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Interaction of colistin and meropenem on a wild-type and a resistant strain of Pseudomonas aeruginosa in-vitro as quantified in a mechanism-based model
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 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, meropenem, combination, Pseudomonas aeruginosa
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-188302OAI: oai:DiVA.org:uu-188302DiVA: diva2:577182
Available from: 2012-12-14 Created: 2012-12-14 Last updated: 2013-04-29
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 170
Keyword
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
Identifiers
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)
Opponent
Supervisors
Available from: 2013-01-18 Created: 2012-12-14 Last updated: 2013-02-11Bibliographically approved
2. Optimization of Colistin Dosage in the Treatment of Multiresistant Gram-negative Infections
Open this publication in new window or tab >>Optimization of Colistin Dosage in the Treatment of Multiresistant Gram-negative Infections
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

As multidrug resistance in Gram-negative bacilli increases, the old antibiotic colistin has rapidly gained attention as one of few last line treatment options in the form of colistin methanesulfonate (CMS), which is hydrolyzed to colistin both in vitro and in vivo. There is a dearth of knowledge on fundamental aspects of colistin, including pharmacokinetics and optimal dosing regimens. The aim of this thesis was to improve the basis for optimal colistin therapy.

To be able to study colistin, an LC-MS/MS assay method was developed which is sensitive, specific and useful in both in vivo and in vitro studies. Using this method we detected a significant loss of colistin during standard laboratory procedures. This loss was characterized and quantified, the hypothesis being that the loss is mainly caused by adsorption to labware.

The pharmacokinetics of colistin was studied in two populations of critically ill patients, one with normal renal function and one with renal replacement therapy. Plasma concentrations were assayed with the method above, and population modeling was employed to describe the data. The results include a previously unseen, long elimination half-life of colistin. The data from the population on renal replacement therapy was described without modeling, and showed that both CMS and colistin are cleared by hemodiafiltration.

Combination therapy is an approach that is often used when treating patients infected with multidrug-resistant pathogens. The thesis discusses how the joint effect of antibiotics can be measured using colistin and meropenem as a model, and proposes a method for testing antibiotic combinations. Furthermore, a PKPD model was adapted to describe the pharmacodynamics of the combination.

In conclusion, a specific and sensitive method for analysis of colistin was developed and the adsorption of colistin to materials was described. The assay method has been well accepted internationally. The pharmacokinetics of colistin and CMS was described in two important patient populations, partly with surprising results that have influenced dosages of colistin worldwide. The pharmacodynamics of combination therapy was investigated and quantified, and the methods applied could be further developed into clinically useful tools for selection of antibiotic combinations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 56 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 889
Keyword
Colistin, CMS, Pharmacology, Pharmacokinetics, PKPD, Antibiotics, Combination therapy, Pharmacometrics, Dosing regimens, Antibiotic resistance
National Category
Infectious Medicine Pharmacology and Toxicology Microbiology in the medical area
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:uu:diva-197724 (URN)978-91-554-8640-2 (ISBN)
Public defence
2013-05-20, Hörsalen, Klinisk mikrobiologi, Dag Hammarskjölds väg 17, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-04-26 Created: 2013-04-02 Last updated: 2013-08-30Bibliographically approved

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Mohamed, Ami Fazlin

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