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The long read: Is it too late to halt the spread of antimicrobial resistance?

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?

History of AMR

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.

Fears for the future

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.”

AMR action plans

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.

What part should pharmacists play?

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.

What does the future hold?

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”.