Pharmacokinetics and clinical effects of cefozopran in pediatric patients

An investigation was made into pharmacokinetics and clinical effects of the newly developed cephem antibiotic for injection, cefozopran (SCE-2787, CZOP), in pediatric patients. In 26 patients in whom pharmacokinetics were investigated, peak serum concentrations of CZOP administered at doses of 10, 20 and 40 mg/kg by i.v injection were 21.3 ± 10.0 (mean ± standard deviation), 51.0 ± 9.9 and 68.3 ± 0.7 μg/ml, respectively. Serum concentrations at 6 hours after administration were 2.9 ± 17.2.3 ± 0.9 and 4.6 ± 2.6 μg/ml, with the levels roughly above MIC₉₀s for dominating pathogenic bacteria being maintained until 6 hours after treatment. Urine concentrations were in the range between 200 and 560 μg/ml at 4 to 6 hours after dosing Cumulative urine excretion accounted for 70 to 80% of dose. In 11 patients in whom pharmacokinetic investigations were performed, peak serum concentrations of CZOP administered at doses of 10, 20 and 40 mg/kg by 30- min. i. v. drip infusion were 37.1, 66.3 ± 25.5 and 95.7 ± 8.9 μg/ml, respectively. Serum concentrations at 6 hours after dosing were 1.6, 2.3 ± 0.8 and 3.0 ± 0.4 μg/ml, respectively, with the levels above MIC₉₀s for dominating pathogenic bacteria also being maintained until 6 hours after administration. Urine concentrations were 190 μg/ml or more until 8 hours after dosing and the cumulative urinary excretion accounted for 50 to 70% of dose. In 9 patients with meningitis in whom CZOP penetration into cerebrospinal fluid was investigated, concentrations in the fluid of the compound i.v. injected at doses from 40 to 53 mg/kg were in the range between 1.6 and 43.4 μg/ml exceeding MICs for pathogenic bacteria at 1 to 1.5 hours after dosing. In all of the 38 patients in whom pharmacokinetic investigations and clinical evaluations were performed, CZOP was good to excellent (excellent in 22 patients and good in 16 patients). Also in bacteriological evaluations, all of the 31 strains of investigated pathogenic bacteria were eradicated. The clinical efficacy rates for the 335 subjects for clinical evaluations were 97.0% (195/201) for patients in whom pathogenic bacteria were detected (group A), and 95.5% (128/134) for patients in whom no pathogenic bacteria were detected (group B). In bacteriological evaluations, the eradication rates of Gram-positive and Gram-negative bacteria were 96.3% (77/80) and 04.5% (155/164), respectively, with the eradication rate in total being 95.1% (232/244). Safety investigations were performed in 364 patients. Adverse reactions were reported in 11 patients (3.0%), including diarrhea (aqueous stool and soft stool) in 7 patients (1.9%) and drug rash (rash, eruption and wheal) in 4 patients (1.1%). Abnormal laboratory test values were noted in 54 patients, including eosinophilia in 20 patients (6.3%) and elevated GPT in 20 patients (63%). The adverse reactions and abnormal laboratory test values were not serious, disappearing or improving during the continued treatment period or as a result of discontinuation of the treatment. Serum and urine concentrations of CZOP, when administered by i.v injection and 30-min iv drip infusion at doses of 10, 20 and 40 mg/kg, were higher than the MICs for pathogenic bacteria until 6 hours after dosing. The drug also showed favorable penetration into cerebrospinal fluid. It was therefore considered that CZOP was a highly useful drug for the treatment of pediatric infections with sufficient bacteriological and clinical efficacy when administered at a dose of 40 to 80 mg/kg three to four times daily.