Efficacy of bezlotoxumab in patients receiving metronidazole, vancomycin, or fidaxomicin for treatment of Clostridium difficile infection (CDI)

Background:  MODIFY I and MODIFY II were global, randomized, double-blind, placebo-controlled trials of the efficacy and safety of the anti-C. difficile toxin B monoclonal antibody bezlotoxumab (bezlo) for the prevention of CDI recurrence in adults receiving standard of care (SOC) antibiotic treatment (metronidazole, vancomycin, or fidaxomicin) for primary or recurrent CDI.  Because the primary endpoint (CDI recurrence) could be influenced by the SOC antibiotic, randomization was stratified by this factor and a pre-specified analysis was conducted to assess clinical cure (initial clinical response) and CDI recurrence based on the SOC antibiotic received.

Methods:  The monoclonal antibody or placebo (normal saline) was administered with SOC antibiotics.  SOC antibiotics were given at the discretion of the health care provider in accordance with treatment guidelines or approved labeling at recommended doses and duration (10 to 14 days).  The primary endpoint, CDI recurrence, was defined as a new episode of diarrhea (≥3 unformed stools in 24 hours) and positive stool test for toxigenic C. difficile after clinical cure of the baseline CDI episode.  Clinical cure was defined as SOC antibiotics given for ≤14 days, and no diarrhea for 2 consecutive days after completing SOC.  Data from MODIFY I and MODIFY II were combined to provide increased precision for estimating treatment effects.

Results:  Subjects most commonly received oral metronidazole (48.5%) or oral vancomycin (alone or with IV metronidazole, 48.5%) as their SOC antibiotic.  A total of 3.6% of subjects received oral fidaxomicin (alone or with IV metronidazole). Subjects with a recurrent CDI more often received vancomycin (71%), while subjects with primary CDI more often received metronidazole (60%).  Consistent with the overall study results, clinical cure rates were similar in the bezlo and placebo groups regardless of the SOC antibiotic received (table).  CDI recurrence rates were lower among subjects who received bezlo compared with those who received placebo in all 3 SOC subgroups (table).

Conclusion:  Subjects given bezlotoxumab demonstrated significantly less CDI recurrence regardless of choice of SOC antibiotics.  Bezlotoxumab did not affect the initial clinical response at end of SOC therapy.