Journal of Antimicrobial Chemotherapy, Vol 41, 25-41, Copyright © 1998 by The British Society for Antimicrobial Chemotherapy
DM Livermore
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.
ORIGINAL ARTICLES
Beta-lactamase-mediated resistance and opportunities for its control
Central Public Health Laboratory, London, UK. d.m.livermore@mds.amw.ac.uk
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