Abstract
Background: The effectiveness of antibiotics for the treatment of severe bacterial infections in newborns in resource-limited settings has been determined by empirical evidence. However, such an approach does not warrant optimal exposure to antibiotic agents, which are known to show different disposition characteristics in this population. Here we evaluate the rationale for a simplified regimen of gentamicin taking into account the effect of body size and organ maturation on pharmacokinetics. The analysis is supported by efficacy data from a series of clinical trials in this population. Methods: A previously published pharmacokinetic model was used to simulate gentamicin concentration vs. time profiles in a virtual cohort of neonates. Model predictive performance was assessed by supplementary external validation procedures using therapeutic drug monitoring data collected in neonates and young infants with or without sepsis. Subsequently, clinical trial simulations were performed to characterize the exposure to intra-muscular gentamicin after a q.d. regimen. The selection of a simplified regimen was based on peak and trough drug levels during the course of treatment. Results: In contrast to current World Health Organization guidelines, which recommend gentamicin doses between 5 and 7.5 mg/kg, our analysis shows that gentamicin can be used as a fixed dose regimen according to three weight-bands: 10 mg for patients with body weight <2.5 kg, 16 mg for patients with body weight between 2.5 and 4 kg, and 30 mg for those with body weight >4 kg. Conclusion: The choice of the dose of an antibiotic must be supported by a strong scientific rationale, taking into account the differences in drug disposition in the target patient population. Our analysis reveals that a simplified regimen is feasible and could be used in resource-limited settings for the treatment of sepsis in neonates and young infants with sepsis aged 0–59 days.
Highlights
Bacterial infections persist as a global health problem (UNICEF, 2018)
The WHO recommends the use of gentamicin in combination with ampicillin or amoxicillin as empirical therapy for sepsis in newborns and infants (0–59 days old) (World Health Organization, 2015)
Recent clinical trials in this vulnerable population, such as AFRINEST and SATT have shown promising findings, in that high efficacy rates have been achieved with a dosing regimen that can be implemented
Summary
Bacterial infections persist as a global health problem (UNICEF, 2018). Children mortality remains exceptionally high during the first month of life, with more than 99% of neonatal deaths occurring in developing countries. The recommended initial empirical therapy for a neonate with suspected bacterial sepsis and/or meningitis includes ampicillin and an aminoglycoside (Zaidi et al, 2011; Polin et al, 2012; World Health Organization, 2015; Seale et al, 2015). Acceptability or affordability issues, this is due to the complexity of the recommended dosing regimens, which have been introduced into clinical practice in a rather empirical manner Such an approach does not warrant optimal exposure of newborns to antibiotic agents, which show a different disposition profile in this population (Cella et al, 2010a; Medellin-Garibay et al, 2015; Samardzic et al, 2016). The analysis is supported by efficacy data from a series of clinical trials in this population
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