Kappeler, Natascha; (2014) Point-of-care sensors for therapeutic antibotic monitoring. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Antibiotics are some of the most effective drugs saving uncountable lives since their introduction more than 70 years ago. However, drug-resistant bacteria are rapidly spreading and posing one of the gravest threats to human health. Furthermore, the evolution of resistance is outpacing the discovery and development of new antibiotics. Therefore, stewardship of our existing and precious antibiotics is urgently needed. The objective of this thesis is to develop point-of-care sensors for therapeutic antibiotic monitoring, particularly for vancomycin, which not only allow prudent antibiotic use, but very importantly lead to better health outcomes associated with lower healthcare costs. The sensor development is approached with two different detection techniques: I) colourimetric detection via visible spectroscopy, and II) nanomechanical detection via cantilever array sensors. I) The thesis’ main focus was to develop a colourimetric vancomycin assay that builds on the point-of-care bench top device ‘Pelorus’ of our industrial partner – Sphere Medical Ltd. in Cambridge, UK. The assay could be successfully developed and benchmarked to UCLH’s gold standard. It includes extraction from whole serum prior to a labelling reaction that permits subsequent quantification via visible spectroscopy. Free and bound drug concentrations can be quantified within minutes, which is crucial for the determination of antibacterial activity and an advantage over current routine assays. Furthermore, the labelling reaction produced a novel molecule, which was structurally characterised. The developed assay could be patented with recent PCT entry. II) Nanomechanical detection of active free antibiotic concentration in human serum via cantilever arrays could be demonstrated. Combined with equilibrium theory, it led to better understanding of the biophysical mode of action improving treatment, dosage and drug discovery. It could be published in an article in Nature Nanotechnology. This project has been early stage proof-of-concept work. The next step towards commercialisation should involve clinical evaluation from whole blood and may further extend to multi-analyte and hand-held sensors for therapeutic monitoring.

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