Host Inflammation Drives Low-Exposure Nephrotoxicity in Critically Ill Patients Receiving Polymyxin B: A Prospective...

Current consensus guidelines recommend targeting a polymyxin B (PMB) steady-state area under the curve (AUC_ss,24h) of 50.0-100.0 mg·h/L to balance clinical efficacy and safety; however, the predictive utility of this exposure threshold for PMB-associated acute kidney injury (PMB-AKI) remains inconsistent in real-world settings. In this prospective cohort study of 96 critically ill patients, PMB-AKI occurred in 49.0%. stratified analysis revealed that maintaining target exposure (50.0-100.0 mg·h/L) significantly improved clinical success (68.0% vs. 45.8%) without increasing renal risk compared to underexposure (<50.0 mg·h/L). Multivariate analyses identified AUC_ss,24h, septic shock, and concomitant vancomycin as independent predictors of nephrotoxicity. While concentration-driven control is essential for efficacy, we found that within the target window, AKI risk was primarily driven by baseline white blood cell (WBC) count and concomitant vancomycin (AUROC = 0.734). Restricted cubic spline and predictive margin analyses identified a WBC threshold of 7.85 × 10⁹/L as a key risk differentiator (specificity: 83.3%; F1-score: 0.805). Integrating these variables into a prognostic nomogram yielded a distinct net clinical benefit across a decision curve threshold window of 20% to 70%. These findings demonstrate that mitigating PMB-AKI requires a bimodal surveillance strategy: while concentration-driven exposure control remains essential, clinical monitoring must pivot toward host-centered inflammatory dynamics and polypharmacy when drug exposure is maintained within or below the conventional target window.