Severe C. Difficile Infection: Vancomycin or Metronidazole as First-Line Therapy?

Nurse gives elderly male patient nutrition through Total Parenteral Nutrition (TPN) device through a port in the man's chest.

By Martina M. McGrath, MD
February 16, 2017

In 2011, there were almost half a million cases of Clostridium difficile (C. diff) infection in the US and 29,000 patients died from this disease.1 Initially recognized in the 1970s, a more virulent strain appeared in the early 2000s with increased associated mortality. Now one of the commonest health care-associated infections, C. diff has a disproportionate impact on patients who are frail, immunosuppressed, and malnourished. Between 15 and 50% of patients can suffer from recurrent C. diff infection, leading to increased health care costs and further risk of complications.

Oral metronidazole is recommended as first-line therapy for C. diff infection, while vancomycin is currently recommended for treatment failures and in severe cases.2 However, it is unclear if either agent is associated with decreased risk of recurrent disease or affects mortality. Using a VA Healthcare System database, Stevens and colleagues examined these questions in a propensity-matched cohort study.3 They analyzed data from 47,471 patients, subdividing them into unknown severity, mild-moderate, or severe C. diff infection, on the basis of the presence of leukocytosis (WCC >15×109/mL) and elevated serum creatinine greater than 1.5 times baseline value.

In this cohort, 16-20% of patients developed recurrence within eight weeks. Thirty-day mortality was 6.7% in the mild-moderate group, and 19.3% in severe cases. The investigators used a 1:4 matching algorithm to distribute patients between groups, and as a result ~20% of patients in each severity cohort was treated with vancomycin. The unadjusted risk of recurrence was similar across all levels of severity, and did not vary with treatment with either metronidazole or vancomycin. No difference in 30-day mortality was seen in those patients with mild-moderate C. diff who were treated with either metronidazole or vancomycin. However, in patients with severe C. diff infection, those who were treated with vancomycin had a 4.5% reduction in absolute risk of mortality as compared to metronidazole (RR 0.79, 95% CI 0.65-0.97). This effect was translated into a number needed to treat with vancomycin to prevent one death from severe C. diff infection, of 25.

Concerns regarding cost and the emergence of vancomycin-resistance Enterococci have limited the widespread use of vancomycin for treatment of C. diff infection. The findings of this study would agree with this approach for patients with mild-moderate disease, and vancomycin does not appear to give any benefit in decreasing recurrence rates, an important consideration for care of these patients. However, in those with severe disease, treatment with vancomycin is associated with superior 30-day survival and should be first-line therapy.3

  1. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. New England Journal of Medicine 2015;372:825.
  2. Cohen SH, Gerding DN, Johnson S, 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;31:431-55.
  3. Stevens VW, Nelson RE, Schwab-Daugherty EM, et al. Comparative Effectiveness of Vancomycin and Metronidazole for the Prevention of Recurrence and Death in Patients With Clostridium difficile Infection. JAMA Internal Medicine 2017.

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Headshot of Dr. McGrathDr. Martina McGrath is an Instructor in Medicine at Harvard Medical School, and a member of the Renal Division, Department of Medicine, at Brigham and Women’s Hospital, both in Boston. Dr. McGrath is the Medical Editor for the Trends in Medicine blog.

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