The effects on beta-lactam susceptibility of phenotypic induction and genotypic derepression of beta-lactamase synthesis.
We have compared the ability of beta-lactam antibiotics to induce beta-lactamase synthesis and antagonize the in-vitro activity of other beta-lactams and also to select mutants with derepressed beta-lactamase synthesis amongst representative Gram-negative bacilli that produce inducible beta-lactamases. Both imipenem and cefoxitin were potent inducers of beta-lactamase and were able to antagonize the activity of other beta-lactams against isolates of Enterobacter cloacae, Citrobacter freundii and Pseudomonas aeruginosa when the two beta-lactams were present simultaneously. However, there was no antagonism for any compound against any of the organisms when the imipenem or cefoxitin was removed immediately before susceptibility to the other compounds was measured. Cefotaxime was a less potent inducer of beta-lactamase and failed to antagonize the activity of other compounds, even when present concurrently with them. Neither imipenem nor cefoxitin induced beta-lactamase synthesis in a strain of Escherichia coli, nor did they antagonize the activity of other beta-lactams against this strain. Imipenem was compared with cefotaxime and cefoxitin as an agent for the selection of beta-lactam-resistant variants. Resistant variants were obtained from isolates of Ent. cloacae, C. freundii and P. aeruginosa when cefotaxime or cefoxitin was used as the selective agent. Most of them synthesized beta-lactamase constitutively and showed reduced susceptibility to a wide range of beta-lactams, but not to imipenem. Variants with reduced susceptibility to imipenem were obtained only from the two isolates of P. aeruginosa. They did not show cross resistance to other beta-lactams and were not distinguishable from the parent strains in beta-lactamase production.
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002439:Cefotaxime / Q000494:pharmacology; D002440:Cefoxitin / Q000494:pharmacology; D002954:Citrobacter / Q000187:drug effects; D004352:Drug Resistance, Microbial; D004754:Enterobacter / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005838:Genotype; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D015378:Imipenem; D010641:Phenotype; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013845:Thienamycins / Q000494:pharmacology*; D001618:beta-Lactamases / Q000096:biosynthesis* / Q000235:genetics
D000900:Anti-Bacterial Agents; D013845:Thienamycins; D002440:Cefoxitin; D015378:Imipenem; D001618:beta-Lactamases; D002439:Cefotaxime