ACTIVITY OF A BROAD-SPECTRUM CEPHALOSPORIN (RO-48-8391) ALONE AND IN COMBINATION WITH 2 NOVEL BETA-LACTAMASE INHIBITORS (RO-48-5545 AND RO-48-8724)

The susceptibility of a group of beta-lactamase-producing and drug-res istant Gram-positive and Gram-negative organisms was tested against a novel cephalosporin (Ro 48-8391) alone and in combination with two bri dged carbacephem beta-lactamase inhibitors (Ro 48-5545 or Ro 48-8724) and compared with that of ceftriaxone, ceftazidime, and cefepime (repr esentative ''third- and fourth-generation'' cephalosporins), imipenem, and a combination of piperacillin and tazobactam. Five hundred and on e selected clinical isolates were tested using the reference broth mic rodilution method (National Committee for Clinical Laboratory Standard s). Ro 48-8391 has a spectrum of activity and potency most similar to ceftriaxone but with improved activity against Gram-positive species. The two beta-lactamase inhibitors, Ro 48-5545 and Ro 48-8724, have mod est antimicrobial activity. When combined with Ro 48-8391, the beta-la ctamase 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 beta-lactamase enzyme-producing Escherichia coli and Klebsie lla pneumoniae, and against Enterobacteriaceae with ''stably derepress ed'' Bush-Jacoby-Medeiros gr. 1 enzymes (ceftazidime-resistant Enterob acter and Citrobacter). Ro 48-5545 and Ro 48-8724 appear to be promisi ng beta-lactamase inhibitors with potential application against chromo somal- 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 comm only isolated species of clinically important bacteria. Further effort s are necessary to find a penicillin or cephem with activity more comp lementary to that of the tested beta=lactamase inhibitors and the Ro 4 8-8391 compound could be focused for therapeutic use in serious strept ococcal infections. (C) 1998 Elsevier Science Inc.