The FDA has approved ceftobiprole medocaril sodium for injection (Zevtera) for the treatment of Staphylococcus aureus bloodstream infections (SAB), acute bacterial skin and skin structure infections (ABSSSI) in adults, and community-acquired bacterial pneumonia (CABP) in adult and pediatric patients. This approval introduces a new cephalosporin antibiotic to combat these bacterial infections, backed by data from four clinical trials.
Efficacy Against Staphylococcus aureus Bloodstream Infections (SAB)
The approval for SAB was based on the phase 3 ERADICATE trial (NCT03138733), which compared ceftobiprole to daptomycin. In this study, 390 patients were randomized 1:1 to receive either ceftobiprole or daptomycin. The primary outcome was overall treatment success, encompassing survival, bacteremia clearance, symptom improvement, and the absence of new bacterial complications. Ceftobiprole demonstrated non-inferiority to daptomycin, with overall treatment success rates of 69.8% and 68.7%, respectively.
Treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI)
Ceftobiprole's efficacy in treating ABSSSI was evaluated in the phase 3 TARGET study (NCT03137173), comparing it to vancomycin plus aztreonam. The study randomized 679 patients 1:1 to receive either ceftobiprole or vancomycin plus aztreonam for 5 to 14 days. The primary endpoint was early clinical response 48 to 72 hours after treatment and investigator-assessed clinical success. Ceftobiprole was found to be non-inferior to vancomycin plus aztreonam, with early clinical success rates of 91.3% vs 88.1% and investigator-assessed clinical success rates of 90.1% vs 89.0%, respectively.
Community-Acquired Bacterial Pneumonia (CABP) in Adults and Pediatrics
Two phase 3 trials assessed ceftobiprole for CABP. The adult study involved 638 patients randomized 1:1 to ceftobiprole or ceftriaxone with or without linezolid for 5 to 14 days. The primary outcome was clinical cure rates, which demonstrated the non-inferiority of ceftobiprole compared to ceftriaxone with or without linezolid (76.4% vs 79.3%, respectively).
The pediatric study included 138 patients randomized 2:1 to receive ceftobiprole or a standard-of-care cephalosporin for 7 to 14 days. Early clinical response rates at day 4 were 95.7% and 93.2% for the ceftobiprole and standard-of-care groups, respectively. Clinical cure rates were 90.4% and 97.7%, respectively, indicating similar efficacy between the treatments.
Safety Profile
Clinical trials have associated ceftobiprole with hypersensitivity reactions. Although rare (< 2%), these reactions can be fatal and should be avoided in patients with known severe hypersensitivity to other cephalosporins. Common adverse reactions observed in more than 10% of patients included anemia, nausea, and increased hepatic enzymes. Less common but more serious adverse effects leading to treatment discontinuation included vomiting, rash, and urticaria.
Dosage and Administration
Ceftobiprole requires reconstitution with sterile water for injection or 5% dextrose solution before infusion. For SAB, it is administered as a 667-mg intravenous (IV) dose every 6 hours on days 1 to 8 and every 8 hours thereafter for up to 42 days. For ABSSSI and CABP, the dosage is 667 mg IV every 8 hours for 5 to 14 days. Each infusion should be administered over 2 hours at a concentration of 2.67 mg/mL. For pediatric CABP patients, the dose is 20 mg/kg (max 667 mg/dose) every 8 hours at a concentration of 5.33 mg/mL for those older than 3 months and younger than 12 years, and 13.3 mg/kg (max 667 mg/dose) every 8 hours at 2.67 mg/mL for patients aged 12 to 18 years.
Dose adjustments are necessary for patients with renal impairment, with reduced doses recommended for adult patients with a creatinine clearance less than 50 mL/min/1.73 m2 and pediatric patients with an eGFR less than 50 mL/min/1.73 m2.
