Effect of adjunctive inhalation on the association between plasma AUC/MIC of polymyxin B and clinical efficacy in MDR gram-negative infections.

OBJECTIVES

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

METHODS

In this prospective observational cohort study, adults with multidrug-resistant Gram-negative bacterial infections receiving polymyxin B  ≥ 48 h were enrolled and assigned to IV or IV + IH groups. Plasma samples were analysed by validated HPLC-MS/MS. PPK models were developed with NONMEM. Clinical efficacy at the 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. The typical clearance was 2.61 L/h, with creatinine clearance and total bile acids identified as significant covariates. In the overall cohort, no significant differences in AUCss,24h or AUCss,24h/MIC were observed between clinical success and failure (P = 0.591 and 0.143, respectively). In the IV group, AUCss,24h/MIC was significantly higher in responders (P = 0.005), and an ROC analysis suggested an exploratory efficacy threshold of 94.4; 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, respectively).

CONCLUSIONS

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