Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile

Published

Van Nood E, et al. "Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile". The New England Journal of Medicine. 2013. 368(5):407-415.
PubMed • Full text • PDF

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, small observational studies and case series have shown promising results. However, this study is the first RCT to confirm the efficacy of fecal transplant in recurrent CDAD.

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:

1. Donor feces infusion through nasoduodenal tube preceded by 4 days of oral vancomycin and bowel lavage with 4L of polyethylene glycol
2. Vancomycin 500 mg orally four times per day for 14 days
3. 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