SAN DIEGO, CA—A post-hoc analysis of data pooled from the largest multicenter, randomized, double-blinded, head-to-head clinical trials to date involving patients with Clostridium difficile-associated diarrhea treated with oral vancomycin and oral metronidazole presented at IDWeek 2012 has shown statistically superior clinical success with oral vancomycin.
Two Phase 3, double-dummy, active-control, parallel-design efficacy and safety trials compared tolevamer (a “toxin-binding resin”) to vancomycin (125mg orally four times daily) and metronidazole (375mg orally four times daily) in patients with primary or recurrent Clostridium difficile-associated diarrhea. Subjects were treated for 10 days with a 4-week follow up. Tolevamer was shown to be inferior.
From these trials, Stuart Johnson, MD, of Edward Hines, Jr. VA Hospital, Hines, IL, pooled data to compare vancomycin to metronidazole. The primary endpoint was resolution of diarrhea and severe abdominal pain due to Clostridium difficile-associated diarrhea on Day 10 (defined as clinical success). Secondary endpoints included time to resolution of diarrhea, recurrence of Clostridium difficile-associated diarrhea, and adverse events.
Treatments were compared through logistic and proportional hazards regression models. Uni- and multivariate logistic regression analysis (OR 95% CI) was performed to assess potential factors impacting the primary outcome. Kaplan-Meier estimates were performed for time to resolution of diarrhea.
A total of 537 subjects were evaluated for efficacy (259 treated with vancomycin, 278 treated with metronidazole); 29% of subjects had severe Clostridium difficile-associated diarrhea, 78% had primary Clostridium difficile-associated diarrhea, and 23% had infection due to a BI strain.
Overall, vancomycin significantly enhanced clinical success (81.1% vs. 72.7%; OR [95% CI]: 1.681 [1.114, 2.537], P>0.05). Factors related to clinical success consisted of treatment naïve status, primary Clostridium difficile-associated diarrhea, and mild-to-moderate Clostridium difficile-associated diarrhea. Through multivariate analysis, treatment with vancomycin, treatment-naïve status, and mild/moderate disease severity were significantly associated with clinical success.
Median time to resolution of diarrhea was 5 days for each group. Recurrence was seen in 20.6% of vancomycin-treated subjects and 23% of metronidazole-treated subjects.
The proportion of patients noting treatment-emergent adverse events were similar between groups. Discontinuation due to adverse events was more frequent with metronidazole (11.2%) than vancomycin (6.5%). More subjects experienced nephrotoxicity-related adverse events with vancomycin (12 subjects [4.6%]) than metronidazole (3 subjects [1%]); these were seen for the most part among older patients.