Cephalothin , a New Cephalosporin with a Broad Antibacterial Spectrum

GODZESKI, C. W. (Eli Lilly & Co., Indianapolis, Ind.), GORDON BRIER, AND D. E. PAVEY. Cephalothin, a new cephalosporin with a broad antibacterial spectrum. I. In vitro studies employing the gradient plate technique. Appl. M\licrobiol. 11:122-127. 1963. Cephalothin is 7(thiophene-2-acetamido) cephalosporanic acid; it was prepared by N-acylation of the nucleus of cephalosporin C, 7-aminocephalosporanic acid. Cephalothin had a broad spectrum of antibiotic activity that was essentially uniaffected by human serum or inoculum level, the activity of penicillinase, or pH variation of the growth medium. In vitro development of resistance by staphylococci could not be demonstrated, but the gram-negative organisms did develop a stepwise type of resistance to the antibiotic. Staphylococci made resistant in vitro to 5-methyl-3phenyl-4-isoxazole penicillin were also resistant to cephalothin and to 6-(2,6-dimethoxybenzamido) penicillin; however, the mechanism of resistance to each antibiotic may have differed. Some complications involved in the laboratory evaluation methods currently in use in the field of antibiotics are examined. Since Newton and Abraham (1956) announced the isolation of cephalosporin C, a second hydrophilic penicillinlike antibiotic from the fermentation broth of a culture of a Cephalosporium (I.M.I. 49137), there has been much speculation concerning the possible production of a series of new antibiotics similar to the ever-growing number of penicillins. The design and production of new semisvnthetic penicillins depended upon the preparation of 6aminopenicillanic acid either by chemical means (Sheehan, 1958; Sheehan and Henery-Logan, 1959) or through fermentation procedures (Batchelor et al., 1959). The structure analysis of cephalosporin C (Abraham and Newton, 1961) and the preparation of 7-aminocephalosporanic acid (7-ACA; Loder, Newton, and Abraham, 1961) from the parent compound similarly opened the way to new cephalosporins with, it was hoped, different biological and chemical activities. The same publication (Loder et al., 1961) that announced the preparation of 7-ACA also presented data on some new cephalosporins formed by N-acylation and noted that these cephalosporins differed in their antistaphylococcal activity and were relatively insensitive to purified Bacillus ce'eus penicillinase. The present report deals with the biological nature of a new cephalosporin (Chauvette et al., 1962) which has been assigned the generic name cephalothin. Chemically it is 7-(thiophene-2-acetamido) cephalosporanic acid (I). The structure is shown with the parent compound of the series, cephalosporin C (II). CHi-C-NH-CHH CH2 o()