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 (...
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2025-04-01
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| author | Verena Gotta Chantal Csajka Antonia Glauser Christoph Berger Marc Pfister Paolo Paioni |
| author_facet | Verena Gotta Chantal Csajka Antonia Glauser Christoph Berger Marc Pfister Paolo Paioni |
| author_sort | Verena Gotta |
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| description | <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<sub>trough</sub>) > 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<sub>8mg/L</sub>). <b>Results</b>: The predicted risk of C<sub>trough</sub> > 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<sub>8mg/L</sub>. Achievement of 100% fT>MIC<sub>8mg/L</sub> may require prolonged infusion time even under high-dose treatment. Future research is required to evaluate potentially age-dependent safety thresholds. |
| format | Article |
| id | doaj-art-4b89641e7973425fa7949c17f61bbf52 |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-04-01 |
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| series | Pharmaceutics |
| spelling | doaj-art-4b89641e7973425fa7949c17f61bbf522025-08-20T03:47:58ZengMDPI AGPharmaceutics1999-49232025-04-0117554410.3390/pharmaceutics17050544Risk of Potentially Neurotoxic Exposure in Infants Under High-Dose Cefepime Treatment—A Pharmacometric Simulation StudyVerena Gotta0Chantal Csajka1Antonia Glauser2Christoph Berger3Marc Pfister4Paolo Paioni5Pediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, 4031 Basel, SwitzerlandCenter for Research and Innovation, University Hospital and University of Lausanne, 1011 Lausanne, SwitzerlandSwissPedDose, 8008 Zurich, SwitzerlandSwissPedDose, 8008 Zurich, SwitzerlandPediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, 4031 Basel, SwitzerlandDivision of Infectious Diseases, University Children’s Hospital Zurich, 8008 Zurich, Switzerland<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<sub>trough</sub>) > 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<sub>8mg/L</sub>). <b>Results</b>: The predicted risk of C<sub>trough</sub> > 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<sub>8mg/L</sub>. Achievement of 100% fT>MIC<sub>8mg/L</sub> may require prolonged infusion time even under high-dose treatment. Future research is required to evaluate potentially age-dependent safety thresholds.https://www.mdpi.com/1999-4923/17/5/544cefepimeneurotoxicityinfantsneonateschildrenpharmacokinetics |
| spellingShingle | Verena Gotta Chantal Csajka Antonia Glauser Christoph Berger Marc Pfister Paolo Paioni Risk of Potentially Neurotoxic Exposure in Infants Under High-Dose Cefepime Treatment—A Pharmacometric Simulation Study Pharmaceutics cefepime neurotoxicity infants neonates children pharmacokinetics |
| title | Risk of Potentially Neurotoxic Exposure in Infants Under High-Dose Cefepime Treatment—A Pharmacometric Simulation Study |
| title_full | Risk of Potentially Neurotoxic Exposure in Infants Under High-Dose Cefepime Treatment—A Pharmacometric Simulation Study |
| title_fullStr | Risk of Potentially Neurotoxic Exposure in Infants Under High-Dose Cefepime Treatment—A Pharmacometric Simulation Study |
| title_full_unstemmed | Risk of Potentially Neurotoxic Exposure in Infants Under High-Dose Cefepime Treatment—A Pharmacometric Simulation Study |
| title_short | Risk of Potentially Neurotoxic Exposure in Infants Under High-Dose Cefepime Treatment—A Pharmacometric Simulation Study |
| title_sort | risk of potentially neurotoxic exposure in infants under high dose cefepime treatment a pharmacometric simulation study |
| topic | cefepime neurotoxicity infants neonates children pharmacokinetics |
| url | https://www.mdpi.com/1999-4923/17/5/544 |
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