Treatment of Severe C. difficile-Associated Diarrhea: Vancomycin vs. Metronidazole

Neil M. Ampel, MD

Journal Watch. 2007;6(8) 

Among patients with severe disease, the clinical cure rate was significantly higher with vancomycin than with metronidazole.


Clostridium difficile is the most common cause of nosocomial diarrhea in acute-care settings. Until now, the two available therapies for C. difficile-associated diarrhea (CDAD), vancomycin and metronidazole, had been compared in only two prospective, randomized trials -- neither of them blinded or placebo-controlled. Moreover, these studies did not distinguish between mild and severe CDAD.

Now, researchers in Illinois have conducted a single-center, double-blind study in which patients with diarrhea and either C. difficile toxin A in the stool or documented pseudomembranous colitis were randomized to receive vancomycin 125 mg or metronidazole 250 mg, each plus placebo, four times daily. Patients were stratified by CDAD severity, with severe disease defined as ≥2 points (1 point each for age >60 years, temperature >38.3°C, serum albumin level <2.5 mg/dL, or peripheral white blood cell count >15,000 cells/mm3; 2 points each for endoscopic evidence of pseudomembranous colitis or ICU treatment). Cure was defined as resolution of diarrhea by day 6 of treatment and a negative C. difficile stool toxin assay at days 6 and 10 of treatment.

A total of 150 participants completed 10 days of therapy; 69 of them had severe CDAD. For patients with severe disease, the cure rate was significantly higher with vancomycin than with metronidazole (97% vs. 76%; P=0.02). However, for patients with mild CDAD, the difference was much smaller (98% vs. 90%; P=0.36). No significant differences were seen in relapse rates or adverse events between the two therapies. Factors significantly associated with metronidazole treatment failure were serum albumin level <2.5 mg/dL, presence of pseudomembranous colitis, and ICU admission.


These findings support several other observations that metronidazole has become increasingly less effective in the treatment of CDAD (see Journal Watch Infectious Diseases Jul 8 2005). However, metronidazole is still currently recommended as first-line therapy by several society guidelines, principally because it is less expensive than vancomycin and because of concern that using vancomycin might increase the prevalence of vancomycin-resistant organisms in the intestinal lumen. Such recommendations should be reevaluated in light of the accumulating data.

-- Neil M. Ampel, MD


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