Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile
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Clinical Question
Among patients with recurrent C. difficile-associated diarrhea, how does fecal transplant compare with vancomycin in terms of relapse?
Bottom Line
Fecal transplant is associated with fewer relapses than vancomycin among patients with recurrent C. difficile-associated diarrhea.
Major Points
Prior use of antibiotics disturbs the normal gut microbiome and increases the risk of C. difficile-associated diarrhea (CDAD). Current treatment for recurrent CDAD involves additional courses of antibiotics including metronidazole, vancomycin (Vancomycin vs. Metronidazole in C. difficile Diarrhea; 2007), rifaximin, and fidaxomicin (Fidaxomicin vs. Vancomycin for C. difficile Diarrhea; 2011). Together, these treatments have a failure rate of up to 25% on first recurrence, which increases with subsequent recurrences.
Alternatively, fecal tranplant aims to restore the normal gut microbiome by introducing healthy bacterial flora through infusion of stool obtained from a healthy human donor. Since it was first described in 1958
This single center, open-label trial randomized 43 patients with recurrent CDAD to one of three arms: fecal transplant, oral vancomycin, or oral vancomycin plus bowel lavage. The study was stopped early after an interim analysis demonstrated that fecal transplant was curative in 94% of cases, whereas standard vancomycin was curative only 27% of the time. Having long been a measure of last resort because of acceptability and practicality, this trial suggests that fecal transplant should be considered for first line therapy among patients with recurrent CDAD.
Guidelines
IDSA/SHEA CDAD (2017, adapted):
- For second or subsequent recurrence, consider fecal microbiota transplantation (strong recommendation, moderate quality of evidence).
Design
- Single center, open-label, parallel group, randomized, controlled trial
- N=43 patients with recurrent CDAD
- Fecal transplant (n=17)
- Oral vancomycin (n=13)
- Oral vancomycin with bowel lavage (n=13)
- Setting: single center in Amsterdam
- Enrollment: 2008 - 2010
- Analysis: Intention to treat
- Primary outcome: Cure without relapse after 10 weeks
Population
Inclusion Criteria
- Age ≥18 years with ≥3 month life expectancy
- Relapse of CDAD after ≥1 course of antibiotics (≥10 days of vancomycin ≥125 mg QID or metronidazole 500 TID)
- ≥3 loose or watery stools per day for ≥2 consecutive days or ≥8 loose stools in 48 hours
- Positive C. difficile toxin stool test
Exclusion Criteria
- Immunocompromised state
- Recent chemotherapy
- HIV+ with CD4 <240
- Prolonged prednisone
- Pregnancy
- Antibiotics used for other indications
- ICU admission or requiring vasopressor therapy
Baseline Characteristics
- Age: 69 years
- BMI: 22.6
- Female: 43%
- Karnofsky performance status: 52
- Median recurrences of CDI: 3
- Previous failure of tapered vancomycin: 57%
- Antibiotic use before CDI: 98%
- Hospital-acquired CDI: 62%
- Inpatient admission: 31%
- Days of antibiotic use for CDI since first diagnosis: 55
- Use of proton-pump inhibitor: 81%
- ICU admission in prior month: 4%
- Feeding tube present: 17%
- Median stool frequency per 24 hr: 5
- Median leukocyte count: 8,000 per mm3
- Albumin: 3.8 g/dL
- Median creatinine: 1.1 mg/dL
Interventions
- Randomized to one of three arms:
- Donor feces infusion through nasoduodenal tube preceded by 4 days of oral vancomycin and bowel lavage with 4L of polyethylene glycol
- Vancomycin 500 mg orally four times per day for 14 days
- Vancomycin 500 mg orally four times per day for 14 days with bowel lavage on day 4 or 5
- Donors screened for HIV, HTLV-1 and 2, Hepatitis A, B and C, CMV, EBV, Treponema pallidum, Strongyloides stercoralis, and Entamoeba histolytica
- Donor feces screened for parasites, C. difficile, enteropathogenic bacteria
- Cure defined as absence of diarrhea or 3 consecutive negative toxin stool tests despite persistent diarrhea
- Relapse defined as positive C. difficile toxin stool test
Outcomes
Comparisons are fecal transplant vs. vancomycin vs. vancomycin with bowel lavage.
Primary Outcome
- Cure without relapse after 10 weeks
- 94% vs. 31% vs. 23% (CRR 3.05; 99.9% CI 1.08-290.05; P<0.001)
Secondary Outcomes
- Median time to recurrence
- 35 vs. 23 vs. 25 days
Adverse Events
- Adverse events in fecal transplant arm included diarrhea, cramping, and belching on the day of infusion and a couple of cases of constipation and infection during follow-up.
Criticisms
- Patients at high risk for C. difficile recurrence were excluded, including immunocompromised patients, critically ill ICU patients, and patients requiring antibiotics to treat other infections.
Funding
- Netherlands Organization for Health Research and Development
- Netherlands Organization for Scientific Research
Further Reading
- ↑ Kelly CP. "Fecal Microbiota Transplantation — An Old Therapy Comes of Age". N Engl J Med. 2013; 368:474-475
- ↑ McDonald LC et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin. Infect. Dis. 2018. 66:987-994.