resize_shutterstock_443084233-convertedThe US Food and Drug Administration (FDA) have approved bezlotoxumab injection (ZINPLAVA®, Merck) to reduce the recurrence of Clostridium difficile infection (CDI) in patients aged 18 years or older1-3.

The human monoclonal antibody is specifically indicated for adults who are taking an antibiotic for CDI and are at risk of becoming infected again. Not an antibiotic itself, bezlotoxumab binds to and neutralizes toxin B, one of several toxins produced by C difficile and the one considered central to the life-threatening virulence of the bacteria. Bezlotoxumab is administered intravenously (IV) as a single dose of 10 mg/kg over 1 hour3. ZINPLAVA® is indicated to reduce recurrence of Clostridium difficile infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at high risk for CDI recurrence. ZINPLAVA is not indicated for the treatment of CDI. ZINPLAVA is not an antibacterial drug. ZINPLAVA should only be used in conjunction with antibacterial drug treatment of CDI2.

CDI is caused by bacteria that produce toxins, including toxin B. Symptoms of CDI include mild-to-severe diarrhea, abdominal pain and fever. The incidence of recurrent CDI is higher in certain patient populations, including people 65 years of age or older and those with compromised immune systems2. Clostridium difficile (C. difficile) caused almost half a million infections among patients in the United States in a single year, according to a study released by the Centers for Disease Control and Prevention (CDC) 4. Approximately 29,000 patients died within 30 days of the initial diagnosis of C. difficile. Of those, about 15,000 deaths were estimated to be directly attributable to C. difficile infections, making C. difficile a very important cause of infectious disease death in the United States. More than 80 percent of the deaths associated with C. difficile occurred among Americans aged 65 years or older. C. difficile causes an inflammation of the colon and deadly diarrhea4.

Previous studies indicate that C. difficile has become the most common microbial cause of healthcare-associated infections in U.S. hospitals and costs up to $4.8 billion each year in excess health care costs for acute care facilities alone. Studies have found that 1 out of every 5 patients with a healthcare-associated C. difficile infection experienced a recurrence of the infection and 1 out of every 9 patients aged 65 or older with a healthcare-associated C. difficile infection died within 30 days of diagnosis. Although more than 150,000 of the half a million infections in the new study were community-associated and thus had no documented inpatient health care exposure, a separate recent CDC study found that 82 percent of patients with community-associated C. difficile infections reported exposure to outpatient health care settings such as doctor’s or dentist’s offices in the 12 weeks before their diagnosis; this finding underscores the need for improved antibiotic use and infection control in these settings as well. It is estimated that more than 50 percent of antibiotics are prescribed unnecessarily in outpatient settings for upper respiratory infections like cough and cold illness, most of which are caused by viruses4.

In June, the FDA’s Antimicrobial Drugs Advisory Committee voted 10 to 5, with 1 abstention, to recommend approval of bezlotoxumab, primarily on the basis of two phase 3 trials that were randomized, multicenter, double-blinded, and placebo-controlled. Nausea, fatigue, fever, and headache were among the most common adverse events experienced on the day of infusion, or the day after, according to Merck. They also made the list of the most common adverse events within 4 weeks of infusion. Twelve weeks out, heart failure emerged as a serious adverse reaction3.

Heart failure was reported more commonly in the two Phase 3 clinical trials in ZINPLAVA® treated patients compared to placebo treated patients. These adverse reactions occurred primarily in patients with underlying congestive heart failure (CHF). In patients with a history of CHF, 12.7% (15/118) of ZINPLAVA® treated patients and 4.8% (5/104) of placebo-treated patients had the serious adverse reaction of heart failure during the 12-week study period. Additionally, in patients with a history of CHF, there were more deaths in ZINPLAVA® treated patients [19.5% (23/118)] than in placebo-treated patients [12.5% (13/104)] during the 12-week study period. The causes of death varied, and included cardiac failure, infections, and respiratory failure. In patients with a history of CHF, ZINPLAVA® (bezlotoxumab) should be reserved for use when the benefit outweighs the risk2.

The most common adverse reactions occurring within 4 weeks of infusion with a frequency greater than placebo and reported in ≥4% of patients treated with ZINPLAVA and Standard of Care (SoC) antibacterial drug therapy vs placebo and SoC antibacterial drug therapy included nausea (7% vs 5%), pyrexia (5% vs 3%) and headache (4% vs 3%). Serious adverse reactions occurring within 12 weeks following infusion were reported in 29% of ZINPLAVA® treated patients and 33% of placebo-treated patients. Heart failure was reported as a serious adverse reaction in 2.3% of ZINPLAVA® treated patients and 1.0% of placebo-treated patients2.

In ZINPLAVA® treated patients, 10% experienced one or more infusion specific adverse reactions compared to 8% of placebo-treated patients, on the day of or the day after, the infusion. Infusion specific adverse reactions reported in ≥0.5% of patients receiving ZINPLAVA and at a frequency greater than placebo were nausea (3%), fatigue (1%), pyrexia (1%), dizziness (1%), headache (2%), dyspnea (1%) and hypertension (1%). Of these patients, 78% experienced mild adverse reactions, and 20% of patients experienced moderate adverse reactions. These reactions resolved within 24 hours following onset2.

Readers of this blog are highly encouraged to read the links/references provided below thoroughly to gain additional perspective on this topic. Interested parties should also read other pertinent scientific publications on this topic readily available in the published scientific literature.