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Reference - MODIFY I and MODIFY II trials (N Engl J Med 2017 Jan 26;376(4):305) (level 2 [mid-level] evidence)
- C. difficile infection, a common cause of hospital-acquired diarrhea, has a high risk of recurrence.
- Two nearly identical randomized trials assessed the effects of adding single IV infusions of the monoclonal antibody bezlotoxumab alone, bezlotoxumab plus actoxumab, or saline to standard antibiotic therapy in 2,655 adults with C. difficile infection.
- Bezlotoxumab alone compared to saline reduced recurrence within 12 weeks from 26.6% to 16.5%; actoxumab had no additional benefit.
Clostridium difficile infection is one of the most common causes of hospital-acquired diarrhea, with rising incidences in community settings and previously low-risk populations (JAMA 2015 Jan 27;313(4):398, Infect Control Hosp Epidemiol 2010 May;31(5):431). It can be treated with certain antibiotics, but about 25% of patients develop a recurrent infection, with an increased risk with each episode (JAMA 2015 Jan 27;313(4):398, Anaerobe 2015 Aug;34:59, Clin Infect Dis 2016 Mar 1;62(5):574). For reducing recurrence, 2 nearly identical trials assessed the effect of adding the monoclonal antibody bezlotoxumab (targeting C. difficile toxin B) alone or in combination with actoxumab (targeting C. difficile toxin A) to standard antibiotic therapy for C. difficile infection (metronidazole, vancomycin, or fidaxomicin for 10-14 days). In these trials, 2,655 adults (median age 66 years) with primary or recurrent C. difficile infection were randomized to a single 60-minute IV infusion of bezlotoxumab 10 mg/kg alone, bezlotoxumab 10 mg/kg plus actoxumab 10 mg/kg, or saline at a median 3 days after the start of their antibiotic regimen. One of the trials also had an actoxumab alone group (with 232 patients), but randomization into that group was stopped due to poor outcomes at an interim analysis. Among the entire cohort, 27.5% had at least one previous episode of C. difficile infection within the previous 6 months, and 14.2% had at least two episodes in their lifetime. Bowel movements were self-reported via telephone for about 12 weeks after the infusion.
These results focus on the bezlotoxumab alone and saline groups; patients having bezlotoxumab plus actoxumab had similar rates of most outcomes as patients having bezlotoxumab alone. In pooled analyses of both trials, 80% of patients in each group reported an initial cure (no diarrhea for 2 consecutive days after the full course of antibiotic therapy). Recurrence (an initial cure followed by a new episode of C. difficile infection) within 12 weeks of infusion was reported by 16.5% with bezlotoxumab alone and 26.6% with saline (p < 0.0001, NNT 10, with an adjusted absolute risk difference of 10% [95% CI 6%-14%]). Subgroup analyses show a greater (but not significantly so) risk reduction with bezlotoxumab in patients who were older or who had a prior C. difficile infection. The bezlotoxumab alone and saline groups had similar rates of most adverse events, with infusion-specific reactions in 10.3% with bezlotoxumab and 7.6% with saline, serious adverse events within 4 weeks of infusion in 19.8% vs 21.4%, and serious drug-related adverse events within 4 weeks in 0.5% vs. 0.3%. Additional analyses reported in the FDA Drug Approval Package for bezlotoxumab (2016) suggest possible heart-related complications with bezlotoxumab. Cardiac failure was observed in 2.2% with bezlotoxumab and 0.9% with saline. Also, in subgroup analyses of 222 patients with baseline congestive cardiac failure, bezlotoxumab was associated with greater rates of serious adverse events (in 53.4% vs. 48%), cardiac failure-related serious adverse events (in 12.7% vs. 4.8%), and death (in 19.5% vs. 12.5%)
These trials show that the addition of a single IV infusion of bezlotoxumab 10 mg/kg to standard antibiotic therapy for C. difficile infection reduces the risk of C. difficile infection recurrence within 12 weeks by about 10%. However, the confidence interval in absolute risk difference has a more modest lower bound of 6%, and bezlotoxumab did not lower risk to negligible levels: 16.5% still had a recurrence. One limitation of this study is that the reliance on self-reporting adds some uncertainty to all outcome rates. Also, additional research is needed to better determine who would benefit most from adjunct bezlotoxumab (e.g., patients at increased risk for recurrence and without heart failure, as subgroup analyses suggest), whether or not efficacy depends on the specific choice of antibiotic therapy, and how bezlotoxumab may interact with fecal microbiota transplantation or other therapies. Nevertheless, given the importance of reducing C. difficile infection rates, bezlotoxumab may be an option as adjunct treatment to reduce recurrence in some adults having antibiotic therapy for C. difficile infection.
For more information, see the Clostridium difficile infection topic in DynaMed Plus. DynaMed users click here.