Pharmacokinetic/Pharmacodynamic Based Breakpoints of Polymyxin B for Bloodstream Infections Caused by Multidrug-Resistant Gram-Negative Pathogens

The latest PK/PD findings have demonstrated negligible efficacy of intravenous polymyxins against pulmonary infections. We investigated pharmacokinetic/pharmacodynamic (PK/PD)-based breakpoints of polymyxin B for bloodstream infections and the rationality of the recent withdrawal of polymyxin suscep...

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Bibliographic Details
Published in:Frontiers in pharmacology 2022-01, Vol.12, p.785893-785893
Main Authors: Bian, Xingchen, Liu, Xiaofen, Hu, Fupin, Feng, Meiqing, Chen, Yuancheng, Bergen, Phillip J, Li, Jian, Li, Xin, Guo, Yan, Zhang, Jing
Format: Article
Language:English
Subjects:
bloodstream infection
Monte-Carlo simulation
Pharmacology
PK/PD analysis
polymyxin B
susceptibility breakpoint
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Summary:The latest PK/PD findings have demonstrated negligible efficacy of intravenous polymyxins against pulmonary infections. We investigated pharmacokinetic/pharmacodynamic (PK/PD)-based breakpoints of polymyxin B for bloodstream infections and the rationality of the recent withdrawal of polymyxin susceptibility breakpoints by the CLSI. Polymyxin B pharmacokinetic data were obtained from a phase I clinical trial in healthy Chinese subjects and population pharmacokinetic parameters were employed to determine the exposure of polymyxin B at steady state. MICs of 1,431 recent clinical isolates of , and collected from across China were determined. Monte-Carlo simulations were performed for various dosing regimens (0.42-1.5 mg/kg/12 h via 1 or 2-h infusion). The probability of target attainment, PK/PD breakpoints and cumulative fraction of response were determined for each bacterial species. MIC of polymyxin B was 1 mg/L for and 0.5 mg/L for and . With the recommended polymyxin B dose of 1.5-2.5 mg/kg/day, the PK/PD susceptible breakpoints for and were 2, 1 and 1 mg/L respectively for bloodstream infection. For Chinese patients, polymyxin B dosing regimens of 0.75-1.5 mg/kg/12 h for and 1-1.5 mg/kg/12 h for and were appropriate. Breakpoint determination should consider the antimicrobial PK/PD at infection site and delivery route. The recent withdrawal of polymyxin susceptible breakpoint by CLSI primarily based on poor efficacy against lung infections needs to be reconsidered for bloodstream infections.
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2021.785893