Binding affinity for penicillin-binding protein 2a correlates with in vivo activity of beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus

Abstract

The beta-lactam antibiotics ticarcillin, nafcillin, imipenem, and ampicillin, which differ in antibacterial activity against methicillin-resistant strains of Staphylococcus aureus, were examined for affinity to penicillin-binding protein (PBP) 2a, which mediates methicillin resistance. The relative efficacy of each antibiotic was compared to vancomycin in a rabbit model of aortic valve endocarditis caused by either a methicillin-susceptible or methicillin-resistant strain of beta-lactamase-producing S. aureus. beta-lactamase inhibitors clavulanate and sulbactam were used in combination with ticarcillin and ampicillin, respectively. All beta-lactam antibiotics were effective against the susceptible strain. beta-lactam antibiotic activity in vitro and in vivo against the resistant strain correlated with its affinity for binding to PBP 2a. Lack of efficacy of beta-lactam antibiotics for the resistant strain was due to an inability to eradicate the resistant subpopulation of cells. Vancomycin was the most effective agent.