Ceftezole, a new cephalosporin derivative, was compared with cefazolin, cephaloridine, and cephalothin. Data obtained indicate that it is a broad-spectrum antibiotic, with almost identical antimicrobial activity against pathogenic organisms isolated from patients. The therapeutic effect of ceftezole on experimental infections in mice was similar to that of cefazolin and was superior to that of cephalothin. The binding of ceftezole to serum proteins was somewhat less than that of cefazolin. The concentrations of ceftezole in the sera of test animals and human volunteers were determined after intramuscular injection of 20 mg/kg and after a single dose of 500 mg, respectively. The concentration of ceftezole in the serum of volunteers peaked at 24.9 mug/ml 15 min after injection and remained effective (about 2.6 mug/ml) at 4 h. The half-life in serum under the same conditions was 56 min, i.e., about one-half that of cefazolin. The 24-h urinary recovery rate was 87.5%. Most of the administered ceftezole was excreted unchanged mainly through the urinary tract. The biliary excretion rate in SD strain rats after intramuscular injection of 20 mg/kg was about 4.4%. As compared with commercially available cephalosporins, ceftezole was second only to cefazolin in biliary excretion rate. Various tissue levels of ceftezole in animals were higher than cephalothin but, with the exception of renal levels in the early stage after administration, were lower than cefazolin.

The pharmacokinetics offosmidomycin was investigated in animals and humans after parenteral and oral dosing. In dogs the serum concentration was 54.8 ,ug/ml at 0.25 h after an intravenous dose of 20 mg/kg, and the half-life was 1.14 h. Peak concentration was 41.4 ;ig/ml after an intramuscular dose of 20 mg/kg and 16.6 ,g/ ml after an oral dose of 40 mg/kg. In volunteers, the serum concentration 0.25 h after dosing was 157 jig/ml after an intravenous dose of 30 mg/kg, 12.3 ,ug/ml after an intramuscular dose of 7.5 mg/kg, and 2.45 j,g/ml after an oral dose of 500 mg. More than 90% of the given dose was excreted in the 24-h urine in rats and dogs after parenteral dosing with 20 mg/kg. The 24-h urinary recovery was 45.8% of the given dose in rats after oral dosing with 100 mg/kg and 37.8% in dogs after oral dosing with 40 mg/kg. In volunteers 85.5% of the intravenous dose (30 mg/kg), 66.4% of the intramuscular dose (7.5 mg/kg), and 26.0% of the oral dose (500 mg) were excreted unchanged in the 24-h urine. In the multiple-dose study, there was no accumulation of fosmidomycin in the serum even after 21 consecutive intramuscular dosings of 1 g every 6 h or 29 consecutive 0.5-h drip infusions of 2 g every 6 h. Biliary excretion was extremely low in rats. Fosmidomycin was well distributed to the tissues of rats after parenteral and oral dosing. The lymph concentrations in dogs were nearly the same as serum concentrations. Serum protein binding was low (4% or less) to mouse, rat, dog, and human serum.

The pharmacokinetic profile of ceftizoxime was studied in mice, rats, dogs, and monkeys given the drug in a single parenteral dose. The serum data after an intravenous injection were analyzed by the two-compartment open model. Cefotiam, cefmetazole, cefotaxime, and cefamandole were used as reference drugs. High concentrations of ceftizoxime were attained in the sera of all test animals and in the tissues of rats after parenteral dosing. The serum concentrations of ceftizoxime were higher than those of the other antibiotics in large animals (dogs and monkeys), but were lower in small animals (mice and rats). About 80% of ceftizoxime was excreted unchanged in the 24-h urine of all species tested. The biliary excretion of ceftizoxime was low: 3.7% in rats and 0.59% in dogs. However, therapeutically significant concentrations of ceftizoxime were found in the bile of dogs. Ceftizoxime was stable in biological fluids such as serum, urine, and tissue homogenates, but cefotaxime was unstable in rat tissue homogenates. Binding of ceftizoxime to serum protein in all species was the lowest of all the antibiotics: 31% for humans, 17% for dogs, and 32% for rats.Ceftizoxime, a new parenteral cephalosporin derivative, is more active against various gramnegative bacilli, including the opportunistic pathogens such as Enterobacter, Citrobacter spp., and Serratia marcescens, than such cephalosporins as cefotiam, cefuroxime, cefotaxime, and cefmetazole (5). In the present study the pharmacokinetics, metabolism in animals, binding to serum protein, and stability of ceftizoxime were evaluated. Cefotiam, cefamandole, cefotaxime, and cefinetazole, all recently developed cephalosporins, were used as reference drugs.MATERIALS AND METHODSAntibiotics. The compounds used in this study included ceftizoxime (FK 749, Fujisawa, Japan), cefotiam (SCE 963, Takeda, Japan), cefamandole (Eli IJlly & Co., Indianapolis, Ind.), cefmetazole (CS 1170, Sankyo, Japan), and cefotaxime (HR 756, HoechstRoussel, West Germany).Animals. The animals used in this study included 6-week-old male JCL:ICR strain mice, 6-week-old male JCL:SD strain rats, 7.5-to 15.0-kg male beagle dogs, and 5.8-to 9.1-kg male rhesus monkeys. Dosing. The antibiotics for injection were dissolved in 0.9% saline. The drugs were given in a dose of 20 mg/kg to all test animals. The volumes were: 0.25 ml per animal by the intravenous (i.v.) and subcutaneous routes to mice; 5 ml/kg of body weight by the intramuscular (i.m.) and i.v. routes to rats; and 0.5 ml/kg of body weight by the i.m. and i.v. routes to dogs and monkeys.Serum sampling. Blood samples were collected: (i) from the carotid artery of mice at specified intervals after injection; (ii) by heart puncture from rats; (iii) from the antecubital veins of dogs and monkeys. The antibiotic concentrations in the serum were bioassayed using standard solutions prepared with control serum of the respective species of animals.Pharmacokinetic analysis. The serum concentration-time data were fitted to a two-compartment open model (4) using Marqu...

A new in vitro model was devised for evaluating the bactericidal activity of antibiotics undqr dynamic conditions. This model accurately reproduced the observed serum levels of antibiotics after intravenous dosing. The apparatus consists of two vessels which correspond to the central and peripheral compartments of a two-compartment open model. The volume of medium in each vessel and flow rates of media were determined from the pharmacokinetic parameters calculated from the observed serum levels selected for simulation. The bactericidal activity of cefazolin against strains of Escherichia coli and Klebsiella pneumoniae showing different minimal inhibitory concentrations was investigated with the apparatus simulating serum levels after intravenous injection, and the bactericidal activity was evaluated with respect to the relationship between the minimal inhibitory concentration and the serum levels.Previously (10) (1) where A is the extrapolated concentration of the a phase at t = 0; B is the extrapolated concentration of the ,B phase at t = 0; C is the serum concentration at time t, a is the first-order elimination rate constant of the a phase; ,B is the first-order elimination rate constant of the f8 phase; and t is the time after injection. Serum concentrations simulated in the kinetic model were analyzed by the two-compartment open model, and the following pharmacokinetic parameters were determined by Marquardt's nonlinear leastsquares regression analysis, using a FACOM 230/38 digital computer (Fujitsu Co., Ltd., Tokyo, Japan): a

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The bactericidal activity of cefazolin, cephaloridine, and cephalothin in a simulated intramuscular study (500 mg) and a simulated intravenous drip infusion study (2 g/2 h) is reported. In both model systems, the bactericidal activity of cefazolin surpassed that of cephalothin, and there were certain differences between cefazolin and cephaloridine in the simulated intramuscular study when human serum was used as a medium. In a routine reference static system, the drug levels were constant at the simulated peak level of each cephalosporin by both routes. In this system the three cephalosporins were equal in activity. In a third experiment, the effect of drug concentrations and exposure time on bactericidal activity of the cephalosporins was studied. The bactericidal activity of cephaloridine was the strongest of the three drugs when exposure time was 2 h and drug concentration was less than four times the minimal inhibitory concentration. At concentrations above four times the minimum inhibitory concentration, all three cephalosporins were equal in activity when the exposure time was 2 h.In laboratory evaluation of an antibiotic, antibacterial efficacy is assessed totally on in vitro and in vivo antibacterial activities, stability in the body fluids, and pharmacokinetics. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration, however, only indicate the in vitro antibacterial activity of an antibiotic in contact with bacteria at a fixed concentration for about 20 h, whereas in the actual treatment of infections antibiotic levels obtained in the body change in proportion to the pharmacokinetic characteristics of the antibiotic administered. Bacteria are exposed to antibiotic levels which change more rapidly than the determination time for MICs and minimal bactericidal concentrations. A more accurate method, therefore, is needed to obtain infornation on the efficacy of antibiotics by using simulated antibiotic levels in the human body.For this purpose, an in vitro model system simulating human serum levels by intramuscular (i.m.) and intravenous (i.v.) drip infusion were devised, and the bactericidal activity of commercially available cephalosporins, i.e., cefazolin, cephaloridine, and cephalothin, was investigated. MATERIALS AND METHODSTest antibiotics and bacteria. Cefazolin was provided by Fujisawa Pharmaceutical Co., Ltd.; cephaloridine and cephalothin were provided by Eli Lilly & Co. Escherichia coli 308, a clinical isolate, was used as the test organism. The MICs of cefazolin, cephaloridine, and cephalothin against the test strain are 3.13, 3.13, and 12.5,ug/ml, respectively.In vitro model system. Heart infusion (HI) broth (Difco Laboratories) and human serum (Consera, Nissui Seiyaku) were used as the test media. In vitro model systems simulating human serum levels of the test antibiotics after i.m. injection (500 mg) or after i.v. drip infusion were prepared by the previously described method (7). To simulate rising drug levels, high concentrations of each test antibiotic were adde...

An experimental local infection system has been developed in which exudates are induced with croton oil in granuloma pouches ofrats. This system provided a suitable model for the evaluation of the therapeutic effect of two antibiotics, cefazolin and cephalothin. Exudate levels of cefazolin were found to be higher than those of cephalothin, and these levels correlated with the higher serum level of cefazolin. The therapeutic effect of cefazolin, after intramuscular injection of 20 mg of each antibiotic per kg, was superior to that of cephalothin in eradicating both Staphylococcus aureus and Escherichia coli.Evaluation of a new antibiotic usually includes measurements of the levels of its agent in the blood, urine, and tissue homogenates and in vivo estimates of activity against systemic infections in experimental animals. Such studies provide an overall assessment of efficiency and pharmacokinetic characteristics. Their results may or may not be pertinent to the levels of the antimicrobial agent attained at the site of infection and the activity of the drug against the local lesions.In the present study, we investigated the penetration of cefazolin and cephalothin into exudates in granuloma pouches induced by croton oil in rats. Exudate levels and bactericidal activities of the test antibiotics after parenteral administration were studied to assess the activity of these drugs against local lesions MATERIALS AND METHODS Drugs. The following drugs were used: cefazolin (Fujisawa Pharmaceutical Co., Ltd.), cephalothin (Eli Lilly and Co.), and other reagents ofguaranteed grade.Animals. Sprague-Dawley strain rats aged 5 to 6 weeks were used.Organisms. A standard strain of Staphylococcus aureus 209P JC-1 (minimum inhibitory concentration [MIC]-cefazolin, 0.1 ,.g/ml; cephalothin, 0.05 jig/ml) and a clinical isolate of Escherichia coli 312 (MIC -cefazolin, 1.56 Ag/ml; cephalothin, 12.5 ,ug/ ml) were used.Procedure for formation of granuloma pouches and determination of antibiotic levels. Granuloma pouches were induced in rats by the following procedure: 25 ml of air was injected deep into the loose connective tissue between the shoulders with a 27-gauge needle. This was immediately followed by injection of 1 ml of 1% croton oil solution in olive oil into the resulting air space with the same needle (7). Seven days after formation of the granuloma pouch, with or without infection induced by the test organisms, rats were given a single intramuscular (i.m.) injection of cefazolin or cephalothin (20 mg/kg), and levels of the two antibiotics were measured in the sera and exudates. Analytical values ofthe exudates were obtained with a Technicon Autoanalyzer (Table 1). The antibiotic levels were assayed by the disk method using Bacillus subtilis ATCC 6633 as the test organism (5). Standard solutions for bioassay were prepared with the serum for serum levels and with the exudate for exudate levels.Inoculation of test organisms into the granuloma pouch. The test organisms were cultured overnight at 37°C on heart infusion agar slan...