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A Pharmacokinetic-Pharmacodynamic Model developed for Colistin on Pseudomonas aeruginosa in-vitro with Evaluation of Population PK Variability on Simulated Baterial Killing
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. (Antibiotics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
(English)Manuscript (preprint) (Other academic)
Keyword [en]
Colistin, PKPD model, Pseudomonas aeruginosa, variability
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
URN: urn:nbn:se:uu:diva-188305OAI: oai:DiVA.org:uu-188305DiVA: diva2:577202
Available from: 2012-12-14 Created: 2012-12-14 Last updated: 2013-02-11
In thesis
1. Pharmacokinetic and Pharmacodynamic Modeling of Antibiotics and Bacterial Drug Resistance
Open this publication in new window or tab >>Pharmacokinetic and Pharmacodynamic Modeling of Antibiotics and Bacterial Drug Resistance
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Exposure to antibiotics is an important factor influencing the development of bacterial resistance.  In an era where very few new antibiotics are being developed, a strategy for the development of optimal dosing regimen and combination treatment that reduces the rate of resistance development and overcome existing resistance is of utmost importance. In addition, the optimal dosing in subpopulations is often not fully elucidated. The aim of this thesis was to develop pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PKPD) models that characterize the interaction of antibiotics with bacterial growth, killing and resistance over time, and can be applied to guide optimization of dosing regimens that enhance the efficacy of mono- and combination antibiotic therapy.

A mechanism-based PKPD model that incorporates the growth, killing kinetics and adaptive resistance development in Escherichia coli against gentamicin was developed based on  in vitro time-kill curve data. After some adaptations, the model was successfully applied for similar data on colistin and meropenem alone, and in combination, on one wild type and one meropenem-resistant strain of Pseudomonas aeruginosa.

The developed population PK model for colistin and its prodrug colistin methanesulfonate (CMS) in combination with the PKPD model showed the benefits for applying a loading dose for this drug. Simulations predicted the variability in bacteria kill to be larger between dosing occasions than between patients. A flat-fixed loading dose followed by an 8 or 12 hourly maintenance dose with infusion duration of up to 2 hours was shown to result in satisfactory bacterial kill under these conditions.

Pharmacometric models that characterize the time-course of drug concentrations, bacterial growth, antibacterial killing and resistance development were successfully developed. Predictions illustrated how PKPD models based on in vitro data can be utilized to guide development of antibiotic dosing, with examples advocating regimens that (i) promote bacterial killing and reduce risk for toxicity in preterm and term newborn infants receiving gentamicin, (ii) achieve a fast initial bacterial killing and reduced resistance development of colistin in critically ill patients by application of a loading dose, and (iii) overcome existing meropenem resistance by combining colistin and meropenem

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 73 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 170
Pharmacometrics, pharmacokinetics, pharmacodynamics, modeling, antibiotics, resistance, combination, Gram-negative bacteria, gentamicin, colistin, meropenem, newborn infants, critically ill patients
National Category
Pharmaceutical Sciences Infectious Medicine
Research subject
Infectious Diseases; Pharmaceutical Science
urn:nbn:se:uu:diva-188306 (URN)978-91-554-8568-9 (ISBN)
Public defence
2013-02-08, B41, Uppsala Biomedical Center, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2013-01-18 Created: 2012-12-14 Last updated: 2013-02-11Bibliographically approved

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Mohamed, Ami
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