Efficacy and Safety of Oral Vancomycin (V) Versus Oral Metronidazole (M) for Treatment of Clostridium difficile Associated Diarrhea (CDAD): Pooled Results from Two Randomized Clinical Trials

Background: V and M are commonly used for treatment of CDAD (aka, CDI). Head-to-head trials are limited but data suggest improved outcomes in patients with severe CDAD treated with V. Tolevamer, a “toxin-binding resin,” was inferior to V and M in two large randomized clinical trials. We compared V vs M for CDAD from these trials.

Methods: Data were pooled, in a post-hoc analysis, from 2 Phase 3, multi-center, randomized, double-blind, double-dummy, active control, parallel-design efficacy and safety trials at 209 sites. Subjects with primary or recurrent CDAD were treated with V (125mg QID) or M (375mg QID) for 10 days with 4-wk follow up.  The primary end-point was resolution of diarrhea and abdominal pain (clinical success). Secondary evaluations included time to resolution of diarrhea (TTROD), recurrence of CDAD, and adverse events (AEs). Treatments were compared via logistic and proportional hazards regression models and uni- and multivariate logistic regression analysis (OR 95% CI) was performed to assess potential factors impacting the primary outcome. Kaplan-Meier estimates were used for TTROD.

Results: 537 subjects were evaluated for efficacy (V: 259; M: 278); 53% age > 65 yrs, 29% had severe CDAD, 78% were being treated for primary CDAD, and 23% had infection due to a BI strain (aka, NAP1/027). Overall, V significantly improved clinical success [81.1% vs 72.7%; OR (95% CI): 1.681 (1.114, 2.537), p= 0.0134]. Factors associated with clinical success included treatment naïve status, primary CDAD, and mild/moderate CDAD. In multivariate analysis, treatment with V, treatment naïve status, and mild/moderate disease severity remained significantly associated with clinical success. Median TTROD was similar between groups (5 days). Recurrence rates were 20.6% (V) and 23.0% (M). The proportion of subjects reporting related treatment emergent AEs was similar between groups. AE discontinuations were more frequent with M (11.2% vs 6.5%). More subjects experienced nephrotoxicity-related AEs with V [n=12 (4.6%)] than M [n=3 (1.0%)], predominantly among older subjects.

Conclusion: CDAD clinical success was statistically superior for V compared to M in the largest multicenter, randomized, blinded, head-to-head clinical trials conducted to date.