Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of Aerosolized Colistin in a Mouse Lung Infection Model

Abstract

Optimized dosage regimens of aerosolized colistin (as colistin methanesulfonate [CMS]) are urgently required to maximize bacterial killing against multidrug-resistant Gram-negative bacteria while minimizing toxicity. This study aimed to develop a mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model (MBM) for aerosolized colistin based upon PK/PD data in neutropenic infected mice and to perform a deterministic simulation with the PK of aerosolized colistin (as CMS) in critically ill patients. time-kill experiments were carried out with three different strains of An MBM was developed in S-ADAPT and evaluated by assessing its ability to predict the PK/PD index associated with efficacy in mice. A deterministic simulation with human PK data was undertaken to predict the efficacy of current dosage regimens of aerosolized colistin in critically ill patients. In the final MBM, the total bacterial population for each isolate consisted of colistin-susceptible and -resistant subpopulations. The antimicrobial efficacy of aerosolized colistin was best described by a sigmoidal model whereby colistin enhanced the rate of bacterial death. Deterministic simulation with human PK data predicted that an inhalational dosage regimen of 60 mg colistin base activity (CBA) every 12 h is needed to achieve a ≥2-log bacterial reduction (as the number of CFU per lung) in critically ill patients at 24 h after commencement of inhaled therapy. In conclusion, the developed MBM is a useful tool for optimizing inhalational dosage regimens of colistin. Clinical studies are warranted to validate and refine our MBM for aerosolized colistin.

Novel Polymyxin Combination with the Antiretroviral Zidovudine Exerts Synergistic Killing against NDM-Producing Multidrug-Resistant Klebsiella pneumoniae

“…3). The proposed MBM utilized a capacity-rated limited growth model, and polymyxin B was assumed to enhance the rate of natural death of bacteria, as previously reported (35). Zidovudine was assumed to slow the bacterial replication rate and was implemented in the model as a decrease in VG max .…”

“…Bacterial cells were partitioned into three preexisting subpopulations with different susceptibilities to polymyxin B and zidovudine. The number of subpopulations necessary to describe the data was based on model discrimination performed using the Akaike information criterion (AIC) or the log likelihood ratio test (reported as Ϫ1 ϫ log likelihood in S-ADAPT), biological plausibility of the parameter estimates, visual inspection of the fitted function, and goodness of fit plots (35).…”

Synergy of nebulized phage PEV20 and ciprofloxacin combination against Pseudomonas aeruginosa

“…Dosing regimens for inhaled antibiotics are influenced by the pattern of drug-resistance of the target bacteria, the mechanism of action and aerosol performance of the drugs, as well as the release rate of formulation. To optimize dosing strategy, ratios of area under the curve (AUC) in plasma or epithelial lining fluid over MICs can be used in the modelling of PD/PK of inhalation antibiotics [36] . A single dose of dry powder ciprofloxacin (PulmoSphere ™ ) approved for inhalation is 32.5 mg [4] , while 100 mg of nebulized liposome ciprofloxacin has been used in clinical trials [37] .…”

An overview of colistin resistance, mobilized colistin resistance genes dissemination, global responses, and the alternatives to colistin: A review

“…Furthermore, the researchers in the literature spotted a light on re-evaluating the dosage regimens of colistin for the treatment of lung infections. Therefore, Lin et al [90] aimed to develop a mechanism-based PK/PD model (MBM) that would determine the time course of the colistin concentrations in the epithelial lining fluid, the plasma, and the bacterial concentrations, post the administration of different dosage regimens of colistin in neutropenic infected mice. Furthermore, Lin et al [90] compared the newly developed MBM and a previously developed population PK model of aerosolized CMS and they formed colistin in critically ill patients, to predict the efficacy of inhalational dosage regimens of colistin (as CMS) in humans.…”