PHARMACOKINETIC AND CLINICAL EVALUATIONS OF CEFTRIAXONE IN NEONATES AND PREMATURE INFANTS

Abstract

Following a one shot injection with ceftriaxone (CTRX) 10 mg/kg or 20 mg/kg into 23 neonates (1 to 24 days old) including premature infants, plasma levels of CTRX were measured up to 12 hours post-dose in some cases and up to 72 hours post-dose in others and also urinary levels and urinary recovery rates were determined up to 12 hours post-dose. Furthermore, clinical, bacteriological and infection-prophylactic effects of CTRX were evaluated by the intravenous administration with the mean dose of CTRX of 47.7mg/kg once daily or half the dose twice daily for 9 days on the average into 46 infants (0 to 6 months old) including neonates and premature infants; i. e., 21 cases with actual or suspected bacterial infections for the evaluation of clinical and bacteriological effects and 25 without bacterial infection for the evaluation of prophylactic effects against bacterial infection. The safety of CTRX was evaluated in 53 cases including 7 which were omitted from the efficacy evaluation due to adverse reactions and also in some cases from clinical laboratory parameters. The following is a summary of the results obtained:
1. Following the administration with CTRX 10 mg/kg into each of the neonates 6, 12, 13 and 21 days old (the 21 old one was premature), plasma levels of CTRX in these subjects reached their peaks at 5 minutes post-dose at levels of 59.38, 53.13, 37.50 and 50.00μg/ml, respectively. The peak levels were similar to each other with an exception of the rather low level in the 13 day-old neonate. The plasma half-life times of CTRX in these subjects were 9.762, 7.775, 7.330 and 8.149 hours, respectively: The younger the infant the longer the half-life tended to be except the premature cases. Similarly, the younger the infant the larger the AUC was except for the premature case with the AUC values of 511.169, 324.714, 236.346 and 326.825μg·hr/ml, respec-tively. The Vds were 0.709, 1.004, 1.316 and 0.696 liters, respectively, and the value for 13 day-old neonate was the largest. Urinary levels of CTRX reached between 42.00 and 298.30μg/ml at some time within 12 hours post-dose in any cases. Urinary recovery rates in 12 hours post-dose were 79.98, 52.00, 56.82 and 60.14%, respectively.
2. By the administration of CTRX 20mg/kg to each of subjects in the following 5 age groups; 3 premature infants aged younger than 3 days, 4 neonates aged 4 to 7 days, 3 premature infants aged 4 to 7 days, 5 neonates aged 8 to 28 days and 4 premature infants aged 8 to 28 days, the plasma level reached its peak at 5 minutes post-dose in any of the subjects in any of the groups: Average peak levels in these groups were 83.34, 77.35, 109.39, 95.63 and 100.79μg/ml, respectively. A dose-response relationship was observed between 10mg/kg and 20mg/kg dose levels. Mean plasma half-lives were 15.528, 6.661, 10.546, 9.145 and 10.379 hours, respec-tively thus the younger the infant was, the longer it tended to be except for the group of neo-nates aged 4 to 7 days. Furthermore, half-lives tended to be longer in premature infants than in neonates regardless of age. The mean AUCs were 850.894, 348.329, 639.233, 572.205 and 616.240 pg·hr/ml, respectively, and AUCs in the premature infants younger than 3 day old were the largest. AUCs tended to be larger in premature infants than in neonates regardless of age. Mean Vds were 1.025, 1.676, 1.091, 1.440 and 1.087 liters: Vds tended to be larger in neonates than in premature infants.
Urinary levels of CTRX reached between 34.10 and 782.00μg/ml at some time in 12 hours post-dose. Urinary recovery rates in 12 hours were 23.15, 37.08, 41.64, 28.47 and 27.16%, respec-tively, and the rate in the group of premature infants aged younger than 3 days was the lowest.
3. The clinical efficacy rate was 85.7% in 21 infants with actual or suspected bacterial in-fection.