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

Background 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(ss,24 h)) threshold are still limited. This study aimed to examine exposure-response/toxicity relationship for polymyxin B to establish an AUC(ss,24 h) threshold in a real-world cohort of patients. Methods Using a validated Bayesian approach to estimate AUC(ss,24 h) from two samples, AUC(ss,24 h) 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. Results 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(ss,24 h) 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(ss,24 h) 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(ss,24 h) 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(ss,24 h). Conclusions For critically ill patients, AUC(ss,24 h) 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.

Automated summary

This study aimed to establish an AUC(ss,24 h) threshold for polymyxin B, finding that an AUC(ss,24 h) threshold of 50-100 mg h/L was associated with decreased nephrotoxicity while assuring clinical efficacy for critically ill patients.