(5, 9). The stabilities of penem antibiotics to human and porcine renal dehydropeptidase I were reported previously (2, 16). SY5555 was evaluated, and its activity was compared with those of widely used oral cephalosporins, i.e., cefaclor, cefixime, and cefteram (10). Part of this work has been presented previously (3).MATERIALS AND METHODS Antimicrobial agents. SY5555 was supplied by Suntory Co., Ltd., Tokyo, Japan. The following antimicrobial agents were also tested: cefixime, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan; cefteram, Toyama Chemical Co., Ltd., Tokyo, Japan; benzylpenicillin, Meiji Seika, Ltd., Tokyo, Japan; cephaloridine, Nihon Glaxo Co., Ltd., Tokyo, Japan; and methicillin, Banyu Pharmaceutical Co., Ltd., Tokyo, Japan.

In in vitro susceptibility tests, the new penem 429

The in-vitro synergic activities of BRL42715, a new beta-lactamase inhibitor, clavulanic acid, sulbactam, and tazobactam combined with ampicillin, piperacillin, cephalothin, or cefoperazone were tested against various bacteria producing known types of beta-lactamase. BRL42715 showed the best synergistic activity among the inhibitors tested against strains producing penicillinases of type I, II, III, V, and that from Klebsiella pneumoniae, cephalosporinases, and oxyiminocephalosporinases (except that from Klebsiella oxytoca). Clavulanic acid combined with the beta-lactams tested showed the best synergic activity of the inhibitors against strains producing type IV penicillinase and oxyiminocephalosporinase from K. oxytoca. The 50% inhibitory doses of BRL42715 were superior to those of clavulanic acid against various types of beta-lactamases except for type IV penicillinase and the oxyiminocephalosporinase from K. oxytoca. The inhibitory activity of BRL42715 against cephalosporinases from various bacteria was 10(4) to 10(6)-fold greater than that of clavulanic acid. The synergic effects of BRL42715 and clavulanic acid on the activity of piperacillin were compared against six clinical isolates of bacteria resistant to piperacillin. The synergic activity of BRL42715 was greater than that of clavulanic acid in all six isolates.

The interactions of E1040 with cephalosporinase from Citrobacter freundii, including affinity and hydrolysis, were studied in comparison with those of cefotaxime and ceftazidime. E1040 showed a higher stability at low drug concentrations and a much lower affinity for the enzyme than did cefotaxime or ceftazidime. These enzymological properties explain the high activity of E1040 against cephalosporinase-producing C. freundii.

The antibacterial and bactericidal activities and the stability of FK037 to Β-lactamases were investigated and compared with those of cefpirome, flomoxef, ceftazidime, ceftizoxime, and vancomycin. Against clinical isolates of methicillin-sensitive and methicillin-resistant Staphylococcus aureus, FK037 was less active than vancomycin but more potent than the other drugs tested. Among highly methicillin-resistant staphylococci (MIC for methicillin: 200 mg/l or higher), none of the strains were highly resistant to FK037 (MIC = 100 mg/l) unlike the other cephalosporins. With the exception of Enterococcus faecalis, FK037 had an activity equipotent to that of cefpirome and far superior to those of flomoxef, ceftazidime and ceftizoxime against other gram-positive clinical isolates. The activity of FK037 against Pseudomonas aeruginosa and Pseudomonas cepacia was equipotent to that of cefpirome but 2- to 4-fold less active than that of ceftazidime. FK037 inhibited 90% of Enterobacter cloacae and Citrobacter freundii growth at a concentration of 6.25 mg/l; it was as active as cefpirome and much more active than ceftazidime. Against the other gram-negative bacteria tested, FK037 was equipotent to cefpirome and ceftazidime and was more effective than flomoxef. FK037, like cefpirome, portrayed a high stability to various Β-lactamases except type II penicillinase and oxyimino-cephalosporinase (CXase). FK037 scored an MIC range of 0.013-6.25 mg/l against numerous Β-lactamase-producing bacterial strains with the exception of some CXase-producing strains and a cephalosporinase-producing C. freundii; and against strains other than P. aeruginosa FK037 was as active as cefpirome and 2- to 32-fold more active than ceftazidime. FK037 displayed highly potent activities against cephalosporinase-producing E. cloacae, C. freundii and Serratia marcescens which were resistant to flomoxef and ceftizoxime. FK037 was highly bactericidal against S. aureus and Escherichia coli at its MIC or higher.