Clinical question: Does administration of monoclonal antibodies to C. difficile toxins A and B, in addition to standard-of-care antibiotics, prevent recurrent infection?
Background: Currently, no therapy has been approved to prevent recurrent C. difficile infection. A new approach to the prevention of recurrent C. difficile infection is the administration of monoclonal antibodies against C. difficile toxins (in addition to antibiotic therapy) as a form of passive immunity. Actoxumab and bezlotoxumab are fully human monoclonal antibodies that bind and neutralize C. difficile toxins A and B, respectively. In humans, the level of circulating antibodies against toxin A or toxin B has been correlated with protection against primary and recurrent C. difficile infection.
Study design: Two (MODIFY [MK-6072 and MK-3415A in Participants Receiving Antibiotic Therapy for Clostridium Difficile Infection] I and MODIFY II) double-blind, randomized, placebo-controlled, phase III trials.
Setting: 322 sites (~68% inpatient) in 30 countries from Nov. 1, 2011, through May 22, 2015.
Synopsis: Trials pooled data from 2,174 adults who were receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infections. Participants received an infusion of either bezlotoxumab, actoxumab plus bezlotoxumab, or placebo for MODIFY II; actoxumab alone was also given in MODIFY I. The primary endpoint was recurrent infection within 12 weeks.
The rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% vs. 28%; 95% CI, −15.9 to −4.3; P less than .001; MODIFY II: 16% vs. 26%; 95% CI, −15.5 to −4.3; P less than .001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% vs. 28%; 95% CI, −17.4 to −5.9; P less than .001; MODIFY II: 15% vs. 26%; 95% CI, −16.4 to −5.1; P less than .001).
The serious adverse events were similar with most groups, the exception being actoxumab alone. Given the higher rate of recurrent infection and deaths in the actoxumab group from interim analysis, the enrollment was discontinued in MODIFY I.
Investigators did admit that safety assessments were limited because of the relatively small number of patients who received bezlotoxumab, making it difficult to detect potentially serious but low-frequency toxic effects.
Bottom line: In patients receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection, a single intravenous infusion of bezlotoxumab was associated with a significantly lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo.
Citation: Wilcox MH, Gerding DN, Poxton IR, et al. “Bezlotoxumab for prevention of recurrent Clostridium difficile infection.” N Engl J Med. 2017 Jan 26;376(4):305-17.
Dr. White is an instructor in the Division of Hospital Medicine, Loyola University Chicago.