Ceftobiprole: First Cephalosporin with Activity Against Methicillin‐Resistant Staphylococcus aureus

Abstract

Ceftobiprole medocaril is the first member of a new series of advanced cephalosporins with activity against methicillin-resistant Staphylococcus aureus (MRSA). The drug received an approvable letter from the United States Food and Drug Administration (FDA) in March 2008 and from Health Canada in June 2008 for the treatment of complicated skin and skin structure infections including diabetic foot infections. Ceftobiprole exerts its antibacterial activity by inhibiting the penicillin-binding proteins (PBPs) involved in cell wall synthesis. It has an established stability against hydrolysis by many gram-positive beta-lactamases and a higher affinity for various PBPs (such as PBP2a of MRSA or PBP2x of Streptococcus pneumoniae), which leads to a wider spectrum of activity compared with older beta-lactams. Ceftobiprole activity does not cover extended-spectrum beta-lactamase-producing Enterobacteriaceae and some other pathogens, including Enterococcus faecium or Acinetobacter baumanii. Generally well tolerated, with nausea and taste disturbance being the most common adverse events, ceftobiprole appeared noninferior to empiric therapy in several clinical trials. Ceftobiprole is available only for intravenous administration; recommended dosage regimens have not been approved by the FDA as of this writing. However, based on the Canadian package insert, expected dosage recommendations are 500 mg as a 1-hour intravenous infusion every 12 hours for the treatment of complicated skin and skin structure infections caused by certain gram-positive pathogens, and 500 mg as a 2-hour infusion every 8 hours when susceptible gram-negative or both gram-positive and susceptible gram-negative pathogens are involved. Dosage adjustments are indicated for patients with moderate or severe renal impairment, and dosage recommendations are expected to be 500 or 250 mg, respectively, as a 2-hour infusion every 12 hours. Several precautions regarding hypersensitivity and drug incompatibility are reported. Ceftobiprole represents a promising option for the treatment of mono- and polymicrobial infections caused by multidrug-resistant gram-positive and susceptible gram-negative pathogens, but further toxicity and safety studies are warranted.

Microtiter Plate-Based Assay for Inhibitors of Penicillin-Binding Protein 2a from Methicillin-Resistant Staphylococcus aureus

“…To demonstrate the utility of the one-step microtiter plate-based assay described here for the characterization of inhibitors of PBP2a, it was used to characterize PBP2a inhibition by ceftobiprole (Fig. 4), a new ␤-lactam designed to inhibit PBP2a and provide a ␤-lactambased treatment option for MRSA infections (2,12,18). The results from the assay of variable concentrations of ceftobiprole versus a fixed concentration of BIO-AMP are shown in This K i app of 6 M is greater than the MIC of ceftobiprole against MRSA of 1.9 M (1 g/ml) (reviewed in reference 18).…”

Ceftaroline

“…Their pharmacokinetics are summarized in Table 1 and spectrum of activity are summarized in Table 2. Ceftobiprole, also commonly referred to as a fifth-or advanced-generation cephalosporin, 31,32 was not approved by the FDA and was recently withdrawn from Switzerland and Canada markets. The second-generation agents can be divided into 2 subgroups, those with activity against Haemophilus influenza (cefuroxime), and the cephamycins (cefoxitin and cefotetan), with activity against anaerobic bacteria.…”

Treatment of Methicillin-Resistant Staphylococcus aureus Surgical Site Infections

“…39,40 Two double-blind, randomized trials have been conducted to assess the safety and efficacy of ceftobiprole for the treatment of complicated skin and skin structure infections with promising data related to clinical cure rates compared with vancomycin Ϯ ceftazidime. It has limited anaerobic coverage.…”