Beta-lactamase-mediated resistance and opportunities for its control.
Clinical use of beta-lactams has selected for beta-lactamase-producing organisms. Numerous beta-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 beta-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 alpha-methoxy group. In carbapenems, stability is achieved by incorporation of a simple trans-6-hydroxyethyl group. Beta-lactamase-inhibitory activity occurs in many beta-lactam classes but only clavams and penicillanic acid sulphones have been developed specifically as beta-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 beta-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. Beta-lactamase-stable beta-lactams and inhibitor combinations overcome many existing resistance mechanisms but are themselves selecting new resistances. Few new beta-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.
Livermore
D M
DM
Central Public Health Laboratory, London, UK. d.m.livermore@mds.amw.ac.uk
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism*; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D001618:beta-Lactamases