Biomarker-Driven Pharmacokinetics and Efficacy of Polymyxin B in Critically Ill Patients with XDR-GN Pneumonia.

Background

Achieving pharmacokinetic/pharmacodynamic (PK/PD) targets is critical for improving treatment success, particularly in critically ill patients. This study investigates the role of inflammatory biomarkers and their influence on the PK/PD characteristics of polymyxin B (PMB) in patients with extensively drug-resistant Gram-negative (XDR-GN) bacterial nosocomial pneumonia.

Methods

Serial blood and/or bronchoalveolar lavage fluid (BALF) samples were collected at specified time points and analyzed for PMB and/or inflammatory biomarkers, including IL-6 and IL-10. Clinical data were also recorded, and their correlations with PK parameters were further analyzed.

Results

Among the 27 enrolled patients, 22 (81.5%) achieved treatment success. The pharmacokinetic parameters of PMB included a maximum plasma concentration (Cmax) of 8.3 µg/mL, clearance (CL) of 1.55 L/h, volume of distribution (Vd) of 30.44 L, half-life (t1/2) of 19.56 h, steady-state area under the plasma concentration-time curve from time 0 to 24 h (AUCss,0-24h) of 110.08 h·µg/mL, and a plasma protein-binding ratio of 85.53%. The AUCss,0-24h metric was identified as a robust predictor of clinical efficacy, with an optimal cutoff value of 77.27 h·µg/mL. Notably, 48.15% of patients achieved the target AUCss,0-24h range of 50-100 h·µg/mL, with 76.95% of these patients attaining treatment success. Another 48.15% of patients exceeded this target, and 92.31% of this subgroup achieved treatment success. PMB demonstrated limited pulmonary penetration, with an epithelial lining fluid (ELF)/plasma ratio of 15.69% [16.86, 18.15]. Furthermore, TNF-α and the IL-6/IL-10 ratio were significantly correlated with PMB PK parameters.

Conclusions

Our and others' studies suggest heterogeneity of PMB PK parameters in critically ill patients. The majority of critically ill patients achieved or surpassed the recommended PK/PD targets and attained treatment success through intravenous administration of PMB at a simplified fixed dose. However, PMB did not achieve satisfactory pulmonary concentrations, suggesting that its efficacy may involve alternative mechanisms. The modulation of inflammatory responses may play a pivotal role in the treatment of severe infections, highlighting the potential for biomarker-guided therapeutic strategies.