Developing tailored dosing recommendations for ciprofloxacin in critically ill children using a population approach based on total and unbound concentrations

Abstract

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.

Keywords: Ciprofloxacin; Dose individualization; Intensive care unit; Paediatrics; Plasma protein binding; Population pharmacokinetics.