Partnership against Biofilm-associated Expression, Acquisition and Transmission of AMR

A relatively recent advance in microbiology is the finding that the majority of infections are caused by bacterial biofilms. Biofilms are structured communities of bacteria found on surfaces that become embedded within a self-produced extracellular polymeric matrix. Biofilms can form on tissues or on biomedical surfaces, such as blood catheters or implants, where they act as a reservoir of potential healthcare-associated infection. Bacteria living in biofilms can tolerate much higher antibiotic concentrations compared to planktonic bacteria and survive long enough to evolve antimicrobial resistance (AMR). They form persistent, hard-to-treat infections and exhibit an intrinsic biology that promotes the development and transmission of AMR. The goal of our consortium is to determine how bacteria adapt to antimicrobials during biofilm formation on surfaces coated with antimicrobials, how AMR mutations are acquired and evolve within mature biofilms, and how population dynamics within biofilms affect the transmission of AMR. We address the hypothesis that understanding the contribution of biofilms to AMR acquisition and spread will lead to the development of novel
antimicrobial strategies and medical devices that are more effective in preventing biofilm-associated infection and AMR. Our team provides facilities and clinical research governance for experimental and translational medicine. Our synergy of leading laboratory, clinical and translational research across Europe will ensure the best chance to develop novel and successful interventions and therapeutic outcomes.

The research objectives of this consortium are to i) determine how P. aeruginosa adapts during biofilm formation on surfaces coated with antimicrobials, ii) how AMR mutations are acquired and evolve within mature biofilms, iii) how population dynamics within biofilms affect the transmission of AMR, and iv) translate these findings into clinical practice.

To achieve this we will first screen for combinations of antibiotics and antimicrobials that select for/against antibiotic resistance using in vitro models that mimic clinical situations and enable prediction of in vivo antibacterial biomaterial performance, including flow and blood serum components. Surfaces tested will include glass, and other more relevant biomaterials such as polymethylmethacrylate, stainless steel, polyethylene, and polyurethane. Antimicrobials that represent different modes of inhibition/killing and chemical classes will be tested using microtiter and agar plate models to facilitate large scale screening of antibiotic-antimicrobial combinations, and knock-out libraries to identify AMR-related genes. Effective combinations will be chosen for in-depth investigations on their effect on transcriptional and evolutionary adaptations, biophysical properties during adhesion and of mature biofilms, and also the population dynamics of resistant and susceptible genotypes using Macro- and micro-flow chambers. Based on the screening outcome, and the obtained mechanistic understanding, we will then study clinical specimens isolated from patients. As clinical examples we will focus on central venous catheters which are impregnated with chlorhexidine and silver sulphadiazine and are treated with multiple antibiotics when infected, or alternatively endotracheal tubes that are coated with sulfadiazine.

These findings will aim to provide clinical recommendations for improved administration of antibiotics/antimicrobials in combination with medical device materials to mitigate against biofilm-associated AMR

The purpose of our collaboration is to provide a step change in the understanding of antimicrobial agent interaction with biofilms on medical materials and to develop new strategies and guidelines that can rapidly enter clinical trials. The desired impact will be to lower the burden of biofilm infections for patients, and to reduce the transmission and occurrence of AMR in clinical settings through a smarter choice of biomaterials coated with antimicrobials used in combination with antibiotics. Specifically, the impact of our work will be to:

1) Enhance the quality of life of patient groups with biofilm-related infections on medical devices, where infections are prevented and treated more effectively. Timescale 35 years from award (initial projected first benefits of new guidelines and recommendations) - 10 years (completely new interventions in late phase clinical trials).

2) Benefit Healthcare Trusts/Services responsible for managing medical device infection, including Policy makers in antimicrobial prescribing and Healthcare Associated Infection (HCAI) management.

3) Benefit industry and pharmaceutical partners for access to new antimicrobial technologies and antimicrobial combinations identified to take through to clinical trials. Therefore enhancing economic benefits by attracting investment in medical device technologies.

4) Benefit academic collaborators (internal and external to participating institutions) engaged in basic science research and understanding of biofilm-associated infection.

5) Contribute to the training and development of research staff linked to the present proposal (established researchers, postdoctoral scientists, PhD students) who will gain experience in international and multidisciplinary collaborative research and its management.