Pharmacokinetic and clinical studies on cefodizime in the pediatric field pediatric study group of cefodizime (Chairman: Ryochi fujii)

A multi-center open study was conducted to investigate cefodizime (CDZM), a newly developed cephem antibiotic, from pharmacokinetic, bacteriological and clinical aspects, in the pediatric field with the participation of 17 institutions and their related facilities. The results are summarized as follows: Serum concentrations and urinary excretion: The pharmacokinetics in pediatric patients was investigated with a dose of 20 mg/kg, via a bolus intravenous injection or intravenous drip infusion over 30 or 60 minutes. The results were nearly the same as those in adult patients. Mean serum concentrations 5 minutes after a bolus intravenous injections were: 105.5, 264.0 and 461.7 µg/ml with 10, 20 and 40 mg/kg, respectively, and T 1/2 (β)'s for the 3 dosages were 1.75, 1.92 and 1.88 hours, respectively. With 30-minute intravenous drip infusion, mean serum concentrations at the end of infusion were: 90.5 µg/ml with a dose level of 10 mg/kg, 178.3 µg/ml with 20 mg/kg, and 322.8 µg/ml with 40 mg/kg, and T 1/2 (β)'s for these dosages were 1.90, 2.15 and 1.93 hours, respectively. With 60-minute intravenous drip infusion, mean serum concentrations at the end of infusion were: 66.3 µg/ml with a dose level of 10 mg/kg, 136.0 µg/ml with 20 mg/kg and 259.2 µg/ml with 40 mg/kg, and T 1/2 (β)'s for these dosages were 1.43, 2.05 and 1.46 hours, respectively. In 8 hours after administration of CDZM, urinary excretion rates were 82.1, 77.7 and 76.5% for bolus intravenous injections of 10 mg/kg, 20 mg/kg and 40 mg/kg, respectively, and 83.3, 71.3 and 68.1% for 30-minute intravenous drip infusions of 10 mg/kg, 20 mg/kg and 40 mg/kg, and 84.4 and 84.3% for 60-minute intravenous drip infusions of 20 mg/kg and 40 mg/kg, respectively. Concentrations in cerebrospinal fluid: Penetrations into cerebrospinal fluid in patients with purulent meningitis reached levels of 1.96-9.48 [xg/ml with administration of CDZM at 50 mg/kg in acute cases within 6 days after onset. The penetration rates of CDZM were about a median range among injectable β-lactam agents. Clinical results: Of 457 cases treated with CDZM, 53 cases were excluded from the clinical evaluation. Clinical efficacies were evaluated as “excellent” in 126 and “good” in 78 out of 221 cases from which causative agents were isolated, with an efficacy rate of 92.3%. Efficacies were “excellent” in 97 and “good” in 69 out of 183 cases from which pathogens were not isolated, giving an efficacy rate of 90.7%. With regard to microbiological effect on pathogens, 213 out of a total of 230 strains isolated as pathogens were eliminated with a high eradication rate of 92.6%. Among Gram-positive bacteria, 31 out of 32 strains of Streptococcus pneumoniae were suc-cessfully eliminated with a high eradication rate of 96.9%. An excellent elimination activity of CDZM was also noted against Streptococcus pyogenes, with all 6 strains of this species were eliminated. On the whole, 64 out of 76 strains of Gram-positive bacteria were eliminated, giving an eradication rate of 84.2%. For Gram-negative bacteria, the following causative microbes were eliminated including all the strains of Brarihamella catarrhalis (15), Escherichia coli (21), Klebsiella pneumoniae (4), Haemophilus influenzae (82) and Proteus mirabilis (4). In total, 149 out of 154 strains of Gram-negative bacteria were eradicated with a very high eradication rate of 96.8%. The clinical effects of the drug by causative agents were evaluated as “good” or “excellent” in 204 out of 221 cases with an efficacy rate of 92.3%. Noteworthy was the effectiveness of CDZM against mixed infections of 2 or 3 species; the drug was effective in 30 out of 33 cases, the rate being as high as 90.9%. Of 35 cases which had not been responsive to other antibiotics, 33 cases responded to CDZM? with “good” or “excellent” result with a high efficacy rate of 94.3%. Side effects and laboratory tests: The safety was evaluated in a total of 449 cases including 45 cases which were excluded from the clinical analysis because, to these cases, CDZM was not applicable. Side effects noted were diarrhea, loose stool, rash, itching, perleche, vascular pain etc., with most symptoms due to digestive tract disorders. Laboratory tests revealed abnormal values of S-GOT, S-GPT, eosinophil and platelet. These abnormal values were similar to those caused by other cephalosporin antibiotics in the severity. One each abnormal values for Al-P, direct bilirubin, LAP and T-GTP were noted. However, these side effects and abnormalities in laboratory tests were not serious and all were normalized by discontinuation of the drug or even while the continuation of drug administration. From pharmacokinetic and clinical points of view, the usual dosage and administration recommendable is 20 mg/kg/dose of CDZM with a bolus intravenous injection or drip infusion, 3 times daily, by which a sufficient therapeutic effectiveness appears obtainable.