A simplified amoxicillin regimen with dose frequency based on post-natal age in neonates with confirmed or suspected
Mispah Mukap1,2, Corin Sprod1,2, Okhee Yoo3
1School of Medicine, University of Papua New Guinea, Port Moresby, Papua New Guinea.
Insights
Optimizing amoxicillin dosing in neonates is crucial for treating infections. A new regimen balances effective treatment with reduced neurotoxicity risk, improving infant care outcomes.
Area of Science:
- Pharmacology
- Neonatal Medicine
- Infectious Diseases
Background:
- Amoxicillin and gentamicin are first-line empiric therapies for neonatal infections.
- Current dosing guidelines for amoxicillin in neonates lack standardization regarding dose, frequency, and age adjustments.
- Variability in dosing can lead to suboptimal therapeutic outcomes or increased toxicity risks.
Purpose of the Study:
- To develop a population pharmacokinetic (PK) model for amoxicillin in neonates with sepsis.
- To design optimized amoxicillin dosing regimens balancing efficacy and safety.
- To evaluate existing and proposed dosing strategies through simulation.
Main Methods:
- A prospective, observational PK study involving 177 neonates receiving intravenous amoxicillin in Papua New Guinea.
- Population PK modeling to characterize amoxicillin disposition in neonates.
- PK-pharmacodynamic (PK-PD) target attainment simulations using various dosing regimens and minimum inhibitory concentrations (MICs).
- Assessment of neurotoxicity risk based on amoxicillin concentrations exceeding 140 mg/L.
Main Results:
- Existing amoxicillin regimens (50 or 100 mg/kg) showed a high risk of potential neurotoxic concentrations (24.9% and 84.5%).
- The standard 30 mg/kg PNG regimen resulted in underdosing when administered twice daily between 3 and 7 days post-natal age (PNA).
- A proposed 30 mg/kg regimen (twice daily for first 2 days PNA, thrice daily thereafter) optimized PK-PD target attainment while minimizing toxicity risk.
Conclusions:
- Optimized amoxicillin dosing is essential for effective neonatal sepsis treatment.
- A simplified dosing regimen of 30 mg/kg, adjusted by PNA frequency, offers an improved therapeutic window.
- Proposed fixed volume doses (52 mg for <3 kg, 104 mg for ≥3 kg) facilitate practical administration and enhance safety.
Abstract:
Amoxicillin plus gentamicin is the recommended first-line empiric therapy for neonates with infection. Guidelines vary widely in dose (mg/kg), dose frequency, and adjustments according to post-menstrual age (PMA) and post-natal age (PNA). We aimed to develop a population pharmacokinetic (PK) model for amoxicillin in neonates with clinical evidence of sepsis and design optimal dosing regimens. One hundred seventy-seven neonates receiving intravenous amoxicillin for infection were enrolled in a prospective, observational PK study in Papua New Guinea (PNG). The probability of PK-pharmacodynamic target attainment (PK-PD PTA) was determined based on minimum inhibitory concentrations (MIC) and the proportion of time concentrations that remained above these values (%T > MIC). Neonates with concentrations > 140 mg/L were considered to be at increased risk of amoxicillin neurotoxicity. A population PK model was developed. Simulations tested existing guidelines and proposed simplified regimens. The median PMA and PNA were 38 (37-40) weeks and 0 (0-2) days, respectively. From simulations, existing regimens with 50 or 100 mg/kg doses were associated with higher potential neurotoxic concentrations (24.9% and 84.5%, respectively). With the existing 30 mg/kg PNG regimen, neonates receiving twice-daily dosing between 3 and 7 days were systematically underdosed. A proposed 30 mg/kg regimen, with twice-daily dosing for the first 2 days PNA and three times daily from day 3, provides an optimal balance between the probability of PK-PD target attainment while minimizing toxicity. For fixed volume dosing, using 52 mg (0.25 mL of 250 mg in 1.2 mL) for those <3 kg and 104 mg (0.5 mL) for those ≥3 kg is proposed.
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