PHARMACOKINETIC, BACTERIOLOGICAL AND CLINICAL STUDIES ON CEFOZOPRAN IN THE PEDIATRIC FIELD

Abstract

Cefozopran (CZOP, SCE-2787), a newly developed parenteral cephem antibiotic, was administered to children with bacterial infections. We determined its antibacterial activity, pharmacokinetics, efficacy and safety in these patients.
1. Antibacterial activity
MICs of cefmetazole, ceftazidime, cefuzonam, flomoxef and CZOP were determined against a total of 19 strains. For Gram-positive cocci, MICs of CZOP ranged from 0.39 to 0.78μg/ml against Staphylococcus aureus(3 strains), from 0.05 to 6.25μg/ml against Streptococcus pneumoniae(5 strains), and 12.5μg/ml against Enterococcus faecalis(1 strain). These MICs were generally similar to those of other cephems, but the MIC of CZOP against E. faecalis was lower than those of the other cephems examined. For Gram-negative bacilli, MICs of CZOP were 25μg/ml against Citrobacter freundii(1 strain), and 6.25μg/ml against Pseudomonas aeruginosa(1 strain). These values were similar to or lower than those of other cephems, MICs of CZOP against Haemophilus influenzae(7 strains) ranged from 0.1 to 0.39μg/ml. However, the MIC of CZOP against Serratia marcescens(1 strain) was higher than 100μg/ml, and CZOP was as ineffective as the other cephems against this organism.
2. Pharmacokinetics
CZOP was administered to children at 20 or 40mg/kg via intravenous injection, and determinations were made for its serum concentrations, urinary concentrations and concentrations in cerebrospinal fluid (CSF) using the bioassay.
Serum concentrations at 30 minutes after administration were 60.4μg/ml with a dose of 20mg/kg to one patient and 93.9 and 99.0μg/ml with 40mg/kg to two patients. The corresponding half-lives were 1.55 hours for 20mg/kg administration, and 1.10 and 3.41 hours for 40mg/kg, while the AUCs were 136.5μg·hr/ml for 20mg/kg, and 194.4 and 264.5μg·hr/ml for 40mg/kg.
The rates of urinary recovery in the first 8 hours after administration were 45.0% in the patient receiving 20mg/kg, and 84.6 and 97.6% in the two patients receiving 40mg/kg.
The concentrations in the CSF determined in 3 patients with purulent meningitis ranged from 2.6 to 16.0μg/ml 1 hour after administration, and the CSF/serum concentration ratio ranged from 6.5 to 39.0%.
These values for pharmacokinetic parameters obtained in the bioassay were similar to those obtained using HPLC.
3. Clinical evaluation
Forty-eight patients were clinically evaluated. Of these patients, 75% were less than 3 years of age and there were slightly more male children than female children. Most of the patients were administered with about 20mg/kg of CZOP 3 or 4 times per day, and were treated for 6 to 10 days. Forty-six of the 48 patients including 2 with purulent meningitis showed excellent or good clinical responses, yielding an efficacy rate of 95.8%. One patient with pharyngo-laryngitis, 3 with sinusitis, 2 with purulent meningitis, 7 with urinary tract infections, 1 with impetigo, 3 with staphylococcal scalded skin syndrome and 2 with phlegmon were rated as having excellent or good clinical responses to the treatment. The efficacy rate was 96.2%(25/26) against pneumonia, and 2 of 3 patients with purulent lymphadenitis were rated as showing good clinical responses. Causative organisms were detected in 18 cases and 22 strains were isolated. With regard to Gram-positive cocci, one strain each of S. aureus, Staphylococcus epidermidis and E. faecalis that were identified, and 5 detected strains of S. pneumoniae were all eradicated. One strain of Enterococcus faecium was decreased in number upon treatment. With regard to Gram-negative bacilli, eight of 9 H. influenzae strains were eradicated, but 1 strain was unchanged in number upon treatment.