Risk of Potentially Neurotoxic Exposure in Infants Under High-Dose Cefepime Treatment—A Pharmacometric Simulation Study

<b>Background:</b> Optimal dosing of cefepime in infants 1-2 months remains undefined. <b>Objectives</b>: We aimed to quantify the risk of potentially neurotoxic exposure with high-dose cefepime (50 mg/kg/8 h) in infants 1-2 months of age, as compared to adjacent age groups (neonates, infants 2-12 months) and lower dose treatment (50 mg/kg/12 h). <b>Methods</b>: Pharmacometric simulations were performed using two published population pharmacokinetic models combined with demographic data, including serum creatinine, for neonates and infants ≤ 12 months. Adult-derived safety thresholds for potential neurotoxicity were defined as steady-state trough concentration (C_trough) > 20 or > 35 mg/L, respectively. The corresponding probability of target attainment (PTA) was calculated as free concentration, 50% of the time during the dosing interval above the minimal inhibitory concentration (MIC) breakpoint of 8 mg/L (<i>Pseudomonas</i> spp.) (50% fT>MIC_8mg/L). <b>Results</b>: The predicted risk of C_trough > 20 (>35) mg/L under high-dose cefepime was 40-54% (12-22%) in infants 1-2 months while providing high PTA (100%). It was predicted to be 1.3-1.7 fold higher in neonates (model 1), and reduced 1.8-2.4 fold in infants 2-12 months (model 1), or to be similar (model 2), respectively. Both models predicted approximately 2-4 fold reduced risk using lower dose treatments while maintaining high PTA (≥97%). <b>Conclusions</b>: The risk of potential neurotoxic concentrations in infants > 1 month treated with cefepime 50 mg/kg/8 h is high if defined by adult safety thresholds. Lower dose cefepime in infants 1-2 months could be a safe option without compromising PTA, if defined as 50% fT>MIC_8mg/L. Achievement of 100% fT>MIC_8mg/L may require prolonged infusion time even under high-dose treatment. Future research is required to evaluate potentially age-dependent safety thresholds.