Bacteria. The 853 isolates of gram-negative species and 296 isolates of gramn-positive species were predominantly of recent clinical origin from numerous sources of broad geographical distribution. The isolates were stored as described previously (2, 4). The 3-lactamase-producing strains used to generate the data in Table 3

BMY 28100, a new oral cephalosporin with a (Z)-propenyl side chain at the 3 position and a phydroxyphenylglycyl substituent at the 7 position, was evaluated in comparison with cefaclor and cephalexin and, when appropriate, ampicillin and vancomycin. In vitro, BMY 28100 was more active than the reference cephalosporins against streptococci, Staphylococcus aureus, Staphylococcus epidermidis, Listeria nionocytogenes, Haemophilus influenzae, Propionibacterium acnes, Clostridiunm perfrigens, and Clostridium difficile. BMY 28100 was comfparable to cefaclor and more active than eephalexin against Staphylococcus saprophyticus and ampicillin-susceptible strains of Branhamella cattarhalis; but against ampicillin-resistant strains of B. cattarhalis, BMY 28100 was comparable to cephalexin and more active than cefaclor. Against Neisseria gonorrhoeae, BMY 28100 was comparable to cephalexin, but less active than cefaclor. Members of the family Enterobacteriaceae overall were equally susceptible to BMY 28100 and cefaclor but were less susceptible to cephalexin. In human serum, BMY 28100 was 45% protein bound. After an oral dose to mice, 82% of the drug was recovered in urine. The oral therapeutic efficacy of BMY 28100 in systemically infected mice reflected its activity in vitro.Whereas parenteral cephalosporins have been prepared with an array of side chains at the 3 and 7 positions, structural requirements for good gastrointestinal absorption have limited the choice of side chains for oral cephalosporins. The number of distinct substituents at the 3 position on oral cephalosporins currently in clinical use is small, and all substituents at the 7 position are of a single design: a native or modified phenyglycyl radical. Recent attempts to deviate from this pattern have yielded compounds with a broader spectrum of activity against gram-negative organisms but reduced gastrointestinal absorption and little antistaphylococcal activity (4, 9, 13; T. Suematsu, H. Sakamoto, and K. Takai, Proc. 14th Int. Congr. Chemother., p. 1147-1148 , abstr. no. 595, 1985).BMY 28100 is a new oral cephalosporin of conventional design. It has a (Z)-propenyl side chain at the 3 position and ap-hydroxyphenylglycyl substituent at position 7 (Fig. 1)

The bioavailability and therapeutic properties of BL-S 640 in rodents were compared with those of cephalothin, cephaloridine, and cefazolin after parenteral administration, and cephalexin after oral administration. When given intramuscularly in dosages of 5 to 40 mg/kg, peak concentrations of BL-S 640 in the blood of mice were proportional to dose, but when given orally, they were proportional only up to a dose of 25 mg/kg. After either route of administration, the concentration of BL-S 640 in the blood declined at a slower rate than that of the control compounds. Rats The bioavailability and therapeutic properties of BL-S 640 were assessed by determining its concentration in blood, the percentage of recovery in urine, and the efficacy of the drug in the treatment of experimental infections after parenteral or oral administration to rodents. In studies using the parenteral route of administration, BL-S 640 was compared with cephalothin, cephaloridine, and cefazolin; in those involving the oral route, cephalexin was the control compound. MATERIALS AND METHODSCephalosporins and bacteria. The antimicrobial agents and microorganisms used in this study have been described previously (1).Antibiotic concentration in blood. Male SwissWebster mice, weighing 20 (±1) g, were given 0. Recovery in urine. Male Sprague-Dawley rats, weighing 200 (±10) g, received a dose of 50 mg of cephalosporin per kg in 5 ml of Tween-CMC by gavage. Four rats were used per compound. The animals were fasted for 18 h before dosing. Although water was available ad libitum, the animals were hydrated with 5 ml of water at 3 and 6 h after dosing. The rats were housed individually in metabolism cages, and urine specimens were collected over dry ice during intervals of 0 to 6 and 6 to 24 h after drug administration. Portions (0.03 ml) of appropriate dilutions of urine were placed on paper disks (6.35 mm in diameter), and the antibiotic activity was assayed by the diffusion technique on seed agar inoculated with B. subtilis ATCC 6633. A standard line relating the diameter of the inhibition zone to drug concentration was obtained by assaying the compounds at known concentrations in urine collected from untreated control animals.Treatment of systemically infected mice. Male Swiss-Webster mice, weighing 20 (41) g, were challenged intraperitoneally with 0.5 ml of a bacterial suspension containing sufficient organisms to kill untreated animals within 72 h. The suspending medium for Streptococcus pneumoniae, Streptococcus pyogenes, and Klebsiella pneumoniae was brain heart infusion broth (Difco). Staphylococcus aureus no. 2 was suspended in broth containing 2% mucin; the remaining organisms were suspended in medium containing 4%

Biological and physicochemical properties of BL-S786 were compared with those of cephalothin, cephaloridine, and cefazolin. With few exceptions, BL-S786 was more active than the reference compounds against major gram-negative pathogenic species and its antibacterial spectrum was broader than that of cephalosporins currently available for clinical use. Although BL-S786 was generally less active than the control cephalosporins against gram-positive pathogens, it inhibited their growth at concentrations that should readily be achieved in humans after standard parenteral dosage. Streptococcus faecalis, a species relatively unsusceptible to cephalosporins in general, was an exception. BL-S786 was an effective bactericidal agent for strains of various gram-negative organisms. After intramuscular administration to mice, BL-S786 achieved high concentrations in blood, and its biological half-life was longer than that of the other three cephalosporins.BL-S786 (Fig. 1) is a new semisynthetic cephalosporin with a broad spectrum of antibacterial activity. The following is a report on biological and physicochemical properties of BL-S786 in comparison with those pfcephalothin, cephaloridine, and cefazolin, three cephalosporins widely used clinically in the United States and abroad. MATERIALS AND METHODSCephalosporins. BL-S786, 7-[a-(2-aminomethylphenyl)acetamidol-3-[(1-carboxymethyltetrazol-5-ylthio)methyl]-3-cephem-4-carboxylic acid, was synthesized by members of the Product Development Department, Bristol Laboratories (W.

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