Acute toxicity is a dose-limiting factor for intravenous polymyxin B: A safety and pharmacokinetic study in healthy Chinese subjects

Liu, Xiaofen; Chen, Yuancheng; Yang, Heqing; Li, Jian; Yu, Jingwei; Yu, Zhenwei; Cao, Guoying; Wu, Xiaojie; Wang, Yu; Wu, Haijiang; Fan, Yaxin; Wang, Jingjing; Wu, Jiang; Jin, Yi; Guo, Beining; Hu, Jiali; Bian, Xingchen; Li, Xin; Zhang, Jing

doi:10.1016/j.jinf.2021.01.006

Cited by 38 publications

(28 citation statements)

References 36 publications

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“…For other CRE species, the CFRs ranged from 76.31 to 79.99%, with no administration regimen achieving 90%. However, it is important to note that polymyxin poses a risk of nephrotoxicity ( Vattimo M de et al, 2016 ; Liu et al, 2021 ; Zeng et al, 2021 ), especially when administered in large dosage. Data indicated that the tolerated maximum dosage of polymyxin B is 3 mg/kg per day ( Liu et al, 2021 ), although the maximum dosage of polymyxin B is the most effective of all regimens according to simulation; attention should be paid to monitoring renal function when applied.…”

Section: Discussionmentioning

confidence: 99%

The Monte Carlo Simulation of Three Antimicrobials for Empiric Treatment of Adult Bloodstream Infections With Carbapenem-Resistant Enterobacterales in China

et al. 2021

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Introduction: The aim of this study was to predict and evaluate three antimicrobials for treatment of adult bloodstream infections (BSI) with carbapenem-resistant Enterobacterales (CRE) in China, so as to optimize the clinical dosing regimen further.Methods: Antimicrobial susceptibility data of blood isolates were obtained from the Blood Bacterial Resistance Investigation Collaborative Systems in China. Monte Carlo simulation was conducted to estimate the probability target attainment (PTA) and cumulative fraction of response (CFR) of tigecycline, polymyxin B, and ceftazidime/avibactam against CRE.Results: For the results of PTAs, tigecycline following administration of 50 mg every 12 h, 75 mg every 12 h, and 100 mg every 12 h achieved > 90% PTAs when minimum inhibitory concentration (MIC) was 0.25, 0.5, and 0.5 μg/mL, respectively; polymyxin B following administration of all tested regimens achieved > 90% PTAs when MIC was 1 μg/mL with CRE; ceftazidime/avibactam following administration of 1.25 g every 8 h, 2.5 g every 8 h achieved > 90% PTAs when MIC was 4 μg/mL, 8 μg/mL with CRE, respectively. As for CFR values of three antimicrobials, ceftazidime/avibactam achieved the lowest CFR values. The highest CFR value of ceftazidime/avibactam was 77.42%. For tigecycline and ceftazidime/avibactam, with simulated regimens daily dosing increase, the CFR values were both increased; the highest CFR of tigecycline values was 91.88%. For polymyxin B, the most aggressive dosage of 1.5 mg/kg every 12 h could provide the highest CFR values (82.69%) against CRE.Conclusion: This study suggested that measurement of MICs and individualized therapy should be considered together to achieve the optimal drug exposure. In particular, pharmacokinetic and pharmacodynamic modeling based on local antimicrobial resistance data can provide valuable guidance for clinicians for the administration of empirical antibiotic treatments for BSIs.

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Section: Discussionmentioning

confidence: 99%

The Monte Carlo Simulation of Three Antimicrobials for Empiric Treatment of Adult Bloodstream Infections With Carbapenem-Resistant Enterobacterales in China

et al. 2021

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“…A single-center, randomized, open-label phase I clinical trial of intravenous polymyxin B (0.75 and 1.5 mg/kg) were conducted in healthy Chinese subjects ( Liu et al, 2021 ). The liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay of polymyxin B was employed to determine the concentrations as previously reported ( Liu et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

“…The interindividual and residual variabilities were best described by an exponential model and a proportional model, respectively. Age and gender were included in the final PK model ( Liu et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…Clinical breakpoints were determined by epidemiological cut-offs, PK/PD breakpoints and clinical efficacy ( Li et al, 2015 ). To acquire PK/PD breakpoints, we conducted a PK study in healthy Chinese volunteers ( Liu et al, 2021 ) and collected 1,431 isolates of P. aeruginosa , A. baumannii and K. pneumoniae from patients across China for PK/PD analysis. This study will provide useful information of PK/PD breakpoints for polymyxin B in patients and evaluate polymyxin dosing regimens for bloodstream infections caused by different bacterial species.…”

Section: Introductionmentioning

confidence: 99%

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

Bian

Liu

et al. 2022

Front. Pharmacol.

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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.

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“…Related literature reports PMB neurotoxicity characterized by perioral sensory abnormalities, ataxia, or both. Monitoring has found that patient’s signs and symptoms begin in the first few days of PMB treatment and diminish or resolve as treatment continues or the dose decreases Reported neurotoxicity includes disturbances such as dizziness (lightheadedness), altered sensation (e.g., dizziness) (numbness and sensory abnormalities affecting mainly the face), nausea, vomiting, muscle weakness, and peripheral neuropathy ( Phe et al, 2014 ; Liu et al, 2021 ). More severe neurological reactions may also occur.…”

Section: Introductionmentioning

confidence: 99%

Visualizing the Potential Impairment of Polymyxin B to Central Nervous System Through MR Susceptibility-Weighted Imaging

et al. 2021

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Polymyxin B (PMB) exert bactericidal effects on the cell wall of Gram-negative bacteria, leading to changes in the permeability of the cytoplasmic membrane and resulting in cell death, which is sensitive to the multi-resistant Gram-negative bacteria. However, the severe toxicity and adverse side effects largely hamper the clinical application of PMB. Although the molecular pathology of PMB neurotoxicity has been adequately studied at the cellular and molecular level. However, the impact of PMB on the physiological states of central nervous system in vivo may be quite different from that in vitro, which need to be further studied. Therefore, in the current study, the biocompatible ultra-uniform Fe3O4 nanoparticles were employed for noninvasively in vivo visualizing the potential impairment of PMB to the central nervous system. Systematic studies clearly reveal that the prepared Fe3O4 nanoparticles can serve as an appropriate magnetic resonance contrast agent with high transverse relaxivity and outstanding biosafety, which thus enables the following in vivo susceptibility-weighted imaging (SWI) studies on the PMB-treated mice models. As a result, it is first found that the blood-brain barrier (BBB) of mice may be impaired by successive PMB administration, displaying by the discrete punctate SWI signals distributed asymmetrically across brain regions in brain parenchyma. This result may pave a noninvasive approach for in-depth studies of PMB medication strategy, monitoring the BBB changes during PMB treatment, and even assessing the risk after PMB successive medication in multidrug-resistant Gram-negative bacterial infected patients from the perspective of medical imaging.

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Acute toxicity is a dose-limiting factor for intravenous polymyxin B: A safety and pharmacokinetic study in healthy Chinese subjects

Cited by 38 publications

References 36 publications

The Monte Carlo Simulation of Three Antimicrobials for Empiric Treatment of Adult Bloodstream Infections With Carbapenem-Resistant Enterobacterales in China

The Monte Carlo Simulation of Three Antimicrobials for Empiric Treatment of Adult Bloodstream Infections With Carbapenem-Resistant Enterobacterales in China

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

Visualizing the Potential Impairment of Polymyxin B to Central Nervous System Through MR Susceptibility-Weighted Imaging

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