British Society for Antimicrobial Chemotherapy 53 Regent Place Birmingham B1 3NJ bsac.org.uk antibiotic action.com

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1 1 Written Evidence Submitted by the British Society of Antimicrobial Chemotherapy (BSAC) to the Science and Technology's inquiry on Antimicrobial resistance (AMR). 1 Introduction to the (BSAC) Founded in 1971, and with members worldwide, BSAC exists to facilitate the acquisition and dissemination of knowledge of all aspects of antimicrobial (antibiotic) use. BSAC aims to improve the prevention, diagnosis and treatment of infections by promoting the development, discovery and appropriate and effective use of antimicrobial agents through education, research, national programme of surveillance and national methodologies, promoting evidence based practice, audit and quality improvement measures and engagement with people and organisations. BSAC provides advice to government, policy makers, its membership, the wider medical profession and the public on all issues relating to antimicrobial agents, the appropriate and effective use of antibiotics, and the management of community and hospital acquired infection(s). BSAC has provided support for the activities on AMR by the Department of Health and Chief Medical Officer. To achieve effective treatment and management of infections it is essential that patients have timely access to appropriate and effective therapies. With increasing reports of antimicrobial resistance amongst pathogens, in 2010 BSAC identified the urgent need to address antimicrobial resistance at a national and strategic level. This led to the establishment of the public awareness initiative Antibiotic Action (antibiotic action.com) and the BSAC Chair in Public Engagement currently held by Professor Laura JV Piddock (University of Birmingham). BSAC also provides the secretariat for the APPG on Antibiotics, chaired by Mr Jamie Reed, MP. 2 How has antimicrobial resistance developed in the past decade? Reports of microorganisms, especially bacterial pathogens, resistant to antimicrobial agents have continued to increase over the past decade with the emergence and spread of multi drug resistant (MDR) bacteria such as extensively drug resistant tuberculosis (XDR TB) and carbapenem resistant Enterobacteriaceae (CRE). Many of these bacteria have emerged in countries where healthcare systems are weak and antibiotic use is uncontrolled. Infections by MDR pathogens are difficult to treat, as they are resistant to 1 st and 2 nd line antimicrobial agents, often requiring the use of combination therapy and/or older or more toxic agents. Furthermore if infection caused by MDR bacteria is not suspected clinically or treated rapidly there is an increased risk of morbidity and mortality for the individual patient as well as potential transmission of the pathogen to other patients. Some bacteria are resistant to all currently available antibiotics resulting in untreatable infections. The very real concern is that the numbers of such infections will increase in UK patients.

2 2 Published reports and EU surveillance data indicate that the numbers of antibiotic resistant bacteria are increasing. However, incidence and prevalence of resistance are unknown because many people with infections are diagnosed clinically and treated empirically without any specimens taken for microbiological testing. Even when samples are taken and bacteria are grown in the laboratory, antimicrobial susceptibility testing is only carried out for a limited range of drugs. Over the past decade in high and low income countries antibiotic resistant bacteria have emerged in the community. The most prominent examples are community acquired MRSA, especially problematic in the USA, Escherichia coli or Klebsiella pneumonia producing extended spectrum betalactamases (ESBL) and carbapenemase producing Enterobacteriaceae. In the UK, much of the current problem is seen in community patients with urinary tract infections due to ESBL producing bacteria. As a result there is on going controversy over how much of the problem with antimicrobial resistance is due to antibiotic prescribing and emergence of resistance in the community rather than in hospitals. 3 What are the gaps in our knowledge about antimicrobial resistance? There are a numerous gaps: 1. A true understanding of the actual burden of antimicrobial resistance is required: How it occurs How it is spread The magnitude of the cost to Society The World Economic Forum s decision in January 2013 to place antibiotic resistance on the global risk register was based upon a handful of studies; these are considered by many to represent an underestimate of the true burden. 2. The full extent of antimicrobial resistance is not known. This is mainly detected in clinical specimens processed in hospital diagnostic laboratories (note points 8 and 9 below). A study of carriage of resistant bacteria in the general population is required. 3. Incidence and prevalence of multi drug resistant bacteria across all healthcare sectors. Extension of proven methodologies for systemic surveillance, e.g. BSAC Resistance Surveillance Programme [bsacsurv.org] into a national centrally supported mandatory scheme would address this knowledge gap in a cost effective manner. However, it is essential to clarify the purpose of enhanced surveillance, what would be gained from closing this knowledge gap, why information is needed and what it would be used for [need to guard against stamp collecting data and only collect data that will be used proactively towards achievement of defined outcomes]. 4. Evidence suggests that one contributory factor to the selection and spread of antibiotic resistant bacteria is the inappropriate use of antimicrobials. Currently, no UK data are collected and there is no accurate mechanism by which (1) antimicrobial prescribing and administration across primary and secondary care can be monitored; and (2) antimicrobial use can be correlated with the incidence

3 3 of antibiotic resistant bacterial infections. Whilst data is collected on ambulatory usage, there is no uniform way to collect data across the four UK health administrations and a delay in data provision hinders timely analysis and reporting and of data. 5. Effective antimicrobial use (prudent use/antimicrobial stewardship) is an essential component to strategies to minimise antibiotic resistance; this includes national strategies such as the Department of Health Start smart then focus. The extent to which such initiatives have been implemented across the UK is however unknown. Furthermore, the medical undergraduate curriculum does not provide a good understanding of infection or antibiotic prescribing and so many doctors are unable to enact such strategies due to a lack of basic knowledge to inform their prescribing decisions. This needs to be rectified at the earliest opportunity. 6. National/local stewardship initiatives play a central role in reducing the risk of antibiotic resistant infections. Effective programmes include the measurement of outcomes and there is a clear need for all clinical care groups and hospitals to have (1) A programme of activities/interventions aimed at improving the use of antibiotics in the treatment of infections and measurement of their success, the latter undertaken by the clinical teams and through engagements with national clinical specialty groups (e.g. acute medicine, trauma, general practice); and (2) Audit and benchmarking of improved antibiotic use. 7. Many current stewardship initiatives do not address fundamental issues associated with antibiotic resistance. Effectively addressing antibiotic resistance at a patient level requires A greater understanding of antibiotic resistance The contributions of different medical interventions (e.g. antibiotics, surgery) Improved diagnostic techniques (urgently required) to target interventions more effectively A multi disciplinary team approach to optimize patient outcomes in the management of complex infections (e.g. infections associated with implanted prosthetic material/devices, endocarditis). 8. The relationship between laboratory tests used to suggest susceptibility and the clinical response when administered to a patient has not been established for many drug/bacteria combinations. This requires the collection of patient outcome data, infecting organism and therapies used. Patient outcome data following antimicrobial therapy is required. Under the current system there is often the belief that no news or failure to request further tests is an indicator of a treatment success. Accurate data on treatment failure is lacking. 9. Testing for antimicrobial resistance has traditionally relied on phenotypic methods which may be inconsistent/unreliable for some drugs e.g. M. tuberculosis and pyrazinamide. Furthermore, the relationship between phenotypic susceptibility in vitro and clinical response in vivo has not been determined for many bacteria/ drug combinations. The advent of rapid molecular diagnostic tests for detection of mutations genes conferring resistance to antibiotics has been beneficial e.g. Hain and GeneXpert tests for M. tuberculosis. However, these tests only target a limited range of genes and antibiotic resistances. Bacterial whole genome sequencing (WGS) is an emerging technology,

4 4 which has the potential to address these deficiencies and provide speedier clinical management of patients but studies to determine the correlation between genotypic and phenotypic tests are required before WGS can be implemented in routine clinical care. Whilst making headline news, the impact in primary and secondary care outside of large well funded centres of excellence (e.g. ability to interpret WGS data by non WGS experts in time/cost beneficial manner) needs to be determined. 10. Hospital based reporting of antibiotic resistant infections has improved markedly over the last decade but is frequently limited to a small number of pathogens (e.g. Staphylococcus aureus, E. coli and glycopeptide resistant enterococci) and indications (e.g. bacteraemia) as is exemplified by the mandatory PHE surveillance programme in England. Information relating to complex infections associated with a significant risk of antibiotic resistance, (e.g. implant associated infections) is not generally collected. Information required regarding complex infections with a significant risk of antibiotic resistance, such as implant associated infection, is not collected at a national level. Systematic surveillance for antimicrobial resistance would address this knowledge gap. 11. Understanding of the basic biology of antibiotic resistance is essential to minimising the spread of antibiotic resistant bacteria and would also feed into drug discovery programmes by seeking new treatments unaffected by known resistance mechanisms. 12. Evidence of the impact of veterinary, agricultural, domestic and other uses of antimicrobials on the development of antibiotic resistant infections in people. Much work on the food borne pathogens Campylobacter and salmonella was done in the 1990s/early 2000s in the UK, mostly funded by Defra. Unfortunately, this programme was cut in Data arising from this research clearly showed that antibiotic resistant bacteria emerged in animals entering the food chain. However, due to the curtailment of this programme research programmes were incomplete and additional data is urgently required so that evidence based decisions can be made as to whether the use of antibacterial compounds of the same chemical classes as those used in human medicine should be discontinued. 4 Is there sufficient research and investment into new antibiotics or other treatments and methods to ensure continued protection against infection? If not, how could this be rectified? No. Due to multiple mergers between pharmaceutical companies, future development costs vs. other therapeutic areas and perceived no return of investment on antibacterial drugs many companies have left this therapeutic area. As widely reported in the literature and various reports worldwide this has left a huge discovery and development void with no new antibacterial drugs to treat Gram negative bacterial infections close to the market. This could be rectified as follows: New approaches and incentives for Pharma are required to ensure continued industry commitment to the development of new antimicrobials which does not represent an attractive proposition for Pharma when compared to new chemical entities in other areas of medicine e.g. cardiology, respiratory, etc. Companies are faced with the high costs of development, uncertainties over

5 5 regulatory success and obtaining a product licence, expectations that antibiotics are low cost treatments and uncertainties over duration of efficacy before their agents become resistant. The risks are just too high for some. Therefore, the research, regulatory and financial models that govern the development and marketing of antibacterial agents need to be reassessed and redefined including consideration, introduction and implementation of (1) Changes to clinical trial design. There are discussions being held at the European Medicines Agency and the USA Food and Drugs Administration that will hopefully bring about changes in the clinical trial paradigm. An ideal outcome would be new and clear guidelines that mean requisite studies to obtain a licence are feasible and not subject to change during the research and development process, thus helping incentivise companies return to market; (2) Measures to increase return on investment, such as patent extension, to balance the risk benefit ratio companies face when developing antibiotics; and (3) Realistic pricing of antibiotics to reflect their true value to society and the economy breaking the low cost/on demand expectations and perceptions that surround antibiotic cost and availability. New approaches to funding and incentives to encourage academic research. Compared to the other therapeutic areas, such as neurosciences, and because effective treatment of bacterial infections underpin all areas of medicine, antibacterial research is sorely underfunded. Even within the disciplines of Microbiology or Infection and Immunity there is a significant lack of funding. A report in progress for the APPG on Antibiotics has reviewed the public funding of Bacteriology and Antibacterials in the UK since This has revealed a maximum of 1.45% of the total funding available for research by agencies such as the Wellcome Trust, BBSRC, MRC, NIHR and Defra is spent on antibacterial research. This figure differs to those provided by these agencies which are for antimicrobial research, which includes research on viruses, fungi, eukaryotic microorganisms such as malaria and parasites as well as bacteria. Significant new funding is required for research on mechanisms of antibiotic resistance, drug discovery (chemistry and biology) and for research to translate any discoveries and facilitate drug development. There is a lack of antibacterial expertise in the decision making committees at funding agencies; this has led, in part, to the underfunding of this discipline. Learning lessons from the past successes and failures by drawing on the experience of those in Pharma who have a track record in antibiotic discovery, research and development is essential. Many of the most experienced in the field have retired and we risk, but cannot afford, to lose the legacy they can offer. Experts in antibiotic research should be supported before the skill base in the UK is entirely lost. As the majority of antibacterial discovery is likely to be outside of Pharma, there needs to be a mechanism and new funding to bridge the gap between academic discovery, early development by small medium enterprises and licensing by Pharma. The National Health Service provides a unique environment to explore the risk benefit of introducing numerous proposed interventions to minimise the impact of antibiotic resistant bacteria. Due to a lack of funding mechanism, this resource has been under utilised. The current NIHR call on antimicrobial resistance will hopefully rectify this.

6 6 5 What measures (including behavioural change) have been most effective in controlling the spread of resistant pathogens, and could such measures be used to control other pathogens? In hospital settings the measures most effective in controlling MRSA are applicable to controlling the spread of MDR bacteria include hand hygiene, patient isolation, use of appropriate contact precaution, environmental decontamination, rapid detection and treatment. To implement these measures for Gram negative bacteria will require new diagnostic tests and isolation facilities in most hospitals. When considering behavioural changes those that have been demonstrated to be most effective have been multi faceted and address personal attitudes, peers attitudes, subjective norms and perceived barriers to change. The most effective schemes have been implemented using multiple communication methods. Improved outcomes are seen when information is directed at prescribers, at patients through prescribers and at prescribers through patients. Successful antibiotic stewardship initiatives should aim to improve the outcome of patients treated for infection. Therefore, studies aiming to change antibiotic prescribing must look at patient outcome rather than just focus on the intervention itself (usually reducing the amount of antibiotic prescribed) and the impact on resistance. There are many studies looking at changing antibiotic prescribing, but very few looking at improving antibiotic prescribing. Studies that improve prescribing improve not only professional understanding and practice but should as a consequence lead to improved patient outcomes. 6 What global coordination and action is required to fight antimicrobial resistance and is the UK contributing enough towards cross border initiatives? A fully funded global surveillance programme and global / region specific action plan to monitor and contain antimicrobial resistance are needed. The WHO already has global surveillance programmes in place for specific pathogens e.g. influenza viruses (to inform vaccine design), M. tuberculosis and HIV (for drug resistance). However, these are limited in their scope and, other than influenza surveillance; do not provide data in a timely fashion. The European CDC conducts surveillance schemes for antimicrobial resistance (EARS Net) and antimicrobial consumption (ESAC Net). The UK contributes to these initiatives, however, participation is voluntary and the number of participating laboratories submitting data varies year on year, resulting in biased sampling. These schemes should be extended to include bacteria isolated from animals and from food. The pharmaceutical industry has also established initiatives e.g. Study for Monitoring Antimicrobial Resistance Trends (SMART) funded by MSD. Possible options include developing a national/eu/global mandatory surveillance programme for specific bacteria/antimicrobial resistances to collect comprehensive unbiased data which could be used to inform national strategy and contribute to international surveillance programmes. This will require political will and significant funding as it will require clinical, laboratory and IT support to be remotely feasible.

7 7 Outside the UK, controlling the spread of resistant pathogens in the community poses a much greater challenge as evidenced by the spread of XDR TB in South Africa and the detection of carbapenemase producing Enterobacteriaceae in water supplies in India. In resource constrained settings the control of these bacteria is likely to require improvements in healthcare infrastructure, infection control education, regulation of antimicrobial prescribing, and development of antimicrobial stewardship. In both settings implementation of systematic surveillance for drugresistant bacteria could potentially provide an early warning system to detect the emergence of new antimicrobial resistances. Other considerations include investigating the effects of non human use of antibiotics (e.g. in agriculture) on antimicrobial resistance in humans. The UK should work collaboratively via the World Health Organisations on identifying practical solutions to aid the global stewardship agenda. 7 What are the strengths and weaknesses of the Government s strategy for tackling antimicrobial resistance? What changes might be made to further strengthen the Government s action plan? The strategy s strength is that it identifies and outlines the strategic aims and priorities for action in tackling AMR. The three main weaknesses are that it: Was published without an action plan or clear timeframe for delivery/projected outcomes It focuses on aims and aspirations rather than standards and how these will be achieved or supported. It focuses on antibiotic resistance causing infection in hospitalised patients rather than those outside in the wider community. In the UK much of the current problem with antibioticresistant pathogens is seen in community patients. A BSAC review of the Department of Health UK Antibiotic Strategy 2000 revealed over 20 unmet recommendations for action in relation to strengthening systems, initiating research, supporting the development, implementation and measurement of national surveillance and stewardship programmes. We postulate that the majority of these failed due to lack of infrastructure, IT and the financial resources necessary to take the recommendations forward. The Department of Health Antimicrobial Resistance Strategy 2013 includes many similar, if not the same, recommendations. Therefore, we recommend that to successfully implement the 2013 strategy the reasons that so many of the 2000 strategy recommendations were not successfully implemented should be established. We further recommend that the government departments work collaboratively with professional and learned societies in delivering the 2013 strategy to extend on, develop and take forward systems and methodologies that are already in place by stakeholders such as BSAC (e.g. in the UK BSAC is establishing a UK wide Point Prevalence Survey system to enable the collection and publication of longitudinal data on antimicrobial consumption in hospital settings). There is not enough time or funding available to re invent the wheel.

8 8 8 Recommendations for action by the Government or others that we would like the committee to consider In addition to all points raised above, many of which include recommendations for action, BSAC recommends that to improve and embed in clinical practice, undergraduate and postgraduate education in all healthcare professional courses must include the diagnosis, management and control of infection and the use of antibiotics. End