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Quantification of Joint Antibacterial Effects of Colistin and Meropenem in Vitro against Pseudomonas aeruginosa and Acinetobacter baumannii
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Inst. för kliniska vetenskaper, Lunds Universitet.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

As multidrug resistance in Gram-negative bacilli increases, colistin has rapidly gained much attention as one of few last line treatment options. An important part of therapeutic regimens with colistin has been the use of combinations, although there are no reliable methods available for testing combinations, and that the interpretation of joint effects is lacking. In addition, results of combination tests have been varying, with some results indicating no benefit of combinations while others indicate the opposite. The aims of this study were to describe the PD of colistin and meropenem in combination using clinically relevant concentrations of the drugs, to investigate some key endpoints for measuring effect, and to propose a possible path toward testing clinical strains with regard to joint effects.

Eight isolates of P. aeruginosa and A. baumannii, with and without meropenem resistance, were exposed to meropenem and colistin separately and in combination over one dosage interval in an in vitro kinetic model. The PD endpoints were initial kill rate, maximum kill, net kill and area under the bactericidal curve (AUBC). Checkerboard assays were performed for comparison.

Compared to the single drug exposures, the combination increased the effect with all endpoints in three of the strains, including one resistant to meropenem. The AUBC was significantly (paired t-test, p<0.05) lowered in three of the strains.

The chosen endpoints reflect different features of drug effect, and may be important to discern in some patient populations. Kill rate, maximum kill and net kill are point-based endpoints and focusing on only one of them (e.g. net kill by tradition) lead to wasting of potentially important information. AUBC reflects a compressed measure of the whole dosage interval that probably is relevant to most patients and can be used in evaluating joint effect easily and robustly by a simple t-test. The combination of meropenem and colistin is a useful option for treatment of multidrug resistant infections.

National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
URN: urn:nbn:se:uu:diva-197723OAI: oai:DiVA.org:uu-197723DiVA: diva2:613942
Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2013-04-29
In thesis
1. 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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