Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of Aerosolized Colistin in a Mouse Lung Infection Model
Open Access
- 1 March 2018
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 62 (3), e01965-17
- https://doi.org/10.1128/aac.01965-17
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. In vivo time-kill experiments were carried out with three different strains of Pseudomonas aeruginosa . 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 E max 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 10 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.Funding Information
- HHS | National Institutes of Health (R01 AI111965, R01 AI132681)
- Department of Health | National Health and Medical Research Council (APP1065046)
This publication has 47 references indexed in Scilit:
- Pharmacokinetic/Pharmacodynamic (PK/PD) Indices of Antibiotics Predicted by a Semimechanistic PKPD Model: a Step toward Model-Based Dose OptimizationAntimicrobial Agents and Chemotherapy, 2011
- Development of a New Pre- and Post-Processing Tool (SADAPT-TRAN) for Nonlinear Mixed-Effects Modeling in S-ADAPTThe AAPS Journal, 2011
- fAUC/MIC is the most predictive pharmacokinetic/pharmacodynamic index of colistin against Acinetobacter baumannii in murine thigh and lung infection modelsJournal of Antimicrobial Chemotherapy, 2010
- Attenuation of Colistin Bactericidal Activity by High Inoculum of Pseudomonas aeruginosa Characterized by a New Mechanism-Based Population Pharmacodynamic ModelAntimicrobial Agents and Chemotherapy, 2010
- Development and Qualification of a Pharmacodynamic Model for the Pronounced Inoculum Effect of Ceftazidime against Pseudomonas aeruginosaAntimicrobial Agents and Chemotherapy, 2009
- Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of AmericaClinical Infectious Diseases, 2009
- Polymyxins RevisitedClinical Microbiology Reviews, 2008
- Population Pharmacokinetics at Two Dose Levels and Pharmacodynamic Profiling of FlucloxacillinAntimicrobial Agents and Chemotherapy, 2007
- Semimechanistic Pharmacokinetic/Pharmacodynamic Model for Assessment of Activity of Antibacterial Agents from Time-Kill Curve ExperimentsAntimicrobial Agents and Chemotherapy, 2007
- Comparative Pharmacodynamics of Gentamicin against Staphylococcus aureus and Pseudomonas aeruginosaAntimicrobial Agents and Chemotherapy, 2006