Abstract
The activities of beta-lactam antibiotics were compared against Enterobacter cloacae clinical isolates and mutants which had inducible, stably-derepressed, and basal expression of a pI 8.4 subtype of the Ia chromosomal beta-lactamase. These activities were correlated with the results of studies of the beta-lactamase-lability and beta-lactamase-inducer-power of the antibiotics. Cefoxitin and ampicillin were labile, and induced beta-lactamase production strongly at concentrations below their MIC values. Consequently, beta-lactamase-inducible and beta-lactamase-stably-derepressed organisms were highly resistant (MIC greater than 256 mg/L) to these antibiotics, whereas enzyme-basal strains and mutants were much more susceptible (MIC 1-16 mg/L). Imipenem also induced beta-lactamase production strongly at concentrations below its MIC, but was more stable than ampicillin and cefoxitin. It was active against enzyme-inducible and stably-derepressed organisms at 0.25-0.5 mg/L and against beta-lactamase-basal organisms at 0.06-0.25 mg/L. Thus the beta-lactamase afforded only very low-level protection against imipenem; this appeared to be by a non-hydrolytic mechanism, with the enzyme binding to the antibiotic in a relatively stable complex. This complex, which probably was an intermediate in a hydrolytic pathway, was isolated by gelfiltration chromatography and shown to have a breakdown half-life of 47 +/- 2 min. Cefotaxime, ceftriaxone and mezlocillin were labile to the pI 8.4 beta-lactamase but induced beta-lactamase production weakly at concentrations below their MIC values. Consequently, beta-lactamase-inducible and beta-lactamase-basal organisms remained equally susceptible (MIC 0.06-4 mg/L), but stably-derepressed organisms were considerably more resistant (MIC greater than 64 mg/L) to these antibiotics.