FUNDAMENTAL STUDIES ON CEFOPERAZONE (T-1551) Sensitivity Studies of the Clinical Isolatesand Passagc of the Drug into the CSF in Experimental Staphylococcal Meningitis in Rabbits

• Published in: CHEMOTHERAPY Vol. 28; no. Supplement6; pp. 575 - 583
• Main Authors: HARUTA, TSUNEKAZU, MORIKAWA, YOSHIRO, KOBAYASHI, YUTAKA, FUJIWARA, TORU
• Format: Journal Article
• Language: Japanese
• Published: Japanese Society of Chemotherapy 25.10.1980
• ISSN: 0009-3165; 1884-5894
• DOI: 10.11250/chemotherapy1953.28.Supplement6_575

A new cephalosporin, cefoperazone (CPZ, T-1551), was evaluated in regard to MICs to 131 strains of various clinical isolates and passage into the CSF in experimental staphylococcal meningitis in rabbits, and the following results were obtained. 1) MICs of CPZ to 15 strains of Staphylococcus aureus were higher than those of cefazolin by fourfold, and those to gram-negative rods were superior to those of cefazolin. However, CPZ was much affected by the inoculum size. Peak concentrations of MIC distribution at the inoculum size of 106/ml of the following isolates were as follows; E. coli (32 strains), 0.1-0.8μml: Salmonella typhi (3), 0.4μg/ml: Salmonella Group B (1), 0.8μg/ml: Klebsiella pneumoniae (5), 0.4μg/ml: Klebsiella oxytoca (43), 0.8-1.6μg/ml: Proteus mirabilis (8), 0.8-3.1μg/ml: Proteus vulgaris (1), 6.3μg/ml: Proteus morganii (2), 0.8-1.6μg/ml: Proteus rettgeri (1), 25μg/ml: Enterobacter (3), 0.8-50μg/ml: Citrobacter (2), 1.6-3.1μg/ml: Serratia marcescens (5), 0.8-3.1μg/ml: and Pseudomonas aeruginosa (10), 3.1μg/ml. 2) Blood and CSF concentrations of the drug were determined at 30-min interval following a single one shot intravenous injection of 100mg/kg in 6 rabbits with experimental staphylococcal meningitis. Peak concentration in CSF was obtained 60-min after the injection, i.e., 6.7±1.39μg/ml, with a CSF/serum ratio of 6.4%. 3) Other 5 rabbits with experimental meningitis were given the same dose similarly, and blood and CSF concentrations were determined at 15-min interval for 8 times and twice at 30-min interval, 10 times in total. Pharmacokinetics of CPZ were evaluated on the basis of the above results. Two out of 5 rabbits gave very high CSF concentrations. An average of CSF concentrations of other 3 rabbits was maximal at 45 min, i.e., 6.57±0.66μg/ml; the area under the curve (AUC) up to 3 hrs, 666.68 min·μg/ml: percentage of CSF/serum ratio of the AUC, 13.7%: T1/2 of CSF concentration, 54.2 min, i.e., 1.31 times higher than that of blood. These results were better than those reported with penicillin G, methicillin and cephalothin, and almost comparable to those of ampicillin and cefazolin. 4) Protein binding rate of the drug in human subjects and rabbits was about 86% and was the second highest among cephalosporins next to cefazolin. Combined results of the previous and present studies suggested that the extent of passage of the cephalosporins into the CSF was not always correlated with the protein binding rate and demonstrated that there was no relationship between the disappearance rate from the CSF of a cephalosporin and its protein binding rate. 5) The above results appeared to indicate that CPZ is a potent new antibiotic in the treatment of bacterial meningitis in human subjects. The drug should first be tried clinically in ampicillin-resistant Haemophilus influenzae meningitis.