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General Information
Zevtera (ceftobiprole medocaril sodium) is a cephalosporin antibacterial.
Zevtera is specifically indicated for the treatment of:
- Adult patients with Staphylococcus aureus bloodstream infections (bacteremia) (SAB), including those with right-sided infective endocarditis caused by methicillin-susceptible and methicillin-resistant isolates.
- Adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following gram-positive and gram-negative microorganisms: Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, and Klebsiella pneumoniae.
- Adult and pediatric patients (3 months to less than 18 years old) with community-acquired bacterial pneumonia (CABP) caused by susceptible isolates of the following gram-positive and gram-negative microorganisms: Staphylococcus aureus (methicillin- susceptible isolates), Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Escherichia coli, and Klebsiella pneumoniae.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zevtera and other antibacterial drugs, Zevtera should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
Dosing/Administration
Recommended Dosage and Administration for SAB, ABSSSI and CABP in Adult Patients
The recommended dosage is shown below. The duration of treatment in adult patients is up to 42 days for SAB and 5 days to 14 days for ABSSSI and CABP. Administer each prepared intravenous infusion solution of Zevtera over 2 hours at a concentration of 2.67 mg/mL to adult patients.
Indication | Dose | Frequency |
SAB | 667 mg | Every 6 hours on Days 1 to 8; Every 8 hours from Day 9 |
ABSSSI | 667 mg | Every 8 hours |
CABP | 667 mg | Every 8 hours |
Recommended Dosage and Administration for CABP in Pediatric Patients (3 months to less than 18 years old)
For treatment of pediatric patients with CABP, the recommended dosage is shown below, based on patient age and weight. The duration of treatment for CABP in pediatric patients (3 months to less than 18 years old) is 7 days to 14 days. Administer each prepared intravenous infusion solution of Zevtera over 2 hours at a concentration of 2.67 mg/mL for patients 12 years to less than 18 years old and at a concentration of 5.33 mg/mL for patients greater than or equal to 3 months to less than 12 years old.
Pediatric Age Group | Dose | Frequency |
12 years to less than 18 years old | 13.3 mg/kg (up to 667 mg/dose) | Every 8 Hours |
3 months to less than 12 years old | 20 mg/kg (up to 667 mg/dose) | Every 8 Hours |
Mechanism of Action
Zevtera (ceftobiprole medocaril sodium) is a cephalosporin with bactericidal activity by inhibition of bacterial cell wall synthesis. Ceftobiprole has in vitro activity against gram-positive and gram-negative bacteria, including methicillin-resistant and susceptible Staphylococcus aureus. Bactericidal activity is mediated through binding to essential penicillin-binding proteins (PBPs) and inhibiting their transpeptidase activity, which is essential for the synthesis of the peptidoglycan layer of the bacterial cell wall. Ceftobiprole has a high affinity for S. aureus PBPs 1 – 4, including PBP2a in methicillin-resistant Staphylococcus aureus, and PBP2x and PBP2b in penicillin-resistant Streptococcus pneumoniae
Side Effects
Adverse effects associated with the use of Zevtera may include, but are not limited to, the following:
- SAB (adult patients): anemia, nausea, hypokalemia, vomiting, hepatic enzyme and bilirubin increased, diarrhea, blood creatinine increased, hypertension, leukopenia, and pyrexia
- ABSSSI (adult patients): nausea, diarrhea, headache, injection site reaction, hepatic enzyme increased, rash, vomiting, and dysgeusia
- CABP Adult Patients: nausea, hepatic enzyme increased, vomiting, diarrhea, headache, rash, insomnia, abdominal pain, phlebitis, hypertension, and dizziness
- CABP Pediatric Patients (3 months to less than 18 years of age: vomiting, headache, hepatic enzyme increased, diarrhea, infusion site reaction, phlebitis and pyrexia
Clinical Trial Results
The FDA approval of Zevtera was supported by clinical efficacy and safety data from the phase 3 studies ERADICATE (SAB) and TARGET (ABSSSI), and a phase 3 study in CABP.
ERADICATE
In this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated S. aureus bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome was overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia-related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%.
The final analysis included 387 patients. A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively) and the percentage of patients with microbiologic eradication (82.0% and 77.3%).
TARGET
The randomized, double-blind, active-controlled, parallel-group, multicenter, phase 3 noninferiority study compared ceftobiprole with vancomycin plus aztreonam. The Food and Drug Administration-defined primary efficacy endpoint was early clinical response 48-72 hours after treatment initiation in the intent-to-treat (ITT) population. Noninferiority was defined as the lower limit of the 95% CI for the difference in success rates (ceftobiprole minus vancomycin/aztreonam) >-10%.
A total of 679 patients were randomized to ceftobiprole (n = 335) or vancomycin/aztreonam (n = 344). Early clinical success rates were 91.3% and 88.1% in the ceftobiprole and vancomycin/aztreonam groups, respectively, and noninferiority was demonstrated (adjusted difference: 3.3%; 95% CI: -1.2, 7.8). Investigator-assessed clinical success at the TOC visit was similar between the 2 groups, and noninferiority was demonstrated for both the ITT (90.1% vs 89.0%) and clinically evaluable (97.9% vs 95.2%) populations. Both treatment groups displayed similar microbiological success and safety profiles.
CABP
This was a multicentre, double-blind study in which 706 patients with CAP severe enough to require hospitalization were randomized to ceftobiprole or to a course of ceftriaxone ± linezolid (comparator group). Clinical and microbiological outcomes were determined 7-14 days after completion of therapy (test-of-cure visit). For the 469 clinically evaluable patients, cure rates were 86.6% vs. 87.4% for ceftobiprole and comparator, respectively [95% confidence interval (CI) of the difference, -6.9% to 5.3%]; in the intention-to-treat (ITT) analysis of 638 CAP patients, these cure rates were 76.4% vs. 79.3%, respectively (95% CI of the difference, -9.3% to 3.6%). A typical bacterial pathogen was identified in 29% of the ITT population. Microbiological eradication rates in the 144 microbiologically evaluable patients were 88.2% and 90.8% for the respective treatment groups.