Tackling antimicrobial resistance in chronic liver disease
Patients with Chronic Liver disease (CLD) are particularly vulnerable to Antimicrobial Resistance (AMR), in addition, there is an escalating liver health crisis in the UK. Since 1970, deaths due to liver disease have increased by 400%, the biggest cause of death in 35–49-year-olds. CLD patients need recurrent antibiotic courses as they often develop severe infections, resulting in hospitalisation and death. They are vulnerable to infection due to bowel-barrier damage and increased ‘unfriendly’ bowel-bacteria, which emit substances, that disrupt the immune system. Up to 25% of CLD patients take daily antibiotics particularly associated with AMR. Healthcare facilities are known breeding grounds for resistant bacteria and 37% of patients with advanced cirrhosis are re-admitted to hospital within 30 days.
Faecal microbiota transplantation (FMT) is the transfer of stool, donated by a healthy individual, to a patient to replace their ‘bad’ gut bacteria. We have demonstrated in a recently completed NIHR-RfPB funded PROFIT trial: PROspective, randomised placebo-controlled feasibility trial of Faecal Microbiota Transplantation in cirrhosis NCT02862249] that FMT was well tolerated and safe. We found that 20% of patients recruited were colonised with AMR bacteria, however, FMT removed the antibiotic-resistant bacteria and their genes from these patients. We are working to inform policymakers that FMT, may have the utility to reduce antibiotic usage, and AMR carriage, reduce healthcare utilisation and costs and ultimately improve outcomes in this vulnerable group of patients. Targeting AMR in CLD could make a very real impact on the global burden of AMR and on the NHS nationally. We have set up a consortium of experts, conducted patient focus groups and produced a policy document along with a 7-minute educational animation. The promotion of these developments our new FMT PROMISE trial and our research findings were launched at The Houses of Parliament on the 22nd of March 2022.
Prof. Shawcross and I successfully applied to the NIHR to investigate the effect of Feacal Microbiota Transplant (FMT) on the AMR gene carriage [Policy Research Programme (25-01-IA) Tackling antimicrobial resistance in chronic liver disease].
The project ran three arms consecutively:
• Wet lab generation of data including resistome analysis and intestinal metabolome analysis to determine the effect of FMT on AMR.
• Establishment of an AMR in Chronic liver disease Advisory Research Steering Group.
• Generation of a Policy Briefing Document and a ‘Policy Engagement’ with the relevant stakeholders.
The data generated supports FMT as playing an important role in enteric pathogen reduction, altering the gut microbiota to promote inflammatory restoration of the gut barrier, and reducing AMR [Poster Uploaded].
Prof. Shawcross and I, have established an eminent Advisory Group to determine what should be the UK’s policy on the use of FMT to tackle AMR in liver cirrhosis. The Advisory Group includes leading scientists and clinicians, patient focus groups, members of the Department of Health, the All-Party Parliamentary Group Liver Health, the British Liver Trust and the National Institute of Health Research, the Gut Microbiota for Health Expert Panel, MICROB-PREDICT and EF-Clif (large EU Microbiome & Liver consortiums) to name just a few, and this application is on behalf of all involved.
In conjunction with a stakeholder the Policy Institute at King’s, we have produced a policy document [Uploaded]. In addition, we have conducted three NIHR-funded Patient participation groups, in conjunction with the British Liver Trust. The workshops were to increase awareness and acceptance of FMT in liver cirrhosis and the upcoming PROMISE trial, additionally informing about antimicrobial resistance; culminating in a 7-minute educational animation [Uploaded]. Our research findings, animation, policy document and the new PROMISE trial were launched at The Houses of Parliament on the 22nd of March 2022.
The results of this study and the Policy Document are in the process of being published in high-impact peer-reviewed journals and will be disseminated widely amongst key stakeholders, policymakers, NHS organisations, patient representative bodies and the wider media to ensure broad readership. We are continuing to engage with the All-Party Parliamentary Group (APPG) on Liver Health and the British Society of Gastroenterology Gut Microbiota for Health Expert Panel. In collaboration with The Policy Institute, we have established a UK Anti-Microbial Resistance consortium of key stakeholders to disseminate findings on the manipulation of the microbiome to treat AMR in chronic liver disease which is anticipated to influence and impact NHS and UK government policy.
FMT could have a profoundly positive impact on both health and the economy, yet there is no infrastructure in place to deliver the treatment. This means it is not currently possible to conduct wider clinical trials or to roll out this life-saving treatment across the NHS. Realising the potential of FMT requires strategic investment in expanding the existing infrastructure. Some of these critical changes are longer-term, such as the development of a national database. Others could make a difference right now, such as collecting stool samples at the same time as blood donations. This is a crucial first step in developing an infrastructure that supports FMT research and treatment.
We intend to investigate the mechanisms of FMT on intestinal barrier function and AMR further. Collectively, it may be possible to alter the gut microbiota to promote barrier repair and restore immune tolerance reducing the incidence of infection and AMR. Further large randomised controlled trials of FMT administered over a longer duration are now needed, to address several of the questions this study has highlighted. We are investigating this at King’s College London in further detail in the upcoming NIHR EME-funded PROMISE trial [NIHR130730]; where patients will be dosed every 90 days over 2 years. https://fundingawards.nihr.ac.uk/award/NIHR130730.
The paradigm shift and the impact that this type of research could have on changing the way that we treat patients with chronic liver disease (CLD) is immense and far-reaching. To potentially be able to reduce the susceptibility and incidence of infection in this group of individuals that will lead to less prescription of antibiotics, reduced hospitalisations and incidence of AMR would be of huge societal benefit. The development of novel therapies that can favourably manipulate the gut microbiome has the potential to have a huge real-world impact on the millions of people who suffer from cirrhosis or liver failure. This change in the therapeutic landscape would influence clinical guidelines within the decade and particularly lead to a reduction in the blanket use of prophylactic antibiotics where AMR rapidly develops. Understanding how manipulation of the gut microbiome in patients with CLD could reduce the carriage of AMR could have significant health and environmental impact. Gastrointestinal colonisation with multidrug-resistant organisms (MDROs) serves as a hot-spot for AMR gene transfer and a reservoir for re-transmission into the environment via untreated hospital wastewater into environmental water bodies. This is in line with tackling AMR in a One Health setting and aligns with the United Kingdom government white paper, a 5-year plan to tackle AMR [Gove & Hancock, Tackling AMR 2019–2024 https://UK_AMR_5_year_national_action_plan.pdf]
Work is already being undertaken in conjunction with the Policy Institute at KCL to estimate the potential impact both on healthcare provision and reduction in loss of life, as well as, to the potential of cost savings to the National Health Service (NHS). Treating AMR infections have been estimated to cost the NHS in the UK £180million pounds/year. In addition to this, the Lancet Commission on liver disease suggested that tackling liver disease could have an enormous cost saving of £11.7billion to the NHS. Carriage of MDRO was directly linked to a worsening of 28-day mortality (p<0.001) and increased hospital admissions (p<0.001). Therefore, we estimate that at least 27% of all patients with advanced chronic liver disease in the UK could potentially benefit from the use of FMT to eradicate infection and carriage of MDROs. This could equate to a potential saving of £3.16 billion to the NHS. Patients with cirrhosis requiring admission to hospital have high short-term morbidity and mortality. They frequently develop organ dysfunction which necessitates admission to high dependency or intensive care. The resource burden that this places on the NHS is immense and we showed at King’s College Hospital that the effective cost of an intensive care survivor was £51,376. Patients with cirrhosis who develop multiorgan failure cost significantly more and have prolonged lengths of stay. Those who survive to discharge have a 30-day readmission rate of 37%, with 14% being re-admitted within 7-days. Liver transplant is a last-resort measure to save the life of patients with end-stage cirrhosis, if patients with cirrhosis are infected with MDROs, they may no longer be eligible for transplantation. We call on policymakers, health care leaders and practitioners, researchers, and people both with and at risk of liver diseases to work together to end the scourge of AMR which disproportionately affects people with liver disease. We believe the findings of the work conducted thus far support the application for further funding to conduct a Policy Laboratory with the relevant stakeholders. To address the following actions: 1. Raise awareness that antimicrobial resistance (AMR) is a huge threat to health, food security and development. AMR is a particular problem for the rapidly growing number of people in the UK with chronic liver disease. 2. Fund research into AMR through an NIHR themed funding call. Prioritising research into new or alternative antimicrobial treatments in patients with chronic diseases such as liver disease. The preliminary data is very promising, but we need further research into the treatment of AMR. The mechanisms of action of faecal microbiota transplantation (FMT) need to be determined to develop further treatments. We would agree with the UK’s governments five-year national action plan and others, that the challenges of developing new therapeutics require a better understanding of the host response to the microbiome and investigations of bacterial virulence factors and novel therapeutics. 3. Earmarking funds for infrastructure to roll out this treatment nationally We are missing out on a source of income into the UK economy, and potential benefits to patients because the infrastructure is not in place for national or international clinical trials using FMT to be conducted in the UK. 4. Regulation of FMT to ensure adequate safety To protect patients and the public, FMT should be regulated as a medical procedure. Guidelines and governance systems should be in place to ensure the treatment is safe and ethical. Advances in the microbiome space often challenge existing regulations and create new regulatory needs as well as opportunities. Single points of access for early and close dialogue between developers and regulators, exemplified in the therapeutic area by the MHRA Innovation office, would ensure that pitfalls are avoided. Providing easy access to regulatory advice would help innovators navigate the regulatory system and understand the requirements. For example, The European Commission has moved to regulate FMT as a substance of Human Origin and new EU regulations will come into force shortly, and the UK is likely to have to follow suit. In line with the government’s white paper, a 5-year plan to tackle antimicrobial resistance (AMR), the expected impact of our research findings would be to lower the burden of infection by targeting the transmission of AMR in an at-risk community. Developing faecal microbiota transplantation as a therapy for AMR, replacing the need for antibiotic prophylaxis and recurrent antibiotic prescription in cirrhotic patients. We are working closely with The Policy Institute KCL, The British Liver Trust and The APPG for Liver Disease and the expected impact is that, with their assistance, we will be able to inform NHS, DHSC and government policy.
Managing penicillin allergy in primary care: an important but neglected aspect of antibiotic stewardship
Penicillins are generally highly effective, narrow-spectrum, inexpensive antibiotics and are the first line recommended treatment for many infections. Around 6-10% of people in the UK have an allergy to penicillins listed in their medical records but, importantly, as few as 1 in 10 of them are truly allergic. This means that a significant proportion of patients are potentially restricted access to highly effective penicillins. Incorrect penicllin allergy records are associated with antimicrobial resistance (AMR), as well as health outcomes (mortality, treatment failure, surgical site infection), altered antibiotic prescribing and resource use (e.g. longer hospital stays), and this is being recognised at the policy level. However, management of penicillin allergy in primary care is challenging, with awareness and access to penicillin allergy testing limited. We have conducted a programme of work trying to address this gap. Through a completed rapid review, and a qualitative study with 31 patients and 19 primary care physicians, we have gained an in-depth understanding of patient and primary care clinician views of managing penicillin allergy in primary care. This allowed us to identify barriers and facilitators to penicillin allergy management and attending/referring for testing. These barriers were then mapped to behaviour change theories in order to describe the proposed mechanisms of change. Based on these findings, we have designed and developed intervention materials for both patients and clinicians to address their concerns and information needs. These intervention materials are now being used as part of the ‘ALABAMA’ trial examining if a new pre-emptive ‘penicillin allergy assessment pathway’ that targets patients assessed as low risk of true allergy can be clinically effective in improving patient health outcomes and antibiotic use. If the trial finds that this new approach to allergy assessment is effective and efficient, this would justify more patients being assessed and allocation of appropriate resources.
1. The study findings have been disseminated through four publications 1-4, including in a high impact allergy journal2. The rapid review and a qualitative study showed that 1) clinicians would benefit from information about penicillin allergy testing to be able to use these services appropriately, and to discuss referral with patients; 2) patients might be more motivated to seek testing if they were more informed regarding its benefits; 3) good communication between primary and secondary care would facilitate the updating of medical records, and promote better patient education. Capturing patients and clinicians views is critical to achieving a deeper understanding of the barriers and opportunities for improved clinical practice for patient benefit.
2. The findings from the rapid review and qualitative study we have conducted identified behavioural aspects, which can be modifiable. These were systematically mapped onto the behaviour change theories and used to produce intervention materials for both clinicians and patients. We produced an intervention consisting of two booklets for patients, and a handout for clinicians, which can be used if the ‘ALABAMA’ trial shows effectiveness. This can have an impact on antibiotic prescribing and consumption, a key component of antibiotic stewardship.
3. The importance of these findings has been acknowledged by selection for the NIHR Evidence Alert as a study most likely to be of interest to the public and professionals and inform changes to policy and practice. The Alert highlighted the importance of checking penicillin allergy records and further research needed in this area (NIHR Evidence – Are you sure you are allergic to penicillin? Professionals and patients are urged to double-check – Informative and accessible health and care research).
Infographics about antibiotics: making facts accessible
Why is this important?
Health communication is key for health and well-being. Public misconceptions about antibiotic use persist despite the efforts of costly antibiotic awareness campaigns. These campaigns have often followed a top-down approach and have not sought input from the public in their design or content. This is a fundamental gap.
Communities need to see antibiotic campaign messages as relevant and accessible to them to influence health seeking behaviour and antibiotic use. One such group where better engagement is needed are parents or carers of young children. Preschool children have the highest antibiotic prescribing rate in the UK.
What did we do?
We developed a series of bespoke evidence-directed infographics (‘visuals’) about antibiotics for three common childhood infections and evaluated their potential for increasing parents’ understanding and knowledge recall.
This research had three phases.
Phase 1: identify and summarise scientific evidence for the use of antibiotics for three common childhood infections (sore throat, acute cough and otitis media) [rapid literature review]
Phase 2: co-produce a series of ‘visuals’ (evidence-directed infographics) for each infection with parents of young children, and information design specialists to test its face- and content validity [iterative qualitative focus groups]
Phase 3: test the feasibility of evidence-directed infographics in increasing parents’ understanding and recall about antibiotics through a national online parent survey [before-after national representative online survey in the UK]
What did we find?
We iteratively co-produced ten evidenced-directed infographics. Parents found the evidence displayed in the EBIs novel and relevant to their families. The way the information was displayed influenced parents’ understanding. Parents preferred one health message per visual.
In the national survey of parents (n=998), infographics improved knowledge recall by more than a third across the board (34%, IQR 20-46% p<0.001). Survey respondents confirmed that the visuals were novel and potentially useful, corroborating our focus group findings.
1. Parents and children
Graphically representing evidence succinctly has the potential to change parents’ perceptions about antibiotics for common self-limiting childhood infections where antibiotics do have any additional treatment benefit. This is key to engage parents with awareness campaigns. Empowering parents to co-create relevant and straightforward health information will promote better understanding and confidence amongst parents caring for their child. Working in tandem with parents will ensure that communication strategies are not wasted and reach the intended audience.
2. Health and Care Services
Enhancing parental ability to care for their child with a respiratory tract infection at home effectively is of national significance given the context of limited NHS resources and ease the added pressures on NHS staff.
The findings have strong potential for scalability in the NHS. Longer term, this participatory approach will shape how researchers and decision-makers globally could translate complex topics into meaningful forms that engage parents in real-world settings, responsive to variation in disease epidemiology, at a fraction of the cost of typical public-facing campaigns, and that could also be adapted to parents’ needs in resource-poor settings where access to healthcare is significantly less available.
Effective public health communication is key to a nation’s health. Part of the problem is that the core elements of information namely its content, format, and delivery are not integrated. The information format needs to ‘fit into the daily lives’ of people, so that the information is memorable. This is where information design and visual images are critical. Information also needs to reach its intended audience in an efficient and sustainable manner and be shown to work in ‘real world’ settings.
Thus, we will test whether our co-produced infographics [the intervention], can help parents’ knowledge recall and self-efficacy over a six-month period in over 1,500 parents, by running a trial in ‘real-world settings’ with a commercial partner who support families from pregnancy to preschool.