No abstract

The in vitro antibacterial spectrum of L-658,310, a newsemisynthetic cephalosporin, was compared with ceftazidime, aztreonam and piperacillin against a wide variety of randomly selected human clinical isolates. The compound was found to be a broad spectrum bactericidal agent that was more potent than any of the comparison drugs against glucose nonfermenting bacteria. It has especially potent activity against Pseudomonas aeruginosa including multiply-resistant strains. The superior activity of L-658,310 against this group of organisms is attributed to the presence of the dihydroxy substituents on the 2-methylisoindoline moiety of the compound. L-658,310 is not cross-resistant with either imipenem, ceftazidime or piperacillin (representatives of three different classes of /3-lactam compounds) against P. aeruginosa. The lack of cross-resistance with ceftazidime extends to other glucose nonfermenters and several strains of Enterobacteriaceae as well. The compoundis active against bacteria known to possess either R-plasmid-or chromosomally-mediated /5-lactamases. L-658,310 (Fig. 1) is a novel injectable cephalosporin1>2) synthesized at the Okazaki Research Laboratories of the Banyu Pharmaceutical Co., Ltd., Japan, an affiliate of Merck & Co., Inc., U.S.A. It is designated by Banyu as BO-1236. The compound has four functional groups, three of which are responsible for the outstanding microbiological activity of the compound. The cis alkoximino substituent on the a carbon atom of the 7-/5acylamino group is responsible for the stability of the compound to bacterial /3-lactamases3'4) and the £-em-dimethyl substituents add the anti-Pseudomonas activity to the compound4"*0. This activity is both enhanced and extended to other glucose non-fermenting bacteria by the dihydroxy substituents on the 2-methylisoindoline moiety, which by itself, especially in these organisms, is thought to facilitate the entry of the compound into the cell. The fourth group, the 3-methyl-lmethylpyrrolidium position of the molecule is thought to be responsible for the relatively long serum half-life7~9) of the compound. Summarized in this paper are the in vitro antibacterial spectrum and associated antibacterial properties of L-658,310.

The in vitro activity of seven antibiotics against 52 isolates of Neisseria gonorrhoeae was determined. Against penicillinase-producing Neisseria gonorrhoeae, ceftriaxone was the most active agent (MIC90 0.015 micrograms/ml), followed by ceftizoxime and norfloxacin (MIC90 0.03-0.125 micrograms/ml). Against spectinomycin-resistant Neisseria gonorrhoeae, the most active agents were ceftizoxime, ceftriaxone and norfloxacin (MIC90 0.015-0.125 micrograms/ml). Ceftizoxime, ceftriaxone and norfloxacin were also the most active agents against tetracycline-resistant Neisseria gonorrhoeae (MIC90 0.06-0.125 micrograms/ml). Overall, the rank order of activity from the most to the least active agent was as follows: ceftizoxime (MIC90 0.015 micrograms/ml); ceftriaxone (MIC90 0.06 micrograms/ml); norfloxacin (MIC90 0.125 micrograms/ml); cefoxitin (MIC90 2 micrograms/ml); tetracycline (MIC90 8 micrograms/ml); penicillin (MIC90 greater than 8 micrograms/ml); and spectinomycin (MIC90 greater than 128 micrograms/ml).

Seventy-four cefoxitin-resistant Bacteroides fragilis group isolates were tested by the serial twofold agar dilution method for susceptibility to imipenem and other agents in medium with and without 5% sheep blood.Imipenem (MIC for 90% of strains tested, 1 ,ug/ml) and metronidazole (MIC for 90% of strains tested, 2 ,ug/ml) were the two most active agents. The addition of 5% sheep blood to the medium had little or no effect on the activity of the antibiotics tested.