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.