By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a selective, fully human monoclonal antibody directed at Clostridium difficilie toxin B. Binding of toxin B neutralizes its toxic effect. Bezlotoxumab is marketed as Zinplava.
Bezlotoxumab is indicated to reduce recurrence of C. difficile infection (CDI) in patients ≥ 18 years of age who are receiving antibacterial treatment of CDI and are at high risk for CDI recurrence.1
The recommended dose is a single dose of 10 mg/kg administered intravenously over 60 minutes during antibacterial treatment.1 Bezlotoxumab is available as a single-dose vial containing 1 g of bezlotoxumab or 25 mg/mL.
Bezlotoxumab neutralizes the effect of toxin B and reduces the rate of recurrence of CDI.
In subjects with underlying congestive heart failure, the frequency of heart failure was 12.7% in those randomized to bezlotoxumab compared to 4.8% in the placebo group.1 More deaths were associated with this population (19.5% vs. 12.5%). Bezlotoxumab was associated with infusion-specific adverse reactions in 10% of subjects compared to 8% for placebo. Other adverse events vs. placebo include nausea (7% vs. 5%), pyrexia (5% vs. 3%), and headache (4% vs. 3%).
The efficacy and safety of bezlotoxumab was assessed in two similar randomized, double-blind, placebo-controlled studies in subjects receiving standard of care (SoC) antibacterial treatment (metronidazole, vancomycin, or fidaxomicin) for a confirmed diagnosis of CDI.1 Subjects were randomized to a single-dose of bezlotoxumab or placebo. In study one, 403 patients were randomized to bezlotoxumab and 404 to placebo. Study two randomized 407 and 399, respectively. The median time for the single-dose bezlotoxumab infusion was three days after the start of SoC (range -1 to 14). The efficacy endpoint was clinical cure, and those who achieved cure were assessed for recurrence through 12 weeks after infusion. Clinical cure was defined as no diarrhea for two consecutive days following the completion of ≤ 14 days of treatment. Recurrence was defined as development of a new episode of diarrhea and positive stool test of toxigenic C. difficile. Sustained clinical response was defined as clinical cure and no recurrence through 12 weeks after infusion. Sustained clinical response was 60.1% for bezlotoxumab vs. 55.2% for placebo in study one, and 66.8% vs. 52.1%, respectively, for study two. Statistical significance was achieved in study two only. Recurrence was significantly lower with bezlotoxumab (17.4% vs. 27.6% and 15.7% vs. 25.7%, respectively).
C. difficile is the leading cause of antibiotic-associated diarrhea. Two endotoxins (A and B) are secreted by the disease-causing strains.2 The original Phase III studies included bezlotoxumab, actoxumab (antibody to toxin A), or the combination. Treatment with actoxumab or the combination provided no benefit; therefore, only bezlotoxumab was marketed.3 Toxin B is thought to be primarily responsible for disease symptoms.2 The drug appears to have marginal effect in producing sustained clinical effect but appears to reduce recurrence. The effect may be greater in those with high risk of CDI recurrence. These include ≥ 65 years of age, history of CDI in the past six months, immunocompromised state, severe CDI at presentation, or C. difficile ribotype 027. In patients with a history of congestive heart failure, risk vs. benefit must be assessed before treatment.1 The cost for bezlotoxumab was not available at the time of this review. It is expected to be available in the first quarter of 2017.
- Zinplava Prescribing Information. Merck & Co., Inc. October 2016.
- Carter GP, Chakravorty A, Pham Nguyen TA, et al. Defining the roles of TcdA and TcdB in localized gastrointestinal disease, systemic organ damage, and the host response during clostridium difficile infections. MBio 2015 Jun 2;6:e00551. doi: 10.1128/mBio.00551-15.
- Merck. Pivotal Phase 3 Studies of Bezlotoxumab, Merck’s Investigational Antitoxin to Prevent clostridium difficile Infection Recurrence, Met Primary Endpoint. Available at: http://bit.ly/1F9lrXv. Accessed Nov. 21, 2016.