Vancomycin and metronidazole are both used as first-line treatment for C. difficile infections (CDI), but vancomycin may be superior in reducing 30-day mortality, according to a new study. In a retrospective, propensity-matched cohort study evaluating patients presenting with CDI from the VA system, more than 47,000 patients (96% men) were evaluated. Initial treatment was 95.6% with metronidazole and 4.4% vancomycin. The 2,068 vancomycin patients were case-matched with more than 8,000 metronidazole patients for the evaluation. There was no difference in the risk of recurrence between patients treated with vancomycin vs. those treated with metronidazole. However, those treated with vancomycin were less likely to die across all severity cohorts (relative risk [RR], 0.86; 95% confidence interval [CI], 0.74-0.98). No difference in mortality was observed in patients with mild disease, but vancomycin significantly reduced the risk of all-cause, 30-day mortality in patients suffering from severe CDI (adjusted RR, 0.79; 95% CI, 0.65-0.97; adjusted risk difference, -0.04; 95% CI, -0.007 to -0.01). The authors concluded that although the recurrence rates were similar among patients treated with vancomycin and metronidazole, the risk of 30-day mortality was reduced in patients treated with vancomycin, especially for those suffering from severe CDI. Although metronidazole generally is recommended as first-line therapy, these findings may justify use of vancomycin, especially in sicker patients (JAMA Intern Med. Published online Feb. 6, 2017. doi:10.1001/jamainternmed.2016.9045).