β-Lactamase-mediated resistance and opportunities for its control

Abstract

Clinical use of β-lactams has selected for β-lactamase-producing organisms. Numerous β-lactamases are known, and sequencing allows them to be divided into four Classes, A to D, with Classes A and C being the most important. Pharmaceutical chemists have responded to the spread of β-lactamase-producing organisms by developing stable agents and inhibitors. Stability in penicillins and cephalosporins is achieved by attaching a bulky substituent to the amino group of 6-aminopenicillanic acid or 7-aminocephalosporanic acid, or by replacing the hydrogen on carbon 6 (penicillins) or 7 (cephalosporins) with an α-methoxy group. In carbapenems, stability is achieved by incorporation of a simple trans-6-hydroxyethyl group. β-Lactamase-inhibitory activity occurs in many β-lactam classes but only clavams and penicillanic acid sulphones have been developed specifically as β-lactamase inhibitors. These inhibit most Class A and some Class D enzymes but act poorly against Class B and C enzymes. Their success is affected by the amount of enzyme, the permeability of the bacterial cell wall, the partner β-lactam and the pH. Piperacillin/tazobactam, which combines a good inhibitor of Class A enzymes with a broad-spectrum, easily-protected penicillin, has wide activity against common pathogens, the major exceptions being strains of Enterobacter, Serratia and Citrobacter freundii that produce large amounts of Class C enzymes, and Gram-positive cocci with modified penicillin-binding proteins. β-Lactamase-stable β-lactams and inhibitor combinations overcome many existing resistance mechanisms but are themselves selecting new resistances. Few new β-lactams able to overcome these resistances are advanced in development and consequently the opportunities for control lie mostly in the more prudent use of compounds already available.