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.[5] In MRSA, the mecA gene located on the staphylococcal chromosome cassette mec encodes PBP2a.[6] 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.[7] Currently available β-lactams are not equipped to acylate PBP2a within this groove.[8] Ceftobiprole possesses a vinylpyrrolidinone moiety at position 3, which aids in the interaction with PBP2a.[5] As such, ceftobiprole is active against resistant S. aureus isolates due to mecA production of PBP2a.
Davies et al.[9] 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
Comments