Importance of extracellular and cell-bound beta-lactamase in mediating resistance of Staphylococcus aureus to mezlocillin

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Abstract
Most penicillin-resistant staphylococci release a considerable portion of their beta-lactamase into the surrounding medium. Accumulation of this exoenzyme in conventional susceptibility test systems may result in a rapid inactivation of hydrolyzable antibiotics. Since under in vivo conditions the concentration of extracellular beta-lactamase should depend on the site of infection, susceptibility of Staphylococcus aureus to mezlocillin, a broad-spectrum penicillin, was measured in an open test model which prevented build-up of exoenzyme. The staphylococcal cells were immobilized and incubated between two membrane filters, and the excreted beta-lactamase was washed out by a constant flow of broth containing the antibiotic. Two test strains which produced large amounts of extracellular beta-lactamase and which were found to be resistant in the broth dilution test proved to be susceptible to mezlocillin in the open test model. This indicates that resistance to mezlocillin as measured by the broth dilution method was mediated predominantly by the extracellular enzyme fraction. Experiments performed with small infective doses in a model of peritoneal infection in leukopenic mice suggest that mezlocillin exhibits a therapeutic effect against beta-lactamase-producing staphylococci under certain in vivo conditions in which build-up of extracellular beta-lactamase does not occur.