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

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

doi:10.3389/fphar.2021.785893

Abstract

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 Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae 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. MIC90 of polymyxin B was 1 mg/L for P. aeruginosa and 0.5 mg/L for A. baumannii and K. pneumoniae. With the recommended polymyxin B dose of 1.5–2.5 mg/kg/day, the PK/PD susceptible breakpoints for P. aeruginosa, A. baumannii and K. pneumoniae 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 P. aeruginosa and 1–1.5 mg/kg/12 h for A. baumannii and K. pneumoniae 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.

Highlights

Carbapenem-resistant Gram-negative bacteria are a serious threat to global health
Studies in animals clearly show reduced bacterial killing in lung infection models compared to thigh infection models with equivalent parenteral dosage regimens (Cheah et al, 2015; Landersdorfer et al, 2018), and substantially lower concentrations of polymyxin B in epithelial lining fluid (ELF) compared to plasma have been reported following intravenous administration (He et al, 2013)
Given that higher polymyxin concentrations can be achieved elsewhere in the body, the Clinical and Laboratory Standards Institute (CLSI) decision to remove the susceptible category for polymyxins based primarily on lung infection data may not be justified for other infection sites such as the bloodstream

Summary

Introduction

Carbapenem-resistant Gram-negative bacteria are a serious threat to global health. In China, approximately 20–30% of Pseudomonas aeruginosa and Klebsiella spp. and >70% of Acinetobacter spp. are carbapenem resistant (http://www.chinets.com/). The newly developed β-lactam/β-lactamase inhibitor combinations (such as ceftazidime-avibactam and ceftolozanetazobactam) have mitigated the situation, none of them is active against metallo-β-lactamase-producing Enterobacterales, P. aeruginosa or carbapenemase-producing A. baumannii (Yahav et al, 2020) Given many of these carbapenem-resistant bacteria remain susceptible to polymyxins (polymyxin B and colistin), this once abandoned class of antibiotics is often the only viable treatment option were revived and being listed on the reserve list of antibiotics by WHO (Jian et al, 2019). Studies in animals clearly show reduced bacterial killing in lung infection models compared to thigh infection models with equivalent parenteral dosage regimens (Cheah et al, 2015; Landersdorfer et al, 2018), and substantially lower concentrations of polymyxin B in epithelial lining fluid (ELF) compared to plasma have been reported following intravenous administration (He et al, 2013) Such data clearly suggests relatively low unbound concentrations are achieved in pulmonary fluids (He et al, 2013). Given that higher polymyxin concentrations can be achieved elsewhere in the body (e.g., blood), the CLSI decision to remove the susceptible category for polymyxins based primarily on lung infection data may not be justified for other infection sites such as the bloodstream

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Conclusion