Impact of Febrile State on Vancomycin Clearance in Pediatric Patients: Insights From Population Pharmacokinetic
Ryota Tanaka1, Ayato Sawaguchi2,3, Tomoyuki Mizuno4,5
1Department of Clinical Pharmacy, Oita University Hospital, 1-1 Idaigaoka, Hasama, Yufu, Oita, 879-5593, Japan. rtanaka@oita-u.ac.jp.
Insights
Febrile neutropenia and fever significantly increase vancomycin (VCM) clearance in children. Higher VCM doses are needed for febrile pediatric patients to achieve therapeutic levels.
Area of Science:
- Pediatric pharmacology
- Pharmacokinetics
- Infectious diseases
Background:
- Augmented renal clearance is common in pediatric febrile neutropenia.
- Fever impacts antimicrobial elimination, including vancomycin (VCM).
- Optimal VCM dosing in febrile pediatric patients requires further quantification.
Purpose of the Study:
- Quantify the impact of febrile neutropenia and fever on VCM clearance in pediatric patients.
- Identify optimal VCM dosing regimens considering age and renal function.
- Evaluate VCM target exposure attainment in pediatric populations.
Main Methods:
- Retrospective study of pediatric inpatients receiving VCM.
- Population pharmacokinetic analysis using a two-compartment model.
- Monte Carlo simulations to assess target AUC attainment.
Main Results:
- Increased VCM clearance was associated with estimated glomerular filtration rate and body temperature ≥38°C.
- Fever (BT ≥38°C) increased VCM clearance by 27%.
- Febrile patients required 1.2-1.3-fold higher daily VCM doses than afebrile patients.
Conclusions:
- Renal function and fever significantly increase VCM clearance in pediatric patients.
- Standard VCM dosing may be insufficient for febrile children.
- Higher initial VCM doses and individualized dosing based on temperature and renal function are recommended.
Objective:
Augmented renal clearance is increasingly recognized in pediatric patients with febrile neutropenia (FN), leading to enhanced elimination of renally cleared antimicrobials including vancomycin (VCM). Although fever‑associated hemodynamic changes may accelerate VCM clearance, their quantitative impact in the hospital-based general pediatric cohort remains unclear. The primary objective of this study was to quantify the effects of FN and infection-associated fever on VCM clearance in pediatric patients and to identify optimal dosing regimens across age and renal function strata.
Methods:
This retrospective study included inpatients aged < 18 years receiving VCM with therapeutic drug monitoring. Population pharmacokinetic analysis was performed using a two‑compartment model with allometric scaling and maturation functions. Monte Carlo simulations were conducted to evaluate the probability of attaining a target area under the concentration-time curve (AUC48-72h) of 400-600 μg*h/mL across dosing regimens.
Results:
A total of 129 patients and 214 VCM concentrations were analyzed. Estimated glomerular filtration rate and daily maximum body temperature (BT) ≥ 38°C were independently associated with increased VCM clearance. BT ≥ 38°C increased VCM clearance by 27%, and the final model showed robust predictive performance. Simulation analyses demonstrated that febrile patients required approximately 1.2-1.3‑fold higher daily VCM doses than those of afebrile patients across all age groups and renal function categories.
Conclusion:
Renal function and BT ≥ 38°C significantly increase VCM clearance in pediatric patients. Standard dosing may be insufficient in febrile patients, and higher initial doses should be considered. Incorporating body temperature and renal function into dosing decisions may improve target exposure attainment.
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