Study setting and patient population
This was a retrospective cross-sectional quantitative study conducted at the Neonatal Unit of the Maternity ward at the Windhoek Central Hospital in Windhoek, Namibia. The data were derived from two population pharmacokinetic studies in which one set of neonates were receiving gentamicin and the other were receiving amikacin in the same neonatal unit using the same methodology. Data for gentamicin were collected from 44 neonates starting from 4 July 2019 to 29 December 2019, while data for amikacin were collected from 35 neonates from 25 July 2020 to 7 December 2020 (all data were collected over a total period of 1 year). The patients who were receiving gentamicin were not the same patients as those on amikacin. Patients who were included in the study were those who had two reported drug concentrations, and at least one serum creatinine measurement.
Aminoglycoside therapy was prescribed against either suspected or confirmed sepsis. Gentamicin in combination with a penicillin such as penicillin G or ampicillin was indicated as first-line in prophylaxis against suspected neonatal sepsis where there are risk factors such as premature birth, very low (and extremely low) birthweight (VLBW and ELBW), and respiratory distress syndrome (RDS). Amikacin was given in combination with piperacillin/tazobactam as second-line therapy if signs of sepsis persisted even after the gentamicin course had been completed.
Gentamicin therapy was initiated soon after birth, while treatment with amikacin was only initiated around day 5 when the gentamicin course had been completed with no improvement in the patient’s condition. All neonates who received amikacin had first been treated with gentamicin as first-line.
Aminoglycoside dose was administered by the ward nurses as a slow intravenous bolus injection via a cannula and two blood samples were withdrawn by venipuncture thereafter. Each one sample was taken at a time falling in either of the following sampling blocks: 4-6 minutes (0.06-0.10 h), 6-180 minutes (0.1-3.0 h), or 180-320 minutes (3-5.4 h). Blood samples were collected into sterile 500 µL serum separating tubes (SST), centrifuged and serum stored in Eppendorf tubes at -20 oC to await analysis.
Serum creatinine concentration measurements were done by the enzymatic method using the Cobas® 6000 analyzer (Roche Diagnostics, IN, USA). Gentamicin and amikacin concentrations were measured using the Indiko Plus™ autoanalyzer (Thermo Fisher Scientific Inc, CA, USA). The lower limit of quantifications for gentamicin and amikacin were stated given by the manufacturer as 0.3 µg/mL and 0.8 µg/mL, respectively.
The two reported drug concentrations were plotted onto semi-logarithmic graph paper to estimate the half-life, Cmax, and the time to reach the target trough concentration which was <1 µg/mL for both gentamicin and amikacin. The eGFR was estimated by using the Schwartz method for estimating creatinine clearance in paediatrics (equation 1):
where: Factor is 0.43 in term neonates or 0.33 in preterm neonates.
The results were summarized using descriptive statistics such as median, range, and percentages. A two-tailed unpaired t-test was used in Excel (Microsoft Excel, Redmond, WA, USA) to compare means. A p<0.05 was taken to be the critical value for statistical significance.
The study was approved by the University of Namibia Human Research Ethics Committee and the Research Committee of the Ministry of Health & Social Services in Namibia. Informed consent was first sought and obtained from the mothers of the newborns before they were included in this study.