Antibiotic Resistance

Transcription

1 Meeting the challenge of Antibiotic Resistance The Swedish Experience Background documents for exploratory discussion on opportunities for Chinese-Swedish collaboration in the area of antibiotic resistance April 2009

2 Meeting the challenge of Antibiotic Resistance The Swedish Experience Background and Introduction Antibiotic resistance - exploring the opportunities of Chinese-Swedish cooperation Bacterial infections are still one of the major causes of disease globally and effective antibacterial agents play a critical role in the health systems. The emergence and spread of antibiotic resistant bacteria has now reached a state where many of the developments in modern medicine are threatened. Many public health experts consider antibiotic resistance as one of, if not the greatest public health threat of the 21st century. Furthermore, one important dimension of the problem is that the innovation-pipeline for new classes of antibiotics is virtually empty. International collaborative efforts are also needed to adress this issue. The growing problem of resistance can only be addressed through global collaboration. The World Health Assembly has realized the need for improving the containment of antimicrobial resistance (WHA 58.27). In accordance with the Memorandum of Understanding between the Government of The Peoples Republic of China and The Government of the Kingdom of Sweden concerning Health cooperation, antibiotic resistance is one of the fields selected in the Plan ofaction signed in September There are already many examples of Chinese-Swedish collaboration within the areas of health and infectious diseases and Chinese experts have been actively involved in the initiation of the Sida-supported network ReAct - Action onantibiotic Resistance,( In September 2008, the Swedish Minister for Elderly Care and Public Health met with her Chinese colleague and the issue of antibiotic resistance was again raised as an area for collaboration that was to be further explored. Here we provide background documents outlining the Swedish experience in this area as well as challenges and opportunities for future collaborative efforts.

3 Meeting the challenge of Antibiotic Resistance The Swedish Experience List of documents 1. Background and Introduction: Antibiotic resistance exploring the opportunities of Chinese-Swedish cooperation * 2. Antibiotic resistance The faceless threat, Cars O, Nordberg P 3. Meeting the challenge of antibiotic resistance * Cars O, Högberg LD, Murray M, Nordberg O, Sivaraman S, Lundborg CS, So AD,Tomson G 4. WHO Policy Perspectives & Global Strategy 5. Improving the containment of antimicrobial resistance, (World Health Assembly) 6. Consumers and providers could they make better use of antibiotics? Nordberg P, Stålsby Lundborg C,Tomson G 7. Economic aspects of Antibiotic Resistance A fact sheet from ReAct 8. Decline in Antibacterial Innovation A fact sheet from ReAct 9. The ReAct Antibiotic Innovation Study Expert voices on a critical need, Tickell S 10. Variation in antibiotic use in the European Union, Cars O, Mölstad S, Melander A. 11. Antibiotic resistance in China a major future challenge, Heddini A, Cars O, Qiang S,Tomson G 12. Strama A Swedish working model for containment of antibiotic resistance Mölstad S, Cars S, Struwe J 13. Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme, Mölstad S, Erntell M, Hanberger H, Melander E, Norman C, Skoog G, Stålsby Lundborg C, Söderström A, Torell E, Cars O * Also in chinese

4 应对抗生素耐药性素耐药性的挑战 瑞典的经验 就中瑞在抗生素耐药性领域合作的机会进行探索性讨论的背景文件 2009 年 3 月

5 应对抗生素耐药性的挑战 瑞典的经验 背景和介绍 抗生素耐药性 - 探索中瑞合作的机会 纵观全球, 细菌感染仍然是引起疾病的主要原因之一 有效的抗菌药物在医疗卫生体系中起着至关重要的作用 目前, 抗生素耐药菌的出现和传播, 其发展势态之广泛, 已经对许多现代医学的发展造成威胁 许多公共卫生专家认为, 抗生素耐药性如果不是 21 世纪对公共卫生的最大威胁, 起码也是最大威胁之一 此外, 这个问题另一个重要的方面是, 抗生素新药种的创新渠道已告枯竭 要解决这个问题, 也得需要付诸国际间的合作努力 日益加剧的耐药性问题只有通过全球性合作才能得到解决 世界卫生大会已经意识到, 有必要加强对抗生素耐药性 (WHA 58.27) 的控制对策 根据中华人民共和国和瑞典王国关于卫生合作的谅解备忘录, 抗生素耐药性是 2007 年 9 月签署的行动计划中所选定的领域之一 中国和瑞典在卫生和传染疾病领域中已有许多合作的例子 中国专家也积极地参与到由瑞典国际开发署 (Sida) 支持的对抗生素耐药性采取行动的创举中来了 从事这一行动网络的组织称为 应对抗生素抗药性行动 (ReAct 简称再度行动组织 ), 详情请参见网址 瑞典老年护理和公共卫生大臣于 2008 年 9 月与中国同行会晤, 其间再次将抗生素耐药性的问题作为一个有待进一步探索的合作领域提了出来 在此, 我们谨提供一些背景文件, 其中概述了瑞典在这个领域的经验, 以及我们在未来合作中将面临的挑战和机遇

6 应对抗生素耐药性的挑战 瑞典的经验 文件目录 1. 背景和介绍抗生素耐药性 - 探索中瑞合作的机会 2. 抗生素耐药性 - 无形的威胁, 作者 :Cars O, Nordberg P 3. 应对抗生素耐药性素耐药性的挑战, 作者 :Cars O, Högberg LD, Murray M, Nordberg O, Sivaraman S, Lundborg CS, So AD,Tomson G 4. 世界卫生组织的政策 远景和全球远景和全球策略 5. 加强对抗生素耐药性素耐药性的控制政策 ( 世界卫生大会 ) 6. 消费者和供应者 - 他们能更好的使用抗生素吗? 作者 :Nordberg P, Stålsby Lundborg C,Tomson G 7. 从经济层面看抗生素耐药性 - 应对抗生素抗生素抗药性行动药性行动组织 (ReAct 简称再度行动组织 ) 的案例报道 8. 抗生素创新的衰退 - 应对抗生素抗生素抗药性行动药性行动组织 (ReAct 简称再度行动组织 ) 的案例案例报道 9. 应对抗生素抗生素抗药性行动药性行动组织组织对抗生素开发创新的开发创新的研究 - 危急中专家的专家的呼声作者 :Tickell S 10. 欧盟内部抗生素使用使用的差异, 作者 :Cars O, Mölstad S, Melander A. 11. 抗生素耐药性素耐药性在中国 - 一项未来的重大挑战作者 :Heddini A, Cars O,Qiang S, Tomson G 12. 严控 - 瑞典对抗生素耐药性实施控制的工作模式作者 :Mölstad S, Cars S, Struwe J 13. 抗生素使用的持续减少和细菌耐药性的降低瑞典抗生素合理使用与抗药性监督战略计划 (Strama) 的 10 年随访报告 作者 :Mölstad S, Erntell M, Hanberger H, Melander E, Norman C, Skoog G, Stålsby Lundborg C, Söderström A, Torell E, Cars O

7 THE GLOBAL THREAT OF ANTIBIOTIC RESISTANCE: Exploring Roads towards Concerted Action A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY 2004 BACKGROUND DOCUMENT Antibiotic resistance The faceless threat Otto Cars, Per Nordberg Apotential post-antibiotic era is threatening present and future medical advances. The current worldwide increase in resistant bacteria and, simultaneously, the downward trend in the development of new antibiotics have serious implications. Resistant bacteria dramatically reduce the possibilities of treating infectious diseases effectively and multiply the risks of complications and a fatal outcome for patients with infections of the blood. Most vulnerable are those with weakened immune defences, such as cancer patients, malnourished children and people who are HIV-positive, for whom adequate therapy to prevent and treat severe infections is often necessary for their survival. In addition, antibiotic resistance jeopardises advanced medical procedures such as organ transplantations and implants of prostheses, where antibiotics are crucial for patient safety and to avoid complications. Mortality as a result of infectious diseases represents one-fifth of global deaths 1 ; respiratory infections are the leading killer, causing nearly four million deaths annually (Figure 1). These deaths are to some extent regarded as preventable with increased access to health care and medicines. However, the global emergence and spread of bacteria that resist antibiotics is raising the question as to whether this is still the case, especially in parts of the world where second and third line antibiotics are unavailable. Considering that the escalating medical and economic consequences of antibiotic resistance are generally well known by medical professionals and political actors, the inertia surrounding the issue is difficult to explain. The vagueness of the international response and the failure to translate existing knowledge into concrete action are serious problems. This complacency on the part of global society needs urgently to be replaced by concerted action to reduce the present and future consequences of antibiotic resistance. Figure 1. Global mortality from infectious diseases. millions of death, worldwide, all ages A GLOBAL PROBLEM Source: World Health Report In the late 1940s, after less than a decade of penicillin being used to treat patients with infectious diseases, unresponsive strains of the bacterium Staphylococcus aureus, the leading cause of hospital-acquired infections, were detected in English hospitals. 2 A striking example of biological evolution had begun: bacterial strains with natural and acquired resistance were being selected as a result of the use of antibiotics. About a decade later the first report on resistance to the second generation of penicillins arrived; it came from a Boston hospital, where methicillin-resistant strains of Staphylococcus aureus (MRSA) had been identified. 3 MRSA has become a symbol of antibiotic-resistant bacteria and is without doubt one of the best-studied pathogens. Since the 1980s the frequency of isolates of MRSA among Staphylococcus aureus has increased from close to zero to

8 A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY BACKGROUND DOCUMENT nearly 70 per cent in Japan and the Republic of Korea, 30 per cent in Belgium and around 40 per cent in the United Kingdom and the United States. It was discovered that mechanisms of resistance could be spread horizontally between different strains and different bacteria and that, consequently, clones with multiresistant qualities could develop. The problem soon became serious for other pathogens as well. Infections caused by multiresistant bacterial strains such as Acinetobacter and Stenotrophomonas can in some cases no longer be treated with modern antibiotics and the only available treatment is an old antibiotic, colistin, earlier rejected for clinical purposes due to its toxic side effects. Globally, escalating levels of the multiresistant intestinal pathogens Salmonella and Shigella cause severe infections that are difficult to treat, especially in children. In Shigella strains from Indonesia, Thailand and India per cent resistance is seen for two or more antibiotics. 4 Resistance to remaining effective therapy, such as fluoroquinolones, is steadily increasing, and the industry pipeline for antibiotics against important intestinal pathogens is running dry. No country on its own can isolate itself from resistant bacteria. Antibiotic resistance is a growing international problem affecting both current and future generations. Resistance that develops in one area of a country may easily spread nationwide. Globalisation, with increased migration, trade and travel, has widened the range for infectious diseases. A resistant strain of Streptococcus pneumoniae, first identified in Spain, was soon afterwards found in Argentina, Brazil, Chile, Taiwan, Malaysia, the USA, Mexico, The Philippines, the Republic of Korea, South Africa and Uruguay (Figure 2). 5 Such examples underline the fact that no single country can protect itself from the threat of resistant bacteria as pathogens are spreading across international, cultural and ethnic boundaries. Although the effects of antibiotic resistance are more documented in industrialised countries, there is a greater potential for harm in the developing world, where many of the second and third line therapies for drug-resistant infections are unavailable and unaffordable. SYSTEM FAILURE A thorough inventory of biological compounds with antibiotic activity followed the introduction of penicillin. Substances with different target mechanisms to attack bacteria were developed into new categories of antibiotics by the pharmaceutical industry and were eagerly used by Figure 2. Global spread of the penicillin-resistant Pneumococcus strain 23F. medical professionals in their clinical practice. For many years, society s medical needs for antibacterial drugs were met by the pharmaceutical industry. An apparent symbiosis between the interests of the community and those of the industry prevailed. In the 1970s, innovative research to develop new antibiotics gradually waned, and the focus of research and development shifted to the fine-tuning of existing products. As resistance to antibiotics accelerated, the fragile relationship between the community and the pharmaceutical industry began to break down. New antibiotics almost instantly faced the problem of the evolution of bacterial resistance after being put on the market and the short durability of antibacterial drugs was giving pharmaceutical companies cold feet. The industry began increasingly to weigh up its liabilities towards shareholders on the one hand and public trust and accountability to the community at large on the other. Difficulties arose as financial performance confronted the common good. The cleft between public and private interests grew wider with the development of national and international drug policies aimed at containing resistance and restricting and rationalising the use of antibiotics. Sharpened demands from regulatory bodies have increased the development cost of new medicines, and prioritising measures to secure optimal returns on investment have driven the industry into other pharmaceutical areas with bigger and safer markets. At present, the industry s ventures are shifting from therapy for acute conditions towards long-term treatment of chronic diseases. Prospective investments in antibiotics are more than ever competing with drugs for musculo-skeletal and neurological diseases with 10 or 15 times greater net present value, a measure used by the industry to predict the potential success of products. However, the need for antibiotics is anticipated to remain consistently high. From a broad societal perspective, the industry might be expected to supply communities with good drugs at affordable prices and provide reliable information on them. Today, this is not the case. 2

9 A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY BACKGROUND DOCUMENT THE CAUSES OF RESISTANCE Resistance is a natural biological outcome of antibiotic use. The more we use these drugs, the more we increase the speed of emergence and selection of resistant bacteria. In human use, around 80 per cent of antibiotic consumption takes place in the community and at least half of this is considered based on incorrect indications, mostly viral infections. 6 The mechanisms behind this overuse are many and intricate. The short-term advantages of antibiotic use for patients, health care workers and drug distributors seem to overweigh concerns about future consequences (Figure 3). The almost overwhelming complexity of factors influencing Figure 3. Individual advantages versus future consequences Once resistant strains are selected, their spread is promoted by factors such as overcrowding and poor hygiene. One example is day care centres, which provide ample opportunities for the transmission of infectious diseases and, in particular, the emergence of resistant Streptococcus pneumoniae. The combination of the presence of young, susceptible children suffering from recurrent infections and the use of multiple, often broad-spectrum antibiotics makes such environments ideal for the carriage and transmission of these bacteria. In the hospital setting, some bacterial clones have been more successful than others in spreading extensively. One example of the rapid dissemination of such epidemic clones is the MRSA epidemic in England and Wales where the frequency of MRSA among Staphylococcus aureus in blood cultures increased from less than 5 per cent in 1994 to present levels of just below 50 per cent (Figure 4). 11 Figure 4. The frequency of MRSA among blood cultures with Staphylococcus aureus. England & Wales Source Cars/Nordberg antibiotic consumption includes cultural conceptions, patient demands, diagnostic uncertainty, economic incentives, the level of training among health staff and pharmacists, and advertising to prescribers, consumers and providers from the pharmaceutical industry. In Europe, antibiotic consumption is four times higher in France than in the Netherlands 7 although the burden of disease is very similar in the two countries. Studies from some developing countries show that several antibiotics are generally prescribed at each consultation. 8 The relationship between antibiotic use and resistance is complex. Underuse, through lack of access to antibiotics, inadequate dosing and poor adherence to therapy, may play as important a role in driving resistance as overuse. 9 The use of broad-spectrum antibiotic agents as a substitute for precise diagnostics or to enhance the likelihood of therapeutic success increases the rate of selection of resistant bacteria. In addition, counterfeit and substandard drugs contribute to sub-optimal concentrations of antibiotics, failing to control bacterial populations that are considered a risk factor for developing resistance. It is estimated that over 50 per cent of antibiotics worldwide is purchased privately, from pharmacies or in the informal sector from street vendors, without prescriptions. Half of the purchases are for one-day treatments or less, an example reflecting the magnitude of the problem. 10 ANTIBIOTICS FOR NON-HUMAN USE Following their success in medicines for human beings, antibiotics have been increasingly used to treat and prevent diseases in animals, fish and plants. Besides this, sub-therapeutic doses of antibiotics have been shown to have growthenhancing effects and have for decades been intensively used in animal-rearing practices. In Europe and North America, antibiotic use in the animal sector constitutes around half of the total consumption. 12 In 1987 more than 90 per cent of the drugs used on animals in the United States was administered without veterinary consultation. 13 Within the European Union most antibiotics in feedstuff have been prohibited for a number of years, but in many countries large numbers of animals, irrespective of their health status, are exposed daily to sub-therapeutic concentrations of 3

10 A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY BACKGROUND DOCUMENT antibiotics. Some growth promoters belong to groups of antibiotics, such as glycopeptides, that are essential drugs in human medicine for the treatment of serious, potentially life-threatening infections. Emerging multiresistant bacteria from farm animals are transmitted to humans mainly through the food chain or by direct contact. The parallel emergence in animals of resistant strains, especially of Salmonella and Campylobacter, is continuously bringing in new clones that cause infections in human beings. THE CONSEQUENCES For many years, medical professionals have defined antibiotic resistance as a major public health problem. The issue has also received increased attention from several international bodies and is now more generally recognised as a threat to global health. Still, the consequences have not been sufficiently convincing to place this issue high on the political agenda. There may be several reasons for this. Firstly, public funding for research on antibiotic resistance has been low. In most industrialised countries the problem has been considered an annoying but inevitable side effect of antibiotic use, and the epidemiological and societal aspects of antibiotic resistance have been neglected while the research agenda has been decided by the pharmaceutical industry. This way of looking at the problem has been detrimental and has caused a situation where today we face many fundamental knowledge gaps including the health and economic consequences of antibiotic resistance, especially in the community. Secondly, to describe the public health consequences of antibiotic resistance is difficult and challenging because the problem of resistance involves diverse pathogens, transmitted in unique ways, which cause a wide range of diseases. The consequences for the patient, such as a prolonged disease or increased mortality, which could be attributable to antibiotic resistance, are hidden within a variety of clinical syndromes and the present difficulties of measuring this resistance. Since antibiotic resistance is not of itself a disease entity, invisibility characterises the issue, making it unknown and faceless for many people outside the medical field. Thirdly, because of the previously continuous development of new antibacterial agents it has been possible, in countries where new drugs are affordable, to change the therapy to new antibiotics when resistance levels to older ones have become uncomfortably high. This has not been possible in poor countries where many of the second and third line therapies for drug-resistant infections are unavailable, making the potential harm of resistance to first line antibiotics considerably greater. The limited numbers of antibiotics in these countries are becoming increasingly inadequate for treating infections, and necessary antibiotics to deal with infections caused by resistant pathogens are absent from many essential drug lists. 14 The situation is now changing in industrialised countries, too. Because of the virtually empty pipeline of new drugs, clinicians are now facing a situation where the likelihood of success from empiric antibiotic treatment is reduced and where patients are sometimes infected with bacteria resistant to all available antibiotics. MORTALITY, COSTS AND ECOLOGY Through the selection pressure caused by antibiotic use, a large pool of resistance genes has been created. Today, we are starting to see the tip of the iceberg. Slowly, the health impact is emerging. In the case of bloodstream infections from MRSA, mortality is repeatedly being shown to be two to three times higher than in infections with non-resistant strains. 15,16,17 Failure of the initial antibiotic regimen due to resistant bacteria increases the risks of secondary complications and a fatal outcome, underscoring the clinical dilemma of empirical therapy and the prevailing lack of rapid diagnostic tests. Recently, a study in intensive care demonstrated significantly higher mortality among patients that received inadequate empirical therapy, compared with those given adequate therapy (42 vs. 17 per cent). 18 Consequently, there is a clear justification for initial broadspectrum therapy in severe infections. This moves us into a vicious circle where increasing levels of resistance necessitate the use of broader, more potent antibiotics to secure patient survival but where using these reserve antibiotics escalates the problem as resistance develops and creates a situation where effective antibiotics are lacking. 19 Besides the medical consequences of antibiotic resistance, the problem is associated with large societal costs. The most concrete example is the cost of drugs, as new empirical treatments are needed to combat resistant pathogens. In 1997, estimates of the annual health care costs associated with the treatment of resistant infections in the US reached over USD 7 billion. In a district general hospital in the United Kingdom, the cost of containing an MRSA outbreak in 1995 was greater than 400,000. The figures produced so far probably underestimate the total current costs of resistance as they are limited to health care costs, the majority of these being incurred by the health care system. 20 4

11 A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY BACKGROUND DOCUMENT Further, none of these calculations include any estimate of costs to be incurred by future generations, which almost certainly will be larger than those being experienced currently. The economic and health costs of resistance, serious enough in the industrialised world, are often made more severe in developing countries. The economic, health and infrastructure systems of these countries, resulting in irregular supply and availability of drugs and often a dependence on unofficial sources, have led to extensive and inappropriate use of drugs, resulting in infections from strains far more resistant than those currently encountered in industrialised countries. Antibiotic resistance is a global and intergenerational issue. The ecological consequences are basically still unknown. Use of antibacterial drugs during the last 60 years has upset the balance in which microorganisms coexisted for millions of years. Antibiotic compounds can currently be detected in liquid waste at animal feedlots and fish-breeding locations, in lakes and ground-water supplies. Ecological niches outside the health care sector are changing, as bacteria formerly susceptible to antibiotics develop resistance to them. What are the long-term health consequences and potential environmental effects of reduced microbial diversity in the global microbial flora through antibiotic use? Similarities with other environmental problems can be seen, such as global warming and the reduction of the ozone layer where the approaching impact is difficult to predict. WHAT NOW? Although the full magnitude of the consequences for society is still unclear, awaiting more data before taking further action to contain the development of resistant bacteria is not an appealing option. Continued complacency is unjustifiable and even unethical in contexts where the lack of effective antibiotics is most imminent. International collective action is essential, yet responsibility for health remains predominantly national. Consequently, there is a potentially significant disparity between the problems and potential solutions associated with antibiotic resistance and the institutions and mechanisms available to deal with them. Comprehensive recommendations on rationalising antibiotic use, from the World Health Organization, the European Union and other multilateral organisations, get lost when it comes to translating them into action plans in individual countries. The difficulties of enforcing these recommendations on a global level are evident. Presently, the links between the well-formulated strategies at the level of global society and their acceptance by national policy makers are weak. To identify these barriers so as to prevent the message from repeatedly being returned to sender is a major challenge. To reverse the downward trend in research and development of new antibiotics is another. The prevailing perplexity of governments in the face of the need to balance commercial and community interests in this issue must be resolved. At present, public and private interests are at odds society s continuously high needs contrasting with the diminished accountability of the pharmaceutical industry. Incentives for the development of new antibacterial drugs with novel mechanisms of action are essential. But how to get out of this impasse? To attract the industry sufficiently to return to investing in new antibiotics may require concrete measures, including reducing the costs of research and development as well as securing the longer use of products. These ideas are not new. In the area of neglected diseases an orphan drug system has developed to stimulate production of necessary drugs. Extended patents have also been discussed as a way of directing industry investments. Increasing the returns on investment is the obvious key factor in promoting drug development within the existing framework; but can alternative options be found outside the existing structures? Using a public health approach to fill preventive and curative gaps in respect of diseases where the industry has lost interest would be an attractive path to explore. How do we prevent the same pattern from continuously repeating itself: one in which medical experts meet and compare escalating figures of resistant bacteria from different parts of the world, discuss worst-case scenarios but fail to reach out successfully either to politicians or to society as a whole? Obviously, current efforts are not enough to make the problem of antibiotic resistance a national political priority in any country; therefore, other ways must be explored. Politicians are predictable. They will certainly remain inactive as long as political passivity outweighs the will to initiate action on this issue. Building strong public awareness is vital if policy makers are to be stirred from their present dormant state into taking action. 5

12 A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY BACKGROUND DOCUMENT REFERENCES: 1. WHO (2003). Shaping the future, World Health Report Cohen ML. Epidemiology of drug resistance: Implications for a postantimicrobial era. Science 1992;257: Barrett FF, McGehee RF, Finland M. Methicillin-resistant Staphylococcus aureus at Boston City hospital. N Engl J Med 1968;279: Okumura J, Osaka K, Okabe N, Widespread Multi- Antimicrobial Resistant Shigella in Asia: What Does It Mean? Abstract No. AM 011, International Conference on Improving Use of Medicines, Smith R D, Coast J, Antimicrobial resistance: a global response, Bulletin of the World Health Organisation 2002;80: Wise R, Hart T, Cars O et al. Antimicrobial resistance is a major threat to public health. BMJ 1998;317: Cars O, Mölstad S, Melander A. Variation in antibiotic use in the European Union. Lancet 2001;357: Radyowijati, A. and Haak, H, Determinants of Antimicrobial use in the developing world, USAID, Bureau of Global Health, The Child Health Research Project Special Report, WHO, Global strategy for containment of antimicrobial resistance, 2001, WHO/CDC/CSR/DRS/2001.2, Geneva. 10. WHO-EMRO, Agenda item 11(a): Antimicrobial resistance and rational use of Antimicrobial agents, WHO website: rational/amr.ppt. 49th Session of the Regional Committee for the Eastern Mediterranean; 30 September - 3 October 2002, Cairo, Egypt. (Accessed 30 June 2004). 11. Health Protection Agency, UK. Staphylococcus aureus bacteraemia laboratory reports and methicillin susceptibility: England and Wales lab_data_staphyl.htm. (Accessed 30 June 2004). 12. WHO fact sheet on Antimicrobial resistance, 2002, (Accessed 30 June 2004). 13. Stöhr K, Problems from antimicrobial use in farming. Essential Drug Monitor, 2000, Issue no : Fasehun F, The antibacterial paradox: essential drugs, effectiveness, and cost. Bull World Health Organ, 1999; 77(3): Turnidge J, Impact of Antibiotic Resistance on the Treatment of Sepsis. Scandinavian Journal of Infectious Diseases, (2003); 35: Eva Melander Whitby M, McLaws ML, Berry G. Risk of death from methicillin-resistant Staphylococcus aureus bacteremia: a meta-analysis. Med J Austr 2002;175(5): Cosgrove SE, Sakoulas EN, Schwaber MJ, Karchmer, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a metaanalysis. Clin Infect Dis 2003;36: Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest, 1999 Feb; 115(2): Paterson D, Rice L B, Empirical antibiotic choice for the seriously ill patients: Are minimization of selection resistant organisms and maximization of individual outcome mutually exclusive? Clinical Infectious Diseases, 2003; 36: Smith R, Beaglehole R, Woodward D, Drager N, Global Public goods for health. Oxford University Press,

13 ANALYSIS Meeting the challenge of A concerted global response is needed to tackle rising rates of antibiotic resistance. Without it, we risk returning to the pre-antibiotic era warn Otto Cars and colleagues Antibiotics changed the world. Since their discovery almost eight decades ago, they have revolutionised the treatment of infections, transforming once deadly diseases into manageable health problems. The growing phenomenon of bacterial resistance, caused by the use and abuse of antibiotics and the simultaneous decline in research and development of new medicines, is now threatening to take us back to a pre-antibiotic era. Without effective treatment and prevention of bacterial infections, we also risk rolling back important achievements of modern medicine such as major surgery, organ transplantation, and cancer chemotherapy. Data from low income and middle income countries indicate that, because of the development of resistance to first line antibiotics, 70% of hospital acquired neonatal infections could not be successfully treated by using WHO s recommended regimen. 1 A recently published study of Tanzanian children confirmed that ineffective treatment of bloodstream infections due to antibiotic resistance predicts fatal outcome independently of underlying diseases. 2 In that hospital based study, mortality from bloodstream infections caused by Gram negative bacteria was more than double the mortality from malaria. Antibiotic resistance is becoming important in high income countries. In England and Wales, for example, the number of registered deaths in which meticillin resistant Staphylococcus aureus (MRSA) is mentioned increased from less than 50 in 1993 to more than 1600 in In 2007 there was a slight decrease. 3 The European Centre for Disease Prevention and Control, in its first epidemiological report on communicable diseases in Europe, states that the most important disease threat in Europe is from micro-organisms that have become resistant to antibiotics. 4 5 The emergence of antibiotic resistance is further complicated by the fact that bacteria and their resistance genes are travelling faster and further. 6 7 We are facing not only epidemics but pandemics of antibiotic resistance. 8 Airlines now carry more than two billion passengers annually, vastly increasing the opportunities for rapid spread of infectious agents, including antibiotic resistant bacteria, internationally. 9 The spread of resistance is also facilitated by worldwide distribution of food. 10 Another important factor is poor hygiene in hospitals as well as in the community, augmenting the rapid spread of antibiotic resistant bacteria in vulnerable populations. Different degrees of sensitivity to antibiotics exhibited by Staphylococcus aureus JOHN DURHAm/SPL Unblocking collective action Although the essential components of control of antibiotic resistance have long been well known, success has been limited in changing policies and efficiently responding to the problem The relative lack of data on the morbidity and mortality attributable to antibiotic resistance, including the economic impact on individuals as well as on health care and societies, may explain the weak reaction from politicians, public health workers, and consumers to this threat to public health. Individual stakeholders might well recognise the problem, but because it is complex, antibiotic resistance often becomes no one s responsibility, which blocks collective action. Action is urgently needed in three key areas: leadership on international and national levels, change in the behaviour of consumers and providers, and the development of antibacterial agents to match current public health needs. International and national leadership International organisations In 1998, the World Health Assembly adopted a resolution urging member states to take action on the problem of antimicrobial resistance. 13 In 2000, the World Health Organization requested a massive effort to prevent the health care catastrophe of tomorrow, 7 and shortly thereafter presented a global strategy for the containment of antimicrobial resistance, calling for a multidisciplinary and coordinated approach. 14 However, sufficient financial and human resources to implement the strategy were never provided. Member states recognised this lack of leadership and initiated a new resolution, adopted by the World Health Assembly in 2005, requesting the director general to strengthen WHO s leadership role in containing antimicrobial resistance and to provide more technical support. 15 Little has taken place to implement the resolution. The difficulties of enforcing these recommendations on a global level are evident, and the links between the well formulated strategies at the level of global society and the acceptance level by national policymakers are weak. WHO, international professional organisations, and other international 726 BMJ 27 september 2008 Volume 337

14 ANALYSIS antibiotic resistance stakeholders must provide coordination and resources for generating up to date information on the burden and the magnitude of antibiotic resistance at regional and subregional levels. Evidence is needed on effective interventions for prevention and control of antibiotic resistance at national and local levels, and more emphasis on prevention of infectious diseases is needed. Solving basic problems such as lack of safe drinking water, poor nutrition, and dysfunctional sanitation will go a long way toward curbing the needless use of antibiotics as quickfix solutions to avoidable diseases. 7 At national level Strategies for containing antibiotic resistance in low income countries are still blocked by patients poverty and weak health systems, 16 and many high income countries with well developed regulations and policies lack coordinated strategies against antibiotic resistance. Although the European Union has responded to the resistance problem, antibiotics are still sold over the counter without a prescription in some EU countries, violating existing laws and regulations, and in all countries self medication with leftover medicines occurs. 17 The root causes of certain behaviours need to be tackled, and the ultimate responsibility for coordinating the work lies with the government. National mandated multidisciplinary programmes can move from recommendations to implementation and audits. 18 For example, in Sweden the government is funding Strama, a nationwide multidisciplinary and multifaceted action programme against antibiotic resistance. Antibiotic sales have been reduced without measurable negative consequences, and resistance remains low. 19 In Chile, after a mass media campaign, regulatory measures were implemented to make antibiotics available by prescription only, resulting in an initial decrease of 35% in antibiotic sales. 20 All antibiotic use, appropriate or not, uses up some of the effectiveness of that antibiotic Behavioural change Social constraints and cultural views of infectious conditions influence the use of antibiotics. 21 Although the public s demand for antibiotics often is perceived as high even for conditions without a clinical indication for antibiotic treatment, studies have shown that this demand is overestimated by the prescriber, 24 and antibiotics could therefore successfully be replaced by better information and follow-up. The role of the patients as consumers is growing stronger. They need access to information and knowledge to reduce their expectations of antibiotics in self limiting infections, and doctors need new tools to help them justify their treatment decisions. 25 It could be unrealistic to expect people to restrict their antibiotic use in favour of a common good to prevent resistance but if the arguments for restricting the use of antibiotics can be made sufficiently convincing, reduced demand from the consumer may be the strongest force driving change. Studies increasingly emphasise the risk for the individual when taking an antibiotic, including the risks of becoming a long term carrier of antibiotic resistant bacteria, which might confer a greater risk in a subsequent severe infection. Reliable information on the adverse effects of antibiotics on the microbiological flora might provide a stronger incentive for not using antibiotics unnecessarily than would more general messages about risks for society through the development of resistance. For prescribers and other drug providers, multifaceted interventions including so called academic detailing are effective to increase adherence to recommendations in both high income settings and low income settings. Developing new antibacterials For many years, needs for antibacterial drugs were met by the pharmaceutical industry, and the apparent symbiosis between the interests of the community and those of the industry prevailed. Today we see a different scenario. Existing antibiotics are losing their effect at an alarming pace, but development of new antibiotics is declining. More than a dozen new classes of antibiotics were developed in the 1930s through the 1960s, but only two new classes have been developed since then. 30 Nor does the trend of declining innovation seem to be reversing. In a study of the top 15 pharmaceutical companies, only 1.6% of drugs in development were antibiotics, none of which were from novel classes and leaving need unmet for multiresistant Gram negative infections. 31 Summary points Antibiotics are a prerequisite for many of the advanced technologies in today s healthcare Although antibacterial resistance is growing, development of new antibiotics has declined A new paradigm in which antibiotics are considered as a non-renewable resource is needed The know-do gap in control of bacterial resistance to antibiotics must be tackled on international, national, and individual levels With existing incentives, current levels of innovation are clearly inadequate. 32 Proposals on how to break this trend have been put forward. Some have suggested arrangements that would increase the anticipated revenue by lengthening the period of patent protection or exclusivity over data submitted for drug registration. However, antibiotics already have small markets and emergence of resistance may further reduce the expected return of investment, so these incentives are likely to do little to stimulate greater innovation for antibacterials. 33 There are also scientific challenges for development of new antibiotics. 34 If today s market cannot deliver what the public needs, we must envisage other approaches that better engage both public and private sector resources. 35 One model is product development partnerships (PDPs), arrangements between public organisations and private companies to develop drugs when markets otherwise fail to meet public health priorities. This approach is now used for some drug projects targeting other neglected infectious diseases, such as malaria and tuberculosis. 36 Mechanisms creating supplements or replacing revenues in small and resource poor markets are another approach. Advanced market commitments (AMCs) create a fund that guarantees a certain price for drugs that meet therapeutic targets where there is a demand for the drug. A recent example is the pneumococcal vaccine AMC. 37 A gap analysis of drugs currently under development in light of current resistance patterns and trends would give priority to the most urgently needed antibiotics and give incentives for developing antibacterials with new mechanisms of action. But no matter how innovation is accelerated, any public investment must be matched by public health BMJ 27 september 2008 Volume

15 ANALYSIS accountability. The use of new antibiotics must be safeguarded by regulations and practices that ensure rational use, to avoid repeating the mistakes we have made by overusing the old ones. Another lack is efficient and affordable diagnostics with high sensitivity and specificity to distinguish bacterial from viral diseases, and to identify resistance patterns in bacteria. Such diagnostics would reduce inappropriate use of antibiotics and minimise the delays of treatment, thereby saving lives. Moving to concerted action A fundamentally changed view of antibiotics is needed. They must be looked on as a common good, where individuals must be aware that their choice to use an antibiotic will affect the possibility of effectively treating bacterial infections in other people. All antibiotic use, appropriate or not, uses up some of the effectiveness of that antibiotic, diminishing our ability to use it in the future. 38 ReAct Action on Antibiotic Resistance believes that for current and future generations to have access to effective prevention and treatment of bacterial infections as part of their right to health, all of us need to act now. The window of opportunity is rapidly closing. Otto Cars professor, Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden otto.cars@medsci.uu.se Liselotte Diaz Högberg researcher, Department of Medical Sciences, Uppsala University Mary Murray freelance consultant; member of the WHO expert panel on national drug policy; visiting research fellow and freelance consultant on rational use of medicines, Wee Jasper, University of South Australia School of Pharmacy and Medical Sciences, Adelaide, Australia Olle Nordberg former executive director, Dag Hammarskjöld Foundation, Uppsala Satya Sivaraman journalist, New Delhi, India Cecilia Stålsby Lundborg associate professor and professor, Division of International Health (IHCAR), Department of Public Health Sciences, Karolinska Institutet, Stockholm and Nordic School of Public Health, Göteborg, Sweden Anthony D So director, Program on Global Health and Technology Access, Terry Sanford Institute of Public Policy, Duke University, Durham, NC, USA Göran Tomson professor international health system research and director of doctoral programme, Division of International Health (IHCAR), Department of Public Health Sciences, Karolinska Institutet, Stockholm and Medical Management Centre (MMC), Karolinska Institutet, Stockholm Accepted: 15 May 2008 Contributors and sources: OC, LDH, MM, SS, CSL, and ADS are members of the international secretariat and all authors are active members of ReAct Action on Antibiotic Resistance ( a growing global network of individuals and organisations working towards the mission that current and future generations should have access to antibiotic treatment as a part of their right to health. ReAct was initiated in 2004 by Strama, the Swedish strategic programme against antibiotic resistance ( the Dag Hammarskjöld Foundation ( and the Division of International Health (IHCAR) at Karolinska Institutet, Stockholm, Sweden. Supported by the Swedish Development Cooperation Agency (Sida), ReAct is working towards five objectives: identify and facilitate removal of critical evidence gaps that block action to contain antibiotic resistance; develop strategic options to remove barriers to innovation of new antibiotics and diagnostics; advocate for better access to and use of effective and affordable antibiotics for those in need; promote global consensus for a new paradigm on the use of antibiotics; increase awareness of antibiotic resistance as a threat to global public health and engage key stake holders in action. Competing interests: None declared. Provenance and peer review: Not commissioned; externally peer reviewed. 1 Zaidi AK, Huskins WC, Thaver D, Bhutta ZA, Abbas Z, Goldmann DA. Hospital-acquired neonatal infections in developing countries. Lancet 2005;365: Blomberg B, Manji KP, Urassa WK, Tamim BS, Mwakagile DS, Jureen R, et al. Antimicrobial resistance predicts death in Tanzanian children with bloodstream infections: a prospective cohort study. BMC Infect Dis 2007;7:43. 3 National Statistics. MRSA deaths decrease in 2007www. statistics.gov.uk/cci/nugget.asp?id= European Centre for Disease Prevention and Control. Annual epidemiological report on communicable diseases in Europe. December europa.eu/pdf/ecdc_epi_report_2007.pdf 5 ReAct Action on Antibiotic Resistance. Burden of resistance to multi-resistant gram-negative bacilli (MRGN). 1 March snowfall.se/stopresistance/react_burden%20of%20 resistance%20to%20multi%20resist%20and%20 Gram%20negative%20Bacilli%20MRGN.pdf 6 Grundmann H, Aires-de-Sousa M, Boyce J, Tiemersma E. Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat. Lancet 2006;368: World Health Organization. Report on infectious diseases 2000: overcoming antimicrobial resistance index.html 8 Cantón R, Coque TM. The CTX-M β-lactamase pandemic. Current Opinion in Microbiology 2006;9: World Health Organization. World health report 2007: a safer future: global public health security in the 21st century Butaye P, Michael G B, Schwarz S, Barrett TJ, Brisabois A, White DG. The clonal spread of multidrug-resistant nontyphi Salmonella serotypes. Microb Infect 2006;8: Huovinen P, Cars O. Control of antimicrobial resistance: time for action. BMJ 1998;317: Hawkey PM. Action against antibiotic resistance: no time to lose. Lancet 1998;351: World Health Assembly. Emerging and other communicable diseases: antimicrobial resistance. May append/microb_wha5117.pdf 14 World Health Organization. Global strategy for containment of antimicrobial resistance www. who.int/drugresistance/who_global_strategy_english. pdf 15 World Health Assembly. Improving the containment of antimicrobial resistance. May med/apua/chapters/wha58_27-en.pdf 16 Okeke IN, Aboderin OA, Byarugaba DK, Ojo KK, Opintan JA. Growing problem of multidrug-resistant enteric pathogens in Africa. Emerg Infect Dis 2007;13(11) Grigoryan L, Haaijer-Ruskamp FM, Johannes Burgerhof GM, Mechtler R, Deschepper R, Tambic-Andrasevic A, et al. Self-medication with antibiotics in the general population: a survey in nineteen European countries. Emerg Infect Dis 2006;12(3). vol12no03/ htm 18 Carbon C, Cars O, Christiansen K. Moving from recommendation to implementation and audit: part 1. Current recommendations and programs: a critical commentary. Clin Microbiol Infect 2002;8(suppl 2): Mölstad S, Erntell M, Hanberger H, Melander E, Norman C, Skoog G, et al. Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme. Lancet Infect Dis 2008;8: Bavestrello FL, Cabello MA, Casanova Z, Dunny. Impact of regulatory measures on antibiotic sales in Chile. Rev Méd Chile 2002;130: Harbarth S, Samore MH. Antimicrobial resistance determinants and future control. Emerg Infect Dis 2005;11(6). vol11no06/ htm 22 Chen C, Chen YM, Hwang KL, Lin SJ, Yang CC, Tsay RW, et al. Behavior, attitudes, and knowledge about antibiotic usage among residents of Changhua, Taiwan. J Microbiol Immunol Infect 2005;38: Trepka M, Belongia E, Chyou P-H, Davis J, Schwartz B. The effect of a community intervention trial on parental knowledge and awareness of antibiotic resistance and appropriate antibiotic use in children. Pediatrics 2001;107:6. 24 Macfarlane J, Holmes W, Macfarlane R, Britten N. Influence of patients expectations on antibiotic management of acute lower respiratory tract illness in general practice: questionnaire study. BMJ 1997;315: Del Mar C. Prescribing antibiotics in primary care. BMJ 2007;335: Sjölund M, Wreiber K, Andersson DI, Blaser MJ, Engstrand L. Long-term persistence of resistant Enterococcus species after antibiotics to eradicate Helicobacter pylori. Ann Intern Med ;139: Nasrin D, Collignon PJ, Roberts L, Wilson EJ, Pilotto LS, Douglas RM. Effect of beta lactam antibiotic use in children on pneumococcal resistance to penicillin: prospective cohort study. BMJ 2002;324: Dollman WB, LeBlanc VT, Stevens L, O Connor PJ, Turnidge JD. A community-based intervention to reduce antibiotic use for upper respiratory tract infections in regional South Australia. Med J Aust 2005;182: Awad AI, Eltayeb IB, Baraka OZ. Changing antibiotics prescribing practices in health centers of Khartoum State, Sudan. Eur J Clin Pharmacol 2006;62: Infectious Diseases Society of America. Bad bugs, no drugs: as antibiotic discovery stagnate and a public health crisis brews. July badbugsnodrugs.html 31 Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE Jr. Trends in antimicrobial drug development: implications for the future. Clin Infect Dis 2004;38: Projan SJ. Why is big pharma getting out of antibacterial drug discovery? Curr Opin Microbiol 2003;6: Outterson K, Samora JB, Keller-Cuda K. Will longer antimicrobial patents improve global public health? Lancet Infect Dis 2007;7: Payne D, Tomasz A. The challenge of antibiotic resistant bacterial pathogens: the medical need, the market, and prospects for new antimicrobial agents. Curr Opin Microbiol 2004;7: Cars O, So A, Högberg L, Manz C. Innovating for bacterial resistance. ESCMID News 2007;2: Moran M. A breakthrough in R&D for neglected diseases: new ways to get the drugs we need. PLoS Med 2005;2:e Document prepared by the World Band and GAVI under the guidance of Governments of Italy, Canada, and the United Kingdom. AMC Pilot Proposal. 7 September Laxminarayan R, Malani A, Howard D, Smith DL. Extending the cure: policy responses to the growing threat of antibiotic resistance. Alexandria: Resources for the Future, and_downloads.html Cite this as: BMJ 2008;337:a1438 Professor Cars discusses the implications of antibiotic resistance in a video interview on bmj.com. 728 BMJ 27 september 2008 Volume 337

16 分析 应对抗生素耐药性的挑战 要解决抗生素耐药性不断增长的问题, 有必要寻求一种全球一致的反应 否则, 我们将我们将面临 后抗生素时代 的境地 这是乌托 卡尔斯 Otto Cars 和他的同事发出的警告 抗生素改变了这个世界 抗生素自问世后的近 80 年来, 革命性地改变了感染性疾病的治疗 它将曾经是致命性的疾病变成了可被控制的健康问题 然而, 使用和滥用抗生素引起的抗生素耐药性不断上升和与此同时发生的新药研发走下坡路的现象正威胁着要把我们拉回到 后抗生素时代, 即回到抗生素发现之前人们面对的对细菌性感染束手无策的黑暗年代 我们面临的威胁还有, 现代医学的重要成果, 如重大外科手术 器官移植和癌症化疗等都会因对细菌感染失去有效的防治而前功尽弃 根据一些来自低收入和中等收入国家的数据表明, 由于一线抗生素耐药性的产生,70% 的医源性新生儿感染无法通过世界卫生组织推荐的治疗方案成功治愈 1 最近发表的一项对坦桑尼亚儿童所做的研究证实, 由于抗生素耐药性所造成的血液感染治疗无效, 预示着致死的结局并非原发病本身所致 2 根据那家医院的研究, 由革兰氏阴性菌引起的血液感染死亡率是疟疾死亡率的两倍以上 金黄色葡萄球菌对抗生素不同程度敏感性的表现 抗生素耐药性问题在高收入国家正变得显著 例如, 在英格兰和威尔斯, 死因记录中提及耐甲氧西林金黄色葡萄球菌 (MRSA) 的死亡人数由 1993 年的不足 50 例增加到 2006 年的 1600 例以上 这个数字在 2007 年略有下降 3 欧洲疾病预防与控制中心在其第一期关于欧洲传染性疾

17 病的流行病学报告中指出, 欧洲面临的最大的疾病威胁来自于对抗生素已经产生耐药性的微生物 4, 5 使抗生素耐药性这一问题变得更为复杂的是, 细菌及其耐药基因的传播越来越快, 越来越广 6, 7 我们面对的不仅是抗生素耐药性地方性的流行, 而且是全球性的大流行 8 航空业每年运送 20 亿以上的乘客, 从而极大地增加了包括抗生素耐药性细菌在内的各种感染性病源在国际上迅速传播的机会 9 世界范围的食品销售也为耐药性的传播提供了便利 10 还有一个重要因素是, 医院及社区中不良的卫生状况成为抗生素耐药细菌得以在易感人群中迅速传播 疏通集体行动虽然对抗生素耐药性实行控制的基本要素早为人所知, 但要在改变政策和有效应对上取得成功还是受到限制 11, 12 由于抗生素耐药性引起的发病率和死亡率数据的相对缺乏, 以及经济因素对个人 卫生保健和社会的影响, 可能是政治家 公共卫生工作者, 和消费者对这一公共卫生威胁反应微弱的原因 个别利益相关者也许充分认识到抗生素耐药性的问题 但因其复杂性, 这个问题的责任在谁往往无人承担, 所以无法形成集体的行动 为此, 我们迫切需要在三个关键领域采取行动 : 国际和国家层次的领导, 消费者和供应商行为的改变, 以及适应当前公共健康需求的抗菌药开发 国际和国家层次的领导 国际组织 1998 年世界卫生大会通过一项决议, 敦促各会员国在抗生素耐药性问题上采取行动 年, 世界卫生组织要求以广泛的努力来防止 明天的卫生保健危机 7 此后不久, 世卫组织还出台了一项全球战略, 呼吁以多学科和协调一致的途径来遏制抗微生物药物耐药性 14 然而, 实现这一战略的财力 人力从来是供不应求的 各会员国意识到世卫组织对此战略领导力薄弱, 因而在 2005 年世界卫生大会上提出并通过了一项新的决议, 提请世卫总干事加强世界卫生组织在遏制抗生素耐药性战略上的领导作用, 并提供更多的技术支持 15 这项决议在实施方面还看不出有什么行动 这些建议要在全球范围实施, 困难是显而易见的 国际社会所制定的周全战略与各国决策者的接受程度, 二者之间的衔接显得薄弱 世界卫生组织 国际性专业组织和其它国际间利益相关方必须进行协调和提供资源, 及时收集不同区域抗生素耐药问题的严重程度 既要证明, 对国家和地方一级预防和控制抗生素耐药性工作实行有效干预是势在必行, 但更需要强调对传染性疾病的预防 解决安全饮用水的缺乏 营养不良以及不良的卫生状况等这些基本问题, 将极大地有助于避免疾病的发生, 从而减少不必要地使用抗生素这一速效方法 7 国家层次 BMJ 2008 年 9 月 27 日 第 337 卷 BMJ 27 september 2008 Volume 337

18 在低收入国家, 由于病人的贫困和薄弱的卫生系统, 遏制抗生素耐药性的战略的实施迄今仍然受到阻碍, 16 而许多已具有完善法规和政策的高收入国家尚缺乏协调一致的对付抗生素耐药性的策略 尽管欧盟已对耐药性问题作出了回应, 抗生素仍在一些国家无处方地被销售, 有违现行法律和规章 另外, 在所有国家都存在用剩余药自我治疗的问题 17 这些行为必须在根子上得到解决, 而协调开展这些工作地最终责任在于政府 国家制定的多学科计划可以一步步从建议走向实施, 从实施走向审核 18 例如, 瑞典政府直接资助了一个全国性的 多学科 多方位的应对抗生素耐药性的行动计划 瑞典抗生素合理使用与抗药性监督战略计划 (Strama 简称严控 ) 从此, 抗生素的销售在不出现明显负面影响的情况下降了下来, 耐药状况也保持在低水平上 19 智利在通过大众媒体进行大量的宣传之后, 实施了所有抗生素为处方药的监管措施, 措施一经实施, 抗生素的销售量就下降了 35% 20 行为的改变对感染病状的社会局限性看法和文化观念都会影响到抗生素的使用 21 公众对抗生素的需求偏高, 即使是在没有临床指征需用抗生素治疗的情况下也亦如此 22, 23 有研究表明, 这种需求被处方医师进一步高估了 24 因此, 如果对病人提供更详细的信息和随诊有可能成功地替代抗生素的使用 患者作为消费者的作用正在日益增强, 他们需要得到信息和知识, 以减少他们为控制自身感染对抗生素的期待 同时, 医生们需要新的手段来为治疗方案找到合适的理由 25 指望人们为了公共利益防止耐药性从而限制他们使用抗生素是不切实际的 但如果限制使用抗生素的理由足以令人信服, 使消费者降低这种要求, 这将是引发行为改变最大的驱动力 研究结果还进一步强调个人使用抗生素的风险, 包括这个人有可能成为抗生素耐药细菌长期携带者的危险, 26, 27 以及由此可能引起的更大危险 续发的严重感染 抗生素对微生物菌群产生副作用的可靠信息也许更能促使人们不到不得已不去使用抗生素 这比泛泛地宣传耐药性发展对社会的危害更有说服力 对于处方医师和其他药物供应者而言, 包括学术细述在内的多方位干预能有 28, 29 效地使他们坚持同样的建议, 而不论对象是高收入阶层还是低收入阶层 抗生素开发创新多年来, 制药工业一直能满足社会对抗菌药物的需求, 这是因为社会的利益和工业界的利益之间明显的共生占了上风 今天, 我们将看到的是另一番景象 : 现有的抗生素正以惊人的速度失去药效, 而研发新型抗生素的速度正持续下降 人们在 20 世纪 30 年代到 60 年代之间推出了十多个类别的抗生素, 但从那以后仅开发了两个新品种 30 发新药的快速下降趋势似乎看不到逆转 一项针对全球排名前 15 位的制药公司的调研指出, 新开发的药物中, 抗生素只占 1.6%, 而创新类的细菌药物一例也没有 而且, 针对多重耐药的革兰氏阴性菌感染的抗生素仍然缺乏 31 目前创新的水平在现行激励制度下是显然不够的 32 人们已就如何打破这种趋势提出了许多建议, 其中包括通过延长专利保护期或药品注册资料专属权来增加预期回报 然而, 抗生素的市场已经较小, 耐药性的出现可能会进一步降低预期的投资回报 所以, 这些激励措施有可能很难激发新抗菌药物的研发出现更大的革新 33 同时, 新抗生素研发也面临着来自科学层面的挑战 34

19 假如今天市场所提供的不能满足大众的需求, 我们必须考虑用其它途径来更好地吸引公共和私营部门的资源 35 有一种模式叫 产品开发合作伙伴关系 (PDPs), 即当市场不能满足公共卫生优先考虑的目标时, 由产品开发合作伙伴关系在公共组织和私人公司之间作出安排, 开发新型药物 这种途径现已用于一些被人们忽略的传染性疾病的药品项目, 如疟疾和肺结核 36 另外的途径是建立补充机制, 或将资金配置到弱小和资金匮乏的市场中去 一种叫先进市场承约 (AMCs) 的机制, 它建立起一项基金, 从而保证某些药品价格在需要时能适应治疗目标 最近一个此类的例子是肺炎疫苗 AMC 37 目前正在根据耐药性模式和趋势对药物供求差距进行分析, 它能够把最迫切需要的抗生素放在最优先的地位, 并鼓励开发有新的作用机制的抗菌药物 但无论创新进程如何推动, 所有的公共投资都必须与公众卫生的责任相适应 新抗生素的使用必须在规章上和操作上得到保护, 以保障其合理使用, 从而避免重复我们过度使用旧抗生素时所犯过的错误 另一个所缺乏的是有效的和负担得起的诊断学水准 它要求有高度的敏感性和高度的特异性, 能够精准地鉴别细菌性疾病和病毒性疾病, 以及细菌的耐药模式 只有这样的诊断水准, 才能减少抗生素的不当使用, 减少治疗的延误, 从而挽救生命 走向一致的行动我们需要对抗生素的认识有一个根本性的改变 抗生素被看作是对大家有共同好处的东西 而每个人都必须意识到, 他们在选择使用抗生素时将有可能影响到别人是否能有效地医治细菌感染 所有抗生素在使用时, 无论合适与否, 都在 耗尽 那种抗生素的某些有效性, 降低它在未来使用的效力 38 应对抗生素耐药性行动组织 (ReAct 简称再度行动组织 ) 坚信, 现在和未来的世世代代, 人们都同样拥有获得有效预防和治疗细菌性感染的权利, 这是他们健康权的一部分 因此, 我们所有的人都必须现在就行动起来 机会之窗正在迅速关闭 要点总结在当今的医疗保健体系中, 抗生素是许多先进技术的一个先决条件 随着抗生素耐药性不断攀升, 新抗生素的开发反而已在下降 有必要形成一种新的理念, 即抗生素是一种不可再生性资源 必须在国际 国家和个人多层面上解决在抗生素耐药细菌控制上存 Otto Cars: 瑞典乌普萨拉大学医学科学系, 传染病学教授,otto.cars@medsci.uu.se Liselotte Diaz Högberg: 乌普萨拉大学医学科学系, 研究员 Mary Murray: 特约顾问, 世界卫生组织在国家政策的专家小组成员 ; 合理使用药物领域访问学者和特约顾问 ;Wee Jasper, 澳大利亚阿得雷德南澳大学药物及医疗科学院 Olle Nordberg: 瑞典乌普萨拉 Dag Hammarskjöld 基金会前执行董事长 BMJ 2008 年 9 月 27 日 第 337 卷 BMJ 27 september 2008 Volume 337

20 Satya Sivaraman: 印度新德里, 记者 Cecilia Stålsby Lundborg: 瑞典斯德哥尔摩卡罗琳斯卡医学院公共卫生系国际健康部 (IHCAR) 付教授 ; 哥德堡北欧公共卫生学院教授 Anthony D So: 美国达拉谟杜克大学, 特里桑福德公共政策研究所, 全球卫生和技术普及计划主席 Göran Tomson: 瑞典斯德哥尔摩卡罗琳斯卡医学院国际卫生系统研究教授和博士课程主任, 公共卫生系国际健康部 (IHCAR), 医疗管理中心 (MMC) 接收 :2008 年 5 月 15 日 贡献和来源 :OC, LDH, MM, SS, CSL 和 ADS 来自国际秘书处, 所有作者都是 应对抗生素抗药性行动 组织的活跃成员 应对抗生素抗药性行动 组织是一个不断发展的个体及团体的全球网络组织, 共同为达到当今和未来世世代代的人都有机会获得将抗生素治疗作为他们健康权的一部分的目标而努力,2004 年由瑞典瑞典抗生素合理使用与抗药性监督战略计划 (Strama) Dag Hammarskjöld 基金 ( 和瑞典斯德哥尔摩卡罗琳斯卡医学院公共卫生系国际健康部 (IHCAR) 发起的瑞典应对抗生素抗药性的战略规划, 见 由瑞典国际开发署 (Sida) 支持 应对抗生素抗药性行动 正在朝着五个目标努力 : 识别和清除一切鸿沟和障碍, 为限制抗生素耐药性采取行动 ; 发展战略替代, 为新抗生素和新诊断的革新扫清障碍 ; 主张人们在有需要时能很好地得到并享用有效的 支付得起的抗生素 ; 在使用抗生素方面, 促进形成全球一致的新理念 ; 提高人们对抗生素耐药性的认知程度, 看到它是对全球公共卫生的威胁, 并敦促利益相关的各关键方面采取行动 1. Zaidi AK, Huskins WC, Thaver D, Bhutta ZA, Abbas Z, Goldmann DA. Hospital-acquired neonatal infections in developing countries. Lancet 2005;365: Blomberg B, Manji KP, Urassa WK, Tamim BS, Mwakagile DS, Jureen R, et al. Antimicrobial resistance predicts death in Tanzanian children with bloodstream infections: a prospective cohort study. BMC Infect Dis 2007;7: National Statistics. 3 MRSA deaths decrease in 2007www.statistics.gov.uk/cci/nugget.asp?id= European Centre for Disease Prevention and Control. Annual epidemiological report on communicable diseases in Europe. December ReAct Action on Antibiotic Resistance. Burden of resistance to multi-resistant gram-negative bacilli (MRGN). 1 March ti%20resist%20and%20gram%20negative%20bacilli%20mrgn.pdf 6. Grundmann H, Aires-de-Sousa M, Boyce J, Tiemersma E. Emergence and resurgence of meticillinresistant Staphylococcus aureus as a public-health threat. Lancet 2006;368: World Health Organization. Report on infectious diseases 2000: overcoming antimicrobial resistance Cantón R, Coque TM. The CTX-M β-lactamase pandemic. Current Opinion in Microbiology 2006;9: World Health Organization. World health report 2007: a safer future: global public health security in the 21st century Butaye P, Michael G B, Schwarz S, Barrett TJ, Brisabois A, White DG. The clonal spread of multidrug-resistant non-typhi Salmonella serotypes. Microb Infect 2006;8: BMJ 2008 年 9 月 27 日 第 337 卷 BMJ 27 september 2008 Volume 337 BMJ 2008 年 9 月 27 日 第 337 卷 BMJ 27 september 2008 Volume 337

21 11. Huovinen P, Cars O. Control of antimicrobial resistance: time for action. BMJ 1998;317: Hawkey PM. Action against antibiotic resistance: no time to lose. Lancet 1998;351: World Health Assembly. Emerging and other communicable diseases: antimicrobial resistance. May World Health Organization. Global strategy for containment of antimicrobial resistance World Health Assembly. Improving the containment of antimicrobial resistance. May Okeke IN, Aboderin OA, Byarugaba DK, Ojo KK, Opintan JA. Growing problem of multidrugresistant enteric pathogens in Africa. Emerg Infect Dis 2007;13(11) Grigoryan L, Haaijer-Ruskamp FM, Johannes Burgerhof GM, Mechtler R, Deschepper R, Tambic- Andrasevic A, et al. Self-medication with antibiotics in the general population: a survey in nineteen European countries. Emerg Infect Dis 2006;12(3) Carbon C, Cars O, Christiansen K. Moving from recommendation to implementation and audit: part 1. Current recommendations and programs: a critical commentary. Clin Microbiol Infect 2002;8(suppl 2): Mölstad S, Erntell M, Hanberger H, Melander E, Norman C, Skoog G, et al. Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme. Lancet Infect Dis 2008;8: Bavestrello FL, Cabello MA, Casanova Z, Dunny. Impact of regulatory measures on antibiotic sales in Chile. Rev Méd Chile 2002;130: Harbarth S, Samore MH. Antimicrobial resistancedeterminants and future control. Emerg Infect Dis 2005;11(6) Chen C, Chen YM, Hwang KL, Lin SJ, Yang CC, Tsay RW, et al. Behavior, attitudes, and knowledge about antibiotic usage among residents of Changhua, Taiwan. J Microbiol Immunol Infect 2005;38: Trepka M, Belongia E, Chyou P-H, Davis J, Schwartz B. The effect of a community intervention trial on parental knowledge and awareness of antibiotic resistance and appropriate antibiotic use in children. Pediatrics 2001;107: Macfarlane J, Holmes W, Macfarlane R, Britten N. Influence of patients expectations on antibiotic management of acute lower respiratory tract illness in general practice: questionnaire study. BMJ 1997;315: Del Mar C. Prescribing antibiotics in primary care. BMJ 2007;335: Sjölund M, Wreiber K, Andersson DI, Blaser MJ, Engstrand L. Long-term persistence of resistant Enterococcus species after antibiotics to eradicate Helicobacter pylori. Ann Intern Med ;139: Nasrin D, Collignon PJ, Roberts L, Wilson EJ, Pilotto LS, Douglas RM. Effect of beta lactam antibiotic use in children on pneumococcal resistance to penicillin: prospective cohort study. BMJ 2002;324: Dollman WB, LeBlanc VT, Stevens L, O Connor PJ, Turnidge JD. A community-based intervention to reduce antibiotic use for upper respiratory tract infections in regional South Australia. Med J Aust 2005;182: Awad AI, Eltayeb IB, Baraka OZ. Changing antibiotics prescribing practices in health centers of Khartoum State, Sudan. Eur J Clin Pharmacol 2006;62: Infectious Diseases Society of America. Bad bugs, no drugs: as antibiotic discovery stagnate and a public health crisis brews. July Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE Jr. Trends in antimicrobial drug development: implications for the future. Clin Infect Dis 2004;38: Projan SJ. Why is big pharma getting out of antibacterial drug discovery? Curr Opin Microbiol 2003;6: Outterson K, Samora JB, Keller-Cuda K. Will longer antimicrobial patents improve global public health? Lancet Infect Dis 2007;7: Payne D, Tomasz A. The challenge of antibiotic resistant bacterial pathogens: the medical need, the market, and prospects for new antimicrobial agents. Curr Opin Microbiol 2004;7: Cars O, So A, Högberg L, Manz C. Innovating for bacterial resistance. ESCMID News 2007;2: Moran M. A breakthrough in R&D for neglected diseases: new ways to get the drugs we need. PLoS Med 2005;2:e302.

22 37. Document prepared by the World Band and GAVI under the guidance of Governments of Italy, Canada, and the United Kingdom. AMC Pilot Proposal. 7 September Laxminarayan R, Malani A, Howard D, Smith DL. Extending the cure: policy responses to the growing threat of antibiotic resistance. Alexandria: Resources for the Future, Cite this as: BMJ 2008;337:a1438 Cars 教授在 bmj.com 的一个视频采访讨论对抗生素耐药性的影响 Translation 翻译 Shi-Jin Zhang MD, PhD, Researcher,Dept of Physiology and Pharmacology (fyfa), Karolinska Institutet, Stockholm, Sweden 张世瑾,MD,PhD, 瑞典斯德哥尔摩卡罗琳斯卡医学院生理药理系研究员 The Nordic Confucius Institute in Stockholm 北欧斯德哥尔摩孔子学院 BMJ 2008 年 9 月 27 日 第 337 卷 BMJ 27 september 2008 Volume 337

23 WHO/CDS/CSR/DRS/ DISTR: GENERAL ORIGINAL: ENGLISH WHO Global Strategy for Containment of Antimicrobial Resistance World Health Organization

24 WHO/CDS/CSR/DRS/ ORIGINAL: ENGLISH DISTRIBUTION: GENERAL WHO Global Strategy for Containment of Antimicrobial Resistance World Health Organization

25 Acknowledgements The World Health Organization (WHO) wishes to acknowledge with gratitude the significant support from the United States Agency for International Development (USAID) and additional assistance for this work from the United Kingdom Department for International Development and the Ministry of Health, Labour and Welfare, Japan. This strategy is the product of collaborative efforts across WHO, particularly in the clusters of Communicable Diseases, Health Technology and Pharmaceuticals, and Family and Community Health, with significant input from the staff at WHO Regional Offices and from many partners working with WHO worldwide. In particular, WHO would like to acknowledge the important contributions made to the drafting of the strategy by Professor W Stamm, Professor ML Grayson, Professor L Nicolle and Dr M Powell, and the generosity of their respective institutions Infectious Diseases Department, Harborview Medical Center, University of Washington, Seattle, USA; Infectious Diseases and Clinical Epidemiology Department, Monash Medical Centre, Monash University, Melbourne, Australia; Department of Internal Medicine, University of Manitoba, Winnipeg, Canada; Medicines Control Agency, London UK that enabled them to spend time at WHO. WHO also wishes to thank all those who participated and contributed their expertise in the consultations (see Annex B) and those individuals and organizations that provided valuable comments on drafts of this document. World Health Organization 2001 This document is not a formal publication of the World Health Organization (WHO), and all rights are reserved by the Organization. The document may, however, be freely reviewed, abstracted, reproduced and translated, in part or in whole, but not for sale or for use in conjunction with commercial purposes. The views expressed in documents by named authors are solely the responsibility of those authors. The designations employed and the presentation of the material in this document, including tables and maps, do not imply the expression of any opinion whatsoever on the part of the secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. Designed by minimum graphics Printed in Switzerland

26 Contents Executive Summary 1 Summary of recommendations for intervention 3 Part A. Introduction and background 9 Introduction 11 Antimicrobial resistance is a global problem that needs urgent action 11 A global problem calls for a global response 12 Implementation of the WHO Global Strategy 13 Background 15 What is antimicrobial resistance? 15 Appropriate use of antimicrobials 15 Surveillance of antimicrobial resistance 15 The prevalence of resistance 16 Conclusion 16 Part B. Appropriate antimicrobial use and emerging resistance: issues and interventions 19 Chapter 1. Patients and the general community 21 Chapter 2. Prescribers and dispensers 25 Chapter 3. Hospitals 31 Chapter 4. Use of antimicrobials in food-producing animals 37 Chapter 5. National governments and health systems 41 Chapter 6. Drug and vaccine development 47 Chapter 7. Pharmaceutical promotion 51 Chapter 8. International aspects of containing antimicrobial resistance 55 Part C. Implementation of the WHO Global Strategy 61 Introduction 63 Prioritization and implementation 63 Implementation guidelines 66 Monitoring outcomes 66 Summary 67 Recommendations for intervention 68 Tables 71 Suggested model framework for implementation of core interventions 76 References 83 Annexes 93 Annex A. National Action Plans 95 Annex B. Participation in WHO Consultations 96 iii

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28 Executive Summary EXECUTIVE SUMMARY Deaths from acute respiratory infections, diarrhoeal diseases, measles, AIDS, malaria and tuberculosis account for more than 85% of the mortality from infection worldwide. Resistance to first-line drugs in most of the pathogens causing these diseases ranges from zero to almost 100%. In some instances resistance to second- and thirdline agents is seriously compromising treatment outcome. Added to this is the significant global burden of resistant hospital-acquired infections, the emerging problems of antiviral resistance and the increasing problems of drug resistance in the neglected parasitic diseases of poor and marginalized populations. Resistance is not a new phenomenon; it was recognized early as a scientific curiosity and then as a threat to effective treatment outcome. However, the development of new families of antimicrobials throughout the 1950s and 1960s and of modifications of these molecules through the 1970s and 1980s allowed us to believe that we could always remain ahead of the pathogens. By the turn of the century this complacency had come to haunt us. The pipeline of new drugs is running dry and the incentives to develop new antimicrobials to address the global problems of drug resistance are weak. Resistance costs money, livelihoods and lives and threatens to undermine the effectiveness of health delivery programmes. It has recently been described as a threat to global stability and national security. A few studies have suggested that resistant clones can be replaced by susceptible ones; in general, however, resistance is slow to reverse or is irreversible. Antimicrobial use is the key driver of resistance. Paradoxically this selective pressure comes from a combination of overuse in many parts of the world, particularly for minor infections, misuse due to lack of access to appropriate treatment and underuse due to lack of financial support to complete treatment courses. Resistance is only just beginning to be considered as a societal issue and, in economic terms, as a negative externality in the health care context. Individual decisions to use antimicrobials (taken by the consumer alone or by the decision-making combination of health care worker and patient) often ignore the societal perspective and the perspective of the health service. The World Health Assembly (WHA) Resolution of 1998 (1) urged Member States to develop measures to encourage appropriate and costeffective use of antimicrobials, to prohibit the dispensing of antimicrobials without the prescription of a qualified health care professional, to improve practices to prevent the spread of infection and thereby the spread of resistant pathogens, to strengthen legislation to prevent the manufacture, sale and distribution of counterfeit antimicrobials and the sale of antimicrobials on the informal market, and to reduce the use of antimicrobials in food-animal production. Countries were also encouraged to develop sustainable systems to detect resistant pathogens, to monitor volumes and patterns of use of antimicrobials and the impact of control measures. Since the WHA Resolution, many countries have expressed growing concern about the problem of antimicrobial resistance and some have developed national action plans to address the problem. Despite the mass of literature on antimicrobial resistance, there is depressingly little on the true costs of resistance and the effectiveness of interventions. Given this lack of data in the face of a growing realization that actions need to be taken now to avert future disaster, the challenge is what to do and how to do it. The WHO Global Strategy for Containment of Antimicrobial Resistance addresses this challenge. It provides a framework of interventions to slow the emergence and reduce the spread of antimicrobial-resistant microorganisms through: 1

29 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ reducing the disease burden and the spread of infection improving access to appropriate antimicrobials improving use of antimicrobials strengthening health systems and their surveillance capabilities enforcing regulations and legislation encouraging the development of appropriate new drugs and vaccines. The strategy highlights aspects of the containment of resistance and the need for further research directed towards filling the existing gaps in knowledge. The strategy is people-centred, with interventions directed towards the groups of people who are involved in the problem and need to be part of the solution, i.e. prescribers and dispensers, veterinarians, consumers, policy-makers in hospitals, public health and agriculture, professional societies and the pharmaceutical industry. The strategy addresses antimicrobial resistance in general rather than through a disease-specific approach, but is particularly focused on resistance to antibacterial drugs. Much of the responsibility for implementation of the strategy will fall on individual countries. Governments have a critical role to play in the provision of public goods such as information, in surveillance, analysis of cost-effectiveness and cross-sectoral coordination. Given the complex nature of antimicrobial resistance, the strategy necessarily contains a large number of recommendations for interventions. Prioritization of the implementation of these interventions needs to be customized to national realities. To assist in this process an implementation approach has been defined together with indicators for monitoring implementation and outcomes. Recognition that the problem of resistance exists and the creation of effective national intersectoral task forces are considered critical to the success of implementation and monitoring of interventions. International interdisciplinary cooperation will also be essential. Improving antimicrobial use must be a key action in efforts to contain resistance. This requires improving access and changing behaviour; such changes take time. Containment will require significant strengthening of the health systems in many countries and the costs of implementation will not be negligible. However, such costs must be weighed against future costs averted by the containment of widespread antimicrobial resistance. 2

30 Summary of recommendations for intervention Patients and the general community & prescribers and dispensers The emergence of antimicrobial resistance is a complex problem driven by many interconnected factors, in particular the use and misuse of antimicrobials. Antimicrobial use, in turn, is influenced by an interplay of the knowledge, expectations and interactions of prescribers and patients, economic incentives, characteristics of the health system(s) and the regulatory environment. In the light of this complexity, coordinated interventions are needed that simultaneously target the behaviour of providers and patients and change important features of the environments in which they interact. These interventions are most likely to be successful if the following factors are understood within each health setting: which infectious diseases and resistance problems are important which antimicrobials are used and by whom what factors determine patterns of antimicrobial use what the relative costs and benefits are from changing use what barriers exist to changing use. Although the interventions directed towards providers and patients are presented separately (1 and 2) for clarity, they will require implementation in an integrated fashion. 1 PATIENTS AND THE GENERAL COMMUNITY Education 1.1 Educate patients and the general community on the appropriate use of antimicrobials. 1.2 Educate patients on the importance of measures to prevent infection, such as immunization, vector control, use of bednets, etc. 1.3 Educate patients on simple measures that may reduce transmission of infection in the household and community, such as handwashing, food hygiene, etc. 1.4 Encourage appropriate and informed health care seeking behaviour. 1.5 Educate patients on suitable alternatives to antimicrobials for relief of symptoms and discourage patient self-initiation of treatment, except in specific circumstances. 2 PRESCRIBERS AND DISPENSERS Education 2.1 Educate all groups of prescribers and dispensers (including drug sellers) on the importance of appropriate antimicrobial use and containment of antimicrobial resistance. 2.2 Educate all groups of prescribers on disease prevention (including immunization) and infection control issues. 2.3 Promote targeted undergraduate and postgraduate educational programmes on the accurate diagnosis and management of common infections for all health care workers, veterinarians, prescribers and dispensers. 2.4 Encourage prescribers and dispensers to educate patients on antimicrobial use and the importance of adherence to prescribed treatments. 2.5 Educate all groups of prescribers and dispensers on factors that may strongly influence their prescribing habits, such as economic incentives, promotional activities and inducements by the pharmaceutical industry. Management, guidelines and formularies 2.6 Improve antimicrobial use by supervision and support of clinical practices, especially diagnostic and treatment strategies. SUMMARY OF RECOMMENDATIONS FOR INTERVENTION 3

31 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ Audit prescribing and dispensing practices and utilize peer group or external standard comparisons to provide feedback and endorsement of appropriate antimicrobial prescribing. 2.8 Encourage development and use of guidelines and treatment algorithms to foster appropriate use of antimicrobials. 2.9 Empower formulary managers to limit antimicrobial use to the prescription of an appropriate range of selected antimicrobials. Regulation 2.10 Link professional registration requirements for prescribers and dispensers to requirements for training and continuing education. Hospitals Although most antimicrobial use occurs in the community, the intensity of use in hospitals is far higher; hospitals are therefore particularly important in the containment of antimicrobial resistance. In hospitals it is crucial to develop integrated approaches to improving the use of antimicrobials, reducing the incidence and spread of hospital-acquired (nosocomial) infections, and linking therapeutic and drug supply decision-making. This will require training of key individuals and the allocation of resources to effective surveillance, infection control and therapeutic support. 3 HOSPITALS Management 3.1 Establish infection control programmes, based on current best practice, with the responsibility for effective management of antimicrobial resistance in hospitals and ensure that all hospitals have access to such a programme. 3.2 Establish effective hospital therapeutics committees with the responsibility for overseeing antimicrobial use in hospitals. 3.3 Develop and regularly update guidelines for antimicrobial treatment and prophylaxis, and hospital antimicrobial formularies. 3.4 Monitor antimicrobial usage, including the quantity and patterns of use, and feedback results to prescribers. Diagnostic laboratories 3.5 Ensure access to microbiology laboratory services that match the level of the hospital, e.g. secondary, tertiary. 3.6 Ensure performance and quality assurance of appropriate diagnostic tests, microbial identification, antimicrobial susceptibility tests of key pathogens, and timely and relevant reporting of results. 3.7 Ensure that laboratory data are recorded, preferably on a database, and are used to produce clinically- and epidemiologicallyuseful surveillance reports of resistance patterns among common pathogens and infections in a timely manner with feedback to prescribers and to the infection control programme. Interactions with the pharmaceutical industry 3.8 Control and monitor pharmaceutical company promotional activities within the hospital environment and ensure that such activities have educational benefit. Use of antimicrobials in food-producing animals A growing body of evidence establishes a link between the use of antimicrobials in food-producing animals and the emergence of resistance among common pathogens. Such resistance has an impact on animal health and on human health if these pathogens enter the food chain. The factors affecting such antimicrobial use, whether for therapeutic, prophylactic or growth promotion purposes, are complex and the required interventions need coordinated implementation. The underlying principles of appropriate antimicrobial use and containment of resistance are similar to those applicable to humans. The WHO global principles for the containment of antimicrobial resistance in animals intended for food (2) were adopted at a WHO consultation in June 2000 in Geneva. They provide a framework of recommendations to reduce the overuse and misuse of antimicrobials in food animals for the protection of human health. Antimicrobials are widely used in a variety of other settings outside human medicine, e.g. horticulture and aquaculture, but the risks to human health from such uses are less well understood and they have not been included in this document. 4

32 4 USE OF ANTIMICROBIALS IN FOOD- PRODUCING ANIMALS This topic has been the subject of specific consultations which resulted in WHO global principles for the containment of antimicrobial resistance in animals intended for food *. A complete description of all recommendations is contained in that document and only a summary is reproduced here. Summary 4.1 Require obligatory prescriptions for all antimicrobials used for disease control in food animals. 4.2 In the absence of a public health safety evaluation, terminate or rapidly phase out the use of antimicrobials for growth promotion if they are also used for treatment of humans. 4.3 Create national systems to monitor antimicrobial usage in food animals. 4.4 Introduce pre-licensing safety evaluation of antimicrobials with consideration of potential resistance to human drugs. 4.5 Monitor resistance to identify emerging health problems and take timely corrective actions to protect human health. 4.6 Develop guidelines for veterinarians to reduce overuse and misuse of antimicrobials in food animals. * who_global_principles.html National governments and health systems Government health policies and the health care systems in which they are implemented play a crucial role in determining the efficacy of interventions to contain antimicrobial resistance. National commitment to understand and address the problem and the designation of authority and responsibility are prerequisites. Effective action requires the introduction and enforcement of appropriate regulations and allocation of appropriate resources for education and surveillance. Constructive interactions with the pharmaceutical industry are critical, both for ensuring appropriate licensure, promotion and marketing of existing antimicrobials and for encouraging the development of new drugs and vaccines. For clarity, interventions relating to these interactions with the industry are shown in separate recommendation groups (6 and 7). 5 NATIONAL GOVERNMENTS AND HEALTH SYSTEMS Advocacy and intersectoral action 5.1 Make the containment of antimicrobial resistance a national priority. Create a national intersectoral task force (membership to include health care professionals, veterinarians, agriculturalists, pharmaceutical manufacturers, government, media representatives, consumers and other interested parties) to raise awareness about antimicrobial resistance, organize data collection and oversee local task forces. For practical purposes such a task force may need to be a government task force which receives input from multiple sectors. Allocate resources to promote the implementation of interventions to contain resistance. These interventions should include the appropriate utilization of antimicrobial drugs, the control and prevention of infection, and research activities. Develop indicators to monitor and evaluate the impact of the antimicrobial resistance containment strategy. Regulations 5.2 Establish an effective registration scheme for dispensing outlets. 5.3 Limit the availability of antimicrobials to prescription-only status, except in special circumstances when they may be dispensed on the advice of a trained health care professional. 5.4 Link prescription-only status to regulations regarding the sale, supply, dispensing and allowable promotional activities of antimicrobial agents; institute mechanisms to facilitate compliance by practitioners and systems to monitor compliance. 5.5 Ensure that only antimicrobials meeting international standards of quality, safety and efficacy are granted marketing authorization. 5.6 Introduce legal requirements for manufacturers to collect and report data on antimicrobial distribution (including import/ export). 5.7 Create economic incentives for the appropriate use of antimicrobials. SUMMARY OF RECOMMENDATIONS FOR INTERVENTION 5

33 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ Policies and guidelines 5.8 Establish and maintain updated national Standard Treatment Guidelines (STGs) and encourage their implementation. 5.9 Establish an Essential Drugs List (EDL) consistent with the national STGs and ensure the accessibility and quality of these drugs Enhance immunization coverage and other disease preventive measures, thereby reducing the need for antimicrobials. Education 5.11 Maximize and maintain the effectiveness of the EDL and STGs by conducting appropriate undergraduate and postgraduate education programmes of health care professionals on the importance of appropriate antimicrobial use and containment of antimicrobial resistance Ensure that prescribers have access to approved prescribing literature on individual drugs. Surveillance of resistance, antimicrobial usage and disease burden 5.13 Designate or develop reference microbiology laboratory facilities to coordinate effective epidemiologically sound surveillance of antimicrobial resistance among common pathogens in the community, hospitals and other health care facilities. The standard of these laboratory facilities should be at least at the level of recommendation Adapt and apply WHO model systems for antimicrobial resistance surveillance and ensure data flow to the national intersectoral task force, to authorities responsible for the national STGs and drug policy, and to prescribers Establish systems for monitoring antimicrobial use in hospitals and the community, and link these findings to resistance and disease surveillance data Establish surveillance for key infectious diseases and syndromes according to country priorities, and link this information to other surveillance data. 6 DRUG AND VACCINE DEVELOPMENT 6.1 Encourage cooperation between industry, government bodies and academic institutions in the search for new drugs and vaccines. 6.2 Encourage drug development programmes which seek to optimize treatment regimens with regard to safety, efficacy and the risk of selecting resistant organisms. 6.3 Provide incentives for industry to invest in the research and development of new antimicrobials. 6.4 Consider establishing or utilizing fast-track marketing authorization for safe new agents. 6.5 Consider using an orphan drug scheme where available and applicable. 6.6 Make available time-limited exclusivity for new formulations and/or indications for use of antimicrobials. 6.7 Align intellectual property rights to provide suitable patent protection for new antimicrobial agents and vaccines. 6.8 Seek innovative partnerships with the pharmaceutical industry to improve access to newer essential drugs. 7 PHARMACEUTICAL PROMOTION 7.1 Introduce requirements for pharmaceutical companies to comply with national or international codes of practice on promotional activities. 7.2 Ensure that national or international codes of practice cover direct-to-consumer advertising, including advertising on the Internet. 7.3 Institute systems for monitoring compliance with legislation on promotional activities. 7.4 Identify and eliminate economic incentives that encourage inappropriate antimicrobial use. 7.5 Make prescribers aware that promotion in accordance with the datasheet may not necessarily constitute appropriate antimicrobial use. 6

34 8 INTERNATIONAL ASPECTS OF CONTAINING ANTIMICROBIAL RESISTANCE 8.1 Encourage collaboration between governments, non-governmental organizations, professional societies and international agencies to recognize the importance of antimicrobial resistance, to present consistent, simple and accurate messages regarding the importance of antimicrobial use, antimicrobial resistance and its containment, and to implement strategies to contain resistance. 8.2 Consider the information derived from the surveillance of antimicrobial use and antimicrobial resistance, including the containment thereof, as global public goods for health to which all governments should contribute. 8.3 Encourage governments, non-governmental organizations, professional societies and international agencies to support the establishment of networks, with trained staff and adequate infrastructures, which can undertake epidemiologically valid surveillance of antimicrobial resistance and antimicrobial use to provide information for the optimal containment of resistance. 8.4 Support drug donations in line with the UN interagency guidelines*. 8.5 Encourage the establishment of international inspection teams qualified to conduct valid assessments of pharmaceutical manufacturing plants. 8.6 Support an international approach to the control of counterfeit antimicrobials in line with the WHO guidelines**. 8.7 Encourage innovative approaches to incentives for the development of new pharmaceutical products and vaccines for neglected diseases. 8.8 Establish an international database of potential research funding agencies with an interest in antimicrobial resistance. 8.9 Establish new, and reinforce existing, programmes for researchers to improve the design, preparation and conduct of research to contain antimicrobial resistance. * Interagency Guidelines. Guidelines for Drug Donations, revised Geneva, World Health Organization, WHO/EDM/PAR/ ** Counterfeit drugs. Guidelines for the development of measures to combat counterfeit drugs. Geneva, World Health Organization, WHO/EDM/QSM/99.1. SUMMARY OF RECOMMENDATIONS FOR INTERVENTION 7

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36 PART A Introduction and background

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38 Introduction INTRODUCTION Antimicrobial resistance is a global problem that needs urgent action Deaths from acute respiratory infections, diarrhoeal diseases, measles, AIDS, malaria and tuberculosis account for more than 85% of the mortality from infection worldwide (3). Resistance to first-line drugs in the pathogens causing these diseases ranges from zero to almost 100%. In some instances resistance to second- and thirdline agents is seriously compromising treatment outcome. Added to these major killers is the significant global burden of hospital-acquired (nosocomial) infections usually caused by resistant pathogens, the emerging problems of antiviral resistance and the increasing threats of drug resistance in parasitic diseases such as African trypanosomiasis and leishmaniasis. The massive increases in trade and human mobility brought about by globalization have enabled the rapid spread of infectious agents, including those that are drug resistant. While richer countries, to a large extent, are still able to rely on the latest antimicrobials to treat resistant infections, access to these life-saving drugs is often limited or totally absent in many parts of the world. Urgent global action is needed, as outlined below. Costs of resistance The relentless emergence of antimicrobial resistance has an impact on the cost of health care worldwide. Ineffective therapy due to antimicrobial resistance is associated with increased human suffering, lost productivity and often death. Despite a dearth of data on the costs of resistance (4), there is growing consensus about the following points. In many regions the prevalence of resistance among common pathogens to readily available cheap antimicrobials is so high that these agents are now of limited clinical effectiveness. Increasingly, this results in difficult choices: to spend money on cheap useless drugs, to use more effective but more expensive drugs to treat a fraction of the population needing treatment, or to increase health care expenditure. Ineffective therapy leads to increased costs associated with prolonged illness, more frequent hospital admissions and longer periods of hospitalization. In addition, resistant pathogens in the hospital environment result in hospital-acquired infections which are expensive to control and extremely difficult to eradicate. The use of antimicrobials outside the field of human medicine also has an impact on human health. Resistant microorganisms in food-producing animals may have major financial implications for both farmers and consumers. Resistant animal pathogens in some food products, especially meat, may cause infections in humans that are difficult to treat. In addition, loss of public confidence in the safety of food affects the demand for products, with potentially serious economic effects on the farming sector. Risk management and national security Antimicrobial resistance threatens other health care gains. For example, co-infection with HIV and antimicrobial-resistant pathogens, e.g. tuberculosis, salmonellosis, other sexually transmitted infections, may result in rapid disease progression in the infected individual and has a potential multiplier effect on the dissemination of resistant pathogens to the rest of the population thereby placing more demands on health care resources. The emergence of antimicrobial resistance is regarded as a major future threat to the security and political stability of some regions (5). Antimicrobial resistance is frequently irreversible Although a few studies (6,7) have suggested that resistant clones can be replaced by susceptible ones, 11

39 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ resistance is generally slow to reverse or is irreversible. This suggests that interventions to stop the development of resistance should be implemented early, before resistance becomes a problem. The earlier interventions are implemented, the slower will be the development of resistance (4). However, this implies taking action before the prevalence of resistant infections climbs, based on decisions made whilst the number of people suffering resistant infections is low. Antimicrobial resistance is only just beginning to be considered as a societal issue and, in economic terms, as a negative externality (8,9). Individual decisions to use antimicrobials (taken by the consumer alone or by the decision-making combination of prescriber and patient) often ignore the societal perspective and the perspective of the health service. A dwindling supply of new antimicrobials The development of new antimicrobial agents effective against resistant pathogens and of alternative approaches such as vaccines is crucial to reduce the future impact of resistance. However, new agents are expensive and time-consuming to develop. Interest in antimicrobial research and development among the research-based pharmaceutical industry has declined as infectious diseases in richer country populations appear to have been conquered and as priorities have shifted to the development of lifestyle drugs. Unless the current rate of emerging resistance is controlled and slowed to preserve the life of existing drugs, this decline in new antimicrobial development, even if reversed now, is likely to result in the absence of effective therapies for some pathogens within the next ten years. A global problem calls for a global response There can be no doubt that antimicrobial resistance poses a global challenge. No single nation, however effective it is at containing resistance within its boundaries, can protect itself from the importation of resistant pathogens through travel and trade. The global nature of resistance calls for a global response, not only in the geographic sense, i.e. across national boundaries, but also across the whole range of sectors involved. Nobody is exempt from the problem, nor from playing a role in the solution. The response of the World Health Organization is to: raise awareness of the problems posed by antimicrobial resistance promote the sharing of information about and understanding of resistance provide strategic and technical guidance on interventions to contain resistance assist Member States to implement these interventions stimulate research to address the knowledge gaps and improve understanding of antimicrobial resistance and to encourage research and development of new antimicrobial agents. Development of the WHO Global Strategy Following the Resolution on Antimicrobial Resistance in 1998 (1), WHO has worked with many partners to develop the WHO Global Strategy for Containment of Antimicrobial Resistance (referred to as the WHO Global Strategy hereafter). The aim of this strategy is to provide, for all Member States, a framework of interventions to stimulate the prevention of infection, to slow the emergence of resistance and to reduce the spread of resistant microorganisms, in order to reduce the impact of resistance on health and health care costs, while improving access to existing agents and encouraging the development of new agents. The strategy has been formulated on the basis of expert opinion, published evidence, commissioned reviews and the deliberations of international and national bodies (see Annex B) on the key factors contributing to antimicrobial resistance and the interventions needed for its containment. Based on these inputs, a series of recommendations is proposed, directed towards the aims stated above. Part B of this document provides a summary of the evidence on which the recommendations are based. It is important to recognize that much remains to be learnt about the interplay between the factors responsible for the emergence and spread of resistance and the optimization and cost-effectiveness of appropriate interventions. However, the urgency of the situation requires that implementation of the WHO Global Strategy moves forward on the evidence currently available. 12

40 Implementation of the WHO Global Strategy The approach to implementation is crucial to its efficacy and success. Much of the responsibility for implementing interventions will fall on individual Member States. There are certain actions that only governments can assure, including the provision of public goods such as information, surveillance and analysis of cost-effectiveness of interventions, and the cross-sectoral coordination critical for an effective response (10). Given the large number of recommendations for the containment of antimicrobial resistance presented here, there is a practical need for prioritization and customization to the individual national setting. To assist in the implementation of the WHO Global Strategy, an approach to defining a smaller core set of recommendations is presented (Part C). Furthermore, since antimicrobial resistance is a clearly a global issue, international interdisciplinary cooperation is critical and the areas in which this can be most effective are outlined (Part B, Chapter 8). INTRODUCTION 13

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42 Background BACKGROUND What is antimicrobial resistance? Resistance to antimicrobials is a natural biological phenomenon. The introduction of every antimicrobial agent into clinical practice has been followed by the detection in the laboratory of strains of microorganisms that are resistant, i.e. able to multiply in the presence of drug concentrations higher than the concentrations in humans receiving therapeutic doses. Such resistance may either be a characteristic associated with the entire species or emerge in strains of a normally susceptible species through mutation or gene transfer. Resistance genes encode various mechanisms which allow microorganisms to resist the inhibitory effects of specific antimicrobials. These mechanisms offer resistance to other antimicrobials of the same class and sometimes to several different antimicrobial classes. All antimicrobial agents have the potential to select drug-resistant subpopulations of microorganisms. With the widespread use of antimicrobials, the prevalence of resistance to each new drug has increased. The prevalence of resistance varies between geographical regions and over time, but sooner or later resistance emerges to every antimicrobial. While much evidence supports the view that the total consumption of antimicrobials is the critical factor in selecting resistance, the relationship between use and resistance is not a simple correlation. In particular, the relative contribution of mode of use (dose, duration of therapy, route of administration, dosage interval) as opposed to total consumption is poorly understood. Paradoxically, underuse through lack of access, inadequate dosing, poor adherence and sub-standard antimicrobials may play as important a role as overuse. There is consensus, however, that the inappropriate use of antimicrobial agents does not achieve the desired therapeutic outcomes and is associated with the emergence of resistance. For this reason, improving use is a priority if the emergence and spread of resistance is to be controlled. Appropriate use of antimicrobials The WHO Global Strategy defines the appropriate use of antimicrobials as the cost-effective use of antimicrobials which maximizes clinical therapeutic effect while minimizing both drug-related toxicity and the development of antimicrobial resistance. The general principles of appropriate antimicrobial use (11) are the same as those for all other medicinal products. An additional dimension for antimicrobials is that therapy for the individual may affect the health of society as a result of the selective pressure exerted by all use of antimicrobial agents. In addition, therapeutic failures due to drug-resistant pathogens or superinfections lead to an increased potential for the spread of these organisms throughout hospitals and the community. Although these risks occur even when antimicrobials are used appropriately, inappropriate use increases the overall selective pressure in favour of drug-resistant microorganisms. The choice of an appropriate antimicrobial agent may be straightforward when the causative pathogen(s) is/are known or can be presumed with some certainty from the patient s clinical presentation. However, in the absence of reliable microbiological diagnosis or when several pathogens may be responsible for the same clinical presentation, empiric treatment, often with broad-spectrum antimicrobials, is common. Ideally, the choice of antimicrobial should be guided by local or national resistance surveillance data and treatment guidelines. The reality is often far removed from this ideal. Surveillance of antimicrobial resistance Surveillance of antimicrobial resistance is essential for providing information on the magnitude and trends in resistance and for monitoring the effect of interventions. The actions taken on the basis of surveillance data will depend on the level at which the data are being collected and analysed. For example, local surveillance data should be used to guide clinical management and to update treat- 15

43 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ ment guidelines, educate prescribers and guide infection control policies. The frequency at which surveillance information is updated is also important given that the rise in prevalence of a resistance phenotype may be rapid and the implementation of policy changes is often slow. Nationally collected surveillance data may be used to inform policy decisions, update national formularies or lists of essential drugs and standard treatment guidelines and evaluate the costeffectiveness of interventions. Since resistance is a global problem, international collation of resistance data may also have a useful role (see Chapter 8). National surveillance systems WHO and its partners have been successful in supporting the surveillance of drug-resistant tuberculosis in many countries (12,13). Despite the many ongoing activities worldwide in monitoring resistance among other bacteria, few countries have well-established national networks that regularly collect and report relevant data. In many developing countries and countries whose economies are in transition, microbiology laboratory facilities and information networks will require considerable strengthening before reliable surveillance of resistance is a reality. Standardization of methods to detect resistance Current methods for monitoring antimicrobial resistance can be classified as in vivo, in vitro and molecular methods. The extent to which each of these is used depends on the pathogen/disease and the facilities available. In vivo methods or therapeutic efficacy tests are the gold standard for monitoring resistance to antimalarial drugs (14) but are not used routinely to monitor resistance in other pathogens. However, linking clinical outcome of treatment with in vitro detection of resistance is of critical importance to understand the predictive value of in vitro tests. In vitro methods are the techniques of choice for monitoring resistance in the vast majority of bacterial pathogens, including Mycobacterium tuberculosis. However, there is no single international standard method. Different methods have gained popularity in different parts of the world at least ten different methods for antimicrobial susceptibility tests are used in Europe and more than twelve worldwide. International quality assurance standards can help to overcome the potential difficulties arising from the use of different methods. Modern techniques have enabled the development and application of molecular methods to determine the presence of specific resistance genes in microbes. They are most widely used to detect genotypic resistance in viruses such as HIV and HBV and, in the future, may form the basis of systems to monitor antiviral resistance. However these molecular methods rely on sophisticated technology that is not available in many settings. Epidemiologically valid patient selection Currently, epidemiological methods are not applied in most resistance surveillance studies. The terms incidence and prevalence tend to be used interchangeably and usually refer to the number of resistant isolates among the total number of isolates surveyed. In contrast, from a public health standpoint, one of the goals of surveillance is to detect the incidence of resistant infections among the total number of infections in a population (15). Further bias arises since tests to detect resistance are performed on a subset of patients presenting for treatment who may be more likely to have failed empiric therapy previously or to have other complications. Much greater epidemiologic rigour and more active surveillance approaches are needed to better understand the impact of resistance. In this respect, surveillance of drug resistance in tuberculosis is more advanced than that of other bacteria (12). Surveillance of antimicrobial resistance is fundamental to understanding trends in resistance, to developing treatment guidelines accurately and to assessing the effectiveness of interventions appropriately. Without adequate surveillance, the majority of efforts to contain emerging antimicrobial resistance will be difficult. The prevalence of resistance The prevalence of resistance varies widely between and within countries, and over time. Data on the prevalence of resistance in acute respiratory infections, diarrhoeal diseases, malaria, tuberculosis and gonorrhoea can be found in recent reviews (16,17,18,19,20,21). Conclusion While it is difficult to quantify the total impact of resistance on health, published data clearly indicate that morbidity and mortality are increased by delays in administering effective treatment for infections caused by resistant pathogens. The pro- 16

44 longed illness and hospitalization of patients with resistant infections and the additional procedures and drugs that they may require carry financial implications. There may also be economic implications for the patient in terms of lost productivity. Antimicrobial-resistant infections in food-producing animals may have major financial implications for both farmers and consumers. In addition, antimicrobial resistance diverts financial resources that could otherwise be used for improving health and threatens the success of global efforts to combat the major infectious diseases of poverty. In this light, implementation of the WHO Global Strategy can be considered appropriate risk management to protect current health care initiatives and the availability of treatment for future generations. BACKGROUND 17

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46 PART B Appropriate antimicrobial use and emerging resistance: issues and interventions

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48 CHAPTER 1 Patients and the general community Recommendations for intervention Education 1.1 Educate patients and the general community on the appropriate use of antimicrobials. 1.2 Educate patients on the importance of measures to prevent infection, such as immunization, vector control, use of bednets, etc. 1.3 Educate patients on simple measures that may reduce transmission of infection in the household and community, such as handwashing, food hygiene, etc. 1.4 Encourage appropriate and informed health care seeking behaviour. 1.5 Educate patients on suitable alternatives to antimicrobials for relief of symptoms and discourage patient self-initiation of treatment, except in specific circumstances. Introduction Patient-related factors are major drivers of inappropriate antimicrobial use and therefore contribute to the increasing prevalence of antimicrobial resistance. In particular, the perception of patients that most episodes of suspected infection require antimicrobial therapy notably influences the prescribing practices of providers. The direct-toconsumer marketing by the pharmaceutical industry increasingly influences patient expectations and behaviour. Patient-related factors that are thought to contribute to the problem of antimicrobial resistance include the following: patients misperceptions self-medication advertising and promotion poor adherence to dosage regimens. Patients misperceptions Many patients believe that most infections, regardless of etiology, respond to antimicrobials and thus expect to receive a prescription from their physician for any perceived infection. In a study by Macfarlane et al., 85% of patients thought their respiratory symptoms were caused by infection and 87% believed that antimicrobials would help. One-fifth of these patients specifically asked their physician to prescribe an antimicrobial (22). Another study showed that patients expectations for a prescription were met 75% of the time by prescribers (23). In a survey of 3610 patients conducted by Branthwaite and Pechère (24), over 50% of interviewees believed that antimicrobials should be prescribed for all respiratory tract infections with the exception of the common cold. It was noted that 81% of patients expected to see a definite improvement in their respiratory symptoms after three days and that 87% believed that feeling better was a good reason for cessation of antimicrobial therapy. Most of these patients also believed that any remaining antimicrobials could be saved for use at a later time. Physicians perceptions of patient expectations are clearly also crucial (see Chapter 2). Many patients believe that new and expensive medications are more efficacious than older agents; this belief is shared by some prescribers and dispensers and often results in the unnecessary use of the newer agents. In addition to causing unnecessary health care expenditure, this practice encourages the selection of resistance to these newer agents as well as to older agents in their class. Patients commonly misunderstand the pharmacological actions of antimicrobial agents. Experience suggests that many people do not know the difference between antimicrobials and other classes of drugs and thus will not understand the issues of resistance uniquely related to antimicrobials. In the Philippines, isoniazid is viewed as a vitamin for the lungs and mothers purchase isoniazid syrup for children with weak lungs in CHAPTER 1. PATIENTS AND THE GENERAL COMMUNITY 21

49 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ the absence of documented tuberculosis (25). Patients also fail to recognize that many brand names may actually be the same antimicrobial resulting in the unnecessary overstocking of some agents. For example, specific patient demand caused one pharmacy in South India to stock more than 25 of the 100 or so brands of co-trimoxazole available (26). A greater interaction between health providers and consumers for health and drug (antimicrobial)-related education has been proposed (27). The WHO Action Programme on Essential Drugs convened a consultation to address the need for public education in rational drug use (28) and has since produced a document Rational Drug Use: Consumer Education and Information (29). This document discusses the practical issues and dilemmas related to the need for rational drug use education, its priority and content, underlying principles and target population. In a study carried out in Peru, a multifaceted educational intervention directed at the community using media, face-to-face meetings and training on the use of medicines was successful in decreasing the inappropriate use of antidiarrhoeals and antimicrobials for simple diarrhoea (30). Self-medication Self-medication with antimicrobials is often cited as a major factor contributing to drug resistance (31). In a Brazilian study, it was determined that the three most common types of medication used by villagers were antimicrobials, analgesics and vitamins. The majority of antimicrobials were prescribed by a pharmacy attendant or were purchased by the patient without prescription (32) despite having prescription-only legal status. In addition to obvious uncertainty as to whether the patient has an illness that will benefit from antimicrobial treatment, self-medicated antimicrobials are often inadequately dosed (33) or may not contain adequate amounts of active drug, especially if they are counterfeit drugs (34). This is especially important in the treatment of diseases such as tuberculosis. Advertising and promotion Direct-to-consumer advertising allows pharmaceutical manufacturers to market medicines directly to the public via television, radio, print media and the Internet. Where permitted, this practice has the potential to stimulate demand by playing on the consumer s relative lack of sophistication about the evidence supporting the use of one treatment over another (35). These advertising methods are apparently quite effective, since pharmacists are frequently able to guess the feature advertisements of the previous day s television programmes based upon daily customer requests for specific medications (31). A survey of physicians in the USA demonstrated that, on average, each had encountered seven patients within the previous six months who had specifically requested prescription-only drugs as a result of direct-to-consumer advertising (36). Over 70% of the physicians reported that requests from patients as a result of direct-to-consumer advertisements had led them to prescribe a pharmaceutical agent that they might not have otherwise chosen. In a telephone survey of consumers regarding direct advertising, 66% believed that advertisements for medications would provide useful information but 88% said that they would seek out more information about a drug that they saw advertised on television or in print before purchasing it. On the other hand, only one-third of interviewees agreed with the statement that most people would know if they were being misled by the advertisements (37). Recently, the United States Food and Drug Administration proposed new guidelines that lift previous restrictions on direct-to-consumer advertising and allow pharmaceutical manufacturers greater freedom on advertised health claims. A two-year evaluation period was proposed to assess the impacts and implications of these guidelines (27). Advertising and promotion can also be used to improve the appropriate use of antibiotics. Public education campaigns in India, which include the use of mass media such as television, appear to have effectively educated even illiterate populations about antimicrobial resistance in some regions (Bhatia, personal communication). Interventions to address the effects of advertising and promotion are discussed in Chapter 7. Poor adherence to dosage regimens In a 1988 literature search, over 4000 English language articles were available on the topic of patient adherence to dosing instructions, more than 75% of which had been published within the previous ten years (38). In the majority of studies, it was reported that a lack of patient understanding and provider communication led to most 22

50 instances of non-adherence (39,40). Patients who fail to complete therapy have a higher likelihood of relapse, development of resistance and need for re-treatment; this applies especially to those patients requiring prolonged treatment, e.g. those with tuberculosis or HIV infection. Previous antimicrobial treatment and excessive duration of treatment are considered two of the most important factors in the selection of resistant microorganisms (41,42). Many methods have been used to ensure adherence to antimicrobial therapy. These include the use of fixed dose combinations to minimize the number of tablets or capsules, special calendars, blister packing, DOT (directly observed therapy) for tuberculosis (12,13,43,44), other course-of-therapy packaging using symbols in labelling, and more simplified therapy (45,46). Directly observed therapy, short-course (DOTS) is the WHO strategy for TB control that has been shown to significantly decrease acquired resistance in tuberculosis (47,48). Education of patients on the name, dosage, description and common adverse effects of their medication(s) has been used to increase adherence (49) (see also Chapter 5, Recommendations). Price is a powerful factor in determining how consumers use antimicrobials economic hardship can lead to early cessation of therapy. For example, antimicrobials are purchased in single doses in many developing countries and are taken for only a fraction of the recommended effective duration, until the patient feels better. This practice has the potential for fostering the selection of resistant microorganisms and therefore has a higher likelihood of treatment failure (50,51). This is especially important for diseases such as tuberculosis and endocarditis (43,52). Government schemes which subsidize the cost of certain preferred antimicrobials are one economic means of improving the appropriateness of antimicrobial use. Where insurance systems exist, charging differential co-payments to patients, with lower payments for the more desirable drugs, may encourage appropriate use. CHAPTER 1. PATIENTS AND THE GENERAL COMMUNITY 23

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52 CHAPTER 2 Prescribers and dispensers CHAPTER 2. PRESCRIBERS AND DISPENSERS Recommendations for intervention Education 2.1 Educate all groups of prescribers and dispensers (including drug sellers) on the importance of appropriate antimicrobial use and containment of antimicrobial resistance. 2.2 Educate all groups of prescribers on disease prevention (including immunization) and infection control issues. 2.3 Promote targeted undergraduate and postgraduate educational programmes on the accurate diagnosis and management of common infections for all health care workers, veterinarians, prescribers and dispensers. 2.4 Encourage prescribers and dispensers to educate patients on antimicrobial use and the importance of adherence to prescribed treatments. 2.5 Educate all groups of prescribers and dispensers on factors that may strongly influence their prescribing habits, such as economic incentives, promotional activities and inducements by the pharmaceutical industry. Management, guidelines and formularies 2.6 Improve antimicrobial use by supervision and support of clinical practices, especially diagnostic and treatment strategies. 2.7 Audit prescribing and dispensing practices and utilize peer group or external standard comparisons to provide feedback and endorsement of appropriate antimicrobial prescribing. 2.8 Encourage development and use of guidelines and treatment algorithms to foster appropriate use of antimicrobials. 2.9 Empower formulary managers to limit antimicrobial use to the prescription of an appropriate range of selected antimicrobials. Regulation 2.10 Link professional registration requirements for prescribers and dispensers to requirements for training and continuing education. Introduction Prevention of infection should be the primary goal to improve health and reduce the need for antimicrobial therapy. Where appropriate, vaccine uptake should be improved to achieve this. Both the emergence and maintenance of resistant microorganisms are promoted by antimicrobial use. Furthermore, once they are widespread, resistant strains are difficult to replace by their susceptible counterparts. Early action to optimize prescribing patterns and to reduce inappropriate use is thus crucial. The difficulty is that multiple factors influence prescribers and dispensers in deciding when to use antimicrobials. These factors appear to vary in importance depending on geographical region, social circumstances and the prevailing health care system. Often, the most important factors are interlinked. Many traditional approaches to improving antimicrobial use rely on providing correct information about drugs or diseases, with the implicit assumption that prescribers and dispensers will incorporate the new knowledge and make appropriate adjustments in their practice. However, experience and reviews of well-designed research studies (53,54,55) have shown that this is rarely the case. Effective interventions to improve antimicrobial use must address the underlying causes of current practice and barriers to change (56). Lack of knowledge and training Lack of knowledge about differential diagnoses, infectious diseases and microbiology and about the appropriate choice of antimicrobials for various infections all play a role in inappropriate prescribing practices (34). Even in developed countries, 25

53 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ the pharmacology of antimicrobial agents, their modes of action and spectrum of activity and issues relating to resistance receive limited coverage in medical school curricula, resulting in poorly informed prescribers (57). It is not uncommon for drug company sales representatives and the commercially oriented publications they provide to be the main sources of information for prescribers (58). Lack of knowledge is a major factor responsible for inappropriate antimicrobial use globally. In one study in China, 63% of antimicrobials selected to treat proven bacterial infections were found to be inappropriate (59). In a retrospective study in Viet Nam, more than 70% of patients were prescribed inadequate dosages (60). Gumodoka et al. (61) reported that one in four patients in their medical districts received antimicrobials by injection and that approximately 70% of these injections were unnecessary. Studies in many European countries and in the USA demonstrate widespread unnecessary use of antimicrobials in patients with viral upper respiratory tract infections (62). Printed materials are the most common and least expensive educational interventions but inappropriate prescribing is rarely due to a lack of knowledge alone. Many studies have found that the use of printed material only, without other forms of supporting interventions, is ineffective in altering prescribing behaviours (63,64,65). Continuing education and in-service training programmes have traditionally involved lectureand seminar-style presentations oriented to the presentation of factual information. A large body of research has shown that these approaches are not necessarily the most effective for improving practice (66). Academic detailing, or unadvertisements, and educational programmes directed to physicians have been shown to decrease antimicrobial use/misuse (67,68,69,70). One consistently successful method has been educational outreach, which consists of brief, targeted, faceto-face educational visits to clinicians by specially trained staff (67,71,72). In developing countries where individual educational outreach visits may not be practical or cost-effective, interactive problem-oriented educational sessions with small groups of physicians, paramedics, or pharmacy counter attendants have demonstrated similar success, especially when sessions are repeated over time or reinforced with improved clinical supervision (53). Another promising approach involves engaging local opinion leaders in the process of disseminating targeted educational messages to their peer group (73,74). Unfortunately, none of these studies looked at resistance as an outcome or impact indicator. Increasing problem-based pharmacotherapy training for medical and paramedical students can have a positive impact on long-term good prescribing habits. The use of a WHO manual (75) designed to support problem-based learning for medical students has been demonstrated to have a positive impact on prescribing skills of students in seven medical schools (76). In countries with limited resources, the dispensing of antimicrobials by unauthorized persons lacking appropriate knowledge is common. In a study of 40 randomly selected health facilities in Ghana, only 8.3% of dispensers had received formal training (77). Bruneton et al. (78) found that drug sellers in seven sub-saharan African countries frequently recommended antimicrobials not present on the regions Essential Drugs List and rarely suggested that the patient should consult a physician. Improving the drug education of non-physician prescribers and dispensers is another recommended step in improving drug use. A study in Ghana showed that educational interventions aimed at dispensers significantly improved drug use by increasing the percentage of appropriately labelled containers and by increasing patient knowledge of their medications (77). Interventions targeted at local drug sellers in the Philippines significantly improved their quality of practice (79). Lack of access to information Even relatively well-trained prescribers often lack the up-to-date information required to make appropriate prescribing decisions. This tends to result in the excessive use of newer antimicrobial agents, often with a broader spectrum of action. Conversely, lack of surveillance data and updated treatment guidelines may lead to the inappropriate prescription of older antimicrobials which are either no longer effective due to the emergence of resistance or should have been replaced by newer agents with improved cost-effectiveness or reduced toxicity. Use of clinical practice guidelines is a core managerial strategy in every health system for improving diagnosis and therapy. Despite the abundance of guidelines, research has shown that they have little effect on clinical practice unless they are actively disseminated (80). Factors that increase the likelihood of guidelines being adopted 26

54 include local involvement of end-users in the process of development, the presentation of key elements in a simple algorithm or protocol, and dissemination in a multi-component programme that includes interactive education, monitoring of adherence and reinforcement of positive changes. A combination of national prescribing guidelines and educational campaigns on the appropriate use of antimicrobials targeted at prescribers has had some success in reducing the prevalence of specific antimicrobial resistance (7). There has also been some success in the use of educational campaigns targeted at prescribers and patients to recognize that not all infections require the use of antimicrobials. Included in one such campaign was a message to parents discouraging them from sending their sick children to day care in order to reduce the opportunities for transmission of infection (81). Lack of diagnostic support Lack of access to or use of appropriate diagnostic facilities and slow or inaccurate diagnostic results encourage prescribers to cover the possibility that infection may be responsible for a patient s illness, even when this is not the case (58). In particular, the lack of accurate tests at point-of-care to achieve a rapid diagnosis is a significant problem for many diseases and is an area in which future research could be very beneficial. Empiric treatment of infections with a reasonably well-defined clinical presentation is more likely to be appropriate than that of infections with an undifferentiated presentation e.g. malaria presenting as fever alone. In this latter situation the differential diagnosis may be wide and therefore empiric treatment protocols will necessarily need to be broad leading to a higher likelihood of unnecessary antimicrobial therapy. A careful history and access to adequate diagnostic facilities allow the differential diagnosis to be narrowed and therapy more targeted. A study of barefoot doctors in a district of Bangladesh found that antimicrobials were prescribed for 60% of all patients seen in areas without diagnostic services a higher rate than noted in other districts (82). Other studies have had similar findings (83,84). In developed countries, empiric antimicrobial therapy is sometimes considered to be more cost-effective than awaiting laboratory proof of infection before commencing treatment. For conditions such as acute respiratory infections, diarrhoea and malaria in children, and sexually transmitted disease in adults, treatment algorithms have been developed (55,85,86). These diagnostic and treatment algorithms are based on detailed research studies, generally in resourcepoor regions, in which the patients clinical presentations have been correlated with subsequent microbiological confirmation of disease. This syndromic approach is particularly useful in health care settings where diagnostic capabilities are limited, since it allows a rational approach to determining the need for antimicrobial therapy and the most appropriate agents. Fear of bad clinical outcomes Prescribers may overuse antimicrobials because they fear that their patients may suffer poor outcomes in the absence of such therapy. Prescribing just to be safe increases when there is diagnostic uncertainty, lack of prescriber knowledge regarding optimal diagnostic approaches, lack of opportunity for patient follow-up, or fear of possible litigation (87,88). Perception of patient demands and preferences Prescribers perceptions regarding patient expectations and demands substantially influence prescribing practices (22,23,58,87,89). Although these perceptions may be incorrect, they can lead to a perpetual cycle whereby patients who repeatedly receive unnecessary antimicrobials develop the misconception that antimicrobials are frequently necessary for most ailments and therefore request them excessively (22,90). Prescribers and dispensers may also respond to patient demand for particular formulations of antimicrobials, e.g. capsules rather than tablets. In some cultural settings, antimicrobials given by injection are considered more efficacious than oral formulations. This tends to be associated with the overprescribing of broadspectrum injectable agents when a narrowspectrum oral agent would be more appropriate (61). In an effort to reduce re-consultation of patients, Macfarlane et al. (23) utilized a patient information leaflet regarding coughs. Among patients not prescribed antimicrobials, those given the educational leaflet appeared less likely to re-consult; this result, however, was not statistically significant. The use of delayed prescribing techniques has been proposed when physicians feel pressured by their patients into prescribing antimicrobials (45,87). Some physicians say that CHAPTER 2. PRESCRIBERS AND DISPENSERS 27

55 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ they promise a free return visit if the patient feels that a re-consultation is necessary because they did not receive antimicrobials (87). Economic incentives Many health providers practise in environments with financial incentives to prescribe or dispense greater numbers of drugs overall or of specific types. Prescribers may fear the potential loss of future patient custom and revenue if they do not respond to perceived demands for antimicrobials (91). Furthermore, in some countries, prescribers profit from both prescribing and dispensing antimicrobials, such that it is in their financial interest to prescribe antimicrobials even when they are not clinically indicated. Additional profit is sometimes gained by recommending newer more expensive antimicrobials in preference to older cheaper agents. In countries where physicians are poorly paid, pharmaceutical companies have been known to pay commissions to prescribers who use their products (92). Other less direct incentives such as financial support for attendance at meetings, entertainment, or payment for enrolling patients in marketing research studies may also influence prescribing practices. Even in health systems where there is no overt incentive to prescribe, there is usually no incentive not to prescribe (8). It is desirable to minimize financial conflicts of interest in therapeutic decision-making by health providers, such as allowing physicians to profit from dispensing drugs that they prescribe or allowing pharmacists who sell drugs to prescribe them as well. Coast et al. (9) and Smith and Coast (93) explored economic perspectives of policies used to decrease antimicrobial resistance. They discuss techniques such as regulation (controlling prescription practices by means of policies and guidelines or by enforcing a global limit to the prescription of antimicrobials), permits (allowing physicians to prescribe up to a certain quantity of antimicrobials per permit) and charges (levying taxes on antimicrobials). In their model, they suggest that the use of permits may offer a method for reducing antimicrobial resistance. Several countries have introduced health provider reimbursement strategies that are designed to encourage physicians to limit overall use of medicines and often to share in the resulting financial savings. Examples of these strategies are capitation payments that include pharmaceutical costs, general practice fundholding (94) and bonuses tied to practice pharmaceutical budgets. While these strategies may reduce inappropriate use of antimicrobials, they may also reduce appropriate use. Nevertheless, a number of Scandinavian studies have suggested that national antibiotic policies together with changes in reimbursement policy can be safe and effective (95,96,97). Peer pressure and social norms In focus group studies, prescribers expressed concern that, if they did not prescribe antimicrobials, patients would seek other sources of care where they could obtain antimicrobials (91). In addition, the physician offering the latest and often the most expensive and broad-spectrum antibiotic may be perceived to be the most informed and desirable source of care. Understanding prescribing patterns is crucial to identifying areas for potential intervention to improve use (58). Drug use patterns and prescribing behaviour, including the influence of various social and patient pressures, can be described using the indicators and methods in the WHO manual How to investigate drug use in health facilities (98). After undertaking interventions to improve drug use, these same indicators can be used to measure impact. Factors associated with the prescriber s working environment In busy clinical practices, health care providers may not have time to explain to patients why they have chosen to prescribe or not prescribe antimicrobial therapy (99). Some clinicians in this situation may believe it is simply most time-effective to prescribe an antimicrobial. Lack of privacy in consultation facilities may also impact on prescribing behaviour since some conditions, such as urinary tract sepsis and sexually transmitted diseases, require diagnostic specimens and/or physical examination that are difficult to undertake in public. The lack of opportunity for health care workers to follow up their patients to assess progress after treatment and poor continuity of care in general negatively influence communication and the development of trust between the patient and health care provider. It is thus often easier for both prescriber and patient if an antimicrobial agent is prescribed on first contact. 28

56 Lack of appropriate legislation or enforcement of legislation Absence of appropriate legislation or its enforcement may result in the proliferation of locations where untrained or poorly trained persons dispense antimicrobials, leading to overuse and inappropriate use (see Chapter 5). Inadequate drug supply infrastructure In many parts of the world, the ability of prescribers and dispensers to provide appropriate antimicrobial therapy is limited by the lack of availability of the necessary drugs (100). CHAPTER 2. PRESCRIBERS AND DISPENSERS 29

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58 CHAPTER 3 Hospitals CHAPTER 3. HOSPITALS Recommendations for intervention Management 3.1 Establish infection control programmes, based on current best practice, with the responsibility for effective management of antimicrobial resistance in hospitals and ensure that all hospitals have access to such a programme. 3.2 Establish effective hospital therapeutics committees with the responsibility for overseeing antimicrobial use in hospitals. 3.3 Develop and regularly update guidelines for antimicrobial treatment and prophylaxis, and hospital antimicrobial formularies. 3.4 Monitor antimicrobial usage, including the quantity and patterns of use, and feedback results to prescribers. Diagnostic laboratories 3.5 Ensure access to microbiology laboratory services that match the level of the hospital, e.g. secondary, tertiary. 3.6 Ensure performance and quality assurance of appropriate diagnostic tests, microbial identification, antimicrobial susceptibility tests of key pathogens, and timely and relevant reporting of results. 3.7 Ensure that laboratory data are recorded, preferably on a database, and are used to produce clinically- and epidemiologically-useful surveillance reports of resistance patterns among common pathogens and infections in a timely manner with feedback to prescribers and to the infection control programme. Interactions with the pharmaceutical industry 3.8 Control and monitor pharmaceutical company promotional activities within the hospital environment and ensure that such activities have educational benefit. Introduction Hospitals are a critical component of the antimicrobial resistance problem worldwide. The combination of highly susceptible patients, intensive and prolonged antimicrobial use, and crossinfection has resulted in nosocomial infections with highly resistant bacterial pathogens such as multi-resistant Gram-negative rods, vancomycinresistant enterococci (VRE) and methicillinresistant Staphylococcus aureus (MRSA) as well as resistant fungal infections. Some of these resistant strains have now spread outside the hospital causing infections in the community. Hospitals are also the eventual site of treatment for many patients with severe infections due to resistant pathogens acquired in the community, including penicillin-resistant Streptococcus pneumoniae, multi-resistant salmonellae and multi-resistant Mycobacterium tuberculosis. In the wake of the AIDS epidemic, the prevalence of such infections can be expected to increase, both in the community and in hospitals. Hospitals can thus serve both as a point of origin of and as a reservoir for highly resistant pathogens which may later enter the community or chronic care facilities. Infection control Transmission of highly resistant bacteria from patient to patient within the hospital environment (nosocomial transmission) amplifies the problem of antimicrobial resistance and may result in the infection of patients who are not receiving antimicrobials. Transmission of antimicrobial-resistant strains from hospital personnel to patients or vice versa may also occur. The key element in minimizing such horizontal transmission of infection within hospitals is careful attention to infection control practices (101). Failure to implement simple infection control practices such as handwashing and changing gloves before and after contact with patients is common (102,103,104,105). In some cases, especially in resource-poor regions, this may be due to the ab- 31

59 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ sence of suitable handwashing facilities. However, inadequate handwashing is generally due to lack of recognition of its importance in maintaining good infection control, understaffing or health care worker forgetfulness. Regardless of the reasons, poor infection control practices result in the increased dissemination of resistant bacterial strains in hospital and health care facilities. The spread of resistance appears to be widening as patients move more rapidly from intensive care wards to general wards and then to the community or between hospitals and nursing homes (51,106,107). Infections can also be transmitted via nonsterile injection and surgical equipment. In a study of health facilities in Tanzania, 40% of supposedly sterilized needles and syringes were bacterially contaminated (61). Poor decontamination or failures in sterilization of equipment can have an enormous impact on the spread of viral infections such as HIV (108), hepatitis B and C. Re-use of single-use needles and syringes has played a major role in the spread of viral hepatitis following immunization programmes in some countries and among intravenous drug users (109,110,111,112). Any practice that permits the spread of infection permits the spread of resistant infections. Infection control activities are best coordinated by an active and effective infection control programme. The SENIC study, conducted by the Centers for Disease Control (CDC) and which included a large sample of hospitals in the USA, demonstrated that hospitals having infection control programmes with both active surveillance and control elements were effective in reducing rates of nosocomial infection (113,114,115). In particular, interventions such as education and motivation programmes, improvement of equipment, and performance feedback can increase adherence to improved handwashing (104). Barrier precautions have been shown to be effective in reducing infection transmission rates and thereby the spread of resistance. Mayer et al. (116) showed that improved handwashing and the use of gloves and gowns decreased infection rates. With respect to the control of antimicrobial resistance within the hospital setting, the major evidence of effectiveness stems from the management of outbreaks or clusters of resistant infections. In these situations, a variety of techniques including targeted cohorting of infected patients, enhanced surveillance, isolation or rigorous barrier precautions, early discharge and alteration in antimicrobial usage have been effective. The key elements of an effective infection control programme include: development and implementation of appropriate barrier precautions (handwashing, wearing of gloves and gowns) and isolation procedures adequate sterilization and disinfection of supplies and equipment the use of aseptic techniques for medical and nursing procedures training of health care personnel in appropriate sterile techniques and infection control procedures maintenance of appropriate disinfection and sanitary control of the hospital environment, including air active surveillance of infections and antimicrobial resistance, with data analysis and feedback to prescribers and other staff recognition and investigation of outbreaks or clusters of infections. The programme should have a qualified chairperson and staff and adequate resources to accomplish these goals. The most effective infection control team consists of a physician (preferably trained in infectious diseases), a microbiologist, infection control nurses, pharmacist(s) and hospital management representatives, with the responsibility for the day-to-day management of resistance issues. Increased efficiency may be achieved by an overlap in the membership of the infection control team and the hospital therapeutics committee. Appropriate facilities for optimal infection control practices, including sufficient basins and clean towels to regularly wash hands between patient contacts, may be difficult to achieve in some countries. Nevertheless, such facilities are vital if nosocomial transmission of infections is to be controlled. Handwashing, isolation practices, sufficient beds (and space between them), as well as clean ventilation are needed in hospitals to prevent the spread of bacteria, including resistant strains. Control of antimicrobial use in hospitals Hospitals provide an important training ground for students to learn about prescribing practices. Unfortunately, antimicrobial prescribing in hospitals is often irrational. In an analysis of prescrib- 32

60 ing practices in ten studies from teaching hospitals worldwide, 41% to 91% of all antimicrobials prescribed were considered inappropriate (117). Patterns of prescribing become entrenched and, if they are not consistent with appropriate antimicrobial treatment guidelines, they may have an enormous effect on the emergence of resistant pathogens and on the pharmacy budget of a hospital if the drugs are expensive. For many clinicians, a common source of information regarding hospital antimicrobial use is the literature provided by pharmaceutical representatives. Such information is less likely to be objective than national or regional treatment guidelines (see Chapter 7). Antimicrobial prophylaxis for surgical procedures is a common reason for excessive prescribing in many hospitals. Numerous studies have outlined those procedures in which patients benefit from such prophylaxis and those in which they do not (118,119,120,121,122,123,124), but inappropriate prophylaxis is still widely used. A further problem is the continuation of antimicrobials, initially administered as prophylaxis, well beyond the required 12 to 24 hour postsurgical period without clear medical indication other than the opinion of the surgeon. Such prescribing patterns result in high rates of antimicrobial exposure among hospitalized patients, potentially leading to high colonization rates of resistant nosocomial pathogens and antibioticassociated diarrhoea. For these reasons a variety of approaches have been utilized to modify antimicrobial prescribing practices within the hospital setting. These have the overall goal of reducing the total consumption of antimicrobials and of altering the type of usage in favour of regimens less likely to foster the emergence of resistant strains. Hospital therapeutics committees An active and effective hospital therapeutics committee is considered a key element for the control of antimicrobial usage in hospitals, although there are only limited published data to support this view and there are few data regarding the impact of hospital therapeutics committees in developing countries. However, their beneficial role in the promotion of rational prescribing habits, monitoring of drug usage and cost containment is well established in developed countries (125,126). For this reason, the establishment of such a committee is considered important. The premise that any clinician should be allowed to use any antimicrobial considered necessary without any peer-review process is generally inconsistent with optimizing antimicrobial use. All clinicians should be prepared to justify their antimicrobial usage patterns. The following activities represent some of the key roles of an effective therapeutics committee. Development of written policies and guidelines for appropriate antimicrobial usage in the hospital, based on local resistance surveillance data. Policies should be developed locally, with broad input and consensus from health care providers and microbiologists. Selection and provision of appropriate antimicrobials in the pharmacy after consideration of local clinical needs. Establishment of formal links with an infection control committee, preferably with some overlap in membership. Definition of an antimicrobial utilization review programme, with audit and feedback on a regular basis to providers, and promotion of active surveillance of the nature and amount of antimicrobial use in the hospital. Overseeing antimicrobial use through a system of monitoring the quantity used and the indications for use. With regard to the last point, it is important to recognize that such seemingly basic data collection can be difficult to undertake accurately, even in the best medical centres. Nevertheless, accurate antimicrobial usage information is crucial to rational decision-making and the interpretation of antimicrobial resistance data. In systems where prescribing data are collected routinely, utilization review (or audit) combined with feedback of performance data to prescribers has become a common strategy to influence patterns of prescribing practice. The success of audit and feedback programmes is mixed (127). Audit and feedback programmes using manually collected samples of prescribing data and simple performance indicators have been successful at improving antibiotic prescribing in some developing country settings (53). Although a decrease in resistance prevalence can be achieved with the use of control programmes, once monitoring is relaxed, the prevalence of drug-resistant organisms may quickly increase again (128). CHAPTER 3. HOSPITALS 33

61 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ Formularies Hospital formularies, or lists of drugs routinely stocked by the hospital pharmacy for inpatient and outpatient use, guide the parallel processes of antimicrobial selection, procurement and supply, and represent a means for decreasing inappropriate antimicrobial prescribing and reducing expenditures. In conjunction with clinical guidelines, formularies encourage the proper use of preferred drugs within each category of antimicrobial. Antimicrobial formularies should relate to local or regional treatment guidelines and should ideally be based on relative efficacy, cost-effectiveness data and local patterns of resistance (129). This, however, is difficult in many hospitals. In a USA survey in which a great majority of hospitals had implemented formularies as a method of decreasing antimicrobial costs, many noted that expenditures actually increased this was usually considered to be due to drug resistance (130). Although some authors have suggested that a restrictive hospital formulary may actually contribute to the selection of resistant bacteria by narrowing and focusing selective pressures, there are few data to support this view (131). Thus, formularies are useful in avoiding the unnecessary keeping in stock of a range of antimicrobials that duplicate their spectrum and in reinforcing the importance for clinicians to understand an appropriate range of antimicrobials well. However, the specific effectiveness of a formulary in reducing the emergence of antimicrobial resistance is unclear. Cycling of antibiotics The cycling of antimicrobials within a health care institution has been suggested as a possible intervention to decrease drug resistance. This technique alternates formulary antimicrobials between drug classes every couple of months and theoretically reduces the selective pressure of one antimicrobial class (132). However, in a recent review of the topic, there was no evidence that cycling reduced antimicrobial resistance (133). Cycling may have only a temporary effect on resistance patterns and ultimately may simply replace one resistance problem with another (134). Use of clinical practice or treatment guidelines Clinical practice guidelines (80) can improve decision-making and therefore improve patient care. They should be developed locally or regionally with wide input and consensus and should utilize information from local surveillance data whenever possible. Programmes that utilize clinical practice guidelines supported by other interventions such as education and peer review are more effective than those without such support (135). In an observational study of one hospital with a computerized prescribing guideline system that encouraged appropriate use of antimicrobials, trend analysis showed that resistance patterns in selected hospital-acquired infections stabilized over a seven-year period (136). Another study noted a reduction in one type of resistance when controls on selected agents were applied, but an increase in resistance to other antimicrobials which were not controlled the so-called squeezing the balloon effect (137). Nevertheless, treatment guidelines are particularly useful in resource-poor countries where they can be used to streamline treatment protocols and limit the range of antimicrobials stocked in pharmacies. However, such treatment guidelines need to be developed carefully and their implementation reviewed regularly. Their appropriateness is dependent on accurate and updated resistance surveillance and clinical outcome data. Other techniques to control or modify antimicrobial use in hospitals Several types of innovative tools to guide antimicrobial prescribing and dispensing have been tested; some have been shown to be effective in changing antimicrobial use in hospital settings. Antimicrobial order forms have been used with mixed success, showing improvement in antimicrobial prescribing in some hospitals but not in others (138,139,140). Automatic review of the use of selected antimicrobials by a consultant or automatic cessation of antimicrobial administration after a defined period may also reduce unnecessary use (46). However, these control measures are either labour-intensive or require reasonably sophisticated computerized pharmacy records both of which are not generally available. Integrated interventions Multi-disciplinary and integrated approaches to reduce antimicrobial use in hospitals have been proposed as a solution (105,141,142,143). Hospital administrators, clinicians, infectious diseases specialists, infection control practitioners, microbiologists, clinical epidemiologists and 34

62 hospital pharmacists all have a role but coordination of their activities is vital. Such activities include the selection of formulary drugs, the development of formulary-based guidelines, monitoring and evaluating drug use, surveillance and reporting of bacterial resistance patterns, detection and appropriate care of patients with resistant organisms, and promotion and monitoring of basic infection control practices (143). Interactions with the pharmaceutical industry must also be considered, including appropriate control of the access of sales representatives to clinical staff and monitoring industry-sponsored educational programmes for providers. Targeted antimicrobial control policies in combination with improved hygiene and education have reduced antimicrobial resistance in some settings (144,145). However, in one study, prescriber education combined with hospital antimicrobial control policies led to decreased antimicrobial costs and improved prescribing, but only limited change in resistance (146). The microbiology laboratory and antimicrobial resistance Delayed or incorrect laboratory diagnostic data frequently result in prolonged empiric antimicrobial therapy (see also Chapters 2 and 5). The hospital microbiology laboratory plays an important role in the recognition and surveillance of antimicrobial resistance, both within the hospital and in the community. The laboratory must provide high quality diagnostic testing to correctly identify infection and accurate antimicrobial susceptibility testing to guide appropriate treatment. Appropriately trained personnel, adequate supplies, materials and equipment, and internal quality control and external quality assurance procedures, are essential. The laboratory should produce and disseminate meaningful local surveillance data both with respect to the predominant pathogens/syndromes and their antimicrobial resistance patterns. The laboratory should work closely with hospital infection control personnel, with the hospital therapeutics committee and with providers to ensure that appropriate antimicrobials are tested and reported in order to recognize outbreaks or unusual infections and identify trends in antimicrobial resistance. Software tools such as WHONET are available to facilitate analysis and data sharing (147). Depending on resources, the laboratory should also provide specialized testing, e.g. molecular typing of bacterial strains, to assist epidemiological investigations. Interactions between the hospital and the community Following discharge from hospital, patients may still be colonized or infected with resistant bacteria acquired in hospital. In general, little action is necessary in such circumstances if the patient is healthy and discharged home. However, this is the likely mechanism through which highly resistant hospital-acquired pathogens eventually become widespread in the community. Of greater concern is the transfer of such patients to chronic care facilities where they have been shown to be the source of strains that subsequently spread throughout the facility. Patients known to be colonized or infected with resistant pathogens upon discharge to a care facility should generally be identified so that appropriate precautions can be taken. CHAPTER 3. HOSPITALS 35

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64 CHAPTER 4 Use of antimicrobials in food-producing animals This topic has been the subject of specific consultations which resulted in WHO global principles for the containment of antimicrobial resistance in animals intended for food *. A complete description of all recommendations is contained in that document and only a summary is reproduced here. Recommendations for intervention Summary 4.1 Require obligatory prescriptions for all antimicrobials used for disease control in food animals. 4.2 In the absence of a public health safety evaluation, terminate or rapidly phase out the use of antimicrobials for growth promotion if they are also used for treatment of humans. 4.3 Create national systems to monitor antimicrobial usage in food animals. 4.4 Introduce pre-licensing safety evaluation of antimicrobials with consideration of potential resistance to human drugs. 4.5 Monitor resistance to identify emerging health problems and take timely corrective actions to protect human health. 4.6 Develop guidelines for veterinarians to reduce overuse and misuse of antimicrobials in food animals. Introduction Antimicrobial use in food-producing animals may affect human health by the presence of drug residues in foods and particularly by the selection of resistant bacteria in animals. The consequences of such selection include: * principles.html an increased risk for resistant pathogens to be transferred to humans by direct contact with animals or through the consumption of contaminated food or water the transfer of resistance genes from animal to human bacterial flora. Increasingly, data suggest that inappropriate antimicrobial use poses an emerging public health risk (148,149,150,151). Factors associated with the emergence of antimicrobial resistance in food-producing animals and the farming industry appear to be similar to those responsible for such resistance in humans. Inadequate understanding about and training on appropriate usage guidelines and the effects of inappropriate antimicrobial use on resistance are common among farmers, veterinary prescribers and dispensers. There are three modes of antimicrobial use in animals prophylaxis, treatment and growth promotion. Overall, the largest quantities of antimicrobials are used as regular supplements for prophylaxis or growth promotion in the feed of animal herds and poultry flocks. This results in the exposure of a large number of animals, irrespective of their health, to frequently subtherapeutic concentrations of antimicrobials (152). Furthermore, a lack of diagnostic services and their perceived high cost means that most therapeutic antimicrobial use in animals is empiric, rather than being based on laboratory-proven disease. For animals and birds that are farmed in large herds or flocks, the identification of a few ill individuals generally results in the entire herd or flock being treated to avoid rapid dissemination and stock losses. Clearly this is a different situation to most human diseases where decisions are generally made about the need for individual therapy, rather than the empiric treatment of an entire population. In addition to these issues, veterinarians in some countries earn as much as 40% or more of their income by the sale of drugs, so there is a disincentive to limit antimicrobial use (153,154). CHAPTER 4. USE OF ANTIMICROBIALS IN FOOD-PRODUCING ANIMALS 37

65 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ As in human medicine, inefficient and inadequately enforced regulatory mechanisms regarding antimicrobial supply contribute to excessive and inappropriate drug use. Discrepancies between regulatory requirements and prescribing/dispensing realities for animal antimicrobial use are often worse than in human medicine (155). In addition, antimicrobials that are used as growth promoters are generally not even considered as drugs and are either not licensed or licensed solely as feed additives. Poor manufacturing quality assurance in some settings results in the supply of sub-standard drugs. Marketing practices of antimicrobials for therapeutic, prophylactic or growth promoter purposes in animals by private industry influence the prescribing patterns and behaviour of veterinarians, feed producers and farmers. In North America and Europe it is estimated that about 50% in tonnage of all antimicrobial production is used in food-producing animals and poultry (156). The increased intensity of meat production under crowded industrialized conditions contributes to the increased use of antimicrobials since they are used in subtherapeutic doses as growth promoters, given as prophylaxis for disease prevention and used therapeutically for the treatment of infected animals. In addition, the impact of antimicrobial metabolites and nonmetabolized drug in animal sewage that is released into the environment is not clear. Use of antimicrobials as growth promoters Some antimicrobials, particularly those that target Gram-positive bacteria, are associated with an increase in the rate of animal growth when they are provided in subtherapeutic quantities in stock feed to food-producing animals. The mechanism of this effect is uncertain. However, these drugs also alter the gut flora of exposed animals such that they frequently contain bacteria that are resistant to the antimicrobial used. When such antimicrobial growth promoters belong to a class similar to that of antimicrobials used in human medicine, these resistant animal bacteria are often also resistant, i.e. cross-resistant, to important human use antimicrobials (157). Five growth promoters (bacitracin, tylosin, spiramycin, virginiamycin and avoparcin [a similar agent to vancomycin]) have recently been banned by the European Union due to fears of such cross-resistance (158,159). Scientific data strongly suggest that avoparcin use in animals contributes to an increased pool of vancomycin-resistant enterococci (VRE) (160, 161). However, the extent to which the microbial gene pool in animals contributes to the prevalence of VRE colonization and infection in humans is less well defined. VRE cause serious infections, mainly in hospitalized immunocompromised patients. Such infections are difficult to cure due to the limited number of effective treatment options and are thus associated with increased morbidity and mortality. There are also concerns that the genes that cause resistance to vancomycin may spread from enterococci to other bacteria, such as Staphylococcus aureus, for which vancomycin is one of the drugs of last resort. Studies in Denmark have shown that the ban of avoparcin in animals has led to a reduction in the prevalence of VRE in poultry and pigs (162,163). Similarly, studies in Germany and the Netherlands suggest that banning avoparcin has led to a reduction in the prevalence of VRE in healthy individuals in the community (164,165). Sweden banned the use of growth promoters in livestock and poultry in 1987 and focused on the implementation of disease prevention methods that did not involve antimicrobials and on the prudent use of antimicrobials for therapeutic purposes. The subsequent national antimicrobial consumption has reduced by approximately 50% (166,167). Furthermore, the prevalence of antimicrobial resistance in pathogenic bacteria isolated from animals in Sweden has been maintained at a low prevalence since 1985 (168). Use of antimicrobials that affect foodborne pathogens such as Salmonella and Campylobacter spp. Non-typhoidal Salmonella spp. and Campylobacter jejuni are among the most commonly identified causes of bacterial diarrhoea in humans. Such species are generally transmitted to humans via food or direct contact with animals (169). Data demonstrate that antimicrobial use in animals selects for resistance among non-typhoidal Salmonella spp., thus limiting the effective available treatment options (170,171,172). A recent example is a clone of Salmonella typhimurium DT104 that has become prevalent in many countries including the UK, Germany and the USA it is resistant to commonly used agents including ampicillin, tetracycline, streptomycin, chloramphenicol and sulphonamides (171,173,174). Multi-drug resistance has likewise been noted in other Salmonella spp. (175). 38

66 Following the introduction of fluoroquinolones for use in food-producing animals, the emergence of Salmonella serotypes with reduced susceptibility to fluoroquinolones has been observed in countries such as France, Germany, Ireland, the Netherlands, the Russian Federation, Spain and the UK (176,177,178). Little has been documented about the impact of this resistance on human health to date, but there is concern about the potential human health consequences. This has been substantiated by a recent outbreak of quinolone-resistant S. typhimurium DT104 resulting in treatment failures in hospitalized patients in Denmark (179). The introduction of fluoroquinolone use in poultry has been associated with a dramatic rise in the prevalence of fluoroquinolone-resistant Campylobacter jejuni isolated in live poultry, poultry meat and from infected humans (180,181, 182). Prior to fluoroquinolone use in poultry, no resistant strains were reported in individuals without previous exposure to these agents (178,183). Because of their broad antibacterial spectrum, fluoroquinolones are often used for empiric treatment of gastrointestinal infections in severely ill or immunocompromised patients. Fluoroquinolone resistance among Campylobacter spp. is associated with a higher rate of clinical treatment failure than for susceptible strains when fluoroquinolones are used for treatment of disease (184,185,186). A recent review by APUA (187) provides further material on this topic. CHAPTER 4. USE OF ANTIMICROBIALS IN FOOD-PRODUCING ANIMALS 39

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68 CHAPTER 5 National governments and health systems Recommendations for intervention Advocacy and intersectoral action 5.1 Make the containment of antimicrobial resistance a national priority. Create a national intersectoral task force (membership to include health care professionals, veterinarians, agriculturalists, pharmaceutical manufacturers, government, media representatives, consumers and other interested parties) to raise awareness about antimicrobial resistance, organize data collection and oversee local task forces. For practical purposes such a task force may need to be a government task force which receives input from multiple sectors. Allocate resources to promote the implementation of interventions to contain resistance. These interventions should include the appropriate utilization of antimicrobial drugs, the control and prevention of infection, and research activities. Develop indicators to monitor and evaluate the impact of the antimicrobial resistance containment strategy. Regulations 5.2 Establish an effective registration scheme for dispensing outlets. 5.3 Limit the availability of antimicrobials to prescription-only status, except in special circumstances when they may be dispensed on the advice of a trained health care professional. 5.4 Link prescription-only status to regulations regarding the sale, supply, dispensing and allowable promotional activities of antimicrobial agents; institute mechanisms to facilitate compliance by practitioners and systems to monitor compliance. 5.5 Ensure that only antimicrobials meeting international standards of quality, safety and efficacy are granted marketing authorization. 5.6 Introduce legal requirements for manufacturers to collect and report data on antimicrobial distribution (including import/export). 5.7 Create economic incentives for the appropriate use of antimicrobials. Policies and guidelines 5.8 Establish and maintain updated national Standard Treatment Guidelines (STGs) and encourage their implementation. 5.9 Establish an Essential Drugs List (EDL) consistent with the national STGs and ensure the accessibility and quality of these drugs Enhance immunization coverage and other disease preventive measures, thereby reducing the need for antimicrobials. Education 5.11 Maximize and maintain the effectiveness of the EDL and STGs by conducting appropriate undergraduate and postgraduate education programmes of health care professionals on the importance of appropriate antimicrobial use and containment of antimicrobial resistance Ensure that prescribers have access to approved prescribing literature on individual drugs. Surveillance of resistance, antimicrobial usage and disease burden 5.13 Designate or develop reference microbiology laboratory facilities to coordinate effective epidemiologically sound surveillance of antimicrobial resistance among common pathogens in the community, hospitals and other health care facilities. The standard of these laboratory facilities should be at least at the level of recommendation 3.6. CHAPTER 5. NATIONAL GOVERNMENTS AND HEALTH SYSTEMS 41

69 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ Adapt and apply WHO model systems for antimicrobial resistance surveillance and ensure data flow to the national intersectoral task force, to authorities responsible for the national STGs and drug policy, and to prescribers Establish systems for monitoring antimicrobial use in hospitals and the community, and link these findings to resistance and disease surveillance data Establish surveillance for key infectious diseases and syndromes according to country priorities, and link this information to other surveillance data. Introduction Placing antimicrobial resistance high on the national agenda should be a priority in tackling the problem of resistance. National governments and health care systems can have considerable impact on limiting the emergence and development of antimicrobial resistance through the introduction of legislation and policies concerning the development, licensing, distribution and sale of antimicrobial agents. Health and pharmaceutical regulations shape the way antimicrobials are used. Key regulatory frameworks include professional licensing, the ability to prescribe and dispense medicines, drug registration, product quality, pricing and movement of drugs in the supply system. Although pharmaceutical regulations represent a powerful tool, implementing them to influence patterns of antimicrobial use can be a two-edged sword, achieving both intended and unintended effects. For example, active enforcement of regulations regarding the sale of antimicrobials without prescription in pharmacies and drug shops may reduce unnecessary use while at the same time limiting access to appropriate therapy, especially among the poor. The unintended effects of proposed regulations should be carefully considered before and monitored during their implementation. National governments also have the responsibility for coordinating surveillance networks and for directing educational efforts to improve understanding about appropriate antimicrobial use. Government legislation drug licensing Marketing authorization Many countries have legislation that requires all medicinal products to undergo licensure before being placed on the market. Marketing authorization usually follows a detailed assessment of data provided by the applicant, generally by a designated government department and sometimes with input from an expert advisory group(s). Some countries are willing to license new medicines based on their prior approval in other countries, such as the USA or EU. Whatever the process, the fundamental requirement is that the data should support the quality, safety and efficacy of the product (188,189). The use of antimicrobials that do not meet appropriate standards in each of these three areas has implications for human health and for antimicrobial resistance. Quality As with all medicinal products, control of the quality of antimicrobial agents is vital for the delivery of accurate dosage units to patients doses that have been shown to be safe and effective in clinical trials (188,189,190). Antimicrobial agents containing less than the stated dose may produce suboptimal levels of circulating drug, which may result in both therapeutic failure and selection of drug-resistant strains. Similar problems may arise as a result of counterfeit products, which commonly contain little or none of the active substance stated on the label and may even contain entirely different active ingredients. The Counterfeit Intelligence Bureau estimated that, in 1991, 5% of all the world s trade was in counterfeit goods, with this percentage likely to be higher for pharmaceuticals since they are easily transportable (191). Excessive drug content may lead to concentrations in the body associated with certain adverse events. Unnecessarily high concentrations may also lead to a marked disruption of the normal flora and an increased risk of superinfections such as fungal disease and C. difficile enterocolitis. Government-initiated inspection of drug manufacturing plants for adherence to Good Manufacturing Practice (GMP) with certification for defined time periods, adherence to the product specifications agreed upon at the time of licensure, and the elimination of unauthorized medicines from the market are essential. Strict controls limiting drug importation and exportation to those products and manufacturers that have been inspected and approved can serve to reduce 42

70 the risks posed by substandard and counterfeit medicines. Countries that carry out spot checks and drug analyses are able to make a major contribution to reducing the production of poor quality and counterfeit products. Safety and efficacy The scope and quality of data presented to support the safety and efficacy of new drugs are determined mainly by the requirements of the US Food and Drug Administration (FDA), the European Commission, and the Japanese Ministry of Health, Labour and Welfare (MHLW) (188,189, 192). The individual regulations issued by these bodies, together with the activities of the International Conference on Harmonisation (193), have greatly influenced the content and conduct of preclinical and clinical development programmes for pharmaceuticals. Dossiers meeting these international standards are generally acceptable worldwide, although there may be additional local stipulations. In this way, all countries may benefit from high quality development programmes that better identify the safety and efficacy of new drugs. In one sense, the emergence of resistance associated with the use of a particular antimicrobial could be viewed as an adverse event. However, current regulatory and licensure bodies do not regard the emergence of resistance in this manner. Countries that do not have systems for the adequate assessment of safety and efficacy before and after drug licensure face an increased risk of exposure to drugs of inferior efficacy and unacceptable toxicity, as well as a potentially higher market penetration of counterfeit drugs. The establishment of Assessment Report Sharing Schemes has facilitated assessment of the safety and efficacy of antimicrobial agents by resourcepoor countries. Participating countries are able to request detailed reports of pharmaceutical, preclinical and clinical data that have been prepared by drug regulatory authorities in other countries. The Product Evaluation Report (PER) network and the arrangements made by the European Agency for the Evaluation of Medicinal Products (EMEA) are examples of schemes which allow countries access to information to assist in making licensing decisions. In addition, regional associations of regulatory bodies, e.g. AFDRAN in Africa, have contributed to the application of similar standards and requirements for drug approvals in many countries. Prescribing information Wherever there are formal procedures for drug licensure, the content of the prescribing information is subject to approval by the licensing authorities. Requirements for international alignment on the essential content of the prescribing information and on the reporting of safety data have led to the development of core datasheets by many pharmaceutical companies (194,195). These describe the minimal prescribing information, including contraindications, warnings and potential adverse reactions, which should be available to users in all countries where the product is marketed. However, it may not be feasible for all companies, especially those that are large and multinational, to regularly audit compliance with the use of core datasheets in all regions or to require that national or regional offices fully adopt stated corporate standards. Also, in countries where there are inadequate regulations to ensure the availability of prescribing information to prescribers and users, health care professionals may have little or no access to independently-assessed material regarding antimicrobial agents (see also Chapters 2 and 7). Failure to specify precisely in the prescribing information the types of infections for which safety and efficacy have been demonstrated in clinical trials may serve to encourage antimicrobial use for conditions that have not been studied. An example is the use of the term lower respiratory infections instead of specifying the types of pneumonia or bronchitis that were studied. Thus, without careful attention to detail and to translation, even the approved prescribing information may inadvertently encourage inappropriate antimicrobial use. The product literature usually reflects the dosage regimens shown to be efficacious in clinical trials for each indication. Identification of optimal antimicrobial treatment regimens for various diseases is important to ensure that the drug is given in an appropriate dose and for an appropriate duration to maximize the likelihood of cure, while minimizing the risk of toxicity. Low dose regimens may be associated with less toxicity, but may result in insufficient drug concentrations at the site of infection to effect bacterial eradication and may therefore encourage the development of resistance among target pathogens. In contrast, higher dose regimens may result in greater effects on the host s normal flora increasing the likelihood of superinfections, including those caused by highly resistant nosocomial pathogens. How- CHAPTER 5. NATIONAL GOVERNMENTS AND HEALTH SYSTEMS 43

71 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ ever, clinical trials to support antimicrobial drug approval are almost always designed to show equivalence to a licensed comparative agent. Therefore there is a tendency to use perhaps unnecessarily high dose or long duration regimens so as to avoid any risk of treatment failure (196, 197,198). Companies are often reluctant to explore a variety of dosage and treatment regimens in clinical trials with a new drug because of the study costs involved and the risk of failing to meet the specified regulatory requirement (199). Dose regimens in clinical trials are often chosen by comparing the pharmacokinetics of the drug in man with the in vitro susceptibilities of the main target pathogens. Increasingly, the pharmacokinetic and pharmacodynamic characteristics of new antimicrobial agents are being used in pre-clinical studies to better predict the optimal clinical dosing regimens in man (200,201,202). While this approach does not replace clinical trials, the pharmaceutical industry and regulatory authorities have both recognized that this may also have benefits in terms of reducing the risk of selecting for drug-resistant organisms. Government legislation control of drug supply, distribution and sales Some countries are unable to control the supply, distribution and sale of medicines. In many regions there is minimal control over public access to antimicrobials and these can be purchased over the counter without prescription (34,203). There are also marked international differences in the types of retail outlets that provide access to prescription-only and non-prescription drugs, as well as whether these outlets require government registration. Where there is adequate legislation regarding the licensure of medicinal products, a legal classification system generally determines the mode of sale, supply and dispensing. In such countries, antimicrobial agents are almost uniformly prescription-only medicines (POM), with dispensing restricted to registered outlets and by suitably qualified personnel (204). In reality, however, the degree of drug law enforcement and the penalties imposed for infringements vary enormously between countries. For example, all systemic antibacterial agents are legally subject to prescription control in the EU, yet they can be purchased over the counter in pharmacies in several EU member states (205). Antimicrobials can be purchased without prescription in many resource-poor countries (59,129,206). In a study of chemist shops in Nairobi, it was noted that 64% of chemists sold antimicrobials without physicians prescriptions and most sold incomplete treatment courses at the request of the patient (207). In a study of a rural village in Bangladesh, 95% of all medications consumed were obtained from pharmacies with only 8% having been prescribed by graduate physicians; one-third of these medications were antimicrobials (208). Poor enforcement of prescription-only regulations is almost universally associated with inappropriate antimicrobial usage. Although the cost of antimicrobial agents without prescription is generally carried by the patient, in some regions this may actually be less expensive than the combined costs of a time-consuming visit to a distant and/or very busy health care facility and the physician s consulting fee. Therefore, depending on the structure and funding of the national health care system, restricting antimicrobial agents to prescription-only may actually limit the access of many patients to these drugs, even when they are really needed. On the other hand, requiring a prescription for access to antimicrobial agents provides an opportunity to dissuade patients from unnecessary antimicrobial therapy and hopefully results in a trained health care worker selecting the drug and the treatment regimen. This potential point of intervention should help reduce inappropriate antimicrobial usage, especially if accompanied by an education programme on the appropriate use of antimicrobial agents (see Chapter 2). With or without implementation of prescription-only access to antimicrobial agents, legislation that restricts the sale of antimicrobials to registered outlets would allow local policing and prevention of over-the-counter non-prescription sales. Ideally, such registered outlets should be staffed by personnel with at least a basic knowledge of antimicrobials. Legislation that compels registered outlets to keep records of the sources of drugs purchased and quantities sold would allow the auditing of antimicrobial sales and possibly of usage data. Such surveillance may result in greater restriction of the sales of counterfeit and substandard medicines. However, in regions where prescribers earn a considerable portion of their income either by directly dispensing antimicrobials or via subsequent pharmacy sales, such legislation is likely to be less effective. These circumstances provide a disincentive to appropriate antimicrobial prescribing and prescribers are more likely to recommend antimicrobial use, particularly the more expensive agents, regardless of whether 44

72 cheaper drugs may be just as appropriate (see also Chapter 2). Government legislation inspection and enforcement The existence of appropriate legislation regarding the manufacture, licensure, sale, supply and dispensing of antimicrobial agents cannot improve the quality and appropriate use of these drugs unless it is enforced. Individual countries may not have the financial or human resources needed to support policing activities by suitably qualified personnel. There may be reluctance on the part of governments to take action because the introduction of restrictions could prove unpopular with patients, physicians and the pharmaceutical industry. Increasing international recognition of inspections of manufacturing plants by teams from other countries has relieved the burden on some governments and facilitated the quality control of medicines and adherence to Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP) and Good Clinical Practice (GCP). The possibility of expanding these international cooperative efforts by using suitably qualified staff from non-governmental organizations (NGOs) to aid policing efforts in other areas of drug law compliance may be worthy of serious consideration by some countries (see also Chapter 8). Health care systems and drug policies Health care systems The organization and funding of health care systems varies between countries, with a mixture of public- and privately-funded health care facilities and diagnostic laboratories being common. The structure and organization of these systems can be an important factor in determining the reliability and practicality of data collection regarding antimicrobial use, surveillance of antimicrobial resistance and the impact of resistance on clinical outcomes. In addition, the system may have a direct influence on undergraduate medical curricula, on the existence and maintenance of registration systems for all health care professionals, and on the attention paid to their continuing professional education and accreditation. Whether or not antimicrobials are prescription-only, undergraduate and postgraduate medical and pharmacist education concerning appropriate antimicrobial use is vital (see Chapter 2), as is the need for evidencebased prescribing information. Surveillance of resistance and antimicrobial use Surveillance of both antimicrobial resistance and antimicrobial use are fundamental to the effective implementation of any strategy for the containment of antimicrobial resistance, as a means to monitor the efficacy of various interventions. However, designing and implementing comprehensive surveillance systems that are practical, costeffective and interlink with the national healthcare system is a challenge. It is likely that in many resource-poor countries, laboratory facilities and information networks will require considerable strengthening before reliable surveillance of resistance can be undertaken. Epidemiologically sound surveillance of resistance in key pathogens, using standardized microbiological methods, may be developed on the basis of an existing laboratory surveillance system for antimicrobial resistance and routine diagnostic microbiology (see Part A, Background). To assist in this aim, WHO is developing Surveillance standards for antimicrobial resistance which propose practical epidemiological methods for several infections and key pathogens (209). Where possible, such surveillance should be integrated with other national and hospital laboratory services to maximize efficiency and ensure surveillance of clinically relevant isolates (see Chapter 3). Measurement of antimicrobial usage could be approached through the registration of outlets that dispense antimicrobials, requiring them to maintain accurate records of antimicrobial supply and sales. Incomplete patient adherence to treatment protocols means that antimicrobial dispensing data will not necessarily be the same as antimicrobial consumption, but it is likely to be the most accurate achievable surrogate available. Targeted research to measure the correlation between the quantity of antimicrobials dispensed and the quantity consumed could be used to adjust national dispensing data, providing a more accurate assessment of antimicrobial consumption. Establishing surveillance systems of antimicrobial usage and control of drug supply and dispensing outlets will require a major commitment from national governments in countries which do not currently have effective prescription-only regulations for antimicrobials. Implementation of an integrated surveillance system for antimicrobial resistance and antimicrobial usage will require national governments to re-assess many regulatory aspects of their health care system, including legislation related to drug licensure (including quality, safety and efficacy) and drug supply, distribution and sales. CHAPTER 5. NATIONAL GOVERNMENTS AND HEALTH SYSTEMS 45

73 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ Essential Drugs Lists and policies In 1977 the first WHO Model List of Essential Drugs was developed to promote the availability of a selected number of drugs, including antimicrobials, and their rational use. The Model List has been revised regularly and serves as a guide for countries in determining their national drug policies. At present over 120 countries have implemented an Essential Drugs List. A retrospective study of prescribing practices in Ethiopia found a significant decrease in the prescribing of nonessential drugs after the introduction of an Essential Drugs List (210). Studies have demonstrated that in those areas in which an Essential Drugs Programme is in operation, significantly more essential drugs are available, significantly fewer injections and antimicrobials are utilized, and drug stocks last about three times longer than in regions without such a programme. Thus, such programmes appear to improve access to essential drugs, especially when they are supported by educational programmes and follow-up (83,117). Establishing national treatment guidelines Evidence-based national treatment guidelines encourage appropriate antimicrobial prescribing. Using local laboratory and clinical surveillance data on antimicrobial resistance, these guidelines can be appropriately modified for community and hospital use in various regions, but should be updated regularly. The use of such guidelines is most effective when combined with supportive interventions such as educational training and supervision programmes (83,211). 46

74 CHAPTER 6 Drug and vaccine development Recommendations for intervention 6.1 Encourage cooperation between industry, government bodies and academic institutions in the search for new drugs and vaccines. 6.2 Encourage drug development programmes which seek to optimize treatment regimens with regard to safety, efficacy and the risk of selecting resistant organisms. 6.3 Provide incentives for industry to invest in the research and development of new antimicrobials. 6.4 Consider establishing or utilizing fast-track marketing authorization for safe new agents. 6.5 Consider using an orphan drug scheme where available and applicable. 6.6 Make available time-limited exclusivity for new formulations and/or indications for use of antimicrobials. 6.7 Align intellectual property rights to provide suitable patent protection for new antimicrobial agents and vaccines. 6.8 Seek innovative partnerships with the pharmaceutical industry to improve access to newer essential drugs. Introduction The pharmaceutical industry is the predominant source of new antimicrobial agents and new disease prevention modalities, including novel vaccines and immunomodulating therapies. It is vital that there are incentives for companies to invest resources into research and development in these areas even though the development of other types of medicinal products may ultimately be more profitable. Encouraging research into vaccines and antimicrobial agents that will predominantly be used in low-resource countries poses particular challenges given the need for pharmaceutical companies to make a profit. However, the continuation and expansion of anti-infective drug and vaccine research is now a crucial issue for all nations given the emergence of antimicrobial resistance among human pathogens. New drug and vaccine development The fact that there are currently several novel antimicrobial agents and vaccines in clinical trials reflects the awareness of the industry of the problems of antimicrobial resistance and the enormous investment by some companies in anti-infective drug development. At the same time, however, there are concerns within the industry that efforts to encourage the more appropriate use of antimicrobials may have a negative impact on sales. This concern may potentially discourage companies from either initiating or maintaining investment in antimicrobial research and development. An overall drop in the antimicrobial-generated revenues of pharmaceutical companies may also influence the quantity of antimicrobial agents and vaccines that they donate, or provide at reduced cost, to some regions of the world. Schemes that encourage investment in antimicrobial and vaccine research must therefore recognize the need for companies to recoup their development costs as well as make a profit from post-licensing sales. A range of incentives to the industry, including both push and pull mechanisms, are currently under discussion (212). Some countries, such as Australia, have devised provisions by which companies which conduct research aimed at identifying new therapies and which perform some sections of the development programme in the home country can benefit from tax reductions and incentive payments. This approach also attracts some companies to establish research facilities in supportive countries, which may have employment and other benefits. Drug discovery may also be stimulated by cooperative research agreements between companies and academic institutions. These agreements can stimulate basic science research and the sharing of knowledge which may speed up the identification CHAPTER 6. DRUG AND VACCINE DEVELOPMENT 47

75 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ of promising compounds or vaccines. This approach may potentially reduce overall costs by reducing the duplication of research activities (see Chapter 8). Public-private partnerships are increasingly being exploited for speeding up drug discovery and development and addressing unmet medical needs where the market opportunities are less attractive (213). Vaccines Vaccines potentially provide a major means of limiting the clinical impact of emerging antimicrobial resistance. Pneumococcal and Haemophilus influenzae type b (Hib) vaccines have had a dramatic effect in reducing the incidence of clinical disease in some age groups and regions (214, 215,216,217). Recent studies of a nonavalent pneumococcal conjugate vaccine demonstrated a significant reduction in the carriage of penicillinresistant and cotrimoxazole-resistant strains of S. pneumoniae in children nine months after vaccination, compared to controls (214). Thus, by reducing the incidence of disease and carriage of resistant strains, pneumococcal vaccination may limit the impact of antimicrobial resistance. When the information is available, knowledge of a patient s vaccination status for pneumococcal, Hib and other diseases may aid the differential diagnosis if the patient presents with an acute illness and thereby allow narrower-spectrum agents to be employed for empiric therapy. Vaccines have also proven effective for some diarrhoeal diseases and enteric fever. A number of typhoid vaccine preparations are now available, but their use has previously been limited mainly to travellers to endemic areas. With the new oral preparations, wider use may now be more feasible once they can be produced at reasonable cost. Given recent outbreaks of ciprofloxacin-resistant typhoid fever, vaccination has been suggested as an adjunct to sanitation measures in some regions (218,219,220,221). Vaccines for other diarrhoeal diseases such as shigellosis, cholera, E. coli ETEC and rotavirus are also under trial (218). As the medical treatment of HIV, hepatitis B and C becomes more widespread, antiviral resistance will become a major limiting factor. Childhood vaccination against hepatitis B, either universal or targeted to high risk groups depending on the prevalence of hepatitis B in the population, is a very cost-effective means of controlling the disease and avoiding the problems of resistance (109,222,223). Effective vaccines against hepatitis C and HIV could likewise have enormous clinical impact. Licensure and patent protection To hasten the licensure of some new products, fasttrack evaluation of innovative medicines is offered by some licensing authorities (188,224), allowing truly innovative products to reach the public domain as early as possible. Such schemes benefit both the companies and the community although careful post-licensure surveillance of adverse effects is vital. Some products may be considered clinically useful but of limited commercial value due to infrequent disease occurrence for these, some countries provide special licensure under an orphan drug scheme which has variable eligibility requirements. The safeguarding of intellectual property rights is a major concern to the pharmaceutical industry. There may be opportunities to encourage research by furthering international agreements and cooperation on innovative new approaches to patents and time-limited exclusivity arrangements. Time-limited exclusivities on new clinically useful formulations and/or additional indications for use on some current agents might serve to stimulate the additional pharmaceutical and clinical studies which are needed to support licensure for these additional indications. Clinical development programmes Clinical development programmes are designed to undertake trials which will support drug registration. These programmes offer possibilities to investigate not only the most effective treatment regimens but also those which are least likely to result in the emergence of antimicrobial resistance. However, these pre-registration clinical trials rarely assess the degree to which in vitro susceptibility data correlate with the in vivo clinical outcomes of infected patients receiving treatment. Although these correlations are of vital clinical importance, such trials can be difficult to perform. In most pre-registration clinical antimicrobial trials, the number of treatment failures is generally too few to allow such assessments and, in any case, the primary goal of these studies is to assess equivalence of efficacy or drug toxicity, not the correlation between in vitro and in vivo outcomes. In addition, a number of design features of licensure studies make such correlations even more difficult. Firstly, some protocols require that enrolled patients found to be infected with pathogens that 48

76 are resistant in vitro to one of the trial drugs should be withdrawn from the study. However, others allow such patients to continue receiving trial therapy if they are doing well, despite in vitro resistance. Such design issues have an important impact on the ability to accurately analyse correlation data. Furthermore, the site of infection may influence the level of antimicrobial penetration and therefore the likely concentrations of active drug available under routine dosing conditions, e.g. drug concentrations in cerebrospinal fluid are generally lower than those achievable in serum. Therefore, in vitro definitions of resistance will depend on potentially achievable drug concentrations in vivo, meaning that the MIC breakpoints for individual pathogens may need to vary depending on the site of infection. Since clinical trials with antimicrobials are almost exclusively designed to demonstrate equivalence to an approved comparative agent, this means that results cannot be used as a basis for recommending one treatment over another. Thus, these studies generally do not provide clear evidence on which to base guidelines for the best choice of antimicrobial or the optimal mode of management of a particular infection. In addition, clinical drug trials have not been designed to determine the most appropriate duration of antimicrobial therapy. Many scientists and clinicians believe that shorter treatment courses for many infections may be as effective as longer courses (225). Potential benefits of shorter course therapies are to decrease disruption of the normal flora and the selective pressure of antimicrobials favouring drug-resistant microorganisms. Shorter durations of therapy are also likely to encourage patient adherence (see Chapter 1). It should be noted that, at the present time, relatively few clinical antimicrobial studies are conducted on paediatric populations and that this may be an area for greater attention in the future. Microbiological and pharmacological issues A number of important microbiological and pharmacological features of antimicrobials appear to influence their likelihood of selecting and promoting resistant strains (51,226). Pharmacodynamic and pharmacokinetic parameters can be used to help identify the optimal dose and dosing intervals for each antimicrobial (202). The parameters most appropriate in terms of encouraging the emergence of resistance have been investigated and debated extensively (132,227,228). In addition, the use of antimicrobials in combinations has been suggested for some infections, since a reduced incidence of resistance has been noted with combination therapy (229,230). Cost-effectiveness Cost-effectiveness studies are increasingly becoming a major component of clinical development programmes. While these are not required for licensure, they may be needed in some countries for negotiations on drug supply contracts. While companies may have some cost-effectiveness data available, few release such data to the public. Many published cost-effectiveness studies are at risk of bias in favour of the new agent, since few studies of older agents, that are often no longer patentprotected, are undertaken due to insufficient research funding support. Furthermore, studies focus neither on the cost of resistance nor on the clinical impact of resistance and there is a need for new approaches to incorporate such evaluations into cost-effectiveness studies (8). Thus, current clinical development programmes rarely support decision-making regarding the cost-effectiveness or optimal dose of various antimicrobials. However, such programmes may provide some unique opportunities to gain more useful information in future if innovative modifications are made to current trial designs. CHAPTER 6. DRUG AND VACCINE DEVELOPMENT 49

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78 CHAPTER 7 Pharmaceutical promotion CHAPTER 7. PHARMACEUTICAL PROMOTION Recommendations for intervention 7.1 Introduce requirements for pharmaceutical companies to comply with national or international codes of practice on promotional activities. 7.2 Ensure that national or international codes of practice cover direct-to-consumer advertising, including advertising on the Internet. 7.3 Institute systems for monitoring compliance with legislation on promotional activities. 7.4 Identify and eliminate economic incentives that encourage inappropriate antimicrobial use. 7.5 Make prescribers aware that promotion in accordance with the datasheet may not necessarily constitute appropriate antimicrobial use. Introduction National governments have an important legislative role in ensuring the appropriate manufacture, licensure and sale of antimicrobials (see Chapter 5) and also an important responsibility in ensuring that these drugs are promoted in a fair and accurate manner. Government controls on drug promotional activities and compliance of the pharmaceutical industry with both legislation and agreed codes of practice are important factors if appropriate antimicrobial use is to be encouraged. The power of promotional activities Promotional activites include drug advertisements in the media and over the Internet, personal contacts during visits from company representatives, sponsored symposia and guest lectures or lecture tours funded by companies, and other inducements to prescribe a particular product or brand. The target audience for promotional activities depends on the product and the local regulatory environment, but generally includes doctors, phar- macists, dentists, nurses and the general community. The close relationships between drug promotion, prescribing habits and drug sales have been demonstrated in several studies (34,231). Since drug promotion increases usage, it may be assumed that it can contribute to the prevalence of antimicrobial resistance, particularly if it results in increased inappropriate use of antimicrobial agents. Promotional literature and prescribing information A number of studies have shown that advertisements and other promotional literature distributed by companies at conferences and symposia are major influential sources of information for health professionals (231,232). Indeed, the content of advertisements and literature provided by companies may be the only readily accessible sources of information on antimicrobial agents in some countries. In the absence of legislation or its enforcement for promotional materials to reflect approved prescribing information, companies may present to potential prescribers, suppliers and users a very selective and biased view of the efficacy and safety of a drug. It has been suggested that physicians may not even be aware of these influences. Avorn et al. (232) found that most prescribers believed that drug advertisements and pharmaceutical representatives played a role of minimal importance in influencing prescribing patterns whereas academic sources of information were very important yet the opposite appeared to be true. This finding was supported by a study of prescribing habits of physicians in Peru (231). The study concluded that advertising materials distributed by pharmaceutical companies appeared to be a key source of information for prescribers, despite claims by more than two-thirds of the physicians surveyed that their primary source of drug information came from medical literature. A review of the literature on the interactions between physicians and the pharmaceutical industry concluded that there was strong evidence that these 51

79 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ interactions influence prescribing behaviour (233). Thus, pharmaceutical promotional material that contains misinformation may ultimately encourage inappropriate antimicrobial use and the emergence of resistance. Promotional materials must not only reflect approved prescribing information correctly but must also be accurate, comprehensive and up to date. Particular difficulties may be encountered with older antimicrobials for which the initially licensed indications may now be considered excessively broad or vague, e.g. upper respiratory infections, and may no longer reflect current thinking on the optimal evidence-based management of certain infections. Although pharmaceutical companies may apply to update sections of the prescribing information, they are unlikely to do so voluntarily if there is a risk of a negative impact on sales. Licensing authorities may require that the prescribing information be updated or modified but are unlikely to do so without strong evidence to support the changes, due to the possibility of a legal challenge from companies. Furthermore, the fact that many older agents are no longer patent-protected means that license holders may not consider that the drug s market value warrants such applications and effort. Prescribers Promotion of products to health professionals informs prescribers about the range of drugs available and alerts them to the availability of new agents. Inherently, pharmaceutical marketing results in the highlighting of potential benefits and advantages of new agents over existing agents to the extent allowable. Under these circumstances it is often difficult for prescribers to identify the most appropriate role of the new agents within the context of existing protocols. Promotional materials often emphasize simple messages in preference to more complex ones, not infrequently resulting in over-prescribing. It is also difficult to regulate the provision of inducements such as meals, event tickets, and travel to conferences. These perks may serve as rewards for using a company s products and as enticements to prescribe newly-introduced drugs (234,235). This may also encourage prescribers to prescribe using brand names rather than generic names, which may markedly increase specific company sales in those countries which do not allow pharmacists to substitute between brands of the same active substance when dispensing prescriptions (see Chapter 2). Patients Health care professionals in all countries, including those subject to prescription control, often feel pressured by patients to prescribe antimicrobials for minor infections which do not need specific therapy (see Chapter 2). Direct-to-public advertisements in countries with prescription-only restrictions on antimicrobial agents may enhance the pressures on health care professionals to prescribe when their clinical judgement suggests that specific therapy is unnecessary. In addition, advertising on the Internet is gaining market penetration yet is difficult to control with legislation due to poor enforceability. To counter this problem, education campaigns directed at health care professionals and the general public are underway in some countries where antimicrobial agents are available by prescription only. The aim of such a campaign in the UK, ongoing in 2000, was to inform all parties about those infections least likely to require antimicrobial treatment thereby reducing patient expectation of the need for an antimicrobial agent. Data on the effects of such efforts are awaited. The effects of direct-to-public promotion on total and specific antimicrobial usage are likely to be much greater in countries where these agents are available without prescription. In these circumstances, even promotion in accordance with the prescribing information is likely to result in unnecessary antimicrobial use as purchasers are less able to fully appreciate the information provided and to weigh the possible risks and benefits. Inappropriate antimicrobial use as a result of overthe-counter availability may therefore be greatly exacerbated by direct-to-public advertising. Sales Pharmaceutical promotion directed towards health care professionals who sell antimicrobials may result in a conflict of interest. The desire to profit from making the sale and/or to favour a particular company s product in expectation of rewards may override clinical judgement. In this manner, the decision regarding the necessity for treatment and the choice of the most suitable agent are less likely to reflect appropriate clinical management. Sales of antimicrobial drugs through outlets not staffed by health care professionals are likely to be driven predominantly by profit margins with only limited potential for control of antimicrobial usage. 52

80 Control of drug promotion Legislation and enforcement Where licensing, supply and sales legislation are in place, the regulation of promotional activities is frequently linked to the legal classification of medicines (236,237,238). In such countries, e.g. the European Union, it is common to restrict the promotion of prescription-only products to health professionals, whereas over-the-counter medicines may be promoted to the general public. Certain countries, e.g. the USA, adopt a middle course by allowing direct promotion to the public while enforcing restricted access to prescription-only products. Promotional activities that are considered acceptable, and the regulations regarding them, vary by country. Any legislation applicable to promotional activities may be supplemented by voluntary codes that have been agreed nationally between companies, or internationally between federations of pharmaceutical companies. Advertisements in peer-reviewed journals, magazines and newspapers and broadcast via radio or television can be reviewed and made subject to controls. However, the advent of advertising on the Internet has provided a means by which companies can circumvent regulations, reaching wide audiences and global markets with unrestrained messages about their products. Codes of practice In addition to legislative control mechanisms, there are various codes of practice regarding appropriate promotional activities that have been drawn up by national and international associations of pharmaceutical companies (239,240,241). Unfortunately, these codes vary between countries and in the manner in which they are executed (235), such that there are many pharmaceutical companies that have not agreed to any such code of practice. When these companies market products in countries in which there is little or no governmental control on promotional activities, there is no way of monitoring the situation and preventing misinformation to health care professionals and to the public. Some pharmaceutical associations carry out inspections of the promotional activities of their members in order to monitor compliance. Companies may also complain to these associations about the activities of rivals when these seem to go beyond the agreed codes of practice. Several non-governmental organizations undertake audits and investigate complaints regarding some forms of promotion (234). Whereas none of these bodies has legal empowerment, they may exert considerable pressure to improve compliance with voluntary codes of practice and internationally accepted standards. Nevertheless, despite these codes and monitoring activities, there is clearly a need for greater effort to ensure that health professionals receive accurate information regarding the efficacy and safety of antimicrobial agents (117) and of the problems of antimicrobial resistance. CHAPTER 7. PHARMACEUTICAL PROMOTION 53

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82 CHAPTER 8 International aspects of containing antimicrobial resistance Recommendations for intervention 8.1 Encourage collaboration between governments, non-governmental organizations, professional societies and international agencies to recognize the importance of antimicrobial resistance, to present consistent, simple and accurate messages regarding the importance of antimicrobial use, antimicrobial resistance and its containment, and to implement strategies to contain resistance. 8.2 Consider the information derived from the surveillance of antimicrobial use and antimicrobial resistance, including the containment thereof, as global public goods for health to which all governments should contribute. 8.3 Encourage governments, non-governmental organizations, professional societies and international agencies to support the establishment of networks, with trained staff and adequate infrastructures, which can undertake epidemiologically valid surveillance of antimicrobial resistance and antimicrobial use to provide information for the optimal containment of resistance. 8.4 Support drug donations in line with the UN interagency guidelines*. 8.5 Encourage the establishment of international inspection teams qualified to conduct valid assessments of pharmaceutical manufacturing plants. 8.6 Support an international approach to the control of counterfeit antimicrobials in line with the WHO guidelines**. * Interagency guidelines. Guidelines for Drug Donations, revised Geneva, World Health Organization, WHO/ EDM/PAR/99.4. **Counterfeit drugs. Guidelines for the development of measures to combat counterfeit drugs. Geneva, World Health Organization, WHO/EDM/QSM/ Encourage innovative approaches to incentives for the development of new pharmaceutical products and vaccines for neglected diseases. 8.8 Establish an international database of potential research funding agencies with an interest in antimicrobial resistance. 8.9 Establish new, and reinforce existing, programmes for researchers to improve the design, preparation and conduct of research to contain antimicrobial resistance. Background the changing global context of public health Multiple global factors are influencing the epidemiology of infectious diseases, the contexts in which they need to be managed, and thus the demands on health care systems. Increasing urbanization, with its associated overcrowding and inadequate housing, poor sanitation and lack of clean water supplies, has a major influence on the burden of infectious disease. Pollution and environmental change, including deforestation, changing weather patterns and desertification, may also affect the incidence and distribution of infectious diseases. Demographic changes resulting in a growing proportion of elderly people and the expanding use of modern medical interventions are increasing the risks of acquiring infections, especially those caused by multi-resistant hospital pathogens. The AIDS epidemic has greatly enlarged the population of immunocompromised patients at risk of infections. Changing patterns of lifestyle also have an effect, e.g. the increase in cigarette smoking in many societies and the consequent increase in associated respiratory diseases, including pneumonia. An increased incidence of infections leads to more antimicrobial use and consequently a greater selection pressure in favour of resistant microorganisms. Furthermore, the increased food requirements of expanding populations may promote an CHAPTER 8. INTERNATIONAL ASPECTS OF CONTAINING ANTIMICROBIAL RESISTANCE 55

83 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ increased use of antimicrobial agents in agriculture, in turn contributing to the emergence of antimicrobial resistance in zoonotic pathogens. Increases in global trade and travel have increased the speed with which both infectious diseases and resistant microorganisms can spread between continents. A call for international cooperative action Containing antimicrobial resistance must involve concerted international action. While the majority of the interventions recommended in earlier chapters of this document are directed at the national level, interventions also need to be undertaken at an international level. It is no longer justifiable for countries to exempt themselves from taking action to contain resistance, since inaction will have both national and international consequences. At the same time it is important to recognize the barriers to action and work to remove them. Antimicrobial resistance is a multi-faceted problem which calls for a multi-sectoral response, but it is a challenge to get all the sectors on board when the magnitude of the problem is unknown. There is a lack of coordination between different groups and disciplines working in this field and even a lack of knowledge that the different groups exist. Thus messages concerning antimicrobial use and resistance are often confusing and conflicting. Many countries lack the money, the skilled professionals and sufficient laboratory capacity to tackle even the definition of the size of the problem of resistance. Closer cooperation between national governments and agencies, professional societies, non-governmental organizations (NGOs) and international agencies would raise the importance of antimicrobial resistance and its threat to health and development up the political agenda and provide additional resources for the implementation of the containment strategy. The development of consistent messages is critical. International organizations and NGOs can be particularly effective in raising the awareness of their members and the public about the importance of antimicrobial resistance and in lobbying governments about the issue so that antimicrobial resistance is seen by governments as being important. By including the containment of antimicrobial resistance in their aims and objectives, relevant NGOs and professional societies can educate their members. Furthermore, such international organizations can encourage both the health and education sectors of national governments to ensure that sufficient education on infectious disease, antimicrobial use and infection control is provided to all students in health care professions. Experience of the successful implementation of interventions to contain resistance is a resource that should not be wasted; sharing information between nations should be given high priority to maximize the success of national strategies. These are areas in which organizations such as WHO can and should play a leading role. A summary of currently available national programmes and strategies to contain antimicrobial resistance is shown in Annex A; some of these have been analysed in more detail (187). Legal issues associated with antimicrobial resistance Existing laws at international level require reporting of a limited number of infectious diseases (242) but do not extend to any systematic reporting of antimicrobial resistance. In the revision of the International Health Regulations (IHR) currently under evaluation, potential international threats posed by resistant infections could be recognized. Some countries have now made certain multiresistant pathogens, e.g. MRSA, notifiable at the national level. However, the global nature of the antimicrobial resistance problem means that national legal measures alone are insufficient. At the same time, the creation of new international duties would be undermined if not incorporated into national law (88). Antimicrobial resistance as a Global Public Good for Health The concept of Global Public Goods for Health (GPGH) and their development to assist in the prevention and containment of communicable diseases is growing in importance (243,244). In the context of the current review by the Commission for Macroeconomics and Health, epidemiologically sound surveillance of antimicrobial use, resistance and the overall burden of infectious diseases is an important component of GPGH. These are public goods which have quasi-universal health benefits in terms of countries, populations and generations, both current and future, or at least meet the needs of current generations without foreclosing development options for future generations (243). Given the increasing ease of trans- 56

84 mission of infectious diseases between populations and across national boundaries, and the importance to future generations of the current development of resistance, antimicrobial resistance is clearly a global public bad for health, with the inverse, i.e. the containment of resistance, thus being a global public good for health. Given that there is no global government as final arbiter, the challenge is to determine how the containment of antimicrobial resistance as a GPGH can be implemented so as to benefit the world s people. The large number of participants, e.g. governments, private sector, NGOs and citizens, complicates coordination of effort, especially in an area such as this where there is significant technical uncertainty. The potential for free riding (nations benefiting from the action of others without reciprocation) and prisoners dilemma (lack of communication resulting in a suboptimal decision for all parties compared to the decision which could have occurred with improved communication) are significant considerations. Thus, identifying who will define the global political agenda, the priorities for resource allocation and the enforcement of penalties if needed, are important international issues if the containment of antimicrobial resistance is to successfully become a GPGH. There are also practical problems in seeking to implement global initiatives under the banner of the GPGH concept. For example, there may be financial and technological barriers to accessing information about containing antimicrobial resistance. Some countries may not be able to collaborate on certain global initiatives, such as surveillance or adhering to certain treatment protocols, due to deficiencies in their health care infrastructure in this context, strengthened health systems may themselves become a GPGH. Nevertheless, GPGH aspects of containment could be of great benefit. For instance, surveillance systems could include mechanisms for alerting governments about the emergence of new resistant strains. The maintenance of a global database regarding antimicrobial resistance could be valuable to individual nations, although the differences worldwide in interpretation of laboratory susceptibility tests currently pose a challenge to this idea. The availability of a database on the distribution of antimicrobials could assist countries, especially those with limited resources, to undertake such data collection independently. Data gathering is likely to be most effective if coordinated, or at least facilitated, internationally. International surveillance Surveillance of antimicrobial resistance and antimicrobial use should be performed at local and national levels to guide clinical management and infection control, to monitor treatment guidelines and to update lists of essential drugs. Surveillance is also a critical tool to monitor the effectiveness of interventions to contain resistance. International collaboration on surveillance may also be of value, to share information as an early warning of new or unusual resistance events. At present there are no formal mechanisms or international legal instruments that require reporting (see above); such resistance events are detected through research studies published in scientific journals. Furthermore, surveillance for rare events such as a new resistance phenotype has different requirements in terms of populations to test and sample size, etc. from those required for routine surveillance. Given the lack of standardization of methods and the worldwide lack of national surveillance systems generating epidemiologically valid data on antimicrobial resistance, the first priority should be at the national level. International organizations and donors should contribute to the strengthening of laboratory capacity in developing countries such that diagnostic services and resistance surveillance can be provided effectively. The development of international surveillance standards is needed for example, WHO antimicrobial resistance surveillance standards (209), WHO guidelines for the management of drug-resistant tuberculosis (245) and WHO protocols for detection of antimalarial drug resistance (14). International agencies, professional societies and the pharmaceutical industry could play a role in defining the mechanisms for the establishment and maintenance of an international resistance alert. In addition, assurance should be sought from the editorial boards of international scientific journals that public notification of an international alert does not jeopardise subsequent publication. International cooperation should also be sought to extend the availability of External Quality Assurance Schemes to resource-poor nations to assist in improving the quality of surveillance data from microbiology laboratories. Antimicrobial quality and availability Drug donations Generous drug donations by pharmaceutical companies, either in the form of actual drug or by release of patent, have had a dramatic effect on the CHAPTER 8. INTERNATIONAL ASPECTS OF CONTAINING ANTIMICROBIAL RESISTANCE 57

85 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ availability of treatment in complex emergencies and in elimination and eradication programmes for certain disabling diseases in resource-poor settings e.g. leprosy, onchocerciasis (river blindness) and lymphatic filariasis. Such donations should be strongly encouraged, but in certain situations may need to be better coordinated to optimize the selection of drugs provided and their distribution and accessibility to avoid duplication and wastage. Donors may inadvertently promote inappropriate use of antimicrobials, thereby contributing to the resistance problem, through supporting donations that are inappropriate in terms of the type and quantity of drug, or because a lack of local infrastructure and capacity prevents the appropriate use of the donated drugs. Thus, donor agencies should ensure that the advice they give to governments in drawing up their national health plans takes into account antimicrobial resistance issues. International action should be taken to ensure that all donations follow the interagency guidelines (246). Alternatively, financial donations to countries to ensure the purchase of the most effective antimicrobials for their needs together with strategies for distribution and use may be more appropriate. International programmes concerned with drug donations should have capacity-building, training and supervision components, and should be evaluated using indicators that are relevant at the community level, i.e. at household and primary health care facility, where most antimicrobial use takes place. International inspections of pharmaceutical manufacturing National quality control of medicines and the monitoring of compliance with Good Manufacturing Practice (GMP) are important to ensure that products meet the required standards. Some countries, e.g. in the EU, already accept findings of inspections that have been performed by appropriately qualified persons from another country. However, not all countries have the resources to perform regular detailed inspections of manufacturing plants; consequently, these do not get inspected unless they are the target of an inspection by a team from another country into which the product(s) is/are exported. In these instances, there may be scope for more extensive sharing of inspection reports between the authorities of the originator country and the inspecting country. It may also be possible to set up international GMP inspection teams, made up of employees of larger agencies who might contribute a limited number of hours per year to the team. Such teams might conduct inspections of a selection of manufacturing sites at the invitation of, and on behalf of, licensing authorities in resource-poor countries. Assessment report sharing schemes Drug licensing authorities in many resource-poor countries are often willing to license new medicines on the basis of their prior approval by other regulatory agencies, e.g. the US FDA or the EU. In other countries, where a formal national review of application dossiers is performed, the assessment of safety and efficacy of new medicinal products has sometimes been assisted by the existence of certain assessment report sharing schemes. Expansion of such schemes might benefit regulatory authorities thereby expediting the licensing of new drugs. The WHO Certification Scheme is an international voluntary agreement, devised to enable countries with limited regulatory capacity to obtain partial assurance from exporting countries concerning the safety, quality and efficacy of the products they plan to import. The scheme requires that the regulatory authorities of exporting countries issue certificates when requested by importing countries. Counterfeits Antimicrobials are among the most frequently counterfeited drugs (191). Such drugs have potentially major clinical consequences in terms of treatment failure and prolonged, or even increased, suffering. Concerted action to reduce the distribution of counterfeit drugs is beyond the scope of this document and will require the implementation of a separate coordinated package of interventions. National and international authorities should collaborate to ensure the enforcement of relevant laws. International codes of good marketing practice Adherence to national and international codes of marketing practices (240) is critical to maintaining and improving the quality and accuracy of drug promotion practices. The effective policing of adherence to these codes of practice requires international commitment, cooperation and supervision (see also Chapter 7). 58

86 Research and development of new drugs and vaccines Research and development of new drugs and vaccines is expensive and time-consuming. The establishment of international research networks and further international cooperation on the standardization of new drug registration requirements could assist pharmaceutical companies with drug development programmes and so facilitate the availability of new drugs and vaccines. International collaboration to improve and standardize clinical trial designs in order to optimize the clinical relevance of the data produced would be helpful. More trials are needed that aim not only to demonstrate equivalence of the new drug to the comparative agent but also to assist in identifying regimens which optimize treatment while minimizing resistance emergence. Such studies are required for products already on the market as well as for new antimicrobials. There is currently a general lack of interest among companies in developing therapies for infections that primarily affect resource-poor regions of the world. Innovative incentives, both push and pull mechanisms, need to be carefully considered in collaboration with the pharmaceutical industry, so as to facilitate research into drugs and vaccines that would have dramatic health benefits but would likely not be profitable to develop. International agreements and cooperation on intellectual property rights, and new approaches to patents and to time-limited exclusivity arrangements should also be considered, particularly as a means to stimulate additional pharmaceutical and clinical studies to support the licensure of older products for additional, previously unregistered, indications. Research to address knowledge gaps Understanding all the issues associated with antimicrobial resistance is probably impossible, but it is clear that there are a number of key knowledge gaps. A clear research agenda highlighting the most important knowledge gaps needs to be defined to guide future research efforts. In this manner, new data that are important to understanding and combating resistance can be channelled back to improve future containment initiatives. To avoid potentially wasteful duplication of effort and finances, international cooperation to develop a common, shared research agenda should be encouraged. Defining a summary of major gaps in the current knowledge regarding antimicrobial resistance and its successful containment, and keeping this summary up to date, could aid this process. The various research-funding bodies have different priorities in terms of geographical and scientific emphasis, and process individual application protocols rather than using one generic format. The creation of a single entry point through which researchers could access information about potential funding agencies, including specific contact details, their areas of interest and application requirements, could be extremely beneficial. This may also assist greater coordination of effort between the various grant-giving bodies and avoid unnecessary duplication. WHO may be well placed to provide such a service if grant-giving bodies were prepared to collaborate. The quality of research proposals is the key to their likelihood of getting funding and producing useful data. Thus, programmes that educate potential researchers on the preparation of highquality research proposals would serve to improve the overall quality of research and reduce wasted research time and money. Greater coordination of international effort to provide such training, either via the Internet or by means of targeted workshops, could be most beneficial. International support for national antimicrobial resistance containment Much of the responsibility for implementing interventions will fall on national governments and there are certain actions that only governments can assure, including the provision of public goods. However, many countries will need significant financial and technical support to address the problem of antimicrobial resistance within the wider priorities of strengthened health systems and disease control and prevention programmes. By directing bilateral support to antimicrobial containment, international donors can play a major role in the containment of antimicrobial resistance, not only for the benefit of individual countries, but for the global good. CHAPTER 8. INTERNATIONAL ASPECTS OF CONTAINING ANTIMICROBIAL RESISTANCE 59

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88 PART C Implementation of the WHO Global Strategy

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90 Implementation of the WHO Global Strategy Introduction To control the most prevalent infectious diseases, especially those that are related to poverty and for which vaccines are not available, antimicrobials need to be used more wisely, and in some cases, more widely. Appropriate access to effective antimicrobial agents is a major public health issue. Although many patients, especially in sub- Saharan Africa, continue to die as a result of inadequate access to antimicrobials, an emerging problem globally is the widespread indiscriminate use of antimicrobials, especially antibacterial agents. As a result, many antimicrobials have now become less effective due to the emergence of resistance. Simply expanding access to antimicrobials is thus not sufficient; priority must also be given to their appropriate use. Antimicrobial resistance affects a very broad range of human diseases, including tuberculosis, malaria, AIDS and infections caused by other bacterial, viral, fungal and parasitic pathogens (12,13,14,43,247,248). Despite this wide range of pathogens, the factors responsible for the emergence of resistance are very similar, with excessive and inappropriate drug usage being the key drivers. Thus the broad management approach to containing antimicrobial resistance is similar for each of these pathogens and diseases, although there are some differences such as clinical presentation, diagnostic difficulty, treatment strategies and resistance detection, which are summarized in Table 1. Effective implementation of the WHO Global Strategy needs to recognize and be coherent with these differences. The various factors identified to be responsible for the emergence of antimicrobial resistance have been discussed in the Part B Issues and interventions, and recommendations for interventions have been developed on the basis of these factors. However, the identification and prioritization of those factors especially relevant in each national and regional context is more difficult. In addition, given the large number of recommendations for intervention (hereafter referred to simply as interventions) set out in the WHO Global Strategy, there is a practical need to identify priorities. The identification of a core set of interventions to contain resistance could provide great assistance to governments and health care workers charged with the responsibility of implementing national policy. Prioritization and implementation STEP 1 The diseases requiring antimicrobial therapy can be used as the basis for the first step in prioritization. National priorities for the containment of antimicrobial resistance can be guided by identifying those diseases that are major problems in the country. On the basis of the evidence used to formulate the WHO Global Strategy, the factors most relevant for antimicrobial resistance in selected diseases can be identified (see Tables 2 5). For each of these factors, those groups of interventions that are likely to be most effective are indicated. In this manner, the process for selecting the necessary interventions to limit emerging antimicrobial resistance can be based on the diseases most prevalent in the country. In some instances, the interventions may be the most challenging to implement. Countries in which all major disease infections are common will need to address all groups of interventions. Bacterial infections (other than tuberculosis) The bacterial infections which contribute most to human disease are also those in which emerging antimicrobial resistance is most evident. In this document they are grouped as four key diseases: diarrhoea (Table 2) respiratory tract infections and meningitis (Table 3) sexually transmitted infections (Table 4) hospital-acquired infections (Table 5) IMPLEMENTATION OF THE WHO GLOBAL STRATEGY 63

91 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ The problems related to resistance to the treatments-of-choice for these diseases are presented in detail in accompanying documents (19,20,21,101). Tables 2 5 summarize the important factors influencing the emergence and spread of resistance and set out the groups of interventions which need to be implemented to make an impact. Tuberculosis Tuberculosis is a leading cause of morbidity and mortality worldwide and resistance to antituberculous therapy has increased dramatically in recent years with evidence of substantive clinical treatment failures and increased person-to-person transmission (12,13,43). The spread of HIV infection, with its associated immunosuppression, has resulted in an enormous increase in TB cases, most frequently among resource-poor communities and in regions with weak health care systems. Inadequate treatment, including insufficient drugs (inadequate supply or mono-therapy), poor quality drugs, and/or poor adherence to treatment regimens have been major factors in the emergence of multi-drug resistant TB (MDR-TB). Although tuberculosis is a bacterial infection, it is considered different enough to warrant a distinct focus. In addition, WHO has initiated approaches to the containment of anti-tuberculosis drug resistance. Faced with the global emergency of tuberculosis, WHO adopted the DOTS (directly observed treatment, short-course) intervention strategy for effective TB control (245,249). The principles of DOTS are the following: government commitment to a National Tuberculosis Programme case detection through case-finding by sputum smear microscopy examination of TB suspects in general health facilities standardized short-course chemotherapy to, at least, all smear-positive TB cases under directly observed therapy (DOT) under proper case management conditions regular uninterrupted supply of all essential anti-tb drugs monitoring system for programme supervision and evaluation. The implementation of DOTS, presently in 119 countries (12,43), prevents the generation of MDR-TB through the cure of drug-susceptible TB patients, who will evolve to MDR-TB if they are not properly treated under a DOTS-based programme. However, the control of existing MDR- TB also has an extremely high priority. The Global Project on Anti-Tuberculosis Drug Resistance Surveillance (managed jointly by WHO and the International Union against Tuberculosis and Lung Disease) has identified high prevalence of MDR-TB in some countries of Eastern Europe, Latin America, Africa, and Asia (12,245,250). MDR-TB does not respond as effectively as drugsusceptible TB to short-course chemotherapy with first-line drugs (48). Therefore, WHO and its partners have launched DOTS-Plus (43,247,251) to manage MDR-TB with second-line drugs. DOTS-Plus includes the five components of DOTS together with other aspects regarding longterm (18 24 months) therapeutic regimens with second-line drugs, and the use of drug susceptibility testing for diagnosis and therapeutic followup. Recommendations for therapeutic regimens for the treatment of MDR-TB were compiled by a panel of experts convened by WHO (245,249). Pilot projects with some of the recommended treatment regimens are underway to assess the feasibility and cost-effectiveness of using secondline drugs under programme conditions. Surveillance for drug resistance at the pilot sites is a prerequisite. Data generated through this initiative will be used to design evidence-based policy guidelines for the management of MDR-TB, which in turn will play a critical role in the containment of drug resistance in tuberculosis. Thus, many of the interventions that will need to be implemented to contain resistance in other bacterial infections, such as political commitment, improvement in national regulatory frameworks, drug distribution and educational initiatives regarding antimicrobial resistance, are in line with, and will further support, current initiatives to contain drug-resistant tuberculosis. Intervention priorities have been identified for tuberculosis (Table 6). Malaria The majority of deaths in malarious areas continue to be due to the lack of drug availability (252). However, emerging resistance is also greatly undermining the efficacy of antimalarial treatment regimens in many regions and is likely to pose a major problem worldwide in the future. As summarized in Table 7, one of the key drivers behind the emergence of antimalarial resistance is poor patient understanding about the 64

92 disease and its appropriate treatment, resulting in indiscriminate short-course therapy with antimalarial agents. In addition, inappropriate prescribing/dispensing and ineffective drug distribution systems encourage such behaviour. The frequent lack of appropriate diagnostic facilities makes the decision to treat difficult, since malaria so frequently presents in an undifferentiated manner, as fever with, or without, headache. Thus, without the ability to confirm the diagnosis, the tendency is to treat every patient with a fever with antimalarials if they reside in a malaria endemic region. Systems for surveillance of antimicrobial resistance are often weak and thus unable to inform about the need to change treatment guidelines. Despite early promising data, it appears that vaccines effective against malaria are still some years away (253). The priority for the containment of antimalarial resistance is thus to concentrate on the implementation of intervention groups 1, 2, 5 and 6. This is in line with WHO policy as expressed in a document in preparation by the WHO Regional Office for Africa (254). Viral infections With the increasing development and use of effective antiretroviral agents, resistance is becoming apparent. In vitro resistance to antiretroviral agents among HIV strains appears to correlate with prior antiretroviral therapy and with clinical treatment failure (255,256,257,258,259). Highly effective combination therapy is considered to be less associated with the emergence of resistance. However, this is a rapidly progressing area of scientific research in which the factors that drive resistance are less clearly defined than for bacterial infections and malaria. As the knowledge base expands, a prioritization of interventions can be developed. At present it seems clear that improved patient and prescriber education (Intervention Groups 1 and 2), government regulations regarding licensure and surveillance of resistance (Intervention Group 5) and issues of drug and vaccine development (Group 6) will all be important. Conclusion of Step 1 Given the disease-specific aspects of containment of antimicrobial resistance associated with tuberculosis, malaria and HIV infections and the programmes already in place, it is proposed that the first phase of implementation of the WHO Global Strategy should be directed to bacterial infections other than tuberculosis. The valuable lessons that will be learned during this first phase should impact on the implementation approaches used for containment of resistance in tuberculosis, malaria and viral infections. However, due to the commonality of factors leading to antimicrobial resistance in all diseases, many of the interventions, instigated for containing resistance in bacterial infections such as political commitment, regulatory framework, laboratory strengthening, surveillance and education will also contribute to resistance containment in other diseases at national level. STEP 2 Defining a core set of interventions to contain antibacterial resistance While prioritization by disease group provides some direction for implementation, the identification of a core set for national implementation is required, within each group of interventions. This is particularly relevant to intervention groups 1, 2, 3, 5 and 7. Issues related to group 4 (use of antimicrobials in food-producing animals) have recently been the subject of an extensive consultative process at WHO and primarily involve interventions in the agricultural industry (2). Thus they are not considered further here. Interventions relating to drug and vaccine development and international aspects of containing antimicrobial resistance are extremely important, but since they depend on supra-national factors, a number of which involve the (multi-national) research-based pharmaceutical industry, their prioritization at national level is less relevant. Implementation of the WHO Global Strategy at national level therefore requires prioritization among interventions in groups 1, 2, 3, 5 and 7. The prioritization presented in Step 3 is based on available evidence (summarized in Part B); where evidence is lacking, it is based on the consensus of a suitably qualified group of experts convened by WHO for this purpose. STEP 3 Intra-group prioritization of interventions Interventions within each group have been prioritized according to the relative merits of each intervention and ranked according to sequence and importance of implementation. This complex task required consideration of multiple factors relating to each intervention including: IMPLEMENTATION OF THE WHO GLOBAL STRATEGY 65

93 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ overall importance of the intervention to improving the appropriate use of antimicrobials and containing antimicrobial resistance likely impact, allowing for the expected cost of implementation complexity of implementation considering the capacity of various health care systems and political realities time required for implementation and the expected lag period before outcomes could be expected the accuracy with which most health care systems could assess the efficacy of each intervention the interrelationship between various interventions, including the need to undertake some interventions in a logical sequence. Inter-group prioritization of interventions Following the prioritization within each group, interventions were ranked according to their overall importance and timing (sequence) of implementation without consideration of their group. Although it was recognized that some priorities might vary depending on the health care system in which they are to be implemented, it was found that this consideration did not impact to any significant extent on the priority given to the majority of very high priority interventions. The results of Step 3 are shown in Table 8. Interventions are grouped according to those which should be undertaken first, through to those which, although important, are either dependent on the implementation of the earlier interventions or are of lower priority. Within each priority i.e. first, second, third, interventions are not ranked but listed in numerical order only and should be considered of equal importance. For example, for group 1, both interventions 1.2 and 1.3 are considered to be of similar priority for implementation, but both 1.2 and 1.3 are given higher priority than either 1.1 (second priority) or 1.4 and 1.5 (third priority). Comparisons across the groups of interventions are more difficult but are important to achieve a logical and effective implementation. Within the national reality, consideration of the sectors involved in implementation of the interventions should allow a plan of action to be elaborated. It must be emphasized that this prioritization process only provides a guide to implementation and is not a rigid set of rules. Differences in national circumstances, health care systems and burden of the different infections may influence the practicality with which some interventions can be implemented and the local importance of one intervention over another in a manner that is not accurately reflected in Table 8. However, Table 8 provides a working guide to the prioritization and sequence of implementation of interventions in groups 1, 2, 3, 5 and 7. Implementation guidelines Effective implementation requires a number of key features, including a clear action plan, delegation of authority and power to act, resources and sound mechanisms to assess the effectiveness of interventions, allowing feedback of results to influence future implementation strategies. Thus, interventions identified in the prioritization process as being of fundamental and first priority (see Table 8) have been considered in greater detail, specifically identifying the following aspects as important for successful implementation: the optimal approach to implementation who should initiate the intervention, undertake and manage the intervention, and evaluate the intervention what process and outcome indicators should be used for evaluation. The proposed guidelines for implementation are detailed in Suggested Model Framework for Implementation of Core Interventions. Monitoring outcomes Ability to monitor the process to ensure that interventions are appropriately designed and targeted and their impact on the use of antimicrobials and the prevalence of resistance will be crucial to the successful implementation of the WHO Global Strategy. Without accurate information about antimicrobial usage and antimicrobial resistance and their respective trends, the impact of interventions will be difficult to interpret. Thus, an early priority in the implementation of the WHO Global Strategy for all countries should be the establishment of an appropriate framework to monitor accurately antimicrobial use and antimicrobial resistance (Intervention Group 5). 66

94 Summary This model implementation plan for the WHO Global Strategy is a guide only. Differences in national circumstances, health care systems and prevalent diseases may influence the approaches taken by governments to contain antimicrobial resistance. However, this is a complex area in which it is often difficult to see the wood for the trees. The stepwise approach described above attempts to highlight the interventions that are most important and to identify a logical sequence for implemention. The manner in which the WHO Global Strategy for Containment of Antimicrobial Resistance is implemented will depend largely on the decisions and actions of each nation, but the consequences are likely to be felt worldwide. IMPLEMENTATION OF THE WHO GLOBAL STRATEGY 67

95 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ Recommendations for intervention 1. PATIENTS AND THE GENERAL COMMUNITY Education 1.1 Educate patients and the general community on the appropriate use of antimicrobials. 1.2 Educate patients on the importance of measures to prevent infection, such as immunization, vector control, use of bednets, etc. 1.3 Educate patients on simple measures that may reduce transmission of infection in the household and community, such as handwashing, food hygiene, etc. 1.4 Encourage appropriate and informed health care seeking behaviour. 1.5 Educate patients on suitable alternatives to antimicrobials for relief of symptoms and discourage patient self-initiation of treatment, except in specific circumstances. 2. PRESCRIBERS AND DISPENSERS Education 2.1 Educate all groups of prescribers and dispensers (including drug sellers) on the importance of appropriate antimicrobial use and containment of antimicrobial resistance. 2.2 Educate all groups of prescribers on disease prevention (including immunization) and infection control issues. 2.3 Promote targeted undergraduate and postgraduate educational programmes on the accurate diagnosis and management of common infections for all health care workers, veterinarians, prescribers and dispensers. 2.4 Encourage prescribers and dispensers to educate patients on antimicrobial use and the importance of adherence to prescribed treatments. 2.5 Educate all groups of prescribers and dispensers on factors that may strongly influence their prescribing habits, such as economic incentives, promotional activities and inducements by the pharmaceutical industry. Management, guidelines and formularies 2.6 Improve antimicrobial use by supervision and support of clinical practices, especially diagnostic and treatment strategies. 2.7 Audit prescribing and dispensing practices and utilize peer group or external standard comparisons to provide feedback and endorsement of appropriate antimicrobial prescribing. 2.8 Encourage development and use of guidelines and treatment algorithms to foster appropriate use of antimicrobials. 2.9 Empower formulary managers to limit antimicrobial use to the prescription of an appropriate range of selected antimicrobials. Regulation 2.10 Link professional registration requirements for prescribers and dispensers to requirements for training and continuing education. 3. HOSPITALS Management 3.1 Establish infection control programmes, based on current best practice, with the responsibility for effective management of antimicrobial resistance in hospitals and ensure that all hospitals have access to such a programme. 3.2 Establish effective hospital therapeutics committees with the responsibility for overseeing antimicrobial use in hospitals. 3.3 Develop and regularly update guidelines for antimicrobial treatment and prophylaxis, and hospital antimicrobial formularies. 3.4 Monitor antimicrobial usage, including the quantity and patterns of use, and feedback results to prescribers. Diagnostic laboratories 3.5 Ensure access to microbiology laboratory services that match the level of the hospital, e.g. secondary, tertiary. 3.6 Ensure performance and quality assurance of appropriate diagnostic tests, microbial identification, antimicrobial susceptibility tests of key pathogens, and timely and relevant reporting of results. 3.7 Ensure that laboratory data are recorded, preferably on a database, and are used to produce clinically- and epidemiologically-useful surveillance reports of resistance patterns among common pathogens and infections in a timely manner with feedback to prescribers and to the infection control programme. Interactions with the pharmaceutical industry 3.8 Control and monitor pharmaceutical company promotional activities within the hospital environment and ensure that such activities have educational benefit. 4. USE OF ANTIMICROBIALS IN FOOD-PRODUCING ANIMALS This topic has been the subject of specific consultations which resulted in WHO global principles for the containment of antimicrobial resistance in animals intended for food *. A complete description of all rec- * principles.html 68

96 ommendations is contained in that document and only a summary is reproduced here. Summary 4.1 Require obligatory prescriptions for all antimicrobials used for disease control in food animals. 4.2 In the absence of a public health safety evaluation, terminate or rapidly phase out the use of antimicrobials for growth promotion if they are also used for treatment of humans. 4.3 Create national systems to monitor antimicrobial usage in food animals. 4.4 Introduce pre-licensing safety evaluation of antimicrobials with consideration of potential resistance to human drugs. 4.5 Monitor resistance to identify emerging health problems and take timely corrective actions to protect human health. 4.6 Develop guidelines for veterinarians to reduce overuse and misuse of antimicrobials in food animals. 5. NATIONAL GOVERNMENTS AND HEALTH SYSTEMS Advocacy and intersectoral action 5.1 Make the containment of antimicrobial resistance a national priority. Create a national intersectoral task force (membership to include health care professionals, veterinarians, agriculturalists, pharmaceutical manufacturers, government, media representatives, consumers and other interested parties) to raise awareness about antimicrobial resistance, organize data collection and oversee local task forces. For practical purposes such a task force may need to be a government task force which receives input from multiple sectors. Allocate resources to promote the implementation of interventions to contain resistance. These interventions should include the appropriate utilization of antimicrobial drugs, the control and prevention of infection, and research activities. Develop indicators to monitor and evaluate the impact of the antimicrobial resistance containment strategy. Regulations 5.2 Establish an effective registration scheme for dispensing outlets. 5.3 Limit the availability of antimicrobials to prescription-only status, except in special circumstances when they may be dispensed on the advice of a trained health care professional. 5.4 Link prescription-only status to regulations regarding the sale, supply, dispensing and allowable promotional activities of antimicrobial agents; institute mechanisms to facilitate compliance by practitioners and systems to monitor compliance. 5.5 Ensure that only antimicrobials meeting international standards of quality, safety and efficacy are granted marketing authorization. 5.6 Introduce legal requirements for manufacturers to collect and report data on antimicrobial distribution (including import/export). 5.7 Create economic incentives for appropriate use of antimicrobials. Policies and guidelines 5.8 Establish and maintain updated national Standard Treatment Guidelines (STGs) and encourage their implementation. 5.9 Establish an Essential Drugs List (EDL) consistent with national STGs and ensure the accessibility and quality of these drugs Enhance immunization coverage and other disease preventive measures, thereby reducing the need for antimicrobials. Education 5.11 Maximize and maintain the effectiveness of the EDL and STGs by conducting appropriate undergraduate and postgraduate education programmes of health care professionals on the importance of appropriate antimicrobial use and containment of antimicrobial resistance Ensure that prescribers have access to approved prescribing literature on individual drugs. Surveillance of resistance, antimicrobial usage and disease burden 5.13 Designate or develop reference microbiology laboratory facilities to coordinate effective epidemiologically sound surveillance of antimicrobial resistance among common pathogens in the community, hospitals and other health care facilities. The standard of these laboratory facilities should be at least at the level of recommendation Adapt and apply WHO model systems for antimicrobial resistance surveillance and ensure data flow to the national intersectoral task force, to authorities responsible for the national STGs and drug policy, and to prescribers Establish systems for monitoring antimicrobial use in hospitals and the community, and link these findings to resistance and disease surveillance data Establish surveillance for key infectious diseases and syndromes according to country priorities, and link this information to other surveillance data. IMPLEMENTATION OF THE WHO GLOBAL STRATEGY 69

97 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ DRUG AND VACCINE DEVELOPMENT 6.1 Encourage cooperation between industry, government bodies and academic institutions in the search for new drugs and vaccines. 6.2 Encourage drug development programmes which seek to optimize treatment regimens with regard to safety, efficacy and the risk of selecting for resistant organisms. 6.3 Provide incentives for industry to invest in the research and development of new antimicrobials. 6.4 Consider establishing or utilizing fast-track marketing authorization for safe new agents. 6.5 Consider using an orphan drug scheme where available and applicable. 6.6 Make available time-limited exclusivity for new formulations and/or indications for use of antimicrobials. 6.7 Align intellectual property rights to provide suitable patent protection for new antimicrobial agents and vaccines. 6.8 Seek innovative partnerships with the pharmaceutical industry to improve access to newer essential drugs. 7 PHARMACEUTICAL PROMOTION 7.1 Introduce requirements for pharmaceutical companies to comply with national or international codes of practice on promotional activities. 7.2 Ensure that national or internationally codes of practice cover direct-to-consumer advertising, including advertising the Internet. 7.3 Institute systems for monitoring compliance with legislation on promotional activities. 7.4 Identify and eliminate economic incentives that encourage inappropriate antimicrobial use. 7.5 Make prescribers aware that promotion in accordance with the datasheet may not necessarily constitute appropriate antimicrobial use. 8. INTERNATIONAL ASPECTS OF CONTAINING ANTIMICROBIAL RESISTANCE 8.1 Encourage collaboration between governments, non-governmental organizations, professional societies and international agencies to recognize the importance of antimicrobial resistance, to present consistent, simple and accurate messages regarding the importance of antimicrobial use, antimicrobial resistance and its containment, and to implement strategies to contain resistance. 8.2 Consider the information derived from the surveillance of antimicrobial use and antimicrobial resistance, including the containment thereof, as global public goods for health to which all governments should contribute. 8.3 Encourage governments, non-governmental organizations, professional societies and international agencies to support the establishment of networks, with trained staff and adequate infrastructures, which can undertake epidemiologically valid surveillance of antimicrobial resistance and antimicrobial use to provide information for the optimal containment of resistance. 8.4 Support drug donations in line with the UN interagency guidelines*. 8.5 Encourage the establishment of international inspection teams qualified to conduct valid assessments of pharmaceutical manufacturing plants. 8.6 Support an international approach to the control of counterfeit antimicrobials in line with the WHO guidelines**. 8.7 Encourage innovative approaches to incentives for the development of new pharmaceutical products and vaccines for neglected diseases. 8.8 Establish an international database of potential research funding agencies with an interest in antimicrobial resistance. 8.9 Establish new, and reinforce existing, programmes for researchers to improve the design, preparation and conduct of research to contain antimicrobial resistance. * Interagency guidelines. Guidelines for Drug Donations, revised Geneva, World Health Organization, WHO/ EDM/PAR/99.4. **Counterfeit drugs. Guidelines for the development of measures to combat counterfeit drugs. Geneva, World Health Organization, WHO/EDM/QSM/

98 TABLE 1. COMPARISON OF DISEASE-RELATED RESISTANCE ISSUES Issues Bacterial infections TB Malaria HIV Appropriate use important Yes Yes Yes Yes Inappropriate use contributes to resistance Yes Yes Yes Yes Need for new drug development Yes Yes Yes Yes Detection of pathogen Reasonably easy Easy Easy Easy & feasible Detection of in vitro resistance Reasonably easy Feasible but Difficult, expensive Difficult, expensive & feasible expensive rarely feasible limited availability IMPLEMENTATION OF THE WHO GLOBAL STRATEGY Treatment indication Generally pathogen- Pathogen-based Frequently Pathogen-based based (± resistance) syndromic Observed treatment No Yes DOT No No Antimicrobial treatment Single agent Multiple agents 1 agent Multiple agents Short duration Long duration Short duration Lifelong HIV interaction Some: Massive: Possibly Especially Personal & nosocomial risk nosocomial risk Potential impact of one Yes Little Some Yes programme on another Some antibiotics Except: e.g. doxycyline, e.g. cotrimoxazole + could affect malaria Rifampicin use on sulphadoxine- isoniazid prophylaxis resistance. Staph. spp. pyrimethamine 71

99 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ TABLE 2. BACTERIAL INFECTIONS (OTHER THAN TUBERCULOSIS): DIARRHOEAL DISEASES Pathogens Important factors Human Human Misuse in animal Surveillance Vaccines misuse in misuse in & agricultural of antibacterial potentially useful the community hospitals industry resistance important future option Campylobacter spp. +/ Shigella spp. ++ +/ ++ Salmonella spp: S. typhi & S. paratyphi Non-typhoidal salmonellae / Vibrio cholerae Diarrhoeal disease overall +/++ ++/ /+ High priority interventions: Group 1 Patients and the general community Group 2 Prescribers and dispensers Group 4 Use of antimicrobials in food-producing animals Group 5 National governments and health systems Group 7 Pharmaceutical promotion High High High Moderate priority priority priority priority Intervention Intervention Intervention Intervention Groups Groups Group Group 1, 2, 5 & 7 4 & TABLE 3. BACTERIAL INFECTIONS (OTHER THAN TUBERCULOSIS): RESPIRATORY TRACT INFECTIONS AND MENINGITIS Pathogens Important factors Human Human Misuse in animal Surveillance Vaccines misuse in misuse in & agricultural of antibacterial potentially useful the community hospitals industry resistance important future option Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitidis Respiratory disease overall / High Moderate High High priority priority priority priority Intervention Intervention Intervention Intervention Groups Groups Group Group 1, 2, 5 & 7 3 & High priority Interventions: Group 1 Patients and the general community Group 2 Prescribers and dispensers Group 5 National governments and health systems Group 6 Drug and vaccine development Group 7 Pharmaceutical promotion 72

100 TABLE 4. BACTERIAL INFECTIONS (OTHER THAN TUBERCULOSIS): SEXUALLY TRANSMITTED INFECTIONS Pathogens Important factors Human Human Misuse in animal Surveillance Vaccines misuse in misuse in & agricultural of antibacterial potentially useful the community hospitals industry resistance important future option Neisseria gonorrhoeae Haemophilus ducreyi Treponema pallidum Chlamydia trachomatis IMPLEMENTATION OF THE WHO GLOBAL STRATEGY Sexually transmitted disease overall High High priority priority Intervention Intervention Groups Group 1, 2, 5 & 7 5 High priority interventions: Group 1 Patients and the general community Group 2 Prescribers and dispensers Group 5 National governments and health systems Group 7 Pharmaceutical promotion TABLE 5. BACTERIAL INFECTIONS (OTHER THAN TUBERCULOSIS) : HOSPITAL-ACQUIRED INFECTIONS Pathogens Important factors Human Human Misuse in animal Surveillance Vaccines misuse in misuse in & agricultural of antibacterial potentially useful the community hospitals industry resistance important future option Gram-positive spp: Staphyloccus aureus Streptococci + Enterococci +++ +/++ ++ Gram-negative spp: Escherichia coli Enterobacter spp Klebsiella spp Pseudomonas aeruginosa Fungi ++ Hospital-acquired infections overall + ++/ High High Moderate High priority priority priority priority Intervention Intervention Intervention Intervention Groups Groups Group Group 1, 2, 5 & 7 3 & High priority interventions: Group 1 Patients and the general community Group 2 Prescribers and dispensers Group 3 Hospitals Group 5 National governments and health systems Group 7 Pharmaceutical promotion 73

101 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ TABLE 6. TUBERCULOSIS Pathogens Important factors Human Human Misuse in animal Surveillance Vaccines misuse in misuse in & agricultural of antibacterial potentially useful the community hospitals industry resistance important future option Mycobacterium tuberculosis / Tuberculosis overall High priority interventions: Group 1 Patients and the general community Group 2 Prescribers and dispensers Group 5 National governments and health systems TABLE 7. MALARIA Pathogens High High Moderate priority priority priority Intervention Intervention Intervention Groups Group Group 1, 2 & Important factors Human Human Misuse in animal Surveillance Vaccines misuse in misuse in & agricultural of antibacterial potentially useful the community hospitals industry resistance important future option Plasmodium vivax / ovale / malariae + + Plasmodium falciparum / Malaria overall / High High Moderate priority priority priority Intervention Intervention Intervention Groups Group Group 1, 2 & High priority interventions: Group 1 Patients and the general community Group 2 Prescribers and dispensers Group 5 National governments and health systems 74

102 TABLE 8. PRIORITIZATION OF INTERVENTIONS: CORE SET FOR NATIONAL IMPLEMENTATION (EXCLUDING GROUPS 4 AND 6) Intervention Group Priority of implementation Fundamental First Second Third 1. Patients and the general community Prescribers and dispensers IMPLEMENTATION OF THE WHO GLOBAL STRATEGY Hospitals National governments and health systems Pharmaceutical promotion

103 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ Suggested model framework for implementation of core interventions (excluding group 4) INTERVENTIONS PRIORITY OF IMPLEMENTATION : FUNDAMENTAL Intervention 5.1 Implementation: Who should initiate: Who should undertake and manage: Make the containment of antimicrobial resistance a national priority. Create a national intersectoral task force (membership to include health care professionals, veterinarians, agriculturalists, pharmaceutical manufacturers, government, media representatives, consumers and other interested parties) to raise awareness about antimicrobial resistance, organize data collection and oversee local task forces. For practical purposes such a task force may need to be a government task force which receives input from multiple sectors. Allocate resources to promote the implementation of interventions to contain resistance. These interventions should include the appropriate utilization of antimicrobial drugs, the control and prevention of infection, and research activities. Develop indicators to monitor and evaluate the impact of the antimicrobial resistance containment strategy. Develop a National Strategy and make it a national priority Ministry of Health Other interested parties should contribute (e.g. Professional Societies) WHO to assist and contribute National Intersectoral Task Force appointed by the Ministry of Health Sufficient resources should be allocated Who should evaluate: Process Indicators: Outcome Indicators: WHO through the Regional Offices Appointment of the National Intersectoral Task Force Allocation of sufficient resources Has a National Strategy been developed? Intervention 5.13 Implementation: Who should initiate: Who should undertake and manage: Who should evaluate: Process Indicators: Outcome Indicators: Designate or develop reference microbiology laboratory facilities to coordinate effective epidemiologically sound surveillance of antimicrobial resistance among common pathogens in the community, hospitals and other health care facilities. The standard of these laboratory facilities should be at least at the level of recommendation 3.6. Establishment by government mandate Ministry of Health Sufficient resources should be allocated Reference laboratories accountable to Government Health Department Internal and external, (e.g. international), quality assurance programmes and performance assessments National Intersectoral Task Force audit Evidence of overseeing national resistance surveillance Documentation of resistance data Regular communication of resistance data to National Intersectoral Task Force and Government Health Department Commitment to teaching and training of laboratory staff including technology transfer 76

104 INTERVENTIONS INTERVENTION PRIORITY: FIRST Intervention 1.2 Implementation: Who should initiate: Who should undertake and manage: Educate patients on the importance of measures to prevent infection, such as immunization, vector control, use of bednets, etc. Develop a National Strategy and make it a national priority Ministry of Health Other interested parties should contribute (e.g. Professional Societies) WHO to assist and contribute National Intersectoral Task Force (e.g. appointed by the Ministry of Health) Sufficient resources should be allocated IMPLEMENTATION OF THE WHO GLOBAL STRATEGY Who should evaluate: Process Indicators: Outcome Indicators: WHO through the Regional Offices Ministry of Health Appointment of the National Intersectoral Task Force Allocation of sufficient resources Has a National Strategy been developed? Immunization rates Intervention 1.3 Implementation: Who should initiate: Who should undertake and manage: Who should evaluate: Process Indicators: Outcome Indicators Educate patients on simple measures that may reduce transmission of infection in the household and community, such as handwashing, food hygiene, etc. Develop a National Strategy and make it a national priority Ministry of Health Other interested parties should contribute (e.g. Professional Societies) WHO to assist and contribute National Intersectoral Task Force (e.g. appointed by the Ministry of Health) Sufficient resources should be allocated WHO through the Regional Offices Ministry of Health Appointment of the National Intersectoral Task Force Allocation of sufficient resources Has a National Strategy been developed? Interventions 2.1 and 2.2 Implementation: Who should initiate: Who should undertake and manage: 2.1 Educate all groups of prescribers and dispensers (including drug sellers) on the importance of appropriate antimicrobial use and containment of antimicrobial resistance. 2.2 Educate all groups of prescribers on disease prevention (including immunization) and infection control issues. Develop a National Strategy and make it a national priority Identify interested organizations and opinion leaders, educators and sources of appropriate information National Intersectoral Task Force Organizations delegated by the National Intersectoral Task Force 77

105 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ INTERVENTIONS INTERVENTION PRIORITY: FIRST (continued) Who should evaluate: Process Indicators: Outcome Indicators: Intervention 2.3 Implementation: Who should initiate: Ministry of Health National Intersectoral Task Force Professional organizations, universities, delegated organizations Opinion leaders identified, quantitative and qualitative assessments of educational exposure Levels of knowledge, attitudes and beliefs about antibiotic use, awareness of antimicrobial resistance and disease prevention issues in target populations Promote targeted undergraduate and postgraduate educational programmes on the accurate diagnosis and management of common infections for all health care workers, veterinarians, prescribers and dispensers. Develop a National Strategy and make it a national priority Identify interested organizations and opinion leaders, educators and sources of appropriate information Create and/or strengthen in-service training, professional development and continuing education for all health care workers appropriate to local context and problems. National Intersectoral Task Force delegating to suitable interested organizations and opinion leaders Who should undertake and manage: Who should evaluate: Process Indicators: Outcome Indicators: Organizations delegated by the National Intersectoral Task Force National Intersectoral Task Force Professional organizations, universities and organizations delegated by the National Intersectoral Task Force Opinion leaders identified Curriculum developed and implemented; quantitative and qualitative assessments of educational exposure Levels of knowledge, attitudes and skills regarding management of common infections and containment of antimicrobial resistance Intervention 2.8 Implementation: Who should initiate: Who should undertake and manage: Who should evaluate: Process Indicators: Outcome Indicators: Encourage development and use of guidelines and treatment algorithms to foster appropriate use of antimicrobials. National Intersectoral Task Force delegating to suitable interested organizations, opinion leaders and educators Use of evidence-based principles of effective guideline development, including maximal participation of health care providers most involved in managing the condition, involvement of end-users, systematic review and appraisal of evidence, involvement of consumers National Intersectoral Task Force Organizations delegated by the National Intersectoral Task Force National Intersectoral Task Force Organizations delegated by the National Intersectoral Task Force Production of guidelines and dissemination plan Level of uptake and indicators of appropriate use of antimicrobials among target health care providers 78

106 INTERVENTIONS INTERVENTION PRIORITY: FIRST (continued) Intervention 3.1 Implementation: Who should initiate: Establish Infection Control Programmes, based on current best practice, with the responsibility for effective management of antimicrobial resistance in hospitals and ensure that all hospitals have access to such a programme. Establishment by government mandate Where possible the infection control programme should be part of hospital (public and private) accreditation Sufficient resources should be allocated for implementation Hospital management delegating to an infection control committee IMPLEMENTATION OF THE WHO GLOBAL STRATEGY Who should undertake and manage: Who should evaluate: Process Indicators: Outcome Indicators: Infection Control Committee National Intersectoral Task Force Ideally, external audit by a competent authority delegated by the National Intersectoral Task Force; in the absence of external evaluation, use benchmarking to other comparable institutions Infection control strategies, policies, guidelines documented Evidence of relevant data collection Data being used to reduce rates of hospital-acquired infection and antimicrobial resistance below an agreed target Intervention 3.5 Implementation: Who should initiate: Who should undertake and manage: Who should evaluate: Ensure access to microbiology laboratory services that match the level of the hospital, e.g. secondary, tertiary. Hospital management, through government if appropriate Sufficient resources should be allocated for establishment and maintenance of laboratories Hospital management in consultation with appropriately trained staff and learned societies Microbiologists, or medical/scientific staff adequately trained in microbiology Benchmarking by Microbiology and Hospital management to other laboratories servicing similar institutions about range of diagnostic and susceptibility tests Process Indicators: Implementation of Recommendations 3.6 and 3.7 Outcome Indicators: Implementation of Recommendations 3.6 and 3.7 Intervention 3.6 Implementation: Who should initiate: Who should undertake and manage: Who should evaluate: Process Indicators: Ensure performance and quality assurance of appropriate diagnostic tests, microbial identification, antimicrobial susceptibility tests of key pathogens, and timely and relevant reporting of results. Microbiology laboratory Microbiology laboratory management Microbiology laboratory management An internal and external (national or international) quality assurance programme National Laboratory accreditation schemes where they exist Evidence of participation in quality assurance activities 79

107 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ INTERVENTIONS INTERVENTION PRIORITY: FIRST (continued) Outcome Indicators: Interventions 5.3 and 5.5 Implementation: Who should initiate: Who should undertake and manage: Who should evaluate: Process Indicators: Performance level in quality assurance activities Continuing laboratory accreditation, where accreditation schemes exist 5.3 Limit the availability of antimicrobials to prescription-only status, except in special circumstances when they may be dispensed on the advice of a trained health care professional. 5.5 Ensure that only antimicrobials meeting international standards of quality, safety and efficacy are granted marketing authorization. Ministry of Health establishing and delegating to a Government Drug Regulation Authority Ministry of Health delegating to a Government Drug Regulation Authority National Intersectoral Task Force Government Drug Regulation Authority National Intersectoral Task Force Ministry of Health via Government Drug Regulation Authority National Intersectoral Task Force Presence of appropriate legislation Categorization of drugs, GMP inspection in place, restriction of drugs to registered outlets Outcome Indicators: Results of Regulations enforcement number of inspections, prosecutions, etc. Interventions 5.8 and 5.9 Implementation: Who should initiate: Who should undertake and manage: Who should evaluate: Process Indicators: Outcome Indicators 5.8 Establish and maintain updated national Standard Treatment Guidelines (STGs) and encourage their implementation. 5.9 Establish an Essential Drugs List (EDL) consistent with the national STGs and ensure the accessibility and quality of these drugs. National Intersectoral Task Force to establish a suitable Committee consisting of interested organizations, opinion leaders and educators Government Drug Regulation Authority National Intersectoral Task Force to establish a suitable Committee consisting of interested organizations, opinion leaders and educators Government Drug Regulation Authority Ministry of Health National Intersectoral Task Force Ministry of Health National Intersectoral Task Force Production of national Standard Treatment Guidelines and EDL Plan for implementation and dissemination Level of uptake, including indicators of appropriate use of antimicrobials among target health care providers and use of EDLs 80

108 INTERVENTIONS INTERVENTION PRIORITY: FIRST (continued) Intervention 5.11 Implementation: Who should initiate: Maximize and maintain the effectiveness of the EDL and STGs by conducting appropriate undergraduate and postgraduate education programmes of health care professionals on the importance of appropriate antimicrobial use and containment of antimicrobial resistance. Ministry of Health National Intersectoral Task Force delegating to universities and other training institutions, including suitable interested organizations, opinion leaders and educators Ministry of Health National Intersectoral Task Force IMPLEMENTATION OF THE WHO GLOBAL STRATEGY Who should undertake and manage: Who should evaluate: Process Indicators: Outcome Indicators: Training institutions and organizations delegated by the National Intersectoral Task Force Professional bodies responsible for registration of health care professionals National Intersectoral Task Force Training institutions and organizations delegated by the National Intersectoral Task Force Curriculum developed and implemented; quantitative and qualitative assessments of educational exposure Presence of specific registration requirements for health care professionals Levels of knowledge, attitudes and skills regarding appropriate antimicrobial use and containment of antimicrobial resistance Assessment of Registration suitability based on continuing education on antimicrobial use and containment of antimicrobial resistance 81

109

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120 Annexes

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122 ANNEX A National Action Plans ANNEX A Canada: European Union: France: Norway: Sweden: United Kingdom: USA (Centers for Disease Control and Prevention, Atlanta): 95

123 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ ANNEX B Participation in WHO Consultations WHO Global Strategy for the Containment of Antimicrobial Resistance Workshop to develop the framework document (260) Geneva, 4 5 February 1999 List of participants Dr Tasleem Akhtar, Pakistan Medical Research Council, Shahnaki-e-Jamurait Sector G5/2, Islamabad, Pakistan Dr Susan Bacheller, Office of Health and Nutrition, USAID/G/PHN/HN/HPSR, Washington, USA Dr Richard Bax, Director and Vice-President, Antiinfective Therapeutic Unit, Clinical Research and Development, SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK Dr Tom Bergan, President, International Society of Chemotherapy, Institute of Medical Microbiology, Rikshospitalet (National Hospital), Oslo, Norway Dr Nancy Blum, United States Pharmacopeia, Rockville, USA Dr Otto Cars, Department of Infectious Diseases, Uppsala University Hospital, Uppsala, Sweden Dr Keryn Christiansen, Clinical Microbiologist, Department of Microbiology & Infectious Diseases, Royal Perth Hospital, Western Australia Dr Andres de Francisco, International Health Specialist, Global Forum for Health Research, c/o World Health Organization, 1211 Geneva 27, Switzerland Dr David Fidler, Indiana University School of Law, 211 South Indiana Avenue, Bloomington IN , USA Professor Widjoseno Gardjito, Department of Surgery, Dr Soetomo Hospital, Jalan Professor Dr Moestopo 6 8, Surabaya 60286, Indonesia Dr Judy Gilley, (British Medical Association), Cornwall House Surgery, Cornwall Road, London N3 1LD, UK Dr Neal Halsey, Director of Division of Disease Control, Johns Hopkins University, Baltimore, USA Professor Pentti Huovinen, Antimicrobial Research Laboratories, National Public Health Institute, Turku, Finland Dr Keith Klugman, The South African Institute for Medical Research, PO Box 1038, Johannesburg 2000, South Africa Dr Richard Laing, Associate Professor, Department of International Health, Boston University School of Public Health, 715 Albany St, Boston, MA , USA Dr David Lee, Deputy Director, Drug Management Program, Management Sciences for Health, Arlington, USA Dr Joel Lexchin, 121 Walmer Road, Toronto, Canada Dr Donald E Low, Microbiologist-in-Chief, Mount Sinai Hospital, The Toronto Hospital, Toronto, Canada Dr Peter Mansfield, Director, MaLAM, Australia Dr Shaheen Mehtar, Western Cape, South Africa Dr Le Van Phung, Central Biomedical Laboratory, Hanoi Medical School, Hanoi, Vietnam Dr Mair Powell, Medicines Control Agency, Market Towers, Room 1534, 1 Nine Elms Lane, London, UK Dr Gro Ramster Wesenberg, Norwegian Medicine Control Authority, Sven Oftedsalsvei 6, Oslo 0950, Norway Dr Dennis Ross-Degnan, DACP, Drug Policy Research Group, Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, USA Dr Budiono Santoso, Department of Clinical Pharmacology, Faculty of Medicine, Gadjah Mada University Sekip, Yogyakarta, Indonesia Dr Anthony Savelli, Director, Rational Pharmaceutical Management, Management Sciences for Health, Arlington, USA Dr Ben Schwartz, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, USA Dr Wing Hong Seto, Department of Microbiology, Queen Mary Hospital, Hong Kong Dr Walter Stamm, Head, Division of Allergy and Infectious Diseases, University of Washington, Seattle, USA Professor Mark Steinhoff, Department of International Health, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, USA 96

124 Dr J Todd Weber, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, USA Dr H Wegener, Danish Zoonosis Centre, National Veterinary Laboratory, Copenhagen, Denmark Professor M Wierup, Swedish Animal Health Service, Johanneshov, Sweden Representatives from USAID Dr Susan Bacheller Dr Anthony Boni Dr Caryn Miller WHO Global Strategy for the Containment of Antimicrobial Resistance Prioritization and Implementation Workshop Geneva, September 2000 List of participants Dr Samuel Azatyan, Head of the Department of Pharmacovigilance and Rational Use of Drugs, Armenian Drug and Medical Technology Agency (ADMTA), Yerevan, Armenia Dr Luis Bavestrello, Infectious Diseases Specialist and Clinical Pharmacologist, Jefe, Unidad de infectología, Hospital dr. Gustavo Fricke, Viña del Mar, Chile Dr Mike Bennish, Director, Africa Centre for Health and Population Studies, Mtubatuba, South Africa Dr Richard E Besser, Respiratory Diseases Branch (C- 23), Centers for Disease Control and Prevention, Atlanta, USA Dr Christopher C Butler, Senior Lecturer, Department of General Practice, University of Wales College of Medicine, Llanedeyrn Health Centre, Cardiff, UK Dr John Chalker, Management Services for Health, Arlington, USA Professor Ranjit Roy Chaudhury, National Institute of Immunology, Shahid Jeet Sing Marg, New Delhi, India Dr Narong Chayakula, Secretary General, Food and Drug Administration, Ministry of Public Health, Muang, Nonthaburi, Thailand Professor Thomas Cherian, Christian Medical College, Vellore, India Mrs Parichard Chirachanakul, Food and Drug Administration, Ministry of Public Health, Muang, Nonthaburi, Thailand Dr Scott Fridkin, Medical Epidemiologist, Hospital Infections Program (E-55), Centers for Disease Control and Prevention, Atlanta, USA Dr Marcelo F Galas, Profesional Servicio Antimicrobianos, Instituto Nacional de Enferme-dades Infecciosas ANLIS Dr. Carlos G. Malbran, Buenos Aires, Argentina Dr Manuel Guzmán-Blanco, President of the Committee on Antibiotics of the Sociedad Panamericana de Infectología, (Pan American Society of Infectious Diseases), Unidad de Microbiología y Enf. Infecciosas, Hospital Vargas, Centro Médico de Caracas, Caracas, Venezuela Professor King Holmes, University of Washington, Harborview Medical Center, Seattle, USA Dr Abdulrahman Hassan Ishag, Hospitals Administration, Department of Curative Medicine, Ministry of Health, Riyadh, Kingdom of Saudi Arabia Professor KK Kafle, Institute of Medicine, TU Teaching Hospital, Kathmandu, Nepal Dr Adeeba Kamarulzaman, Associate Professor, Head, Infectious Diseases Unit, Department of Medicine, University Malaya, Kuala Lumpur, Malaysia Dr Göran Kronvall, Clinical Microbiology MTC, Karolinska Hospital, Stockholm, Sweden Dr David Lee, Deputy Director, Drug Management Program, Management Services for Health, Arlington, USA Dra Alina Llop, Directora del Laboratorio Nacional de Referencia de Microbiología, Sub-Directora Instituto Medicina Tropical Pedro Kouri, La Habana, Cuba Mrs Precious Matsoso, Department of Health, Pretoria, South Africa Dr Thomas O Brien, Microbiology Laboratory, Brigham and Women s Hospital, Boston, USA Dr David Ofori Adjei, Director, Nogouchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra, Ghana Dr Philip Onyebujo, Department of Health, Pretoria, South Africa Associate Professor Neil Paget, Royal Australasian College of Physicians, Sydney, Australia Dr Ricardo Pérez-Cuevas, Investigador Asociado, Unidad de Investigacion Epidemiologica y en Servicios de Salud CMN Siglo XXI, Instituto Mexicano del Seguro Social, Mexico, Mexico Dr Mair Powell, Medical Assessor, Licensing Division, Department of Health, Medicines Control Agency, London, UK Dr Dennis Ross-Degnan, Associate Professor, Drug Policy Research Group, Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, USA Professor Sidorenko Sergei, Department of Microbiology, Russia Medical Academy of Postgraduate Studies, National Research Centre of Antibiotics, Moscow, Russia ANNEX B 97

125 WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICROBIAL RESISTANCE WHO/CDS/CSR/DRS/ Dr Richard Smith, Senior Lecturer, Health Economics Group, School of Health Policy and Practice, University of East Anglia, Norwich, UK Soeparmanto, Dr Sri Astuti S, Kepala Badan Litbang Kesehatan, Head, National Institute of Health Research and Development, Jakarta, Indonesia Dr Christian Trigoso, Head of the Bacteriology Department, Instituto de Laboratorio de Salud, La Paz, Bolivia Dr Peet Tüll, Medical Director, Division of Communicable Diseases Control, The National Board of Health and Welfare, Stockholm, Sweden Associate Professor John Turnidge, Women s and Children s Hospital, North Adelaide, Australia Dr Kris Weerasuriya, Professor of Pharmacology and Secretary of the Drug Evaluation Sub-Committee (DESC), Ministry of Health, Department of Pharmacology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka Representatives from WHO Regional Offices Dr Massimo Ciotti, Communicable Diseases, WHO Regional Office for Europe, Copenhagen Dr Sudarshan Kumari, Regional Advisor, Blood Safety and Clinical Technology, WHO Regional Office for South East Asia, New Delhi, India WHO Meeting on International Aspects of the Containment of Antimicrobial Resistance Geneva, January 2001 List of participants Alliance for the Prudent Use of Antibiotics (APUA) Kathleen T Young, Executive Director, Boston, USA American International Health Alliance Thomas O Brien, Head, Department of Microbiology, Brigham and Women s Hospital, Boston, USA James P Smith, Executive Director, Washington, USA Centers for Disease Control and Prevention (CDC) David Bell, Assistant to the Director for Antimicrobial Resistance, National Center for Infectious Diseases, Atlanta, USA Conféderation Mondiale de L Industrie de la Santé Animale (COMISA) Anthony J Mudd, Vice President/Secretary General, Representative Body of the Worldwide Animal Health Industry, Brussels, Belgium European Commission Luxembourg Hartmut Buchow, Euroforum Building, Luxembourg European Society for Clinical Microbiology and Infectious Disease (ESCMID) Peter Schoch, ESCMID Basel, Switzerland Global Forum for Health Research Andres De Francisco, Senior Public Health Specialist, c/o World Health Organization, Geneva, Switzerland International Association of Medical Laboratory Technologists (IAMLT) Martha A Hjálmarsdóttir, President, Reykjavík, Iceland International Committee of the Red Cross Ann Aerts, Head of Health Services, Geneva, Switzerland International Council of Nurses Tesfamicael Ghebrehiwet, ICN Consultant, Nursing & Health Policy, Geneva, Switzerland International Council of Women Pnina Herzog Ph. C.M.R. Pharm.S., President, Jerusalem, Israel International Federation of Infection Control (IFIC) Anna Hambraeus, Division for Hospital Control, University Hospital, Uppsala, Sweden International Federation of Pharmaceutical Manufacturers Association (IFPMA) Peter Hohl, Pharma Research Preclinical Infectious Diseases, F. Hoffmann La Roche Ltd, Basel, Switzerland Patricia Hogan, Senior Manager, Pfizer Inc., New York, USA Tony White, Anti-Infectives Strategic Product Development, Smithkline Beecham Pharmaceuticals, Harlow, Essex,UK International Pharmaceutical Federation (FIP) Diane Gal, FIP Project Coordinator, Den Haag, The Netherlands International Society of Chemotherapy Jean-Claude Pechère, Secrétaire général, Université de Génétique et Microbiologie, Université de Geneva CHU, Geneva 4, Switzerland International Society for Infectious Diseases (ISID) Keryn Christiansen, Co-Chair, ISID Antibiotic Task Force, Department Microbiology and Infectious Diseases, Royal Perth Hospital, Perth, Australia Permanent Mission of Norway to the United Nations Office and other International Organizations at Geneva O Christiansen, Counsellor, Geneva, Switzerland The Wellcome Trust Robert E Howells, Director of Science Programmes, London, UK Richard Lane, Head of International Programmes, London, UK 98

126 UNICEF Abdel W El Abassi, UNICEF, New York, USA USAID Rational Pharmaceutical Management Project John Chalker, Arlington, USA UK Department of Health Jane Leese, Senior Medical Officer, Skipton House, London, UK US Department of Health and Human Services /National Institute of Allergy and Infectious Diseases Marissa A Miller, Antimicrobial Resistance Program Officer, Bethesda, Maryland, USA World Self-Medication Industry (WSMI) Jerome A Reinstein, Director-General, London, UK World Trade Organization João Magalhães, Counsellor, Agriculture and Commodities Division, Centre William Rappard, Geneva, Switzerland World Veterinary Association Herbert P Schneider, Vice-President, AGRIVET Consultants, Windhoek, Namibia WHO Temporary Advisors M Lindsay Grayson, Austin and Repatriation Medical Centre, Melbourne, Australia Stuart B Levy, President APUA, Boston, USA Jean-Claude Pechère, also representing the International Society of Chemotherapy Mair Powell, Medicines Control Agency, London, UK Richard Smith, School of Health Policy and Practice, University of East Anglia, Norwich, UK Representatives from WHO David Heymann, Executive Director, Communicable Diseases Guénaël Rodier, Director CSR Hans Troedsson, Director CAH ANNEX B 99

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128 WHO Policy Perspectives on Medicines 10 Containing antimicrobial resistance April 2005 World Health Organization Geneva The problem of antimicrobial resistance Antimicrobial resistance (AMR) is one of the world s most serious public health problems. Many of the microbes (bacteria, viruses, protozoa) that cause infectious disease no longer respond to common antimicrobial drugs (antibacterial drugs including antibiotics, antiviral and antiprotozoal drugs). The problem is so serious that unless concerted action is taken worldwide, we run the risk of returning to the pre-antibiotic era when many more children than now died of infectious diseases and major surgery was impossible due to the risk of infection. The major infectious diseases kill over 11 million people per year. Box 1 shows some AMR prevalence rates, which can vary widely between and within countries, and over time. Box 1 AMR global prevalence rates Malaria chloroquine resistance in 81/92 countries Tuberculosis (TB) 0 17% primary multi-drug resistance HIV/AIDS 0 25% primary resistance to at least one antiretroviral drug Gonorrhoea 5 98% penicillin resistance in Neisseria gonorrhoeae Pneumonia and bacterial meningitis 0 70% penicillin resistance in Streptococcus pneumoniae Diarrhoea: shigellosis 10 90% ampicillin resistance, 5 95% cotrimoxazole resistance Hospital infections 0 70% resistance of Staphylococcus aureus to all penicillins and cephalosporins Source: WHO country data, Emergence of AMR is a natural phenomenon that follows use of antimicrobials but it is being accelerated by inappropriate antimicrobial use. Higher consumption is associated with higher resistance levels (Fig.1). Estimates suggest that perhaps half of all antibiotic consumption may be unnecessary. In many countries, antimicrobials are bought directly from drug outlets without a prescription or advice from a trained health professional. Figure 1 Correlation between penicillin-resistant (non-susceptible) pneumococci and out-patient antibiotic use (showing bands with 95% confidence intervals) Penicillin-resistant S.pneumoniae (%) Taiwan, China Greece Spain Portugal France Total antibiotic use (DDD/1000 population/day) Doctors response to AMR has been to switch patients from older antibiotics to newer ones, but new development of these is declining as the pharmaceutical industry has shifted from antibiotics to developing other medicines with potentially larger markets (e.g. for chronic non-infectious illness). Even if new antibiotics are developed, resistance to them would also develop; so prudent use of antibiotics is essential to maintain their effectiveness for future generations. Serious clinical and financial consequences result from AMR. Morbidity and mortality are increased by delays in administering effective treatment for infections caused by resistant microorganisms. Prolonged illness and hospitalisation are costly and the use of drugs other than first-line drugs may increase costs 100-fold (Fig. 2) making them unaffordable for many USA Canada Ireland Luxembourg Iceland Austria Belgium Italy Germany UK Australia Sweden Denmark Finland Netherlands Norway Source: Albrich WC, Monnet DL and Harbarth S, Emerg Infect Dis.; 2004; 10(3):514 7 Page 1: WHO Policy Perspectives on Medicines Containing antimicrobial resistance

129 Figure 2 Cost ratio of alternative drugs to firstline antimicrobials for common acute infections Cost ratio to first-line drug Gonorrhoea Malaria Shigellosis Pneumonia Cost per patient with first-line drug (US$) Source: Adapted from WHO Model Formulary, WHO clinical guidelines and Management Sciences for Health s 2004 International Drug Price Indicator Guide governments and patients especially in developing countries. Measuring the problem through surveillance Surveillance is critical to containing the problem of AMR and requires monitoring over time the magnitude and trends in AMR and antimicrobial use and using the data to design interventions and measure their impact. Epidemiological surveillance of antimicrobial resistance Resistance varies widely with geographical location, type of community and level of health facility. Therefore local surveillance data should be used to guide clinical management and update clinical guidelines, educate prescribers and guide infection control policies. Data should distinguish between hospital nosocomial and community-acquired infections and should exclude duplicate isolates from the same patient. A national antimicrobial surveillance system should consist of: national reference microbiology laboratory facilities to coordinate epidemiologically sound surveillance of AMR in common pathogens in the community, hospitals and other health care facilities; a network of laboratories, all with adequate internal and external quality assurance, that regularly collect and report relevant resistance data and provide quality microbiological diagnostic services. Surveillance of antimicrobial use Antimicrobial use should be monitored in terms of the type and degree of irrational use and several Alternative drugs 4th 3rd 2nd well-established methods exist. Aggregate antimicrobial drug consumption data can be used to identify the most expensive and highly used antimicrobials, or to compare actual consumption with expected consumption (from morbidity data). Anatomical Therapeutic Classification (ATC) / Defined Daily Dose (DDD) methodology can be used to compare antimicrobial consumption across institutions, regions and countries. Indicators can be used to investigate antimicrobial use in primary health care, e.g.: % patients prescribed antibiotics; % of upper respiratory tract cases (usually viral) treated with antibiotics; % of diarrhoeal cases (usually viral) treated with antibiotics; % cases with infections treated in accordance with clinical guidelines. Focused antimicrobial use evaluation (drug utilization review) can identify problems concerning the use of specific antimicrobials or the treatment of specific infections, particularly in hospitals. Reasons underlying inappropriate use should be investigated intermittently and include diagnostic insecurity, prescriber knowledge and habit, unrestricted availability of antimicrobials, overwork, inappropriate promotion of antimicrobials, profit motives and fear of litigation. Understanding such reasons allows appropriate, effective corrective strategies to be chosen. Core national strategies to contain AMR Core national strategies to contain AMR are summarised below, based on WHO s Global Strategy for Containment of AMR and Promoting Rational Use of Medicines: Core Components. 1. Mandated multidisciplinary national task force to coordinate policies and strategies to contain AMR Many factors contribute to how antimicrobials are used. Therefore, a multidisciplinary approach is needed to develop, implement and evaluate interventions to promote optimal use of antimicrobials and improve infection control programmes. An adequately resourced task force is needed to coordinate policy and strategies at national level, in both the public and private health sectors. The form of the task force may vary, but it should always involve government (ministry of health), the national reference microbiology laboratory, the health professions (doctors, pharmacists, nurses), academia, the national drug regulatory authority, pharmaceutical industry, consumer groups and NGOs involved in health care. The impact on AMR and use is better if multiple interventions are implemented in a coordinated way. Single interventions are likely to have little impact. Page 2: WHO Policy Perspectives on Medicines Containing antimicrobial resistance

130 The task force should liaise with all the stakeholders involved in non-human use (including the ministry of agriculture) to develop a national containment programme (see section 10). In addition, the task force should liaise with those responsible for implementing and monitoring population-wide infection control programmes. Such programmes include: safe water and sanitation; immunization if people do not contract infectious diseases they do not need antibiotics; public education on hygiene and prevention, e.g. hand washing, bed nets, condoms; TB, HIV and malaria control programmes; cross-infection control in hospitals. Knowing how well these programmes are being implemented is essential in deciding where to focus efforts to contain resistance. 2. National reference microbiology laboratory coordinating a network of reliable diagnostic microbiology laboratories Epidemiologically sound surveillance of AMR in key pathogens, using standardised microbiological methods, can be developed on the basis of existing laboratories undertaking diagnostic services and surveillance. To ensure reliable, good quality, epidemiologically sound data, a coordinating national reference laboratory is needed. This laboratory should establish standardised methods, provide external quality assurance for all the participating laboratories and take part in external quality assurance. Many antimicrobials are prescribed unnecessarily because prescribers are unsure of the diagnosis. Diagnostic procedures help to ensure that antimicrobials are prescribed only when needed. For example, using malaria blood smears in hospitals helps to ensure that patients with malaria are treated with antimalarials and not with unnecessary antibiotics. Sputum microscopy for TB helps to ensure that TB patients are treated with anti-tb drugs and not with inappropriate antibiotics. Quality control for diagnostic procedures, including microscopy, is vital, or false diagnoses will be made or true diagnoses missed, and prescribers will not trust the laboratory. 3. Public education on preventing infection and reducing transmission People should have the skills and knowledge to make informed decisions about how to prevent infection and reduce transmission of infectious diseases through simple, cheap and effective measures. Such measures include prevention of: diarrhoeal disease through hand washing, using safe water sources and containers, boiling unsafe water and using latrines; malaria through the use of bed nets impregnated with insecticide; sexually transmitted infections through the use of condoms; certain infectious diseases through routine childhood vaccination (diptheria, measles, pertussis, Haemohilus influenzae, pneumococcus) and epidemic vaccination (meningitis, typhoid); HIV/AIDS and hepatitis B and C through the avoidance of injections (unless oral medicines cannot be used, in which case a sterile needle and syringe must be used). Governments have a responsibility to provide unbiased information to the community. They can run targeted public education campaigns, taking into account cultural beliefs and the influence of social factors. The important message is that antimicrobials should only be used to treat certain specific diseases; their use in other contexts is ineffective and counterproductive, since they can accelerate the emergence of AMR. Education on preventive measures can be introduced into school health education or into adult education, e.g. literacy and antenatal programmes. 4. Provider education on diagnosis and management of common infections, antimicrobial use, containment of AMR, disease prevention, infection control All providers, including doctors, pharmacists, nurses, paramedical workers, and drug sellers, should be taught about the issues surrounding AMR. Topics include accurate diagnosis and management of common infections, antimicrobial use, infection control and disease prevention. This education should be provided through: undergraduate training for pre-service students; postgraduate training and continuing professional development (CPD) programmes for all cadres of in-service personnel including intern doctors. Unfortunately, relevant AMR topics are often omitted in education programmes, opportunities for CPD are limited, and CPD is not a compulsory licensure requirement. Also, CPD activities are often heavily dependent upon pharmaceutical companies, which may be more interested in promoting their own antimicrobial sales. Governments should therefore support financially efforts by universities and national professional associations to give independent CPD covering AMR issues; promote the provision of unbiased information to prescribers; and regulate drug promotional activities. 5. Development, updating and use of essential medicines lists and clinical guidelines Evidence-based, regularly updated essential medicines lists and clinical guidelines, for each level of care, Page 3: WHO Policy Perspectives on Medicines Containing antimicrobial resistance

131 are vital for promoting rational use of medicines. Antimicrobial guidelines and treatment algorithms for infectious diseases may further aid rational use of antimicrobials. If there are reliable data, local AMR trends for infectious diseases should be considered when deciding upon inclusion of each antimicrobial. Governments should ensure that: public sector medicine procurement is based on the national medicines list; all training institutions include the national clinical guidelines in their training programmes; public sector reimbursement policies are based on the national essential medicines list or clinical guidelines. When possible the shortest effective course of antimicrobial therapy (as indicated by the evidence) should be adopted in the guidelines. Shorter courses of antimicrobial therapy are associated with the development of less resistance than longer courses. The use of fixed-dose combinations, particularly for HIV, TB and malaria is associated with increased patient adherence and will be less likely to stimulate AMR emergence as compared to single-drug treatments. 6. Infection Control Committees to implement infection control programmes in hospitals Hospitals and nursing homes are breeding grounds for the development and spread of AMR due to the close proximity of patients who have infections and are receiving antimicrobials. An Infection Control Committee (ICC) is responsible for administering infection control programmes in hospitals. The ICC should include, as a minimum, an infection control nurse in small hospitals and a clinical microbiologist, infectious disease specialist and surgeon in larger hospitals. The ICC should liaise closely with the Drug and Therapeutics Committee (DTC) or its antimicrobial sub-committee. An ICC should undertake: active surveillance of infections and AMR in order to detect, and manage, outbreaks of nosocomial (hospital-acquired) infection; this requires regular collation and assessment of resistance data from a microbiology laboratory; investigation and management of outbreaks or clusters of susceptible and resistant infections; interventions to prevent infections, including health worker and patient education; development and implementation of policies and procedures to prevent the transmission of infections (Box 2). 7. Drug and Therapeutics Committees and antimicrobial subcommittees to promote the safe, effective use of antimicrobials Drug and Therapeutics Committees (DTCs) and their antimicrobial sub-committees have been successful in industrialised countries in promoting more rational, cost-effective use of medicines and antimicrobials in hospitals (Box 3). Governments may encourage hospitals and local health authorities to have DTCs by making it an accreditation requirement. Members should represent all the major specialities, the pharmacy and the administration, and declare any potential conflict of interest (such as shares in a wholesaler supplying the hospital). A clinical microbiologist and infectious disease specialist should sit on both the antimicrobial subcommittee (or DTC) and the ICC. 8. Restriction of availability of antimicrobials This reduces misuse and may be done in two ways. (1) Restricting antimicrobial availability to prescription-only from licensed outlets Misuse of antimicrobials may be curbed by enforcing regulations to limit their availability to licensed Box 2 Preventing transmission of infections in hospitals 1. Hand washing or alcohol-based rinses by staff between patients and before undertaking any procedures e.g. injections. 2. Use of barrier precautions, e.g. wearing gloves and gowns for certain agreed procedures. 3. Adequate sterilization and disinfection of supplies and equipment. 4. Use of sterile techniques, together with protocols, for medical and nursing procedures, e.g. bladder catheterization, administration of injections, insertion of intravenous cannulas, use of respirators, sterilization of equipment, other surgical procedures. 5. Maintenance of appropriate disinfection or sanitary control of the hospital environment, including: adequate ventilation; cleaning of the wards, operating theatre, laundry, etc.; provision of adequate water supply and sanitation; safe food handling; safe disposal of infectious equipment, e.g. dirty needles; safe disposal of infectious body fluids, e.g. sputum. 6. Isolation of infectious patients from other non-infected patients, e.g. separation of suspected and proven sputumpositive TB cases (particularly from HIV-positive patients). 7. Visiting policies such as preventing visitors with infections from visiting patients who may be immuno-compromised, e.g. patients with AIDS or leukaemia or premature babies. 8. Training of health-care staff in appropriate sterile techniques and infection control procedures. Page 4: WHO Policy Perspectives on Medicines Containing antimicrobial resistance

132 Box 3 Responsibilities of the DTC or antimicrobial committee developing, adapting, or adopting clinical guidelines for infectious diseases and antimicrobial guidelines, using local AMR data if possible; selecting cost-effective, safe antimicrobials for the formulary, using local AMR data if possible; monitoring antimicrobial consumption and use patterns; developing policies on the use of antimicrobials by level of prescriber; this includes limiting certain antimicrobials to use only with approval by the DTC or senior prescriber; implementing and evaluating strategies to improve antimicrobial use (including drug use evaluation, and liaison with the ICC); providing on-going staff education on antimicrobial use (training and printed materials); liaising with the ICC with regard to assessing and using local AMR data. outlets upon receipt of a prescription written by a licensed prescriber. If the availability of all antimicrobials cannot be controlled by this method, certain ones (e.g. vancomycin for methicillin-resistant Staphylococcus aureus and the newer cephalosporins and fluoroquinolones) should be restricted in this way. (2) Classification of antimicrobials by level of prescriber and based on local conditions Classification of antimicrobials is applicable at all levels of health care. In primary health care facilities and hospitals without laboratories, it may not be possible to distinguish between restricted and very restricted and the two categories may be treated as one. Antimicrobials for non-restricted use by any prescriber are safe, effective and reasonably priced, e.g. amoxicillin, and may be prescribed without approval by senior prescribers or the antimicrobial and infection control subcommittees. Restricted antimicrobials may be more expensive and/or have a wider spectrum of activity, e.g. ceftriaxone or vancomycin. They should only be used for (1) specific infections known to be sensitive to the antimicrobial (after culture and susceptibility testing), or (2) empirical emergency treatment of suspected serious or life-threatening infections pending the result of culture and sensitivity testing. Use of these antimicrobials would require countersignature by a senior physician who has the approval of the DTC for such an activity. Very restricted antimicrobials are those such as linezolid or meropenem that should be reserved for lifethreatening infections where culture and sensitivity testing has indicated resistance to other effective and less expensive antimicrobials. Approval for use in each individual patient must be given by the clinical microbiologist or the DTC itself. 9. Granting marketing authorisation only to antimicrobials meeting international standards of quality, safety and efficacy Poor quality antimicrobials may result in under-dosage, leading to poor patient outcome and increased AMR through the selection of resistant organisms. The increasing quantity of counterfeit and substandard antimicrobials available worldwide requires vigilance by governments, importers, retailers, the pharmaceutical industry and health professionals. Ensuring quality through enforced regulation, good procurement practice and post-marketing surveillance is essential to containing AMR. 10. Controlling non-human use of antimicrobials Only about half of all antibiotics are consumed by humans. Most of the rest are added to animal feed Box 4 Controlling non-human use of antimicrobials (1) Surveillance by data collection from manufacturers, distributors including feed mills, pharmacies, veterinarians, farmers, and animal producers. The data should cover: AMR in animals; antimicrobial use in food animals for infections, prophylaxis and as growth promoters; national import and export of bulk chemicals with potential antimicrobial use; levels of antimicrobial agent residues in food from animal sources. (2) Reducing and eventually stopping use of all antimicrobial growth promoters in food animals by: banning growth promoters used in human therapeutics, or known to select for cross-resistance to antimicrobials used in humans, as soon as possible; replacing all growth promoters with safer non-antimicrobial alternatives (e.g. improved animal hygiene) as soon as possible. (3) Establishing an effective regulatory and control system for all antimicrobials used in agriculture: registration of all antimicrobial products used for food animals and in agriculture; ensuring that all antimicrobial products used for food animals and in agriculture are of adequate quality and are manufactured according to good manufacturing practices; licensing of manufacturers, distributors, and personnel selling or prescribing any antimicrobial products used for food animals or in agriculture. (4) Education of all stakeholders in the agricultural sector on AMR and the appropriate use of antimicrobial products. Page 5: WHO Policy Perspectives on Medicines Containing antimicrobial resistance

133 WHO/PSM/ Original: English (particularly pigs and poultry) for mass treatment against infectious diseases or for growth promotion. Antimicrobials are also added to water to treat fish diseases and sprayed on to food crops to treat disease (e.g. fire blight in apples). Most antimicrobials registered for human use are also registered for animal use but regulation, such as licensing of prescribers, dispensers and outlets, is much less stringently applied in the agricultural sector. Although the majority of human AMR results from human use, there is evidence of significant spread of certain resistant bacteria (e.g. salmonella, campylobacter, enterococcus) from animals to humans. Box 4 lists the major recommendations to control non-human use. Conclusion A national programme is needed to undertake surveillance of antimicrobial use and resistance and, based on this data, to develop, implement and evaluate strategies to contain AMR. Critical to success are: 1. an adequately funded, mandated, multidisciplinary, national task force to coordinate strategies to contain AMR; 2. a national reference microbiology laboratory to coordinate a network of reliable diagnostic microbiology laboratories; 3. government investment in the health system infrastructure to ensure the controlled availability of appropriate antimicrobials, and adequately trained personnel to prescribe and dispense them. Key Documents World Health Organization. How to Investigate Drug Use in Health Facilities: Selected Drug Use Indicators. Geneva: WHO; 1993 (WHO/DAP/93.1). World Health Organization. WHO Global Principles for the Containment of Antimicrobial Resistance in Animals Intended for Food: Report of a WHO Consultation. Geneva: WHO; 2000 (WHO/CDS/CSR/APH/2000.4). World Health Organization. WHO Global Strategy for Containment of Antimicrobial Resistance. Geneva: WHO; 2001 (WHO/CSR/DRS/2001.2). World Health Organization. Surveillance Standards for Antimicrobial Resistance. Geneva: WHO; 2001 (WHO/CSR/DRS/2001.5). World Health Organization. Infection Control Programmes to Control Antimicrobial Resistance. Geneva: WHO; 2001 (WHO/CSR/DRS/2001.5). World Health Organization. Promoting Rational Use of Medicines: Core Components. WHO Policy Perspectives on Medicines No.5, Geneva: WHO; 2002 (WHO/EDM/2002.3). World Health Organization. Monitoring Antimicrobial Usage in Food Animals for the Protection of Human Health: Report of a WHO Consultation. Geneva: WHO; 2002 (WHO/CDS/CSR/ EPH/ ). World Health Organization. Implementing Antimicrobial Drug Resistance Surveillance and Containment for HIV, Tuberculosis and Malaria: An Outline for National Programmes. Geneva: WHO; 2003 (WHO/CDS/RMD/2003.2). World Health Organization. Drug and Therapeutics Committees: A Practical Guide. Geneva: WHO; 2004 (WHO/EDM/PAR/ ). All documents available on Contacts in WHO Regional Offices: Regional Office for Africa: Dr Jean-Marie Trapsida Coordinator, Essential Drugs and Medicines Policy Tel: trapsidaj@afro.who.int Regional Office for the Americas: Dr Jorge A.Z. Bermudez Essential Medicines, Vaccines and Health Technologies Tel: bermudej@paho.org Regional Office for the Eastern Mediterranean: Dr Zafar Mirza Regional Adviser, Essential Medicines and Biologicals Tel: mirzaz@emro.who.int Regional Office for Europe: Mr Kees de Joncheere Pharmaceuticals Tel: cjo@who.dk Regional Office for South-East Asia: Dr Krisantha Weerasuriya Regional Adviser, Essential Drugs and Medicines Policy Tel: (ext 26314) weerasuriyak@whosea.org Regional Office for the Western Pacific: Dr Budiono Santoso Regional Adviser Tel: santosob@wpro.who.int Contacts at WHO Headquarters: Medicines Policy and Standards Health Technology and Pharmaceuticals Cluster WHO Headquarters, Geneva, Switzerland: Dr Hans V. Hogerzeil Director, Medicines Policy and Standards Tel: hogerzeilh@who.int Dr Clive Ondari Team Coordinator, Policy, Access and Rational Use Tel: ondaric@who.int Dr Lembit Rägo Team Coordinator, Quality and Safety: Medicines Tel: ragol@who.int World Health Organization All rights reserved. Publications of the World Health Organization can be obtained from Marketing and Dissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: ; fax: ; bookorders@who.int). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there Page may 6: not WHO yet Policy be full Perspectives agreement. on Medicines Containing antimicrobial resistance The World Health Organization does not warrant that the information contained in this publication is complete and correct and shall not be liable for any damages incurred as a result of its use.

134 FIFTY-EIGHTH WORLD HEALTH ASSEMBLY WHA58.27 Agenda item May 2005 Improving the containment of antimicrobial resistance The Fifty-eighth World Health Assembly, Having considered the report on rational use of medicines by prescribers and patients; Acknowledging that the containment of antimicrobial resistance is a prerequisite for attaining several of the internationally agreed health-related goals contained in the United Nations Millennium Declaration; Recalling the recommendations of the Second International Conference on Improving Use of Medicines (Chiang Mai, Thailand, 2004); Recalling also the findings of relevant WHO reports, including Priority medicines for Europe and the world, 1 and the Copenhagen Recommendation from the European Union conference on The Microbial Threat (Copenhagen, 1998); Aware that the spread of antimicrobial resistance recognizes no national boundaries and has reached proportions that require urgent action at national, regional and global levels, especially in view of the decreasing development of new antimicrobial agents; Recalling previous resolutions WHA39.27 and WHA47.13 on the rational use of drugs, WHA51.17 on antimicrobial resistance, and WHA54.14 on global health security; Recognizing the efforts of WHO in collaboration with governments, universities, the private sector and nongovernmental organizations to contain antimicrobial resistance, thereby contributing to prevention of the spread of infectious diseases; Noting that, despite some progress, the strategy for containment of antimicrobial resistance has not been widely implemented; 2 Wishing to intensify efforts to contain antimicrobial resistance and to promote rational use of antimicrobial agents by providers and consumers in order to improve global health security; 1 Document WHO/EDM/PAR/ Document WHO/CDS/CSR/DRS/

135 WHA58.27 Re-emphasizing the need for a coherent, comprehensive and integrated national approach to promoting the containment of antimicrobial resistance; Convinced that it is time for governments, the health professions, civil society, the private sector and the international community to reaffirm their commitment to ensuring that sufficient investment is made to contain antimicrobial resistance, 1. URGES Member States: (1) to ensure the development of a coherent, comprehensive and integrated national approach to implementing the strategy for containment of antimicrobial resistance taking account, where appropriate, of financial and other incentives that might have a harmful impact on policies for prescribing and dispensing; (2) to enhance rational use of antimicrobial agents, including through development and enforcement of national standard practice guidelines for common infections, in public and private health sectors; (3) to strengthen, as appropriate, their legislation on availability of medicines in general and of antimicrobial agents in particular; (4) to mobilize human and financial resources in order to minimize the development and spread of antimicrobial resistance, in particular by the promotion of the rational use of antimicrobial agents by providers and consumers; (5) to monitor effectively and to control nosocomial infections; (6) to monitor regularly the use of antimicrobial agents and the level of antimicrobial resistance in all relevant sectors; (7) to share actively knowledge and experience on best practices in promoting the rational use of antimicrobial agents; 2. REQUESTS the Director-General: (1) to strengthen the leadership role of WHO in containing antimicrobial resistance; (2) to accelerate the implementation of resolutions WHA51.17 and WHA54.14 concerning the containment of antimicrobial resistance by expanding and strengthening the provision of technical support to Member States, at their request; (3) to collaborate with other relevant programmes and partners in order to promote the appropriate use of antimicrobial agents in the context of the rational use of medicines, by scaling up interventions proven to be effective and to provide support for the sharing of knowledge and experience among stakeholders on best practice; (4) to provide support for the generation of up-to-date information on antimicrobial resistance at regional and subregional levels and to make this available to Member States and other parties; 2

136 WHA57.27 (5) to provide support for gathering and sharing of evidence on cost-effective interventions for prevention and control of antimicrobial resistance at national and local levels; (6) to report to the Sixtieth World Health Assembly, and subsequently on a regular basis, on progress achieved, problems encountered and further actions proposed in implementing this resolution. Ninth plenary meeting, 25 May 2005 A58/VR/9 = = = 3

137 THE GLOBAL THREAT OF ANTIBIOTIC RESISTANCE: Exploring Roads towards Concerted Action A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY 2004 BACKGROUND DOCUMENT Consumers and Providers could they make better use of antibiotics? Per Nordberg, Cecillia Stålsby Lundborg, Göran Tomson Antibiotic use is seen as a critical factor in the emergence of resistant bacteria. The impact of irrational use, including inadequate dosing and poor adherence to therapy, is potentially just as important as high consumption. 1 At the same time, limited access to antibiotics in many parts of the world is contributing to high mortality from bacterial infections. Often, irrational behaviour from a biomedical perspective may be perfectly logical for the human being and in the context of the cultural sphere surrounding her. Understanding the reasons that individuals use antibiotics in a particular way is crucial if one is to influence their actions. Containment of antibiotic resistance has been established as a Global Public Good for Health and the rationalising of consumer and provider behaviour is an essential component in achieving this goal. 2 In this article, the aim has been to examine the interplay between prescribers, dispensers and consumers, to visualise incentives for individuals to use antibiotics and to determine how health system factors influence human behaviour. The approach is global, but the main focus is on low- and middle-income countries where the problems are most prominent and where most people live. HEALTH SYSTEMS IN TRANSITION Health sector reforms from the late 1980s were driven mainly by the World Bank, with support from a number of bilateral aid agencies, and emphasised the need to redefine the relationship between the state, service providers, users and other health-related organisations. 3,4 Privatisation and deregulation were promoted and focused on private financial and human resources management. Emphasis was laid on mixed public and private mechanisms to improve cost control and increase cost recovery, including user charges, prepayment schemes and insurance. A push for stronger contractual arrangements with private sector providers reflected the prevailing ideological view of the potentially greater quality and efficiency of the private sector. Figure 1. Health systems: improving performance. Source: World Health Report The complex issue of antibiotic resistance necessitates a systems view, including functions and objectives, where policy makers have the overall role of regulating and prioritising among services (Figure 1). Major challenges accompanied the health sector reforms. Privatisation of services, drug supply and drug distribution has dramatically increased geographical access to antibiotics without securing their rational use. In many low- and middle-income countries, drug distribution has been taken over almost completely by the private sector. In Vietnam, market-oriented reforms resulted in the number of private pharmacies increasing from none in 1986 to over 6,000 in 1992; during the same period there was a sixfold increase in the annual per capita consumption of pharmaceuticals, with antibiotics representing the highest proportion of the increase. 5,6 Over 50 per cent of the antibi-

138 A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY BACKGROUND DOCUMENT otics globally is estimated to be bought directly from pharmacies or informal sale outlets without prescriptions, 7 underlining the increasingly important function of pharmacies or other drug outlets as the first and possibly only contact with health services. Secondly, health systems in low-income countries often have problems with lack of human resources, an obstacle that is prominent at present in sub-saharan Africa. 8 Also, few countries have systems in place for knowledge transfer and quality control. Consequently, the quality of both services and medicines varies extensively and problems, including false and substandard antibiotics, continue. A third challenge is the financing of health systems. In industrialised countries financial mechanisms range from general taxation in Scandinavia to private health insurance in the United States. In most developing countries, including the two largest, China and India, the financing of health services mainly, including expenditure on drugs, consists of out-of-pocket payments from patients. 9 In China, reforms have created a situation where prescribing of drugs generates revenues to the 100,000 public hospitals. Additionally, we see the mushrooming of private drug outlets and clinics in all continents, where a substantial part of the staffs income is generated through prescribing, dispensing and sales of drugs, including antibiotics. 10 The responsiveness of the systems to meet patient expectations is another challenge. In the case of antibiotics, drug policies are intended to restrict unnecessary use, which often arises from the high patient demand for receiving antibiotics for most infections. In all cases, human beings and their behaviour matter. Public health services may be limited owing to shortages of medicines, materials and trained personnel. 8,11,12 Frequently, payments are required for people to get attention from the staff as health providers have developed their own livelihood strategies to compensate for low incomes. 4,13 Lack of drugs results in referral to other dispensary units, possibly far away from the clinic. In actual practice, so-called free services can be quite expensive and time-consuming. Private detailers sometimes provide an easily accessible, low-cost alternative to public or private clinics (Picture 1). The social distance between the actors is less apparent and it is easier for people to remain anonymous in cases where privacy is important. Certain illnesses, such as STIs, are connected with social stigmatisation and tend to drive people away from regular health services, to pharmacies or even to the local market. 14 This is an unfortunate development as adequate treatment of STIs demands good knowledge on the part of dispensers, so as to limit the spread of highly resistant pathogens as well as reducing the spread of HIV. 15 Picture 1. Indian market place, informal drug vendors CONSUMERS IN THE SYSTEM In the society of today, where people are becoming increasingly individualistic, health care is considered the same as any other commodity. Through system changes consumers have been given opportunities to act individually in unregulated contexts, which are often profit-driven. In respect of diseases where the emerging resistance is most imminent, e.g. respiratory infections, sexually transmitted infections (STI) and diarrhoeal diseases, there are also parallel, high levels of self-initiated treatment without health personnel being consulted first. What incentives are driving people to direct purchase of antibiotics in pharmacies? whenever I get these symptoms and go to a doctor, he gives me the same medicine and charges me 10 rupees. So why not just buy the medicine? Dua V et al Antibiotic use is to a great extent influenced also by cultural preferences and beliefs. Even if the settings are dramatically different in industrialised and developing coun- 2

139 A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY BACKGROUND DOCUMENT tries, the demands for antibiotics are there in both. Actual and perceived patient demands increase the prescribing of antibiotics. At the same time, patients in some situations accept prescriptions they believe unnecessary, out of politeness towards the physician. Dispensers and prescribers often belong to the same ethnic or geographical groups as their patients or customers, and to a high extent share their perceptions of health, illnesses and antibiotics. 16 In many contexts antibiotics are perceived as strong medicines, capable of curing almost any kind of disease. Cultural reinterpretation into traditional medicine is common. Colour, shape and taste are viewed as important qualities in determining drug efficacy. Multi-coloured capsules are perceived as particularly powerful in certain cultures as different colours imply combinations of several medicines. Common for many low-income countries in Africa and Asia is the high use of injections, which are thought to be more potent than pills. Injectable antibiotics are for sale in local shops along with needles and syringes, resulting in unsafe use of high-tech medicines at household level. 14 Newer, more expensive drugs are generally considered more powerful and make people willing to buy them even if they cannot afford a full course. PROVIDERS IN THE SYSTEM The role of the pharmacist has changed over the past two decades, especially in industrialised countries, from being a supplier of drugs to a team member involved in the provision of health care in hospitals and community pharmacies. Pharmacists bridge sectors and in many contexts function like physicians, providing advice along with medicines and taking part in the diagnostic process. 17 However, drug dispensers range from competent, qualified pharmacists to shopkeepers without any formal training, and the quality of services is therefore limited in many settings. Furthermore, antibiotics are frequently available in market places and offered to people by mobile salesmen without any training at all. In some developing countries, such as India, the presence of untrained staff in private drug stores is the norm. Consumers lack of knowledge of appropriate antibiotic use translates into low levels of demand on the dispensers professional skills, making them vulnerable to the business interests of the salesman. 10,17 Good Pharmacy Practice guidelines from WHO were published in 1996, intended to improve the drug supply, enhance the quality of advice to patients, promote rational and economic prescribing, and increase the appropriate use of medicines. However, to improve practice at private drug outlets where these qualities are frequently absent remains a major challenge. In an Indian setting over 90 per cent of customers did not know the type of medication being prescribed and only 3.5 per cent were aware that an antimicrobial drug was being delivered. 18 Regulatory measures and qualification demands are harder to implement in the private sector, and in many cases drug distributors are without any therapeutic guidelines and monitoring. Ignorance of existing regulatory measures is widespread and enforcement of regulations is often non-existent. Prescribing of antibiotics is influenced by numerous factors indicating that incentives and barriers may be as important as knowledge in the use of antibiotics (Figure 2). In practice, barriers in the general environment include financial disincentives such as lack of reimbursement and lack of liability. The prevailing opinion is influenced by opinion leaders, staff knowledge, which is often obsolete, and drug company advocacy. If public services become dependent on fee incomes from patients there may be little to distinguish them from private enterprises, operating in the interest of their owners rather than of the general public. 10 In some countries user fees are directly linked to the salaries of public health care providers, creating unsound incentives for prescribing of antibiotics and other medicines. 3,10 Potential dual roles for the physician, as doctor and dispenser, will further increase the use of costly drugs and result in treatment where several antibiotics are combined. Examples from sub-saharan Africa and China show how doctors earn their living by taking advantage of people s beliefs, giving injections with one or several antibiotics to children with common colds. In the overlap between the public and private sectors, where physicians both work within the public health care system and give private consultations, this problem is clearly demonstrated. As physicians turn aside from their regular practice their way of prescribing antibiotics changes dramatically, in favour of more expensive products. Commitments made to the pharmaceutical industry may be one of several reasons, as companies have been known to pay commissions to prescribers who use their products. 3

140 A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY BACKGROUND DOCUMENT Figure 3. The complexity of factors influencing prescribing Source: Tomson, 1990 Unfavourable doctor-patient ratios mean that doctors constantly have to deal with an overload of patients. Consequently, no time exists for proper clinical investigations and possible other diagnostics, and this time constraint promotes the use of prescriptions as a means of terminating the consultation. 14,19 These conditions limit the possibilities for rational prescribing and increase the number of drugs prescribed per patient, distorting the value of prescriptions as the correlation to diagnose is low. In a study of public health centres in Ghana the average number of drugs prescribed varied from three to nine per patient, including at least one or two antibiotics. 20 Refusal to prescribe antibiotics, even for non-bacterial diseases, would sometimes be considered highly irrational, according to local cultural criteria. 14,19 Along with the potential loss of clientele there is also the fear among prescribers that the outcome may be poor or even fatal without antibiotic treatment. In industrial countries physicians might fear legal consequences if they fail to secure adequate treatment in every situation, leading to over-prescribing to relieve the doctor of anxiety. Uncertainty in diagnostics, together with limited possibilities to follow up patients progress, creates further concern over the outcome. This uncertainty leads to overkill in treatment as the fear of not covering the bacteria causing the infection enhances the choice of an antibiotic with a broader spectrum or combinations of several agents. The lack of diagnostic tools makes it difficult for the prescriber to have the right arguments to convince the patient and himself that antibiotics are not needed in the individual case. IMPROVING BEHAVIOUR Successful attempts to rationalise antibiotic use have been carried out in The Netherlands, Australia and Sweden with national programmes focusing on good surveillance of resistance, alert responses to outbreaks, guidelines to prescribers, good pharmacy practice and methods to increase the awareness of all stakeholders. Can one generalise from such experiences? It must be said that too often there is too little information about different interventions in relation to content, context and costs, thereby making it difficult to draw conclusions. Interventions in developing countries have emphasised increased access rather than rational use. Improvements in antibiotic use have been achieved locally in different settings. But how should one proceed so as to implement evidence-based programmes in a larger context based on existing structures within the country? To bridge the gap between scientific evidence and patient care we need an in-depth understanding of the barriers to and the incentives for changing behaviour. In general, the focus has been primarily on prescribers working within public health systems, which we know represent the source of only a small proportion of the drugs delivered to patients worldwide. How do we approach the private sector where irrational use is widespread? And how can we reach individuals and influence their demand for antibiotics? When planning complex changes in practice, we need to take into account the nature of the intervention, the characteristics of the professionals and patients involved and also the social, organisational, economic and political contexts. INFLUENCING THE PROFESSIONALS To address the growing private sector is a major challenge. In a study carried out in 68 pharmacies in Hanoi a clusterrandomised experiment consisting of a multifaceted intervention was applied. 21 Treatment of sexually transmitted infections improved tenfold. The adherence to national treatment guidelines in this field has been easier to implement as the use of a syndromic approach with a combination of several antibiotics actually increased the income for pharmacists. When the same intervention package was applied in Bangkok the improvements were less successful, showing the importance of the context when designing an intervention. 22 Attempts to rationalise prescribing practices through only the provision of correct information about antibiotics, their side effects and proper use, with the intention that pre- 4

141 A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY BACKGROUND DOCUMENT scribers and dispensers will incorporate such knowledge into their practice, have generally been a failure. Printed materials to prescribers have proven remarkably ineffective in changing behaviour. The more active approach educational outreach with brief, targeted, face-to-face visits to clinicians by specially trained staff has been more successful. Interactional group discussions, including both prescribers and patients, have shown highly effective in decreasing the overuse of injections in Indonesia. 23 In another study small group face-to-face method was compared with large seminars in improving the appropriate use of drugs in acute diarrhoea. Both ways were effective, and although the small group faceto-face intervention did not appear to offer greater impacts over large seminars, the training is far less costly than the seminar and it might easier be feasibly implemented in the existing supervisory structure of the health system in developing countries. 24 Clinical guidelines have been shown to have little effect on practice unless they are actively disseminated. 25 Local involvement is a way to increase the likelihood of guidelines being adopted as well as giving feedback to the prescriber. In industrialised countries, with functioning and accessible health systems, delayed prescribing techniques where parents are informed about the natural course and advised to use their prescription only if symptoms progress, has been successful in limiting antibiotic use for acute inflammation of the middle ear. 26 REACHING THE CONSUMER It might seem unlikely that people will be willing to restrict their individual use of antibiotics in favour of the common good, for example to prevent resistance and safeguard antibiotic treatment for future generations. At the same time the demand from the consumer may be the strongest driving force for change if the arguments for restricting the use of such drugs can be made sufficiently convincing. The perception among patients that most infections require antibiotic therapy is evidently influencing the prescribing practices of providers. This was recognised early on by observers of market forces, and direct-to-consumer marketing by the pharmaceutical industry increasingly influences patient expectations and behaviour. Subsequently, companies are marketing medicines directly to the public via television, radio, print media and the internet. To stimulate demand by playing on the consumer s relative lack of knowledge about the evidence supporting the use of one treatment over another has been shown to be highly effective. Pharmacists have frequently been able to guess the content of a particular day s television advertisements from subsequent daily customer requests for specific medications. Over 70 per cent of the physicians in an US study reported that requests from patients as a result of direct-to-consumer advertisements had resulted in their being given prescriptions for medicines that they might not otherwise have chosen. 27 Can the same power of community members be used to turn back the trend of excessive antibiotic use? Increased knowledge among consumers of the potential future consequences of antibiotic overuse might be a counterbalancing influence and lead to initiatives on their part to restrict the use of antibiotics. Few interventions have addressed antibiotic use from the consumer s perspective. Media campaigns have been used successfully to increase consumer awareness in Australia and Sweden. LEGISLATION, REGULATIONS AND ENFORCEMENTS Although pharmaceutical regulations represent a powerful tool, implementing these in order to influence patterns of antibiotic use could at the same time limit access to essential therapy in settings where health clinics are distant or unaffordable for most people. However, requiring a prescription from a trained health worker for access to antibiotics hopefully results in a more rational selection of drugs and treatment regimens. In Chile, ever-increasing antibiotic consumption led to a national initiative in the late 1990s where professionals, consumers and policy makers, in cooperation with the industry, gathered around the issue. Regulatory measures, requiring prescriptions for the sale of antibiotics, were followed by a substantial decrease in total antibiotic use in the country. 28 Other examples indicate less success. In all member states of the European Union (EU) antibiotics are prescription only drugs, but over-the-counter sales remain common in some EU countries, reflecting a prevailing insufficiency in enforcement of existing regulations. In the South, in both low- and middle-income countries, pharmacies are often small family businesses and work on minimal profit margins, and regulations on drug distribution may be overlooked as a way to achieve a reasonable income. Legislation regarding the standard of the outlets where antibiotic distribution is permitted is another critical issue, as is a minimum qualification level for the personnel running them. In these areas too, regulations often exist, but prove ineffective as enforcement is lacking. 5

142 A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY BACKGROUND DOCUMENT CHANGE There is a need for better change models to influence consumer or professional behaviour. A 10-step model based on state of change has been suggested for inducing change in professional behaviour. A process that begins by creating awareness, interest and understanding among professionals is much more likely to lead to acceptance and integration of the new knowledge into daily practice (Figure 3). Promotion of rational use of antibiotics is still poorly integrated into health systems. To achieve long-term improvements, antibiotic use and resistance must be integrated in the curriculum of medical students, health workers and pharmacists. It is necessary not only to focus on the biomedical perspective of antibiotic resistance but also to address the behavioural aspects of prescribing and dispensing. Careful examination of the theories and practices of change is required in this process of bringing about a better use of antibiotics, and the multidisciplinary meeting at the Dag Hammarskjöld Foundation, Uppsala is an important first step in this direction. Figure 3. A 10-step model for including change in professional behaviour Orientation Insight Acceptance Change Maintenance 1) Promote awareness of innovation 2) Stimulate interest and involvement 3) Create understanding 4) Develop insight into own routines 5) Develop positive attitude to change 6) Create positive intentions/decision to change 7) Try out change in practice Perception of practical barriers (time, staff, money) Opportunity to try to change on small scale 8) Confirm value of change Whether first experiences positive or negative Degree of cooperation experienced and reaction of pat. and colleagues Side effects (e.g. higher costs) 9) Integrate new practice into routines 10) Embed new practice in organization Degree of support from management Grol, Wensing:2004 6

143 A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5 7 MAY BACKGROUND DOCUMENT REFERENCES: 1. WHO, WHO Global strategy for containment of antimicrobial resistance, WHO/CDC/CSR/DRS/2001.2, Geneva, Smith R, Beaglehole R, Woodward D. and Drager N, Global Public Goods for Health, Oxford University Press, Whitehead M, Dahlgren G. and Evans T, Equity and health sector reforms: can low-income countries escape the medical poverty trap? The Lancet, 2001; 358: Standing H, An overview of changing agendas in health sector reforms, Reproductive health matters, 2002;10(20): Chuc et al, Management of childhood acute respiratory infections at private pharmacies in Vietnam, in The Annuals of Pharmacotherapy, 2001;35: Chalker et al STD management by private pharmacies in Hanoi: practise and knowledge of drug sellers, Sexually Transmitted Infections, 2000;76(4): WHO-EMRO, Agenda item 11(a): Antimicrobial resistance and rational use of Antimicrobial agents, WHO website: rational/amr.ppt. Accessed 30 June 2004, 49th Session of the Regional Committee for the Eastern Mediterranean; 30 September 3 October 2002, Cairo, Egypt. 8. WHO, Shaping the future, World Health Report Dong et al, Association between health insurance and antibiotics prescribing in four counties in rural China, in Health Policy, 1999;48: Mills et al, What can be done about the private health sector in lowincome countries? Bulletin of the World Health Organization, 2002;80: Van der Geest S. and Whyte S. R, The Context of medicines in developing countries, Kluwer Academic Publishers, Velásquez G, Madrid Y. and Quick J, Health reform and drug financing: selected topic-health economics and drugs, DAP series No. 6, WHO/DAP/98.3, action programme on essential drugs, WHO, Geneva, Standing H, Health systems: improving performance, World Health Report Whyte S. R, Van Der Geest S. and Hardon A, Social lives of Medicines, Cambridge University Press, Gilson L et al, Cost-effectiveness of improved treatment services for sexually transmitted diseases in preventing HIV-1 infection in Mwanza Region, Tanzania, The Lancet, 1997;350: Radyowijati A. and Haak H., Determinants of Antimicrobial use in the developing world, USAID, Bureau of Global Health, The Child Health Research Project Special Report, Cederlöf C. and Tomson G, Private pharmacies and the Health Sector Reform in Developing Countries Professional and Commercial Highlights, Journal of Social and Administrative Pharmacy, 1995;12(3): Dua et al, The use of antimicrobial drugs in Nagpur, India. A window on medical care in a developing country, Social Science and Medicine, 1994;38(5): Sachs L. and Tomson G., Medicines and culture a double perspective on drug utilisation in a developing country, Social Science and Medicine, 1992;34(3): Bosu W. K, Survey of antibiotic prescribing pattern in government health facilities of the Wassa west district of Ghana, East African Medical journal, 1997 Mar; 74(3): Chuc NT, Larsson M, Do NT, Diwan VK, Tomson GB, Falkenberg T. Improving private pharmacy practice: a multi-intervention experiment in Hanoi, Vietnam, J Clin Epidemiol Nov; 55(11): Chalker et al, Effectiveness of a multi-component intervention on dispensing practices at private pharmacies in Vietnam and Thailand A randomised controlled trial, submitted for publication July 2003, IHCAR Karolinska Institutet. 23. Hadiyono JE, Suryawati S, Danu SS, Sunartono, Santoso B. Interactional group discussion: results of a controlled trial using a behavioural intervention to reduce the use of injections in public health facilities, Soc Sci Med Apr;42(8): Santoso B, Suryawati S, Prawaitasari JE, Small group intervention vs formal seminar for improving appropriate drug use, Soc Sci Med Apr;42(8): Erratum in: Soc Sci Med 1996 Jul;43(1):I. 25. Grimshaw J. M. and Russell I. T, Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations The Lancet, 1993;342: Little et al, Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media, British Medical Journal, 2001;322: Lipsky L. A. and Taylor, C. A, The opinions and experiences of family physicians regarding direct-to-consumer advertising, Journal of Family Practice, 1997;45: Bavestrello L, Cabello A, Impact of Regulatory Measures on Antibiotic Sales in Chile, International Conference on Improving Use of Medicines 2004, Abstract ID: AM003. 7

144 A fact sheet from ReAct Action on Antibiotic Resistance, First edition 2007 Last updated May 2008 Economic aspects of antibiotic resistance u Resistance to antibiotics results in an extensive increase in costs to the patient and family, the hospital, and society, due to the need for the use of more expensive drugs for second line treatment, more tests and much longer stays in hospital, as well as longer sick leave, or even premature death. u However, an even greater economic burden lies in the future and will affect generations to come, when the consequences of current use (and misuse) of antiobiotics could lead to the loss of all the advantages in medical care that they have brought about. Advanced surgical procedures and cancer chemotherapy might be impossible to perform, resulting in enormous costs, economic as well as human. INTRODUCTION n Antibiotics are essential in the prevention and cure of bacterial infections. n The use of antibiotics generates resistance to their effects, reducing their effectiveness in the prevention and cure of disease. n Resistance is associated with antibiotic usage (appropriate or otherwise), and the interaction of microorganisms, people and the environment. n Resistance is therefore not eradicable, but will have to be managed. n Antibiotics are a scarce resource as current use decreases their future value. n This requires an assessment of the balance between the positive effects of using antibiotics and the negative impact of this use on their temporal effectiveness. n Resistance has to be included as a factor when assessing the relative costs and benefits of the use of antibiotics. DEFINITION OF THE PROBLEM n In economic terminology, resistance is a negative externality. That is, it has an undesirable effect on people other than the immediate consumer. n This is referred to as an external cost, as it is an undesirable effect (and hence cost) on those other than the consumer making the consumption decision. n This external cost is cross-sectional as it is imposed on people other than the consumer, but also temporal in the sense that when the consequences of resistance have appeared a cost is also borne by the consumer. It has to be remembered that: n we are looking at containment of resistance, not eradication n it is important to assess the optimisation of use of antibiotics over time

145 n in addition to direct costs to the patient, the family and hospital, it is critical to assess social costs and benefits of antibiotic use and strategies to contain resistance (i.e. including positive and negative externalities). These strategies will be wide-ranging and encompass the development of new antibiotics, the use of alternative treatments and prevention of infectious disease. QUALITATIVE CONSEQUENCES OF RESISTANCE Treatment failure is the main contributor to increased costs and can lead to: n additional investigations such as laboratory tests and X-ray examinations n additional or alternative treatments, often much more expensive than drugs used to treat infections caused by sensitive organisms n additional side-effects from more toxic treatments, which have to be managed n longer hospital stay n longer time off work n reduced quality of life n greater likelihood of death due to inadequate or delayed treatment n increased burden on family of infected individual n increases in private insurance coverage n additional cost for hospital when hospital- acquired infection occurs and infection control procedures are required n increased overall healthcare expenditure, including costs of combating transmission n increased cost of disease surveillance n increased costs to firms of absenteeism n possible increase in product prices due to increased costs to firms These consequences, however, relate only to the direct (and some indirect) impacts of resistance itself. Also very important is the impact that resistance will have on the ability to deliver other forms of health care. Antibiotics are the cornerstone of modern medicine that revolutionized medical care during the last half of the previous century. From cradle to grave the role of antibiotics in safeguarding the overall health of human societies is pivotal. So the costs of antibiotic resistance relate to the loss of these benefits and associated treatment possibilities at every stage of human life. Thus, in order to calculate the full economic burden of antibiotic resistance we have to consider the burden of not having antibiotics at all, which at the extreme would probably collapse the entire modern medical system. The figures below vastly under-represent the actual cost of resistance once it begins to affect these other aspects of medical care, such as any surgical therapy. Besides this alarming future scenario antibiotic resistance already has an impact on the care of patients with bacterial infections, which are not yet caused by resistant strains. Broaderspectrum antibiotics are now being prescribed as first-line drugs, when a certain level of resistance has been detected in the area. This often means more expensive drugs, greater risk of side effects, and occasionally more tests to be performed, thus increasing the costs substantially. QUANTITATIVE CONSEQUENCES OF RESISTANCE There are difficulties in assessing the exact costs incurred by antibiotic resistance, one reason being the impact of the underlying disease. By country n Cost to US medical care sector of treatment for patients with infections caused by resistant organisms estimated to be $4-7 bn per year. 1, 2 By institution n Cost to a general hospital of containing a 5-week outbreak of MRSA approximately 500, By disease n Tuberculosis double the cost of standard treatment ($13,000- $30,000) 4 ; multidrug resistant tuberculosis, MDRTB treatment cost increased to $180, 000 (CDC estimate). 5 n Vancomycinresistant enterococci infections average extra cost of $12,766 per case in comparison with controls, due for example to more and longer ICU admissions and additional hospitalization days; patients also more often discharged to long-term facilities, thereby increasing costs beyond hospitalization. 6 n Infections with ESBL producing Enterobacteriacae costs and hospital charges increased 1.56 and 1.71 respectively in two studies. 7, 8 u ReAct links a wide range of individuals, organisations and networks around the world taking concerted action to respond to antibiotic resistance. u Our vision is that current and future generations of people around the globe should have access to effective treatment of bacterial infections. u ReAct believes that antibiotics should be used appropriately, their use reduced when of no benefit and their correct and specific use increased when needed. u ReAct believes that awareness of ecological balance is needed as part of an integral concept of health. 2

146 n Pneumonia caused by penicillinnonsusceptible Streptococcus pneumoniae treatment more expensive than treatment of pneumonia caused by susceptible strains, despite the disease being milder; higher costs due to longer hospital stay (26.8 vs 11.5 days) and more expensive medicines ($736 vs $213). 9 n In a study regarding patients undergoing surgery, the cost of infections due to resistant gramnegative bacilli was compared with infections due to nonresistant strains. The difference in the median hospital cost was $51,000 and the difference in the median cost for antibiotics was more than $1,800 per case. 10 PERSPECTIVES The economics of containing resistance Strategies to contain resistance are many. In a review, studies of strategies that looked at effectiveness and/ or cost-effectiveness were evaluated. 11 It was concluded that studies were generally: n of poor methodological quality (high risk of bias) n from developed nations (principally the USA) n not measuring the cost impact of ABR n micro (institution) not macro (community) n focused on transmission of resistance, not emergence This creates a two-fold problem: n Because of uncertainty, the evaluation of strategies to reduce transmission is easier to undertake than evaluation of strategies to control emergence, and because of discounting of future benefits, strategies to The consequences of current use (and misuse) of antiobiotics could lead to the loss of all the advantages in medical care that they have brought about. reduce transmission are likely to appear more cost-effective than strategies to control emergence. n Micro policies generally to contain transmission are more likely to be rigorously evaluated but macro policies generally to contain emergence are more likely to be socially optimal in the long-term. Urgent needs n More work to develop and undertake macro-economic evaluation. n Assessment of the wider impact of resistance on health care delivery, thus focusing on the wider cost rather than the narrow direct implications of resistance. SUGGESTIONS FOR FURTHER READING n Coast J, Smith R, Miller MR. Superbugs: should antimicrobial resistance be included as a cost in economic evaluation? Health Economics, 1996; 5: n Coast J, Smith RD, Millar MR. An economic perspective on policy for antimicrobial resistance. Social Science and Medicine, 1998; 46: n Coast J, Smith RD, Karcher AM, Wilton P, Millar M. Superbugs II: How should economic evalutation be conducted for interventions which aim to reduce antimicrobial resistance? Health Economics, 2002; 11(7): n Cosgrove SE, Carmeli Y. The impact of Antimicrobial Resistance on Health and Economic outcomes. Clinical Infect Dis 2003; 36: n Wilton P, Smith RD, Coast J, Millar M. Strategies to contain the emergence of antimicrobial resistance: a systematic review of effectiveness and cost-effectiveness. Journal of Health Services Research and Policy, 2002; 7(2): n Smith RD, Yago M, Millar M, Coast J. Assessing the macroeconomic impact of a healthcare problem: the application of computable general equilibrium analysis to antimicrobial resistance. Journal of Health Economics, 2005; 24: n Smith RD, Yago M, Millar M, Coast J. A macro-economic approach to evaluating policies to contain antimicrobial resistance: a case study of methicillin-resistant Staphylococcus aureus (MRSA). Applied Health Economics and Health Policy, 2006; 5:

147 REFERENCES 1. American Society for Microbiology. Report of the ASM task force on antibiotic resistance. Antimicrob. Agents Chemother 1995 (suppl) John JF, Fishman NO: Programmatic role of the Infectious disease physician in controlling antimicrobial costs in the hospital Clin. Infect. Dis 1997; 24: Cox RA, Conquest C, Mallaghan C and Marples RR. A major outbreak of methicillin-resistant Staphylococcus aureus caused by e new phagetype (EMRSA-16) Journal of Hospital Infection 1995; 29: Witon P, Smith RD, Coast J, Millar M et al. Directly observed treatment for multidrug-resistant tuberculosis: an economic evaluation in the United States of America and South Africa. Int. J Tuberc Lung Dis 2001; 5 (12): Rajbhandary SS, Marks SM, Bock NN. Costs of patients hospitalized for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2004; 8: Carmeli Y, Elliopoulos G, Mozaffari E, Samore M: Health and Economic Outcomes of Vancomycinresistant Enterococci. Arch. Intern. Med. 2002; 162: Lautenbach E, Patel JB, Bilker WB, Edelstein PH, Fishman NO. Extended-spectrum beta-lactamaseproducing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes. Clin Infect Dis 2001; 32(8): Schwaber MJ, Navon-Venezia S, Kaye KS, Ben-Ami R, Schwartz D, Carmeli Y. Clinical and economic impact of bacteremia with extendedspectrum-beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother 2006; 50(4): Einarsson S, Kristjansson M, Kristinsson K, Kjartansson G et al. Pneumonia caused by Penicillin-non-susceptible and Penicillin-susceptibler Pneumococci in Adults: A Case- Control study. Scand. J. Infect. Dis 1998; 30: Evans H, Lefrak S, Lyman J, Smith R et al. Cost of Gram-negative resistance. Crit Care Med 2007; 35: Wilton P, Smith RD, Coast J, Millar M, Coast J. Assessing the macroeconomic impact of a healthcare problem: the application of computable general equilibrium analysis to antimicrobial resistance. Journal of Health Economics, 2005; 24: Postal address: ReAct Uppsala University Box 256 SE Uppsala Sweden Visiting address: Drottninggatan 4, 3 tr Uppsala, Sweden Phone: Fax: react@medsci.uu.se Web: 4

148 A fact sheet from ReAct Action on Antibiotic Resistance, First edition May 2007 Decline in Antibacterial Innovation Despite the increasing risk of antibacterial resistance, the number of new antibiotics has actually decreased in the past couple of decades. In the four five-year periods between 1983 and 2002, the number of new drugs introduced has fallen by 56%, from 16 new antibiotics between 1983 and 1987 to 7 new antibiotics between 1998 and The R&D pipeline for the near future does not appear to reverse this trend. In a study of the pipelines of the 15 largest pharmaceutical companies, which were responsible for 93% of antibiotics introduced between 1980 and 2003, there were only 5 antibacterials, or 1.6% of the pipeline for these companies. This contrasts to 5.4% of the pipeline that is dedicated to antiviral drugs New antibacterial agents approved in the United States, Source: Adapted from Spellberg (2004) Antibacterial, 1.6% Antiviral 5.4% Rest of Pipeline 93.0% R&D Pipeline of 15 Largest Pharmaceutical Companies. Source: Data from Spellberg (2004)

149 Major Pharmaceutical Companies Exiting the Market At the same time that the number of antibacterials in the pipeline is decreasing, a number of major pharmaceuticals have abandoned or sold off their antibiotic units: Aventis and Roche spun off their anti-infective business. BMS, Eli Lilly, Wyeth and Procter & Gamble ended discovery of anti-infectives. GlaxoSmithKline downsized its anti-infective discovery. 2 As of 2004, the antibacterial discovery programs of half of large pharmaceutical companies in the United States and Japan had been discontinued or decreased since Lack on Innovative New Drugs Combating antibiotic resistance requires more than just new drugs. Resistance to antibiotics frequently leads to resistance to the whole class of drugs, thus new classes of drugs are required to treat resistant bacteria, not just new drugs in existing classes. Since the discovery of the first antibacterial drugs in the 1930 s, over a dozen classes of antibiotics have been discovered, all but two of which were developed prior to No new classes were discovered in the 1970 s, 80 s or 90 s, and only recently have two new classes become available: Oxazolidinones (in 2000) and Lipopeptides (in 2003). 2, 3 A more in-depth analysis of the entire industry in 2005 paints a more optimistic picture. White found 70 drug candidates in the pipeline ranging from preclinical to pre-registration, 13 of which were in 5 new classes of antibiotics. 4 However, of the 44 candidates whose targets were available, most target gram-positive bacteria. Year Introduced Class of Drug 1935 Sulfonamides 1941 Penicillins 1944 Aminoglycosides 1945 Cephalosporins 1949 Chloramphenicol 1950 Tetracyclines 1952 Macrolides/ Lincosamides/ Streptogramins 1956 Glycopeptides 1957 Rifamycins 1959 Nitroimidiazoles 1963 Quinolones 1968 Trimethoprim 2000 Oxazolidinones 2003 Lipopeptides Antibacterial Pipeline by Bacterial Target 4 Bacterial Target # of candidates in pipeline Gram +Positive including Methicillin-resistant Staphlococcus aureus (MRSA), Glycopeptide/Vanomycinintermediate Staphylococcus aureus (GISA/VISA), Vanomycin-resistant Enterococci (VRE) 31 Respiratory Tract Infections, Multidrug-resistant strepto coccus pneumoniae (MDRSP) + H.influenzae 16 Gram Negative including Extended Spectrum Beta- Lacta mase (ESBL), cefotaxime, quinolone-resistant 7 Non-fermenters / Pseudomonas including carbapenem-resistant 5 Anaerobes 1 * Sum does not equal 44 as some drugs have multiple targets u ReAct links a wide range of individuals, organisations and networks around the world taking concerted action to respond to antibiotic resistance. u Our vision is that current and future generations of people around the globe should have access to effective treatment of bacterial infections. u ReAct believes that antibiotics should be used appropriately, their use reduced when of no benefit and their correct and specific use increased when needed. u ReAct believes that awareness of ecological balance is needed as part of an integral concept of health. 2

150 Additionally, all the drug candidates for new classes of drugs, when targets were disclosed, targeted only Gram Positive and RTI bacteria. There are no new class candidates for gram-negative bacteria. The contrast of White s data with that of Spellberg, which was restricted to the 15 largest pharmaceutical companies, suggests that smaller companies may be playing a larger role in developing new antibiotics. Of the 36 companies that White identifies as current discovers of antibacterials, only 6 are among Spellberg s top 15 largest pharmaceutical companies. Little Incentive to Innovate The priority given to an R&D project is determined, in part, by the net present value (NPV) of the drug, which weighs the expenses against the expected revenues in the future. 5 The higher the potential revenue of the drug, the higher the NPV and the resources a company is willing to risk in developing a treatment. Antibacterials stack very poorly against other therapeutic classes in terms of NPV: 5 Project therapeutic class Risk-adjusted NPV x $1,000,000 Musculoskeletal 1,150 Neuroscience 720 Oncology 300 Vaccines 160 Injectable antibiotic (Gm+) 100 Oral contraceptive 10 Several reasons can account for the relatively weak NPV of antibacterials: 5, 6 n Drug discovery for chronic diseases is more favorable because long-term treatment generates more revenue than the short-term treatment of antibiotics. n A large number of old antibiotics already exist, resulting in a high level of therapeutic competition for newly developed drugs. n R&D programs focus on broad-spectrum antibiotics, which may be counter to public health efforts to encourage narrow spectrum use of such drugs. Discouraging first-line use of new drugs can negatively impact sales. Creating Incentives for Innovation A number of interventions have been proposed for improving innovation in neglected diseases. Several of these mechanisms may also have potential in priming R&D for antibacterials as well. Generally, push mechanisms pay for inputs into the R&D process whether financial, transactional or timewise--that are required to bring a new drug to market, increasing the attractiveness of investing in neglected innovation. Some push mechanisms that have been proposed for neglected disease include: n Public compound libraries provide access to compound libraries to screen for potential antibacterial activity, reducing R&D costs 7, 8 n Patent pooling the collective management on intellectual property reduces transactional costs and IP barriers to innovation 9 While push mechanisms focus on the inputs to R&D, pull mechanisms focus on the outputs by paying for completed projects. Some proposed pull mechanisms have included: n Advanced Market Commitments creates a fund which establishes an agreement with countries and NGOs to pay a pre-determined per-unit price innovations that address a particular need 10 n Prize Funds provides a financial reward for new therapies addressing a specific health 11, 12 threat Product Development Partnerships. While push and pull mechanisms manipulate the current system of innovation, product-development partnerships (PDP) have had an important role in developing the pipeline for neglected diseases. 13 PDPs characteristically leverage the respective expertise of the public and private sectors to create and deliver innovative medicines in neglected diseases. While there were only 16 new drugs developed between 1975 and 1999 for tropical diseases and tuberculosis, 14 a recent study noted that there are currently 63 drug candidates in the pipeline. 13 Fifty percent of the projects were developed by multinational pharmaceutical companies under no profit, no loss models, half of which were developed with PDPs. However, 45% of the 63 projects were developed by PDPs in conjunction with small-scale business. These businesses, which required smaller possible returns on investment, operated under commercial, for-profit models. Drugs with novel mechanisms of action are needed to combat antibiotic resistance, and PDPs have proven effective in targeting such breakthrough therapies. 13 Only 8% of projects developed solely by industry focused on breakthrough therapies, while 49% of PDP projects and 63% of industry projects developed in conjunction with PDPs targeted breakthrough therapies. 3

151 References 1 Spellberg, Brad, et al. Trends in Antimicrobial Drug Development: Implications for the Future. Clinical Infectious Disease. Vol 38, May 1, Wenzel, Richard. The Antibiotic Pipeline- Challenges, Costs, and Values. New England Journal of Medicine, 351 (6) August 5, Powers, John H. Antimicrobial Drug Development Workshop, Presentation co-sponsored by FDA, IDSA, and the International Society of Anti-Infective Pharmacology. April 15-16, As cited in Infectious Disease Society of America, Bad Bugs, No Drugs, July White, Tony. New Antibacterials Inventory. EU Intergovernmental Conference on Antibiotic Resistance. December 9, Projan, Steve. Why is Big Pharma Getting Out of Antibacterial Drug Discovery? Current Opinion in Microbiology. Vol 6, pgs Charles, Patrick and Lindsay Grayson. The dearth of new antibiotic development: why we should be worried and what we can do about it. Medical Journal of Australia. 181 (10): As in the Special Program on Research and Training in Tropical Diseases, 8 As in the European Rare Disease Therapeutic Initiative, 9 As in SARS patent pool proposal. Simon, James, et al. Managing severe acute respiratory syndrome (SARS) intellectual property rights: the possible role of patent pooling. WHO Bulletin. 83 (9), September As in the proposal for a pneumococcal vaccine for developing countries. Levine, Ruth, Michael Kremer, Alice and Albright. Making Markets of Vaccines: Ideas to Action. Center for Global Development Such as Stiglitz, Joe. Scrooge and Intellectual Property Rights. BMJ Vol 333: Such as Love, Jamie and Tim Hubbard. A New Trade Framework for Global Healthcare R&D. PLoS Biology. 2(2): e Moran, Mary. A Breakthrough in R&D for Neglected Diseases: New Ways to Get the Drugs We Need. PLoS Medicine. Vol 2 (9) September Trouiller, Patrice, et al. Drug development for neglected diseases: a deficient market and a public-health failure. Lancet 359: Postal address: ReAct Uppsala University Box 256 SE Uppsala Sweden Visiting address: Drottninggatan 4, 3 tr Uppsala, Sweden Phone: Fax: react@medsci.uu.se Web: 4

152 The Antibiotic Innovation Study: Expert Voices on A Critical Need Sophia Tickell, November 2005

153 The Antibiotic Innovation Study: Expert Voices on A Critical Need November 2005 AcknowledgementS: This report attempts to capture the findings of a number of detailed interviews with experts in the field of drug discovery and development. As author of the report I take full responsibility for this interpretation and for any mistakes it may contain. I would like to thank all interviewees for their time, patience and valuable inputs in and outside the interviews. In particular Jeff Edwards, John Turnidge and Tony White gave generously of their time and expertise in this field, as did Lynn Marks who provided vital insights and knowledge. The report would not have been possible without the active support of the Editorial Board: Professor Otto Cars, Director, Strama; Dr Richard Laing, Medical Officer, Policy and Standards of Medicines, WHO; Dr Anthony So, Director Health and Innovation Program, Duke University; and Niclas Hallstrom, Director, Dag Hammarskjöld Foundation. I would like to thank Otto in particular for always making himself available for comment and insight in spite of a ferociously demanding schedule and multiple other commitments. Sophia Tickell November 2005 This study was supported by grants from the European Society of Clinical Microbiology and Infectious Diseases, ESCMID, and The Swedish Foundation for Strategic Research. Disclaimer: The Antibiotic Innovation Survey interviewed a broad range of decision-makers and stakeholders in the drug development process. The findings, interpretations, and conclusions expressed herein may not necessarily reflect the views of all the interviewees, who took part in this project in their personal capacity. Whilst based on information believed to be reliable, no guarantee can be given that it is accurate or complete.

154 Executive summary The world has woken up to hospital-acquired infections. MRSA regularly makes the headlines, its incidence is monitored and massive efforts are made to control its spread. It is important that this concern is not allowed to obscure an equally worrying reality: the dearth of innovation into new drugs needed to combat resistance. This report is a wake-up call to those who assume that because we have the antibiotics we need today, we will have them tomorrow. It is also a reminder that millions of people across the globe do not even have them today. The Antibiotic Innovation Study was undertaken to find out why there are so few new antibiotics in the pipeline and to ask experts and decision-makers in the drug development process what might be done to address this problem. All interviewed agree on the need for urgent and concerted action on the part of all stakeholders on the understanding that the prevailing market system cannot solve the problem. The study is not an in-depth research project. However, in presenting the views of senior experts it identifies important areas of analysis and signals where possible solutions might be found. The structure of the pharmaceuticals market does not provide the right incentives for sufficient investment in antibiotics to meet rapidly changing medical need. Only two new classes of antibiotics have been discovered in the past thirty years 1. Though new research is being done, much of it builds on existing medicines, and is therefore compromised when tackling resistance. The consequences, already discernible, are growing numbers of sick and untreatable patients and deaths associated with lack of access to effective antibiotics. The prognosis for five to ten years time is grave. There are a range of unmet medical needs in the antibiotic field that will require different solutions. Treatments are needed for new infections and emerging resistances in developed countries, particularly in the field of Gram negatives. Medicines for community-acquired resistant infections are needed in all markets. And new drugs are needed for diseases that predominantly occur in developing countries, such as TB and typhoid fever. Innovation for these countries needs to tackle both formulation and presentation of the treatment. Until now in the pharmaceutical industry s main markets, medical need and the need to make profit for shareholders have been broadly aligned. This is no longer the case and antibiotics now risk becoming subject to the same funding difficulties as the neglected diseases that plague developing countries. Historically much antibiotic research has been done by Big Pharma, yet smaller (Biotech) companies with reduced 1 See footnote 2

155 infrastructure costs and the ability to accept lower profit margins may prove more suited to antibiotic development. However, they will encounter the same difficulties as Big Pharma in obtaining funds for Phase III clinical trials. The reasons for antibiotics relatively poor return on investment are varied and inter-related. First, the most commercially profitable drugs treat the symptoms of chronic diseases. Antibiotics do not make so much money. Second, the pharmaceutical industry has consolidated, leaving fewer people in fewer companies doing antimicrobial research. Third, the science of antibiotic discovery is particularly difficult. Fourth, in a highly genericised market, the overall price antibiotics command is low. Fifth, the push to reduce antibiotic use to prevent the spread of resistance acts as a further disincentive. Sixth, the regulatory environment is increasingly risk averse and is particularly onerous for antibiotics. And finally, given that resistance inevitably develops for all antibiotics over time, the lifespan of these drugs is inherently limited. In light of the limited commercial potential of antibiotics, interviewees agreed that it is appropriate for government to step in to compensate for market failure. The study did not conclude what the precise nature of government intervention should be, but it did throw up interesting ideas. For some, government should work within existing market structures, investing substantially in early research, removing barriers to innovation, redefining what constitutes value for money in antibiotics and paying more for true innovation. Others favoured a more concerted effort that could amount to some sort of public private partnership. Some argued that the current situation should lead to questions as to how to de-link innovation from end-profit for non-commercial medicines. Interviewees identified a number of scientific challenges to antibiotic innovation and options that merit further research. Genomics still has great potential but investors and companies need to be more realistic about the complexity of the science and how long it will take to yield results. The development of a public library of rejected chemical substances could facilitate research into promising leads that are not otherwise pursued. Diagnostics could deliver many significant innovations including: a point of care test to differentiate between viral and bacterial infections; improvements in pre-clinical tests for pharmacology and toxicology for early identification of safety problems; the identification and validation of biomarkers; and the development of alternative biological endpoints to complement clinical endpoints. Successful research into a vaccine that specifically targets antibiotic-resistant bacteria could both prevent the spread of resistant infections and reduce antibiotic use and so avoid future resistance. The regulatory environment is also a vital determinant of antibiotic innovation. Regulations currently come down firmly on the side of risk aversion; a position that could usefully be tested against patient views. The study outlines suggestions on how to remove barriers to innovation in the regulatory process. The whole clinical trial process could be more efficient and amendments made to the rigorous antibiotic trial requirements. There are various possible means of delivering short cuts on Phase III the most expensive of all the trial phases including; improved diagnostics and improving statistical probability measurements. Reducing the number of patients in trials and increasing post-marketing surveillance would help, but the benefits of conditional registration are not straightforward when resistance is factored in. Of existing tools that help facilitate registration, fast track and priority review already work for antibiotics though speeding up the process further would offer particular benefits to smaller companies and help meet the specific antibiotic needs of developing countries. Orphan drug legislation is not necessarily transferable to antibiotics due to a larger and less predictable patient base and because the costs to health budgets could prove prohibitively high. Nor is Orphan Drug appropriate for developing countries which need cheap and simple first-line therapies. Increased prices could provide a financial incentive for antibiotic innovation, though reimbursement authorities would need to calculate health budgets differently and be persuaded of the value associated with the increased price. Even if they were, price increases do not address the financial access barriers posed to developing countries and uninsured people, or the fact that health budgets everywhere are under severe strain. The possibility of producing different categories of antibiotics which are priced differently could be considered. There was unanimous agreement that even if market incentives work for some new antibiotics, other medical needs would still not be met. For some, government intervention should be limited to an injection of capital to support a scouting fund to identify and buy research. For others, government should be involved from start to finish in some sort of formal public private partnership (PPP), including funding early research and advance purchasing agreements. This involvement could facilitate the retention and development of the antimicrobial scientific-knowledge base, currently at risk of being lost. Despite enthusiasm for intervention, reservations about the transferability of existing PPP models to antibiotics were expressed. Any antibiotic resulting from a PPP could have significant commercial potential in richer markets, making management of intellectual property and discussions about price much more complicated than existing agreements. Interviewees acknowledged that the consolidation of technology and knowledge within the pharmaceutical industry means that many scientists lack expertise on key aspects of translational research. Existing PPPs have not solved the question of how to make the project independent of public funding. Nor should it be assumed that a PPP would be capable of meeting developed and developing country needs simultaneously. The study concludes that urgent, concerted action is needed by scientists, doctors, pharmacists, governments, the pharmaceutical industry, regulators, purchasers, investors, patients and insurance firms. If not we will be left, in the words of one interviewee asking 21 st century patients to accept 19 th century medicine.

156 RESEARCH LETTERS Sex (age at Time between Site and Outcome (months onset of onset of AECP type of cancer between diagnosis AECP,years) and cancer of cancer and death) M (62) + 8 years Lung/large cell Deceased (6) F (85) - 1 monthcolon/adeno Alive M (51) + 2 months Lung/adeno Deceased (0) F (70) - 8 months Endometrial/adeno Deceased (13) M (60) + 6 months Stomach/adeno Deceased (16) F (47) + 10 months Stomach/adeno Deceased (11) F (76) + 14 months Colon/adeno Alive F (59) + 12 months Endometrial/adeno Deceased (3) F (39) + 11 months Lung/adeno Deceased (21) M (66) + 1 monthstomach/adeno Deceased (10) Adeno=adenocarcinonia Summary data of AECP patients with cancer observed which gave a RR of 7 7 (95% CI: ). While 0 39 cancers were expected to occur in the latter cohort during their first year of observation, six cancers were observed which gave a RR of 15 4 ( ). IgG antibodies to laminin 5 were not present in the serum of any controls. Patients with AECP had an RR for cancer that was similar to that for malignancy among adults with dermatomyositis; as with dermatomyositis, the RR for cancer in these patients was particularly high in the first year of disease. Several older reports noted an association between bullous pemphigoid and cancer. 4 Whereas several studies have dismissed this association, controversy persists and centers on seronegative patients with mucosal involvement. 5 This potential association was suggested at a time when AECP was not distinguished from bullous pemphigoid, and when most AECP patients would have been thought to be seronegative (based on the lower sensitivity of assays previously used to detect autoantibodies). Accordingly, it is possible that the suggested association between bullous pemphigoid and cancer was based on cohorts including a disproportionate number of patients with AECP. We considered several potential sources of bias. Ascertainment bias could have resulted in the preferential inclusion of patients at high risk of cancer for reasons unrelated to the primary risk factor under study (ie AECP). We thought this bias unlikely since all AECP patients were assembled before any suspected association between disease with cancer. Moreover, patients in this series were not watched more closely for cancer. Most cancers developed after patient enrollment and the relative proportion of patients with cancer was consistent throughout the study, (three cancers after enrolment of ten patients, six cancers after enrolment of 21 patients, and ten cancers in the entire cohort of 35). That 80% of patients with AECP who had cancer died within 21 months of cancer diagnosis also made it unlikely that the diagnosis of cancer in this cohort was fortuitous and early. The comparison of cancer incidence among AECP patients at tertiary care medical centres with that in the general population could have been an invalid comparison; however several studies found the incidence of cancer in patients with bullous pemphigoid (or other skin diseases) at tertiary care medical centers to be approximately 10%, well below the 29% incidence that we found. We also considered the potential bias introduced by forms of treatment. Drugs commonly used in AECP patients (eg, glucocorticosteroids or cytotoxic drugs) can increase cancer risk. However, some patients had relatively mild disease and did not require treatment with such drugs. In those receiving glucocorticosteroids or cytotoxic drugs, the interval between the onset of AECP and cancer was so short that it was unlikely that the drugs caused the cancer. Moreover, cancers identified in AECP patients were solid cancers rather than lymphomas or leukaemias which are more commonly associated with exposure to such drugs. We thank all physicians who referred patients to this study and the Cooperative Human Tissue Network (Philadelphia, PA, USA) for providing serum samples on 50 controls with solid cancers. 1 Yancey KB, Egan CA. Pemphigoid: clinical, histologic, immunopathologic, and therapeutic considerations. JAMA 2000; 284: Domloge-Hultsch N, Gammon WR, Briggaman RA, Gil SG, Carter WG, Yancey KB. Epiligrin, the major human keratinocyte integrin ligand, is a target in both an acquired autoimmune and an inherited subepidermal blistering skin disease. J Clin Invest 1992; 90: Lazarova Z, Hsu R, Yee C, Yancey KB. Human anti-laminin 5 autoantibodies induce subepidermal blisters in an experimental skin graft model. J Invest Dermatol 2000; 114: Schroeter AL. Pemphigoid and malignancy. Clin Dermatol 1987; 5: Hodge L, Marsden RA, Black MM, Bhogal B, Corbett MF. Bullous pemphigoid: the frequency of mucosal involvement and concurrent malignancy related to indirect immunofluorescence findings. Br J Dermatol 1981; 105: Dermatology Branch, Division of Clinical Sciences National Cancer Institute, National Institutes of Health, Bethesda, MD, , USA (C A Egan MD, Z Lazarova MD, T N Darling MD, C A Yee BSc, K B Yancey MD) and Cancer Statistics Branch, National Cancer Institute, National Institutes of Health, Rockville, MD (T Coté MD) Correspondence to: Dr Conleth A Egan, Dermatology Branch, NCI, Building 10 Room 12N238, National Institutes of Health, Bethesda, MD USA, ( tegan@box-t.nih.gov) Variation in antibiotic use in the European Union Otto Cars, Sigvard Mölstad, Arne Melander Data on antibiotic use are not publicly available in most European Union countries. We obtained data for non-hospital antibiotic sales for 1997 from the 15 member states and analysed these according to the Anatomic Therapeutic Chemical classification system, and expressed them as defined daily doses per 1000 people per day. Sales of antibiotics varied more than four-fold: France (36.5), Spain (32.4), Portugal (28.8), and Belgium (26.7) had the highest sales, whereas the Netherlands (8.9), Denmark (11.3), Sweden (13.5), and Germany (13.6) had the lowest. There was also profound variation in use of different classes of antibiotics. Detailed knowledge of antibiotic use is necessary to implement national strategies for optimum antibiotic use, and to address the threat posed by resistant microorganisms. International efforts are needed to counteract the growing problem of antimicrobial resistance. 1 Although antibiotic use at population level is probably an important risk factor, 2 data on antibiotic sales have not been publicly available and few international comparisons have been made. We have assessed and compared non-hospital use of antibiotics in the 15 member states of the European Union (EU). The term antibiotics encompasses both semisynthetic derivatives of antibiotics and wholly synthetic compounds used as antibacterial agents eg, sulphonamides, trimethoprim, and fluoroquinolones. Data for national sales of antibiotics in 1993 and 1997 were purchased from Institute for Medical Statistics (IMS), Health Global Services, UK, for 13 of the 15 EU countries. This private company gathers data from different sources including manufacturers, wholesalers, pharmacies, prescribing doctors, and hospitals, and calculates national estimates. Data from Sweden and Denmark were obtained from the National Corporation of Swedish Pharmacies and the Danish Medicine Agency, respectively. The National Corporation of Swedish THE LANCET Vol 357 June 9, For personal use. Only reproduce with permission from The Lancet Publishing Group.

157 RESEARCH LETTERS 40 Defined daily dose per 1000 inhabitants per day Others* Macrolides and lincosamides J01F Quinolones J01M Trimethoprim J01EA Tetracyclines J01A Cephalosporins J01D Penicillinase-resistant penicillins J01CF Narrow-spectrum penicillins J01CE Broad-spectrum penicillins J01CA 5 0 France Spain Portugal Belgium Luxembourg Italy Greece Finland Ireland UK Austria Germany Sweden Denmark Netherlands Outpatient antibiotic sales in 1997 in the European Union *Includes sulphonamides, penicillinase-resistant penicillins, amphenicols, aminoglycosides, and glycopeptides. Pharmacies collects, stores, and compiles data on all drugs dispensed in Swedish pharmacies, all of which belong to this corporation. Data from Denmark were available only for 1997 and included all outpatient sales from community pharmacies. Hospital sales were obtained from nine countries and accounted for 7 15% of total sales in each country. Because hospital data was not available from other countries, only non-hospital sales were used in the final analysis. Swedish and Danish data were obtained as defined daily dose according to the Anatomic Therapeutic Chemical classification system defined by WHO Collaborating Centre for Drug Statistics Methodology. 3 Defined daily dose is a unit based on the average daily dose used for the main indication of the drug. Sales data from Institute for Medical Statistics Health were examined and adjusted according to the Anatomic Therapeutic Chemical classification. Antibiotics for systemic use (Anatomic Therapeutic Chemical J01) only were included in the subsequent analysis. To make comparison easier, the amount of antibiotic (kg) was converted to defined daily dose (where possible). For antibiotics not given a defined daily dose by WHO, we used the common daily dose in published work. Where such an estimate was not possible (less than 0 01% of total), we excluded data from analysis. Oral defined daily dose was used for antibiotics with different routes of administration. For antibiotics marketed both alone and in combinations (eg, trimethoprim and sulphonamides), amounts of the individual compounds were accounted for separately. For antibiotics combined with a lactamase inhibitor, only the amount of the antibiotic was included. We could compare publicly available data 4 and IMS data on total non-hospital antibiotic use only in Finland. The two sources differed by less than 11%, and showed a similar distribution of antibiotic classes. The number of inhabitants in the EU Broad-spectrum Narrow-spectrum Penicillinase Cephalosporins Tetracyclines Trimethro- Quinolones Macrolides Others* Total penicillins penicillins resistant J01D J01A prim J01M and lincos- J01CA J01CE penicillins J01EA amides J01CF J01F Austria Belgium Denmark FInland France Germany Greece Ireland Italy Luxembourg Portugal Spain Sweden The Netherlands UK Numbers are defined daily dose per 1000 inhabitants per day. *Includes sulphonamides, amphenicols, aminoglycosides, and glycopeptides. Highest defined daily dose. Lowest defined daily dose. Outpatient antibiotic sales in 1997 in the European Union 1852 THE LANCET Vol 357 June 9, 2001 For personal use. Only reproduce with permission from The Lancet Publishing Group.

158 RESEARCH LETTERS was obtained from Eurostat, 5 enabling us to convert sales data to defined daily dose per 1000 inhabitants per day. Seven countries showed an increase in antibiotic use of less than 4% between 1993 and Large increases were noted in Italy (34%) and Luxembourg (12%). A reduction in antibiotic use was seen in five countries: Sweden had the largest (21%) and Greece the smallest (4%). In 1997, there was a more than four-fold variation between countries in non-hospital use of antibiotics. France had the highest use, and the Netherlands, the lowest (figure, table). In 11 of the 15 countries, the most commonly used antibiotic was broad-spectrum penicillin, which varied between 56% (Spain) and 20% (Germany) of total sales. In Finland the most common drug was a tetracycline (28%), in Austria a macrolide (26%) and in Denmark and Sweden narrow-spectrum penicillins (40% and 36%, respectively). Total defined daily dose per 1000 inhabitants of all lactam antibiotics (penicillins and cephalosporins) was six times higher in France (23 0) than in Netherlands (3 6). Cephalosporins were used most in Greece (4 7) and least in the Netherlands (0 12). The highest use of tetracyclines was in Finland (5 5). Quinolones were most widely used in Portugal (4 0) (table). The most important finding in this analysis was the great variation in outpatient antibiotic use. The large variation is unlikely to be caused by differences in frequency of bacterial infections. The pronounced differences between Belgium and the Netherlands are noteworthy because of the close proximity of the countries and their common language. In addition to physicians and patients attitudes to antibiotics, historical backgrounds, cultural and social factors, and disparities in health-care systems might also be important factors in determining prescribing patterns. We did not have sufficient data to describe between-country variability of dose regimens, length of treatment, or availability of antibiotics without prescription. These results strengthen the view that antibiotics could be used more effectively in many countries. Further analyses of antibiotic use by age-group, setting, and indication are required. The threat posed by resistant microorganisms could be reduced if all countries gathered data on antibiotic prescriptions. We therefore encourage EU member states to challenge the IMS data presented in this study and to do comparable epidemiological studies on antibiotic prescribing and resistance. 1 Wise R, Hart T, Cars O, et al. Antimicrobial resistance is a major threat to public health. BMJ 1998; 317: Melander E, Ekdahl K, Jönsson G, Mölstad S. The frequency of penicillin-resistant pneumococci in children is correlated to the community-level utilisation of antibiotics. Pediatr Infect Dis J 2000; 19: ATC Index with DDDs. Oslo: WHO Collaborating Centre for Drug Statistics Methodology, Nordic Statistics on Medicines. Uppsala: Nordic Council on Medicines, Demographic statistics. Brussels: Eurostat, (ISBN ) Department of Infectious Diseases, Uppsala University Hospital, Uppsala (Prof O Cars MD); STRAMA, Swedish Strategic Programme for the Rational Use of Antimicrobial Agents and Surveillance of Resistance, Swedish Institute for Infectious Disease Control, Solna, S , Stockholm, Sweden (O Cars MD, S Mölstad MD, Prof A Melander MD); Unit of Research and Development in Primary Health Care, Mjölby, Östergötland (S Mölstad, MD); NEPI Foundation, Malmö and Stockholm (S Mölstad MD, Prof A Melander MD); Department of Community Medicine, Medical Research Centre, Malmö University Hospital (Prof A Melander MD) Correspondence to: Prof Otto Cars ( otto.cars@smi.ki.se) Western and eastern European trends in testicular cancer mortality Fabio Levi, Carlo La Vecchia, Peter Boyle, Franca Lucchini, Eva Negri Testicular cancer is curable if treated appropriately. We used national mortality data to compare specific death rates from the disorder in western and eastern Europe, the USA, and Japan. Testicular cancer mortality rates have fallen by about 70% in the USA and western Europe since the 1970s. In eastern Europe, however, death rates from testicular cancer have been declining only since the late 1980s, and at a much slower rate than that recorded elsewhere (about 20%). Consequently, many avoidable deaths, mainly in young adults, are still occurring in eastern Europe. Available effective treatment strategies for testicular cancer must be implemented in these countries. Testicular cancer is generally curable if appropriate treatment is given. Despite a rise in the number of patients with testicular cancer since the 1970s, mortality rates have fallen in North America 1 and western Europe. 2 In men aged 45 years and younger, mortality rates fell by about a third in the late 1980s by comparison with rates registered in the 1970s ie, 500 deaths per year in Europe are now prevented. 2 Mortality rates began to decline in the 1980s in Poland, Czechoslovakia, and East Germany, but at a slower rate than that recorded in USA and western Europe. 3 Trends in testicular cancer rates should, therefore, be monitored especially carefully in eastern Europe, to identify whether they continue to drop and at what pace. Cancer of the testis is a good indicator of progress in adult cancer treatment worldwide. Our aim was to do a systematic analysis of trends in testicular cancer mortality in Europe, the USA, and Japan. 2 We derived official death certification numbers from the WHO Database, and recoded them according to the Ninth Revision of the International Classification of Diseases. We obtained estimates of the resident population from the same WHO database. Age-standardised rates were based on the world standard population. 1,2 The figure shows trends in certified mortality from testicular cancer at age years in four broad geographic areas. In the European Union (EU) and in six countries of central and eastern Europe, peak mortality rates (1 6/ and 1 7/ , respectively) were reached in the 1970s. Since that date, mortality rates have fallen in this age group by 67% in the European Union. However, in eastern European countries, after a peak in the late 1970s, the decline in mortality has been Rate per Eastern Europe European Union USA Japan Calendar period Trends in age-adjusted (world population) death certification rates from testicular cancers in men aged years Eastern European countries represented are Bulgaria, Czech Republic, Hungary, Poland, Romania, and Slovakia. THE LANCET Vol 357 June 9, For personal use. Only reproduce with permission from The Lancet Publishing Group.

159 Correspondence Getty Images Computerised clinical decision support in rural China As you note in your Nov 8 Editorial (p 1608), 1 a new draft of the Chinese health-care system reform plan was pub lished on Oct 14, The government understands that improving the qua lity of health care in rural areas is vital. The low quality of the health-care service in rural areas is largely due to the low educational level of many physicians in those areas. Data from the Ministry of Health 2 indicate that, in China as a whole, more than 60% of medical practitioners (excluding assistant medical practitioners) have 3 years or fewer of professional training, and around 30% of the whole medical force has only a senior highschool level of education. The average level of education is even lower in rural areas. 3 It would take too long to retrain most of these doctors to 21st-century stan dards. However, with extra funding, it might be possible to boost their performance by equipping them with a computerised clinical-decision support system. Such systems have greatly improved over the past 30 years. 4,5 A system tailored to rural doctors could work as an electronic manual, allowing physicians to follow diagnostic algorithms, and providing updated treatment plans and prevention guidelines something that rural doctors might never have learned before. A tailored computerised support system for rural doctors in China could be deve loped with today s advanced technology, within a short time, and at low cost. China has acknowledged problems with its health service, and, by leapfrogging ahead to computerassisted diagnosis and treatment, might be able to overcome some of its present difficulties. We declare that we have no conflict of interest. *Wenbin Liang, Colin W Binns, Andy H Lee wenbin.liang@postgrad.curtin.edu.au School of Public Health, Curtin University of Technology, Perth, WA 6102, Australia 1 The Lancet. China unveils plans for health-care reform. Lancet 2008; 372: Ministry of Health of the People s Republic of China. Percentages of medical professionals by sex, age, qualification and title in China health statistics yearbook Beijing: Ministry of Health of the People s Republic of China, Wang J, Kushner K, Frey JJ 3rd, Ping Du X, Qian N. Primary care reform in the Peoples Republic of China: implications for training family physicians for the world s largest country. Fam Med 2007; 39: Berner ES, Webster GD, Shugerman AA, et al. Performance of four computer-based diagnostic systems. N Engl J Med 1994; 330: Garg AX, Adhikari NK, McDonald H, et al. Effects of computerized clinical decision support systems on practitioner performance and patient outcomes: a systematic review. JAMA 2005; 293: Antibiotic resistance in China a major future challenge Longde Wang and colleagues (Nov 1, p 1697) 1 outline the future challenges posed by infectious diseases in the Chinese context. Infectious diseases remain a major problem in China today and Wang and colleagues provide a comprehensive review of current and emerging infectious diseases and their control. Strikingly, however, the increasing threat of antibiotic resistance is only briefly mentioned. The situation with respect to overuse of antibiotics and antibiotic resistance in China is severe. 2 Several factors are involved, including a health system with strong financial incentives for drug prescribing. 3 Around 75% of patients with seasonal influenza are estimated to be prescribed antibiotics, and the rate of antibiotic prescription to inpatients is 80%. 4 In a study of resistance patterns of several common bacteria in China in 1999 and 2001, 5 the mean prevalence of resistance among hospital-acquired infections was as high as 41% and that among community-acquired infections was 26%. China also has the world s most rapid growth rate of resistance (22% average growth in a study spanning 1994 to 2000). 5 The faceless threat of antibiotic resistance is likely to be one of the greatest challenges to global health during the 21st century, with a direct effect on health indicators in lowincome, middle-income, and highincome countries. It is positive that China s new health system reform suggests a pharmaceutical policy that includes a strategy for rational drug use. What happens in China matters for the world. We declare that we have no conflict of interest. *Andreas Heddini, Otto Cars, Sun Qiang, Göran Tomson andreas.heddini@smi.se Centre for Microbiological Preparedness, Swedish Institute for Infectious Disease Control, Nobels väg 18, SE Solna, Sweden (AH); Action on Antibiotic Resistance, Uppsala University, Uppsala, Sweden (OC); Center for Health Management and Policy, Shandong University, Jinan, China (SQ); Division of International Health, Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden (GT) 1 Wang L, Wang Y, Jin S, et al. Emergence and control of infectious diseases in China. Lancet 2008; 372: Reynolds L, McKee M. Factors influencing antibiotic prescribing in China: an exploratory analysis. Health Policy 2008; published online Oct 13. DOI: / j.healthpol Sun Q, Santoro MA, Meng Q, Liu C, Eggleston K. Pharmaceutical policy in China. Health Aff 2008; 27: Zheng Y, Zhou Z. The root causes of the abuse of antibiotics, harm and the rational use of the strategy. Hospital Management Forum 2007; 123: (in Chinese). 5 Zhang R, Eggleston K, Rotimi V, Zeckhauser RJ. Antibiotic resistance as a global threat: evidence from China, Kuwait and the United States. Global Health 2006; 2: 6. Department of Error Clarke SE, Jukes MC, Njagi JK, et al. Effect of intermittent preventive treatment of malaria on health and education in schoolchildren: a clusterrandomised, double-blind, placebo-controlled trial. Lancet 2008; 372: In this Article (July 12), in paragraph four of the Results section (p 134), the second sentence should have read: The effect size was 0 18 (95% CI ) in the counting sounds test and 0 48 ( ) in the code transmission test Vol 373 January 3, 2009