Effect of Adjunctive Inhalation on the Association Between Plasma AUC/MIC of Polymyxin B and Clinical Efficacy in MDR Gram-Negative Infections

ObjectivesTo 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. MethodsThis 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(R). Clinical efficacy at end of treatment was blindly assessed. ResultsForty-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). ConclusionsPlasma 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.