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.
Gotta et al. (Tue,) studied this question.