Laboratory and clinical studies on flomoxef in neonates and premature infants
Motohiro, T.; Maruoka, T.; Nagai, K.; Oki, S.; Tsumura, N.; Sasaki, H.; Aramaki, M.; Koga, T.; Sakata, Y.; Tominaga, K.
Japanese Journal of Antibiotics 46(7): 547-567
1993
ISSN/ISBN: 0368-2781 PMID: 8371491 Document Number: 410978
Flomoxef (FMOX), an oxacephem antibiotic of beta-lactam antibiotic family, was administered to 16 infants including 6 neonates and 10 premature infants at a dose of 20 or 40 mg/kg via intravenous injection, and plasma and urinary concentrations and the urinary recovery were determined. In addition, FMOX was administered via intravenous injection at daily doses averaging 85.5 mg/kg divided into 2 to 4 times for durations averaging 9 days to 96 infants from 0- to 90-day old (mainly neonates and premature infants). In 44 of the 96 infants with bacterial infections, clinical and bacteriological efficacies were evaluated, and prophylactic effects of FMOX were determined in the remaining 52 infants. Adverse reaction and laboratory tests abnormalities were evaluated also. The obtained results are summarized as follows. 1. Upon administration of FMOX at 20 or 40 mg/kg to neonates and premature infants via intravenous injection, plasma concentrations, half-lives and AUC were determined. In 3 neonates of 5, 7 and 16 days of ages administered with 20 mg/kg of FMOX, peak plasma concentrations of 62.5 to 99.7 mu-g/ml were achieved in 5 or 15 minutes after injection. Half-lives of FMOX in these neonates were 1.48 to 1.78 hours and AUC's were 112 to 161 mu-g cntdot hr/ml. The same dose (20 mg/kg) of FMOX was administered to 3 premature infants of 5- 16- and 19-day of ages and initial blood samples were obtained at 5 minutes after injection from the 5-day old subject and at 15 minutes after injection from the 16-and 19-day old subjects. Peak plasma concentrations of 63.6 to 79.9 mu-g/ml were observed in the samples. Half-lives were 1.69 to 2.20 hours and AUC's were 174 to 201 mu-g cntdot hr/ml. When 3 neonates (one 17-day old and two 24-day old subjects) were administered with 40 mg/kg of FMOX, peak plasma concentrations obtained at 5 minutes after injection were 99.7 to 122.0 mu-g/ml. Half-lives were 1.28 to 1.92 hours and AUC's were 170 to 357 mu-g cntdot hr/ml. In 6 premature infants (one 3-day old, one 5-day old and four between 16 and 24 days of ages) administered the same dose, the peak plasma concentrations achieved at 5 minutes after injection were as follows: 113.0 mu-g/ml in the 3-day old, 108.0 mu-g/ml in the 5-day old and between 112.0 and 148.0 mu-g/ml in the other 4 cases, half-lives were 3.85, 2.86 and between 1.70 and 2.25 hours, respectively, and AUC's were 493, 407 and between 310 and 361 mu-g cntdot hr/ml, respectively, for the 3 groups of subjects. 2. Urinary concentrations and urinary recovery rates were also determined for 14 subjects of the 15 subjects for whom plasma concentrations were determined as mentioned above. It was not possible to collect urinary samples in the remaining 1 case (a neonate administered with FMOX at 20 mg/kg). In addition to the 15 cases, a premature infant was administered with FMOX at a dose of 20mg/kg and urinary recovery concentrations and recovery rates were determined though plasma concentrations were not. In the 2 neonates of 5- and 7-day of age who were administered with 20 mg/kg, peak urinary concentrations were reached between 0 and 2 hours after administration at 1,770 and 2,300 mu-g/ml, respectively. Urinary recovery rates in the first 6 hours after injection were 89.3 and 82.0%, respectively. In the 4 premature infants of 5-, 16-, 17- and 19-day of ages who received 20 mg/kg, peak urinary concentrations were between 417 and 2,260 mu-g/ml observed urine samples collected between 0 and 2 hours or 2 and 4 hours after administration. Urinary recovery rates in the first 6 hours after administrations were between 40.4 and 78.0%. In the 3 neonates who received 40 mg/kg (one 17-day and two 24-day olds) peak urinary concentrations were observed either in samples collected between 0 and 2 hours or 2 and 4 hours after administration, with peak concentrations between 1,800 and 4,170 mu-g/ml. Urinary recovery rates in the first 6 hours after administration were between 66.6% and 77.8%. In the 6 premature infants who received the same dose (a 3-day old, a 5-day old and 4 subjects between 16 and 24 days), urinary peak concentration were observed either in samples collected between 0 and 2 hours, between 2 and 4 hours and between 4 and 6 hours, respectively with concentrations of 6,220, 2,750 and between 2,050 and 3,440 mu-g/ml, respectively. Urinary recovery rates in the first 6 hours after administration were, respectively, 38.0, 62.7 and between 66.1 and 83.7%. 3. In the 44 patients with bacterial infections, clinical efficacies of FMOX were excellent in 10 (22.7%), good in 30 (68.2%), fair in 1 (2.3%) and poor in 3 patients (6.8%). The overall efficacy rate was 90.9%. FMOX was effective in the 52 patients who received the drug for prophylaxis. 4. Bacteriological efficacies were evaluable against 12 strains including 9 strains of Staphylococcus aureus, 2 strains of Haemophilus influenzae and a strain of Escherichia coli. Except a strain of H. influenzae (d ecreased), all of the strains were eliminated, hence the elimination rate of 91.7% was obtained. 5. In the evaluation of adverse reactions, 2 patients excluded from the evaluation of clinical effects were included, hence the number of subjects in this phase of the study was 98. A case of mild diarrhea was encountered, and it was considered that this was likely due to FMOX. As abnormal laboratory test results, increase of more than 10% in eosinophiles was observed in 1 subject (1.2%) of 83 patients for whom this test was performed, and abnormalities in GOT alone, and in GOT and GPT were observed in 1 subject each. These effects were considered due to FMOX also.