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Publication Briefs

Study Compares Effectiveness of Two Medications for Veterans with Clostridium Difficile Infection

Over the last two decades, Clostridium difficile infection (CDI) has progressed from a relatively uncommon hospital-acquired infection to a major contributor to morbidity and mortality both in and out of the hospital. Current guidelines recommend metronidazole as initial therapy for most cases of mild to moderate CDI, partly due to concerns over the cost of branded vancomycin and the possible emergence of vancomycin resistance among Enterococcus. However, although an early clinical trial demonstrated no difference in cure rates between vancomycin and metronidazole, subsequent trials suggest that metronidazole is inferior to vancomycin, especially in severe cases. This multi-year comparative effectiveness study evaluated the risk of recurrence and all-cause 30-day mortality among Veterans receiving metronidazole (n=8,069) or vancomycin (n=2,068) for the treatment of mild to moderate and severe CDI from January 2005 through December 2012 in the VA healthcare system. Recurrence was defined as a second positive lab test within 8 weeks of the initial CDI diagnosis, and all-cause mortality was defined as death from any cause within 30 days of the initial CDI diagnosis.


  • Recurrence rates were similar among Veterans treated with vancomycin and metronidazole; however, Veterans with severe CDI treated with vancomycin were about 20% less likely to die from any cause within 30 days than Veterans treated with metronidazole.
  • Overall, Veterans who received vancomycin had a lower risk of mortality compared to Veterans treated with metronidazole (9% vs 11%).
  • Of the Veterans in this study, 4%-6% initially received vancomycin, despite 42% of the episodes having been classified as severe. While the use of vancomycin increased over the study period, by 2012 half of the patients with severe CDI still did not receive vancomycin.


  • Although excess treatment costs of vancomycin relative to metronidazole and the concern for vancomycin-resistant enterococci will likely remain barriers, improved clinical cure and mortality rates may warrant reconsideration of current guidelines, particularly in cases of severe CDI.


  • Patients were not randomized to treatment groups, and therefore may have differed on important characteristics that could have influenced their outcomes.
  • Treatment for CDI can change over time, and investigators did not measure treatment changes that occurred outside of the initial window. This could have resulted in misclassification of exposure.

This study was supported by HSR&D, and Dr. Nelson was supported by an HSR&D Career Development Award. Drs. Stevens and Nelson are part of HSR&D's Informatics, Decision-Enhancement and Analytic Sciences Center (IDEAS 2.0) in Salt Lake City, UT.

PubMed Logo Stevens V, Nelson R, Schwab E, et al. Comparative Effectiveness of Vancomycin and Metronidazole for the Prevention of Recurrence and Death in Patients with Clostridium difficile Infection. JAMA Internal Medicine. April 1, 2017;177(4):546-53.

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