Background: The bactericidal efficacy of aminoglycosides is directly related to peak serum concentration (Cmax), particularly the first one. Transitory high concentrations of aminoglycosides do not result in such a high drug uptake by renal and cochlear tissues because of the saturation of cell binding sites. These observations have led to the concept that less frequent administration of relatively larger doses of aminoglycosides would be of interest in treating infectious diseases.
Objective: Prospective evaluation of a dosing chart of amikacin (Ak) in high-risk neonates suspected of infection within the first 2 days of life. This dosing chart was based on a previous pharmacokinetic population study published elsewhere, treated accordingly to the new once-daily concept of aminoglycoside administration.
Study design: One hundred and seventy-seven neonates (69 females and 108 males; mean gestational age (GA +/-SD: 33.6 +/- 4.1 weeks (W) received Ak regimen dosage according to the following dosing chart: Group (Gr) 1a GA <28 W: 20 mg/kg/42 h; Gr 1b GA 28 </= 31 W: 20 mg/kg/36 h; Gr 2 GA 31 </= 34 W: 18.5 mg/kg/30 h; Gr 3 GA 34 </= 37 W: 17 mg/kg/24 h; Gr 4 GA >/= 37 W: 15.5 mg/kg/24 h. In case of asphyxia, hypoxic episode and intercourse treatment with indomethacin, the interval was systemically increased by 6 h whatever the GA groups. The mean duration time of Ak treatment (+/- 1 SD) was 5.00 +/- 2.01 days (range 2-13). Ak serum concentrations 1 h after completion of 30 min infusion (C1h), and successive Ak serum concentrations just before next administration depending on the difference of interval between each group (so defined minimum serum concentration (Cmin)), were determined in each neonate. Creatininemia during the fist postnatal weeks was used as an index of glomerular filtration rate; brainstem auditory evoked potentials (BEAPs) were used in 139 babies when reaching a postconceptional age of >/= 36 weeks to assess possible ototoxicity, and were compared to values from a group of term and a group of preterm babies, previously defined as our reference control groups.
Results: At day 1 of treatment, there was no correlation between the Ak C1hS and the GA at birth (mean 27.8 +/- 5.21 microgram/ml (+/- 1 SD); median 28; r = -0.003; range 10-40). In the same way, there was no correlation between the first Ak CminS and the GA at birth (mean 3.7 +/- 2.0 microgram/ml (+/- 1 SD); median 3.0; r = -0.33; range 0-10). The lack of correlation between these first observed C1hS and CminS and the GA at birth suggests the validity of our previous established dose regimen recommendations. Analyzing the data between groups, the mean value +/- 1 SD of Ak C1hS at day 1 of treatment was not significantly different (p > 0.05). Concerning the first Ak CminS, a significant difference (p < 0.01) was only observed when comparing groups 1a, 1b and 2 to group 4. However, this significant difference disappeared when comparing the successive next Ak CminS between groups while each interval remained the same, suggesting a positive postnatal maturation of the renal clearance. In the same way, creatininemia showed a significant and normal decrease (p < 0.01) in each group during the first postnatal weeks. Threshold values of BEAPs at 30 dB showed no significant difference (p > 0.05) between the treated groups (preterm group and term group) and the corresponding control groups. While the primary aim of the study was not to test the bactericidal efficacy of this new regimen, the recovery was excellent in 37 babies with proven or highly suspected infectious disease, except in 1 of them who died from septic shock (group B Streptococcus). After 5 years of using this kind of Ak administration in the unit, minimal inhibitory concentration profiles tested in 43 successive bacterial strains collected from inborn patients remained adequate. (ABSTRACT TRUNCATED)