Clinical significance of beta-lactamase induction and stable derepression in gram-negative rods.
Most strains of enterobacteria and Pseudomonas aeruginosa produce chromosomally-determined Class I beta-lactamases. When synthesized copiously these enzymes cause resistance to almost all beta-lactams, except imipenem and, sometimes, carbenicillin and tenocillin. Elevated beta-lactamase production arises transiently, via induction, in Pseudomonas aeruginosa and Enterobacter, Citrobacter, Morganella, indole-positive Proteus and Serratia spp. when these organisms are exposed to beta-lactams. Permanent high-level enzyme production arises via mutation, in the stably-derepressed mutants of these species. These mutants arise spontaneously at high frequency (10(-5) -10(-8). Most early penicillins and first-generation cephalosporins are strong inducers of Class I enzymes at sub-inhibitory concentrations, as are cefoxitin and imipenem. Consequently their MICs reflect what lability these antibiotics have to inducibly-expressed beta-lactamase. Except with imipenem this lability usually is so great that the inducible enzyme causes clinical resistance. Although most other newer cephalosporins and ureidopenicillins are labile to the Class I enzymes they induce poorly below the MIC, and their lability is not reflected in resistance unless secondary inducers (e.g. cefoxitin or imipenem) are present. Although the weak inducer activity of these agents helps to maintain their activity against the inducible cells it renders the drugs highly selective for the pre-existing stably-derepressed mutants. Many cases have been reported where stably-derepressed mutants have overrun inducible populations of bacteria in patients undergoing therapy with beta-lactamase-labile weak inducers such as ureidopenicillin and third-generation cephalosporins.
Livermore
D M
DM
Department of Medical Microbiology, London Hospital Medical College, UK.
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology*; D004352:Drug Resistance, Microbial; D004790:Enzyme Induction; D004794:Enzyme Repression; D006090:Gram-Negative Bacteria / Q000201:enzymology*; D006801:Humans; D001618:beta-Lactamases / Q000096:biosynthesis*; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D001618:beta-Lactamases