BL-S640, a Cephalosporin with a Broad Spectrum of Antibacterial Activity: Bioavailability and Therapeutic Properties in Rodents

Abstract

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%

In Vitro Evaluation of the New Oral Cephalosporin Cefatrizine: Comparison with Other Cephalosporins

“…coli and Klebsiella were inhibited by low concentrations (<8 ,ug/ml) of BL-S640: 81% of E. coli and 70% of K. pneumoniae tested. As predicted, based on previous studies by other workers (5,8,10,11), Serratia and Pseudomonas species were uniformly resistant to >128 ,g of each of the cephalosporins per ml.…”

Susceptibility of Haemophilus influenzae Type b to Cefatrizine, Ampicillin, and Chloramphenicol

“…In vitro, cefatrizine appears to be four-to eightfold more active than cephalexin against most gram-positive bacteria, as well as against Escherichia coli and Klebsiella, Salmonella, and Shigella sp., and approximately 16-fold more active against Proteus mirabilis and Proteus vulgaris strains (1,3,5,7). It is also inhibitory in concentrations theoretically achievable in humans against many strains of cephalexin-resistant Enterobacter sp.…”

“…Cefatrizine (BL-S640) is a new semisynthetic cephalosporin compound which is water soluble and well absorbed by animals after oral administration (4). In vitro, cefatrizine appears to be four-to eightfold more active than cephalexin against most gram-positive bacteria, as well as against Escherichia coli and Klebsiella, Salmonella, and Shigella sp., and approximately 16-fold more active against Proteus mirabilis and Proteus vulgaris strains (1,3,5,7).…”

“…It is also inhibitory in concentrations theoretically achievable in humans against many strains of cephalexin-resistant Enterobacter sp. and P. vulgaris (6) but is inactive against Pseudomonas aeruginosa, Serratia marcescens, and methicillin-resistant staphylococci (1,3,(5)(6)(7).…”

Hydrolysis of 3-acetoxymethyl cephalosporins by lysed whole blood

“…Although antibiotic levels are usually determined in either plasma or serum, in some cases, especially in some rodent studies, levels may be determined more conveniently in whole blood (1,2,3,6). In most cases such whole blood assays will give a satisfactory appraisal of the antibacterial level, especially if an appropriate hematocrit correction is made.…”