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Individualized treatment and control of bacterial infections
Linnaeus University, Faculty of Health and Life Sciences, Department of Medicine and Optometry. Kalmar County Hospital.ORCID iD: 0000-0002-1707-2655
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Infectious diseases cause substantial morbidity and mortality, exacerbated by increasing antibiotic resistance. In critically ill patients, recent studies indicate a substantial variability in β-lactam antibiotic levels when standardized dosing is applied. New methods for characterizing nosocomial outbreaks of bacterial infections are needed to limit transmission. The goals of this thesis were to investigate new strategies towards individualized treatment and control of bacterial infections. 

In Paper I we confirmed high variability in β-lactam antibiotic levels among intensive care unit (ICU) patients from southeastern Sweden, where 45 % failed to reach treatment targets (100 % fT>MIC). Augmented renal clearance and establishing the minimum inhibitory concentration of the bacteria were important for evaluating the risk of not attaining adequate drug levels. In Paper II a rapid ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for simultaneous quantification of 11 commonly used antibiotics was developed and tested in clinical samples. Performance goals (CV<15%) were reached. A microbiological method for quantification of β-lactam antibiotics in serum was developed in Paper III. The method could be important for hospitals without access to an LC-MS method. Paper IV and Paper V investigated ligation-mediated qPCR with high resolution melt analysis (LMqPCR HRMA), for transmission investigation of extended spectrum β-lactamase (ESBL)-producing E. coli and other common bacterial pathogens. Results comparable to the reference method (PFGE) could be achieved within one day in a closed system and confirmed a nosocomial outbreak in Kalmar County. In Paper VI whole genome sequencing followed by bioinformatic analysis resolved transmission links within a nosocomial outbreak due to improved discriminatory power compared to LMqPCR HRMA.

The high proportion of ICU patients with insufficient β-lactam drug levels emphasizes the need for individualized treatment by therapeutic drug monitoring (TDM). TDM is enabled by a highly sensitive method, such as UPLC-MS/MS, but if unavailable, also by a microbial method. Molecular typing methods used for transmission investigation can detect nosocomial outbreaks. LMqPCR HRMA can be used for screening purposes. For enhanced resolution, whole genome sequencing should be used, but always together with a rigorous epidemiological investigation. 

Place, publisher, year, edition, pages
Växjö: Linnaeus University Press, 2017. , 230 p.
Series
Linnaeus University Dissertations, 274/2017
Keyword [en]
therapeutic drug monitoring, intensive care unit, β-lactam antibiotics, antimicrobial drug resistance, molecular typing, whole-genome sequencing
National Category
Microbiology
Research subject
Natural Science, Biomedical Sciences
Identifiers
URN: urn:nbn:se:lnu:diva-60191Libris ID: 20014020ISBN: 978-91-88357-58-8 (print)OAI: oai:DiVA.org:lnu-60191DiVA: diva2:1068353
Public defence
2017-02-16, Hjärnan, Kalmar County Hospital, Kalmar, 13:00 (English)
Opponent
Supervisors
Available from: 2017-02-03 Created: 2017-02-03 Last updated: 2017-02-20Bibliographically approved

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Doctoral thesis (extended summary)(7563 kB)254 downloads
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CiteExportLink to record
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Citation style
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