Aim: The aim of this study was to optimalise netilmicin dosage in low and very low birthweight premature neonates, based on drug serum concentrations obtained during therapeutic drug monitoring (TDM).
Patients and methods: Prospective study of 55 neonates born at gestational age 23-32 (GA) and birthweight between 480 g to 1780 g, with suspected intrauterine infection, in whom netilmicin serum concentration was monitored. Initially the antibiotic was administered every 24 hours (group I: n=16; mean GA=28+/-3 weeks). Peak level was measured 30 minutes after completion of infusion after the 2(nd) dose of the drug, and trough level was measured immediately before administration of the 3(rd) dose of the drug. Due to excessive trough levels, the dosing regimen was modified, prolonging the interval between doses to 48 hours. Such dosing regimen was used in neonates, enrolled in group II (n=39; mean GA=28+/-2 weeks). Pharmacokinetic parameters were evaluated in order to find correlations between them and neonatal maturity, birthweight and creatinine serum concentration. Serum netilmicin concentration was measured by fluorescence polarization immunoassay (FPIA), using TDx/FLx (Abbott Laboratories). Creatinine concentration was measured on the 3(rd) day of life using Cobas Integra 400. All children in the study underwent the first hearing examinations under 3 months of age. After excluding changes which could affect hearing ability, behavioural examination was conducted. If its result was inconclusive or abnormal, the child was referred for ABR (auditory brain stem response) examination. The children were followed-up until they were 2 years old.
Results: Netilmicin peak levels in both groups were within the recommended range (11.33+/-3.27 microg/mL in group I; 13.35+/-5.67 microg/mL in group II). Safe trough level was exceeded in 81.2% neonates in group I and 28.2% in group II. This was observed in the most immature neonates: born 23-27(th) GA, with mean birthweight 805+/-293 g, in whom trough level was on average 2.93 microg/mL and t(0.5) was 20.8 hours. Negative correlation was found between trough level and gestational age (r=-0.524; p<0.001) and birthweight (r= -0.293; p=0.030). Negative correlations was also found between t(0.5) and gestational age (r= -0.489; p<0.001) and birthweight (r=-0.320; p=0.016). No child was diagnosed with hearing impairment in group II and one case in group I.
Conclusions: The results indicate that netilmicin dosage of 6 mg/kg every 48 h can ensure the desired trough and peak levels in premature neonates without the necessity of routine monitoring of antibiotic concentration. However, in very premature neonates (<or=27 GA) the concentration of the drug has to be monitored. Highly significant negative correlation between trough level and GA was found. However, no correlation between creatinine concentration, t(0.5), trough level and peak level was found. No evidence of ototoxicity of netilmicin dosing every 48 h was observed. However, these findings require confirmation in studies on a larger group of patients.