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

Abstract

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

Polymyxin B therapy based on therapeutic drug monitoring in carbapenem-resistant organisms sepsis: the PMB-CROS randomized clinical trial

“…Data from our prospective study indicated there was no correlation between whether ssAUC 0-24 met the criteria and clinical outcomes; however, the 28-day mortality in septic shock patients with a ssAUC 0-24 of polymyxin B between 50 and 100 mg ·h/L showed a decreasing trend, although not statistically significant due to limited sample size; also, AKI increased with increasing AUC, which is consistent with our previous findings in a real-world cohort of patients [ 24 ]. Septic shock is a severe subtype of sepsis with high mortality [ 25 ].…”

The dilemma of antibiotic susceptibility and clinical decision-making in a multi-drug-resistant Pseudomonas aeruginosa bloodstream infection

“…However, when AUC 0-24h, ss achieved ∼100 mg·h/L, the risk of nephrotoxicity also increased. This was consistent with the research by Yang et al (2022b ), in which AUC 0-24h, ss >100 mg/L·h was a significant predictor of AKI in critically ill patients. In addition, Yang et al reported that the trough concentration of 1.2–2.8 mg/L was another index similar to AUC 0-24h, ss of 50–100 mg·h/L (34).…”

Population pharmacokinetic analysis and dosing optimization of polymyxin B in critically ill patients

“…Thus AUC/MIC ≥ 50 was set as the efficacy target, as well as the MIC range was set at 0.25–4 mg L -1 ( Satlin et al, 2020 ). Additionally, considering the nephrotoxicity, AUC ss, 24h >100 mg∙h∙L -1 was chosen as an upper limit of the efficacy target ( Wang et al, 2021 ; Yang et al, 2022 ). In order to take the different ALB levels into account, the data has been divided into three groups based on the clinical guidelines, including the ultra-low ALB level group (21.3–24.9 g L -1 ), the low ALB level group (25–34.9 g L -1 ), and the normal ALB level group (35 –41.5 g L -1 ).…”