ADAPTATION IN NEONATOLOGY OF THE ONCE-DAILY CONCEPT OF AMINOGLYCOSIDEADMINISTRATION - EVALUATION OF A DOSING CHART FOR AMIKACIN IN AN INTENSIVE-CARE UNIT

Background: The bactericidal efficacy of aminoglycosides is directly r elated to peak serum concentration (C-max), particularly the first one . Transitory high concentrations of aminoglycosides do not result in s uch a high drug uptake by renal and cochlear tissues because of the sa turation of cell binding sites. These observations have led to the con cept that less frequent administration of relatively larger doses of a minoglycosides would be of interest in treating infectious diseases. O bjective: 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 popula tion study published elsewhere, treated accordingly to the new once-da ily concept of aminoglycoside administration. Study Design: One hundre d and seventy-seven neonates (69 females and 108 males; mean gestation al age (GA) +/- SD: 33.6 +/- 4.1 weeks (W) received Ak regimen dosage according to the following dosing chart: Group (Gr) 1(a) GA < 28 W: 20 mg/kg/42 h; Gr 1(b) GA 28 less than or equal to 31 W: 20 mg/kg/36 h; Gr 2 GA 31 less than or equal to 34 W: 18.5 mg/kg/30 h; Gr 3 GA 34 les s than or equal to 37 W: 17 mg/kg/24 h; Gr 4 GA greater than or equal to 37 W: 15.5 mg/kg/24 h. In case of asphyxia, hypoxic episode and int ercourse treatment with indomethacin, the interval was systematically 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 con centrations 1 h after completion of 30 min infusion (C-1h), and succes sive Ak serum concentrations just before next administration depending on the difference of interval between each group (so defined minimum serum concentration (C-min)), were determined in each neonate. Creatin inemia during the first postnatal weeks was used as an index of glomer ular filtration rate; brainstem auditory evoked potentials (BEAPs) wer e used in 139 babies when reaching a postconceptional age of greater t han or equal to 36 weeks to assess possible ototoxicity, and were comp ared to values from agroup of term and a group of preterm babies, prev iously defined as our reference control groups. Results: At day 1 of t reatment, there was no correlation between the Ak C(1h)s and the GA at birth (mean 27.8 +/- 5.21 mu g/ml (+/- 1 SD); median 28; r = -0.003; range 10-40). In the same way, there was no correlation between the fi rst Ak C(min)s and the GA at birth (mean 3.7 +/- 2.0 mu g/ml (+/- 1 SD ); median 3.0; r = -0.33; range 0-10). The lack of correlation between these first observed C(1h)s and C(min)s 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 C(1h )s at day 1 of treatment was not significantly different (p > 0.05). C oncerning the first Ak C(min)s, a significant difference (p < 0.01) wa s only observed when comparing groups 1(a), 1(b) and 2 to group 4. How ever, this significant difference disappeared when comparing the succe ssive next Ak C(min)s between groups while each interval remained the same, suggesting a positive postnatal maturation of the renal clearanc e. In the same way, creatininemia showed a significant and normal decr ease (p < 0.01) in each group during the first postnatal weeks. Thresh old values of BEAPs at 30 dB showed no significant difference (p > 0.0 5) between the treated groups (preterm group and term group) and the c orresponding control groups. While the primary aim of the study was no t 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 Strep tococcus). After 5 years of using this kind of Ak administration in th e unit, minimal inhibitory concentration profiles tested in 43 success ive bacterial strains collected from inborn patients remained adequate . Conclusion: We conclude that the proposed dosing chart of Ak adminis tration, even in very high-risk neonates, allows one to achieve adequa te Ak C(1h)s and C(min)s (whatever the CA at birth), while drug-induce d renal and cochlear toxicity is kept minimal. These serum concentrati ons would allow for C-max/MIC ratio of at least 8 to be easily reached , which is now considered as optimal for aminoglycoside treatment.