Pharmacokinetics of polymyxin b loading dose in patients with sepsis caused by polyresistant gram-negative microorganisms

Objective. To conduct a population pharmacokinetic analysis of polymyxin B (PMB) loading dose in patients with sepsis depending on pathogen resistance. Material and methods. To assess pharmacokinetics of PMB in patients with sepsis (n=36), we took blood samples after administration of loading dose and reaching steady-state plasma drug concentrations. PMB concentrations were determined using enzyme-linked immunosorbent assay. Dose simulations (200, 250, 300, and 350 mg) were performed using Monte Carlo method. Results. In the loading dose group (n=10), mean area under pharmacokinetic curve (AUC12) was 28.6±5.6 mg×h/L, maximum concentration — 5.7±1.8 mg/mL. In the steady-state group (n=26), mean AUC12 reached 35.2±15.6 mg×h/L with peak concentration 5.4±1.98 mg/mL. To assess efficacy of loading dose regimens for infection with pathogens with different minimum inhibitory concentrations (MICs), we analyzed probability of target attainment (PTA) for AUC/MICs 50—100 mg×h/L. Modeling the pharmacokinetics of PMB against carbapenem-resistant organisms showed that efficacy decreased significantly (only 23.8%) at maximum dose of 350 mg for MIC 1 mg/mL. Conclusion. Results demonstrated high efficacy of polymyxin B against carbapenem-resistant organisms with MIC ≤0.5 mg/L and probability of target attainment of >99%. However, MIC ≥1 mg/L require high doses (>300 mg) to achieve significant clinical efficacy. At MIC >1 mg/mL, efficacy is significantly reduced even at maximum dose 350 mg.