An area under the concentration-time curve threshold as a predictor of efficacy and nephrotoxicity for individualizing polymyxin B dosing in patients with carbapenem-resistant gram-negative bacteria

• Published in: Critical care (London, England) Vol. 26; no. 1; pp. 320 - 12
• Main Authors: Yang, Jing, Liu, Shaohua, Lu, Jingli, Sun, Tongwen, Wang, Peile, Zhang, Xiaojian
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18.10.2022; BioMed Central; BMC
• Subjects: Acute Kidney Injury - drug therapy; Analysis; Anti-Bacterial Agents - adverse effects; Antibiotics; Area Under Curve; AUCss,24 h threshold; Bacteria; Bayes Theorem; Carbapenems; Care and treatment; Clinical medicine; Creatinine; Critical care; Diagnosis; Dosage and administration; Drug dosages; Drug utilization; Efficacy; Gram-Negative Bacteria; Humans; Infections; Kidney diseases; Klebsiella infections; Laboratories; Methods; Mortality; Nephrotoxicity; Patients; Pharmacokinetics; Physicians; Physiology; Polymyxin; Polymyxin B; Polymyxin B - adverse effects; Prevention; Risk factors; Therapeutic drug monitoring; China; United States > US; AUCss,24 h threshold; Therapeutic drug monitoring; Efficacy; Nephrotoxicity; Polymyxin B
• ISSN: 1364-8535; 1466-609X; 1364-8535; 1366-609X
• DOI: 10.1186/s13054-022-04195-7

Evidence supports therapeutic drug monitoring of polymyxin B, but clinical data for establishing an area under the concentration-time curve across 24 h at steady state (AUC ) threshold are still limited. This study aimed to examine exposure-response/toxicity relationship for polymyxin B to establish an AUC threshold in a real-world cohort of patients. Using a validated Bayesian approach to estimate AUC from two samples, AUC threshold that impacted the risk of polymyxin B-related nephrotoxicity and clinical response were derived by classification and regression tree (CART) analysis and validated by Cox regression analysis and logical regression analysis. A total of 393 patients were included; acute kidney injury (AKI) was 29.0%, clinical response was 63.4%, and 30-day all-cause mortality was 35.4%. AUC thresholds for AKI of > 99.4 mg h/L and clinical response of > 45.7 mg h/L were derived by CART analysis. Cox and logical regression analyses showed that AUC of > 100 mg h/L was a significant predictor of AKI (HR 16.29, 95% CI 8.16-30.25, P < 0.001) and AUC of ≥ 50 mg h/L (OR 4.39, 95% CI 2.56-7.47, P < 0.001) was independently associated with clinical response. However, these exposures were not associated with mortality. In addition, the correlation between trough concentration (1.2-2.8 mg/L) with outcomes was similar to AUC . For critically ill patients, AUC threshold of 50-100 mg h/L was associated with decreased nephrotoxicity while assuring clinical efficacy. Therapeutic drug monitoring is recommended for individualizing polymyxin B dosing.