Open forum infectious diseases · 2026
Cephalexin Model-Informed Dosing Recommendations for Severe Infections: A Pooled Pharmacokinetic Analysis From Infancy to Adulthood.
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Haynes Andrew S, Gonzalez Daniel, Messacar Kevin, Autmizguine Julie, Gwee Amanda, Everts Richard, Anderson Peter
Аннотация
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 1-compartment model with first-order absorption and lag time. Apparent volume and clearance scaled with fat-free mass, and clearance increased with postmenstrual age. Absorption was slower in neonates. Cephalexin 25 mg/kg/dose, maximum 1000 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 1500 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.
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 1-compartment model with first-order absorption and lag time. Apparent volume and clearance scaled with fat-free mass, and clearance increased with postmenstrual age. Absorption was slower in neonates. Cephalexin 25 mg/kg/dose, maximum 1000 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 1500 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.