CP-45,899, a Beta-Lactamase Inhibitor That Extends the Antibacterial Spectrum of Beta-Lactams: Initial Bacteriological Characterization

Abstract

CP-45,899 {3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 4,4-dioxide, [2S-(2alpha,5alpha)]} is an irreversible inhibitor of several bacterial penicillinases and cephalosporinases. In the presence of low concentrations of CP-45,899, ampicillin and other beta-lactams readily inhibit the growth of a variety of resistant bacteria that contain beta-lactamases. CP-45,899 used alone displays only weak antibacterial activity, with the notable exception of its potent effects on susceptible and resistant strains of Neisseria gonorrhoeae. CP-45,899 appears to be somewhat less potent but markedly more stable (in aqueous solution) than the recently described beta-lactamase inhibitor clavulanic acid. The spectrum extensions provided by the two compounds are similar. A 1:1 mixture of CP-45,899 and ampicillin displays marked antimicrobial activity in mice experimentally infected with ampicillin-resistant Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae, and Proteus vulgaris.