An interview with, Professor Elborn and Dr. Dixon, discussing the issues surrounding bacterial respiratory infections associated with chronic lung conditions such as cystic fibrosis, conducted by Alina Shrourou, BSc.
How much of a problem are respiratory infections in chronic conditions such as cystic fibrosis, bronchiectasis and COPD?
In cystic fibrosis, COPD and people with bronchiectasis, there is a chronic infection that we know now is quite complex and is made up of communities of different species of microbiota; not just bacteria, but also fungi and viruses.
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It is possible for patients to have a long-term respiratory infection, causing intermittent episodes of exacerbation where their symptoms increase, often on a background or baseline of continuous symptoms but they flare up and get worse - we call these exacerbations.
These events are very strongly related to quality of life and prognosis, so the events themselves reduce quality of life but we also know that frequent exacerbations across a range of respiratory conditions are associated with reduced survival. These events are a bit like a heart attack to the lungs. They do damage, which is irreparable and that probably drives the further reduction in lung function and the reduction in survival.
What are the biggest challenges currently associated with treating bacterial infections in patients with chronic respiratory conditions?
The main challenges are involved with finding long term treatment that would prevent exacerbations and flare ups. When these events do occur, it is difficult to determine what is the right drug, duration of treatments and context in which to treat these events.
We have a number of treatments which we provide long term, but most of these are in cystic fibrosis and are based on inhaled antibiotic therapy. However, many of the antibiotics that are currently licensed, are only licensed for alternate month treatment, so we end up with complex regimes where patients are given two or potentially three types of inhaled antibiotics but they're rotating those each month.
We don't really know which combinations are most efficacious, and so we are driven by trying to make decisions for individual patients based on very limited evidence.
There is some anticipation that good anti-inflammatory therapy might help in this context, but there are no large-scale studies to help us understand that. We have a relatively limited repertoire of antimicrobial therapies which we know can be effective. Then understanding how we use antibiotics or antibiotics agents in a more effective way to prevent these episodes, is equally important.
We are also still trying to understand how long we should be giving patients antibiotics for, to treat these exacerbations and to restore the inflammation homeostasis in their lungs. However, we are limited by the drugs available and by the approach that we use, which has developed historically and usually involves a 14-day course of IV antibiotics. There are several studies trying to tackle some of these issues. There's a program called 'Stop', in the US, which is testing the hypothesis that in some patients, a shorter time than 14 days might be just as effective as 14 days of treatment, and some individuals may need longer than 14 days - they may need 21 days for example. There is a large pragmatic clinical trial in North America currently running to try to address those issues.
Please outline the work you are involved in at Queen’s University Belfast to help overcome these challenges.
We're running a number of translational clinical trials that are trying to address these issues. The Framework 7 funded a program called CF Matters, using next generation sequencing to determine the bacteria in people with CF. That information was then used to decide in a consensus panel, what additional drugs might be added to the usual IV antibiotics. Although that study is now complete, unfortunately we were not able to demonstrate that the direct therapy based on molecular biome data benefited patients. However, we're still doing some sub-group analysis because it may be that in some patients, there is in fact benefit from an additional drug.
We're also exploring a number of new antibiotic agents in both CF and bronchiectasis; some of which are conventional antibiotics but, others are of a different approach. We’re trying to re-think how we use current antibiotics, attempting to develop some new antibiotics with collaborators in the pharmaceutical industry and looking at new tools to help determine which antibiotics are most effective in individual patients.
What is the importance of AMR resistance and therapy and the need for circumventing AMR in CF and respiratory disorders?
This is a particularly tricky issue. We know that antimicrobial resistance (AMR) develops in people with cystic fibrosis who receive antibiotics. For example, resistance to Pseudomonas aeruginosa increases in individuals with CF, with age and antibiotic exposure. Usually the first infection of Pseudomonas is with a very antibiotic sensitive organism. However, through intrinsic mutations over time, the bacteria develop a resistance profile. It is also possible to cross infect with a resistant Pseudomonas so some patients may acquire a resistant pseudomonas from other patients if there aren't effective infection control procedures in place.
We know that resistance occurs in cystic fibrosis, so what is left to determine, is whether resistance predicts response to treatment. In inhaled antibiotic studies, and in a number of studies looking at this for treatment of exacerbations, there isn't a strong relationship between resistance and successful treatments and this is very much in contrast to treatments of acute infections where resistance is a very good predictor of outcome in, for example, infection or sepsis associated with neutropenia. We are dealing with a different context of chronic infections associated with exacerbations.
It’s not as straight forward as acute infection but we need new and prospective therapies that will circumvent the antimicrobial resistance nature of chronic infections in cystic fibrosis and other chronic lung diseases, and/or use mechanisms that are not genetically determined, providing therapies that would be consistently effective in people with chronic lung infection.
What makes Neem Biotech’s approach to respiratory infections unique?
Neem are coming at it from a non-traditional antibiotic angle involving novel mechanisms of action.
Quorum sensing describes a way in which bacteria communicate, and it drives the production of various factors which allows them to infect and damage tissue. By blocking quorum sensing, it means that the bacteria cannot produce biofilms which then become chronic infections and are very protected both from antibiotics and the host immune system. By approaching this system, we are investigating the possibility of stopping the bacteria from becoming invasive, rather than killing the bacteria per se, as resistance development can be slowed with reduced pressure on the bacteria to reproduce.
Disrupting communication between microbes is likely to make them more amenable to clearance by normal immune pathways and make the microbes more susceptible to antibiotic killing.
We’re excited about this program, because we’re taking the understanding of the biology of bacterial host interaction and translating the science through to the therapies that will work with the immune system to improve outcomes in this condition.
Are there ways in which higher education, industry, health authorities and clinical practitioners can work together more effectively to prove the value and cost benefit of innovations in the field of chronic respiratory infections?
Yes, there are a wide range of initiatives; some of which are generic to healthcare and the use of antibiotics, but there are some specific programs which are now developing in CF.
A couple of years ago, we were able to persuade the CF community in North America, Europe and Australasia to put together a working group that would address key questions around the medical need and assess the evidence around how we currently use antibiotics in people with cystic fibrosis. The outputs of that are in the process of being published.
The outputs identify some of the challenges in identification and laboratory determination of infection; through to what we know, or perhaps more importantly, what we don't know, where the gaps are, and scoping what other future steps we need to take in terms of development of new drugs and how we use the learning from antimicrobial stewardship to improve long term outcomes in people with CF.
We'll be developing some education programs over the next 12 - 24 months that we'll be able to use to help educate healthcare teams looking after people with CF, and for cystic fibrosis patients themselves. We’ve just finished a large survey in both of those sectors to gauge the understanding of these issues so that we can really target the right education to our community. I think that the lack of cystic fibrosis educational materials is huge issue for us as a society and in CF. We need to make a contribution to that by understanding the problem, having the right therapies and the right program of treatment and understanding how antimicrobial stewardship might be really important in long term outcomes for our patients.
Neem are contributing to this initiative by participating in a syndicate that's run by the UK Cystic Fibrosis Trust. It involves academia, the pharmaceutical industry and the Cystic Fibrosis Trust, and it looks at how those groups can work together to improve success in R&D and cystic fibrosis. One of the elements we are involved in is investigating how we develop better, more predictable and translatable models in vitro, ex vivo and in vivo to evaluate potential new cystic fibrosis drugs.
We also have the newly formed Respiratory Innovation Wales - a group that brings together academia, industry and the NHS to try and research respiratory conditions more generally, with an aim of better facilitating the movement of drugs through the system.
What would interdisciplinary respiratory research success look like in the future?
Working together is key. Taking good science from academia and developing that within an industrial environment, being able to link to medical professionals and make that translational leap. I believe there is also value in approaching the NHS to facilitate the clinical development and clinical trials programs. It's really a very collaborative effort and that's why the Respiratory Innovation Wales has been set up to try and help with. Then naturally, that leads to patient inclusion.
How do you expect the success of Neem’s research to impact the existing knowledge base and clinical practice in management of bacterial infections in chronic respiratory conditions?
The introduction of a new class of antibiotic that has a novel mechanism would be a terrific additional therapeutic opportunity in CF and other chronic lung conditions. To be able to modulate the pathogenicity of a bacterium without having a severe impact on the good bacteria that sits in the lung, could really start to move people with devastating diseases such as CF back to have lungs with a much healthier ecosystem and associated with improved health and further increases in survival.
Where can readers find more information?
About Prof. Stuart Elborn
Professor Elborn's main focus is Cystic Fibrosis focused on understanding pathophysiology of infection and inflammation and the translation of new therapies into clinical practice. This programme of work is undertaken with laboratory and clinical collaborators in Queen's University Belfast. This includes a significant commitment from the NICRN (Respiratory Health) where Stuart is PI on 6 current clinical trials. Prof. Elborn has smaller programmes with others in COPD, bronchiectasis, lung cancer including clinical trials. His research is funded by grants from government agencies, charitable bodies, industry and money raised from clinical trials. Professor Elborn has developed a clinical trials network for Respiratory Health funded by the Northern Ireland Research and Development Office.
In all his research, Professor Elborn endeavours to bring scientists and clinicians together to promote inter-disciplinary research. I have been successful in developing programmes of research across disciplines, hospitals and universities in Northern Ireland and across the UK and Europe.
About Dr Graham Dixon
Dr Graham Dixon obtained his PhD in biochemistry at Swansea University and has spent over 25 years in Big Pharma, VC funded and publicly listed biotechnology companies. As Chief Scientific Officer and later Chief Executive Officer he has led over ten positive proof of concept programmes in humans and been a part of several new drug approval programmes in biotechnology companies including Neem Biotech, Onxeo, Sensorion, Addex Therapeutics, Galapagos, Entomed and F2G.