Activity of a broad-spectrum cephalosporin (Ro 48-8391) alone and in combination with two novel β-lactamase inhibitors (Ro 48-5545 and Ro 48-8724)

Abstract

The susceptibility of a group of β-lactamase–producing and drug-resistant Gram-positive and Gram-negative organisms was tested against a novel cephalosporin (Ro 48-8391) alone and in combination with two bridged carbacephem β-lactamase inhibitors (Ro 48-5545 or Ro 48-8724) and compared with that of ceftriaxone, ceftazidime, and cefepime (representative “third- and fourth-generation” cephalosporins), imipenem, and a combination of piperacillin and tazobactam. Five hundred and one selected clinical isolates were tested using the reference broth microdilution method (National Committee for Clinical Laboratory Standards). Ro 48-8391 has a spectrum of activity and potency most similar to ceftriaxone but with improved activity against Gram-positive species. The two β-lactamase inhibitors, Ro 48-5545 and Ro 48-8724, have modest antimicrobial activity. When combined with Ro 48-8391, the β-lactamase inhibitor Ro 48-8724 was superior to the combination of Ro 48-8391 and Ro 48-5545 in spectrum and enzyme inhibition against extended spectrum β-lactamase enzyme-producing Escherichia coli and Klebsiella pneumoniae, and against Enterobacteriaceae with “stably derepressed” Bush-Jacoby-Medeiros gr. 1 enzymes (ceftazidime-resistant Enterobacter and Citrobacter). Ro 48-5545 and Ro 48-8724 appear to be promising β-lactamase inhibitors with potential application against chromosomal- and plasmid-mediated enzymes. Ro 48-8391, although superior to some currently available “third-generation” cephems, was not a well-matched active codrug because of limited activity against several commonly isolated species of clinically important bacteria. Further efforts are necessary to find a penicillin or cephem with activity more complementary to that of the tested β-lactamase inhibitors and the Ro 48-8391 compound could be focused for therapeutic use in serious streptococcal infections.