Cephalexin Model-Informed Dosing Recommendations for Severe Infections: A Pooled Pharmacokinetic Analysis From Infancy to Adulthood

Abstract Background Cephalexin is increasingly used as initial and oral transition therapy for severe infections, but optimal dosing in this setting remains uncertain. Methods Four cephalexin pharmacokinetic (PK) datasets spanning preterm neonates through young adults were pooled to develop a unified population PK model. Simulations estimated probability of target attainment (PTA) and cumulative fractional response (CFR, target attainment weighted across the pathogen MIC distribution) across fT>MIC targets (free drug time above the minimum inhibitory concentration), MIC distributions for methicillin-susceptible Staphylococcus aureus (MSSA) and Enterobacterales, and multiple dosing regimens. Results Seventy-one subjects (age 9 days-29 years) contributed 360 plasma samples, best described by a one-compartment model with first-order absorption and lag time. Apparent volume and clearance scaled with fat-free mass, and clearance increased with post-menstrual age. Absorption was slower in neonates. Cephalexin 25 mg/kg/dose, maximum 1,000 mg, every 8 hours achieved 1-log kill targets for MSSA (PTA ≥98% for 35% fT>MIC at MIC = 4 mg/L); every 6-hour dosing was needed at MIC = 8 mg/L. For Enterobacterales, a 60% fT>MIC target was achieved only in infants <2 months. However, higher-dose regimens (37.5-50 mg/kg, maximum 1,500 mg, every 6 hours) achieved CFRs >90% for 40-50% fT>MIC targets when cefazolin MICs were ≤2 mg/L. Conclusions Cephalexin PK varies with age but is well-captured by a unified size- and maturation-scaled model. These data support dosing within the FDA-approved range for systemic MSSA infections. Higher-dose regimens are necessary for adequate target attainment against Enterobacterales. Appropriately dosed cephalexin represents a viable option for selected severe infections, including oral transition therapy.