Mechanism of beta-lactamase inhibition: differences between sulbactam and other inhibitors

Three different types of beta-lactamases--TEM-2 type penicillinase, a typical cephalosporinase of Citrobacter freundii, and a Proteus vulgaris cephalosporinase with broad substrate range--were studied to determine the inactivation and reactivation kinetics for beta-lactamase inhibitors of these enzymes. Sulbactam, cloxacillin sulfone, clavulanic acid, imipenem, and aztreonam were evaluated. On the basis of the kinetic parameters a minimum scheme for the inactivation of these beta-lactamases by each compound was proposed, and the difference in the features of each of these as progressive and competitive inhibitors were evaluated. The relationship between the kinetic parameters and the synergistic effects of the inhibitors in combination with traditional beta-lactam antibiotics on the bacterial strains producing these beta-lactamases was examined. A close relationship between the synergistic effect, expressed as the FIC index, and a proposed parameter, TN x Ki/Km, was demonstrated. The results of this analysis suggest that sulbactam is a beta-lactamase inhibitor applicable to a wide range of beta-lactamase types.