Fecal Transplant via Retention Enema for Refractory or Recurrent Clostridium difficile Infection

Clostridium difficile infection (CDI) is the leading cause of nosocomial infection and its rates continue to rise. In the United States, the incidence of CDI tripled between 1996 and 2005 (31 per 100 000 vs 84 per 100 000).¹ This has been accompanied by an increase in disease severity, with mortality rates of up to 6.9%.² In addition, nosocomial CDI increases the cost of otherwise matched hospitalizations by 4-fold.³

Metronidazole therapy failure rates for uncomplicated CDI have risen from 2.5% to higher than 18% since 2000.¹ Recurrence rates are as high as 50% in patients older than 65 years and exceed 60% after 2 or more recurrences.^1,4 Accordingly, fecal transplant (FT) serves as an alternative approach. While antibiotics can further disrupt the microbiome, FT aims to reconstitute healthy flora. In uncontrolled case series, clinical resolution rates following FT are 73% to 100% in recurrent or refractory CDI.^5-7 Most reports have evaluated FT via nasogastric tube and colonoscopy, which are cumbersome and costly.^6,7 This report describes FT via retention enema in patients with refractory or recurrent CDI.

Case records were reviewed for 27 patients who underwent FT via retention enema. Inclusion criteria were (1) laboratory-confirmed C difficile toxin using enzyme immunoassay with no other cause for diarrhea; (2) refractory CDI (defined as ongoing diarrhea despite antimicrobial treatment) or recurrent CDI (defined as symptom resolution for at least 2 days after discontinuation of treatment with recurrence of diarrhea); and (3) complete clinical and laboratory documentation by medical chart or telephone review.

Two healthy volunteers served as donors and were evaluated for transmissible pathogens. Blood was screened for hepatitis B surface antigen, hepatitis C antibody, Helicobacter pylori and syphilis serologic markers, human immunodeficiency virus types 1 and 2, and human T-lymphotropic virus types I and II. Stool was processed for enteric bacterial pathogens, C difficile toxin, and ova and parasites. The donors took no antibiotics for 6 months prior to stool donation.

All CDI therapy was discontinued at least 24 hours prior to FT. Approximately 150 g of fresh stool collected was emulsified in 300 mL of sterile water. The supernatant component was administered rectally by enema. If diarrhea recurred within 7 days, the procedure was repeated.

The mean age was 69.4 years (range, 26-87 years) with 14 male subjects (52%) and 22 in-patients (81%). Subjects had a mean duration of diarrhea of 152.6 days. Fever and abdominal pain were documented in 29.6% and 74.1%, respectively.

Prior CDI therapies and clinical outcomes following FT are outlined in the Table. The mean cumulative antibiotic exposure before FT included 24.9 days of metronidazole therapy; 54.6 days of vancomycin monotherapy; 13.6 days of vancomycin taper; and 9.9 days of combined therapy with metronidazole and vancomycin.

After FT, 25 of 27 (93%) experienced clinical resolution. Of these, 22 resolved within 24 hours of transplant. Five patients underwent a second FT because of ongoing diarrhea; 3 had symptom resolution and 2 continued to experience diarrhea despite 2 FTs. There were no relapses or adverse events in the cohort that successfully underwent FT, with a mean follow-up at 427.3 days after transplant.

According to small, uncontrolled studies, the FT success rate is 89% (98 of 110 patients).^5-8 These reports are limited by heterogeneity in delivery modality, publication bias, and small sample sizes. However, the success of FT in refractory and recurrent CDI cannot be overlooked.

There is no consensus on the ideal delivery modality for FT. Previous reports, including the 2 largest series to date, have evaluated nasogastric or colonoscopic infusion.^6,7 However, retention enema is a less invasive, more economical, and more feasible option for both hospitalized and ambulatory patients. In addition, this modality averts some of the risks of nasogastric intubation or colonoscopy, including gastrointestinal perforation.^7,9 Despite its advantages, there have been few data on FT via retention enema.

To our knowledge, this is the largest reported series of patients treated with FT for refractory or recurrent CDI. Although our subjects had a significant burden of disease with prolonged cumulative antimicrobial therapy, our results demonstrate a robust treatment effect, with 25 of 27 cases (93%) responding clinically to FT. In addition, there were no reported adverse events or complications.

Unlike previous cohorts, this study population was balanced by sex. In the largest study of FT by colonoscopy, 17 of 19 patients were female.⁶ Similarly, the largest series using nasogastric intubation, had 13 women among 18 patients.⁷ We report our positive findings with some caution. Delivery by enema may be limited in those unable to retain the infusate. Five elderly patients required another FT, while treatment failed in 2. We speculate that this relates to attenuated sphincter tone in elderly patients. Also, this study was not controlled, and outcome assessment was not blinded. Nonetheless, a strong placebo effect seems unlikely in subjects with prolonged and severe symptoms.

In conclusion, FT via retention enema appears to be an effective and safe treatment for patients with recurrent or refractory CDI.

Correspondence: Dr Lee, St Joseph's Healthcare, 50 Charlton Ave E, Room L424, Hamilton, ON L8N 4A6, Canada (clee@mcmaster.ca).

Author Contributions:Study concept and design: Kassam, Hundal, and Lee. Acquisition of data: Kassam, Hundal, and Lee. Analysis and interpretation of data: Kassam, Hundal, Marshall, and Lee. Drafting of the manuscript: Kassam, Hundal, and Marshall. Critical revision of the manuscript for important intellectual content: Kassam, Hundal, Marshall, and Lee. Statistical analysis: Hundal. Administrative, technical, and material support: Kassam and Hundal. Study supervision: Marshall and Lee.

Previous Presentation: This study was presented at Digestive Disease Week; May 1-5, 2010; New Orleans, Louisiana.