria, including pregnancy, neutropenia, immunocompromised status, intensive care admission, severe colitis not responding to oral vancomycin, allergy or intolerance to oral vancomycin, chronic gastrointestinal diseases that cause chronic diarrhea, bleeding disorder, expected chemotherapy in the next 120 days, or inability to tolerate FMT. The primary outcome was recurrence of symptomatic, laboratory-confirmed CDI within 120 days of the intervention.
Of 140 patients assessed for eligibility, 12 patients in the vancomycin taper arm and 16 in the FMT arm were included in the interim analysis. Most of the patients were women (8/12 and 11/16, respectively) with a history of four to five CDI episodes (range 2-9) before starting the trial. Nine out of 16 (56.2%) patients who received FMT and five out of 12 (41.7%) in the vancomycin taper arm suffered a recurrence of CDI. This happened a median of nine days after FMT and 35 days after starting vancomycin tapering (seven days after finishing the taper). Four of the five patients who failed a vancomycin taper crossed over to FMT, and all four had another recurrence of CDI after the procedure. One of the FMT patients suffered a bowel perforation 35 days after the procedure, which was attributed to long-standing diverticulitis and not the FMT. Furthermore, there were no significant differences in fecal microbiota composition and diversity between the FMT donors and no significant differences between those associated with successful vs. unsuccessful FMT. After 30 patients were randomized, the trial was stopped due to futility.
Most studies of FMT for recurrent CDI have demonstrated a cure rate of about 90%. The present investigation by Hota and colleagues, which found a 44% cure rate for FMT, is notable therefore for being an outlier. There are a couple of possible explanations as to why this occurred. One is that the overall number of patients in the study was small and a larger study may have shown similar outcomes to previous ones. Another is that the methods used by Hota and colleagues were different from those employed by prior investigators. These included the delivery of FMT by enema instead of colonoscopy or nasojejunal tube, randomization of patients as soon as they experienced a recurrence of CDI and not during a symptom-free interval, only performing one FMT as opposed to multiple ones as was done in other studies, the 120-day follow-up, and no attempt to match donors and recipients (e.g., family members). Finally, pretreating patients with oral vancomycin for 14 days might have negatively affected the intestinal microbiota since oral vancomycin can be present in feces four to five days after discontinuation of therapy.
Oral vancomycin tablets have been expensive, and the cost of a six-week taper previously has cost several thousand dollars. The recent availablilty of a generic form has resulted in reduced cost. A study that compared the cost-effectiveness of different treatments found that FMT by colonoscopy was the most cost-effective initial strategy for management of recurrent CDI.1 However, the researchers did not use vancomycin as a taper and their conclusion should be re-examined in light of the findings by Hota and colleagues.
Unfortunately, FMT may not be as effective as previous studies have shown, leading clinicians to overestimate its benefits compared to prolonged courses of vancomycin. However, one also must be aware of the economic impact that oral vancomycin can have on patients and their families, as mentioned above. Perhaps the take-away message from this study can be summarized by the old dictum “an ounce of prevention is worth a pound of cure.” That is, it is far better to prevent CDI than to try to cure it with the therapies currently available.
- Konijeti GG, Sauk J, Shrime MG, et al. Cost-effectiveness of competing strategies for management of recurrent Clostridium difficile infection: A decision analysis. Clin Infect Dis 2014;58:1507-1514.