Comparative Effectiveness of Vancomycin and Metronidazole for the Prevention of Recurrence and Death in Patients With Clostridium difficile Infection

JAMA Intern Med. 2017 Apr 1;177(4):546-553. doi: 10.1001/jamainternmed.2016.9045.


Importance: Metronidazole hydrochloride has historically been considered first-line therapy for patients with mild to moderate Clostridium difficile infection (CDI) but is inferior to vancomycin hydrochloride for clinical cure. The choice of therapy may likewise have substantial consequences on other downstream outcomes, such as recurrence and mortality, although these secondary outcomes have been less studied.

Objective: To evaluate the risk of recurrence and all-cause 30-day mortality among patients receiving metronidazole or vancomycin for the treatment of mild to moderate and severe CDI.

Design, setting, and participants: This retrospective, propensity-matched cohort study evaluated patients treated for CDI, defined as a positive laboratory test result for the presence of C difficile toxins or toxin genes in a stool sample, in the US Department of Veterans Affairs health care system from January 1, 2005, through December 31, 2012. Data analysis was performed from February 7, 2015, through November 22, 2016.

Exposures: Treatment with vancomycin or metronidazole.

Main outcomes and measures: The outcomes of interest in this study were CDI recurrence and all-cause 30-day mortality. Recurrence was defined as a second positive laboratory test result within 8 weeks of the initial CDI diagnosis. All-cause 30-day mortality was defined as death from any cause within 30 days of the initial CDI diagnosis.

Results: A total of 47 471 patients (mean [SD] age, 68.8 [13.3] years; 1947 women [4.1%] and 45 524 men [95.9%]) developed CDI, were treated with vancomycin or metronidazole, and met criteria for entry into the study. Of 47 147 eligible first treatment episodes, 2068 (4.4%) were with vancomycin. Those 2068 patients were matched to 8069 patients in the metronidazole group for a total of 10 137 included patients. Subcohorts were constructed that comprised 5452 patients with mild to moderate disease and 3130 patients with severe disease. There were no differences in the risk of recurrence between patients treated with vancomycin vs those treated with metronidazole in any of the disease severity cohorts. Among patients in the any severity cohort, those who were treated with vancomycin were less likely to die (adjusted relative risk, 0.86; 95% CI, 0.74 to 0.98; adjusted risk difference, -0.02; 95% CI, -0.03 to -0.01). No significant difference was found in the risk of mortality between treatment groups among patients with mild to moderate CDI, but vancomycin significantly reduced the risk of all-cause 30-day mortality among patients with severe CDI (adjusted relative risk, 0.79; 95% CI, 0.65 to 0.97; adjusted risk difference, -0.04; 95% CI, -0.07 to -0.01).

Conclusions and relevance: Recurrence rates were similar among patients treated with vancomycin and metronidazole. However, the risk of 30-day mortality was significantly reduced among patients who received vancomycin. Our findings may further justify the use of vancomycin as initial therapy for severe CDI.

Publication types

  • Comparative Study

MeSH terms

  • Aged
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / adverse effects
  • Clostridioides difficile* / drug effects
  • Clostridioides difficile* / isolation & purification
  • Clostridium Infections* / diagnosis
  • Clostridium Infections* / drug therapy
  • Clostridium Infections* / mortality
  • Clostridium Infections* / prevention & control
  • Feces / microbiology
  • Female
  • Humans
  • Male
  • Metronidazole* / administration & dosage
  • Metronidazole* / adverse effects
  • Middle Aged
  • Retrospective Studies
  • Risk Assessment
  • Secondary Prevention / methods
  • Survival Analysis
  • Treatment Outcome
  • United States / epidemiology
  • Vancomycin* / administration & dosage
  • Vancomycin* / adverse effects


  • Anti-Bacterial Agents
  • Metronidazole
  • Vancomycin