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Developing tailored dosing recommendations for ciprofloxacin in critically ill children using a population approach
Pieter-Jan De Sutter1, Evelyn Dhont2, Daphné Vens3
1Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Belgium.
Insights
Standard ciprofloxacin doses are insufficient for critically ill children, especially those not on mechanical ventilation. Optimized dosing is crucial for achieving therapeutic targets and improving patient outcomes in pediatric intensive care.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Pediatric Critical Care Medicine
- Infectious Disease Pharmacotherapy
Background:
- Optimal ciprofloxacin dosing in critically ill children is challenging due to altered drug disposition.
- Understanding inter-individual variability in drug exposure is essential for effective treatment.
Purpose of the Study:
- Develop a population pharmacokinetic (PK) model for ciprofloxacin in critically ill children.
- Identify predictors of PK variability and evaluate target attainment.
- Provide evidence-based dosing recommendations for tailored therapy.
Main Methods:
- Prospective, open-label, multicentric PK study in 44 critically ill children.
- Intravenous ciprofloxacin administration with serial blood and urine sampling.
- Population PK modeling to analyze total and unbound drug concentrations.
Main Results:
- Ciprofloxacin PK described by an allometrically scaled two-compartment model.
- Clearance influenced by glomerular filtration rate and mechanical ventilation.
- Standard doses achieved suboptimal target attainment (75-80%) for a MIC of 0.25 mg/L.
- Adequate target attainment (≥90%) requires 10 mg/kg q12h (ventilated) or 15 mg/kg q8h (non-ventilated, normal renal function).
Conclusions:
- Standard ciprofloxacin dosing (20-30 mg/kg/day) is inadequate for non-ventilated critically ill children with normal/elevated renal function.
- Intensified dosing regimens are needed to achieve therapeutic targets.
- Further research should evaluate the efficacy and safety of higher ciprofloxacin doses in this population.
Objectives:
Optimal ciprofloxacin dosing in critically ill children is influenced by complex factors affecting drug disposition, including pathophysiological changes and supportive therapies. This study aimed to develop a population pharmacokinetic (PK) model for ciprofloxacin in critically ill children to identify predictors of interindividual variability, evaluate target attainment for both total and unbound exposure, and provide tailored dosing recommendations.
Methods:
A prospective, open-label, multicentric PK study was conducted in 44 critically ill children (<16 years) receiving intravenous ciprofloxacin. Blood and urine samples were collected at two dosing occasions (10 mg/kg every 12 hours) and drug concentrations were assessed in plasma (total and unbound concentrations) and urine. PK parameters were analysed with population PK modelling. Probability of target attainment (PTA) was calculated based on the free or total area under the curve (AUC) and was simulated for different doses of ciprofloxacin.
Results:
Ciprofloxacin PK was best described with an allometrically scaled two-compartment model. Typical fraction unbound ciprofloxacin in plasma, and the fraction excreted unchanged in urine were estimated to be 0.52 (IQR: 0.49-0.56) and 0.89 (IQR: 0.54-0.95), respectively. Clearance was found to be positively influenced by the glomerular filtration rate and negatively influenced when children were on mechanical ventilation. For a MIC of 0.25 mg/L, the study dose achieved a PTA of 75.3% for unbound exposure (fAUC/MIC >72 hours) and 79.7% for total exposure (AUC/MIC >125 hours). Adequate PTA (≥90%) requires 10 mg/kg every 12 hours in ventilated patients and 15 mg/kg every 8 hours (off-label) in nonventilated patients with normal renal function (80-130 mL/min/1.73m2).
Discussion:
Standard dosing regimens of ciprofloxacin (20-30 mg/kg per day) fail to achieve adequate target attainment in nonventilated critically ill children with a normal or elevated renal function. Further research should prospectively evaluate the efficacy and safety of intensified ciprofloxacin dosing regimens.
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