Population Pharmacokinetic Analysis and Pharmacodynamic Evaluation of Sulbactam in Pediatric Patients: Dosing Suggestions for Acinetobacter baumannii Infections

Abstract

Background: This study aims to develop a population pharmacokinetic (PK) model of sulbactam in pediatric patients using pooled data analysis, and to optimize dosing regimens against Acinetobacter baumannii infections.

Methods: Publications were systematically identified with MEDLINE for collecting sulbactam PK data in pediatric patients. Sulbactam PK model was developed using plasma concentration-time data gained from identified literature works. Based on the model, we estimated the probability of attaining the pharmacodynamic (PD) target against A. baumannii.

Results: The data were adequately described by 2-compartment model. Age was a statistically significant covariate in clearance. Aiming for the PD target of 60% of time above minimum inhibitory concentration in free drug concentrations (fT > MIC), the breakpoint MICs were increased by extending infusion time from 0.5 to 4 hours. The breakpoint MICs for 4-hour infusion regimens of 25 mg/kg 4 times daily (100 mg/kg/day) achieved 4 μg/mL in infants (4 weeks to 11 months), children (1-6 years old) and pediatrics (7-16 years old). The breakpoint values for 4-hour infusions of 50 mg/kg 4 times daily (200 mg/kg/day) achieved 8 μg/mL (intermediate range of Clinical and Laboratory Standards Institute criteria) in all age groups.

Conclusions: This population PK analysis and PD evaluation suggest that higher dosing regimen, especially with extended infusion time, should be reasonable for treating A. baumannii infections in pediatric patients.

Keywords: Acinetobacter baumannii; pediatric patients; pharmacodynamics; pharmacokinetics; sulbactam.

Figure 1.

Visual Predictive Check Plots. Visual predictive check plots representing prediction-corrected (Pred Corr) concentration for sulbactam in plasma versus time (hours). Each panel shows observed 10th, 50^th, and 90th percentile points (red lines), and predicted 90% confidence intervals for 10, 50, and 90th percentile points (blue and red areas).

Figure 2.

Probabilities of Attaining the Bactericidal Target for Sulbactam. Probabilities of attaining the bactericidal target for sulbactam (60% fT > MIC), at specific MICs using 0.5-hour or 4-hour infusion regimens (〇 25 mg/kg 4 times daily (q.i.d), 0.5‑hour infusion; △ 50 mg/kg q.i.d, 0.5‑hour infusion; ● 25 mg/kg q.i.d, 4‑hour infusion;▲ 50mg/kg q.i.d, 4‑hour infusion). The dotted lines represent 90% probability.