Polymyxin B Intravenous Administration Strategy Guided by Minimum Inhibitory Concentration in Critically Ill Patients With Pulmonary Infection: Insights From PBPK Modeling

ABSTRACT

Intravenous polymyxin B (PMB) is widely used for treating drug‐resistant gram‐negative pneumonia, though its efficacy in pulmonary infections is considered limited. This study aims to identify patients with severe pulmonary infections suitable for treatment with intravenous PMB alone and to recommend individualized optimal dosing regimens. Physiologically based pharmacokinetic (PBPK) models, developed using data from mice, healthy subjects, and critically ill patients, were employed to predict PMB concentrations in epithelial lining fluid (ELF) and plasma. All models were validated against published pharmacokinetic data, and Monte Carlo simulations were used to evaluate various dosing regimens. The therapeutic target was defined as an ELF steady‐state 24 h area under the concentration‐time curve to minimum inhibitory concentration (AUC _ss,24h /MIC) ≥ 50. Simulations showed that intravenous PMB maintenance regimens of 100 mg, 1.25 mg/kg, or 1.50 mg/kg q12h enabled 94.4%, 82.2%, and 93.5% of critically ill patients to achieve the ELF pharmacokinetic/pharmacodynamic (PK/PD) target for pathogens with an MIC of 1 mg/L. A plasma AUC _ss,24h /MIC threshold of 80.6 was identified as an alternative PK/PD target, with retrospective analysis confirming significantly better outcomes for patients exceeding this threshold ( p  = 0.038), warranting prospective validation. Overall, PBPK modeling supports 100 mg or 1.50 mg/kg q12h as candidate initial intravenous regimens for critically ill patients with pulmonary infections. Dosing adjustments based on MIC and plasma AUC _ss,24h /MIC value are recommended. Adjunctive nebulization or combination therapy is advised for MICs ≥ 2 mg/L, while 50 mg q12h is sufficient for MICs ≤ 0.5 mg/L. Plasma AUC _ss,24h /MIC values exceeding 80.6 may guide individualized dosing when therapeutic drug monitoring is available.