Population pharmacokinetics study on nebulized and intravenous administration of polymyxin B in patients with pneumonia caused by multidrug-resistant gram-negative bacteria

Abstract

Polymyxin B (PMB) remains a last-line therapeutic agent for multidrug-resistant gram-negative bacteria (MDR-GNB) infections. However, reliable pharmacokinetic (PK) data to guide nebulized PMB dosing regimens in critically ill patients are limited. This study aimed to establish a population pharmacokinetic (PopPK) model for PMB in both epithelial lining fluid (ELF) and plasma of critically ill patients with MDR-GNB pneumonia and to optimize dosing regimens. A prospective PK study was conducted in 76 adult patients receiving nebulized PMB either as monotherapy or in combination with intravenous administration. PK data were analyzed using nonlinear mixed-effect modeling, with PMB concentration–time profiles described by a coupled model integrating separate two-compartment models for plasma and ELF. The final model identified albumin levels and age as significant covariates influencing PK variability. Monte Carlo simulations demonstrated that nebulization therapy either alone or combined with intravenous administration significantly enhances ELF concentration and the probability of target attainment. Additionally, Pseudomonas aeruginosa requires higher nebulized doses than Klebsiella pneumoniae and Acinetobacter baumannii. This study develops a PopPK model of PMB in ELF and plasma, providing critical insights to optimize PMB treatment strategies for patients with MDR-GNB pneumonia.