In recent years, isolation rate of methicillin-resistant Staphylococcus aureus(MRSA) has decreased, while the rate of Pseudomonas aeruginosa has increased. This phenomenon may be a result of regulation of use of antibiotics which belongs to the third cephems and extensive preventive measures against hospital acquired infections due to MRSA.
Based on our investigation in which we determined MICs of various antibiotics against P. aeruginosa strains isolated from inpatients, the antibacterial activities of cefclidin (CFCL) was superior to those of other antibiotics.The antibacterial activity of CFCL against P. aeruginosa tested was similar to or stronger than that of tobramycin.

View full abstract

The monobactam antibiotic aztreonam (AZT) was administered by intravenous drip infusion to women with intrauterine infections at 6-hour intervals and its concentrations in the maternal blood, umbilical blood, and umbilical tissue were determined at parturition to evaluate its transport to the umbilicus and fetus, and this accumulation in the tissue. Further, umbilical tissue was cultured to detect bacteria and examined histologically to evaluate the efficacy of AZT its treatment of omphalitis.
Neither maternal nor umbilical blood showed any signs of drug accumulation, and there was a correlation between maternal and umbilical blood levels of AZT and time lapsed after most recent administration. Umbilical tissue levels of AZT tended to increase with time for about 12 hours after the start of administration, but showed no tendency to further rise thereafter. The umbilical tissue cultures were negative for causative pathogens 12 hours or more after the initial dosing. Histological examination of umbilical tissue was negative for omphalitis 12 hours or more after the start of administration in all but one patient.
After the administration of AZT to pregnant women with intrauterine infections, it was detected in the umbilicus and fetus in high concentrations at parturition without appreciable tissue accumulation, newborn infection or adverse reaction. The overall results suggest that AZT is clinical effective when used in the treatment of omphalitis.

View full abstract

Single dose toxicity studies of T-3761 were carried out in mice, rats and dogs, and the following results were obtained.
1. The approximate lethal dose of T-3761 were more than 5,000mg/kg for mice and rats, more than 2,000 mg/kg for dogs with oral administration, and more than 5,000 mg/kg for mice and rats with subcutaneous injection. LD₅₀ values with intravenous injection were 783 mg/kg for male mice, 832 mg/kg for female mice, 341 mg/kg for male rats, and 403 mg/kg for female rats. Two dogs given 200 mg/kg did not die but one of the two treated with 400 mg/kg died after intravenous injection. The approximate lethal dose for dog was 400 mg/kg.
2. Neither abnormal symptoms and macroscopic findings nor deaths were observed in mice and rats treated orally. Granuloma around precipitates of T-3761 at the injection site was seen in mice and rats injected subcutaneously. Slight increase of white blood cell count, serum GOT, CPK and urea nitrogen were transiently found in dogs treated orally. Neither abnormal macroscopic findings nor deaths were observed in dogs treated orally.
3. Decreased motor activity and irregular breathing were observed in mice and rats injected intravenously. In dying animals, tonic or clonic convulsions were observed. Vomiting, hyperemia of ophthalmic mucosa, edema of face, decrease of motor activity, salivation and decrease in body temperature were observed in dogs injected intravenously. At higher doses, scream and tachypnea were observed while injecting. Hematological examinations disclosed that increases in red blood cell count, white blood cell count, hematocrit and hemoglobin were found transiently. In biochemical examinations, increases in serum GOT, GPT, urea nitrogen and creatinine were found transiently. One dog intravenously injected 400 mg/kg, showed tonic convulsion and died.

View full abstract

A three months oral repeated dose toxicity study was carried out in rats at dosages of 1,500,400,100 and 25mg/kg. The following results were obtained.
1. There was no dead rat caused by administration of T-3761. Soft feces were observed in male and female rats at 1,500mg/kg. Body weight gain was slightly suppressed in male rats at 1,500 mg/kg.
2. Crystals which seemed to be test compound in the urinary sediment, were observed in male and female rats at 1,500 and 400mg/kg.
3. There was no abnormality caused by administration of T-3761 in both hematological and ophthalmological examination.
4. Mild increase in total cholesterol (males and females in 1,500mg/kg group, females at 400mg/kg group), phospholipids (males at 1,500 mg/kg group) and A/G ratio (males and females in all treated groups) were observed. However, these biochemical changes were reversible in the recovery period.
5. Dilatation of the cecal lumen was observed in male and/or female rats at 1,500,400,100 mg/kg. However, no histological abnormalities were seen in the mucosa of cecum.
6. Blister and erosion were observed at articular cartilage of knee or hip joints in 2 of the 19 rats at 1,500mg/kg, 1 of the 9 rats at 1,500mg/kg of recovery study and 3 of the 10 rats at 400mg/kg of recovery study.
7. No toxic dose level was regarded to be 100 mg/kg/day in this study.

View full abstract

A three months oral repeated dose toxicity study was carried out in beagle dogs at dosages of 300, 100,30 and 10mg/kg, respectively.The following results were obtained.
1. There was no death of animals during administration at any dose levels. A few to all animals in all T-3761 treated groups complained of pain at the time of extension of limbs.
2. Mild decrease of body weight was observed in 1 of the 10 animals at 300 mg/kg and 1 of the 8 animals at 100 mg/kg, respectively.
3. In urinalysis, crystals which seemed to be the test compound in the urinary sediment, were observed in 5 of the 10 animals at 300 mg/kg and 4 of the 8 animals at 100 mg/kg, respectively.
4. In blood biochemical examination, mild elevation of GPT was observed in 1 of the 10 animals at 300 mg/kg. Increase of A/G ratio was observed in males at 300, 100 and 30 mg/kg, and females at all dose levels.
5. In macroscopic findings at necropsy, blister and erosion were observed at articular cartilage of shoulder, elbow, hip, and/or knee joints in all animals at 300 and 100 mg/kg, 7 of the 8 animals at 30 mg/kg and 1 of the 8 animals at 10 mg/kg.
6. No toxic dose level was less than 10 mg/kg/day in this study.

View full abstract

We carried out reproductive and developmental toxicity studies (i.e. fertility study, teratological study, and perinatal and postnatal study) of T-3761, a new quinolone derivative, in S.D. rats. T-3761 was administered orally at the dose of 60,300 and 1,500mg/kg/day as suspension in 5% acacia solution.
1. Fertility study
T-3761 was administered to male rats for 9 weeks prior to mating and to female rats for 2 weeks prior to mating and until day 7 of gestation. In parent rats, soft stools, slight depression of body weight gain and increase in water intake were observed at the dose of 1,500mg/kg. Cecum weight was increased at the dose of 300 mg/kg and more in male and at the dose of 1,500mg/kg in female. No effects on reproductive performance were discernible in the T-3761 treated groups. In fetuses, external, skeletal and visceral examinations revealed no teratological abnormalities. Slightly retarded ossification, however, was observed at the dose of 1,500mg/kg. From these findings, the no-effect dose of T-3761 in fertility study was considered to be 300 mg/kg/day for parent rats and fetuses.
2. Teratological study
T-3761 was administered from day 7 to day 17 of gestation. In dams, soft stools, transient decrease in food intake, increase in water intake, depression of body weight gain and increase in cecum weight were observed at the dose of 1,500mg/kg. In fetuses, slight increase in incidence of ventricular septal defect and slightly retarded ossification were observed at the dose of 1,500mg/kg. In the postnatal examination, there were no effects in the T-3761 treated groups. From these findings, the no-effect dose of T-3761 in teratological study was considered to be 300 mg/kg/day for dams and next generations.
3. Perinatal and postnatal study
T-3761 was administered from day 17 of gestation to day 21 of lactation. In dams, cecum weight was increased at the dose of 300 mg/kg and more. And soft stools, transient decrease in food intake, increase in water intake, transient depression of body weight gain and slight extension of gestation period were observed at the dose of 1,500mg/kg. In the postnatal examination, there were no effects in the T-3761 treated groups. From these findings, the no-effect dose of T-3761 in perinatal and postnatal study was considered to be 300 mg/kg/day for dams and more than 1,500mg/kg/day for next generations.

View full abstract

Phototoxicity and photoallergenicity tests of T-3761 (oral or percutaneous administration) were carried out in guinea pigs. Phototoxicity test of T-3761 (oral administration) was done in rats, too.
The following results were obtained.
1. Compared with comparative drugs in oral administration, phototoxicity of T-3761 was equal to that of ciprofloxacin, slightly stronger than that of nalidixic acid and weaker than those of ofloxacin, enoxacin, sparfloxacin and lomefloxacin.
2. A sensibility to phototoxicity of T-3761 in rats was weaker than that in guinea pigs.
3. Phototoxicity and photoallergenicity were not observed in application of T-3761 as 10% ointment.
4. Photoallergenicity was not observed in oral administration of T-3761.

View full abstract

We investigated cytotoxicity and mutagenicity of T-3761. The mutagenicity was evaluated using reverse mutation test with bacteria, chromosome aberration test with cultured cells and micronucleus test with mice.
The following results were obtained.
1. Cytotoxicity test: The cell growth was examined using Chinese hamster (V79) cells.
The 50% inhibition doses of T-3761 for cell growth (ID₅₀) were 490μg/ml (cultured for 24 hours) and 220μg/ml (cultured for 48 hours). The inhibitory effect of T-3761 was 2-4 times lower than those of ciprofloxacin or norfloxacin and approximately equal to cephalothin.
2. Reverse mutation test with bacteria: The preincubation method with Salmonella typhimurium TA100, TA98, TA1535, TA1537 and Escherichia coli WP2 uvrA, and the induced mutation frequency (IMF) test with Salmonella typhimurium TA100, TA98 were performed.
The number of revertant colonies were not increased in any strains treated with T-3761 in the presence or absence of S9 mix.
3. Chromosome aberration test: V79 cells were treated with 50-200μg/ml of T-3761 for 24 or 48 hours, and were treated with 400-3,200μg/ml of T-3761 for 6 hours with S9 mix.
The number of cells showing chromosomal aberrations were not increased in any conditions tested for T-3761.
4. Micronucleus test: The male ICR mice were given a single (500-5,000 mg/kg) or five consecutive (150-1,500mg/kg) oral administration of T-3761.
The number of polychromatic erythrocytes with micronuclei were not increased at any dosage groups of T-3761.
From these results, it is concluded that T-3761 has low cytotoxicity, and has no mutagenicity.

View full abstract

Antigenicity studies of T-3761, a new quinolone derivative, were conducted and the following results were obtained.
1. By active systemic anaphylaxis test in guinea pigs, neither immunogenicity nor allergenicity of T-3761 was noted.
2. By homologous 4-hour passive cutaneous anaphylaxis (PCA) test using the serum obtained from these guinea pigs, neither immunogenicity nor allergenicity of T-3761 was noted.
3. The potential of IgE antibody production in mice was examined by heterologous 24-hour PCA test in rats. But neither the potential of IgE antibody production nor allergenicity of T-3761 was noted.
4. By passive hemagglutination assay, we analysed the antibody titer in rats and dogs serum obtained from three-month toxicity repeated dose studies (oral and intravenously administration). But the hemagglutination response was negative and specific antibodies were not detected.

View full abstract