Gentamicin is one of the most commonly used antibiotic in the treatment of neonatal sepsis. Early onset sepsis in neonates is usually due to vertical transmission during vaginal delivery or by ascending contamination of amniotic fluid, from bacteria colonization or infection of the mother’s lower genital tract . It is hydrophilic with a volume of distribution of 0.45L/kg in neonates, which suggests that it is mainly distributed in the intravascular compartment . This property makes gentamicin an ideal agent for this indication as it is able to achieve bloodstream bacterial clearance effectively.
Our institution dosage regimen was revised to once daily dosing in year 1999, as IM injection route. There were 248 neonates involved in the study and the dosage regimen was revised in 2 phases . The same dosage regimen was utilised since, as attainment of therapeutic serum concentration has been observed to be consistent. Findings of current study showed that 91% of peak and 98% of trough concentrations were within therapeutic range. As a result of findings from the present study, we have since revised our therapeutic drug monitoring practice in neonates to only monitor serum trough concentration prior to the 3rd dose of gentamicin. Monitoring of serum peak concentration is reserved for neonates who have inadequate clinical response toward antibiotic treatment at the discretion of physicians. The revised practice has significantly reduced the amount of logistic duties such as reduction in the number of blood sampling, reduction in the cost of laboratory tests as well as reduction in workload of medical staffs.
As gentamicin exhibits concentration dependent kill, its antimicrobial effect can be optimized through administration of a larger dose to achieve higher serum concentration. Once daily dosing of gentamicin has been found to be more efficacious as well as a better safety profile [11, 12]. However, the commonly used drug reference in neonates, Neofax, recommends gentamicin frequency to be prolonged to 36 or 48 hours for neonates with PMA < 35 weeks in their first week of life, with a slightly higher dosage recommendation for different age group .
Gentamicin dosage regimen recommended by Neofax is supported by results from 2 studies [13, 14]. Population pharmacokinetic parameter estimates from study by Stolk and colleagues were calculated from 725 serum gentamicin concentrations obtained in 177 neonates of 24 to 42 weeks' gestational age in their first week of life. The initial peak and trough concentrations were predicted to be 6 to 10mg/L and less than 1mg/L, respectively, based on population pharmacokinetic parameters . In another larger study that involved 1854 neonates with birth weight 390–5200g, postnatal age 0–27 days, Monte Carlo simulations on the basis of validated models were undertaken to evaluate the attainment of target peak (5–12mg/L) and trough (< 0.5mg/L) concentrations. The above standard dosing regimen attained trough concentrations of 1mg/L or less and 0.5mg/L or less in 50% and 17%, respectively, of dose simulations (n = 5,000). Likewise, peak concentrations of 5 to 12mg/L, greater than 12mg/mL, and less than 5mg/L were attained in 75%, 20%, and 6%, respectively, of dose simulations .
Post-antibiotic effect (PAE) allows antibiotic doses to be administered less frequently. The PAE of gentamicin on E. coli was studied by Stubbings et al . When exposed to gentamicin concentration of 5 times above the minimal inhibitory concentration (MIC) for 60 minutes, E. coli RNA synthesis remained inhibited for only 1 hour after gentamicin exposure while DNA synthesis recovered between 2–3 hours, before the onset of growth. Gudmundsson et al. investigated the PAE of beta-lactam and aminoglycosides combination on S. aureus, P. aeruginosa, E. coli and K. pneumonia . When used against S. aureus and P. aeruginosa, the antibiotic combination prolonged PAE by 1.0–3.3 hours but no prolongation was observed against E. coli and K. pneumonia. It remains unknown if gentamicin serum concentration will drop to a sub-therapeutic level with the extended dosing frequency of more than 24 hours, thereby potentially affecting gentamicin efficacy. Future study should focus on developing a validated population pharmacokinetic model which can then be utilised to determine the most appropriate dosage regimen through Monte Carlo simulation.
A total of 47 (6.4%) neonates who received gentamicin failed inpatient hearing screening done using AABR and /or OAE. Aminoglycoside otoxicity is associated with swelling of nerve terminals within 15–18 hours after exposure and death of inner ear hair cells 1–2 days post exposure [17, 18]. There were no association found between gentamicin dose measures and hearing screen failure, while another study suggests long course gentamicin may be responsible for the increased ototoxicity [19, 20]. Mitochondrial DNA mutations have been linked to sensitivity to aminoglycosides and associate with hearing loss in the absence of aminoglycosides exposure .
Aminoglycoside induced nephrotoxicity is characterised by selective targeting of the proximal tubule epithelial cells within the renal cortex. Approximately 5% of the administered dose accumulates within these cells after glomerular filtration . Once inside the cell, aminoglycosides accumulate within lysosomes, the Golgi apparatus and endoplasmic reticulum (ER) causing lysosomal phospholipidosis [23–25]. Leakage of aminoglycosides from the lysosomal structures into the cytoplasm then acts on the mitochondria, activating the intrinsic pathway of apoptosis which in turn leads to formation of reactive oxygen species [25–27]. Renal impairment was found in 2 neonates who received gentamicin, 1 of whom received both gentamicin and amikacin during their hospital stay. The renal function improved with supportive management in one neonate while the other extreme preterm infant developed severe AKI as per the modified KDIGO classification due to umbilical venous catheter extravasation and demised within the first week of life . A retrospective study of nephrotoxin exposure in preterm neonates documented gentamicin exposure in 86.0% of the 107 neonates, 26.2% of whom developed AKI .
Intramuscular gentamicin administration was found to be similar to intravenous route, in term of the serum concentration achieved in this study. This finding is in agreement with previous gentamicin pharmacokinetic studies in neonates [30, 31]. Chow-Tung et al. compared pharmacokinetic profile of gentamicin after IV and IM administration in 16 neonates during their first week of life . Mean serum concentration obtained from both IV and IM route were similar (p > 0.05). Similar findings were reported in the kinetic study by Paisley et al . Intravenous and intramuscular routes of administration for gentamicin were alternated in 11 infants, the resultant serum concentrations did not differ significantly.
Our study was not without limitations. First, the retrospective nature of this study, implies a huge reliance on the documentation of dose administration and blood sampling time by the nurses. Second, missing data for serum creatinine was imputed using last observation carried forward technique. However, most of the neonates had their renal panel checked at least once during the course of gentamicin treatment.
In conclusion, the current institutional gentamicin dosage regimen is safe and effective in attaining therapeutic targets. Intramuscular injection can be an alternative route of administration for gentamicin in neonates.