Investigation of efflux pump biocide and antibacterial resistance mitigation in organisms within biofilms

Lead Research Organisation: University of Huddersfield
Department Name: Biological Sciences

Abstract

Chlorhexidine (CHG) and other bis biguanides are important agents in clinical settings for the disinfection of skin sites, catheters and other medical implants. In all these cases the formation of biofilms is associated with negative clinical outcomes in part due to the protection that biofilms provide against the antimicrobial agents employed. In recent years the challenge presented by biofilms has been exacerbated by the emergence of a reduced susceptibility to CHG amongst pathogens such as Pseudomonas sp and MRSA. this reduced susceptibility is mediated by increased efflux pump activity which prevents the required CHG concentration from accumulation within the bacterial cell. A number of effective efflux pump inhibitors (EPI) exist but these compounds have not been compatible with existing chlorhexidine formulations. In preliminary studies one group of EPIs (cationic dendritic polymers) were successfully integrated into chlorhexidine formulations and showed promise in preliminary investigations. This project will expand on this preliminary data by investigating the impact of a range of formulations against biofilms of clinically relevant isolates in order to develop a new range of anti biofilm chlorhexidine/EPI formulations.

Technical Summary

Chlorhexidine (CHG) and other bis biguanides are important agents in clinical settings for the disinfection of skin sites, catheters and other medical implants. In all these cases the formation of biofilms is associated with negative clinical outcomes in part due to the protection that biofilms provide against the antimicrobial agents employed. In recent years the challenge presented by biofilms has been exacerbated by the emergence of a reduced susceptibility to CHG amongst pathogens such as Pseudomonas sp and MRSA. this reduced susceptibility is mediated by increased efflux pump activity which prevents the required CHG concentration from accumulation within the bacterial cell. A number of effective efflux pump inhibitors (EPI) exist but these compounds have not been compatible with existing chlorhexidine formulations. In preliminary studies one group of EPIs (cationic dendritic polymers) were successfully integrated into chlorhexidine formulations and showed promise in preliminary investigations. This project will expand on this preliminary data by investigating the impact of a range of formulations against biofilms of clinically relevant isolates in order to develop a new range of anti biofilm chlorhexidine/EPI formulations.

Planned Impact

The primary beneficiary will be Gama Healthcare Ltd through bringing to market products that answer the requirement for antibiofilm activity with the added benefit of efflux pump resistance mitigation. These include CHG/alcohol wipes, CHG washcloths, CHG pre-operative bathing products, CHG shampoos and shampoo caps etc. There will also be additional opportunities associated with extending the application to other bisbiguanide biocides. A secondary opportunity may be developed, dependent on IP generation to licence some product variants in certain export markets, or to primary bisbiguanide producers.

There will also be a much wider impact beyond the commercial one associated with a reduction in infection rates and associated fatalities. This will have direct quality of life impacts and financial impacts through a reduction in lost working days for the patients concerned and their family members. There will also be financial savings for the NHS through a reduction in the length of hospital stays and costs associated with treatments for blood stream infections e.g. antibiotics.
The size of these impact can be seen from the fact that the estimated costs associated for those persons which acquire a healthcare associated infection is over £1 billion a year. In the US 1/4 million of blood stream infections are associated with central line contamination and the need for effective disinfection in order to prevent biofilm formation in needless connectors has been recognised by a number of authors. A secondary impact will be on the manufacturers of medical devices, having an effective biofilm treatment and prevention technology for their devices will allow a wider dissemination of their products, potentially open up options for new designs and may extend the in use lifetimes of the products concerned.

Publications

10 25 50
 
Description The main observation is that the efflux pump inhibitors investigated are able to enhance the efficacy of chlorhexidine when applied to Gram negative and Gram positive pathogens in both planktonic systems and biofilms
Exploitation Route The outputs from the project have been taken forward in the form of a number of products based on the project outcomes.
Sectors Healthcare

 
Description The finding will be used by the industrial partner as part of their healthcare product line. The industrial partners are now developing a range of products based on the outcomes from this research. The research has resulted in the funding of PhD programme focussed on the underpinning scientific basis of the products developed. Since the project this programme has received considerable funding from the company to turn the basic research into a range of commercial healthcare products. These will ultimately improve healthcare outcomes by reducing healthcare associated infection.
First Year Of Impact 2018
Sector Healthcare
Impact Types Economic

 
Description Use of Chlorhexidine based sanitisers
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Industrial funding
Amount £50,000 (GBP)
Funding ID n/a 
Organisation GAMA Healthcare 
Sector Private
Country United Kingdom
Start 12/2017 
End 01/2020
 
Title Antibiofilm evaluation 
Description We employed the standard MBEC system in a none standard approach. We used the system to investigate the ability of the test compounds to prevent biofilm formation rather than to remove already established biofilms. This approach has now been used in a range of other project investigating biocidal products. 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact It has allowed a more representative assessment of antibiofilm products and compounds. 
 
Title A liquid antimicrobial composition 
Description The present invention relates to a liquid antimicrobial composition and in particular to such a composition for use in the disinfection of the skin of a human or animal where disinfection of a drug resistant organism may be required. 
IP Reference WO2015145100 
Protection Patent application published
Year Protection Granted
Licensed Commercial In Confidence
Impact The work contained in this project underpinned the patent application and will result in allowing a wider application of a common biocide to a range of healthcare settings
 
Title Chlorhexidine based hygiene products under development 
Description The industrial partner is developing a range of chlorhexidine based product employing the inhibition and biofilm related discoveries generated by this study. 
Type Management of Diseases and Conditions
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2017
Development Status Under active development/distribution
Impact none