Emergence of resistance during beta-lactam therapy of gram-negative infections. Bacterial mechanisms and medical responses.
Some Gram-negative, non-fastidious bacilli, although classified as susceptible by conventional susceptibility testing methods, become resistant during therapy with the newer beta-lactam compounds. Emergence of resistance results primarily from the selection of resistant clones pre-existing within the susceptible bacterial populations. Most of the resistant clones produce large amounts of beta-lactamases which inhibit the beta-lactam antibiotics by hydrolysis, rather than by binding. In addition, resistant clones can limit the penetration of beta-lactam molecules through the outer membrane by a decreased expression of their porins. Less commonly, when beta-lactamase activity together with alteration of the permeability barrier does not prevent the access of the antibiotic molecules to their target, altered penicillin-binding proteins (PBPs) can produce resistance. However, the risk of resistance emerging during therapy varies with the beta-lactam drug administered. Some compounds such as cefpirome, BMY 28142, SCH 34343, or imipenem appear to be associated with a low risk. In addition, emergence of resistance can be reduced by using higher dosages of beta-lactam agents, or by combining them with other drugs such as aminoglycosides or quinolones.
Pechère
J C
JC
Département de Microbiologie, Centre Médical Universitaire, Genève.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002463:Cell Membrane Permeability; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial; D004790:Enzyme Induction; D006090:Gram-Negative Bacteria / Q000378:metabolism; D006602:Hexosyltransferases; D051379:Mice; D008813:Mice, Inbred ICR; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010406:Penicillins / Q000378:metabolism; D010458:Peptidyl Transferases; D010538:Peritonitis / Q000188:drug therapy*; D001618:beta-Lactamases / Q000096:biosynthesis; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D010406:Penicillins; D047090:beta-Lactams; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases