4-year PhD Studentship: Early detection of vascular catheter sepsis and determination of resistance to antibiotic line locks.

Many chemotherapies and intravenous feeds require central venous access to allow the infusion of high osmolality fluids which would thrombose smaller, peripheral veins. Long term vascular catheters allow this access at home and without repeated venepuncture. Their leading cause of morbidity is infection. Microbes infect the lines, build an antibiotic-resistant-biofilm and cause sepsis. Patients can present with life threatening septic shock or low-grade sepsis.

In shock, there is no current way to exclude the line as the cause, so it is removed, also removing an excellent route to resuscitate the patient.

In the case of low grade sepsis where the line is suspected, an attempt is made to “salvage” the catheter by locking concentrated antibiotic in the catheter as a “lock” for 14 days, which blocks the catheter from further use. In 50% of cases the locks fail. We aim to test the line aspirates for molecules that demonstrate the catheter is the source of infection and if it will respond to line locks.

Preliminary in vitro work has found eight molecules conserved across four microbes that predict resistance to antibiotics.

Aims and Objectives

We aim to test the following hypotheses

Hypothesis 1: Vascular catheter sepsis is caused by Biofilm shedding into the lumen of the catheter

Hypothesis 2: The Biofilm maturity will correlate with antibiotic resistance.

Hypothesis 3: The concentration of Biofilm components in the aspirate/supernatant will correlate with Biofilm maturity.

Hypothesis 4: The common infective agents will share Biofilm components.

At the end of the study we aim to have identified a panel of molecules and their concentration that will detect the presence of line sepsis and predict response to antibiotic line locks which can go forward to clinical trials.

Methodology

As the project develops it is expected that further techniques may need to be mastered and applied.

In vitro work

Initially, single and polymicrobial in vitro cultures will need to be made in our novel in vitro model of vascular catheter sepsis. The Biofilms will be assessed by advanced microscopy including confocal laser and scan electron microscopy. The cultures and supernatants will be described with genetic, proteomic and biochemical analysis using techniques such as qPCR, tandem mass tagging and LC-MS and metabolic assays. The supernatants will be tested by ELISA for the known candidate molecules. Our industrial collaborator, Rosa Biotech, will support this work using its high-throughput capabilities.

Ex vivo work

This work will be expanded to vascular catheters that have been explanted for both septic and non-septic indications and the supernatant analysis completed on vascular catheter aspirates and blood tests. Antibiotic concentrations from antibiotic-line-locked aspirates will be assessed for antibiotic concentration both as a study and as a proxy for the diffusion of biofilm products out of the catheter.

The candidate will be taught medical literacy to correlate the findings with clinical outcome. They will develop fluency with both bioinformatics and statistical systems.

Keywords

Vascular catheter sepsis, biofilm, antibiotic line locks.

How to apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences in the Faculty of Health Sciences at the University of Bristol.

Please visit the Faculty of Health Sciences website for details of how to apply