Open AccessLeakage of beta-lactamase: a second mechanism for antibiotic potentiation by amdinocillin
Author(s) -
Christine C. Sanders,
William E. Sanders,
Richard V. Goering,
Richard V. McCloskey
Publication year - 1987
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.31.8.1164
Subject(s) - azlocillin , cefoxitin , mecillinam , cefotaxime , enzyme inducer , enterobacter cloacae , microbiology and biotechnology , antibiotics , penicillin , enzyme , inducer , imipenem , biology , pharmacology , chemistry , escherichia coli , biochemistry , enterobacteriaceae , bacteria , pseudomonas aeruginosa , piperacillin , antibiotic resistance , genetics , gene , staphylococcus aureus
Discrepancies were observed between results of different beta-lactamase induction tests with amdinocillin, which appeared to be a strong inducer in whole-cell assays but a weak inducer in assays with cell-free sonic extracts. Results of a nitrocephin-disk test with constitutive beta-lactamase producers indicated that the positive results obtained in whole-cell assays were due to drug-produced leakage of enzyme from the cell and not to induction. Imipenem was also found to cause leakage of beta-lactamase from a similar number of constitutive enzyme producers, while cefoxitin was much less likely to cause leakage. A split-dose regimen was employed to treat mice infected with a strain of Enterobacter cloacae which appeared to leak enzyme on exposure to amdinocillin. Results indicated that prior treatment with amdinocillin significantly enhanced (P less than 0.025) the efficacy of azlocillin, an enzyme-labile drug, but did not affect the efficacy of cefotaxime, a relatively enzyme-stable drug. Conversely, prior treatment with amdinocillin did not potentiate the efficacy of either azlocillin or cefotaxime in the treatment of mice infected with an Escherichia coli strain that was highly susceptible to all three drugs. Thus, it appears that amdinocillin may potentiate the activity of other beta-lactam drugs not only by binding to a complementary penicillin-binding protein but also by causing leakage of beta-lactamase from the cell. This effect may be related to its ability to bind to penicillin-binding protein 2 and subsequently produce changes in outer membrane permeability.