Journal Article

Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae

Wang, Yu, Zheng, Yang, Fang, Li, Yu, Yunsong, Wu, Hailan, Fan, Yaxin, Chen, Huiying, Bergen, Phillip J., Li, Xi, Sun, Renhua, Zhang, Jing, Li, Wanzhen, Yu, Zhenwei, Zhao, Feng, Liu, Xiaofen, Zhou, Zhihui, Du, Xiaoxing, Guo, Beining, Li, Jian

2022

Overview

Introduction: Polymyxin B is a last-line therapy for carbapenem-resistant microorganisms. However, a lack of clinical pharmacokinetic/pharmacodynamic (PK/PD) data has substantially hindered dose optimization and breakpoint setting. Methods: A prospective, multi-center clinical trial was undertaken with polymyxin B [2.5 mg/kg loading dose (3-h infusion), 1.25 mg/kg/12 h maintenance dose (2-h infusion)] for treatment of carbapenem-resistant K. pneumoniae (CRKP) bloodstream infections (BSI). Safety, clinical and microbiological efficacy were evaluated. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to determine the concentrations of polymyxin B in blood samples. Population pharmacokinetic (PK) modeling and Monte Carlo simulations were conducted to examine the susceptibility breakpoint for polymyxin B against BSI caused by CRKP. Results: Nine patients were enrolled and evaluated for safety. Neurotoxicity (5/9), nephrotoxicity (5/9), and hyperpigmentation (1/9) were recorded. Blood cultures were negative within 3 days of commencing therapy in all 8 patients evaluated for microbiological efficacy, and clinical cure or improvement occurred in 6 of 8 patients. C max and C min following the loading dose were 5.53 ± 1.80 and 1.62 ± 0.41 mg/L, respectively. With maintenance dosing, AUC ss,24 h was 79.6 ± 25.0 mg h/L and C ss,avg 3.35 ± 1.06 mg/L. Monte Carlo simulations indicated that a 1 mg/kg/12-hourly maintenance dose could achieve >90% probability of target attainment (PTA) for isolates with minimum inhibitory concentration (MIC) ≤1 mg/L. PTA dropped substantially for MICs ≥2 mg/L, even with a maximally recommended daily dose of 1.5 mg/kg/12-hourly. Conclusion: This is the first clinical PK/PD study evaluating polymyxin B for BSI. These results will assist to optimize polymyxin B therapy and establish its breakpoints for CRKP BSI.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: bloodstream infection / Breakpoints / Carbapenems / Clinical trials / CRKP / Dosage / Drug dosages / Drug therapy / Hyperpigmentation / Infections / Klebsiella pneumoniae / Liquid chromatography / Mass spectroscopy / Minimum inhibitory concentration / Monte Carlo simulation / Mortality / nephrotoxicity / Neurotoxicity / Patients / Pharmacodynamics / Pharmacokinetics / pharmacokinetics/pharmacodynamics / Pharmacology / Polymyxin B / polymyxins