Project Details
Description
Summary:
Delivering antibiotics (or other drugs) at effective and safe concentrations to unstable, critically ill hospitalized
patients is a daunting problem – for example, for all six antibiotics that are the focus of this work, pharmacokinetic
studies reveal truly wide discrepancies between predicted and actual active concentrations. While important
strides have been made to help physicians make decisions that are most likely to help, and least likely to harm,
an important cornerstone for such approaches is still missing: There are no clinically validated devices that can
rapidly, accurately and precisely measure concentrations of drugs in a manner that would address the long turn-
around-times and prohibitive cost of the central-laboratory-based approach to high-frequency therapeutic drug
monitoring. We approach the problem systematically from the bottom up by building and validating at each step
each of the components needed to overcome such barriers.
As our first challenge (and our first Aim), we focus on high-quality receptors – well characterized and validated
on their own – which could then be widely used and implemented by other groups in different formats, by simply
being ordered “off the shelf”. We identified oligonucleotide-based receptors (aptamers) as such reagents.
Building on our vast preliminary results, we delineate a process that will lead to isolation of sets of receptors,
with each candidate validated on its own in a fluorescent format against gold-standard analytical methods in
patient-derived fluids, under conditions that allow these simple sensors to be applied directly in mix-and-measure
formats (e.g., dialysis effluents, ultrafiltered sera, and extracts from standard SPE columns).
Our second challenge, exacerbated by the highly variable nature of samples collected from critically ill patients,
is cross-reactivity and deviations from standardized conditions. We address these by identifying pairs of
aptamers with orthogonal properties for each antibiotic: One of the aptamers will be used in biosensor modules
(Aim 2) under strictly controlled conditions in conjunction with a commonly used nanomaterial (graphene) and
validated on dialysis effluents and extracts from SPE columns (here, biosensors can be used without pre-
purification) against gold-standard chromatographic methods. The other aptamer from the pair, from an unrelated
family, will be comprehensively validated as the affinity component of extraction modules (Aim 3) on spiked
commercial samples of sera and actual samples from critically ill patients.
Through this approach, we will provide rigorously characterized, standardized components for analysis of
polymyxins, fluoroquinolones, daptomycin, linezolid, and beta lactams, which will enable us (and others) to
combine components into devices, either to be used at the bedside, or as cartridges in automatized analyzers.
In either case, these will facilitate routine high-frequency drug monitoring outside of large, academic hospital
settings. We expect to demonstrate one design of multi-modular devices by the end of this funding period.
Status | Finished |
---|---|
Effective start/end date | 9/1/22 → 5/31/24 |
Funding
- National Institute of Biomedical Imaging and Bioengineering: US$676,189.00
- National Institute of Biomedical Imaging and Bioengineering: US$697,163.00
ASJC Scopus Subject Areas
- Critical Care and Intensive Care Medicine
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.