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Antimicrobial resistance

Introduction

According to the World Health Organisation, antimicrobial resistance (AMR) is resistance of a microorganism to an antimicrobial drug that was originally effective for treatment of infections caused by it. Resistant microorganisms (including bacteria, fungi, viruses and parasites) are able to withstand attack by antimicrobial drugs, so that standard treatments become ineffective and infections persist. Alternative medications or higher doses are therefore required - which may be more costly or more toxic - or treatment fails altogether. AMR is therefore a broader issue than bacterial antibiotic resistance alone, but the scope of this chapter is limited largely to the latter - as this is perhaps of greatest concern

Antibiotic Resistance:

The initial evolution of resistant microorganism strains is a natural phenomenon that occurs when they replicate themselves erroneously (a mutation) or when resistant traits are exchanged between them. The use/misuse of antimicrobial drugs then accelerates the emergence of drug-resistant strains.

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The circles indicate individual bacteria. A yellow bacteria is very sensitive to Antibiotic X, meaning treatment will be successful. A red bacteria is more resistant to Antibiotic X, meaning they may only be sensitive at higher doses/to a longer course of treatment, or treatment may be unsuccessful.

bacteria diagram
bacteria diagram

Antibiotic misuse contributes to resistance in the following ways:

  • Failure to Complete Course of Antibiotics
  • Consider that the bacteria in question are all E coli, a common cause of urinary tract infections, and an appropriate antibiotic is correctly prescribed
  • Some of the individual E coli carry a natural resistance to this antibiotic, meaning they won't be killed immediately, but the majority will be, leaving a very small amount of the pathogen left - with pressure selection meaning they are likely to be more resistant to treatment
  • If the patient forgets to, or purposefully does not complete the full course of antibiotics, these remaining bacteria are then able to replicate and re-colonise, meaning not only does the infection return, but is now resistant to the original treatment (not only in this patient - but to anyone else who catches it)
  • Inappropriate Prescription/Consumption of Antibiotics for Non-bacterial Infections
  • Consider instead that the bacteria are a mixture of different bacteria, none of which are currently/will ever cause infection, and are simply part of the natural flora (ecological community)
  • If an antibiotic is prescribed for an unrelated illness (for example a viral infection), these bacteria will still undergo this pressure selection, and will still develop resistance to this antibiotic.
  • If at a later date this bacteria does cause an infection, or it passes its now-resistant genes to another bacteria, treatment with the same antibiotic will be unsuccessful

What do we know?

AMR is a rapidly growing public health threat for two reasons:

  • The use of antimicrobials has increased so that microbes are exposed to a much larger number/greater concentration of antimicrobials, increasing their chances of developing resistance.
  • For some categories of antimicrobials (particularly antibiotics) there are very limited numbers of new drugs under development to replace those rendered ineffective by rising drug resistance.

Essentially, the demand for new drugs has increased but the supply has dried up. Infections with resistant organisms now occur both in community and hospital populations. The World Health Organisation (WHO) estimates that antibiotics add 20 years to average life expectancy. Currently AMR is responsible for 700,000 deaths per year worldwide but by 2050, it could kill someone every three seconds. In a keynote address at a conference on Combating Antimicrobial Resistance, Dr Margaret Chan, Director-General of WHO stated:

"If current trends continue unabated, the future is easy to predict. Some experts say we are moving back to the pre-antibiotic era. No. This will be a post-antibiotic era. In terms of new replacement antibiotics, the pipeline is virtually dry. The cupboard is nearly bare. A post-antibiotic era means, in effect, an end to modern medicine as we know it. Things as common as strep throat or a child's scratched knee could once again kill"

Though AMR occurs across many strains of bacteria and to a wide range of antibiotics, examples of more noteworthy AMR organisms in England include, but are not limited to:

  • Methicillin-resistant S. aureus (MRSA)
    • MRSA is any strain of Staphylococcus aureus (S. aureus) that has developed multi- resistance to beta-lactam antibiotics, which include the penicillins and the cephalosporins.
    • Through effective prevention and control, the proportion MRSA blood stream infections has fallen from 15% in 2010 to 8% in 2014 (according to DoH data).
  • Panton-Valentine Leukocidin (PVL) toxin
    • Increases in isolates of MRSA producing the PVL toxin (a toxin associated with severe infection) have been observed among submissions to PHE's national reference laboratory, with 117 isolated in 2005 increasing to 1049 isolates in 2010.
  • Extended-spectrum β-Lactamases (ESBLs)
    • ESBLs are enzymes that confer resistance to cephalosporin antibiotics. ESBLs are commonly multi-resistant, and are frequently encoded on mobile plasmids (which transfer this resistance between different strains or even to other species of bacteria).
  • Carbapenemase-producing Enterobacteriaceae (CPE)
    • CPE are bacteria that are resistant to the carbapenem class of antibiotics and have emerged in the UK over the past decade. Enterobacteriaceae are a large family of bacteria that includes perhaps most importantly E coli, but also salmonella, Yersinia, Klebsiella and Shigella.

Public Perception

It is well understood that a key part of the battle against AMR will be public perception and, to this end, research has been carried out world-wide exploring what is generally understood around the subject. The Wellcome Trust recently commissioned work to explore the British public's relationship with antibiotics. This revealed:

  • General confusion regarding AMR terminology. Perhaps unsurprisingly, no-one in the focus groups was familiar with the abbreviation "AMR", but "antimicrobial resistance" also drew blank faces, and even "antibiotic resistance" left the vast majority of participants confused.
  • Many incorrectly believed that it is the patient who builds up a resistance to antibiotics, rather than the bacteria itself.
  • They felt overuse of antibiotics was only harming their chances of future success with treatment, not the wider community.

The study also found that, even with nomenclature clarified, there were still vast misconceptions about appropriate antibiotic use - findings that were shared in a similar survey of the American general public. Many people felt validated when they were prescribed antibiotics, commenting, "It confirms I'm ill", others thought of antibiotics as "a magic pill" to help them get better.

  • In the states, over 40% of respondents indicated that antibiotics were the best choice of treatment for a fever, runny nose or sore throat.
  • According to a UK Department of Health sponsored survey (where 43% incorrectly agreed that 'antibiotics can kill viruses'), those who were prescribed antibiotics for inappropriate reasons were more likely to re-present and request antibiotics the next time they fell ill. Further:
    • 4 in 10 people with a cough or symptoms of a cold, and 6 in 10 people with a throat infection had taken antibiotics in the previous years.
    • 17% believed that antibiotics could be used as an anti-inflammatory agent; 4% believed they can treat asthma, 4% that they can treat hay fever and 4% that they can treat headaches. More than 1 in 10 believed they can be used to treat allergic reactions and 26% that they can treat fungal infections

Perhaps more worryingly, this same Department of Health survey demonstrated even those with better understanding of AMR were just as likely to use antibiotics inappropriately. Though sometimes increased knowledge was associated with more prudent use (more likely to complete a course of antibiotics), sometimes it was associated with more irresponsible activity (more likely to self-medicate and to keep left-over antibiotics for future use).

Even when AMR is well understood, and antibiotics are used responsibly, the scale of the issue is seemingly missed. In the American study discussed, the vast majority agreed that inappropriate antibiotic use contributes to antibiotic resistance (92%), but most (70%) felt that AMR was not a major problem.

Facts, Figures, Trends

In 2016, the Department of Health updated their Antimicrobial Resistance Empirical and Statistical Evidence-Base. In this they discuss increasing antibiotic use and trends in AMR.

Increased use of antibiotics is the primary driver for the development of resistance. The standard measure of use (prescribing) is Defined Daily Dose (DDD) per 1000 population. The majority of antibiotic prescribing occurs in primary care, but in secondary care, broad-spectrum antibiotics (such as cephalosporin, quinolones and co-amoxiclav) are prescribed. Broad spectrum antibiotics are effective against a wide range of bacteria, but are more likely to drive resistance. As will be discussed in greater detail below, a key aim of the current UK Five Year Antimicrobial Resistance Strategy is the conservation and stewarding of currently available antibiotics - this means reducing the number of prescriptions, particularly the number of broad-spectrum prescriptions.

Nationally

  • The 2014 English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) report showed:
  • From 2010-2013, the total use of antibiotics increased by 6%. 2014 data shows prescribing of antibiotics continuing to increase - though at a slower rate (2.4%).
  • The predominant antibiotics used were penicillins (around 13 DDDs per 1000 inhabitants/day), tetracyclines and macrolides (around 4 DDDs per inhabitant/day)
  • There is increasing use of both carbapenems and piperacillin/tazobactam
  • There is decreasing use of both cephalosporins and quinolones
  • The 2011 National Point Prevalence Survey collected information on 52,443 patients :
  • The total number of antimicrobials prescribed was 25,942 to a total of 18,219 patients.
  • 34.7% of patients were thus prescribed antimicrobials, who then received 1.42 types of antimicrobial.

Locally

  • Public Health England has local data available regarding Antibiotic Prescribing, which can be broken down by CCG.
  • CCGs can be compared with other similar ones around the country, most usefully being grouped by deprivation decile and CCG cluster.
  • Reading Local Authority contains North and West Reading CCG , which falls into the 'Second Least Deprived' deprivation decile, and the 'Less deprived areas with better health' CCG cluster, and South Reading CCG, which falls 'Fifth Less Deprived' deprivation decile, and the 'Young adults and university cities' CCG cluster.

Figures 1 & 2 reflect the trends (2010 Quarter 1-2016 Quarter 1) in 'Total number of prescribed antibiotic items per 1000 resident individuals by quarter' for the two CCGs, while Figures 3 & 4 compare the 2016 Q1 data for the CCGs, to their Deprivation Decile and CCG cluster.

Figure 1: North & West Reading CCG - Total number of prescribed antibiotic items per 1000 resident individuals by quarter

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Figure 2: South Reading CCG - Total number of prescribed antibiotic items per 1000 resident individuals by quarter

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Figure 3: Figure 3: North & West Reading CCG - Total number of prescribed antibiotic items per 1000 resident individuals in 2016 Q1 - comparing CCG value, Deprivation Decile and CCG cluster

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Figure 4: Figure 3: North & West Reading CCG - Total number of prescribed antibiotic items per 1000 resident individuals in 2016 Q1 - comparing CCG value, Deprivation Decile and CCG cluster

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The above Figures show the rate of antibiotic drug consumption in the CCG by quarter by taking into account all prescribing at the primary care level. There is clear seasonal variation.

  • North and West Reading CCG: Largely static patterns of prescribing. However, there are fewer prescriptions than its comparative areas - suggesting appropriate antimicrobial stewardship.
  • South Reading CCG: There are largely static patterns of prescribing. However, this CCG sees more prescriptions than its comparative areas - suggesting less strict antimicrobial stewardship.

Figures 5 and 6 show the trends in 'Percentage of prescribed antibiotic items from cephalosporin, quinolone and co-amoxiclav class by quarter' for the two CCGs, while Figures 7 and 8 compare the 2016 Quarter 1 data for the CCGs, to their Deprivation Decile and CCG cluster.

Figure 5: North & West Reading CCG - Percentage of prescribed antibiotic items from cephalosporin, quinolone and co-amoxiclav class by quarter

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Figure 6: South Reading CCG - Percentage of prescribed antibiotic items from cephalosporin, quinolone and co-amoxiclav class by quarter

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Figure 7: North & West Reading CCG - Percentage of prescribed antibiotic items from cephalosporin, quinolone and co-amoxiclav class in 2016 Q1 - comparing CCG value, Deprivation Decile and CCG cluster data

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Figure 8: South Reading CCG - Percentage of prescribed antibiotic items from cephalosporin, quinolone and co-amoxiclav class in 2016 Q1 - comparing CCG value, Deprivation Decile and CCG cluster data

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This indicator specifically shows the percentage of broad spectrum items that are being prescribed by quarter. There is a clear trend of proportionally reduced consumption of these drugs in both CCGs. Further, both CCGs see proportionally fewer prescriptions of these drugs than its comparative areas - suggesting appropriate antimicrobial stewardship.

Trends

The aim of antimicrobial stewardship is to reduce the proportion of bacteria that are resistant to treatment. Data on resistance and trends is most frequently obtained from surveillance systems though, and there are a number of limitations to this approach:

  • They are invariably incomplete because to detect examples of AMR requires laboratory isolation, identification and susceptibility testing of a disease-causing pathogen - which is often not necessary for the clinical management of a patient (especially in the community).
  • It is usually implicitly assumed that trends observed in reported isolates (i.e. where infection has occurred) reflect those occurring in the wider population of (healthy) patients and pathogens.

No local information is available, but the 2015 ESPAUR report and also the annual progress report of the UKs current AMR strategy reviewed the national incidence of infection and the proportion of resistance.

The ESPAUR report found that from 2010 to 2014:

The incidence of

  • E. coli and Klebsiella pneumoniae bloodstream infections increased
  • K. oxytoca, Pseudomonas spp., Enterococcus spp., S. aureus and Acinetobacter spp. bloodstream infections remained constant
  • Streptococcus pneumoniae bloodstream infections declined

Regarding resistance:

  • Though proportionally, resistant to key drugs (e.g. ciprofloxacin, gentamicin and imipenem) have remained constant in E. coli, increased incidence of infections means that more individuals have had a significant antibiotic-resistant infection. Further, statistically significant increases in resistance were found to cefotaxime, co-amoxiclav and piperacillin/tazobactam.
  • The increases in both incidence and antibiotic resistance (to cefotaxime, imipenem and piperacillin/tazobactam) observed in K. pneumoniae bloodstream infections means that the number of individuals with antibiotic-resistant infections has increased substantially.
  • Statistically significant increases in proportions of resistance were also noted in Enterococcus spp. (to vancomycin), but decreases were noted in S. aureus (to methicillin).
  • Resistance in pseudomonas spp., streptococcus pneumonia, gonorrhoea and tuberculosis (TB) have remained stable, though they remain a significant threat.

The Department of Health update showed that between 2013 and 2014:

  • With the exception of Pseudomonas spp., where resistance to carbapenems showed a statistically significant increase, the proportions of isolates of each species resistant to each antibiotic were generally stable.
  • Again however, the increased incidence of some infections (E. coli and K. pneumoniae) means that for these infections the actual numbers of resistant infections is increasing.

National & Local Strategies

The importance of AMR has been recognised now for many years. In an interview shortly after winning the Nobel Prize in 1945 for discovering Penicillin, Alexander Fleming said:

"The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism"

The first World Health Assembly AMR resolution was agreed in 1998 and the need to accelerate progress has been acknowledged by both the WHO and European Commission. The first UK AMR Strategy was published in 2000 and the most recent update was a five year strategy released in 2013.

This represented an ambitious programme to slow the development and spread of AMR and rested on the three pillars of prevent, protect and promote: preventing infection, protecting the antibiotics that we have (stewardship) and promoting the development of new drugs and alternative treatments. Examples of actions currently taken to Tackle AMR in the UK are:

  • Raising Awareness - The European Antibiotic Awareness Day on the 18th November and World Antibiotic Awareness Week from the 14th-20th November (2016) is held each year to raise awareness among health professionals and the public of AMR and appropriate prescribing.
  • Optimising prescribing in Primary Care - To provide support for GPs who are often pressured into giving antibiotics by patients expecting to receive them, a toolkit - Treat Antibiotics Responsibly, Guidance and Education Tool (TARGET) was developed by the Health Protection Agency. Another similar initiative - Stemming the Tide of Antibiotic Resistance (STAR) includes resources for clinicians to share with the public during consultations.
  • Improving antibiotic prescribing in primary care is key part of the 2016-17 Quality, Innovation, Productivity and Prevention (QIPP) programme. This focuses on reducing the number of antibiotics prescribed in primary care through either a 4% (or greater) reduction on 2013/14 performance OR equal to (or below) the England 2013/14 mean performance, reducing the number of Co-amoxiclav, Cephalosporins and Quinolones (antibiotics associated with an increased risk of Clostridium difficile infection) as a proportion of the total number of selected antibiotics prescribed in primary care to be equal to or lower than 10%, OR to reduce by 20% from each CCG's 2014/15 value

These measures are underpinned by authoritative, evidence based guidance developed by NICE and also appear in the Quality and Outcomes Framework (QOF) and supported by the 3 CCGs of Berkshire East (Bracknell & Ascot, Windsor and Maidenhead, Slough) in their Operational Plan 2016/17 and by the 4 CCGs of Berkshire West (Wokingham, Newbury and District, South Reading and North and West Reading) in theirs. These include:

  • Working with the local health economy to set up an Antimicrobial stewardship (AMS) group which will be looking all aspects of AMS, including having a joint strategy that spans primary, secondary and community care
  • Evidence based prescribing, audit programme and education and training

In 2015, all 7 CCGs agreed to prescribing guidelines for use in primary care:

  • The guidelines promote the use of narrow-spectrum antibiotics in preference to broad
  • The audience of users is anticipated to be general practitioners, GP trainees, GP practice nurses, non-medical prescribers, paramedics, hospital emergency department staff and community pharmacists.
  • Optimising prescribing in Hospitals - AMR is tackled in hospitals primarily via reduced transmission (e.g. hand hygiene) and reduced deployment of resistance (e.g. antimicrobial stewardship). Resources like Start Smart then Focus have helped provide guidance on antibiotic stewardship and encourage use of the right drug, right dose and right duration. This is supported by The Berkshire NHS Foundation Trusts Operational Plan 2016/17. The Trust has a programme of education and training on antibiotic prescribing and stewardship. This utilises the MicroGuide app for mobile devices and includes developing a local antibiotic consumption vs resistance monitoring system; greater antibiotic auditing and real-time feedback to prescribers.
  • AMR Research - The UK is helping to shape thinking on AMR and helping develop an international framework of action to harness contributions from all sectors and encourage collaborative working. More information on AMR research is available at Antibiotic research UK, and a good summary of past and present UK AMR research is found in the UK Five Year Antimicrobial Resistance Strategy 2013 to 2018
  • Prescribing in the Veterinary Sector - Antibiotic use is not limited to humans and large quantities of antimicrobials are used in veterinary practice and the fishing and farming industries. While the current evidence suggests that this is not a major cause of resistance in bacteria that affect human health, it does provide a further vehicle for the development of antimicrobial resistance. To this end, there are a number of initiatives to promote the responsible use of antibiotics in animals.

The UK Five Year Antimicrobial Resistance Strategy (2013 to 2018) lists 7 key areas for future action:

  1. Improving infection prevention and control practices in human and animal health, both through enhanced dissemination and implementation of best practice and better use of data and diagnostics
  2. Optimising prescribing practice through implementation of antimicrobial stewardship programmes that promote rational prescribing and better use of existing and new rapid diagnostics
  3. Improving professional education, training and public engagement to improve clinical practice and promote wider understanding of the need for more sustainable use of antibiotics
  4. Developing new drugs, treatments and diagnostics through better collaboration between research councils, academia, industry and others; and by encouraging greater public-private investment in the discovery and development of a sustainable supply of effective new antimicrobials, rapid diagnostics, and complementary tools for use in health, social care, and veterinary systems
  5. Better access to and use of surveillance data in human and animal sectors through new arrangements that facilitate greater consistency and standardisation of the data collected across the system and encourage improved data linkage
  6. Better identification and prioritisation of AMR research needs to focus activity and inform our understanding of AMR. This may identify alternative treatments to new drugs as well as new or improved rapid or point-of-care diagnostic tests for humans and animals
  7. Strengthened international collaboration working with and through a wide range of governmental and non-governmental organisations, international regulatory bodies and others to influence opinion, galvanise support, and mobilise action to deliver the scale of change needed globally

Early in 2016, Lord O'Neill, who led a government review on AMR, called for a £1.5 billion investment in global innovation funding for research by 2020. On 21st September 2016, the United Nations held a High Level Meeting On Antimicrobial Resistance to "summon and maintain strong national, regional and international political commitment in addressing antimicrobial resistance comprehensively and multi-sectorally, and to increase and improve awareness of antimicrobial resistance." The signatories now have two years to report back with an action plan.

What is this telling us?

AMR is a vitally important yet poorly understood issue that requires urgent focus at local and national level. We can't stop bugs becoming resistant to antibiotics, but we can slow the process down. Though certain patient populations, prescribing practices and environments may contribute to resistance more than others, AMR does not then discriminate - it will affect everyone - and everyone has a part to play.

What are we doing in Berkshire?

Recently, a Berkshire-wide AMR stewardship group with representatives from all the main trusts in primary and secondary care has been established. The aim of the group is to concentrate and amalgamate efforts to comply with the strategies listed above. As well as working to improve awareness and understanding of AMR, a good example of this is the Antibiotic Guardian campaign.

Antibiotic Guardian is a PHE-led drive to encourage improved behaviours and engagement on the prudent use and prescription of antibiotics with members of the public and healthcare professionals. Antibiotic Guardians sign up online, and in doing so choose one pledge about how they can personally prevent infections, or make better use of antibiotics. You can be a healthcare professional, a student or educator, or a member of the general public and though PHE were aiming to reach 100,000 Antibiotic Guardians by March 2016, at time of writing, the current pledge count was 32,975.

Public Health England has local data available regarding 'Antibiotic Guardians per 100,000 population per year' as a measure of engagement within the area on antibiotic resistance. Antibiotic Guardians submit half-postcodes during their signup, which are then matched to their CCG catchment area by calendar year.

For the Reading Local Authority (including parts of North and West Reading and South Reading CCGs), Figures 9/10 and 11/12 show the level of engagement with this programme. Using data from the aforementioned PHE profiles, Figures 9/10 show the amount of antibiotic guardians in 2013 and 2014, while Figures 11/12 compare this data to the appropriate deprivation decile and CCG cluster grouping.

Figure 9: North & West Reading CCG - Antibiotic Guardians per 100,000 population per calendar year by CCGs

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Figure 10: South Reading CCG - Antibiotic Guardians per 100,000 population per calendar year by CCGs

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Figure 11: North & West Reading CCG - Antibiotic Guardians per 100,000 population per calendar year by CCGs - comparing CCG value, Deprivation Decile and CCG cluster data

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Figure 12: South Reading CCG - Antibiotic Guardians per 100,000 population per calendar year by CCGs - comparing CCG value, Deprivation Decile and CCG cluster data

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Unfortunately the number of Antibiotic Guardians dropped from 2014-15 for both CCGs. North and West Reading CCG compares poorly to other similar areas (CCG cluster and Deprivation Decile). Though Antibiotic Guardians dropped from 2014-15 in South Reading CCG, it actually compares well to other similar areas (CCG cluster and Deprivation Decile).

What are the key inequalities?

As stated, AMR does not discriminate. Many factors have and will contribute to its impact, but it will impact everyone. It is impossible to predict the path of emerging drug resistance, but it is a trend that has largely run only in one direction so far. What we can be certain of is that, in the absence of interventions to slow the emergence of resistance, the impacts will be felt not just in isolated areas but at a far more fundamental level, across our societies and healthcare systems.

Though antibiotics are primarily used to treat infection, they also play a key role prophylactically in reducing life threatening complications in surgery, chemotherapy and transplantation. In the past, resistant infections were associated predominantly with hospitals and care settings, but over the last decade resistant infections have been seen in the wider community too.

Though certain patient populations may thus be affected by AMR earlier than others (e.g. elderly populations or chronic disease groups), even everyday infections that we now seen as trivial may once again soon be deadly.

Before the availability antimicrobials there was greater inequality in health. Will the restriction of antimicrobials, and the rise of AMR, mean a return to greater health inequalities?

Recommendations

In May 2015, the Sixty-eight World Health Assembly adopted the global action plan on antimicrobial resistance. Within this are the Global Strategy Recommendations. Although the full list is available here - and contains advice for national governments and health systems - recommendations appropriate to the UK and Reading include:

Residents

  • Washing your hands
  • Avoiding contact with sick people, or using the appropriate personal protective equipment
  • Keeping current with vaccinations (humans and animals)
  • Using antibiotic appropriately and as instructed by your doctor - finish prescribed courses, do not share antibiotics and do not feel every infection requires them.

Local Authority

  • Ensure sanitary conditions are maintained
  • Raise awareness of AMR and antimicrobial stewardship

Prescribers and Dispensers

  • Encourage prescribers and dispensers to educate patients on antimicrobial use and the importance of adherence to prescribed treatments.
  • Improve antimicrobial use by supervision and support of clinical practices, especially diagnostic and treatment strategies.
  • Audit prescribing and dispensing practices and utilize peer group or external standard comparisons to provide feedback and endorsement of appropriate antimicrobial prescribing.

PHE

PHE centres should ensure that the ESPAUR report is discussed at meetings, local Quality Surveillance Groups, strategic clinical networks, health protection committees, local infection prevention and control committees.

  • Provide access to AMR data to relevant stakeholders
  • Promote the use of surveillance systems and the Antibiotic Guardian call to action   
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