AUTHOR=Bian Xingchen , Liu Xiaofen , Hu Fupin , Feng Meiqing , Chen Yuancheng , Bergen Phillip J. , Li Jian , Li Xin , Guo Yan , Zhang Jing 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.785893

DOI=10.3389/fphar.2021.785893

ISSN=1663-9812

ABSTRACT=<p>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 <italic>Pseudomonas aeruginosa</italic>, <italic>Acinetobacter baumannii</italic> and <italic>Klebsiella pneumoniae</italic> 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<sub>90</sub> of polymyxin B was 1 mg/L for <italic>P. aeruginosa</italic> and 0.5 mg/L for <italic>A. baumannii</italic> and <italic>K. pneumoniae</italic>. With the recommended polymyxin B dose of 1.5–2.5 mg/kg/day, the PK/PD susceptible breakpoints for <italic>P. aeruginosa, A. baumannii</italic> and <italic>K. pneumoniae</italic> 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 <italic>P. aeruginosa</italic> and 1–1.5 mg/kg/12 h for <italic>A. baumannii</italic> and <italic>K. pneumoniae</italic> 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.</p>