Oral Cephalexin Population Pharmacokinetics and Target Attainment Analysis in Infants 7-60 Days Old

Background There are limited data to guide oral antibiotic dosing in neonates and young infants, particularly for intravenous (IV) to oral transition. Cephalexin is a promising oral treatment for neonatal pathogens, including Enterobacterales and methicillin-susceptible Staphylococcus aureus (MSSA). However, maturational changes in gastrointestinal absorption and kidney function during early infancy complicate extrapolation of dosing from older populations. We evaluated cephalexin pharmacokinetics (PK) and simulated dosing strategies to achieve pharmacodynamic (PD) targets in infants ≤60 days old. Methods This prospective, single-center study enrolled infants 0-60 days receiving cephalexin either as part of routine clinical care or as a single 25 mg/kg study dose. Plasma concentrations were analyzed using non-linear mixed-effects modeling. Simulations assessed the probability of target attainment (PTA) for free time above MIC (fT>MIC) for ≥ 50% and ≥ 70% of the dosing interval across MICs 1-16 mg/L, assuming 10% protein binding. We also simulated the cumulative fractional response (CFR) using typical MIC distributions for Enterobacterales and MSSA. Results The analysis included 144 samples from 33 infants with median post-natal age 31 days (range 9-56) and median gestational age 37 weeks (range 29-41). A one-compartment model with first-order absorption and lag time best described the data. Weight influenced apparent volume of distribution and apparent clearance. Additionally, we identified a maturational effect on absorption rate using post-natal age and on apparent clearance using post-menstrual age. For Enterobacterales, 25 mg/kg/dose every 6 hours achieved >90% CFR for a 50% fT>MIC target. For MSSA, 25 mg/kg/dose every 8 hours was sufficient. Higher or more frequent dosing was required to meet the more stringent 70% fT>MIC target. Conclusions Oral cephalexin can achieve necessary PD targets in infants 7-60 days old. These findings support the use of model-informed dosing strategies to guide safe and effective oral antibiotic use in early infancy, including for IV-to-oral transition.