Antibiotics have saved millions of lives, increased the average human lifespan by 23 years, and continue to be an essential tool in modern medicine. They were discovered almost 100 years ago by Sir Alexander Fleming at St Mary’s Hospital Medical School, now a part of Imperial College London. Although, as with all so-called ‘magic bullets’, there are limitations and for antibiotics it is the rise of antimicrobial resistance.
Antimicrobial resistance (AMR) occurs when disease-causing microbes change over time, meaning that they are harder to treat because they can resist the drug’s effects. This means that in the case of bacteria, bacterial infections are more difficult to treat, or in some cases, impossible.
This is not a problem of the future, but of the now – already at least 700,000 people die annually from drug-resistant diseases. By 2050 drug-resistant microbes will lead to ten million deaths every year if the problem is not solved. This “silent pandemic” must be addressed with urgent action now, or the death toll will continue to creep up.
To help combat antimicrobial resistance, Imperial has scores of interdisciplinary research teams, including the Antimicrobial Research Collaborative (ARC), focusing on the growing threat of antimicrobial resistance, from the role of the GP’s office to informing international policy.
Optimisation is using antimicrobials in a smarter way. Together with the development of new agents, this streamlining of antimicrobial use will help prolong their utility and maximise their effectiveness.
“Sub-optimal use of antimicrobials remains a key driver for antimicrobial resistance, but prescribing is a social process and there are many factors which influence it,” says Dr Esmita Charani, Research Lead for Practice, Design and Engineering at the National Institute of Health Research Health Protection Research Unit (HPRU) in Healthcare Associated Infections and Antimicrobial Resistance.
“Optimising antimicrobial use will require the involvement of a wide range of disciplines from pharmacists, nurses, doctors and epidemiologists to members of the public who need to be made more aware of the threat of AMR”
The roadmap, funded by Wellcome, highlights the complexity of optimising antibiotics, and the global research priorities for the next ten years.
These research priorities span four themes:
- Policy and strategic planning
- Managing medicines and prescriptions
- Using technology to optimise prescriptions
- Societal and cultural behaviours
This optimisation will require societal changes to the way antibiotics are prescribed and requested, tailored and timely doses of antimicrobials, and ensuring that low- and middle- income countries, who are currently disproportionately affected by AMR, also have access to optimally prescribed antimicrobials. Essentially, the more you can personalise treatment, the better and longer antimicrobials will function.
Alison Holmes is Professor of Infectious Diseases and the Director of both the NIHR Health Protection Research Unit in Healthcare Associated Infections and AMR and the Centre for Antimicrobial Optimisation (CAMO). She says:
“Our report highlights that while the development of new antimicrobials is important, more attention is needed on research to optimise the use of existing agents, maximising their usefulness and preserving them as effective treatments for infections for future generations”
Optimisation is required at a primary care, tertiary care, and internationally, if global health security is to be maintained.
For most people in the UK, their main point of contact with healthcare is their GP surgery, and it is here where over 70% of antibiotics in the UK are prescribed - yet only 20% of these prescriptions will benefit patients. The reasons antibiotics are overprescribed in General Practice include:
- Diagnostic uncertainty – sometimes it is hard to know what is causing the symptoms, whether it is viral, bacterial or something else
- Access problems e.g. overwhelming number of patients or a patient cannot make it to the surgery for diagnosis
- A safety net – fear of missing something more serious
Not only are these prescriptions contributing to antimicrobial resistance, but they can also lead to patient side effects. In the long term they can alter the resident microbiota in your gut, which play a key role in metabolism and your immune system.
Stepping up to the challenge
There has already been a 13% decrease in antibiotic consumption in UK primary care between 2014 and 2018. This could be attributed to increased awareness of AMR by the GPs themselves, as well as the impact of government financial incentives like the “Quality Premium scheme” to reduce antibiotic prescription. This decrease, although a step in the right direction, just isn’t enough – drastic changes to the way antibiotics are prescribed must be made, and fast.
Previous studies have shown the benefits of delayed prescribing, exploring alternative treatment options, and quality premiums in antibiotic consumption. However, these programmes have a “finite lifespan” before “GPs go back to old habits” says Dr Benedict Hayhoe, Clinical Lecturer in Primary Care and GP. STEP- UP - a collaborative programme between Imperial, Oxford and Southampton University - is trying to change this by researching not just whether certain interventions work in primary care, but why and how they work.
“The idea is not to reinvent the wheel, but to know why these strategies work, and therefore get them to be effective over the longer term”
This research is helping to develop a theory in the decision-making process behind delayed prescriptions. According to Dr Hayhoe, factors that may influence this are the patient’s symptoms, duration of symptoms, presence of co-morbidities as well as the clinician’s comfort with risk. An additional factor emerging is the importance of integrating patient preference into consultation, allowing for dialogue surrounding the prescription of antibiotics. Improving uptake and sustainability of delayed prescription and exploring alternative treatments, within safe limits, plays a key role in creating antimicrobial stewards, showcasing the responsibility of each healthcare professional in the collective fight against AMR.
Superbugs in secondary care
Hospitals are an ideal location for the transmission of antimicrobial resistant bacteria: patients are in surgery, often immunosuppressed, and healthcare professionals are in direct contact with multiple patients around the hospital. Bacteria that are particularly resistant to most antibiotics are sometimes called “superbugs”, the most infamous being methicillin-resistant Staphylococcus aureus (MRSA).
These bacteria can live for days, even weeks, on hospital surfaces. They do this by “recruiting other bacteria” to their surface where they then “make a protective sugary glue”, a physical barrier known as a biofilm, explains Dr Gerald Larrouy-Maumus, Senior lecturer at Imperial’s MRC Centre for Molecular Bacteriology and Infection. The biofilm then stops bacteria from being killed by cleaning products, making it more likely that vulnerable patients pick up these bacteria, which could lead to infection.
A research team at Imperial’s Institute for Molecular Science and Engineering have been working on the creation of antimicrobial surfaces which could play a key role in the reduction of hospital-acquired infection. These smart surfaces reduce microbial survival by either reducing microbial attachment or killing microbes that do succeed in attaching. Researchers are looking at various options for the optimum smart surfaces including:
- Insect wing mimicry: Cicada wings exhibit antimicrobial properties because they contain tiny spikes. These spikes are particularly effective in puncturing certain types of bacteria including E. Coli and P. aeruginosa. A surface mimicking this activity called “Organosilane” has been created.
- Titanium dioxide (TiO2): When exposed to light at a specific wavelength, TiO2 will ultimately produce a free radical – a highly chemically reactive molecule –that will kill bacteria by attacking the cell membrane.
- Copper alloys: Copper ions have long been known to exhibit antimicrobial properties, and were even used in ancient Greek medicine. The ions interfere with a bacteria’s protein and DNA production mechanism.
Still, each of these surfaces have their caveats, and there is “no ideal candidate” states Dr Jon Otter, Honorary Senior Lecturer at Imperial’s Department of Infectious Disease. Organosilane’s efficacy depends on the cell wall type of the bacteria, and light would have to be regularly applied to TiO2. Even copper, which is the best candidate at the moment, is expensive, in limited supply, and has basic logistical issues - “who would want to sit on a copper toilet seat for example?” says Dr Otter. With this in mind, the team are working on a “new, hybrid alternative”.
For now, explains Dr Otter, to reduce the spread of bacteria in hospitals, the key is to manage patient and staff hygiene using interventions such as hand hygiene in direct patient contact.
Antibiotic use and COVID-19
The changes in healthcare delivery systems with COVID-19 have also generated changes in antibiotic use and AMR.
In the GP surgery there has been an overall decrease in antibiotic prescriptions over the course of the last year. This is likely down to the “access problems to a surgery, COVID-19 testing, case presentation, and the impact of public health measures, such as hand hygiene and mask wearing,” explains Dr Hayhoe. Yet, in the case where antibiotics have been prescribed, there has been an increase in the prescription of certain antibiotics. Broad-spectrum antibiotics are thought to have increased in prescriptions as they target many types of bacteria – useful for a doctor when they cannot see the patient or make a certain diagnosis – but a risk with AMR on the rise.
Bacteria in hospitals
Studies have shown a reduction in gram-negative bacteria in hospitals during COVID-19, which is likely due to a “change in patient mix” at this time explains Dr Otter. Yet, there has also been an increase in the transmission of other kinds of pathogens, which could be due to the “overuse of PPE.” PPE, although essential for protection, does provide increased surfaces for microbes to settle on and be transferred via.
The issue of antimicrobial resistance doesn’t just lie in excessive antibiotic consumption itself, but on other sources that have yet to be explored. Pharmaceutical manufacturing waste is an important but neglected source of antimicrobials and of antimicrobial resistant microbes in the environment, specifically in countries characterised by a prolific pharmaceutical industry. Active Pharmaceutical Ingredients (APIs) are released into the environment when antimicrobials are manufactured. Excessively high concentrations of APIs in the surrounding environment create the conditions for resistant bacteria to multiply and transmit from the environment directly to humans.
Currently 90% of the world’s API production is in India and China, and there is currently no legislation on the limits of what antimicrobial manufacturing waste can be released into the environment. This isn’t just a problem for India and China: 70% of tourists returning from India have resistant bacteria in their gut. Antimicrobial resistance is a global challenge, that requires a global response.
“Antimicrobial resistance is like climate change and COVID-19, it has no borders”
To put limits on manufacturing waste being released into the environment, first the AMR burden of such waste must be established. AMRWATCH is a project at the College which aims to do exactly that. Focusing on selected factories in two regions in India, Puducherry and Chennai, the team will first work to quantify both antibiotic levels and AMR in the receiving environment, helping to define the role of manufacturing in AMR proliferation in those areas. This can then be scaled up to look at the animal and human health impacts, and ultimately translate into pharmaceutical manufacturing waste regulations.
According to Professor Nick Voulvoulis, Professor of Environmental Technology at Imperial’s Centre for Environmental Policy, and Principle Investigator of AMRWATCH, regulations in the future could result in better transparency about supply chains, and manufacturers monitoring and reducing API inputs to the environment.
As a part of the World Health Organisation’s (WHO) World Antibiotic Awareness Week campaign, Imperial instigated an annual antibiotics amnesty. This gives students and staff an opportunity to drop off any unwanted or unused antibiotics to be disposed of in a safe way, as opposed to into the environmental water if they were poured down the sink. Disposal of antibiotics in a safe and contained way is important in preventing bacteria in the environment being exposed to antibiotics, which could contribute to antibiotic resistance.
Responding to the global health threat
Antimicrobial resistance affects everyone. Whether you pay for the best private healthcare or live by a pharmaceutical plant, its consequences are indiscriminate, as highlighted in the research roadmap. AMR is high on the agenda for the World Health Organisation, having declared it one of the top ten global public health threats facing humanity. Action must be taken, now, or the consequences will be “catastrophic” for human health, states Professor Voulvoulis.
Imperial is committed to tackling AMR, with the Antimicrobial Research Collaborative (ARC) working to address the threat of AMR from a ‘one health’ perspective. Nevertheless, “we do not only need support from the College, but from the Government and public” says Dr Larrouy-Maumus. “We have the research, we have people working hard, but between the bench to the public, there is a huge gap.” Closing the gap between the research labs and the translational research is a priority.
“Everything is possible with the right resources”
A lesson from the coronavirus pandemic is that public health is a necessity, not a luxury. Disease can affect everyone and waits for no one. Antimicrobial resistance must be tackled now, starting with the optimisation of antimicrobials, or we will begin to see the pillar of modern medicine come crumbling down.