Clostridium difficile, the most frequent cause of infectious nosocomial diarrhea, recurs in approximately 35% of patients after initial antibiotic therapy. Results from 2 double-blind, randomized, placebo-controlled phase 3 trials showed that bezlotoxumab, a monoclonal antibody against C difficile toxin B, prevented 38% of recurrent C difficile infections (CDI) compared with standard-of-care treatment. The study was published in the New England Journal of Medicine.
Conducted at 322 sites in 30 countries, the MODIFY I and MODIFY II trials (ClinicalTrials.gov identifiers: NCT01241552 and NCT01513239, respectively) enrolled 2655 adult patients receiving standard-of-care antibiotics (metronidazole, vancomycin, or fidaxomicin) for primary or recurrent CDI. The intent of the trials was to determine the efficacy of bezlotoxumab for prevention of recurrent CDI, both as monotherapy and as combined with actoxumab, a monoclonal antibody against C difficile toxin A.
For the MODIFY I trial, patients were randomly assigned to receive a single, 60-minute intravenous infusion of placebo (0.9% saline), bezlotoxumab (10 mg/kg), actoxumab plus bezlotoxumab (10 mg/kg each), or actoxumab monotherapy (10 mg/kg). Patients in MODIFY 2 were randomly assigned to the same treatments, with the exception of actoxumab monotherapy, as that study group was halted after a planned interim analysis because of poor effectiveness.
Both trials demonstrated that patients who received bezlotoxumab alone had lower rates of recurrent C difficile infection within 12 weeks after infusion compared with those who received placebo. The rate of recurrent C difficile infection, defined as a new episode after initial clinical cure, was also lower in the actoxumab plus bezlotoxumab group vs in the placebo group (Table 1). The combination did not confer additional benefit over bezlotoxumab alone.
Table 1. Bezlotoxumab and Actoxumab+Bezlotoxumab Compared With Placebo
The investigators noted several limitations to their research:
- Standard-of-care antibiotics were selected by the investigators and not standardized.
- Time of study infusion relative to the onset of symptoms varied.
- Other therapies in current use for the prevention of recurrent C difficile infection, such as fecal microbiota transplantation, were disallowed.
- Safety assessments were limited because of the small proportion of patients who received bezlotoxumab.
In an email interview with Infectious Disease Advisor, lead investigator Mark H. Wilcox, MD, from the Leeds Teaching Hospitals NHS Trust and University of Leeds, United Kingdom, stated that the results of the study suggest that physicians should now consider which patients could best benefit from use of bezlotoxumab. “These studies showed that bezlotoxumab was particularly effective in patients with risk factors for poor outcome, including older age, immunocompromise, and severe infection. [It is a]lso worth noting that post hoc analyses have provided evidence that fewer recurrent episodes was associated with less chance of admission to hospital, and less future need for CDI treatment antibiotics or fecal microbiota transplantation.”
Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305-317. doi:10.1056/NEJMoa1602615