Mechanisms of resistance to beta-lactam antibiotics in strains of Staphylococcus aureus

There are three major mechanisms of resistance of Staphylococcus aureus to beta-lactam antibiotics: enzyme mediated (penicillinase or beta-lactamase) by which the antibiotic is inactivated; intrinsic, which is not due to drug inactivation, and accounts for methicillin-resistance; and tolerance, in which there is a dissociation of the inhibitory and killing actions of beta-lactam antibiotics. In enzyme-mediated resistance, there are at least three different staphylococcal beta-lactamases, which probably account for differences in the inoculum effect with different cephalosporins. The intrinsic resistance is associated with differences in the affinity of beta-lactams for penicillin-binding proteins, but intrinsic resistance is probably more complex, because the pH of the medium, chelating agents, visible light, and temperature also effect its expression. Tolerance is clearly due to decreased autolytic enzyme activity (reflecting persistance of an enzyme inhibitor) of those tolerant organisms that need 32 (or more) times as much antibiotic for a bactericidal effect as for simple inhibition. T H E R E ARE THREE general types of resistance to the pen-icillins and cephalosporins shown by staphylococci. The best known form of resistance is drug inactivation due to beta-lactam inactivating enzymes properly defined as beta-lactamases. The second form of resistance is intrin-sic, due to some mechanism other than the inactivation of the antibiotic. The third form of resistance is tolerance to the killing action of penicillins and cephalosporins. There is considerable information about details of the first form of resistance, and some about the second and third forms. The clinical importance of the beta-lactamase-mediated resistance has been well recognized since the early 1940s. The importance of intrinsic resistance and tolerance has only recently been appreciated. Evidence indicates that each of the three forms of resistance is present in both Staphylococcus aureus and coagulase-negative staphylo-cocci. Table 1 shows the features of the three forms. There are instances of a single strain having all three forms of resistance. In this article I will summarize the mechanisms of resistance of S. aureus to the beta-lactam antibiotics