Background WHO recommends simplified antibiotics for young infants with sepsis in countries where hospitalisation is not feasible. Amoxicillin provides safe, Gram-positive coverage. This study was done to determine pharmacokinetics, drug disposition and interpopulation variability of oral amoxicillin in this demographic.
Methods Young infants with signs of sepsis enrolled in an oral amoxicillin/intramuscular gentamicin treatment arm of a sepsis trial in Karachi, Pakistan, were studied. Limited pharmacokinetic (PK) sampling was performed at 0, 2–3 and 6–8 hours following an index dose of oral amoxicillin. Plasma concentrations were determined by high-performance liquid chromatography/mass spectrometry. Values of ≥2 mg/L were considered as the effect threshold, given the regional minimal inhibitory concentration (MIC) of resistant Streptococcus pneumoniae.
Results Amoxicillin concentrations were determined in 129 samples from 60 young infants. Six of 44 infants had positive blood cultures with predominant Gram-positive organisms. Forty-four infants contributing blood at ≥2 of 3 specified timepoints were included in the analysis. Mean amoxicillin levels at 2–3 hours (11.6±9.5 mg/L, n=44) and 6–8 hours (16.4±9.3 mg/L, n=20) following the index dose exceeded the MIC for amoxicillin (2.0 mg/L) against resistant S. pneumoniae strains. Of 20 infants with three serum levels, 7 showed a classic dose–exposure profile and 13 showed increasing concentrations with time, implying delayed absorption or excretion.
Conclusion Amoxicillin concentrations in sera of young infants following oral administration at 75–100 mg/kg/day daily divided doses exceeds the susceptibility breakpoint for >50% of a 12-hour dosing interval.
Oral amoxicillin may hold potential as a safe replacement of parenteral ampicillin in newborn sepsis regimens, including aminoglycosides, where hospitalisation is not feasible.
Trial registration number NCT01027429.
- young infants
- oral amoxicillin
- population pharmacokinetics
- SATT Pakistan
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Contributors FM was the principal investigator for the study and oversaw project implementation and data collection and data analysis and wrote the first draft of the manuscript. REP adapted and validated an assay for amoxicillin, conducted amoxicillin assays on plasma samples, advised on data interpretation, wrote appendix 1 and assisted in writing the final version of the manuscript. NB-A helped in data analysis and presentation. SQ provided oral amoxicillin experience and helped in writing the final version of the manuscript. SA-R provided oversight for the pharmacokinetic analysis throughout project and assisted in the writing of the final version of the manuscript. JSB ran simulations on population PK software and helped in the interpretation of the data. GK was senior adviser on study design and implementation, supported the assays in kind and provided assistance in writing the manuscript. AKMZ supervised the project. All authors reviewed and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Disclaimer All the authors met authorship criteria. The findings and conclusions in this paper are those of the authors and do not necessarily represent the views of Save the Children and the WHO. Disclosure forms can be provided by the authors on request.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This amoxicillin PK study was approved by the Ethical Review Committee of the Aga Khan University (1685-Ped-ERC-2010).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.