Regulatory Decision Summary for Zevtera

Zevtera (ceftobiprole medicaril) is a cephalosporin antibiotic drug and has a broad antimicrobial spectrum against a wide variety of gram-positive and gram-negative bacterial pathogens in vitro as well as in vivo. Ceftobiprole 500 mg intravenously administered within 2 hours every 8 hours daily for a treatment duration up to 14 days showed non-inferiority in the clinical cure rates (CCRs) at Test of Cure (TOC) visit as compared with the two-drug combination control (linezolid + ceftazidime) among patients with HAP including VAP. Due to the significant differences in the CCRs and demographic components between the subgroups of HAP excluding VAP and the VAP, the use of ceftobiprole only in Non-VAP subpopulation within HAP is considered clinically beneficial. Per pathogen CCRs as well as microbiological eradicate rates (MERs) showed clinical benefits in HAP caused by various susceptible gram-positive pathogens [that is (i.e), S.aureus including methicillin-resistant S. aureus (MRSA) and S.pneumoniae] and gram-negative pathogens (i.e., E.coli and K. pneumoniae). Although P. aeruginosa was among prevalent gram-negative pathogens in HAP patients in the trial, due to the trial design to permitting concomitant anti-pseudomonal therapy in suspected or proven P.aeruginosa infection cases at baseline, and the fact of the existence of resistant strains in vitro, the use of ceftobiprole is not considered clinically beneficial to HAP (Non-VAP) patients with P.aeruginosa at this time. Likewise, the CCRs and MERs of Non-VAP patients with baseline H.influenza were, with limited number of isolates, lower in the ceftobiprole group (50%, 4/8) than that in the comparator group (75%, 9/12) and therefore not justified to be included in the approved indications for HAP. The 30-day all-cause mortality rates, as well as 30-day pneumonia-specific mortality rates, were comparable among the 2 treatment arms.

Ceftobiprole administered with a similar regimen among adult patients with CAP requiring hospitalization showed non-inferiority in the CCRs at TOC as compared with the comparator group (ceftriaxone ± linezolid) in both the clinically-evaluable (CE) and intent-to-treat (ITT) analysis sets. The majority of patients in both treatment arms had oral switch to cefuroxime axetil (55% in ceftobiprole group versus 58% in the comparator group in the CE set). Only 14% of patients in the comparator group were administered linezolid in the CE set. The CCRs for non-switchers were numerically lower than those who switched but comparable between treatment arms. The clinically effective antimicrobial spectrum of ceftobiprole in HAP and CAP clinical situations were largely overlapping (for example, S. aureus including MRSA and S. pneumoniae for gram-positive pathogens and E.coli and K.pneumoniae for gram-negative pathogens). In addition, ceftobiprole use is considered beneficial in CAP caused by H. influenzae.

Zevtera administered at 500 mg using a 120-minute intravenous infusion every 8 hours for a treatment duration of up to 14 days was safe and well tolerated in the clinical studies. No statistically significant differences were observed between the treatment groups in the overall incidence of adverse events, deaths, serious adverse events, or discontinuations due to adverse events. Dysgeusia, nausea and vomiting were reported at a slightly higher rate in the ceftobiprole group in the CAP study but occurred with similar frequency in the HAP study. Most of these events were mild and moderate in severity and can be managed symptomatically. Seizures were reported more in the ceftobiprole group in the HAP study and were mostly associated with a history of seizure in most of these patients. There were also patients, especially in the intensive care unit (ICU) with high renal clearance (CrCL) >150 mL/min in the HAP study. To mitigate the risk associated with treating some ICU patients with high renal clearance, it is recommended that the baseline CrCL be measured prior to treatment. For this group of patients, a prolongation of infusion duration to 4 hours is recommended. For patients with end-stage renal disease with or without intermittent hemodialysis, Zevtera is recommended to be administered with a reduced dose (250 mg) and a longer interval between doses (24-hour).

Based on the evidence provided, the benefits of Zevtera for the specified indications are considered to outweigh any possible risks at this time.