Evolution of beta-lactamase inhibitors.

In most clinical isolates that are resistant to penicillins, cephalosporins and related compounds, the mechanism of resistance is the production of beta-lactamase enzymes. These enzymes hydrolyze the amide bond in the beta-lactam ring of the compound, producing acidic derivatives that have no antibacterial properties. The rationale for beta-lactamase inhibitors is to overcome this resistance. Early study of beta-lactamase inhibition was begun in the 1940s without success. Interest in beta-lactamase inhibition was renewed with the development of the semisynthetic penicillins in the early 1960s, when it was found that certain of these compounds could function as inhibitors. However, none found clinical application. The screening of microorganisms for possible production of naturally occurring beta-lactamase inhibitors resulted in the discovery of the olivanic acids and, later, clavulanic acid. A formulation of clavulanic acid with amoxicillin was introduced in 1981, and a formulation of clavulanic acid with ticarcillin appeared shortly thereafter. More recently, other beta-lactamase inhibitors have been developed, including sulbactam and tazobactam. A formulation of sulbactam with ampicillin has appeared recently. As a result of beta-lactamase inhibition, amoxicillin and clavulanate and ticarcillin and clavulanate are active against a high proportion of amoxicillin resistant and ticarcillin resistant pathogens. These formulations have been shown to be safe and effective in the treatment of many infections that would not be expected to respond to amoxicillin or ticarcillin alone.