L-658,310, a new injectable cephalosporin. I. In vitro antibacterial properties.

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.

Microcins, gene-encoded antibacterial peptides from enterobacteria

“…Thus, enzymes responsible for the lasso structure of MccJ25 would be of great biotechnological interest given the increased potency and stability of cyclic antimicrobial peptides. Similarly, several years before the isolation of the first natural siderophore-peptide, 14 conjugation with hydroxamate or catecholate siderophores provided vancomycin 254 or cephalosporins 255 with enhanced antibacterial activity compared to unsubstituted antibiotics. Thus, the enzymes involved in MccE492 siderophore modification would also be worth isolating to improve antibacterial activities.…”

In vitro and in vivo evaluation of Ro 09-1428, a new parenteral cephalosporin with high antipseudomonal activity

“…Although ceftazidime and cefpiramide are cephalosporins which inhibit the growth of P. aeruginosa at therapeutically attainable concentrations in blood, this activity leaves room for improvement. Recently, several cephalosporins containing catechol substituents have been reported as having superior antipseudomonal activities compared with those of other P-lactam antibiotics (1)(2)(3)(4)(5)(6)(7)(8)(9)16).…”