Mechanisms of action and antimicrobial activity of ceftobiprole

Abstract

Ceftobiprole, a novel last generation parenteral cephalosporin, has an extended spectrum of activity, notably against methicillin-resistant Staphylococcus aureus (MRSA), ampicillin-susceptible enterococci, penicillin-resistant pneumococci, Enterobacterales and susceptible Pseudomonas aeruginosa. It exerts an inhibitory action on essential peptidoglycan transpeptidases, interfering with cell wall synthesis. The inhibitory action of ceftobiprole through binding to abnormal PBPs like PBP2a in methicillin-resistant staphylococci and PBP2b and PBP2x in the case of β-lactam-resistant pneumococci, ultimately leads to rapid bacterial cell death. In the case of Enterobacterales, ceftobiprole retains activity against narrow spectrum β-lactamases but is hydrolysed by their extended-spectrum counterparts, overexpressed Amp C, and carbapenemases. It is also affected by certain efflux pumps from P. aeruginosa. For anaerobic bacteria, ceftobiprole is active against Gram-positive Clostridioides difficile and Peptococcus spp. and Gram-negative Fusobacterium nucleatum but not against Bacteroides group or other anaerobic Gram-negatives. In in vitro studies, a low propensity to select for resistant subpopulations has been demonstrated. Currently, ceftobiprole is approved for the treatment of community-acquired pneumonia and hospital-acquired pneumonia with the exception of ventilator-associated pneumonia. Ceftobiprole's place in therapy appears to lie mainly in its combined activity against Gram-positive organisms, such as S. aureus and S. pneumoniae alongside that against Gram-negative organisms such as P. aeruginosa.

Figure 1

A: Ceftobiprole, the active cephalosporin. B: Ceftobiprole medocaril, the watersoluble prodrug. Substitution at position 7 of the cephem by an oxyimino aminothiazolyl confers remarkable betalactamase stability and substitution at position 3 with a vinylpyrrolidinone moiety facilitates the association of the molecule with PBP2a and hence facilitates the subsequent acylation reaction.

Figure 2

Ceftobiprole binding to PBPs of different microorganisms in comparison with other beta-lactam compounds [7-12]

Figure 3

MIC distributions of methicillinsusceptible and resistant S. aureus (A), penicillin-susceptible, -intermediate and -resistant S. pneumoniae (B) and ceftazidime-susceptible and -resistant P. aeruginosa (C) isolates recovered from European surveillance studies (data obtained from reference [21])