Vancomycin vs. Metronidazole in C. difficile Diarrhea

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Zar FA, et al. "A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity". Clinical Infectious Diseases. 2007. 45(3):302-7.
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Clinical Question

In patients with Clostridium difficile-associated diarrhea, how does metronidazole compare with vancomycin in regards to effecting a cure and preventing relapse?

Bottom Line

Oral metronidazole is first-line therapy for mild Clostridium difficile-associated diarrhea, while vancomycin should be reserved for severe CDAD.

Major Points

After the millennium it was unclear whether vancomycin or metronidazole should be preferred for first-line treatment of Clostridium difficile-associated diarrhea (CDAD). Earlier data suggested equivalence of the two agents, but these studies were small and non-blinded. There remained many concerns over the blanket administration of vancomycin for CDAD, a frequent occurrence with over one-quarter of infectious disease specialists recommending vancomycin as first-line therapy. Among these concerns was the rise of vancomycin-resistant enterococci (VRE).

This 2007 publication by Zar et al., A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity, describes randomization of 150 patients with CDAD to oral metronidazole or vancomycin. Participants were stratified by disease severity. Severe disease was define by ≥2 points on a score developed for this trial:

  • Age >60 years (1 point)
  • Temperature >38.3°C (1 point)
  • Albumin <2.5mg/dL (1 point)
  • WBC >15,000 cells/mm3 within 48h of enrollment (1 point)
  • Pseudomembranous colitis on endoscopy (2 points)
  • Treatment in ICU (2 points)

Vancomycin was associated with a 13% absolute increase in the rate of cure (P=0.006; NNT 8). This effect remained significant for the severe disease subgroup (absolute increase 21%; NNT 5) but not for mild disease. There was no difference between the two for treatments for recurrence.

The subsequent Fidaxomicin vs. Vancomycin for C. difficile Diarrhea trial (2011) demonstrated that fidaxomicin was non-inferior to vancomycin for cure but was superior for reduction in recurrence. More recently, the Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile trial (2012) demonstrated a more than a 60% absolute increase in the rate of cure of recurrent CDAD over vancomycin.

Guidelines

Published before the 2011 fidaxomicin and 2012 fecal transplant trials.
IDSA/SHEA CDAD (2010):[1]

  • Discontinue treatment with the antibiotic thought to be associated with CDAD occurrence as soon as possible (A-II)
  • Start empirical treatment in severe or complicated CDAD as soon as suspected (C-III)
  • Avoid antiperistaltic agents (C-III)
  • Metronidazole 500 mg po TID for 10-14 days for initial episode of mild-to-moderate CDAD (A-I)
  • Vancomycin 125 mg po QID for 10-14 days for initial episode of severe CDAD (B-I)
  • Vancomycin 500 mg PO QID +/- metronidazole 500 mg IV q8h for severe, complicated CDAD (C-III)
    • If ileus, vancomycin 500 mg in 100 mL NS PR q6h as a retention enema
  • ≥2nd CDAD recurrence with taper or pulse of vancomycin (B-III)
  • Avoid metronidazole after the first recurrence of CDAD, including as a long-term agent, beacause of the risk of neurotoxicity (B-II)
  • Definition of CDAD severity is a matter of expert opinion and is not defined by these guidelines

Design

  • Single center, double-blinded, parallel-group, randomized controlled trial
  • N=150
    • Metronidazole (n=79)
    • Vancomycin (n=71)
  • Setting: Affiliate of University of Illinois at Chicago
  • Enrollment: 1994-2002
  • Follow-up: 21 days
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • Cure
    • Relapse

Population

Inclusion Criteria

  • Diarrhea (>3 nonformed stools/24h), and
    • Clostridium difficile toxin A in stool within 48h of study entry, or
    • Pseudomembranes on endoscopy
  • Ability to receive oral medications

Exclusion Criteria

  • Suspected or proven life-threatening intraabdominal complications (eg, perforated viscus, bowel obstruction)
  • Prior CDAD with failure to respond to either study drug
  • Pregnancy
  • History of allergy to either study drug
  • Treatment with oral vancomycin or parenteral/oral metronidazole during prior 14 days
  • Patients not allowed to receive antidiarrheal medications or drugs with potential activity against Clostridium difficile

Baseline Characteristics

Comparisons are mild vs. severe disease.

  • Mean age: 59 years (severe vancomycin group was 62 years)
  • Male: 55%
  • Prior antibiotics: 100%
  • Antibiotics within 14 days prior to onset: 95%
  • Underlying disease
    • CAD and/or HTN: 70%
    • Malignancy: 20%
    • Chronic pulmonary disease: 20%
    • Diabetes mellitus: 25%
    • CKD: 27%
  • Mean bowel movements: 6/day
  • Temperature >38.3: 41% (61% in severe metronidazole group)
  • Albumin <2.5 mg/dl: 35%
  • WBC >15k: 29%
  • Hospitalized in ICU: 0% vs. 7%
  • Pseudomembranous colitis: 0% vs. 16%

Interventions

  • Randomized to:
    • Metronidazole 250mg PO QID x 10 days, or
    • Vancomycin 125mg PO QID x 10 days
  • Stool assays performed on days 6 and 10 of therapy, and again on day 21 if diarrhea was present.
  • Interviews conducted on days 5, 11, and 21 after completion of therapy.
  • Thirteen patients (6 vs. 7) with severe disease were lost to follow-up or withdrawn due to death or noncompliance.

Outcomes

Comparisons are metronidazole vs. vancomycin.

Primary Outcomes

Cure (resolution by day 6 and negative assays at days 6 and 10)
Mild disease: 90% vs. 98% (P=0.36)
Severe disease: 76% vs. 97% (P=0.02; NNT 5)
All: 84% vs. 97% (P=0.006; NNT 8)
Relapse (recurrence of diarrhea by day 21 after initial cure)
Mild disease: 8% vs. 5% (P=0.67)
Severe disease: 21% vs. 10% (P=0.30)
All: 14% vs. 7% (P=0.27)

Secondary Outcomes

Intolerance
One patient from each group developed nausea/vomiting and was changed to the opposite group; both individuals achieved cure.

Criticisms

  • Performed before the NAP1/BI/027 strain emerged in the US[1]

Funding

Sources not identified in the article

Further Reading

  1. 1.0 1.1 Cohen SH et al. "Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA)." Infection Control and Hospital Epidemiology. 2010;31(5):431-455.