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

## TL;DR

This study uses simulations to assess the risk of neurotoxicity in infants receiving high-dose cefepime, finding that lower doses may be safer while still being effective.

## Contribution

The study introduces pharmacometric simulations to evaluate neurotoxic risk and dosing efficacy in infants under high-dose cefepime treatment.

## Key findings

- High-dose cefepime in infants 1–2 months has a 40–54% risk of neurotoxic exposure.
- Lower doses reduce neurotoxic risk by 2–4 fold while maintaining high treatment effectiveness.
- Achieving full treatment effectiveness may require prolonged infusion times even with high doses.

## Abstract

Background: Optimal dosing of cefepime in infants 1–2 months remains undefined. Objectives: 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). Methods: 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 (Ctrough) > 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 (Pseudomonas spp.) (50% fT>MIC8mg/L). Results: The predicted risk of Ctrough > 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%). Conclusions: 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>MIC8mg/L. Achievement of 100% fT>MIC8mg/L may require prolonged infusion time even under high-dose treatment. Future research is required to evaluate potentially age-dependent safety thresholds.