Ceftobiprole Medocaril Sodium for Injection (Zevtera)

By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

The U.S. Food and Drug Administration (FDA) has approved a new cephalosporin antibacterial for the treatment of three serious infections: bloodstream, skin and skin structure, and community-acquired pneumonia. Ceftobiprole is a fifth-generation cephalosporin with in vitro activity against gram-positive and gram-negative bacteria including multidrug resistant organisms. It was given a priority review and Fast Track and Qualified Infectious Disease Product designations. It will be distributed by Basilea Pharmaceutica International Ltd, Allschwil as Zevtera.

INDICATIONS

Ceftobiprole is indicated for the treatment of adults with Staphylococcus aureus bloodstream infections (bacteremia) (SAB), including those with right-sided endocarditis caused by methicillin-susceptible and -resistant isolates; acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of S. aureus, Streptococcus pyogenes, and Klebsiella pneumoniae; and community-acquired bacterial pneumonia (CABP) caused by susceptible isolates of S. aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenza, Escherichia coli, and K. pneumoniae.¹ It also is indicated for the treatment of pediatric patients with CABP.

DOSAGE

For adults, the recommended dose is 500 mg of ceftobiprole by intravenous infusion (667 mg of ceftobiprole medocaril sodium) every eight hours for ABSSSI and CABP. For SAB, the regimen is every six hours on days 1 to 8 and every eight hours from day 9. The duration of treatment is 5 to 14 days for ABSSSI and CABP and up to 42 days for SAB. The dose for pediatric patients 12-18 years of age is 13.3 mg/kg (up to 667 mg/dose) every eight hours. The dose for pediatric patients ≥ 3 months and < 12 years of age is 20 mg/kg (up to 667 mg/dose) every eight hours. The dosage is reduced in adult patients with creatinine clearance < 50 mL/min. Ceftobiprole is available as the prodrug (ceftobiprole medocaril) in 667 mg single-dose vials.

POTENTIAL ADVANTAGES

Ceftobiprole has in vitro activity against gram-positive and gram-negative bacteria.^1-3 It is bactericidal because of ceftobiprole’s high binding affinity for subtypes of penicillin-binding proteins interfering with peptidoglycan biosynthesis of the bacterial cell wall. Ceftobiprole achieves high concentration due to minimal plasma protein binding.² It is active against methicillin-resistant S. aureus (MRSA), methicillin-resistant coagulase-negative Staphylococci (MR-CoNS), and penicillin-resistant S. pneumoniae. Ceftobiprole does not significantly induce or inhibit cytochrome P450 isoenzymes.¹

POTENTIAL DISADVANTAGES

Ceftobiprole is not active against gram-negative bacteria producing extended-spectrum β-lactamases (ESBLs), such as from the TEM, SHV, or CTX-M families; serine carbapenemases; class B metallo-β-lactamases; and Ambler class D β-lactamases.¹ It is not indicated for ventilator-associated bacterial pneumonia because of associated increase in mortality.¹ Seizures and other central nervous system reactions have been reported with use of other cephalosporins.¹ Compared to comparators, the most common adverse reactions associated with ceftobiprole were nausea and vomiting.¹

COMMENTS

The efficacy of ceftobiprole was demonstrated for the three approved indications in three separate Phase III randomized, active controlled, noninferiority studies. In SAB, ceftobiprole was compared to daptomycin (6 mg/kg up to 10 mg/kg every 24 hours) with or without aztreonam.^1,4 About 30% of study participants received aztreonam. The primary efficacy outcome was overall treatment success at the post-treatment evaluation visit at 70 days after randomization in the modified intention-to-treat population (received study drug and baseline blood culture of S. aureus). This was defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia-related complications, and no receipt of other potentially effective antibiotics. Overall, 6.5% of study participants had infective right-side endocarditis.⁴ The treatment success rate was 69.8% (132/189) for ceftobiprole and 68.7% (136/198) for daptomycin ± aztreonam. All-cause mortality was 9.0% and 9.1%, respectively. Ceftobiprole met the criteria for noninferiority to daptomycin ± aztreonam with respect to overall treatment success.⁴

For ABSSSI, ceftobiprole was compared to vancomycin (1 g or 15 mg/kg every 12 hours plus aztreonam).^1,5 The primary endpoint was early response 48 to 72 hours after start of treatment defined as reduction of primary skin lesion by at least 20%, survival for at least 72 hours, and absence of concomitant antibacterial treatment or additional unplanned surgery. The early response rate was 91.3% (306/335) for ceftobiprole and 88.1% (303/344) for vancomycin/aztreonam. Response rates based on different pathogens appear similar. Ceftobiprole met criteria for noninferiority.⁵

In CABP, ceftobiprole was compared to ceftriaxone ± linezolid.^1,6 The primary efficacy endpoint was clinical cure rate at the test of cure visit (seven to 15 days after end of treatment). Clinical cure was defined as survival with resolution of signs and symptoms of the infection or improvement to such an extent that no further antimicrobial therapy was necessary, improvement or stabilization of chest X-ray findings, and no non-study antibacterial treatment. Cure rates were 76.4% (240/314) for ceftobiprole compared to 79.3% (257/324) for ceftriaxone ± linezolid. The 30-day all-cause mortality rates were 1.6% vs. 2.5%, respectively. Ceftobiprole met the criteria for noninferiority.⁶

CLINICAL IMPLICATIONS

Ceftobiprole is a fifth-generation cephalosporin with a broad spectrum of activity against gram-positive and gram-negative pathogens. It has been shown to be noninferior to a first-line treatment for the approved indications. It is similar to ceftaroline in its antibacterial spectrum but with the added FDA indication for SAB. There are numerous antimicrobial options for ABSSSI and CABP. However, they are limited for SAB, particularly MRSA infection (i.e., vancomycin and daptomycin).⁷ Ceftobiprole may be a viable option for this potentially lethal condition. The cost for ceftobiprole was not available at the time of this review.

REFERENCES

1. Zevtera Prescribing Information. Basilea Pharmaceutica International Ltd. April 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218275s000lbl.pdf
2. Hsu WH, et al. Ceftobiprole medocaril for the treatment of pneumonia. Expert Rev Anti-infect Ther 2023;21:551-563.
3. Tebano G, et al. Antibiotic resistance to molecules commonly prescribed for the treatment of antibiotic-resistant gram-positive pathogens: What is relevant for the clinician? Pathogens 2024;13:88
4. Holland TL, et al. Ceftobiprole for treatment of complicated Staphylococcus aureus bacteremia. N Engl J Med 2023;389:1390-1401.
5. Overcash JS, et al. Ceftobiprole compared with vancomycin plus aztreonam in the treatment of acute bacterial skin and skin structure infections: Results of a phase 3, randomized, double-blind trial (TARGET). Clin Infect Dis 2021;73:e1507-e1517.
6. Nicholson SC, et al. A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation. Int J Antimicrob Agents 2012;39:240-246.
7. Liu C, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: Executive summary. Clin Infect Dis 2011;52:285-292.