Objectives To develop a population pharmacokinetic (PPK) model of polymyxin B (PMB) for intravenous (IV) and combined intravenous plus inhaled (IV+IH) administration in critically ill patients, and evaluate the association between the 24-h steady-state area under concentration–time curve to minimum inhibitory concentration ratio (AUCss,24h/MIC) and clinical outcomes.

Methods This prospective cohort was conducted in the ICU of the Third Xiangya Hospital, Central South University (ethics R19048; ChiCTR1900028602). Adults with multidrug-resistant Gram-negative bacterial infections receiving PMB ≥48 h were enrolled and assigned to IV or IV+IH groups. Serial plasma samples were analyzed by validated LC–MS/MS. The PPK model was developed with NONMEM®. Clinical efficacy at end of treatment was blindly assessed.

Results Forty-three patients were enrolled (IV, n=22; IV+IH, n=21), with an overall clinical success rate of 66.7%. A two-compartment PPK model best described the data, with typical values of clearance (2.6 L/h), central volume (13.6 L), and peripheral volume (17.6 L). Clearance was influenced by creatinine clearance and total bile acids. In the overall cohort, neither AUCss,24h nor AUCss,24h/MIC differed significantly between clinical success and failure (p=0.591 and 0.143). In the IV group, AUCss,24h/MIC was significantly higher in responders (p=0.005) with an ROC-derived efficacy threshold of 94.37; AUCss,24h showed a non-significant trend (p=0.076). No exposure– response relationship was observed in the IV+IH group (p=0.398 and 0.495).

Conclusions Plasma AUCss,24h/MIC appears to be associated with clinical efficacy during IV monotherapy but not in IV+IH regimens, likely due to high pulmonary exposure. Plasma-based PK/PD targets should be applied cautiously when inhalation is added.

The authors have declared no competing interest.

ChiCTR1900028602

This study was supported by the National Natural Science Foundation of China (No. 82373966), the Changsha Natural Science Foundation (No. kq2208360), and the Natural Science Foundation of Hunan Province (No. 2024JJ9329).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Ethics Committee of the Third Xiangya Hospital of Central South University gave ethical approval for this work

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