Centre for Research Excellence in Minimising Antibiotic Resistance in the Community (CRE-MARC)
Who we are
CRE-MARC is an NHMRC-funded Centre for Research which started in Nov 2018 (for 5 years), at $2.5m.
It builds on CREMARA (The Centre for Research Excellence in Minimising Antibiotic Resistance for Acute Respiratory Infections) which was funded by the NHMRC in 2012.
This new Centre for Research Excellence is building on the achievements of CREMARA in acute respiratory infections and extends this research into a second phase of implementation and new work in urine and skin infections.
What CREMARA achieved
The team achieved 91 publications (a combination of articles that provided new knowledge, along with articles that emphasised research translation and practice and policy implications). Many of these articles generated knowledge about effective interventions that general practitioners (GPs) can adopt to reduce their prescribing of antibiotics for acute respiratory infections (ARIs). Additional funding (such as via NHMRC project grants scheme) was obtained to conduct large projects, such as nation-wide cluster randomised trials in general practice. The CREMARA team held two national summit meetings. The 2017 National Roundtable meeting involved presentations from and discussion with the United Kingdom’s Chief Medical Officer Dame Sally Davies, Australia’s Chief Medical Officer Prof Brendan Murphy, and key stakeholders from numerous federal and state government departments, agencies, and other research groups, and a report published in the MJA, and ongoing action planned developed.
The outputs from CREMARA have influenced policy in Government (eg Australian Strategic and Technical Advisory Group on Antimicrobial Resistance, ASTAG), Australian Commission on Safety and Quality in Health Care (ACSQHC); and professional bodies (eg Royal Australian College of GPs (RACGP) and other colleges). CREMARA has also strongly contributed to building research capacity, with 11 PhD scholars and post-doctoral research fellows, and >10 clinician-researchers developing skills in research and research translation in the important field of community antibiotic resistance research. One CREMARA post-doctoral research fellow has recently commenced an academic position in Denmark continuing to work in antibiotic resistance in the community and collaborate with our team.
What is needed next
Three major obstacles remain to reducing antibiotic use in Australian primary care:
- the poor adoption of several effective interventions for improving ARI prescribing, which emphasises that the next steps should be implementation research focussed on improving uptake of these interventions into practice;
- the need to broaden the focus beyond minimising antibiotic use in just acute respiratory infections (ARIs) and to include the two other major antibiotic indications in primary care – skin and soft-tissue infections (SSTIs) and urinary tract infections (UTIs); and
- the well-known, but little understood, problem of very high use of antibiotics in Residential Aged Care Facilities (RACFs).
Why CRE-MARC is needed
The antibiotic resistance crisis will have two substantial public health consequences unless reversed soon: avoidable deaths, and hampered medical care. The first consequence has begun: extrapolating from overseas data1 about 1,600 people in Australia each year die directly from antibiotic resistance. The avoidable mortality will get steadily worse, until 2050, when deaths from currently treatable infections may overtake total cancer deaths.1 The second consequence is the risk that antibiotic resistance poses to now-routine high technology medical care.3 Without reliable antibiotic prophylaxis, procedures such as chemotherapy, bone marrow transplant, much major surgery (including joint prostheses) and invasive diagnostic procedures (including cardiac catheterisation), will become too dangerous to perform.1,4 Many aspects of medical care will retreat into the pre-antibiotic era of the 1930s. The economic consequences of this are catastrophic, dominating even the effects of antibiotic resistance on health, prompting the Chief Medical Officer of the United Kingdom’s National Health Service to declare this threat every bit as serious as terrorism.4, 5
Governments are attempting to provide incentives for the pharmaceutical industry to generate new classes of antibiotics,5 but resistance has been an inevitable consequence of every new class of antibiotic developed to date. Since withholding antibiotics results in the return of susceptibility in the microbiome6, conservation of antibiotics is more likely to be successful at extending the life of the existing antibiotics, and any developed in the future.4 This is the focus of our approach.
For many GPs working in the community this unfolding crisis is not directly obvious. Yet GPs prescribe most of the antibiotic tonnage consumed by humans in Australia.7 Their prescribing of antibiotics is now creating resistance entering the tertiary (hospital) care sector, Figure 1. Exact data are not available in Australia, but in Denmark and Sweden (low community antibiotic-prescribing countries), 90% of antibiotics for human use are prescribed outside hospitals, and 65% by GPs.8,9 Reducing antibiotic usage allows resistance to dissipate6, as the unnecessary metabolic burden of producing resistance genes in the absence of antibiotics puts these organisms at a selective disadvantage.
Some areas of primary care are ripe for this – especially prescribing for common ARIs, for which a wealth of evidence shows that the benefits of antibiotics are small, harms are common, and that not using them is safe.10,11 Other areas of high prescribing are for urinary (UTIs), and skin-and-soft-tissue infections (SSTIs), which therefore is a focus in Stream 3. Other countries, such as Sweden and the Netherlands use less than half the quantity per capita of antibiotics than Australia7 with no increase in serious infections.9
Collaborators
Our team has a wide range of collaborations nationally and internationally that we will use and strengthen to pursue the CRE-MARC vision of improving antibiotic use in the community by: generating new knowledge, translating knowledge to improve clinical care and reduce antibiotic resistance. These collaborations include those between the current CREMARA team, the RACGP, Therapeutic Guidelines Antibiotic Guidelines, the National Prescribing Service, PHNs, universities, research institutes, policy groups and the departments of health.
What CRE-MARC is doing
-
Community antibiotic stewardship research implementation
Implementation studies with several Primary Healthcare Networks (PHNs) and Practice-Based Research Networks, culminating in a randomised trial of interventions known to be effective at reducing antibiotic prescribing.
An extensive literature, much of it synthesised by our team, now details the efficacy of a wide range of different interventions (delayed prescribing, shared decision making, “nudge” poster, audit & feedback, near patient tests or prediction rules) that individually reduce prescribing by GPs. Their different mechanisms suggest that combined effects would be synergistic. Some would be ready for implementing if GPs’ engagement with reduced antibiotic prescribing was strong. Because it is not, the overall effectiveness is small.20 In other words, we know of effective interventions that reduce antibiotic use. However, it is difficult to get GPs to use them, and they receive little attention in GP registrar training programs.
-
Skin and soft-tissue and urinary tract infections
Generating and synthesising evidence about antibiotic benefits and harms for these conditions (which together with ARIs covers >85% indications for antibiotic use in primary care) and developing interventions to improve appropriateness of antibiotic use for them.
The evidence quantifying the benefits of antibiotics for uncomplicated UTIs (eg in young women) provides little evidence in comparison with that for ARIs (which shows that the empirical benefits are much smaller than most patients or their clinicians expect). Nevertheless, for UTIs we are aware of 3 randomised controlled trials (RCTs) comparing antibiotics with non-steroidal anti-inflammatory drugs (NSAIDs) (with another Norwegian trial in progress) but only two RCTS comparing antibiotics against placebo. For most SSTIs, the evidence similarly appears to be weak. This makes it difficult to a) create safe guidelines and b) to design interventions that recommend less use of antibiotics for these largely self-limiting infections. However, the extent and quality of evidence in this area is not accurately known as no formal synthesis of the evidence has been published.
-
Residential aged care facilities
Tackling the problem of very high antibiotic use by exploring the reasons and using information about enablers and barriers to design interventions that improve the appropriateness of antibiotic use.
Residential Aged Care Facilities (RACFs) are known to have very high rates of antibiotic prescribing, with high prevalence of antibiotic use (nearly 10% of residents at any time), of which one-third were for no discernible infection, one-quarter were being used for >6 months, and there was no stop or review date for approximately half of the uses. However, the reasons are incompletely understood, although clearly complex. For example, there are large numbers of GPs who provide care for, and are ultimately responsible for prescribing antibiotics, for residents in RACFs but typically for only a few patients in a RACF. Residents are typically a frail population and have increased susceptibility to infection (for example, from long-term urinary catheters). Additional factors which need to be considered are the economic drivers for profit-driven institutions which operate in a tightly regulated environment. The combination of these factors, and others, means that interventions demonstrated to be effective at reducing antibiotic prescribing in mainstream general practice may be less likely to be effective in RACFs.
-
GP registrars
Developing and evaluating targeted educational interventions.
Ingrained habits of GPs are one contributor to high antibiotic use. But GP registrars have been shown by our researchers to also be high prescribers. Current role models, and other educational effects, are failing to adequately influence GP registrars. Yet it is essential to change their prescribing behaviour while it is still adaptable. Qualitative work has identified several barriers to reduced use of antibiotics, such as interactions with supervisors, practice culture and dealing with clinical uncertainty. Among enablers, our recent (not yet published) work shows that GP registrars are responsive to using delayed prescribing, which has also shown to be successful overseas. We identified an important barrier to reduced prescribing: clinical uncertainty, which especially worries GP registrars (publication under editorial review). We recently demonstrated some interventions successfully reduced antibiotic prescribing for acute bronchitis by 16%, but not undifferentiated ARIs (other specific ARIs were not measured).
-
Addressing other important, but neglected questions
Addressing other important, but neglected, questions about antibiotic resistance by conducting both primary studies and systematic reviews of the literature.
Several questions about antibiotic resistance have not yet been explored by researchers anywhere in the world, yet these issues are potentially very important and could influence national and international practice and policy. These include questions such as:
Does use of two antibiotics simultaneously result in less resistance?
This is common practice in tuberculosis treatment, where antibiotic resistance has been a serious problem since 1948, and indeed was only resolved by the use of multiple antibiotics. However this practice has fallen out of use for common infections in modern times and evidence on whether this is beneficial to recommence is needed.
Which antibiotics are least likely to cause resistance in specific pathogens?
It is common knowledge that some organisms remain sensitive to some antibiotics (e.g. Streptococcus pneumoniae to penicillin) while others (e.g. Staphylococcus aureus) soon develop resistance to many antibiotics. This has not been quantified in the literature, yet data on this would inform clinical decisions for common infections.
Which alternative (symptomatic) treatments to antibiotics are effective for specific infections?
The importance of having synthesised evidence in this area is to assist clinicians to fill the ‘therapeutic vacuum’ left after not using antibiotics. The literature is insufficiently systematically reviewed to allow quantitative comparisons of these treatments with each other, and, especially with antibiotics.
Implementation studies with several Primary Healthcare Networks (PHNs) and Practice-Based Research Networks, culminating in a randomised trial of interventions known to be effective at reducing antibiotic prescribing.
An extensive literature, much of it synthesised by our team, now details the efficacy of a wide range of different interventions (delayed prescribing, shared decision making, “nudge” poster, audit & feedback, near patient tests or prediction rules) that individually reduce prescribing by GPs. Their different mechanisms suggest that combined effects would be synergistic. Some would be ready for implementing if GPs’ engagement with reduced antibiotic prescribing was strong. Because it is not, the overall effectiveness is small.20 In other words, we know of effective interventions that reduce antibiotic use. However, it is difficult to get GPs to use them, and they receive little attention in GP registrar training programs.
Generating and synthesising evidence about antibiotic benefits and harms for these conditions (which together with ARIs covers >85% indications for antibiotic use in primary care) and developing interventions to improve appropriateness of antibiotic use for them.
The evidence quantifying the benefits of antibiotics for uncomplicated UTIs (eg in young women) provides little evidence in comparison with that for ARIs (which shows that the empirical benefits are much smaller than most patients or their clinicians expect). Nevertheless, for UTIs we are aware of 3 randomised controlled trials (RCTs) comparing antibiotics with non-steroidal anti-inflammatory drugs (NSAIDs) (with another Norwegian trial in progress) but only two RCTS comparing antibiotics against placebo. For most SSTIs, the evidence similarly appears to be weak. This makes it difficult to a) create safe guidelines and b) to design interventions that recommend less use of antibiotics for these largely self-limiting infections. However, the extent and quality of evidence in this area is not accurately known as no formal synthesis of the evidence has been published.
Tackling the problem of very high antibiotic use by exploring the reasons and using information about enablers and barriers to design interventions that improve the appropriateness of antibiotic use.
Residential Aged Care Facilities (RACFs) are known to have very high rates of antibiotic prescribing, with high prevalence of antibiotic use (nearly 10% of residents at any time), of which one-third were for no discernible infection, one-quarter were being used for >6 months, and there was no stop or review date for approximately half of the uses. However, the reasons are incompletely understood, although clearly complex. For example, there are large numbers of GPs who provide care for, and are ultimately responsible for prescribing antibiotics, for residents in RACFs but typically for only a few patients in a RACF. Residents are typically a frail population and have increased susceptibility to infection (for example, from long-term urinary catheters). Additional factors which need to be considered are the economic drivers for profit-driven institutions which operate in a tightly regulated environment. The combination of these factors, and others, means that interventions demonstrated to be effective at reducing antibiotic prescribing in mainstream general practice may be less likely to be effective in RACFs.
Developing and evaluating targeted educational interventions.
Ingrained habits of GPs are one contributor to high antibiotic use. But GP registrars have been shown by our researchers to also be high prescribers. Current role models, and other educational effects, are failing to adequately influence GP registrars. Yet it is essential to change their prescribing behaviour while it is still adaptable. Qualitative work has identified several barriers to reduced use of antibiotics, such as interactions with supervisors, practice culture and dealing with clinical uncertainty. Among enablers, our recent (not yet published) work shows that GP registrars are responsive to using delayed prescribing, which has also shown to be successful overseas. We identified an important barrier to reduced prescribing: clinical uncertainty, which especially worries GP registrars (publication under editorial review). We recently demonstrated some interventions successfully reduced antibiotic prescribing for acute bronchitis by 16%, but not undifferentiated ARIs (other specific ARIs were not measured).
Addressing other important, but neglected, questions about antibiotic resistance by conducting both primary studies and systematic reviews of the literature.
Several questions about antibiotic resistance have not yet been explored by researchers anywhere in the world, yet these issues are potentially very important and could influence national and international practice and policy. These include questions such as:
Does use of two antibiotics simultaneously result in less resistance?
This is common practice in tuberculosis treatment, where antibiotic resistance has been a serious problem since 1948, and indeed was only resolved by the use of multiple antibiotics. However this practice has fallen out of use for common infections in modern times and evidence on whether this is beneficial to recommence is needed.
Which antibiotics are least likely to cause resistance in specific pathogens?
It is common knowledge that some organisms remain sensitive to some antibiotics (e.g. Streptococcus pneumoniae to penicillin) while others (e.g. Staphylococcus aureus) soon develop resistance to many antibiotics. This has not been quantified in the literature, yet data on this would inform clinical decisions for common infections.
Which alternative (symptomatic) treatments to antibiotics are effective for specific infections?
The importance of having synthesised evidence in this area is to assist clinicians to fill the ‘therapeutic vacuum’ left after not using antibiotics. The literature is insufficiently systematically reviewed to allow quantitative comparisons of these treatments with each other, and, especially with antibiotics.
Over-arching all these streams, CRE-MARC is strongly contributing to the training and development of a new set of researchers who are able to continue and lead research in this crucial area of population health concern, through training of PhD students, post-doctoral research fellows, and clinician-researchers.
For more information on our research
References
- World Health Organisation. Antimicrobial resistance: global report on surveillance. 2014.
- Centre for Disease Dynamics EP. The state of the world’s antibiotics. 2015.
- WHO. Critically Important Antimicrobials for Human Medicine. Geneva: 2011.
- Davies DS, Grant J, Catchpole M. The drugs don’t work: a global threat: Penguin UK; 2013.
- O’Neill J, Davies S, Rex J, White LJ, Murray R. Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. London: HM Government (UK) and Wellcome Trust, 2014.
- Costelloe C, Metcalfe C, Lovering A, Mant D, Hay AD. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ. 2010;340:c2096.
- Australian Commission on Safety and Quality in Health Care (ACSQHC). AURA 2016: first Australian report on antimicrobial use and resistance in human health Sydney: ACSQHC, 2016.
- Danish Integrated Antimicrobial Resistance Monitoring and Research Programme. DANMAP. Use of Antimicrobial Agents and Occurrence of Antimicrobial Resistance in Bacteria from Food Animals, Food and Humans in Denmark 2015.
- Tyrstrup M, Beckman A, Mölstad S, Engström S, Lannering C, Melander E, et al. Reduction in antibiotic prescribing for respiratory tract infections in Swedish primary care- a retrospective study of electronic patient records. BMC Infectious Diseases. 2016;16(1):709.