Physiologically-based pharmacokinetic modeling to inform dosing regimens and routes of administration of rifampicin and colistin combination against Acinetobacter baumannii

Zhang, Jiayuan; Song, Chu; Wu, Mengyuan; Yue, Jiali; Zhu, Shijiang; Zhu, Peijuan; Oo, Charles; Schlender, Jan‐Frederik; Lv, Zhihua; Zhu, Yue; Sy, Sherwin K. B.; Yu, Mingming

doi:10.1016/j.ejps.2023.106443

Cited by 5 publications

(1 citation statement)

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“…We have previously shown that even though polymyxin-B/amikacin/sulbactam combination can exert synergistic activities against A. baumannii , patients can benefit from localized administration in addition to intravenous route to ensure sufficient drug concentrations at the site of infection such as the lung ( Zhu et al, 2022a , b ; Zhang et al, 2023 ). Due to the poor penetration of both amikacin and polymyxin-B into the lung, inhaled administration of these two drugs can improve probability of treatment success in HAP/VAP.…”

Section: Introductionmentioning

confidence: 99%

Metabolomics revealed mechanism for the synergistic effect of sulbactam, polymyxin-B and amikacin combination against Acinetobacter baumannii

et al. 2023

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IntroductionThe emergence of multidrug-resistant (MDR) Acinetobacter baumannii prompts clinicians to consider treating these infections with polymyxin combination.MethodsMetabolomic analysis was applied to investigate the synergistic effects of polymyxin-B, amikacin and sulbactam combination therapy against MDR A. baumannii harboring OXA-23 and other drug resistant genes. The drug concentrations tested were based on their clinical breakpoints: polymyxin-B (2 mg/L), amikacin (16 mg/L), polymyxin-B/amikacin (2/16 mg/L), and polymyxin-B/amikacin/sulbactam (2/16/4 mg/L).ResultsThe triple antibiotic combination significantly disrupted levels of metabolites involved in cell outer membrane structure including fatty acids, glycerophospholipids, nucleotides, amino acids and peptides as early as 15 min after administration. Amikacin and polymyxin-B alone perturbed a large number of metabolites at 15 min and 1 h, respectively, but the changes in metabolites were short-lived lasting for less than 4 h. In contrast, the combination treatment disrupted a large amount of metabolites beyond 4 h. Compared to the double-combination, the addition of sulbactam to polymyxin-B/amikacin combination produce a greater disorder in A. baumannii metabolome that further confer susceptibility of bacteria to the antibiotics.ConclusionThe metabolomic analysis identified mechanisms responsible for the synergistic activities of polymyxin-B/amikacin/sulbactam against MDR A. baumannii.

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Section: Introductionmentioning

confidence: 99%

Metabolomics revealed mechanism for the synergistic effect of sulbactam, polymyxin-B and amikacin combination against Acinetobacter baumannii

et al. 2023

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Hydrogel-antimicrobial peptide association: A novel and promising strategy to combat resistant infections

Guerrero,

Filho,

Ayala A

et al. 2025

Colloids and Surfaces B: Biointerfaces

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Prediction of tissue exposures of polymyxin-B, amikacin and sulbactam using physiologically-based pharmacokinetic modeling

Wu,

Feng,

et al. 2024

Front. Microbiol.

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BackgroundThe combination antimicrobial therapy consisting of amikacin, polymyxin-B, and sulbactam demonstrated in vitro synergy against multi-drug resistant Acinetobacter baumannii.ObjectivesThe objectives were to predict drug disposition and extrapolate their efficacy in the blood, lung, heart, muscle and skin tissues using a physiologically-based pharmacokinetic (PBPK) modeling approach and to evaluate achievement of target pharmacodynamic (PD) indices against A. baumannii.MethodsA PBPK model was initially developed for amikacin, polymyxin-B, and sulbactam in adult subjects, and then scaled to pediatrics, accounting for both renal and non-renal clearances. The simulated plasma and tissue drug exposures were compared to the observed data from humans and rats. Efficacy was inferred using joint probability of target attainment of target PD indices.ResultsThe simulated plasma drug exposures in adults and pediatrics were within the 0.5 to 2 boundary of the mean fold error for the ratio between simulated and observed means. Simulated drug exposures in blood, skin, lung, and heart were consistent with reported penetration ratio between tissue and plasma drug exposure. In a virtual pediatric population from 2 to <18 years of age using pediatric dosing regimens, the interpretive breakpoints were achieved in 85–90% of the population.ConclusionThe utility of PBPK to predict and simulate the amount of antibacterial drug exposure in tissue is a practical approach to overcome the difficulty of obtaining tissue drug concentrations in pediatric population. As combination therapy, amikacin/polymyxin-B/sulbactam drug concentrations in the tissues exhibited sufficient penetration to combat extremely drug resistant A. baumannii clinical isolates.

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Physiologically-based pharmacokinetic modeling to inform dosing regimens and routes of administration of rifampicin and colistin combination against Acinetobacter baumannii

Cited by 5 publications

References 74 publications

Metabolomics revealed mechanism for the synergistic effect of sulbactam, polymyxin-B and amikacin combination against Acinetobacter baumannii

Metabolomics revealed mechanism for the synergistic effect of sulbactam, polymyxin-B and amikacin combination against Acinetobacter baumannii

Hydrogel-antimicrobial peptide association: A novel and promising strategy to combat resistant infections

Prediction of tissue exposures of polymyxin-B, amikacin and sulbactam using physiologically-based pharmacokinetic modeling

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