Pharmacology and Mechanism of Action
Transpeptidases, or penicillin-binding proteins (PBPs), cross-link polypeptide chains in bacterial cell walls and are the target for β-lactam antibiotics. β-Lactam antibiotics mimic the substrate for PBPs, bind irreversibly by covalent acylation, and incapacitate PBPs, all of which result in cell death. In MRSA, the mecA gene located on the staphylococcal chromosome cassette mec encodes PBP2a. The extended-spectrum cephalosporin, ceftobiprole, was developed specifically to bind to PBP2a of MRSA.[3,5] Crystallography revealed that PBP2a is located in a narrow groove on the bacterial cell surface. Currently available β-lactams are not equipped to acylate PBP2a within this groove. Ceftobiprole possesses a vinylpyrrolidinone moiety at position 3, which aids in the interaction with PBP2a. As such, ceftobiprole is active against resistant S. aureus isolates due to mecA production of PBP2a.
Davies et al. determined the PBP affinity of ceftobiprole in S. aureus, Streptococcus pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole had good affinity (50% inhibitory concentration [IC 50 ] 1 µg/mL) for PBP1, PBP2, PBP3, and PBP4 in a methicillin-susceptible S. aureus (MSSA) isolate and for PBP2a in an MRSA isolate. In S. pneumoniae, ceftobiprole had an IC 50 of 0.06 µg/mL or less for PBP1a, PBP2b, and PBP2x in a penicillin-susceptible isolate and an IC 50 of 1 µg/mL or less for PBP1a and PBP2x in a penicillin-resistant S. pneumoniae isolate. Ceftobiprole exhibited high affinity for PBP1a, PBP2, PBP3, and PBP4 in E. coli. An IC 50 of 0.5 µg/mL or less was shown for PBP1a, PBP1b, PBP3, and PBP4, and no affinity was observed for PBP5/6 in P. aeruginosa. Potent inhibition of multiple PBPs, specifically PBP2a in MRSA, PBP2x in penicillin-resistant S. pneumoniae, and PBP3 in E. coli and P. aeruginosa, explains ceftobiprole's broad activity spectrum.[8,10]
The Annals of Pharmacotherapy. 2008;42(6):806-816. © 2008 Harvey Whitney Books Company
Cite this: Ceftobiprole: An Extended-Spectrum Anti–Methicillin-Resistant Staphylococcus aureus Cephalosporin - Medscape - Jun 01, 2008.