Effect of Adjunctive Inhalation on the Association Between Plasma AUC/MIC of Polymyxin B and Clinical Efficacy in MDR Gram-Negative Infections
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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 (AUC ss,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 AUC ss,24h nor AUC ss,24h /MIC differed significantly between clinical success and failure ( p =0.591 and 0.143). In the IV group, AUC ss,24h /MIC was significantly higher in responders ( p =0.005) with an ROC-derived efficacy threshold of 94.37; AUC ss,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 AUC ss,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.
