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. 2023 Nov 30;77(11):1595-1603.
doi: 10.1093/cid/ciad432.

Oral and Intravenous Amoxicillin Dosing Recommendations in Neonates: A Pooled Population Pharmacokinetic Study

Fleur M Keij  1   2 , Stef Schouwenburg  3   4 , René F Kornelisse  1 , Tim Preijers  3   4 , Fatima Mir  5 , Pieter Degraeuwe  6 , Leo M Stolk  7 , Arianne van Driel  8 , Sandra Kenter  2 , Jacqueline van der Sluijs  9 , Jojanneke Heidema  10 , Paul C P den Butter  11 , Irwin K M Reiss  1 , Karel Allegaert  3   12   13 , Gerdien A Tramper-Stranders  1   2 , Birgit C P Koch  3   4 , Robert B Flint  1   3   4
Affiliations

Oral and Intravenous Amoxicillin Dosing Recommendations in Neonates: A Pooled Population Pharmacokinetic Study

Fleur M Keij et al. Clin Infect Dis. .

Abstract

Background: There is a lack of evidence on oral amoxicillin pharmacokinetics and exposure in neonates with possible serious bacterial infection (pSBI). We aimed to describe amoxicillin disposition following oral and intravenous administration and to provide dosing recommendations for preterm and term neonates treated for pSBI.

Methods: In this pooled-population pharmacokinetic study, 3 datasets were combined for nonlinear mixed-effects modeling. In order to evaluate amoxicillin exposure following oral and intravenous administration, pharmacokinetic profiles for different dosing regimens were simulated with the developed population pharmacokinetic model. A target of 50% time of the free fraction above the minimal inhibitory concentration (MIC) with an MICECOFF of 8 mg/L (to cover gram-negative bacteria such as Escherichia coli) was used.

Results: The cohort consisted of 261 (79 oral, 182 intravenous) neonates with a median (range) gestational age of 35.8 weeks (range, 24.9-42.4) and bodyweight of 2.6 kg (range, 0.5-5). A 1-compartment model with first-order absorption best described amoxicillin pharmacokinetics. Clearance (L/h/kg) in neonates born after 30 weeks' gestation increased with increasing postnatal age (PNA day 10, 1.25-fold; PNA day 20, 1.43-fold vs PNA day 3). Oral bioavailability was 87%. We found that a twice-daily regimen of 50 mg/kg/day is superior to a 3- or 4-times daily schedule in the first week of life for both oral and intravenous administration.

Conclusions: This pooled population pharmacokinetic description of intravenous and oral amoxicillin in neonates provides age-specific dosing recommendations. We conclude that neonates treated with oral amoxicillin in the first weeks of life reach adequate amoxicillin levels following a twice-daily dosing regimen. Oral amoxicillin therapy could therefore be an adequate, cost-effective, and more patient-friendly alternative for neonates worldwide.

Keywords: absorption; amoxicillin; neonates; pharmacokinetics.

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Conflict of interest statement

Potential conflicts of interest. F. M. K. reports an ESPR travel grant. R. F. K. reports participation on a data and safety monitoring board or advisory board for the PROTEA study (Protecting late-moderate preterm infants from respiratory tract infections and wheeze in their first year of life by using bacterial lysates). B. C. P. K. reports grants or contracts from ZonMw, the Dutch government, and the AIDS Foundation and a leadership or fiduciary role with EPASG, EC ESCMID, Council IATDMCT, and UEMS Pharmacology. J. H. reports payment or honoraria for teaching the Dutch pediatric antibiotics course for pediatric trainees and pediatricians. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Nonlinear impact of gestational age and postnatal age on amoxicillin clearance. Dots represent the mean estimated individual clearance values, with colors representing the gestational age of the patient. Solid lines represent gestational age categories observed in the pooled dataset.
Figure 2.
Figure 2.
Exposure to oral amoxicillin (24–48 hours after start) for different dosing regimens in simulated patients (gestational age (GA) range, 34–36 + 6 weeks, and GA range, 37–41 weeks; corresponding current weight was estimated based on real patients). The color intensity of a square represents the mean percentage of target attainment (% ƒT > MIC) of approximately 2500 simulations. Rows show dosing interval: q12 h, 2 times daily; q8 h, 3 times daily; q6 h, 4 times daily. Columns show dosage in mg/kg/day. A, Postnatal age (PNA) range, 0–7 days. B, PNA range 7–28 days. Abbreviations: MIC, minimal inhibitory concentration; q, every; T, time.
Figure 3.
Figure 3.
Percentage of target attainment in a typical patient for oral amoxicillin 100 mg/kg/day q12 h (typical patient postnatal age <7 days) and 150 mg/kg/day q8 h (typical patient >7 days) for a range of MICs during the first day (0–24 hours) and second day (24–48 hours) of treatment. Green highlighted section: primary outcome MIC of 8 mg/L. Abbreviations: MIC, minimal inhibitory concentration; q, every; q8 h; 3 times daily; q12 h; 2 times daily.
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