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26th March 2024
Age and sex are associated with a patient’s likelihood of developing antimicrobial resistance, a new pan-European study has revealed.
Researchers from the London School of Hygiene and Tropical Medicine (LSHTM) found distinct patterns in antimicrobial resistance that correlated with a person’s age, sex, and location in Europe.
Most bacterial species were found to have higher incidence in younger and older age groups, but resistance varied by antibiotic family and also by geographical region.
Overall, males are more likely than females to be resistant to antibiotics, and in some cases, such as Staphylococcus aureus (MSRA), methicillin-resistant infection increased with age.
The researchers hope the findings, published in the journal PLOS Medicine, will reduce the emergence of antibiotic resistance and preserve antibiotic efficacy in the future.
Antimicrobial resistance is a major global public health threat, but little is known about how the prevalence of resistance varies with age and sex.
The researchers analysed patient-level data collected as part of routine surveillance between 2015 and 2019 on bloodstream infections from the European Antimicrobial Resistance Surveillance Network (EARS-Net).
Over 6.5 million isolates were collected from 944,520 individuals (47% female, mean age of 66 years) across 29 European countries, and susceptibility results across 38 different bacterial species and antibiotic combinations, using eight bacterial species, were analysed for resistance.
In 349,448 isolates, the findings were correlated with age and sex metadata collected in 2019. Bayesian multilevel regression models were employed to account for any variations in incidence rates across countries, laboratories, sex, age and year of sample to quantify prevalence of resistance and provide estimates of how country, bacteria and drug family affected variation.
Two of the most clinically important bacteria–antibiotic combinations were analysed in greater depth: aminopenicillin resistance in Escherichia coli and methicillin resistance in Staphylococcus aureus.
The researchers created a simplifying indicative index to show the difference in predicted resistance between two specific age groups: individuals aged 100 years and individuals aged 1 year.
Across Europe, the findings revealed distinct patterns in resistance prevalence by age. Trends often varied more within an antibiotic family, such as fluroquinolones, than within a bacterial species, such as Pseudomonas aeruginosa.
MSRA resistance increased with age in males aged between 1 and 100 years in 72% (n = 21) of countries, and a greater change in resistance was seen in males compared to females. For P. aeruginosa, a peak in resistance to several antibiotics occurs across both sexes at approximately 30 years of age.
A u-shaped pattern of infection incidence with age was seen for most bacterial species, with the young and old being more likely to get infections. The infection incidence was also higher in males than females, with one exception being E. coli, where an elevated incidence was measured in females between the ages of 15 and 40 years.
Aminopenicillin resistance in E. coli decreased across the entire age range from 1 to 100 in both males and females in 93% of the countries studied (n= 27), although the pattern of resistance change was slightly smaller in females.
Resistance rates were found to vary by 38% across a country. For MRSA the change in resistance prevalence between 1 and 100 years ranged up to 0.51 in one country. For aminopenicillin resistance in E. coli, the resistance prevalence varied between 0.16 and -0.27 across individual countries.
Dr Gwen Knight, associate professor and co-director of the Antimicrobial Resistance Centre at LSHTM, said: ‘Our findings highlight important gaps in our knowledge of the spread and selection of antimicrobial resistance and may help us understand why the epidemiology has been difficult to explain through known patterns of antibiotic exposure and healthcare contact.
‘They also suggest there may be value in considering interventions to reduce antimicrobial resistance burden that take into account important variations in antimicrobial resistance prevalence with age and sex.’
She added: ‘In order for us to address this growing threat to public health, we now need data from a wider range of sources to determine the contribution that cultural versus natural history differences have in driving these patterns globally and the role that they play in the increasing rates of antimicrobial resistance being seen.’
In 2023, a study revealed how mixed strain infections within the host play a key role in shaping the emergence of resistance in response to treatment.
18th July 2023
The assumption that pathogen populations within a host are clonal and therefore antimicrobial resistance (AMR) will occur through the emergence of de novo variants has been challenged by a new study offering insight into the mechanism through which AMR is generated.
Published in the journal Nature Communications, the study showed how mixed strain infections within the host play a key role in shaping the emergence of resistance in response to treatment.
Using Pseudomonas aeruginosa – an opportunistic pathogen that is an important cause of hospital-acquired infection – as an example, they studied changes in the genetic diversity and antibiotic resistance of Pseudomonas aeruginosa collected from lower respiratory tract samples from intensive care unit (ICU) patients before and after antibiotic treatment.
The patients were part of the ASPIRE-ICU observational trial of Pseudomonas infection across European hospitals. They were screened for Pseudomonas soon after admission to ICU and at regular intervals thereafter.
Pseudomonas isolates were sampled in an unbiased manner – without a consideration of resistance phenotypes – and up to 12 randomly chosen isolates were collected from all patient samples containing Pseudomonas. These samples were analysed using a combination of phenotypic assays, looking at resistant organisms and genomic analyses to quantify within-patient diversity and antibiotic resistance.
In total, 441 isolates were collected to characterise the diversity of Pseudomonas aeruginosa using lower respiratory tract samples from 35 ICU patients in 12 different hospitals.
The researchers found that while 23 of the 35 patients were colonised with a single strain, roughly a third (12 patients) displayed multiple strains and this strain diversity tended to be high.
Antimicrobial resistance evolved rapidly in patients colonised by diverse Pseudomonas aeruginosa populations, and this occurred through selection of pre-existing resistant strains, showing a clear link between within-host diversity and resistance.
The researchers suggested that this underscored the importance of within-host bacterial diversity as a means for understanding antimicrobial resistance.
They also felt that in future, measuring the diversity of pathogen populations could make it possible to more accurately predict the likelihood of treatment failure for individual patients.
28th April 2023
Antimicrobial resistance is one of the biggest challenges for hospitals and healthcare services to deliver safe and effective healthcare. A 2018 survey estimated that around 33,000 people die each year in the in the European Union and European Economic Area as a direct consequence of an infection due to bacteria resistant to antibiotics.
In 2020, the European Hospital and Healthcare Federation (HOPE) published a position paper on antimicrobial resistance (AMR). Here, the organisation’s chief executive Pascal Garel provides an update and offers his recommendations on prevention policies, fostering the One Health Approach and promoting the development of new antimicrobials.
The ‘One Health’ perspective of the European Commission’s Action Plan provides an opportunity for stakeholders representing different sectors and constituencies to provide expert inputs for improving the implementation of the Plan. This includes experts from the human health, animal health and food production, and environmental disciplines.
Hospital and healthcare providers are clearly important in this regard. Healthcare environments are places where antimicrobial-resistant bacteria emerge and spread, but also where actions can be particularly effective for preventing future outbreaks and ensuring prudent use of antimicrobials.
Other important voices involved in fighting antimicrobial resistance are: medical professionals, nurses, hospital and community pharmacists, students, infection prevention and control specialists and carers. In addition, it is relevant to include organisations with a broader remit, such as public health, health education and research-focused organisations, and those promoting solutions such as rapid diagnostics, vaccines and alternative medicines for veterinary uses.
It is not sufficient to rely exclusively on Member States’ own funding, given that there is a marked north-south and west-east gradient regarding consumption of antimicrobials and AMR prevalence. Moreover, the development and implementation of National Action Plans (NAPs) has been uneven. Over half of the Member States have no action plans, or have plans that are no longer valid or about to expire. A lack of access to funding – including the possibility to combine different funding programmes and projects to complement one another in the longer term – and of other resources, such as laboratory capacities, healthcare resources, infection prevention and control specialists, are often cited as main reasons.
Supplementing national budgets with a dedicated EU-AMR funding mechanism is necessary to close these gaps. Using the European Structural and Investment Funds and providing technical assistance through the European Structural Reform Support Programme is also needed.
The impact of Covid-19 on healthcare budgets and on the ability of hospitals and healthcare facilities to operate effectively should not be underestimated. Health worker shortages, supply issues related to PPE, and persistent budget cuts are stretching many health institutions to the limit. While it is clear that the size and immediacy of the AMR threat will necessitate the diversion of some national and institutional funds, this is not sufficient to solve the issue and could indeed exert a negative impact on other crucial areas, such as the ability to guarantee continuity of care during health security crises.
A key barrier is the need to develop, adopt and fund a long-term vision that exceeds the political mandates of most national governments and hence complicates endorsement and implementation of NAPs. Therefore, the role of the European Commission and of international groups – such as the WHO, G7 and G20 – is vital in avoiding AMR slipping off the political radar and any policies under development merely following a one-sided approach.
More tangible guidance on devising impactful antimicrobial resistance frameworks is required. This goes beyond listing actions to include dedicated funding pooled from different policy areas. Increased political instability and societal divisions – reared also by ‘fake news’ and conspiracy theories online – further complicate this task as decision-makers are primarily focused on short-term quick wins.
The pandemic crisis demonstrated that action can be taken quickly when needed: the problem being that the new EU health budget is the product of a reactive rather than proactive approach. However, the AMR threat is as serious as that of Covid-19, and concrete steps are required to move towards a European Health Union. These steps are driven by values of solidarity, with the European Centre for Disease Prevention and Control given an enhanced health security framework and extended powers for surveillance, preparedness and response planning.
There is growing awareness at national level that certain health-related problems – such as AMR – require enduring and targeted commitment as well as dedicated financial, human and technological resources. The EU One Health Network should be replicated at national level in recognition of the urgency.
We work in partnership with stakeholders representing the agricultural and veterinary areas as part of an AMR Stakeholder Network originally created under the European Health Policy Platform. The One Health perspective draws attention to the interlinkages between excessive uses of antibiotics in food production, animal husbandry and human health, among other things contributing to the rise of non-communicable chronic diseases and the growing threat of infectious diseases and pandemics, both, in turn, requiring functional antibiotic drugs to combat them.
Without being able to speak for the agricultural and veterinary sector, HOPE endorsed the AMR Stakeholder Network’s Roadmap. EU rules banning the routine use of antibiotics and restricting preventative uses to special circumstances are in place. However, the bigger change needed is moving away from highly intensive livestock farming systems involving both routine and excessive use of antibiotics. Available options include altering production systems by reducing stocking density, different breeds and so on; exploring alternatives to antibiotics; and antibiotic stewardship programmes.
Establishing an EU-wide antibiotic formulary is not feasible given the different healthcare needs, patient profiles and antimicrobial prescribing practices at national and regional levels. However, the existing EU Guidelines for the prudent use of antimicrobials in human health should be expanded. This could include more concrete information aimed at different professions. Some harmonised guidance for specific antimicrobials commonly used in all countries could contribute to better prescribing and handling in all Member States.
Member States developing stewardship programmes within the hospital sector, but also covering community and long-term care settings, with the help of EU funding ensures that healthcare professionals are well prepared to tackle multi-drug resistance. This would also facilitate cross-border cooperation and better ensure that AMR protocols are adhered to during serious health crises such as the Covid-19 pandemic.
A multidisciplinary approach to the implementation of stewardship programmes encourages mutual learning and transfer of expertise. This is more effective than offering lectures or encouraging self-study.
Antimicrobial stewardship should be part of educational curricula to inform students and trainees of antimicrobial resistance and encourage prudent use from the outset.
24th August 2018
Kathy Oxtoby looks at the effects of antimicrobial resistance across Europe will be if it goes unchecked and investigates what should be done to tackle it.
It may be a natural phenomenon, but antimicrobial resistance (AMR) has become a global health crisis of similar importance to infectious-disease pandemics, according to the World Health Organization (WHO).
Increasing development and use of antibiotics during the second half of the 20th century has led to bacteria becoming resistant to new antibiotics within months or years of them entering clinical practice.
During the last 15 years, resistance has become a serious issue – largely driven by overuse of antibiotics. New resistance mechanisms have evolved, including the ability for resistance genes to be shared amongst species of bacteria.
“Antibiotics were seen as a cure-all. And although we knew about AMR, we didn’t realise how serious an issue this would become if we didn’t use antibiotics carefully,” says Dr Jacqueline Sneddon, project lead for Scottish Antimicrobial Prescribing Group and chair of Royal Pharmaceutical Society (RPS) Antimicrobial Expert Advisory Group.
So what is the extent of antimicrobial resistance, what are its effects and – crucially – is there still time to halt its rapid spread?
The EU started to take action around AMR in the late 1990s and made its first recommendations to tackle it in 2001. Antibiotic use is the key driver of AMR, so countries where there are higher levels of antibiotic use have higher levels of resistance. In Europe, countries in the south have higher levels of resistance compared to northern Europe, where Scandinavia has the lowest levels.
“The reasons [for AMR variance] are complex but are often based around antimicrobial consumption and infection, prevention and control practices,” says Philip Howard, president of the British Society for Antimicrobial Chemotherapy.
AMR in the UK has been stable for several years, “which is the best case scenario”, given that it cannot be eliminated, says Ms Sneddon. There are some minor differences in resistance rates between the four UK nations and all countries have seen small year on year increases in multi-drug resistant gram negative bacteria.
While AMR rates remain stable in the UK, its consequences can be fatal. According to Public Health England (PHE) it is estimated that at least 5,000 deaths are caused every year in England because antibiotics no longer work for some infections in certain patients.
The English Surveillance Programme for Antimicrobial Utilisation and Resistance’s latest ESPAUR report –published in 2017 – reveals that in England, four in 10 patients with an E.coli bloodstream infection cannot be treated with the most commonly used antibiotic (co-amoxiclav) in hospitals. In addition, almost one in five of these bacteria were resistant to at least one of five other key antibiotics.
The report also showed hospital prescribing has increased year on year, but use of the last resort antibiotics (piperacillin/tazobactam and carbapenems) has reduced by 4% between 2015 and 2016.
But there are fears that in the future the issue of AMR could reach crisis point where antibiotics no longer work, propelling medicine back to the dark ages. Some countries in the world, such as Greece, are already reported to be at crisis point, with hospitals trying to treat patients with infections that are resistant to last line antibiotics.
In the UK, there have been alarming predictions about the situation in 2050 if action is not taken. Lord O’Neill in his review on AMR suggested there could be 10 million deaths per year worldwide.
However, Mr Howard says the current PHE guidance in place to screen patients admitted from overseas hospitals or hospitals with known carbapenemase-producing Enterobacteriaceae (CPE) problems “appears to be working well”.
“The increasing numbers of CPEs are from colonisation identified through screening rather than clinical infections. Hopefully, the current UK drivers to reduce the proportion of broad spectrum and total antibiotics through minimising inappropriate antibiotic prescribing linked to effective infection prevention and control measures will keep the crisis point a long way off,” he says.
However, the future looks bleak if action is not taken. If antimicrobial resistance across Europe goes unchecked, “more people will die from untreatable infections because of a lack of effective antibiotics”, he warns.
For example, the European Centre for Disease Prevention and Control (ECDC) has highlighted this concern in its country level report for Italy published in December 2017, which warns: “If the current trends of carbapenem resistance and colistin resistance in gram-negative bacteria such as Klebsiella pneumoniae and A. baumannii are not reversed, key medical interventions will be compromised in the near future. Untreatable infections following organ transplantation, intensive care or major surgical interventions are now a significant possibility in many Italian hospitals.”
Ms Sneddon says there is a “robust surveillance system in Europe” with countries submitting data on antimicrobial use and resistance to the European Centre for Disease Prevention and Control (ECDC).
The World Health Assembly has encouraged all member states to produce a national action plan (NAP) for AMR. All European countries have a NAP published or in progress.
There is also a European Commission One Health AMR Action Plan form, which was issued in 2017. This action plan is designed to support the EU and its member states in delivering, “innovative, effective and sustainable responses to AMR”, the commission says.
The fight against AMR is a priority for the European Medicines Agency (EMA) and the European Commission (EC).The EMA says it plays, “a vital role in the global fight against AMR” by supporting the development of new medicines and treatment approaches. The agency says it also promotes “responsible use of existing antibiotics” and collects “antimicrobial consumption data to guide policy and research”.
The UK Government has a five-year strategy to tackle AMR (2013-2018), which is shortly due to be updated. PHE says the strategy’s three main aims are to “improve the knowledge and understanding of antimicrobial resistance, conserve and steward the effectiveness of existing treatments, and stimulate the development of new antibiotics, diagnostics and novel therapies”.
Two key goals from PHE CC include reducing inappropriate antibiotic prescribing by 50% by 2021 and reducing gram-negative bloodstream infections by 50% by 2021.
To help guide prescribing in hospitals, PHE has developed the ‘Start Smart then Focus’ toolkit, which provides an outline of evidence-based antimicrobial stewardship in the secondary healthcare setting.
Everyone has a responsibility to tackle AMR, the health body believes. “Without action from all of us, common infections, minor injuries and routine operations will become much riskier,” PHE says.
Mr Howard says hospital pharmacists are central to an effective antimicrobial stewardship (AMS) programme “as they dispense the antibiotics and can control inappropriate use as well as provide antimicrobial consumption data at a very minimum”.
“They are integral to manage shortages of antibiotics. With appropriate investment and training, hospital pharmacy teams can play a key role in AMS programmes,” he says.
Hospital pharmacy’s involvement varies considerably dependant on the availability of hospital pharmacists by country and individual institution. The last global survey on AMS in hospitals from 2012 showed that, on average, there were 18 hours of antimicrobial pharmacy time per week in European hospitals. However, there was great variation from leading the hospital AMS programme to no involvement at all.
Hospital pharmacists are well placed to monitor use of antibiotics, to promote use of local guidelines and educate medical and nursing staff, Ms Sneddon believes. Over the last 15 years, antimicrobial pharmacy has evolved as a new specialism within hospital pharmacy.
“These pharmacists have a specific role in delivering antimicrobial stewardship and providing leadership for the pharmacy team in this area,” she says. And in the UK, all hospitals will now have an antimicrobial pharmacist working as part of a multi-professional antimicrobial team or committee.
Whether they work in clinical/ward roles or are based within the pharmacy department Ms Sneddon says all hospital pharmacists have a role to play in tackling AMR. “Those on the wards can screen prescriptions for antimicrobials to ensure that patients are receiving the correct treatment following local guidelines, can prompt review of intravenous antibiotics for switching to oral, can advise on therapeutic drug monitoring of aminoglycosides and glycopeptides and can educate ward staff about appropriate antibiotic use.
Pharmacists within the pharmacy department who check prescriptions or oversee supply of antibiotics should be familiar with local guidelines and query any use of non-guideline antibiotics, she says.
While many measures are in place to tackle AMR, and hospital pharmacists are clearly well placed to make a difference, is the situation improving?
Based on the latest ECDC report, Gram negative AMR is still growing but Gram positive has decreased. However, there is wide variation at a country level. For antimicrobial consumption, use within in the community has remained the same, but hospital usage has grown, and worryingly no country showed a significant reduction in carbapenems. Like AMR, there is wide variation at a country level on antibiotic consumption.
In the UK, antimicrobial stewardship programmes have been successful in improving the use of antibiotics “by reducing use of broad spectrum antibiotics, increasing compliance with local policies and education staff on appropriate use of antibiotics”, says Ms Sneddon.
But more must be done on a global scale to address AMR she believes. “A global effort is required because antibiotic use in one area of the world can affect us all due to the high level of air travel which can spread resistant bacteria.”
She says action is required at all levels from Government policymakers to healthcare providers and individual clinicians. Protection of critical antibiotics through restrictive policies that are effectively implemented and research to develop new antibiotics “are crucial”, she believes.
And there are “many examples of good practice in use of antibiotics in Europe, USA, South Africa and Australia and we need to learn from others what has worked to inform our own practice”, she adds.
Mr Howard would like to see a formal network of European hospital antimicrobial pharmacists to allow support at a local and national level. He says the more developed countries can support those still developing their AMS programmes.
He explains the AMS (ESGAP) group within ESCMID is developing a network for pharmacists and pharmacologist members. The European Association of Hospital Pharmacists has run some workshops so far, and there have been informal country visits.
In addition, BSAC is an antibiotic charity that provides free six-week course on antimicrobial stewardship in multiple languages, as well as a free electronic book on AMS, “both of which will be useful for European hospital pharmacists”, he says.
But unless the growing tide of Gram negative AMR can be stemmed, higher mortality rates from untreatable infections are inevitable, he warns.
With this threat ever present, Ms Sneddon says, “all pharmacists should be doing something to address AMR, regardless of which country they live in”.
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