Emergence of resistance during therapy with the newer beta-lactam antibiotics: role of inducible beta-lactamases and implications for the future

Abstract

A number of beta-lactam antibiotics that are relatively resistant to hydrolysis by beta-lactamases have been developed. This characteristic has expanded the antibacterial spectrum of the drugs beyond that of their progenitors. However, it also appears responsible for several problems that have been observed with the new drugs, including the development of microbial cross-resistance to multiple beta-lactam antibiotics and occasionally to the aminoglycosides. Strains most often involved are Enterobacter, Serratia, and Pseudomonas-genera that characteristically possess inducible beta-lactamases. Derepression of these enzymes is one mechanism shown to be responsible for the development of resistance to multiple beta-lactam antibiotics. Since in most instances the drugs are not susceptible to hydrolysis by these enzymes, resistance is produced by a nonhydrolytic barrier mechanism; i.e., the beta-lactamases bind the drugs, thus preventing their access to target proteins. Alterations in permeability and in penicillin-binding proteins are other possible mechanisms by which resistance may develop; however, these have not been investigated extensively. In addition to the problem of emergence of resistance, potential problems include the impact of multiply beta-lactam-resistant strains as nosocomial pathogens and antagonism between beta-lactam antibiotics used in combination. Only through a careful assessment of the relative advantages and disadvantages of these new beta-lactam antibiotics can their appropriate place in chemotherapy and chemoprophylaxis be identified.