Gentamicin is widely used to treat neonates at risk of infection and those with suspected or confirmed infections (1). Gentamicin and beta-lactam antibiotics are an effective combination therapy against a wide range of pathogens prevalent in the neonatal stage, such as Streptococcus agalactiae (group B streptococcus), Listeria monocytogenes, Enterococcus faecalis, and most isolates of Escherichia coli (2). Gentamicin is an antibiotic with a concentration-dependent bacterial killing effect, and the challenge in aminoglycoside therapy lies in optimizing dosages to maximize therapeutic benefits while minimizing risks like nephrotoxicity and ototoxicity (3, 4). Traditionally, a 2.5 mg/kg dose of gentamicin every twelve hours was standard (5). Over the past twenty years, adjustments have been made to increase the dose to 5 mg/kg and to prolong dosing intervals to 24–48 h, tailored according to the neonate's postmenstrual age (6–8). This adjustment aims to optimize bactericidal activity through higher gentamicin peak serum levels (>5 μg/ml) and to reduce toxicity risks by avoiding elevated trough levels (>2 μg/ml) (4, 9, 10). Customizing gentamicin dosages requires therapeutic drug monitoring, mainly focusing on trough concentrations to confirm adequate clearance prior to subsequent dosing. Given the significant variability in gentamicin pharmacokinetics among neonates, attributed to ongoing physiological development and organ maturation affecting distribution volume and kidney clearance, there's a pronounced need to understand individual responses to gentamicin therapy (11). This variability is observed even among neonates of similar gestational and postnatal ages (12). Our research thus seeks to investigate determinants of elevated gentamicin trough levels in this population, aiming to refine dosing strategies for improved safety and efficacy.

Navigating the balance between achieving the maximal bactericidal impact and avoiding toxic levels of gentamicin in neonatal sepsis treatment continues to pose a challenge (3). Several dosing regimens have been suggested for neonates depending on gestational age and weight, ranging from 3 to 7.5 mg/kg (17). Most studies recommend dosages of 4–5 mg/kg, resulting in a mean peak concentration of 5.4–11.2 mg/L. In our study, administered gentamicin dosages across different postmenstrual age groups fluctuated between 3.66 and 3.88 mg/kg (Table 1). O'Connor et al. demonstrated that a gentamicin dosing regimen of 3.5 mg/kg achieved therapeutic peak concentrations (>5 µg/ml) in 98% of the neonates (18).

Our multivariate linear regression analysis underscored that dosing intervals extending to 36 and 48 h significantly contribute to lower gentamicin trough levels compared to a 24 h schedule. Notably, none of the neonates receiving gentamicin every 48 h exhibited trough concentrations above 1 µg/ml. This finding substantiates the efficacy of extended interval dosing adjusted for postmenstrual age in preventing elevated gentamicin trough concentrations in preterm neonates with a reduced drug clearance due to kidney immaturity (19).

For neonates aged 35 weeks or more with 24 h dosing intervals, we observed supratherapeutic trough levels (>1 µg/ml) in 36% of cases, albeit not surpassing 2 µg/ml (maximum 1.9 µg/ml). This aligns with findings by DeHoog et al., who argued that existing dosing algorithms aim to maintain serum trough concentrations below 2 µg/ml rather than 1 µg/ml, given the association of higher concentrations with toxicity (9, 20). Although many centers, such as ours, aim trough levels <1 µg/ml, numerous studies suggest that only gentamicin trough concentrations >2 µg/ml are associated with an increased risk of nephrotoxicity and ototoxicity (21, 22). Therefore, implementing a safe threshold of 2 µg/ml would result in less supratherapeutic levels, leading to unnecessary drug monitoring.

The analysis highlighted a significant link between increased serum creatinine levels and higher gentamicin trough concentrations. This finding is consistent with Antolik et al., who stated that neonates with a gestational age of ≥30 weeks with a creatinine concentration ≥1 mg/dl within the first 12–24 h of life were more likely to have an elevated gentamicin trough concentration (>1 µg/ml) than their counterparts with normal creatinine concentrations (23). As aminoglycosides are almost entirely eliminated by the kidneys, clearance of these drugs is directly affected by the patient's glomerular filtration rate (24). Hence, serum creatine values may play an essential role in identifying neonates at risk for elevated serum gentamicin trough concentrations. Kayser et al. further demonstrated the potential for reducing the incidence of elevated trough levels through a creatinine-based dosing algorithm (15). However, the British National Institute for Health and Care Excellence advises against using serum creatinine for monitoring and dosage adjustments in infants on gentamicin, as creatinine levels can be influenced by various factors, including maternal creatinine, infections, and conditions like hypoxic-ischemic encephalopathy (12, 25).

Previous studies in critically ill adults and children indicate that the volume of distribution of gentamicin increases during sepsis (26–28). Lingvall et al. reported a 14% increase in distribution volume in septic neonates, suggesting larger doses may be necessary to achieve therapeutic peak levels in the presence of sepsis (29). This study's finding that higher CRP levels, indicative of sepsis, correlate with lower gentamicin trough concentrations underscores the importance of careful gentamicin use in neonates with suspected infections, especially since those with lower CRP levels are more prone to elevated trough concentrations.

Our findings suggest that a 24 h dosing interval, elevated creatinine levels, and lower CRP levels are linked to higher risks of gentamicin concentrations >1 µg/ml. However, all gentamicin trough levels were within the well-established 2 µg/ml threshold.