A number of new parenteral cephalosporin and cephamycin derivatives with improved use potential over the available marketed products are currently under development. These compounds are reported to have a broader spectrum of antibacterial activity and good stability to a large number of f-lactamases produced by bacterial isolates (2,7,9,11,12,14,15). One such compound is SK&F 75073 [7-D-mandelamido-3-(1-sulfomethyltetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid, disodium salt] a parenteral cephalosporin with broad antibacterial activity and high and extended serum levels (Fig. 1) Efficacy tests: (i) in vitro activity. The minimum inhibitory concentrations (MICs) were determined by the agar dilution method as previously reported (1).The surface of the agar was inoculated with the aid of a Steers apparatus (13). After overnight incubation at 37°C, the MICs were read as the lowest concentration of antibiotic completely inhibiting growth. For determination of effect of serum on antibiotic activity, pooled human serum was added in a final concentration of 50% to Muelier-Hinton broth. The MIC determinations were carried out using microtiter methodology (6). The MICs for the inoculum size experiments were also carried out in Mueller-Hinton broth using the microtiter apparatus.The test medium employed for the staphylococci and the gram-negative bacterial species was Mueller-

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Three new glycopeptide antibiotics, aridicins A, B, and C, produced by Kibdelosporangium aridum have a spectrum of antimicrobial activity in vitro which is similar to that of vancomycin. The antimicrobial activities of these glycopeptides against clinical bacterial isolates were compared with those of vancomycin and other related glycopeptide antibiotics in vitro by agar dilution and microtiter broth dilution tests and in vivo in mouse protection studies. In vitro they were somewhat less effective than vancomycin against strains of Staphylococcus aureus and less active against coagulase-negative Staphylococcus spp. However, they were more active than vancomycin against strains of Streptococcus faecalis and markedly superior to vancomycin and other glycopeptide antibiotics against strains of Clostridium difficile. In experimental infections, aridicin A was effective against strains of S. aureus, S. epidermidis, Streptococcus faecalis, and Streptococcus pyogenes, although its 50% effective doses were higher than those of vancomycin when administered after infection. After subcutaneous administration, aridicin A had a higher peak level in serum and a longer half-life than vancomycin or teicoplanin. The aridicins were markedly superior to vancomycin when administered prior to infection in mouse protection tests, indicating long-acting potential.Aridicins are glycopeptide antibiotics of the vancomycin class which are produced by a new genus of the order Actinomycetales, Kibdelosporangiium aridum ATCC 39922. The production, isolation, spectrum of activity, and chemical characterization of these antibiotics have been reported previously (8, 9). These glycopeptides differ from most members of this class, with the exception of teicoplanin (1). Both the aridicins and teicoplanin (teichomycin) possess a glycolipid constituent and have an acidic isoelectric point. The spectrum of antimicrobial activity in vitro for all of the glycopeptides reported in the literature is similar to that of vancomycin and is limited, probably owing to their molecular size, to gram-positive bacteria (10-12). The microbiological and pharmacokinetic properties of the aridicins were compared with those of vancomycin and other members of this class of antibiotics. MATERIALS AND METHODS Antibiotics

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The synthesis, microbiological profile, and in vivo effectiveness in laboratory animals of a broad-spectrum cephalosporin, 7(fi)-mandelamidocephalosporamc acid (1), are described. A number of derivatives and analogs of 1 were prepared and their structure-activity relationships are discussed.Most of the several cephalosporins that have been found to be clinically useful incorporate at the 7 position an acyl moiety derived from acetic acid, monosubstituted with an appropriate grouping such as thiophene, tetrazole, pyridylthio, or cyano. Structure-activity studies on cephalospor-

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