Meeting the Challenge of Antibiotic Resistance

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 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 ofThe Peoples Republic of China andThe Government of the Kingdom of Sweden concerning Health cooperation, antibiotic resistance is one of the fields selected in the Plan ofAction signed in September 2007.

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,(www.reactgroup.org)

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. 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 应对抗抗生生生素耐药性素耐药性的的挑战挑战

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

应对抗生素耐药性的挑战瑞典的经验

背景和介绍

抗抗抗生抗生生生素耐药性素耐药性－－－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 www.reactgroup.org 。

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。

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. 抗抗抗生抗生生生素耐药性素耐药性－－－无形的的的威胁的威胁，作者：Cars O, Nordberg P

3. 应对抗抗抗生抗生生生素耐药性素耐药性的的的挑战的挑战，，，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. 加强对抗抗抗生抗生生生素耐药性素耐药性的的的控制政策的控制政策（（（世界（世界卫生大会）））

6. 消费者和供应者－－－他们能更好的使用抗抗抗生抗生生生素素素素吗吗吗吗？？？？作者：Nordberg P, Stålsby Lundborg C,Tomson G

7. 从经济层面看抗抗抗生抗生生生素耐药性素耐药性－－－应对抗生素抗抗抗药性行动抗药性行动组织（（（ReAct（ReAct 简称再度行动组织）））的案）的案例例例报道例报道

8.8.8. 抗抗抗生素创新的衰退抗生素创新的衰退－－－应对抗生素抗抗抗药性行动抗药性行动组织（（（ReAct（ReAct 简称再度行动组织）））的）的的的案例案例报道

9. 应对抗生素抗抗抗药性行动抗药性行动组织对对对抗对抗抗抗生生生生素素素素开发创新的开发创新的研究－－－危急中专家的呼声作者：Tickell S

10. 欧盟内部抗生素使用的差异，，，作者，：Cars O, Mölstad S, Melander A.

11. 抗抗抗生抗生生生素耐药性素耐药性在在在中国在中国－－－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

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

potential post-antibiotic era is threatening present Figure 1. Global mortality from infectious diseases. and future medical advances. The current world- millions of death, worldwide, all ages Awide 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. Source: World Health Report 2003. Mortality as a result of infectious diseases represents one-fifth of global deaths1; respiratory infections are the A GLOBAL PROBLEM leading killer, causing nearly four million deaths annually (Figure 1). These deaths are to some extent regarded as pre- In the late 1940s, after less than a decade of penicillin being ventable with increased access to health care and medicines. used to treat patients with infectious diseases, unresponsive However, the global emergence and spread of bacteria that strains of the bacterium Staphylococcus aureus, the leading resist antibiotics is raising the question as to whether this is cause of hospital-acquired infections, were detected in still the case, especially in parts of the world where second English hospitals.2 A striking example of biological evolu- and third line antibiotics are unavailable. Considering that tion had begun: bacterial strains with natural and acquired the escalating medical and economic consequences of anti- resistance were being selected as a result of the use of biotic resistance are generally well known by medical antibiotics. About a decade later the first report on resist- professionals and political actors, the inertia surrounding ance to the second generation of penicillins arrived; it came the issue is difficult to explain. The vagueness of the inter- from a Boston hospital, where methicillin-resistant strains national response and the failure to translate existing of Staphylococcus aureus (MRSA) had been identified.3 knowledge into concrete action are serious problems. This MRSA has become a symbol of antibiotic-resistant bacteria complacency on the part of global society needs urgently to and is without doubt one of the best-studied pathogens. be replaced by concerted action to reduce the present and Since the 1980s the frequency of isolates of MRSA among future consequences of antibiotic resistance. Staphylococcus aureus has increased from close to zero to

A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5–7 MAY 2004 - BACKGROUND DOCUMENT

nearly 70 per cent in Japan and the Republic of Korea, 30 Figure 2. Global spread of the penicillin-resistant Pneumococcus strain 23F. 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 medical professionals in their clinical practice. For many side effects. Globally, escalating levels of the multiresistant years, society’s medical needs for antibacterial drugs were intestinal pathogens Salmonella and Shigella cause severe met by the pharmaceutical industry. An apparent symbiosis infections that are difficult to treat, especially in children. between the interests of the community and those of the In Shigella strains from Indonesia, Thailand and India 80- industry prevailed. In the 1970s, innovative research to 90 per cent resistance is seen for two or more antibiotics.4 develop new antibiotics gradually waned, and the focus of Resistance to remaining effective therapy, such as fluoro- research and development shifted to the fine-tuning of quinolones, is steadily increasing, and the industry pipeline existing products. As resistance to antibiotics accelerated, for antibiotics against important intestinal pathogens is the fragile relationship between the community and the running dry. pharmaceutical industry began to break down. No country on its own can isolate itself from resistant New antibiotics almost instantly faced the problem of bacteria. Antibiotic resistance is a growing international the evolution of bacterial resistance after being put on the problem affecting both current and future generations. market and the short durability of antibacterial drugs was Resistance that develops in one area of a country may easily giving pharmaceutical companies cold feet. The industry spread nationwide. Globalisation, with increased migration, began increasingly to weigh up its liabilities towards share- trade and travel, has widened the range for infectious dis- holders on the one hand and public trust and accountability eases. A resistant strain of Streptococcus pneumoniae, first to the community at large on the other. Difficulties arose as identified in Spain, was soon afterwards found in Argentina, financial performance confronted the common good. The Brazil, Chile, Taiwan, Malaysia, the USA, Mexico, The cleft between public and private interests grew wider with Philippines, the Republic of Korea, South Africa and the development of national and international drug policies Uruguay (Figure 2).5 Such examples underline the fact aimed at containing resistance and restricting and rational- that no single country can protect itself from the threat of ising the use of antibiotics. Sharpened demands from regu- resistant bacteria as pathogens are spreading across inter- latory bodies have increased the development cost of new national, cultural and ethnic boundaries. Although the medicines, and prioritising measures to secure optimal effects of antibiotic resistance are more documented in returns on investment have driven the industry into other industrialised countries, there is a greater potential for pharmaceutical areas with bigger and safer markets. At harm in the developing world, where many of the second present, the industry’s ventures are shifting from therapy for and third line therapies for drug-resistant infections are acute conditions towards long-term treatment of chronic unavailable and unaffordable. 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 SYSTEM FAILURE the potential success of products. However, the need for A thorough inventory of biological compounds with anti- antibiotics is anticipated to remain consistently high. From biotic activity followed the introduction of penicillin. a broad societal perspective, the industry might be expected Substances with different target mechanisms to attack to supply communities with good drugs at affordable prices bacteria were developed into new categories of antibiotics and provide reliable information on them. Today, this is not by the pharmaceutical industry and were eagerly used by the case.

A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5–7 MAY 2004 - BACKGROUND DOCUMENT

THE CAUSES OF RESISTANCE Once resistant strains are selected, their spread is promoted by factors such as overcrowding and poor hygiene. One Resistance is a natural biological outcome of antibiotic use. example is day care centres, which provide ample oppor- The more we use these drugs, the more we increase the tunities for the transmission of infectious diseases and, in speed of emergence and selection of resistant bacteria. In particular, the emergence of resistant Streptococcus pneu- human use, around 80 per cent of antibiotic consumption moniae. The combination of the presence of young, suscep- takes place in the community and at least half of this is tible children suffering from recurrent infections and the considered based on incorrect indications, mostly viral infec- use of multiple, often broad-spectrum antibiotics makes 6 tions. The mechanisms behind this overuse are many and such environments ideal for the carriage and transmission intricate. The short-term advantages of antibiotic use for of these bacteria. In the hospital setting, some bacterial patients, health care workers and drug distributors seem to clones have been more successful than others in spreading overweigh concerns about future consequences (Figure 3). extensively. One example of the rapid dissemination of such The almost overwhelming complexity of factors influencing epidemic clones is the MRSA epidemic in England and Figure 3. Individual advantages Wales where the frequency of MRSA among Staphylococcus versus future consequences 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 1989-2002

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 Netherlands7 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, ANTIBIOTICS FOR NON-HUMAN USE inadequate dosing and poor adherence to therapy, may play Following their success in medicines for human beings, as important a role in driving resistance as overuse.9 The antibiotics have been increasingly used to treat and prevent use of broad-spectrum antibiotic agents as a substitute for diseases in animals, fish and plants. Besides this, sub-thera- precise diagnostics or to enhance the likelihood of therapeutic peutic doses of antibiotics have been shown to have growth- success increases the rate of selection of resistant bacteria. In enhancing effects and have for decades been intensively used addition, counterfeit and substandard drugs contribute to in animal-rearing practices. In Europe and North America, sub-optimal concentrations of antibiotics, failing to control antibiotic use in the animal sector constitutes around half of bacterial populations that are considered a risk factor for the total consumption.12 In 1987 more than 90 per cent of developing resistance. It is estimated that over 50 per cent the drugs used on animals in the United States was admin- of antibiotics worldwide is purchased privately, from phar- istered without veterinary consultation.13 Within the macies or in the informal sector from street vendors, with- European Union most antibiotics in feedstuff have been out prescriptions. Half of the purchases are for one-day prohibited for a number of years, but in many countries treatments or less, an example reflecting the magnitude of large numbers of animals, irrespective of their health status, the problem.10 are exposed daily to sub-therapeutic concentrations of

A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5–7 MAY 2004 - BACKGROUND DOCUMENT

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

A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5–7 MAY 2004 - BACKGROUND DOCUMENT

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

A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5–7 MAY 2004 - BACKGROUND DOCUMENT

REFERENCES:

1. WHO (2003). Shaping the future, World Health Report 2003. 12. WHO fact sheet on Antimicrobial resistance, 2002, http://www.who.int/mediacentre/factsheets/fs194/en/print.html. 2. Cohen ML. Epidemiology of drug resistance: Implications for a post- (Accessed 30 June 2004). antimicrobial era. Science 1992;257:1050-55 13. Stöhr K, Problems from antimicrobial use in farming. Essential Drug 3. Barrett FF, McGehee RF, Finland M. Methicillin-resistant Monitor, 2000, Issue no. 28-29: 10-11. Staphylococcus aureus at Boston City hospital. N Engl J Med 1968;279:441. 14. Fasehun F, The antibacterial paradox: essential drugs, effectiveness, and cost. Bull World Health Organ, 1999; 77(3): 211-216. 4. Okumura J, Osaka K, Okabe N, Widespread Multi- Antimicrobial–Resistant Shigella in Asia: What Does It Mean? 15. Turnidge J, Impact of Antibiotic Resistance on the Treatment of Sepsis. Abstract No. AM 011, International Conference on Improving Use of Scandinavian Journal of Infectious Diseases, (2003); 35: 677-682. Medicines, 2004. 16. Eva Melander Whitby M, McLaws ML, Berry G. Risk of death from 5. Smith R D, Coast J, ‘Antimicrobial resistance: a global response’, methicillin-resistant Staphylococcus aureus bacteremia: a meta-analysis. Bulletin of the World Health Organisation 2002;80:126-133. Med J Austr 2002;175(5):264-7. 6. Wise R, Hart T, Cars O et al. Antimicrobial resistance is a major threat 17. Cosgrove SE, Sakoulas EN, Schwaber MJ, Karchmer, Carmeli Y. to public health. BMJ 1998;317:609-10. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta- 7. Cars O, Mölstad S, Melander A. Variation in antibiotic use in the analysis. Clin Infect Dis 2003;36:53-9. European Union. Lancet 2001;357:1851-53. 18. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial 8. Radyowijati, A. and Haak, H, ‘Determinants of Antimicrobial use in treatment of infections: a risk factor for hospital mortality among the developing world’, USAID, Bureau of Global Health, The Child critically ill patients. Chest, 1999 Feb; 115(2): 462-74. Health Research Project Special Report, 2002. 19. Paterson D, Rice L B, Empirical antibiotic choice for the seriously ill 9. WHO, Global strategy for containment of antimicrobial resistance, patients: Are minimization of selection resistant organisms and maxi- 2001, WHO/CDC/CSR/DRS/2001.2, Geneva. mization of individual outcome mutually exclusive? Clinical Infectious 10. WHO-EMRO, Agenda item 11(a): Antimicrobial resistance and ration- Diseases, 2003; 36: 1006-12. al use of Antimicrobial agents, WHO website: 20. Smith R, Beaglehole R, Woodward D, Drager N, Global Public goods www.int/medicines/organization/par/cd_25th_anniversary/4- for health. Oxford University Press, 2003. 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 1992-2002. http://www.hps.org.uk/infections/topics_az/staphylo/ lab_data_staphyl.htm. (Accessed 30 June 2004).

6 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

ntibiotics changed the world. than double the mortality from malaria. Unblocking collective action Since their discovery almost Antibiotic resistance is becoming important Although the essential components of control eight decades ago, they have in high income countries. In England and of antibiotic resistance have long been well revolutionised the treatment of Wales, for example, the number of registered known, success has been limited in changing infections, transforming once deaths in which meticillin resistant Staphylo- policies and efficiently responding to the prob- Adeadly diseases into manageable health coccus aureus (MRSA) is mentioned increased lem.11 12 The relative lack of data on the mor- problems. The growing phenomenon of bac- from less than 50 in 1993 to more than 1600 bidity and mortality attributable to antibiotic terial resistance, caused by the use and abuse in 2006. In 2007 there was a slight decrease.3 resistance, including the economic impact on of antibiotics and the simultaneous decline The European Centre for Disease Preven- individuals as well as on health care and socie- in research and development of new medi- tion and Control, in its first epidemiological ties, may explain the weak reaction from politi- cines, is now threatening to take us back to report on communicable diseases in Europe, cians, public health workers, and consumers to a pre-antibiotic era. Without effective treat- states that the most important disease threat this threat to public health. ment and prevention of bacterial infections, in Europe is from micro-organisms that have Individual stakeholders might well recog- we also risk rolling back important achieve- become resistant to antibiotics.4 5 nise the problem, but because it is complex, ments of modern medicine such as major The emergence of antibiotic resistance is antibiotic resistance often becomes no one’s surgery, organ transplantation, and cancer further complicated by the fact that bacte- responsibility, which blocks collective action. chemotherapy. ria and their resistance genes are travelling Action is urgently needed in three key areas: Data from low income and middle income faster and further.6 7 We are facing not only leadership on international and national levels, countries indicate that, because of the devel- epidemics but pandemics of antibiotic resist- change in the behaviour of consumers and pro- opment of resistance to first line antibiotics, ance.8 Airlines now carry more than two viders, and the development of antibacterial 70% of hospital acquired neonatal infections billion passengers annually, vastly increas- agents to match current public health needs. could not be successfully treated by using ing the opportunities for rapid spread of WHO’s recommended regimen.1 A recently infectious agents, including antibiotic resist- International and national leadership published study of Tanzanian children con- ant bacteria, internationally.9 The spread of International organisations firmed that ineffective treatment of blood- resistance is also facilitated by worldwide dis- In 1998, the World Health Assembly adopted stream infections due to antibiotic resistance tribution of food.10 Another important factor a resolution urging member states to take predicts fatal outcome independently of is poor hygiene in hospitals as well as in the action on the problem of antimicrobial resist- underlying diseases.2 In that hospital based community, augmenting the rapid spread ance.13 In 2000, the World Health Organiza- study, mortality from bloodstream infections of antibiotic resistant bacteria in vulnerable tion requested a massive effort to prevent the caused by Gram negative bacteria was more populations. “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 policy- JOHN DURHAm/SPL JOHN makers are weak. WHO, international profes- Different degrees of sensitivity to antibiotics exhibited by Staphylococcus aureus sional organisations, and other international

726 BMJ | 27 september 2008 | Volume 337 ANALYSIS antibiotic resistance

24 stakeholders must provide coordination and scriber, and antibiotics could therefore suc- Summary resources for generating up to date information cessfully be replaced by better information points on the burden and the magnitude of antibiotic and follow-up. resistance at regional and subregional levels. The role of the patients as consumers is Antibiotics are a prerequisite for many of the Evidence is needed on effective interventions growing stronger. They need access to infor- advanced technologies in today’s healthcare for prevention and control of antibiotic resist- mation and knowledge to reduce their expec- Although antibacterial resistance is growing, ance at national and local levels, and more tations of antibiotics in self limiting infections, development of new antibiotics has declined emphasis on prevention of infectious diseases and doctors need new tools to help them jus- A new paradigm in which antibiotics are 25 is needed. Solving basic problems such as lack tify their treatment decisions. It could be considered as a non-renewable resource is of safe drinking water, poor nutrition, and dys- unrealistic to expect people to restrict their needed functional sanitation will go a long way toward antibiotic use in favour of a common good to The know-do gap in control of bacterial curbing the needless use of antibiotics as quick- prevent resistance—but if the arguments for resistance to antibiotics must be tackled on fix solutions to avoidable diseases.7 restricting the use of antibiotics can be made international, national, and individual levels sufficiently convincing, reduced demand At national level from the consumer may be the strongest With existing incentives, current levels of Strategies for containing antibiotic resistance force driving change. Studies increasingly innovation are clearly inadequate.32 Propos- in low income countries are still blocked by emphasise the risk for the individual when als on how to break this trend have been put patients’ poverty and weak health systems,16 taking an antibiotic, including the risks of forward. Some have suggested arrangements and many high income countries with well becoming a long term carrier of antibiotic that would increase the anticipated revenue developed regulations and policies lack coor- resistant bacteria,26 27 which might confer a by lengthening the period of patent protec- dinated strategies against antibiotic resistance. greater risk in a subsequent severe infection. tion or exclusivity over data submitted for Although the European Union has responded Reliable information on the adverse effects of drug registration. However, antibiotics already to the resistance problem, antibiotics are still antibiotics on the microbiological flora might have small markets and emergence of resist- sold over the counter provide a stronger ance may further reduce the expected return without a prescription All antibiotic use, appropriate incentive for not using of investment, so these incentives are likely in some EU countries, or not, “uses up” some of the antibiotics unnecessar- to do little to stimulate greater innovation for violating existing laws effectiveness of that antibiotic ily than would more antibacterials.33 There are also scientific chal- and regulations, and general messages about lenges for development of new antibiotics.34 in all countries self medication with leftover risks for society through the development of If today’s market cannot deliver what medicines occurs.17 The root causes of certain resistance. For prescribers and other drug the public needs, we must envisage other behaviours need to be tackled, and the ulti- providers, multifaceted interventions includ- approaches that better engage both public mate responsibility for coordinating the work ing so called academic detailing are effective and private sector resources.35 One model is lies with the government. to increase adherence to recommendations in product development partnerships (PDPs), National mandated multidisciplinary pro- both high income settings and low income arrangements between public organisations grammes can move from recommendations settings.28 29 and private companies to develop drugs when to implementation and audits.18 For example, markets otherwise fail to meet public health in Sweden the government is funding Strama, Developing new antibacterials priorities. This approach is now used for some a nationwide multidisciplinary and multi- For many years, needs for antibacterial drugs drug projects targeting other neglected infec- faceted action programme against antibiotic were met by the pharmaceutical industry, and tious diseases, such as malaria and tubercu- resistance. Antibiotic sales have been reduced the apparent symbiosis between the interests losis.36 Mechanisms creating supplements or without measurable negative consequences, of the community and those of the industry replacing revenues in small and resource poor and resistance remains low.19 In Chile, after prevailed. Today we see a different scenario. markets are another approach. Advanced mar- a mass media campaign, regulatory meas- Existing antibiotics are losing their effect at an ket commitments (AMCs) create a fund that ures were implemented to make antibiotics alarming pace, but development of new anti- guarantees a certain price for drugs that meet available by prescription only, resulting in biotics is declining. More than a dozen new therapeutic targets where there is a demand an initial decrease of 35% in antibiotic sales.20 classes of antibiotics were developed in the for the drug. A recent example is the pneumo- 1930s through the 1960s, but only two new coccal vaccine AMC.37 Behavioural change classes have been developed since then.30 A gap analysis of drugs currently under Social constraints and cultural views of infec- Nor does the trend of declining innovation development in light of current resistance tious conditions influence the use of antibi- seem to be reversing. In a study of the top patterns and trends would give priority to otics.21 Although the public’s demand for 15 pharmaceutical companies, only 1.6% of the most urgently needed antibiotics and antibiotics often is perceived as high even for drugs in development were antibiotics, none give incentives for developing antibacterials conditions without a clinical indication for of which were from novel classes and leaving with new mechanisms of action. But no mat- antibiotic treatment,22 23 studies have shown need unmet for multiresistant Gram negative ter how innovation is accelerated, any public that this demand is overestimated by the pre- infections.31 investment must be matched by public health

BMJ | 27 september 2008 | Volume 337 727 ANALYSIS

accountability. The use of new antibiotics must (Sida), ReAct is working towards five objectives: identify and 2008;8:125-32. 20 Bavestrello FL, Cabello MA, Casanova Z, Dunny. Impact be safeguarded by regulations and practices facilitate removal of critical evidence gaps that block action to contain antibiotic resistance; develop strategic options of regulatory measures on antibiotic sales in Chile. Rev that ensure rational use, to avoid repeating the to remove barriers to innovation of new antibiotics and Méd Chile 2002;130:1265-72. 21 Harbarth S, Samore MH. Antimicrobial resistance mistakes we have made by overusing the old diagnostics; advocate for better access to and use of effective determinants and future control. Emerg Infect ones. and affordable antibiotics for those in need; promote global Dis 2005;11(6). www.cdc.gov/ncidod/EID/ Another lack is efficient and affordable diag- consensus for a new paradigm on the use of antibiotics; vol11no06/05-0167.htm increase awareness of antibiotic resistance as a threat to global 22 Chen C, Chen YM, Hwang KL, Lin SJ, Yang CC, Tsay RW, et nostics with high sensitivity and specificity to public health and engage key stake holders in action. al. Behavior, attitudes, and knowledge about antibiotic usage among residents of Changhua, Taiwan. J Microbiol distinguish bacterial from viral diseases, and Competing interests: None declared. Immunol Infect 2005;38:53-9. to identify resistance patterns in bacteria. Such Provenance and peer review: Not commissioned; externally 23 Trepka M, Belongia E, Chyou P-H, Davis J, Schwartz B. diagnostics would reduce inappropriate use of peer reviewed. The effect of a community intervention trial on parental antibiotics and minimise the delays of treat- knowledge and awareness of antibiotic resistance 1 Zaidi AK, Huskins WC, Thaver D, Bhutta ZA, Abbas Z, and appropriate antibiotic use in children. Pediatrics ment, thereby saving lives. Goldmann DA. Hospital-acquired neonatal infections in 2001;107:6. developing countries. Lancet 2005;365:1175-88. 24 Macfarlane J, Holmes W, Macfarlane R, Britten N. 2 Blomberg B, Manji KP, Urassa WK, Tamim BS, Mwakagile Influence of patients’ expectations on antibiotic Moving to concerted action DS, Jureen R, et al. Antimicrobial resistance predicts management of acute lower respiratory tract illness A fundamentally changed view of antibiotics death in Tanzanian children with bloodstream in general practice: questionnaire study. BMJ is needed. They must be looked on as a com- infections: a prospective cohort study. BMC Infect Dis 1997;315:1211-4. 2007;7:43. 25 Del Mar C. Prescribing antibiotics in primary care. BMJ mon good, where individuals must be aware 3 National Statistics. MRSA deaths decrease in 2007www. 2007;335:407-8. that their choice to use an antibiotic will affect statistics.gov.uk/cci/nugget.asp?id=1067 26 Sjölund M, Wreiber K, Andersson DI, Blaser MJ, 4 European Centre for Disease Prevention and Control. Engstrand L. Long-term persistence of resistant the possibility of effectively treating bacterial Annual epidemiological report on communicable Enterococcus species after antibiotics to eradicate infections in other people. All antibiotic use, diseases in Europe. December 2007. http://ecdc. Helicobacter pylori. Ann Intern Med 2003 16;139:483-7. europa.eu/pdf/ECDC_epi_report_2007.pdf 27 Nasrin D, Collignon PJ, Roberts L, Wilson EJ, Pilotto appropriate or not, “uses up” some of the 5 ReAct—Action on Antibiotic Resistance. Burden of LS, Douglas RM. Effect of beta lactam antibiotic use effectiveness of that antibiotic, diminishing our resistance to multi-resistant gram-negative bacilli in children on pneumococcal resistance to penicillin: ability to use it in the future.38 ReAct—Action (MRGN). 1 March 2007. http://soapimg.icecube. prospective cohort study. BMJ 2002;324:28-30. snowfall.se/stopresistance/ReAct_Burden%20of%20 28 Dollman WB, LeBlanc VT, Stevens L, O’Connor PJ, on Antibiotic Resistance believes that for cur- resistance%20to%20Multi%20resist%20and%20 Turnidge JD. A community-based intervention to reduce rent and future generations to have access to Gram%20negative%20Bacilli%20MRGN.pdf antibiotic use for upper respiratory tract infections in 6 Grundmann H, Aires-de-Sousa M, Boyce J, Tiemersma regional South Australia. Med J Aust 2005;182:617-20. effective prevention and treatment of bacterial E. Emergence and resurgence of meticillin-resistant 29 Awad AI, Eltayeb IB, Baraka OZ. Changing antibiotics infections as part of their right to health, all of Staphylococcus aureus as a public-health threat. Lancet prescribing practices in health centers of Khartoum us need to act now. The window of opportu- 2006;368:874-85. State, Sudan. Eur J Clin Pharmacol 2006;62:135-42. 7 World Health Organization. Report on infectious 30 Infectious Diseases Society of America. Bad bugs, no nity is rapidly closing. diseases 2000: overcoming antimicrobial resistance. drugs: as antibiotic discovery stagnate and a public Otto Cars professor, Infectious Diseases, Department of 2000. www.who.int/infectious-disease-report/2000/ health crisis brews. July 2004. www.idsociety.org/ Medical Sciences, Uppsala University, Uppsala, Sweden index.html badbugsnodrugs.html [email protected] 8 Cantón R, Coque TM. The CTX-M β-lactamase pandemic. 31 Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE Jr. Current Opinion in Microbiology 2006;9:466-75. Trends in antimicrobial drug development: implications Liselotte Diaz Högberg researcher, Department of Medical 9 World Health Organization. World health report 2007: for the future. Clin Infect Dis 2004;38:1279-86. Sciences, Uppsala University a safer future: global public health security in the 21st 32 Projan SJ. Why is big pharma getting out of antibacterial Mary Murray freelance consultant; member of the WHO century. 2007. www.who.int/whr/2007/whr07_en.pdf drug discovery? Curr Opin Microbiol 2003;6:427-30. expert panel on national drug policy; visiting research fellow 10 Butaye P, Michael G B, Schwarz S, Barrett TJ, Brisabois A, 33 Outterson K, Samora JB, Keller-Cuda K. Will longer and freelance consultant on rational use of medicines, Wee White DG. The clonal spread of multidrug-resistant non- antimicrobial patents improve global public health? Jasper, University of South Australia School of Pharmacy and typhi Salmonella serotypes. Microb Infect 2006;8:1891- Lancet Infect Dis 2007;7:559-66. 7. Medical Sciences, Adelaide, Australia 34 Payne D, Tomasz A. The challenge of antibiotic resistant 11 Huovinen P, Cars O. Control of antimicrobial resistance: bacterial pathogens: the medical need, the market, Olle Nordberg former executive director, Dag Hammarskjöld time for action. BMJ 1998;317:613-4. and prospects for new antimicrobial agents. Curr Opin Foundation, Uppsala 12 Hawkey PM. Action against antibiotic resistance: no time Microbiol 2004;7:435-8. Satya Sivaraman journalist, New Delhi, India to lose. Lancet 1998;351:1298-9. 35 Cars O, So A, Högberg L, Manz C. Innovating for bacterial 13 World Health Assembly. Emerging and other resistance. ESCMID News 2007;2:22-4. Cecilia Stålsby Lundborg associate professor and professor, communicable diseases: antimicrobial resistance. May 36 Moran M. A breakthrough in R&D for neglected Division of International Health (IHCAR), Department of Public 1998. http://mednet3.who.int/prioritymeds/report/ diseases: new ways to get the drugs we need. PLoS Med Health Sciences, Karolinska Institutet, Stockholm and Nordic append/microb_wha5117.pdf 2005;2:e302. School of Public Health, Göteborg, Sweden 14 World Health Organization. Global strategy for 37 Document prepared by the World Band and GAVI under Anthony D So director, Program on Global Health and containment of antimicrobial resistance. 2001. www. the guidance of Governments of Italy, Canada, and the Technology Access, Terry Sanford Institute of Public Policy, who.int/drugresistance/WHO_Global_Strategy_English. United Kingdom. AMC Pilot Proposal. 7 September Duke University, Durham, NC, USA pdf 2006. www.vaccineamc.org/files/AMCPilotProposal.pdf 15 World Health Assembly. Improving the containment of 38 Laxminarayan R, Malani A, Howard D, Smith DL. Göran Tomson professor international health system antimicrobial resistance. May 2005. www.tufts.edu/ Extending the cure: policy responses to the growing research and director of doctoral programme, Division of med/apua/Chapters/WHA58_27-en.pdf threat of antibiotic resistance. Alexandria: Resources for International Health (IHCAR), Department of Public Health 16 Okeke IN, Aboderin OA, Byarugaba DK, Ojo KK, Opintan the Future, 2007. www.extendingthecure.org/research_ Sciences, Karolinska Institutet, Stockholm and Medical JA. Growing problem of multidrug-resistant enteric and_downloads.html pathogens in Africa. Emerg Infect Dis 2007;13(11). Management Centre (MMC), Karolinska Institutet, Stockholm Cite this as: BMJ 2008;337:a1438 www.cdc.gov/EID/content/13/11/1640.htm Accepted: 15 May 2008 17 Grigoryan L, Haaijer-Ruskamp FM, Johannes Burgerhof Contributors and sources: OC, LDH, MM, SS, CSL, and ADS GM, Mechtler R, Deschepper R, Tambic-Andrasevic A, are members of the international secretariat and all authors et al. Self-medication with antibiotics in the general Professor Cars are active members of ReAct – Action on Antibiotic Resistance population: a survey in nineteen European countries. Emerg Infect Dis 2006;12(3). www.cdc.gov/ncidod/EID/ (www.reactgroup.org), a growing global network of individuals discusses the vol12no03/05-0992.htm and organisations working towards the mission that current 18 Carbon C, Cars O, Christiansen K. Moving from implications and future generations should have access to antibiotic recommendation to implementation and audit: part treatment as a part of their right to health. ReAct was initiated 1. Current recommendations and programs: a critical of antibiotic in 2004 by Strama, the Swedish strategic programme against commentary. Clin Microbiol Infect 2002;8(suppl 2):92- resistance in a antibiotic resistance (www.strama.se); the Dag Hammarskjöld 106. Foundation (www.dhf.uu.se), and the Division of International 19 Mölstad S, Erntell M, Hanberger H, Melander E, Norman video interview Health (IHCAR) at Karolinska Institutet, Stockholm, Sweden. C, Skoog G, et al. Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up on bmj.com. Supported by the Swedish Development Cooperation Agency of the Swedish Strama programme. Lancet Infect Dis

728 BMJ | 27 september 2008 | Volume 337 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 1 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。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 2 并非原发病本身所致。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 3 以上。这个数字在2007年略有下降。欧洲疾病预防与控制中心在其第一期关于欧洲传染性疾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 4, 5 物。

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 6, 7 8 广。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。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 9 10 上迅速传播的机会。世界范围的食品销售也为耐药性的传播提供了便利。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 13 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。 2000年 7 ，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”。此后不久, 世卫组织还出台 14 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。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 15 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。

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 7 使用抗生素这一速效方法。

国家层次

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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 16 受到阻碍，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 17 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。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。

18 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。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 19 的情况下降了下来，耐药状况也保持在低水平上。智利在通过大众媒体进行大量的宣传之后 20 ，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%。

行为的改变 21 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。公众对抗生素的需求偏 22, 23 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。有研究表明，这种需求被 24 处方医师进一步高估了。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 30 个类别的抗生素，但从那以后仅开发了两个新品种。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

32 目前创新的水平在现行激励制度下是显然不够的。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 33 能很难激发新抗菌药物的研发出现更大的革新。同时，新抗生素研发也面临着来自科学层面 34 的挑战。

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 35 和私营部门的资源。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 36 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。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 37 近一个此类的例子是肺炎疫苗AMC。

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，[email protected] 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 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(www.dhf.uu.se)，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 www.strama.se，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;365:1175-88. 2. 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. 3 MRSA deaths decrease in 2007www.statistics.gov.uk/cci/nugget.asp?id=1067 4. European Centre for Disease Prevention and Control. Annual epidemiological report on communicable diseases in Europe. December 2007. http://ecdc.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 2007. http://soapimg.icecube.snowfall.se/stopresistance/ReAct_Burden%20of%20resistance%20to%20Mul ti%20resist%20and%20Gram%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;368:874-85. 7. World Health Organization. Report on infectious diseases 2000: overcoming antimicrobial resistance. 2000. www.who.int/infectious-disease-report/2000/index.html 8. Cantón R, Coque TM. The CTX-M β-lactamase pandemic. Current Opinion in Microbiology 2006;9:466-75. 9. World Health Organization. World health report 2007: a safer future: global public health security in the 21st century. 2007. www.who.int/whr/2007/whr07_en.pdf 10. 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;8:1891-7.

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 11. Huovinen P, Cars O. Control of antimicrobial resistance: time for action. BMJ 1998;317:613-4. 12. Hawkey PM. Action against antibiotic resistance: no time to lose. Lancet 1998;351:1298-9. 13. World Health Assembly. Emerging and other communicable diseases: antimicrobial resistance. May 1998. http://mednet3.who.int/prioritymeds/report/append/microb_wha5117.pdf 14. World Health Organization. Global strategy for containment of antimicrobial resistance. 2001. www.who.int/drugresistance/WHO_Global_Strategy_English.pdf 15. World Health Assembly. Improving the containment of antimicrobial resistance. May 2005. www.tufts.edu/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). www.cdc.gov/EID/content/13/11/1640.htm 17. 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). www.cdc.gov/ncidod/EID/vol12no03/05- 0992.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):92-106. 19. 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;8:125-32. 20. Bavestrello FL, Cabello MA, Casanova Z, Dunny. Impact of regulatory measures on antibiotic sales in Chile. Rev Méd Chile 2002;130:1265-72. 21. Harbarth S, Samore MH. Antimicrobial resistancedeterminants and future control. Emerg Infect Dis 2005;11(6). www.cdc.gov/ncidod/EID/vol11no06/05-0167.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;38:53-9. 23. 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;315:1211-4. 25. Del Mar C. Prescribing antibiotics in primary care. BMJ 2007;335:407-8. 26. 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 2003 16;139:483-7. 27. 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;324:28-30. 28. 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;182:617-20. 29. Awad AI, Eltayeb IB, Baraka OZ. Changing antibiotics prescribing practices in health centers of Khartoum State, Sudan. Eur J Clin Pharmacol 2006;62:135-42. 30. Infectious Diseases Society of America. Bad bugs, no drugs: as antibiotic discovery stagnate and a public health crisis brews. July 2004. www.idsociety.org/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;38:1279-86. 32. Projan SJ. Why is big pharma getting out of antibacterial drug discovery? Curr Opin Microbiol 2003;6:427-30. 33. Outterson K, Samora JB, Keller-Cuda K. Will longer antimicrobial patents improve global public health? Lancet Infect Dis 2007;7:559-66. 34. 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;7:435-8. 35. Cars O, So A, Högberg L, Manz C. Innovating for bacterial resistance. ESCMID News 2007;2:22- 4. 36. Moran M. A breakthrough in R&D for neglected diseases: new ways to get the drugs we need. PLoS Med 2005;2:e302. 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 2006. www.vaccineamc.org/files/AMCPilotProposal.pdf 38. 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, 2007. www.extendingthecure.org/research_and_downloads.html

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 WHO/CDS/CSR/DRS/2001.2 DISTR: GENERAL

ORIGINAL: ENGLISH WHO GLOBAL WHO STRATEGY CONT FOR

WHO Global

AINMENT OF ANTIMICR OF AINMENT Strategy for Containment of Antimicrobial

OBIAL RESIST OBIAL Resistance NEWHO ANCE

Copies can be obtained from the CDS Information Resource Centre World Health Organization World Health Organization, 1211 Geneva 27, Switzerland fax: +41 22 791 42 85 • email: [email protected] WHO/CDS/CSR/DRS/2001.2 ORIGINAL: ENGLISH DISTRIBUTION: GENERAL

WHO Global Strategy for Containment of Antimicrobial Resistance

World Health Organization 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 Commu- nicable 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 Epidemiol- ogy 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 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

Executive Summary

EXECUTIVE SUMMARY

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

1 — reducing the disease burden and the spread provision of public goods such as information, in of infection surveillance, analysis of cost-effectiveness and — improving access to appropriate anti- cross-sectoral coordination. microbials ■ Given the complex nature of antimicrobial re- — improving use of antimicrobials sistance, the strategy necessarily contains a large

WHO/CDS/CSR/DRS/2001.2 — strengthening health systems and their sur- number of recommendations for interventions. veillance capabilities Prioritization of the implementation of these in- — enforcing regulations and legislation terventions needs to be customized to national — encouraging the development of appropri- realities. To assist in this process an implementa- ate new drugs and vaccines.

OBIAL RESISTANCE • OBIAL RESISTANCE tion approach has been defined together with ■ The strategy highlights aspects of the contain- indicators for monitoring implementation and ment of resistance and the need for further research outcomes. directed towards filling the existing gaps in knowl- ■ Recognition that the problem of resistance edge. exists and the creation of effective national inter- ■ The strategy is people-centred, with interven- sectoral task forces are considered critical to the tions directed towards the groups of people who success of implementation and monitoring of are involved in the problem and need to be part interventions. International interdisciplinary co- of the solution, i.e. prescribers and dispensers, operation will also be essential. veterinarians, consumers, policy-makers in hos- ■ Improving antimicrobial use must be a key pitals, public health and agriculture, professional action in efforts to contain resistance. This requires societies and the pharmaceutical industry. improving access and changing behaviour; such WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL ■ The strategy addresses antimicrobial resistance changes take time. in general rather than through a disease-specific ■ Containment will require significant strength- approach, but is particularly focused on resistance ening of the health systems in many countries and to antibacterial drugs. the costs of implementation will not be negligi- ■ Much of the responsibility for implementation ble. However, such costs must be weighed against of the strategy will fall on individual countries. future costs averted by the containment of wide- Governments have a critical role to play in the spread antimicrobial resistance.

2 Summary of recommendations for intervention

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

3 2.7 Audit prescribing and dispensing practices Diagnostic laboratories and utilize peer group or external stand- 3.5 Ensure access to microbiology laboratory ard comparisons to provide feedback and services that match the level of the hospi- endorsement of appropriate antimicrobial tal, e.g. secondary, tertiary. prescribing. WHO/CDS/CSR/DRS/2001.2 3.6 Ensure performance and quality assurance 2.8 Encourage development and use of guide- of appropriate diagnostic tests, microbial lines and treatment algorithms to foster identification, antimicrobial susceptibility appropriate use of antimicrobials. tests of key pathogens, and timely and rel- 2.9 Empower formulary managers to limit evant reporting of results.

OBIAL RESISTANCE • OBIAL RESISTANCE antimicrobial use to the prescription of an 3.7 Ensure that laboratory data are recorded, appropriate range of selected anti- preferably on a database, and are used to microbials. produce clinically- and epidemiologically- useful surveillance reports of resistance Regulation patterns among common pathogens and 2.10 Link professional registration requirements infections in a timely manner with feed- for prescribers and dispensers to require- back to prescribers and to the infection ments for training and continuing educa- control programme. tion. Interactions with the pharmaceutical industry Hospitals 3.8 Control and monitor pharmaceutical company promotional activities within the hos- Although most antimicrobial use occurs in the pital environment and ensure that such WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL community, the intensity of use in hospitals is far activities have educational benefit. higher; hospitals are therefore particularly important in the containment of antimicrobial resistance. In hospitals it is crucial to develop integrated Use of antimicrobials in food-producing approaches to improving the use of antimicrobials, animals reducing the incidence and spread of hospital-ac- A growing body of evidence establishes a link quired (nosocomial) infections, and linking thera- between the use of antimicrobials in food-produc- peutic and drug supply decision-making. This will ing animals and the emergence of resistance among require training of key individuals and the alloca- common pathogens. Such resistance has an im- tion of resources to effective surveillance, infec- pact on animal health and on human health if tion control and therapeutic support. these pathogens enter the food chain. The factors affecting such antimicrobial use, whether for thera- 3 HOSPITALS peutic, prophylactic or growth promotion purposes, are complex and the required interventions Management need coordinated implementation. The underly- 3.1 Establish infection control programmes, ing principles of appropriate antimicrobial use and based on current best practice, with the containment of resistance are similar to those responsibility for effective management of applicable to humans. The WHO global princi- antimicrobial resistance in hospitals and ensure that all hospitals have access to ples for the containment of antimicrobial resist- such a programme. ance in animals intended for food (2) were adopted 3.2 Establish effective hospital therapeutics at a WHO consultation in June 2000 in Geneva. committees with the responsibility for They provide a framework of recommendations overseeing antimicrobial use in hospitals. to reduce the overuse and misuse of antimicrobials 3.3 Develop and regularly update guidelines in food animals for the protection of human for antimicrobial treatment and prophy- health. Antimicrobials are widely used in a vari- laxis, and hospital antimicrobial formular- ety of other settings outside human medicine, e.g. ies. horticulture and aquaculture, but the risks to 3.4 Monitor antimicrobial usage, including the human health from such uses are less well under- quantity and patterns of use, and feedback stood and they have not been included in this results to prescribers. document.

4 4 USE OF ANTIMICROBIALS IN FOOD- 5 NATIONAL GOVERNMENTS AND PRODUCING ANIMALS HEALTH SYSTEMS This topic has been the subject of specific con- Advocacy and intersectoral action sultations which resulted in “WHO global prin- 5.1 Make the containment of antimicrobial ciples for the containment of antimicrobial resistance a national priority. resistance in animals intended for food”*. A complete description of all recommendations — Create a national intersectoral task is contained in that document and only a sum- force (membership to include health mary is reproduced here. care professionals, veterinarians, agriculturalists, pharmaceutical manu- Summary facturers, government, media repre- 4.1 Require obligatory prescriptions for all sentatives, consumers and other

SUMMARY OF RECOMMENDATIONS FOR INTERVENTION OF RECOMMENDATIONS SUMMARY antimicrobials used for disease control in interested parties) to raise awareness food animals. about antimicrobial resistance, organ- 4.2 In the absence of a public health safety ize data collection and oversee local evaluation, terminate or rapidly phase out task forces. For practical purposes such the use of antimicrobials for growth pro- a task force may need to be a govern- motion if they are also used for treatment ment task force which receives input of humans. from multiple sectors. 4.3 Create national systems to monitor antimi- — Allocate resources to promote the crobial usage in food animals. implementation of interventions to contain resistance. These interventions 4.4 Introduce pre-licensing safety evaluation should include the appropriate utiliza- of antimicrobials with consideration of tion of antimicrobial drugs, the control potential resistance to human drugs. and prevention of infection, and re- 4.5 Monitor resistance to identify emerging search activities. health problems and take timely corrective — Develop indicators to monitor and actions to protect human health. evaluate the impact of the antimicro- 4.6 Develop guidelines for veterinarians to re- bial resistance containment strategy. duce overuse and misuse of antimicrobials in food animals. Regulations 5.2 Establish an effective registration scheme for dispensing outlets. * http:// www.who.int/emc/diseases/zoo/ who_global_principles.html 5.3 Limit the availability of antimicrobials to prescription-only status, except in special circumstances when they may be dis- National governments and health systems pensed on the advice of a trained health care professional. Government health policies and the health care 5.4 Link prescription-only status to regulations systems in which they are implemented play a cru- regarding the sale, supply, dispensing and cial role in determining the efficacy of interven- allowable promotional activities of antimi- tions to contain antimicrobial resistance. National crobial agents; institute mechanisms to commitment to understand and address the prob- facilitate compliance by practitioners and lem and the designation of authority and respon- systems to monitor compliance. sibility are prerequisites. Effective action requires 5.5 Ensure that only antimicrobials meeting the introduction and enforcement of appropriate international standards of quality, safety regulations and allocation of appropriate resources and efficacy are granted marketing for education and surveillance. Constructive in- authorization. teractions with the pharmaceutical industry are 5.6 Introduce legal requirements for manufac- critical, both for ensuring appropriate licensure, turers to collect and report data on anti- promotion and marketing of existing microbial distribution (including import/ antimicrobials and for encouraging the develop- export). ment of new drugs and vaccines. For clarity, in- 5.7 Create economic incentives for the appro- terventions relating to these interactions with the priate use of antimicrobials. industry are shown in separate recommendation groups (6 and 7).

5 Policies and guidelines 6 DRUG AND VACCINE DEVELOPMENT 5.8 Establish and maintain updated national 6.1 Encourage cooperation between industry, Standard Treatment Guidelines (STGs) and government bodies and academic institu- encourage their implementation. tions in the search for new drugs and vaccines. WHO/CDS/CSR/DRS/2001.2 5.9 Establish an Essential Drugs List (EDL) consistent with the national STGs and ensure 6.2 Encourage drug development pro- the accessibility and quality of these drugs. grammes which seek to optimize treat- 5.10 Enhance immunization coverage and other ment regimens with regard to safety, disease preventive measures, thereby re- efficacy and the risk of selecting resistant

OBIAL RESISTANCE • OBIAL RESISTANCE ducing the need for antimicrobials. organisms. 6.3 Provide incentives for industry to invest in Education the research and development of new 5.11 Maximize and maintain the effectiveness antimicrobials. of the EDL and STGs by conducting appro- 6.4 Consider establishing or utilizing fast-track priate undergraduate and postgraduate marketing authorization for safe new education programmes of health care agents. professionals on the importance of appropriate antimicrobial use and containment 6.5 Consider using an orphan drug scheme of antimicrobial resistance. where available and applicable. 5.12 Ensure that prescribers have access to ap- 6.6 Make available time-limited exclusivity for proved prescribing literature on individual new formulations and/or indications for drugs. use of antimicrobials. 6.7 Align intellectual property rights to pro-

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL vide suitable patent protection for new Surveillance of resistance, antimicrobial antimicrobial agents and vaccines. usage and disease burden 6.8 Seek innovative partnerships with the 5.13 Designate or develop reference microbiol- pharmaceutical industry to improve access ogy laboratory facilities to coordinate to newer essential drugs. effective epidemiologically sound surveillance of antimicrobial resistance among common pathogens in the community, 7 PHARMACEUTICAL PROMOTION hospitals and other health care facilities. 7.1 Introduce requirements for pharmaceuti- The standard of these laboratory facilities cal companies to comply with national or should be at least at the level of recom- international codes of practice on promo- mendation 3.6. tional activities. 5.14 Adapt and apply WHO model systems 7.2 Ensure that national or international codes for antimicrobial resistance surveillance of practice cover direct-to-consumer and ensure data flow to the national inter- advertising, including advertising on the sectoral task force, to authorities responsi- Internet. ble for the national STGs and drug policy, 7.3 Institute systems for monitoring compli- and to prescribers. ance with legislation on promotional 5.15 Establish systems for monitoring antimi- activities. crobial use in hospitals and the community, 7.4 Identify and eliminate economic incentives and link these findings to resistance and that encourage inappropriate antimicro- disease surveillance data. bial use. 5.16 Establish surveillance for key infectious 7.5 Make prescribers aware that promotion in diseases and syndromes according to accordance with the datasheet may not country priorities, and link this information necessarily constitute appropriate antimi- to other surveillance data. crobial use.

6 8 INTERNATIONAL ASPECTS OF 8.5 Encourage the establishment of interna- CONTAINING ANTIMICROBIAL tional inspection teams qualified to con- RESISTANCE duct valid assessments of pharmaceutical 8.1 Encourage collaboration between govern- manufacturing plants. ments, non-governmental organizations, 8.6 Support an international approach to the professional societies and international control of counterfeit antimicrobials in line agencies to recognize the importance of with the WHO guidelines**. antimicrobial resistance, to present consist- 8.7 Encourage innovative approaches to ent, simple and accurate messages regard- incentives for the development of new ing the importance of antimicrobial use, pharmaceutical products and vaccines for antimicrobial resistance and its contain- neglected diseases.

ment, and to implement strategies to con- FOR INTERVENTION OF RECOMMENDATIONS SUMMARY tain resistance. 8.8 Establish an international database of potential research funding agencies with 8.2 Consider the information derived from the an interest in antimicrobial resistance. surveillance of antimicrobial use and antimicrobial resistance, including the contain- 8.9 Establish new, and reinforce existing, pro- ment thereof, as global public goods for grammes for researchers to improve the health to which all governments should design, preparation and conduct of re- contribute. search to contain antimicrobial resistance. 8.3 Encourage governments, non-governmental organizations, professional societies and * Interagency Guidelines. Guidelines for Drug international agencies to support the es- Donations, revised 1999. Geneva, World tablishment of networks, with trained staff Health Organization, 1999. WHO/EDM/PAR/ and adequate infrastructures, which can 99.4. undertake epidemiologically valid surveil- **Counterfeit drugs. Guidelines for the develop- lance of antimicrobial resistance and anti- ment of measures to combat counterfeit drugs. microbial use to provide information for Geneva, World Health Organization, 1999. the optimal containment of resistance. WHO/EDM/QSM/99.1. 8.4 Support drug donations in line with the UN interagency guidelines*.

PART A Introduction and background

Introduction

INTRODUCTION

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

11 resistance is generally slow to reverse or is irre- • raise awareness of the problems posed by versible. This suggests that interventions to stop antimicrobial resistance the development of resistance should be imple- • promote the sharing of information about mented early, before resistance becomes a prob- and understanding of resistance lem. The earlier interventions are implemented,

WHO/CDS/CSR/DRS/2001.2 the slower will be the development of resistance • provide strategic and technical guidance on (4). However, this implies taking action before the interventions to contain resistance prevalence of resistant infections climbs, based on • assist Member States to implement these decisions made whilst the number of people suf- interventions fering resistant infections is low. Antimicrobial OBIAL RESISTANCE • OBIAL RESISTANCE resistance is only just beginning to be considered • stimulate research to address the knowledge as a societal issue and, in economic terms, as a gaps and improve understanding of antimi- negative externality (8,9). Individual decisions to crobial resistance and to encourage research use antimicrobials (taken by the consumer alone and development of new antimicrobial or by the decision-making combination of pre- agents. scriber and patient) often ignore the societal perspective and the perspective of the health service. Development of the WHO Global Strategy Following the Resolution on Antimicrobial Re- A dwindling supply of new antimicrobials sistance in 1998 (1), WHO has worked with many The development of new antimicrobial agents partners to develop the WHO Global Strategy for effective against resistant pathogens and of alter- Containment of Antimicrobial Resistance (referred to as the WHO Global Strategy hereafter). The

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL native approaches such as vaccines is crucial to reduce the future impact of resistance. However, new aim of this strategy is to provide, for all Member agents are expensive and time-consuming to States, a framework of interventions to stimulate develop. Interest in antimicrobial research and de- the prevention of infection, to slow the emergence velopment among the research-based pharmaceu- of resistance and to reduce the spread of resistant tical industry has declined as infectious diseases microorganisms, in order to reduce the impact of in richer country populations appear to have been resistance on health and health care costs, while conquered and as priorities have shifted to the improving access to existing agents and encour- development of lifestyle drugs. Unless the current aging the development of new agents. The strat- rate of emerging resistance is controlled and slowed egy has been formulated on the basis of expert to preserve the life of existing drugs, this decline opinion, published evidence, commissioned re- in new antimicrobial development, even if reversed views and the deliberations of international and now, is likely to result in the absence of effective national bodies (see Annex B) on the key factors therapies for some pathogens within the next ten contributing to antimicrobial resistance and the years. interventions needed for its containment. Based on these inputs, a series of recommendations is proposed, directed towards the aims stated above. A global problem calls for a global response Part B of this document provides a summary of There can be no doubt that antimicrobial resist- the evidence on which the recommendations are ance poses a global challenge. No single nation, based. however effective it is at containing resistance It is important to recognize that much remains within its boundaries, can protect itself from the to be learnt about the interplay between the fac- importation of resistant pathogens through travel tors responsible for the emergence and spread of and trade. The global nature of resistance calls for resistance and the optimization and cost-effective- a global response, not only in the geographic sense, ness of appropriate interventions. However, the i.e. across national boundaries, but also across the urgency of the situation requires that implemen- whole range of sectors involved. Nobody is ex- tation of the WHO Global Strategy moves for- empt from the problem, nor from playing a role ward on the evidence currently available. in the solution. The response of the World Health Organiza- tion is to:

12 Implementation of the tainment of antimicrobial resistance presented WHO Global Strategy here, there is a practical need for prioritization and The approach to implementation is crucial to its customization to the individual national setting.

INTRODUCTION efficacy and success. Much of the responsibility To assist in the implementation of the WHO Glo- for implementing interventions will fall on indi- bal Strategy, an approach to defining a smaller core vidual Member States. There are certain actions set of recommendations is presented (Part C). that only governments can assure, including the Furthermore, since antimicrobial resistance is a provision of public goods such as information, clearly a global issue, international interdiscipli- surveillance and analysis of cost-effectiveness of nary cooperation is critical and the areas in which interventions, and the cross-sectoral coordination this can be most effective are outlined (Part B, critical for an effective response (10). Given the Chapter 8). large number of recommendations for the con-

Background

BACKGROUND

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

15 ment guidelines, educate prescribers and guide Modern techniques have enabled the develop- infection control policies. The frequency at which ment and application of molecular methods to surveillance information is updated is also determine the presence of specific resistance genes important given that the rise in prevalence of a in microbes. They are most widely used to detect resistance phenotype may be rapid and the imple- genotypic resistance in viruses such as HIV and

WHO/CDS/CSR/DRS/2001.2 mentation of policy changes is often slow. HBV and, in the future, may form the basis of Nationally collected surveillance data may be systems to monitor antiviral resistance. However used to inform policy decisions, update national these molecular methods rely on sophisticated formularies or lists of essential drugs and stand- technology that is not available in many settings. ard treatment guidelines and evaluate the cost-

OBIAL RESISTANCE • OBIAL RESISTANCE effectiveness of interventions. Since resistance is a Epidemiologically valid patient selection global problem, international collation of resistance data may also have a useful role (see Chapter Currently, epidemiological methods are not ap- 8). plied in most resistance surveillance studies. The terms incidence and prevalence tend to be used in- terchangeably and usually refer to the number of National surveillance systems resistant isolates among the total number of iso- WHO and its partners have been successful in lates surveyed. In contrast, from a public health supporting the surveillance of drug-resistant standpoint, one of the goals of surveillance is to tuberculosis in many countries (12,13). Despite detect the incidence of resistant infections among the many ongoing activities worldwide in moni- the total number of infections in a population (15). toring resistance among other bacteria, few coun- Further bias arises since tests to detect resistance tries have well-established national networks that

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL are performed on a subset of patients presenting regularly collect and report relevant data. In many for treatment who may be more likely to have developing countries and countries whose econo- failed empiric therapy previously or to have other mies are in transition, microbiology laboratory complications. Much greater epidemiologic rig- facilities and information networks will require our and more active surveillance approaches are considerable strengthening before reliable surveil- needed to better understand the impact of resist- lance of resistance is a reality. ance. In this respect, surveillance of drug resistance in tuberculosis is more advanced than that Standardization of methods to detect resistance of other bacteria (12). Surveillance of antimicrobial resistance is fun- Current methods for monitoring antimicrobial damental to understanding trends in resistance, resistance can be classified as in vivo, in vitro and to developing treatment guidelines accurately and molecular methods. The extent to which each of to assessing the effectiveness of interventions ap- these is used depends on the pathogen/disease and propriately. Without adequate surveillance, the the facilities available. In vivo methods or thera- majority of efforts to contain emerging antimi- peutic efficacy tests are the gold standard for moni- crobial resistance will be difficult. toring resistance to antimalarial drugs (14) but are not used routinely to monitor resistance in other pathogens. However, linking clinical outcome of The prevalence of resistance treatment with in vitro detection of resistance is The prevalence of resistance varies widely between of critical importance to understand the predic- and within countries, and over time. tive value of in vitro tests. Data on the prevalence of resistance in acute In vitro methods are the techniques of choice respiratory infections, diarrhoeal diseases, malaria, for monitoring resistance in the vast majority of tuberculosis and gonorrhoea can be found in re- bacterial pathogens, including Mycobacterium tu- cent reviews (16,17,18,19,20,21). berculosis. However, there is no single international standard method. Different methods have gained Conclusion popularity in different parts of the world—at least ten different methods for antimicrobial suscepti- While it is difficult to quantify the total impact of bility tests are used in Europe and more than twelve resistance on health, published data clearly indi- worldwide. International quality assurance stand- cate that morbidity and mortality are increased ards can help to overcome the potential difficul- by delays in administering effective treatment for ties arising from the use of different methods. infections caused by resistant pathogens. The pro-

16 longed illness and hospitalization of patients with financial resources that could otherwise be used resistant infections and the additional procedures for improving health and threatens the success of and drugs that they may require carry financial global efforts to combat the major infectious dis-

BACKGROUND implications. There may also be economic impli- eases of poverty. In this light, implementation of cations for the patient in terms of lost productiv- the WHO Global Strategy can be considered ity. Antimicrobial-resistant infections in appropriate risk management to protect current food-producing animals may have major finan- health care initiatives and the availability of treat- cial implications for both farmers and consumers. ment for future generations. In addition, antimicrobial resistance diverts

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

CHAPTER 1 Patients and the general community

Recommendations for intervention Patients’ misperceptions

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

21 the absence of documented tuberculosis (25). the consumer’s relative lack of sophistication about Patients also fail to recognize that many brand the evidence supporting the use of one treatment names may actually be the same antimicrobial— over another” (35). These advertising methods are resulting in the unnecessary overstocking of some apparently quite effective, since pharmacists are agents. For example, specific patient demand frequently able to guess the feature advertisements

WHO/CDS/CSR/DRS/2001.2 caused one pharmacy in South India to stock more of the previous day’s television programmes based than 25 of the 100 or so brands of co-trimoxazole upon daily customer requests for specific medica- available (26). tions (31). A survey of physicians in the USA dem- A greater interaction between health providers onstrated that, on average, each had encountered and consumers for health and drug (antimicro- seven patients within the previous six months who OBIAL RESISTANCE • OBIAL RESISTANCE bial)-related education has been proposed (27). had specifically requested prescription-only drugs The WHO Action Programme on Essential Drugs as a result of direct-to-consumer advertising (36). convened a consultation to address the need for Over 70% of the physicians reported that requests public education in rational drug use (28) and has from patients as a result of direct-to-consumer since produced a document “Rational Drug Use: advertisements had led them to prescribe a phar- Consumer Education and Information” (29). This maceutical agent that they might not have other- document discusses the practical issues and dilem- wise chosen. mas related to the need for rational drug use edu- In a telephone survey of consumers regarding cation, its priority and content, underlying direct advertising, 66% believed that advertise- principles and target population. In a study car- ments for medications would provide useful ried out in Peru, a multifaceted educational inter- information but 88% said that they would seek vention directed at the community using media, out more information about a drug that they saw

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL face-to-face meetings and training on the use of advertised on television or in print before purchas- medicines was successful in decreasing the inap- ing it. On the other hand, only one-third of inter- propriate use of antidiarrhoeals and antimicrobials viewees agreed with the statement that most people for simple diarrhoea (30). would know if they were being misled by the advertisements (37). Self-medication Recently, the United States Food and Drug Administration proposed new guidelines that lift Self-medication with antimicrobials is often cited previous restrictions on direct-to-consumer adver- as a major factor contributing to drug resistance tising and allow pharmaceutical manufacturers (31). In a Brazilian study, it was determined that greater freedom on advertised health claims. A the three most common types of medication used two-year evaluation period was proposed to assess by villagers were antimicrobials, analgesics and the impacts and implications of these guidelines vitamins. The majority of antimicrobials were pre- (27). scribed by a pharmacy attendant or were purchased Advertising and promotion can also be used to by the patient without prescription (32) despite improve the appropriate use of antibiotics. Public having prescription-only legal status. In addition education campaigns in India, which include the to obvious uncertainty as to whether the patient use of mass media such as television, appear to has an illness that will benefit from antimicrobial have effectively educated even illiterate popula- treatment, self-medicated antimicrobials are often tions about antimicrobial resistance in some inadequately dosed (33) or may not contain regions (Bhatia, personal communication). adequate amounts of active drug, especially if they Interventions to address the effects of advertis- are counterfeit drugs (34). This is especially ing and promotion are discussed in Chapter 7. important in the treatment of diseases such as tuberculosis. Poor adherence to dosage regimens In a 1988 literature search, over 4000 English Advertising and promotion language articles were available on the topic of Direct-to-consumer advertising allows pharmaceu- patient adherence to dosing instructions, more tical manufacturers to market medicines directly than 75% of which had been published within to the public via television, radio, print media and the previous ten years (38). In the majority of stud- the Internet. Where permitted, this practice has ies, it was reported that a lack of patient under- “the potential to stimulate demand by playing on standing and provider communication led to most

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

CHAPTER 2 Prescribers and dispensers

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

25 the pharmacology of antimicrobial agents, their nating targeted educational messages to their peer modes of action and spectrum of activity and group (73,74). Unfortunately, none of these stud- issues relating to resistance receive limited cover- ies looked at resistance as an outcome or impact age in medical school curricula, resulting in poorly indicator. Increasing problem-based pharmaco- informed prescribers (57). It is not uncommon therapy training for medical and paramedical stu-

WHO/CDS/CSR/DRS/2001.2 for drug company sales representatives and the dents can have a positive impact on long-term commercially oriented publications they provide good prescribing habits. The use of a WHO to be the main sources of information for prescrib- manual (75) designed to support problem-based ers (58). learning for medical students has been demon- Lack of knowledge is a major factor responsi- strated to have a positive impact on prescribing OBIAL RESISTANCE • OBIAL RESISTANCE ble for inappropriate antimicrobial use globally. skills of students in seven medical schools (76). In one study in China, 63% of antimicrobials In countries with limited resources, the dispens- selected to treat proven bacterial infections were ing of antimicrobials by unauthorized persons found to be inappropriate (59). In a retrospective lacking appropriate knowledge is common. In a study in Viet Nam, more than 70% of patients study of 40 randomly selected health facilities in were prescribed inadequate dosages (60). Gumo- Ghana, only 8.3% of dispensers had received for- doka et al. (61) reported that one in four patients mal training (77). Bruneton et al. (78) found that in their medical districts received antimicrobials drug sellers in seven sub-Saharan African coun- by injection and that approximately 70% of these tries frequently recommended antimicrobials not injections were unnecessary. Studies in many present on the regions’ Essential Drugs List and European countries and in the USA demonstrate rarely suggested that the patient should consult a widespread unnecessary use of antimicrobials in physician.

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL patients with viral upper respiratory tract infec- Improving the drug education of non-physi- tions (62). cian prescribers and dispensers is another recom- Printed materials are the most common and mended step in improving drug use. A study in least expensive educational interventions but in- Ghana showed that educational interventions appropriate prescribing is rarely due to a lack of aimed at dispensers significantly improved drug knowledge alone. Many studies have found that use by increasing the percentage of appropriately the use of printed material only, without other labelled containers and by increasing patient forms of supporting interventions, is ineffective knowledge of their medications (77). Interventions in altering prescribing behaviours (63,64,65). targeted at local drug sellers in the Philippines sig- Continuing education and in-service training nificantly improved their quality of practice (79). programmes have traditionally involved lecture- and seminar-style presentations oriented to the Lack of access to information presentation of factual information. A large body of research has shown that these approaches are Even relatively well-trained prescribers often lack not necessarily the most effective for improving the up-to-date information required to make practice (66). Academic detailing, or unadvertise- appropriate prescribing decisions. This tends to ments, and educational programmes directed to result in the excessive use of newer antimicrobial physicians have been shown to decrease antimi- agents, often with a broader spectrum of action. crobial use/misuse (67,68,69,70). One consist- Conversely, lack of surveillance data and updated ently successful method has been educational treatment guidelines may lead to the inappropri- outreach, which consists of brief, targeted, face- ate prescription of older antimicrobials which are to-face educational visits to clinicians by specially either no longer effective due to the emergence of trained staff (67,71,72). In developing countries resistance or should have been replaced by newer where individual educational outreach visits may agents with improved cost-effectiveness or reduced not be practical or cost-effective, interactive prob- toxicity. lem-oriented educational sessions with small Use of clinical practice guidelines is a core groups of physicians, paramedics, or pharmacy managerial strategy in every health system for counter attendants have demonstrated similar suc- improving diagnosis and therapy. Despite the cess, especially when sessions are repeated over time abundance of guidelines, research has shown that or reinforced with improved clinical supervision they have little effect on clinical practice unless (53). Another promising approach involves engag- they are actively disseminated (80). Factors that ing local opinion leaders in the process of dissemi- increase the likelihood of guidelines being adopted

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

27 they promise a free return visit if the patient feels bonuses tied to practice pharmaceutical budgets. that a re-consultation is necessary because they did While these strategies may reduce inappropriate not receive antimicrobials (87). use of antimicrobials, they may also reduce appropriate use. Nevertheless, a number of Economic incentives Scandinavian studies have suggested that national

WHO/CDS/CSR/DRS/2001.2 antibiotic policies together with changes in reim- Many health providers practise in environments bursement policy can be safe and effective with financial incentives to prescribe or dispense (95,96,97). greater numbers of drugs overall or of specific types. Prescribers may fear the potential loss of Peer pressure and social norms OBIAL RESISTANCE • OBIAL RESISTANCE future patient custom and revenue if they do not respond to perceived demands for antimicrobials In focus group studies, prescribers expressed con- (91). Furthermore, in some countries, prescribers cern that, if they did not prescribe antimicrobials, profit from both prescribing and dispensing patients would seek other sources of care where antimicrobials, such that it is in their financial they could obtain antimicrobials (91). In addition, interest to prescribe antimicrobials even when they the physician offering the latest and often the most are not clinically indicated. Additional profit is expensive and broad-spectrum antibiotic may be sometimes gained by recommending newer more perceived to be the most informed and desirable expensive antimicrobials in preference to older source of care. cheaper agents. In countries where physicians are Understanding prescribing patterns is crucial poorly paid, pharmaceutical companies have been to identifying areas for potential intervention to known to pay commissions to prescribers who use improve use (58). Drug use patterns and prescrib-

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL their products (92). Other less direct incentives ing behaviour, including the influence of various such as financial support for attendance at meet- social and patient pressures, can be described us- ings, entertainment, or payment for enrolling ing the indicators and methods in the WHO patients in marketing research studies may also manual “How to investigate drug use in health influence prescribing practices. Even in health facilities” (98). After undertaking interventions to systems where there is no overt incentive to improve drug use, these same indicators can be prescribe, there is usually no incentive not to used to measure impact. prescribe (8). It is desirable to minimize financial conflicts Factors associated with the prescriber’s of interest in therapeutic decision-making by working environment health providers, such as allowing physicians to profit from dispensing drugs that they prescribe In busy clinical practices, health care providers may or allowing pharmacists who sell drugs to prescribe not have time to explain to patients why they have them as well. Coast et al. (9) and Smith and Coast chosen to prescribe or not prescribe antimicrobial (93) explored economic perspectives of policies therapy (99). Some clinicians in this situation may used to decrease antimicrobial resistance. They believe it is simply most time-effective to prescribe discuss techniques such as regulation (controlling an antimicrobial. Lack of privacy in consultation prescription practices by means of policies and facilities may also impact on prescribing behav- guidelines or by enforcing a global limit to the iour since some conditions, such as urinary tract prescription of antimicrobials), permits (allowing sepsis and sexually transmitted diseases, require physicians to prescribe up to a certain quantity of diagnostic specimens and/or physical examination antimicrobials per permit) and charges (levying that are difficult to undertake in public. The lack taxes on antimicrobials). In their model, they sug- of opportunity for health care workers to follow gest that the use of permits may offer a method up their patients to assess progress after treatment for reducing antimicrobial resistance. and poor continuity of care in general negatively Several countries have introduced health pro- influence communication and the development vider reimbursement strategies that are designed of trust between the patient and health care pro- to encourage physicians to limit overall use of vider. It is thus often easier for both prescriber medicines and often to share in the resulting and patient if an antimicrobial agent is prescribed financial savings. Examples of these strategies are on first contact. capitation payments that include pharmaceutical costs, general practice fundholding (94) and

28 Lack of appropriate legislation or Inadequate drug supply infrastructure enforcement of legislation In many parts of the world, the ability of prescrib- Absence of appropriate legislation or its enforce- ers and dispensers to provide appropriate antimi- ment may result in the proliferation of locations crobial therapy is limited by the lack of availability where untrained or poorly trained persons dispense of the necessary drugs (100). antimicrobials, leading to overuse and inappropriate use (see Chapter 5).

CHAPTER 2. PRESCRIBERS AND DISPENSERS

CHAPTER 3 Hospitals

CHAPTER 3. HOSPITALS CHAPTER 3.

Recommendations for intervention Introduction Management Hospitals are a critical component of the antimi- 3.1 Establish infection control programmes, based crobial resistance problem worldwide. The com- on current best practice, with the responsi- bination of highly susceptible patients, intensive bility for effective management of antimicro- and prolonged antimicrobial use, and cross- bial resistance in hospitals and ensure that all infection has resulted in nosocomial infections hospitals have access to such a programme. with highly resistant bacterial pathogens such as multi-resistant Gram-negative rods, vancomycin- 3.2 Establish effective hospital therapeutics com- resistant enterococci (VRE) and methicillin- mittees with the responsibility for overseeing resistant Staphylococcus aureus (MRSA) as well as antimicrobial use in hospitals. resistant fungal infections. Some of these resist- 3.3 Develop and regularly update guidelines for ant strains have now spread outside the hospital antimicrobial treatment and prophylaxis, and causing infections in the community. Hospitals hospital antimicrobial formularies. are also the eventual site of treatment for many patients with severe infections due to resistant 3.4 Monitor antimicrobial usage, including the pathogens acquired in the community, including quantity and patterns of use, and feedback penicillin-resistant Streptococcus pneumoniae, results to prescribers. multi-resistant salmonellae and multi-resistant Diagnostic laboratories Mycobacterium tuberculosis. In the wake of the AIDS epidemic, the prevalence of such infections 3.5 Ensure access to microbiology laboratory can be expected to increase, both in the commu- services that match the level of the hospital, nity and in hospitals. Hospitals can thus serve both e.g. secondary, tertiary. as a point of origin of and as a reservoir for highly 3.6 Ensure performance and quality assurance of resistant pathogens which may later enter the com- appropriate diagnostic tests, microbial iden- munity or chronic care facilities. tification, antimicrobial susceptibility tests of key pathogens, and timely and relevant Infection control reporting of results. Transmission of highly resistant bacteria from 3.7 Ensure that laboratory data are recorded, pref- patient to patient within the hospital environment erably on a database, and are used to produce (nosocomial transmission) amplifies the problem clinically- and epidemiologically-useful of antimicrobial resistance and may result in the surveillance reports of resistance patterns infection of patients who are not receiving anti- among common pathogens and infections in microbials. Transmission of antimicrobial-resist- a timely manner with feedback to prescribers ant strains from hospital personnel to patients or and to the infection control programme. vice versa may also occur. The key element in minimizing such horizontal transmission of infection Interactions with the pharmaceutical industry within hospitals is careful attention to infection 3.8 Control and monitor pharmaceutical control practices (101). company promotional activities within the Failure to implement simple infection control hospital environment and ensure that such practices such as handwashing and changing gloves activities have educational benefit. 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 sence of suitable handwashing facilities. However, The key elements of an effective infection con- inadequate handwashing is generally due to lack trol programme include: of recognition of its importance in maintaining — development and implementation of appro- good infection control, understaffing or health care priate barrier precautions (handwashing, worker forgetfulness. Regardless of the reasons, wearing of gloves and gowns) and isolation

WHO/CDS/CSR/DRS/2001.2 poor infection control practices result in the procedures increased dissemination of resistant bacterial strains in hospital and health care facilities. The — adequate sterilization and disinfection of spread of resistance appears to be widening as supplies and equipment patients move more rapidly from intensive care — the use of aseptic techniques for medical

OBIAL RESISTANCE • OBIAL RESISTANCE wards to general wards and then to the commu- and nursing procedures nity or between hospitals and nursing homes — training of health care personnel in appro- (51,106,107). priate sterile techniques and infection con- Infections can also be transmitted via non- trol procedures sterile injection and surgical equipment. In a study of health facilities in Tanzania, 40% of suppos- — maintenance of appropriate disinfection edly sterilized needles and syringes were bacteri- and sanitary control of the hospital envi- ally contaminated (61). Poor decontamination or ronment, including air failures in sterilization of equipment can have an — active surveillance of infections and anti- enormous impact on the spread of viral infections microbial resistance, with data analysis and such as HIV (108), hepatitis B and C. Re-use of feedback to prescribers and other staff single-use needles and syringes has played a major

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL role in the spread of viral hepatitis following im- — recognition and investigation of outbreaks munization programmes in some countries and or clusters of infections. among intravenous drug users (109,110,111,112). The programme should have a qualified chair- Any practice that permits the spread of infection person and staff and adequate resources to accom- permits the spread of resistant infections. plish these goals. The most effective infection Infection control activities are best coordinated control team consists of a physician (preferably by an active and effective infection control pro- trained in infectious diseases), a microbiologist, gramme. The SENIC study, conducted by the infection control nurses, pharmacist(s) and Centers for Disease Control (CDC) and which hospital management representatives, with the included a large sample of hospitals in the USA, responsibility for the day-to-day management of demonstrated that hospitals having infection con- resistance issues. Increased efficiency may be trol programmes with both active surveillance and achieved by an overlap in the membership of the control elements were effective in reducing rates infection control team and the hospital therapeu- of nosocomial infection (113,114,115). In par- tics committee. ticular, interventions such as education and moti- Appropriate facilities for optimal infection vation programmes, improvement of equipment, control practices, including sufficient basins and and performance feedback can increase adherence clean towels to regularly wash hands between to improved handwashing (104). Barrier precau- patient contacts, may be difficult to achieve in tions have been shown to be effective in reducing some countries. Nevertheless, such facilities are infection transmission rates and thereby the spread vital if nosocomial transmission of infections is to of resistance. Mayer et al. (116) showed that im- be controlled. Handwashing, isolation practices, proved handwashing and the use of gloves and sufficient beds (and space between them), as well gowns decreased infection rates. as clean ventilation are needed in hospitals to pre- With respect to the control of antimicrobial vent the spread of bacteria, including resistant resistance within the hospital setting, the major strains. evidence of effectiveness stems from the management of outbreaks or clusters of resistant infec- Control of antimicrobial use in hospitals tions. In these situations, a variety of techniques including targeted cohorting of infected patients, Hospitals provide an important training ground enhanced surveillance, isolation or rigorous for students to learn about prescribing practices. barrier precautions, early discharge and alteration Unfortunately, antimicrobial prescribing in hos- in antimicrobial usage have been effective. pitals is often irrational. In an analysis of prescrib-

32 ing practices in ten studies from teaching hospi- bial considered necessary without any peer-review tals worldwide, 41% to 91% of all antimicrobials process is generally inconsistent with optimizing prescribed were considered inappropriate (117). antimicrobial use. All clinicians should be prepared Patterns of prescribing become entrenched and, if to justify their antimicrobial usage patterns. they are not consistent with appropriate antimi- The following activities represent some of the

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

33 Formularies regionally with wide input and consensus and Hospital formularies, or lists of drugs routinely should utilize information from local surveillance stocked by the hospital pharmacy for inpatient and data whenever possible. Programmes that utilize outpatient use, guide the parallel processes of an- clinical practice guidelines supported by other in- timicrobial selection, procurement and supply, and terventions such as education and peer review are WHO/CDS/CSR/DRS/2001.2 represent a means for decreasing inappropriate more effective than those without such support antimicrobial prescribing and reducing expendi- (135). In an observational study of one hospital tures. In conjunction with clinical guidelines, with a computerized prescribing guideline system formularies encourage the proper use of preferred that encouraged appropriate use of antimicrobials, drugs within each category of antimicrobial. trend analysis showed that resistance patterns in

OBIAL RESISTANCE • OBIAL RESISTANCE Antimicrobial formularies should relate to local selected hospital-acquired infections stabilized over or regional treatment guidelines and should ide- a seven-year period (136). Another study noted a ally be based on relative efficacy, cost-effectiveness reduction in one type of resistance when controls data and local patterns of resistance (129). This, on selected agents were applied, but an increase however, is difficult in many hospitals. In a USA in resistance to other antimicrobials which were survey in which a great majority of hospitals not controlled—the so-called “squeezing the bal- had implemented formularies as a method of loon” effect (137). Nevertheless, treatment guidelines are particularly useful in resource-poor decreasing antimicrobial costs, many noted that countries where they can be used to streamline expenditures actually increased—this was usually treatment protocols and limit the range of considered to be due to drug resistance (130). antimicrobials stocked in pharmacies. However, Although some authors have suggested that a such treatment guidelines need to be developed restrictive hospital formulary may actually con-

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL carefully and their implementation reviewed regu- tribute to the selection of resistant bacteria by nar- larly. Their appropriateness is dependent on rowing and focusing selective pressures, there are accurate and updated resistance surveillance and few data to support this view (131). Thus, formu- clinical outcome data. laries are useful in avoiding the unnecessary keeping in stock of a range of antimicrobials that duplicate their spectrum and in reinforcing the Other techniques to control or modify importance for clinicians to understand an appro- antimicrobial use in hospitals priate range of antimicrobials well. However, the Several types of innovative tools to guide antimi- specific effectiveness of a formulary in reducing crobial prescribing and dispensing have been the emergence of antimicrobial resistance is un- tested; some have been shown to be effective in clear. changing antimicrobial use in hospital settings. Antimicrobial order forms have been used with Cycling of antibiotics mixed success, showing improvement in antimicrobial prescribing in some hospitals but not in The cycling of antimicrobials within a health care others (138,139,140). Automatic review of the use institution has been suggested as a possible inter- of selected antimicrobials by a consultant or vention to decrease drug resistance. This technique automatic cessation of antimicrobial administra- alternates formulary antimicrobials between drug tion after a defined period may also reduce classes every couple of months and theoretically unnecessary use (46). However, these control reduces the selective pressure of one antimicro- measures are either labour-intensive or require bial class (132). However, in a recent review of reasonably sophisticated computerized pharmacy the topic, there was no evidence that cycling records—both of which are not generally avail- reduced antimicrobial resistance (133). Cycling able. may have only a temporary effect on resistance patterns and ultimately may simply replace one Integrated interventions resistance problem with another (134). Multi-disciplinary and integrated approaches to reduce antimicrobial use in hospitals have been Use of clinical practice or treatment guidelines proposed as a solution (105,141,142,143). Hos- Clinical practice guidelines (80) can improve pital administrators, clinicians, infectious diseases decision-making and therefore improve patient specialists, infection control practitioners, care. They should be developed locally or microbiologists, clinical epidemiologists and

34 hospital pharmacists all have a role—but coordi- rials and equipment, and internal quality control nation of their activities is vital. Such activities and external quality assurance procedures, are include the selection of formulary drugs, the essential. The laboratory should produce and dis- development of formulary-based guidelines, moni- seminate meaningful local surveillance data both toring and evaluating drug use, surveillance and with respect to the predominant pathogens/syn-

CHAPTER 3. HOSPITALS CHAPTER 3. reporting of bacterial resistance patterns, detec- dromes and their antimicrobial resistance patterns. tion and appropriate care of patients with resist- The laboratory should work closely with hospital ant organisms, and promotion and monitoring of infection control personnel, with the hospital basic infection control practices (143). Interactions therapeutics committee and with providers to with the pharmaceutical industry must also be con- ensure that appropriate antimicrobials are tested sidered, including appropriate control of the and reported in order to recognize outbreaks or access of sales representatives to clinical staff and unusual infections and identify trends in antimi- monitoring industry-sponsored educational pro- crobial resistance. Software tools such as grammes for providers. Targeted antimicrobial WHONET are available to facilitate analysis and control policies in combination with improved data sharing (147). Depending on resources, the hygiene and education have reduced antimicro- laboratory should also provide specialized testing, bial resistance in some settings (144,145). How- e.g. molecular typing of bacterial strains, to assist ever, in one study, prescriber education combined epidemiological investigations. with hospital antimicrobial control policies led to decreased antimicrobial costs and improved pre- Interactions between the hospital scribing, but only limited change in resistance and the community (146). Following discharge from hospital, patients may still be colonized or infected with resistant bacte- The microbiology laboratory and ria acquired in hospital. In general, little action is antimicrobial resistance necessary in such circumstances if the patient is Delayed or incorrect laboratory diagnostic data healthy and discharged home. However, this is the frequently result in prolonged empiric antimicro- likely mechanism through which highly resistant bial therapy (see also Chapters 2 and 5). The hos- hospital-acquired pathogens eventually become pital microbiology laboratory plays an important widespread in the community. Of greater concern role in the recognition and surveillance of antimi- is the transfer of such patients to chronic care crobial resistance, both within the hospital and in facilities where they have been shown to be the the community. The laboratory must provide high source of strains that subsequently spread through- quality diagnostic testing to correctly identify in- out the facility. Patients known to be colonized or fection and accurate antimicrobial susceptibility infected with resistant pathogens upon discharge testing to guide appropriate treatment. Appropri- to a care facility should generally be identified so ately trained personnel, adequate supplies, mate- that appropriate precautions can be taken.

CHAPTER 4 Use of antimicrobials in food-producing animals

This topic has been the subject of specific consul- — an increased risk for resistant pathogens to tations which resulted in “WHO global princi- be transferred to humans by direct contact ples for the containment of antimicrobial with animals or through the consumption resistance in animals intended for food”*. A com- of contaminated food or water

plete description of all recommendations is con- ANIMALS USE OF ANTIMICROBIALS IN FOOD-PRODUCING CHAPTER 4. — the transfer of resistance genes from ani- tained in that document and only a summary is mal to human bacterial flora. reproduced here. Increasingly, data suggest that inappropriate antimicrobial use poses an emerging public health Recommendations for intervention risk (148,149,150,151). Summary Factors associated with the emergence of anti- 4.1 Require obligatory prescriptions for all microbial resistance in food-producing animals antimicrobials used for disease control in food and the farming industry appear to be similar to animals. those responsible for such resistance in humans. Inadequate understanding about and training on 4.2 In the absence of a public health safety evalu- appropriate usage guidelines and the effects of in- ation, terminate or rapidly phase out the use appropriate antimicrobial use on resistance are of antimicrobials for growth promotion if they common among farmers, veterinary prescribers are also used for treatment of humans. and dispensers. 4.3 Create national systems to monitor antimi- There are three modes of antimicrobial use in crobial usage in food animals. animals—prophylaxis, treatment and growth promotion. Overall, the largest quantities of anti- 4.4 Introduce pre-licensing safety evaluation of microbials are used as regular supplements for antimicrobials with consideration of poten- prophylaxis or growth promotion in the feed of tial resistance to human drugs. animal herds and poultry flocks. This results in 4.5 Monitor resistance to identify emerging health the exposure of a large number of animals, irre- problems and take timely corrective actions spective of their health, to frequently subthera- to protect human health. peutic concentrations of antimicrobials (152). Furthermore, a lack of diagnostic services and their 4.6 Develop guidelines for veterinarians to reduce perceived high cost means that most therapeutic overuse and misuse of antimicrobials in food antimicrobial use in animals is empiric, rather than animals. being based on laboratory-proven disease. For animals and birds that are farmed in large herds Introduction or flocks, the identification of a few ill individuals generally results in the entire herd or flock being Antimicrobial use in food-producing animals may treated to avoid rapid dissemination and stock affect human health by the presence of drug losses. Clearly this is a different situation to most residues in foods and particularly by the selection human diseases where decisions are generally made of resistant bacteria in animals. The consequences about the need for individual therapy, rather than of such selection include: 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 disincen- * http:// www.who.int/emc/diseases/zoo/who_global_ principles.html tive to limit antimicrobial use (153,154).

37 As in human medicine, inefficient and inad- use in animals contributes to an increased pool of equately enforced regulatory mechanisms regard- vancomycin-resistant enterococci (VRE) (160, ing antimicrobial supply contribute to excessive 161). However, the extent to which the microbial and inappropriate drug use. Discrepancies between gene pool in animals contributes to the prevalence regulatory requirements and prescribing/dispens- of VRE colonization and infection in humans is

WHO/CDS/CSR/DRS/2001.2 ing realities for animal antimicrobial use are often less well defined. VRE cause serious infections, worse than in human medicine (155). In addi- mainly in hospitalized immunocompromised tion, antimicrobials that are used as growth pro- patients. Such infections are difficult to cure due moters are generally not even considered as drugs to the limited number of effective treatment and are either not licensed or licensed solely as options and are thus associated with increased OBIAL RESISTANCE • OBIAL RESISTANCE feed additives. Poor manufacturing quality assur- morbidity and mortality. There are also concerns ance in some settings results in the supply of that the genes that cause resistance to vancomy- sub-standard drugs. Marketing practices of cin may spread from enterococci to other bacte- antimicrobials for therapeutic, prophylactic or ria, such as Staphylococcus aureus, for which growth promoter purposes in animals by private vancomycin is one of the drugs of last resort. industry influence the prescribing patterns and Studies in Denmark have shown that the ban behaviour of veterinarians, feed producers and of avoparcin in animals has led to a reduction in farmers. the prevalence of VRE in poultry and pigs In North America and Europe it is estimated (162,163). Similarly, studies in Germany and the that about 50% in tonnage of all antimicrobial Netherlands suggest that banning avoparcin has production is used in food-producing animals and led to a reduction in the prevalence of VRE in poultry (156). The increased intensity of meat healthy individuals in the community (164,165).

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL production under crowded industrialized condi- Sweden banned the use of growth promoters in tions contributes to the increased use of anti- livestock and poultry in 1987 and focused on the microbials since they are used in subtherapeutic implementation of disease prevention methods doses as growth promoters, given as prophylaxis that did not involve antimicrobials and on the for disease prevention and used therapeutically for prudent use of antimicrobials for therapeutic pur- the treatment of infected animals. In addition, the poses. The subsequent national antimicrobial con- impact of antimicrobial metabolites and non- sumption has reduced by approximately 50% metabolized drug in animal sewage that is released (166,167). Furthermore, the prevalence of anti- into the environment is not clear. microbial resistance in pathogenic bacteria isolated from animals in Sweden has been maintained at a low prevalence since 1985 (168). Use of antimicrobials as growth promoters Some antimicrobials, particularly those that Use of antimicrobials that affect food- target Gram-positive bacteria, are associated with borne pathogens such as Salmonella and an increase in the rate of animal growth when they Campylobacter spp. are provided in subtherapeutic quantities in stock Non-typhoidal Salmonella spp. and Campylobacter feed to food-producing animals. The mechanism jejuni are among the most commonly identified of this effect is uncertain. However, these drugs causes of bacterial diarrhoea in humans. Such also alter the gut flora of exposed animals such species are generally transmitted to humans via that they frequently contain bacteria that are re- food or direct contact with animals (169). Data sistant to the antimicrobial used. When such demonstrate that antimicrobial use in animals antimicrobial growth promoters belong to a class selects for resistance among non-typhoidal Salmo- similar to that of antimicrobials used in human nella spp., thus limiting the effective available treat- medicine, these resistant animal bacteria are ment options (170,171,172). A recent example is often also resistant, i.e. cross-resistant, to impor- a clone of Salmonella typhimurium DT104 that tant human use antimicrobials (157). Five growth has become prevalent in many countries includ- promoters (bacitracin, tylosin, spiramycin, ing the UK, Germany and the USA—it is resist- virginiamycin and avoparcin [a similar agent to ant to commonly used agents including ampicillin, vancomycin]) have recently been banned by the tetracycline, streptomycin, chloramphenicol and European Union due to fears of such cross-resist- sulphonamides (171,173,174). Multi-drug resistance (158,159). ance has likewise been noted in other Salmonella Scientific data strongly suggest that avoparcin spp. (175).

38 Following the introduction of fluoroquinolones in the prevalence of fluoroquinolone-resistant for use in food-producing animals, the emergence Campylobacter jejuni isolated in live poultry, of Salmonella serotypes with reduced susceptibil- poultry meat and from infected humans (180,181, ity to fluoroquinolones has been observed in 182). Prior to fluoroquinolone use in poultry, no countries such as France, Germany, Ireland, the resistant strains were reported in individuals with- Netherlands, the Russian Federation, Spain and out previous exposure to these agents (178,183). the UK (176,177,178). Little has been docu- Because of their broad antibacterial spectrum, mented about the impact of this resistance on fluoroquinolones are often used for empiric treat- human health to date, but there is concern about ment of gastrointestinal infections in severely ill the potential human health consequences. This or immunocompromised patients. Fluoro- has been substantiated by a recent outbreak of quinolone resistance among Campylobacter spp. quinolone-resistant S. typhimurium DT104 result- is associated with a higher rate of clinical treating in treatment failures in hospitalized patients ment failure than for susceptible strains when in Denmark (179). fluoroquinolones are used for treatment of disease

The introduction of fluoroquinolone use in (184,185,186). A recent review by APUA (187) ANIMALS USE OF ANTIMICROBIALS IN FOOD-PRODUCING CHAPTER 4. poultry has been associated with a dramatic rise provides further material on this topic.

CHAPTER 5 National governments and health systems

Recommendations for intervention 5.5 Ensure that only antimicrobials meeting in- Advocacy and intersectoral action ternational standards of quality, safety and efficacy are granted marketing authorization. 5.1 Make the containment of antimicrobial SYSTEMS AND HEALTH GOVERNMENTS NATIONAL CHAPTER 5. resistance a national priority. 5.6 Introduce legal requirements for manufacturers to collect and report data on antimicro- — Create a national intersectoral task force bial distribution (including import/export). (membership to include health care professionals, veterinarians, agriculturalists, 5.7 Create economic incentives for the appropri- pharmaceutical manufacturers, govern- ate use of antimicrobials. ment, media representatives, consumers Policies and guidelines and other interested parties) to raise awareness about antimicrobial resistance, 5.8 Establish and maintain updated national organize data collection and oversee Standard Treatment Guidelines (STGs) and local task forces. For practical purposes encourage their implementation. such a task force may need to be a gov- 5.9 Establish an Essential Drugs List (EDL) con- ernment task force which receives input sistent with the national STGs and ensure from multiple sectors. the accessibility and quality of these drugs. — Allocate resources to promote the imple- 5.10 Enhance immunization coverage and other mentation of interventions to contain disease preventive measures, thereby reduc- resistance. These interventions should ing the need for antimicrobials. include the appropriate utilization of antimicrobial drugs, the control and Education prevention of infection, and research 5.11 Maximize and maintain the effectiveness of activities. the EDL and STGs by conducting appro- — Develop indicators to monitor and evalu- priate undergraduate and postgraduate ate the impact of the antimicrobial education programmes of health care pro- resistance containment strategy. fessionals on the importance of appropriate antimicrobial use and containment of anti- Regulations microbial resistance. 5.2 Establish an effective registration scheme for 5.12 Ensure that prescribers have access to approved dispensing outlets. prescribing literature on individual drugs. 5.3 Limit the availability of antimicrobials to prescription-only status, except in special cir- Surveillance of resistance, antimicrobial usage cumstances when they may be dispensed on and disease burden the advice of a trained health care professional. 5.13 Designate or develop reference microbiol- 5.4 Link prescription-only status to regulations ogy laboratory facilities to coordinate effec- regarding the sale, supply, dispensing and tive epidemiologically sound surveillance of allowable promotional activities of antimicro- antimicrobial resistance among common bial agents; institute mechanisms to facilitate pathogens in the community, hospitals and compliance by practitioners and systems to other health care facilities. The standard of monitor compliance. these laboratory facilities should be at least at the level of recommendation 3.6.

41 5.14 Adapt and apply WHO model systems for Government legislation—drug licensing antimicrobial resistance surveillance and Marketing authorization ensure data flow to the national intersectoral task force, to authorities responsible for the Many countries have legislation that requires all national STGs and drug policy, and to pre- medicinal products to undergo licensure before being placed on the market. Marketing authori- WHO/CDS/CSR/DRS/2001.2 scribers. zation usually follows a detailed assessment of data 5.15 Establish systems for monitoring antimicro- provided by the applicant, generally by a desig- bial use in hospitals and the community, and nated government department and sometimes link these findings to resistance and disease with input from an expert advisory group(s). Some

OBIAL RESISTANCE • OBIAL RESISTANCE surveillance data. countries are willing to license new medicines 5.16 Establish surveillance for key infectious dis- based on their prior approval in other countries, eases and syndromes according to country such as the USA or EU. Whatever the process, priorities, and link this information to other the fundamental requirement is that the data surveillance 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 Introduction these three areas has implications for human health Placing antimicrobial resistance high on the na- and for antimicrobial resistance. tional agenda should be a priority in tackling the problem of resistance. National governments and Quality health care systems can have considerable impact on limiting the emergence and development of As with all medicinal products, control of the

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL antimicrobial resistance through the introduction quality of antimicrobial agents is vital for the de- of legislation and policies concerning the devel- livery of accurate dosage units to patients—doses that have been shown to be safe and effective in opment, licensing, distribution and sale of anti- clinical trials (188,189,190). Antimicrobial agents microbial agents. Health and pharmaceutical containing less than the stated dose may produce regulations shape the way antimicrobials are used. suboptimal levels of circulating drug, which may Key regulatory frameworks include professional result in both therapeutic failure and selection of licensing, the ability to prescribe and dispense drug-resistant strains. Similar problems may arise medicines, drug registration, product quality, pric- as a result of counterfeit products, which com- ing and movement of drugs in the supply system. monly contain little or none of the active substance Although pharmaceutical regulations represent a stated on the label and may even contain entirely powerful tool, implementing them to influence different active ingredients. The Counterfeit patterns of antimicrobial use can be a two-edged Intelligence Bureau estimated that, in 1991, 5% sword, achieving both intended and unintended of all the world’s trade was in counterfeit goods, effects. For example, active enforcement of regu- with this percentage likely to be higher for phar- lations regarding the sale of antimicrobials with- maceuticals since they are easily transportable out prescription in pharmacies and drug shops may (191). Excessive drug content may lead to con- reduce unnecessary use while at the same time centrations in the body associated with certain limiting access to appropriate therapy, especially adverse events. Unnecessarily high concentrations among the poor. The unintended effects of pro- may also lead to a marked disruption of the nor- posed regulations should be carefully considered mal flora and an increased risk of superinfections before and monitored during their implementa- such as fungal disease and C. difficile enterocolitis. tion. Government-initiated inspection of drug National governments also have the responsi- manufacturing plants for adherence to Good bility for coordinating surveillance networks and Manufacturing Practice (GMP) with certification for directing educational efforts to improve for defined time periods, adherence to the prod- understanding about appropriate antimicrobial uct specifications agreed upon at the time of use. licensure, and the elimination of unauthorized medicines from the market are essential. Strict controls limiting drug importation and exporta- tion to those products and manufacturers that have been inspected and approved can serve to reduce

42 the risks posed by substandard and counterfeit Prescribing information medicines. Countries that carry out spot checks Wherever there are formal procedures for drug and drug analyses are able to make a major con- licensure, the content of the prescribing informa- tribution to reducing the production of poor tion is subject to approval by the licensing authori- quality and counterfeit products. ties. Requirements for international alignment on the essential content of the prescribing informa- Safety and efficacy tion and on the reporting of safety data have led to the development of core datasheets by many The scope and quality of data presented to sup- pharmaceutical companies (194,195). These port the safety and efficacy of new drugs are describe the minimal prescribing information, determined mainly by the requirements of the US including contraindications, warnings and poten- Food and Drug Administration (FDA), the Euro- tial adverse reactions, which should be available pean Commission, and the Japanese Ministry of

to users in all countries where the product is mar- SYSTEMS AND HEALTH GOVERNMENTS NATIONAL CHAPTER 5. Health, Labour and Welfare (MHLW) (188,189, keted. However, it may not be feasible for all 192). The individual regulations issued by these companies, especially those that are large and mul- bodies, together with the activities of the Interna- tinational, to regularly audit compliance with the tional Conference on Harmonisation (193), have use of core datasheets in all regions or to require greatly influenced the content and conduct of pre- that national or regional offices fully adopt stated clinical and clinical development programmes for corporate standards. Also, in countries where there pharmaceuticals. Dossiers meeting these inter- are inadequate regulations to ensure the availabil- national standards are generally acceptable world- ity of prescribing information to prescribers and wide, although there may be additional local users, health care professionals may have little or stipulations. In this way, all countries may benefit no access to independently-assessed material re- from high quality development programmes that garding antimicrobial agents (see also Chapters 2 better identify the safety and efficacy of new drugs. and 7). In one sense, the emergence of resistance associ- Failure to specify precisely in the prescribing ated with the use of a particular antimicrobial information the types of infections for which safety could be viewed as an adverse event. However, and efficacy have been demonstrated in clinical current regulatory and licensure bodies do not trials may serve to encourage antimicrobial use for regard the emergence of resistance in this man- conditions that have not been studied. An exam- ner. ple is the use of the term “lower respiratory infec- Countries that do not have systems for the tions” instead of specifying the types of pneumonia adequate assessment of safety and efficacy before or bronchitis that were studied. Thus, without and after drug licensure face an increased risk of careful attention to detail and to translation, even exposure to drugs of inferior efficacy and unac- the approved prescribing information may inad- ceptable toxicity, as well as a potentially higher vertently encourage inappropriate antimicrobial market penetration of counterfeit drugs. The use. establishment of Assessment Report Sharing The product literature usually reflects the dos- Schemes has facilitated assessment of the safety age regimens shown to be efficacious in clinical and efficacy of antimicrobial agents by resource- trials for each indication. Identification of opti- poor countries. Participating countries are able to mal antimicrobial treatment regimens for various request detailed reports of pharmaceutical, pre- diseases is important to ensure that the drug is clinical and clinical data that have been prepared given in an appropriate dose and for an appropri- by drug regulatory authorities in other countries. ate duration to maximize the likelihood of cure, The Product Evaluation Report (PER) network while minimizing the risk of toxicity. Low dose and the arrangements made by the European regimens may be associated with less toxicity, but Agency for the Evaluation of Medicinal Products may result in insufficient drug concentrations at (EMEA) are examples of schemes which allow the site of infection to effect bacterial eradication countries access to information to assist in mak- and may therefore encourage the development of ing licensing decisions. In addition, regional as- resistance among target pathogens. In contrast, sociations of regulatory bodies, e.g. AFDRAN in higher dose regimens may result in greater effects Africa, have contributed to the application of simi- on the host’s normal flora increasing the likeli- lar standards and requirements for drug approvals hood of superinfections, including those caused in many countries. by highly resistant nosocomial pathogens. How-

43 ever, clinical trials to support antimicrobial drug Nairobi, it was noted that 64% of chemists sold approval are almost always designed to show antimicrobials without physicians’ prescriptions equivalence to a licensed comparative agent. and most sold incomplete treatment courses at the Therefore there is a tendency to use perhaps request of the patient (207). In a study of a rural unnecessarily high dose or long duration regimens village in Bangladesh, 95% of all medications con-

WHO/CDS/CSR/DRS/2001.2 so as to avoid any risk of treatment failure (196, sumed were obtained from pharmacies with only 197,198). Companies are often reluctant to ex- 8% having been prescribed by graduate physicians; plore a variety of dosage and treatment regimens one-third of these medications were antimicrobials in clinical trials with a new drug because of the (208). Poor enforcement of prescription-only regu- study costs involved and the risk of failing to meet lations is almost universally associated with inap- OBIAL RESISTANCE • OBIAL RESISTANCE the specified regulatory requirement (199). Dose propriate antimicrobial usage. regimens in clinical trials are often chosen by com- Although the cost of antimicrobial agents with- paring the pharmacokinetics of the drug in man out prescription is generally carried by the patient, with the in vitro susceptibilities of the main target in some regions this may actually be less expen- pathogens. Increasingly, the pharmacokinetic and sive than the combined costs of a time-consum- pharmacodynamic characteristics of new antimi- ing visit to a distant and/or very busy health care crobial agents are being used in pre-clinical facility and the physician’s consulting fee. There- studies to better predict the optimal clinical dos- fore, depending on the structure and funding of ing regimens in man (200,201,202). While this the national health care system, restricting anti- approach does not replace clinical trials, the phar- microbial agents to prescription-only may maceutical industry and regulatory authorities actually limit the access of many patients to these have both recognized that this may also have drugs, even when they are really needed. On the

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL benefits in terms of reducing the risk of selecting other hand, requiring a prescription for access to for drug-resistant organisms. antimicrobial agents provides an opportunity to dissuade patients from unnecessary antimicrobial therapy and hopefully results in a trained health Government legislation—control of drug care worker selecting the drug and the treatment supply, distribution and sales regimen. This potential point of intervention Some countries are unable to control the supply, should help reduce inappropriate antimicrobial distribution and sale of medicines. In many re- usage, especially if accompanied by an education gions there is minimal control over public access programme on the appropriate use of antimicro- to antimicrobials and these can be purchased over bial agents (see Chapter 2). the counter without prescription (34,203). There With or without implementation of prescrip- are also marked international differences in the tion-only access to antimicrobial agents, legisla- types of retail outlets that provide access to pre- tion that restricts the sale of antimicrobials to scription-only and non-prescription drugs, as well registered outlets would allow local policing and as whether these outlets require government reg- prevention of over-the-counter non-prescription istration. Where there is adequate legislation sales. Ideally, such registered outlets should be regarding the licensure of medicinal products, a staffed by personnel with at least a basic knowl- legal classification system generally determines the edge of antimicrobials. Legislation that compels mode of sale, supply and dispensing. In such coun- registered outlets to keep records of the sources of tries, antimicrobial agents are almost uniformly drugs purchased and quantities sold would allow prescription-only medicines (POM), with dispens- the auditing of antimicrobial sales and possibly of ing restricted to registered outlets and by suitably usage data. Such surveillance may result in greater qualified personnel (204). In reality, however, the restriction of the sales of counterfeit and substand- degree of drug law enforcement and the penalties ard medicines. However, in regions where prescrib- imposed for infringements vary enormously ers earn a considerable portion of their income between countries. For example, all systemic either by directly dispensing antimicrobials or via antibacterial agents are legally subject to prescrip- subsequent pharmacy sales, such legislation is tion control in the EU, yet they can be purchased likely to be less effective. These circumstances over the counter in pharmacies in several EU mem- provide a disincentive to appropriate antimicro- ber states (205). Antimicrobials can be purchased bial prescribing and prescribers are more likely to without prescription in many resource-poor coun- recommend antimicrobial use, particularly the tries (59,129,206). In a study of chemist shops in more expensive agents, regardless of whether

44 cheaper drugs may be just as appropriate (see also Surveillance of resistance and antimicrobial use Chapter 2). Surveillance of both antimicrobial resistance and antimicrobial use are fundamental to the effective Government legislation—inspection implementation of any strategy for the contain- and enforcement ment of antimicrobial resistance, as a means to monitor the efficacy of various interventions. The existence of appropriate legislation regarding However, designing and implementing compre- the manufacture, licensure, sale, supply and dis- hensive surveillance systems that are practical, cost- pensing of antimicrobial agents cannot improve effective and interlink with the national healthcare the quality and appropriate use of these drugs system is a challenge. It is likely that in many unless it is enforced. Individual countries may not resource-poor countries, laboratory facilities and have the financial or human resources needed to information networks will require considerable support policing activities by suitably qualified

strengthening before reliable surveillance of resist- SYSTEMS AND HEALTH GOVERNMENTS NATIONAL CHAPTER 5. personnel. There may be reluctance on the part of ance can be undertaken. governments to take action because the introduc- Epidemiologically sound surveillance of resist- tion of restrictions could prove unpopular with ance in key pathogens, using standardized micro- patients, physicians and the pharmaceutical indus- biological methods, may be developed on the basis try. Increasing international recognition of inspec- of an existing laboratory surveillance system for tions of manufacturing plants by teams from other antimicrobial resistance and routine diagnostic countries has relieved the burden on some gov- microbiology (see Part A, Background). To assist ernments and facilitated the quality control of in this aim, WHO is developing “Surveillance medicines and adherence to Good Manufactur- standards for antimicrobial resistance” which pro- ing Practice (GMP), Good Laboratory Practice pose practical epidemiological methods for (GLP) and Good Clinical Practice (GCP). The several infections and key pathogens (209). Where possibility of expanding these international coop- possible, such surveillance should be integrated erative efforts by using suitably qualified staff from with other national and hospital laboratory serv- non-governmental organizations (NGOs) to aid ices to maximize efficiency and ensure surveillance policing efforts in other areas of drug law compli- of clinically relevant isolates (see Chapter 3). ance may be worthy of serious consideration by Measurement of antimicrobial usage could be some countries (see also Chapter 8). approached through the registration of outlets that dispense antimicrobials, requiring them to main- Health care systems and drug policies tain accurate records of antimicrobial supply and sales. Incomplete patient adherence to treatment Health care systems protocols means that antimicrobial dispensing data The organization and funding of health care sys- will not necessarily be the same as antimicrobial tems varies between countries, with a mixture of consumption, but it is likely to be the most public- and privately-funded health care facilities accurate achievable surrogate available. Targeted and diagnostic laboratories being common. The research to measure the correlation between the structure and organization of these systems can quantity of antimicrobials dispensed and the quan- be an important factor in determining the reli- tity consumed could be used to adjust national ability and practicality of data collection regard- dispensing data, providing a more accurate assessing antimicrobial use, surveillance of antimicrobial ment of antimicrobial consumption. Establishing resistance and the impact of resistance on clinical surveillance systems of antimicrobial usage and outcomes. In addition, the system may have a di- control of drug supply and dispensing outlets will rect influence on undergraduate medical curricula, require a major commitment from national gov- on the existence and maintenance of registration ernments in countries which do not currently have systems for all health care professionals, and on effective prescription-only regulations for anti- the attention paid to their continuing professional microbials. Implementation of an integrated sur- education and accreditation. Whether or not veillance system for antimicrobial resistance and antimicrobials are prescription-only, undergradu- antimicrobial usage will require national govern- ate and postgraduate medical and pharmacist edu- ments to re-assess many regulatory aspects of their cation concerning appropriate antimicrobial use health care system, including legislation related is vital (see Chapter 2), as is the need for evidence- to drug licensure (including quality, safety and based prescribing information. efficacy) and drug supply, distribution and sales.

45 Essential Drugs Lists and policies regions without such a programme. Thus, such In 1977 the first WHO Model List of Essential programmes appear to improve access to essential Drugs was developed to promote the availability drugs, especially when they are supported by edu- of a selected number of drugs, including anti- cational programmes and follow-up (83,117). microbials, and their rational use. The Model List WHO/CDS/CSR/DRS/2001.2 has been revised regularly and serves as a guide for Establishing national treatment guidelines countries in determining their national drug poli- Evidence-based national treatment guidelines en- cies. At present over 120 countries have imple- courage appropriate antimicrobial prescribing. mented an Essential Drugs List. A retrospective Using local laboratory and clinical surveillance study of prescribing practices in Ethiopia found a OBIAL RESISTANCE • OBIAL RESISTANCE data on antimicrobial resistance, these guidelines significant decrease in the prescribing of non- can be appropriately modified for community and essential drugs after the introduction of an Essen- hospital use in various regions, but should be up- tial Drugs List (210). Studies have demonstrated dated regularly. The use of such guidelines is most that in those areas in which an Essential Drugs effective when combined with supportive inter- Programme is in operation, significantly more ventions such as educational training and super- essential drugs are available, significantly fewer vision programmes (83,211). injections and antimicrobials are utilized, and drug stocks last about three times longer than in

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL

46 CHAPTER 6 Drug and vaccine development

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

47 of promising compounds or vaccines. This hepatitis C and HIV could likewise have enor- approach may potentially reduce overall costs by mous clinical impact. reducing the duplication of research activities (see Chapter 8). Public-private partnerships are increas- Licensure and patent protection ingly being exploited for speeding up drug To hasten the licensure of some new products, fast- WHO/CDS/CSR/DRS/2001.2 discovery and development and addressing unmet medical needs where the market opportunities are track evaluation of innovative medicines is offered less attractive (213). by some licensing authorities (188,224), allowing truly innovative products to reach the public domain as early as possible. Such schemes benefit

OBIAL RESISTANCE • OBIAL RESISTANCE Vaccines both the companies and the community— Vaccines potentially provide a major means of lim- although careful post-licensure surveillance of iting the clinical impact of emerging antimicro- adverse effects is vital. Some products may be bial resistance. Pneumococcal and Haemophilus considered clinically useful but of limited com- influenzae type b (Hib) vaccines have had a mercial value due to infrequent disease occur- dramatic effect in reducing the incidence of clini- rence—for these, some countries provide special cal disease in some age groups and regions (214, licensure under an orphan drug scheme which has 215,216,217). Recent studies of a nonavalent variable eligibility requirements. pneumococcal conjugate vaccine demonstrated a The safeguarding of intellectual property rights significant reduction in the carriage of penicillin- is a major concern to the pharmaceutical indus- resistant and cotrimoxazole-resistant strains of try. There may be opportunities to encourage S. pneumoniae in children nine months after research by furthering international agreements and cooperation on innovative new approaches to

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL vaccination, compared to controls (214). Thus, by reducing the incidence of disease and carriage patents and time-limited exclusivity arrangements. of resistant strains, pneumococcal vaccination may Time-limited exclusivities on new clinically use- limit the impact of antimicrobial resistance. When ful formulations and/or additional indications for use on some current agents might serve to stimu- the information is available, knowledge of a late the additional pharmaceutical and clinical patient’s vaccination status for pneumococcal, Hib studies which are needed to support licensure for and other diseases may aid the differential diag- these additional indications. nosis if the patient presents with an acute illness and thereby allow narrower-spectrum agents to be employed for empiric therapy. Clinical development programmes Vaccines have also proven effective for some Clinical development programmes are designed diarrhoeal diseases and enteric fever. A number of to undertake trials which will support drug regis- typhoid vaccine preparations are now available, tration. These programmes offer possibilities to but their use has previously been limited mainly investigate not only the most effective treatment to travellers to endemic areas. With the new oral regimens but also those which are least likely to preparations, wider use may now be more feasible result in the emergence of antimicrobial resistance. once they can be produced at reasonable cost. However, these pre-registration clinical trials rarely Given recent outbreaks of ciprofloxacin-resistant assess the degree to which in vitro susceptibility typhoid fever, vaccination has been suggested as data correlate with the in vivo clinical outcomes an adjunct to sanitation measures in some regions of infected patients receiving treatment. Although (218,219,220,221). Vaccines for other diarrhoeal these correlations are of vital clinical importance, diseases such as shigellosis, cholera, E. coli ETEC such trials can be difficult to perform. In most and rotavirus are also under trial (218). pre-registration clinical antimicrobial trials, the As the medical treatment of HIV, hepatitis B number of treatment failures is generally too few and C becomes more widespread, antiviral resist- to allow such assessments and, in any case, the ance will become a major limiting factor. Child- primary goal of these studies is to assess equiva- hood vaccination against hepatitis B, either lence of efficacy or drug toxicity, not the correla- universal or targeted to high risk groups depend- tion between in vitro and in vivo outcomes. In ing on the prevalence of hepatitis B in the popu- addition, a number of design features of licensure lation, is a very cost-effective means of controlling studies make such correlations even more diffi- the disease and avoiding the problems of resist- cult. Firstly, some protocols require that enrolled ance (109,222,223). Effective vaccines against patients found to be infected with pathogens that

48 are resistant in vitro to one of the trial drugs should Microbiological and pharmacological issues be withdrawn from the study. However, others A number of important microbiological and phar- allow such patients to continue receiving trial macological features of antimicrobials appear to therapy if they are doing well, despite in vitro influence their likelihood of selecting and promot- resistance. Such design issues have an important ing resistant strains (51,226). Pharmacodynamic impact on the ability to accurately analyse corre- and pharmacokinetic parameters can be used to lation data. Furthermore, the site of infection may help identify the optimal dose and dosing inter- influence the level of antimicrobial penetration vals for each antimicrobial (202). The parameters and therefore the likely concentrations of active most appropriate in terms of encouraging the drug available under routine dosing conditions,

emergence of resistance have been investigated and DEVELOPMENT VACCINE DRUG AND CHAPTER 6. e.g. drug concentrations in cerebrospinal fluid are debated extensively (132,227,228). In addition, generally lower than those achievable in serum. the use of antimicrobials in combinations has been Therefore, in vitro definitions of resistance will suggested for some infections, since a reduced depend on potentially achievable drug concentra- incidence of resistance has been noted with com- tions in vivo, meaning that the MIC breakpoints bination therapy (229,230). for individual pathogens may need to vary depending on the site of infection. Since clinical trials with antimicrobials are Cost-effectiveness almost exclusively designed to demonstrate equiva- Cost-effectiveness studies are increasingly becom- lence to an approved comparative agent, this ing a major component of clinical development means that results cannot be used as a basis for programmes. While these are not required for recommending one treatment over another. Thus, licensure, they may be needed in some countries these studies generally do not provide clear evi- for negotiations on drug supply contracts. While dence on which to base guidelines for the best companies may have some cost-effectiveness data choice of antimicrobial or the optimal mode of available, few release such data to the public. Many management of a particular infection. In addition, published cost-effectiveness studies are at risk of clinical drug trials have not been designed to bias in favour of the new agent, since few studies determine the most appropriate duration of anti- of older agents, that are often no longer patent- microbial therapy. Many scientists and clinicians protected, are undertaken due to insufficient believe that shorter treatment courses for many research funding support. Furthermore, studies infections may be as effective as longer courses focus neither on the cost of resistance nor on the (225). Potential benefits of shorter course thera- clinical impact of resistance and there is a need pies are to decrease disruption of the normal flora for new approaches to incorporate such evalua- and the selective pressure of antimicrobials favour- tions into cost-effectiveness studies (8). Thus, ing drug-resistant microorganisms. Shorter current clinical development programmes rarely durations of therapy are also likely to encourage support decision-making regarding the cost-effec- patient adherence (see Chapter 1). It should be tiveness or optimal dose of various antimicrobials. noted that, at the present time, relatively few clini- However, such programmes may provide some cal antimicrobial studies are conducted on paedi- unique opportunities to gain more useful infor- atric populations and that this may be an area for mation in future if innovative modifications are greater attention in the future. made to current trial designs.

CHAPTER 7 Pharmaceutical promotion

CHAPTER 7. PHARMACEUTICAL PROMOTION PHARMACEUTICAL CHAPTER 7.

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

51 interactions influence prescribing behaviour (233). Patients Thus, pharmaceutical promotional material that Health care professionals in all countries, includ- contains misinformation may ultimately encour- ing those subject to prescription control, often feel age inappropriate antimicrobial use and the pressured by patients to prescribe antimicrobials emergence of resistance. for minor infections which do not need specific

WHO/CDS/CSR/DRS/2001.2 Promotional materials must not only reflect therapy (see Chapter 2). Direct-to-public adver- approved prescribing information correctly but tisements in countries with prescription-only must also be accurate, comprehensive and up to restrictions on antimicrobial agents may enhance date. Particular difficulties may be encountered the pressures on health care professionals to pre- with older antimicrobials for which the initially scribe when their clinical judgement suggests that OBIAL RESISTANCE • OBIAL RESISTANCE licensed indications may now be considered specific therapy is unnecessary. In addition, excessively broad or vague, e.g. upper respiratory advertising on the Internet is gaining market pen- infections, and may no longer reflect current think- etration yet is difficult to control with legislation ing on the optimal evidence-based management due to poor enforceability. To counter this prob- of certain infections. Although pharmaceutical lem, education campaigns directed at health care companies may apply to update sections of the professionals and the general public are underway prescribing information, they are unlikely to do in some countries where antimicrobial agents are so voluntarily if there is a risk of a negative impact available by prescription only. The aim of such a on sales. Licensing authorities may require that campaign in the UK, ongoing in 2000, was to the prescribing information be updated or modi- inform all parties about those infections least likely fied but are unlikely to do so without strong evi- to require antimicrobial treatment—thereby dence to support the changes, due to the possibility reducing patient expectation of the need for an

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL of a legal challenge from companies. Furthermore, antimicrobial agent. Data on the effects of such the fact that many older agents are no longer pat- efforts are awaited. ent-protected means that license holders may not The effects of direct-to-public promotion on consider that the drug’s market value warrants such total and specific antimicrobial usage are likely to applications and effort. be much greater in countries where these agents are available without prescription. In these circum- Prescribers stances, even promotion in accordance with the Promotion of products to health professionals in- prescribing information is likely to result in un- forms prescribers about the range of drugs avail- necessary antimicrobial use as purchasers are less able and alerts them to the availability of new able to fully appreciate the information provided agents. Inherently, pharmaceutical marketing re- and to weigh the possible risks and benefits. sults in the highlighting of potential benefits and Inappropriate antimicrobial use as a result of over- advantages of new agents over existing agents to the-counter availability may therefore be greatly the extent allowable. Under these circumstances exacerbated by direct-to-public advertising. it is often difficult for prescribers to identify the most appropriate role of the new agents within Sales the context of existing protocols. Promotional materials often emphasize simple messages in pref- Pharmaceutical promotion directed towards health erence to more complex ones, not infrequently care professionals who sell antimicrobials may re- resulting in over-prescribing. sult in a conflict of interest. The desire to profit It is also difficult to regulate the provision of from making the sale and/or to favour a particu- inducements such as meals, event tickets, and lar company’s product in expectation of rewards travel to conferences. These perks may serve as may override clinical judgement. In this manner, rewards for using a company’s products and as the decision regarding the necessity for treatment enticements to prescribe newly-introduced drugs and the choice of the most suitable agent are less (234,235). This may also encourage prescribers likely to reflect appropriate clinical management. to prescribe using brand names rather than Sales of antimicrobial drugs through outlets not generic names, which may markedly increase staffed by health care professionals are likely to be specific company sales in those countries which driven predominantly by profit margins with only do not allow pharmacists to substitute between limited potential for control of antimicrobial brands of the same active substance when dispens- usage. ing prescriptions (see Chapter 2).

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

CHAPTER 8 International aspects of containing antimicrobial resistance

Recommendations for intervention 8.7 Encourage innovative approaches to incen- 8.1 Encourage collaboration between govern- tives for the development of new pharma- ments, non-governmental organizations, pro- ceutical products and vaccines for neglected fessional societies and international agencies diseases. to recognize the importance of antimicrobial 8.8 Establish an international database of poten- resistance, to present consistent, simple and tial research funding agencies with an inter- accurate messages regarding the importance est in antimicrobial resistance. of antimicrobial use, antimicrobial resistance RESISTANCE ANTIMICROBIAL OF CONTAINING ASPECTS INTERNATIONAL CHAPTER 8. 8.9 Establish new, and reinforce existing, and its containment, and to implement strat- programmes for researchers to improve the egies to contain resistance. design, preparation and conduct of research 8.2 Consider the information derived from the to contain antimicrobial resistance. surveillance of antimicrobial use and antimicrobial resistance, including the containment Background—the changing global thereof, as global public goods for health to context of public health which all governments should contribute. Multiple global factors are influencing the epide- 8.3 Encourage governments, non-governmental miology of infectious diseases, the contexts in organizations, professional societies and which they need to be managed, and thus the international agencies to support the estab- demands on health care systems. Increasing lishment of networks, with trained staff and urbanization, with its associated overcrowding and adequate infrastructures, which can undertake inadequate housing, poor sanitation and lack of epidemiologically valid surveillance of anti- clean water supplies, has a major influence on the microbial resistance and antimicrobial use to burden of infectious disease. Pollution and envi- provide information for the optimal contain- ronmental change, including deforestation, chang- ment of resistance. ing weather patterns and desertification, may also 8.4 Support drug donations in line with the UN affect the incidence and distribution of infectious interagency guidelines*. diseases. Demographic changes resulting in a growing proportion of elderly people and the ex- 8.5 Encourage the establishment of international panding use of modern medical interventions are inspection teams qualified to conduct valid increasing the risks of acquiring infections, assessments of pharmaceutical manufacturing especially those caused by multi-resistant hospital plants. pathogens. The AIDS epidemic has greatly en- 8.6 Support an international approach to the con- larged the population of immunocompromised trol of counterfeit antimicrobials in line with patients at risk of infections. Changing patterns the WHO guidelines**. of lifestyle also have an effect, e.g. the increase in cigarette smoking in many societies and the con- sequent increase in associated respiratory diseases, including pneumonia. * Interagency guidelines. Guidelines for Drug Donations, revised An increased incidence of infections leads to 1999. Geneva, World Health Organization, 1999. WHO/ more antimicrobial use and consequently a greater EDM/PAR/99.4. selection pressure in favour of resistant microor- **Counterfeit drugs. Guidelines for the development of measures ganisms. Furthermore, the increased food require- to combat counterfeit drugs. Geneva, World Health Organi- zation, 1999. WHO/EDM/QSM/99.1. ments of expanding populations may promote an

55 increased use of antimicrobial agents in agricul- tions can encourage both the health and educa- ture, in turn contributing to the emergence of tion sectors of national governments to ensure that antimicrobial resistance in zoonotic pathogens. sufficient education on infectious disease, antimi- Increases in global trade and travel have increased crobial use and infection control is provided to all the speed with which both infectious diseases and students in health care professions.

WHO/CDS/CSR/DRS/2001.2 resistant microorganisms can spread between Experience of the successful implementation of continents. interventions to contain resistance is a resource that should not be wasted; sharing information A call for international cooperative action between nations should be given high priority to maximize the success of national strategies. These OBIAL RESISTANCE • OBIAL RESISTANCE Containing antimicrobial resistance must involve are areas in which organizations such as WHO concerted international action. While the major- can and should play a leading role. A summary of ity of the interventions recommended in earlier currently available national programmes and strat- chapters of this document are directed at the egies to contain antimicrobial resistance is shown national level, interventions also need to be un- in Annex A; some of these have been analysed in dertaken at an international level. It is no longer more detail (187). justifiable for countries to exempt themselves from taking action to contain resistance, since inaction will have both national and international conse- Legal issues associated with antimicrobial resistance quences. At the same time it is important to recognize Existing laws at international level require report- the barriers to action and work to remove them. ing of a limited number of infectious diseases (242)

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL Antimicrobial resistance is a multi-faceted prob- but do not extend to any systematic reporting of lem which calls for a multi-sectoral response, but antimicrobial resistance. In the revision of the In- it is a challenge to get all the sectors on board when ternational Health Regulations (IHR) currently the magnitude of the problem is unknown. There under evaluation, potential international threats is a lack of coordination between different groups posed by resistant infections could be recognized. and disciplines working in this field and even a Some countries have now made certain multi- lack of knowledge that the different groups exist. resistant pathogens, e.g. MRSA, notifiable at the Thus messages concerning antimicrobial use and national level. However, the global nature of the resistance are often confusing and conflicting. antimicrobial resistance problem means that Many countries lack the money, the skilled pro- national legal measures alone are insufficient. At fessionals and sufficient laboratory capacity to the same time, the creation of new international tackle even the definition of the size of the prob- duties would be undermined if not incorporated lem of resistance. into national law (88). Closer cooperation between national governments and agencies, professional societies, Antimicrobial resistance as a non-governmental organizations (NGOs) and in- Global Public Good for Health ternational agencies would raise the importance of antimicrobial resistance and its threat to health The concept of Global Public Goods for Health and development up the political agenda and pro- (GPGH) and their development to assist in the vide additional resources for the implementation prevention and containment of communicable of the containment strategy. The development of diseases is growing in importance (243,244). In consistent messages is critical. International the context of the current review by the Commis- organizations and NGOs can be particularly sion for Macroeconomics and Health, epidemi- effective in raising the awareness of their mem- ologically sound surveillance of antimicrobial use, bers and the public about the importance of anti- resistance and the overall burden of infectious dis- microbial resistance and in lobbying governments eases is an important component of GPGH. These about the issue so that antimicrobial resistance is are public goods which have quasi-universal health seen by governments as being important. By benefits in terms of countries, populations and including the containment of antimicrobial resist- generations, both current and future, or at least ance in their aims and objectives, relevant NGOs meet the needs of current generations without and professional societies can educate their mem- foreclosing development options for future gen- bers. Furthermore, such international organiza- erations (243). Given the increasing ease of trans-

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

57 availability of treatment in complex emergencies tional GMP inspection teams, made up of em- and in elimination and eradication programmes ployees of larger agencies who might contribute a for certain disabling diseases in resource-poor limited number of hours per year to the team. Such settings e.g. leprosy, onchocerciasis (river blind- teams might conduct inspections of a selection of ness) and lymphatic filariasis. Such donations manufacturing sites at the invitation of, and on

WHO/CDS/CSR/DRS/2001.2 should be strongly encouraged, but in certain situ- behalf of, licensing authorities in resource-poor ations may need to be better coordinated to countries. optimize the selection of drugs provided and their distribution and accessibility to avoid duplication Assessment report sharing schemes and wastage. OBIAL RESISTANCE • OBIAL RESISTANCE Donors may inadvertently promote inappro- Drug licensing authorities in many resource-poor priate use of antimicrobials, thereby contributing countries are often willing to license new medi- to the resistance problem, through supporting cines on the basis of their prior approval by other donations that are inappropriate in terms of the regulatory agencies, e.g. the US FDA or the EU. type and quantity of drug, or because a lack of In other countries, where a formal national review local infrastructure and capacity prevents the of application dossiers is performed, the assess- appropriate use of the donated drugs. Thus, ment of safety and efficacy of new medicinal prod- donor agencies should ensure that the advice they ucts has sometimes been assisted by the existence of certain assessment report sharing schemes. Ex- give to governments in drawing up their national pansion of such schemes might benefit regulatory health plans takes into account antimicrobial re- authorities thereby expediting the licensing of new sistance issues. International action should be drugs. taken to ensure that all donations follow the The WHO Certification Scheme is an inter- WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL interagency guidelines (246). Alternatively, finan- national voluntary agreement, devised to enable cial donations to countries to ensure the purchase countries with limited regulatory capacity to of the most effective antimicrobials for their needs obtain partial assurance from exporting countries together with strategies for distribution and use concerning the safety, quality and efficacy of the may be more appropriate. International pro- products they plan to import. The scheme requires grammes concerned with drug donations should that the regulatory authorities of exporting coun- have capacity-building, training and supervision tries issue certificates when requested by import- components, and should be evaluated using indi- ing countries. cators that are relevant at the community level, i.e. at household and primary health care facility, where most antimicrobial use takes place. Counterfeits Antimicrobials are among the most frequently International inspections of pharmaceutical counterfeited drugs (191). Such drugs have manufacturing potentially major clinical consequences in terms of treatment failure and prolonged, or even in- National quality control of medicines and the creased, suffering. Concerted action to reduce the monitoring of compliance with Good Manufac- distribution of counterfeit drugs is beyond the turing Practice (GMP) are important to ensure scope of this document and will require the im- that products meet the required standards. Some plementation of a separate coordinated package countries, e.g. in the EU, already accept findings of interventions. National and international of inspections that have been performed by authorities should collaborate to ensure the appropriately qualified persons from another enforcement of relevant laws. country. However, not all countries have the resources to perform regular detailed inspections of International codes of good marketing practice manufacturing plants; consequently, these do not get inspected unless they are the target of an Adherence to national and international codes of inspection by a team from another country into marketing practices (240) is critical to maintain- which the product(s) is/are exported. In these in- ing and improving the quality and accuracy of drug stances, there may be scope for more extensive promotion practices. The effective policing of sharing of inspection reports between the authori- adherence to these codes of practice requires ties of the originator country and the inspecting international commitment, cooperation and country. It may also be possible to set up interna- supervision (see also Chapter 7).

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

PART C Implementation of the WHO Global Strategy

Implementation of the WHO Global Strategy

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

63 The problems related to resistance to the treat- are not properly treated under a DOTS-based pro- ments-of-choice for these diseases are presented gramme. However, the control of existing MDR- in detail in accompanying documents TB also has an extremely high priority. The Global (19,20,21,101). Tables 2–5 summarize the impor- Project on Anti-Tuberculosis Drug Resistance tant factors influencing the emergence and spread Surveillance (managed jointly by WHO and the

WHO/CDS/CSR/DRS/2001.2 of resistance and set out the groups of interven- International Union against Tuberculosis and tions which need to be implemented to make an Lung Disease) has identified high prevalence of impact. MDR-TB in some countries of Eastern Europe, Latin America, Africa, and Asia (12,245,250). Tuberculosis MDR-TB does not respond as effectively as drug- OBIAL RESISTANCE • OBIAL RESISTANCE susceptible TB to short-course chemotherapy with Tuberculosis is a leading cause of morbidity and first-line drugs (48). Therefore, WHO and its mortality worldwide and resistance to antituber- partners have launched DOTS-Plus (43,247,251) culous therapy has increased dramatically in to manage MDR-TB with second-line drugs. recent years with evidence of substantive clinical DOTS-Plus includes the five components of treatment failures and increased person-to-person DOTS together with other aspects regarding long- transmission (12,13,43). The spread of HIV in- term (18–24 months) therapeutic regimens with fection, with its associated immunosuppression, second-line drugs, and the use of drug suscepti- has resulted in an enormous increase in TB cases, bility testing for diagnosis and therapeutic follow- most frequently among resource-poor communi- up. Recommendations for therapeutic regimens ties and in regions with weak health care systems. for the treatment of MDR-TB were compiled by Inadequate treatment, including insufficient drugs a panel of experts convened by WHO (245,249).

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL (inadequate supply or mono-therapy), poor qual- Pilot projects with some of the recommended ity drugs, and/or poor adherence to treatment treatment regimens are underway to assess the regimens have been major factors in the emergence feasibility and cost-effectiveness of using second- of multi-drug resistant TB (MDR-TB). line drugs under programme conditions. Surveil- Although tuberculosis is a bacterial infection, lance for drug resistance at the pilot sites is a it is considered different enough to warrant a dis- prerequisite. Data generated through this initia- tinct focus. In addition, WHO has initiated ap- tive will be used to design evidence-based policy proaches to the containment of anti-tuberculosis guidelines for the management of MDR-TB, drug resistance. Faced with the global emergency which in turn will play a critical role in the con- of tuberculosis, WHO adopted the DOTS (di- tainment of drug resistance in tuberculosis. rectly observed treatment, short-course) interven- Thus, many of the interventions that will need tion strategy for effective TB control (245,249). to be implemented to contain resistance in other The principles of DOTS are the following: bacterial infections, such as political commitment, — government commitment to a National improvement in national regulatory frameworks, Tuberculosis Programme drug distribution and educational initiatives regarding antimicrobial resistance, are in line with, — case detection through case-finding by and will further support, current initiatives to con- sputum smear microscopy examination of tain drug-resistant tuberculosis. Intervention TB suspects in general health facilities priorities have been identified for tuberculosis — standardized short-course chemotherapy to, (Table 6). at least, all smear-positive TB cases under directly observed therapy (DOT) under proper case management conditions Malaria — regular uninterrupted supply of all essen- The majority of deaths in malarious areas con- tial anti-TB drugs tinue to be due to the lack of drug availability (252). However, emerging resistance is also greatly — monitoring system for programme super- undermining the efficacy of antimalarial treatment vision and evaluation. regimens in many regions and is likely to pose a The implementation of DOTS, presently in major problem worldwide in the future. 119 countries (12,43), prevents the generation of As summarized in Table 7, one of the key driv- MDR-TB through the cure of drug-susceptible ers behind the emergence of antimalarial resist- TB patients, who will evolve to MDR-TB if they ance is poor patient understanding about the

64 disease and its appropriate treatment, resulting in fections other than tuberculosis. The valuable indiscriminate short-course therapy with antima- lessons that will be learned during this first phase larial agents. In addition, inappropriate prescrib- should impact on the implementation approaches ing/dispensing and ineffective drug distribution used for containment of resistance in tuberculo- systems encourage such behaviour. The frequent sis, malaria and viral infections. However, due to lack of appropriate diagnostic facilities makes the commonality of factors leading to antimicro- the decision to treat difficult, since malaria so bial resistance in all diseases, many of the inter- frequently presents in an undifferentiated man- ventions, instigated for containing resistance in ner, as fever with, or without, headache. Thus, bacterial infections—such as political commit- without the ability to confirm the diagnosis, the ment, regulatory framework, laboratory strength-

tendency is to treat every patient with a fever with ening, surveillance and education—will also STRATEGY WHO GLOBAL THE OF IMPLEMENTATION antimalarials if they reside in a malaria endemic contribute to resistance containment in other region. Systems for surveillance of antimicrobial diseases at national level. resistance are often weak and thus unable to inform about the need to change treatment guide- STEP 2 lines. Despite early promising data, it appears that Defining a core set of interventions to contain vaccines effective against malaria are still some antibacterial resistance years away (253). The priority for the containment of antimalarial resistance is thus to concen- While prioritization by disease group provides trate on the implementation of intervention some direction for implementation, the identifi- groups 1, 2, 5 and 6. This is in line with WHO cation of a core set for national implementation is policy as expressed in a document in preparation required, within each group of interventions. This by the WHO Regional Office for Africa (254). 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 Viral infections recently been the subject of an extensive consulta- With the increasing development and use of tive process at WHO and primarily involve inter- effective antiretroviral agents, resistance is becom- ventions in the agricultural industry (2). Thus they ing apparent. In vitro resistance to antiretroviral are not considered further here. Interventions agents among HIV strains appears to correlate with relating to drug and vaccine development and prior antiretroviral therapy and with clinical treat- international aspects of containing antimicrobial ment failure (255,256,257,258,259). Highly resistance are extremely important, but since they effective combination therapy is considered to be depend on supra-national factors, a number of less associated with the emergence of resistance. which involve the (multi-national) research-based However, this is a rapidly progressing area of pharmaceutical industry, their prioritization at scientific research in which the factors that drive national level is less relevant. resistance are less clearly defined than for bacte- Implementation of the WHO Global Strategy rial infections and malaria. As the knowledge base at national level therefore requires prioritization expands, a prioritization of interventions can be among interventions in groups 1, 2, 3, 5 and 7. developed. At present it seems clear that improved The prioritization presented in Step 3 is based on patient and prescriber education (Intervention available evidence (summarized in Part B); where Groups 1 and 2), government regulations regard- evidence is lacking, it is based on the consensus of ing licensure and surveillance of resistance (Inter- a suitably qualified group of experts convened by vention Group 5) and issues of drug and vaccine WHO for this purpose. development (Group 6) will all be important. STEP 3 Conclusion of Step 1 Intra-group prioritization of interventions Given the disease-specific aspects of containment Interventions within each group have been of antimicrobial resistance associated with tuber- prioritized according to the relative merits of each culosis, malaria and HIV infections and the pro- intervention and ranked according to sequence grammes already in place, it is proposed that the and importance of implementation. This complex first phase of implementation of the WHO task required consideration of multiple factors Global Strategy should be directed to bacterial in- relating to each intervention including:

65 — overall importance of the intervention to process only provides a guide to implementation improving the appropriate use of antimi- and is not a rigid set of rules. Differences in crobials and containing antimicrobial national circumstances, health care systems and resistance burden of the different infections may influence the practicality with which some interventions can — likely impact, allowing for the expected cost

WHO/CDS/CSR/DRS/2001.2 be implemented and the local importance of one of implementation intervention over another in a manner that is not — complexity of implementation considering accurately reflected in Table 8. However, Table 8 the capacity of various health care systems provides a working guide to the prioritization and and political realities sequence of implementation of interventions in

OBIAL RESISTANCE • OBIAL RESISTANCE — time required for implementation and the groups 1, 2, 3, 5 and 7. expected lag period before outcomes could be expected Implementation guidelines — the accuracy with which most health care Effective implementation requires a number of key systems could assess the efficacy of each features, including a clear action plan, delegation intervention of authority and power to act, resources and sound — the interrelationship between various inter- mechanisms to assess the effectiveness of interven- ventions, including the need to undertake tions, allowing feedback of results to influence future implementation strategies. Thus, interven- some interventions in a logical sequence. tions identified in the prioritization process as being of fundamental and first priority (see Table Inter-group prioritization of interventions

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL 8) have been considered in greater detail, specifi- Following the prioritization within each group, cally identifying the following aspects as impor- interventions were ranked according to their over- tant for successful implementation: all importance and timing (sequence) of imple- — the optimal approach to implementation mentation without consideration of their group. Although it was recognized that some priorities — who should initiate the intervention, might vary depending on the health care system undertake and manage the intervention, in which they are to be implemented, it was found and evaluate the intervention that this consideration did not impact to any — what process and outcome indicators significant extent on the priority given to the should be used for evaluation. majority of very high priority interventions. The proposed guidelines for implementation The results of Step 3 are shown in Table 8. In- are detailed in “Suggested Model Framework for terventions are grouped according to those which Implementation of Core Interventions”. should be undertaken first, through to those which, although important, are either dependent on the implementation of the earlier interventions Monitoring outcomes or are of lower priority. Within each priority i.e. Ability to monitor the process to ensure that in- first, second, third, interventions are not ranked terventions are appropriately designed and targeted but listed in numerical order only and should be and their impact on the use of antimicrobials and considered of equal importance. For example, for the prevalence of resistance will be crucial to the group 1, both interventions 1.2 and 1.3 are con- successful implementation of the WHO Global sidered to be of similar priority for implementa- Strategy. Without accurate information about tion, but both 1.2 and 1.3 are given higher priority antimicrobial usage and antimicrobial resistance than either 1.1 (second priority) or 1.4 and 1.5 and their respective trends, the impact of inter- (third priority). ventions will be difficult to interpret. Thus, an Comparisons across the groups of interventions early priority in the implementation of the WHO are more difficult but are important to achieve a Global Strategy for all countries should be the es- logical and effective implementation. Within the tablishment of an appropriate framework to moni- national reality, consideration of the sectors tor accurately antimicrobial use and antimicrobial involved in implementation of the interventions resistance (Intervention Group 5). should allow a plan of action to be elaborated. It must be emphasized that this prioritization

66 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 STRATEGY WHO GLOBAL THE OF IMPLEMENTATION implemention. The manner in which the WHO Global Strategy for Containment of Antimicro- bial Resistance is implemented will depend largely on the decisions and actions of each nation, but the consequences are likely to be felt worldwide.

67 Recommendations for intervention 2.9 Empower formulary managers to limit antimicrobial use to the prescription of an appropri- 1. PATIENTS AND THE GENERAL COMMUNITY ate range of selected antimicrobials.

Education Regulation 1.1 Educate patients and the general community on 2.10 Link professional registration requirements for

WHO/CDS/CSR/DRS/2001.2 the appropriate use of antimicrobials. prescribers and dispensers to requirements for 1.2 Educate patients on the importance of meas- training and continuing education. ures to prevent infection, such as immunization, vector control, use of bednets, etc. 3. HOSPITALS 1.3 Educate patients on simple measures that may OBIAL RESISTANCE • OBIAL RESISTANCE reduce transmission of infection in the house- Management hold and community, such as handwashing, 3.1 Establish infection control programmes, based food hygiene, etc. on current best practice, with the responsibility 1.4 Encourage appropriate and informed health for effective management of antimicrobial care seeking behaviour. resistance in hospitals and ensure that all hos- 1.5 Educate patients on suitable alternatives to pitals have access to such a programme. antimicrobials for relief of symptoms and 3.2 Establish effective hospital therapeutics com- discourage patient self-initiation of treatment, mittees with the responsibility for overseeing except in specific circumstances. antimicrobial use in hospitals. 3.3 Develop and regularly update guidelines for 2. PRESCRIBERS AND DISPENSERS antimicrobial treatment and prophylaxis, and hospital antimicrobial formularies. Education 3.4 Monitor antimicrobial usage, including the

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL 2.1 Educate all groups of prescribers and dispens- quantity and patterns of use, and feedback ers (including drug sellers) on the importance results to prescribers. of appropriate antimicrobial use and containment of antimicrobial resistance. Diagnostic laboratories 2.2 Educate all groups of prescribers on disease 3.5 Ensure access to microbiology laboratory prevention (including immunization) and infec- services that match the level of the hospital, e.g. tion control issues. secondary, tertiary. 2.3 Promote targeted undergraduate and post- 3.6 Ensure performance and quality assurance of graduate educational programmes on the appropriate diagnostic tests, microbial identifi- accurate diagnosis and management of cation, antimicrobial susceptibility tests of key common infections for all health care workers, pathogens, and timely and relevant reporting veterinarians, prescribers and dispensers. of results. 2.4 Encourage prescribers and dispensers to educate 3.7 Ensure that laboratory data are recorded, pref- patients on antimicrobial use and the importance erably on a database, and are used to produce of adherence to prescribed treatments. clinically- and epidemiologically-useful surveil- 2.5 Educate all groups of prescribers and dispens- lance reports of resistance patterns among ers on factors that may strongly influence their common pathogens and infections in a timely prescribing habits, such as economic incentives, manner with feedback to prescribers and to the promotional activities and inducements by the infection control programme. pharmaceutical industry. Interactions with the pharmaceutical industry Management, guidelines and formularies 3.8 Control and monitor pharmaceutical company 2.6 Improve antimicrobial use by supervision and promotional activities within the hospital envi- support of clinical practices, especially diagnos- ronment and ensure that such activities have tic and treatment strategies. educational benefit. 2.7 Audit prescribing and dispensing practices and utilize peer group or external standard compari- 4. USE OF ANTIMICROBIALS IN sons to provide feedback and endorsement of FOOD-PRODUCING ANIMALS appropriate antimicrobial prescribing. This topic has been the subject of specific consulta- 2.8 Encourage development and use of guidelines tions which resulted in “WHO global principles for the and treatment algorithms to foster appropriate containment of antimicrobial resistance in animals use of antimicrobials. intended for food”*. A complete description of all rec-

* http:// www.who.int/emc/diseases/zoo/who_global_ principles.html

68 ommendations is contained in that document and 5.4 Link prescription-only status to regulations re- only a summary is reproduced here. garding the sale, supply, dispensing and allowable promotional activities of antimicrobial Summary agents; institute mechanisms to facilitate 4.1 Require obligatory prescriptions for all anti- compliance by practitioners and systems to microbials used for disease control in food monitor compliance. animals. 5.5 Ensure that only antimicrobials meeting inter- 4.2 In the absence of a public health safety evalua- national standards of quality, safety and efficacy tion, terminate or rapidly phase out the use of are granted marketing authorization. antimicrobials for growth promotion if they are 5.6 Introduce legal requirements for manufacturers also used for treatment of humans. to collect and report data on antimicrobial

4.3 Create national systems to monitor antimicro- distribution (including import/export). STRATEGY WHO GLOBAL THE OF IMPLEMENTATION bial usage in food animals. 5.7 Create economic incentives for appropriate use 4.4 Introduce pre-licensing safety evaluation of of antimicrobials. antimicrobials with consideration of potential resistance to human drugs. Policies and guidelines 4.5 Monitor resistance to identify emerging health 5.8 Establish and maintain updated national Stand- problems and take timely corrective actions to ard Treatment Guidelines (STGs) and encourage protect human health. their implementation. 4.6 Develop guidelines for veterinarians to reduce 5.9 Establish an Essential Drugs List (EDL) consist- overuse and misuse of antimicrobials in food ent with national STGs and ensure the accessi- animals. bility and quality of these drugs. 5.10 Enhance immunization coverage and other disease preventive measures, thereby reducing 5. NATIONAL GOVERNMENTS AND HEALTH SYSTEMS the need for antimicrobials.

Advocacy and intersectoral action Education 5.1 Make the containment of antimicrobial resist- 5.11 Maximize and maintain the effectiveness of the ance a national priority. EDL and STGs by conducting appropriate undergraduate and postgraduate education — Create a national intersectoral task force programmes of health care professionals on the (membership to include health care profes- importance of appropriate antimicrobial use sionals, veterinarians, agriculturalists, and containment of antimicrobial resistance. pharmaceutical manufacturers, government, media representatives, consumers 5.12 Ensure that prescribers have access to approved prescribing literature on individual drugs. and other interested parties) to raise awareness about antimicrobial resistance, organize data collection and oversee local task Surveillance of resistance, antimicrobial usage forces. For practical purposes such a task and disease burden force may need to be a government task 5.13 Designate or develop reference microbiology force which receives input from multiple laboratory facilities to coordinate effective sectors. epidemiologically sound surveillance of antimicrobial resistance among common pathogens — Allocate resources to promote the imple- in the community, hospitals and other health mentation of interventions to contain resist- care facilities. The standard of these laboratory ance. These interventions should include facilities should be at least at the level of rec- the appropriate utilization of antimicrobial ommendation 3.6. drugs, the control and prevention of infection, and research activities. 5.14 Adapt and apply WHO model systems for antimicrobial resistance surveillance and ensure — Develop indicators to monitor and evaluate data flow to the national intersectoral task force, the impact of the antimicrobial resistance to authorities responsible for the national STGs containment strategy. and drug policy, and to prescribers. Regulations 5.15 Establish systems for monitoring antimicrobial 5.2 Establish an effective registration scheme for use in hospitals and the community, and link dispensing outlets. these findings to resistance and disease surveillance data. 5.3 Limit the availability of antimicrobials to prescription-only status, except in special 5.16 Establish surveillance for key infectious diseases circumstances when they may be dispensed on and syndromes according to country priorities, the advice of a trained health care professional. and link this information to other surveillance data.

69 6. DRUG AND VACCINE DEVELOPMENT 8. INTERNATIONAL ASPECTS OF CONTAINING ANTIMICROBIAL RESISTANCE 6.1 Encourage cooperation between industry, government bodies and academic institutions 8.1 Encourage collaboration between govern- in the search for new drugs and vaccines. ments, non-governmental organizations, professional societies and international agencies to 6.2 Encourage drug development programmes recognize the importance of antimicrobial

WHO/CDS/CSR/DRS/2001.2 which seek to optimize treatment regimens resistance, to present consistent, simple and with regard to safety, efficacy and the risk of accurate messages regarding the importance of selecting for resistant organisms. antimicrobial use, antimicrobial resistance and 6.3 Provide incentives for industry to invest in the its containment, and to implement strategies to research and development of new antimi- contain resistance.

OBIAL RESISTANCE • OBIAL RESISTANCE crobials. 8.2 Consider the information derived from the sur- 6.4 Consider establishing or utilizing fast-track veillance of antimicrobial use and antimicrobial marketing authorization for safe new agents. resistance, including the containment thereof, 6.5 Consider using an orphan drug scheme where as global public goods for health to which all available and applicable. governments should contribute. 6.6 Make available time-limited exclusivity for new 8.3 Encourage governments, non-governmental formulations and/or indications for use of organizations, professional societies and inter- antimicrobials. national agencies to support the establishment 6.7 Align intellectual property rights to provide suit- of networks, with trained staff and adequate able patent protection for new antimicrobial infrastructures, which can undertake epidemi- agents and vaccines. ologically valid surveillance of antimicrobial resistance and antimicrobial use to provide 6.8 Seek innovative partnerships with the pharma- information for the optimal containment of ceutical industry to improve access to newer resistance. WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL essential drugs. 8.4 Support drug donations in line with the UN interagency guidelines*. 7 PHARMACEUTICAL PROMOTION 8.5 Encourage the establishment of international 7.1 Introduce requirements for pharmaceutical inspection teams qualified to conduct valid companies to comply with national or inter- assessments of pharmaceutical manufacturing national codes of practice on promotional plants. activities. 8.6 Support an international approach to the 7.2 Ensure that national or internationally codes of control of counterfeit antimicrobials in line practice cover direct-to-consumer advertising, with the WHO guidelines**. including advertising the Internet. 8.7 Encourage innovative approaches to incentives 7.3 Institute systems for monitoring compliance for the development of new pharmaceutical with legislation on promotional activities. products and vaccines for neglected diseases. 7.4 Identify and eliminate economic incentives that 8.8 Establish an international database of potential encourage inappropriate antimicrobial use. research funding agencies with an interest in 7.5 Make prescribers aware that promotion in antimicrobial resistance. accordance with the datasheet may not neces- 8.9 Establish new, and reinforce existing, pro- sarily constitute appropriate antimicrobial use. grammes for researchers to improve the design, preparation and conduct of research to contain antimicrobial resistance.

* Interagency guidelines. Guidelines for Drug Donations, revised 1999. Geneva, World Health Organization, 1999. WHO/ EDM/PAR/99.4. **Counterfeit drugs. Guidelines for the development of measures to combat counterfeit drugs. Geneva, World Health Organi- zation, 1999. WHO/EDM/QSM/99.1.

70 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

IMPLEMENTATION OF THE WHO GLOBAL STRATEGY WHO GLOBAL THE OF IMPLEMENTATION Detection of in vitro resistance Reasonably easy Feasible but Difficult, expensive Difficult, expensive & feasible expensive rarely feasible limited availability

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 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

WHO/CDS/CSR/DRS/2001.2 Campylobacter spp. +/– – +++ ++ –

Shigella spp. ++–+/–++–

Salmonella spp: S. typhi & S. paratyphi ++ – – +++ + OBIAL RESISTANCE • OBIAL RESISTANCE Non-typhoidal salmonellae –/+ – +++ +++ –

Vibrio cholerae + – – +++ +

Diarrhoeal disease overall +/++ ++/++ +++ –/+

➞

➞ ➞

High High High Moderate priority priority priority priority Intervention Intervention Intervention Intervention Groups Groups Group Group 1, 2, 5 & 7 4 & 7 5 6

High priority interventions:

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL 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

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 & 7 5 6

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 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 WHO GLOBAL THE OF IMPLEMENTATION

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 & 7 4 5

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 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

WHO/CDS/CSR/DRS/2001.2 Mycobacterium tuberculosis ++ – – +++ +/–

Tuberculosis overall ++ +++ +

➞

➞ ➞

OBIAL RESISTANCE • OBIAL RESISTANCE High High Moderate priority priority priority Intervention Intervention Intervention Groups Group Group 1, 2 & 5 5 6

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

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL 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

Plasmodium vivax / ovale / malariae +––+–

Plasmodium falciparum +++ – – +++ +/–

Malaria overall ++ +++ +/–

➞

➞ ➞

High High Moderate priority priority priority Intervention Intervention Intervention Groups Group Group 1, 2 & 5 5 6

High priority interventions: Group 1 Patients and the general community Group 2 Prescribers and dispensers Group 5 National governments and health systems

74 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 1.2 1.1 1.4 1.3 1.5

2. Prescribers and dispensers 2.1 2.6 2.4 2.2 2.7 2.5

2.3 2.9 2.10 STRATEGY WHO GLOBAL THE OF IMPLEMENTATION

2.8

3. Hospitals 3.1 3.2 3.5 3.3 3.6 3.4

3.7 3.8

5. National governments and 5.1 5.3 5.2 5.6 health systems 5.13 5.5 5.4 5.7

5.8 5.12 5.9 5.14 5.11 5.15

5.16

7. Pharmaceutical promotion 7.1 7.4

7.2 7.5 7.3

75 Suggested model framework for implementation of core interventions (excluding group 4)

INTERVENTIONS—PRIORITY OF IMPLEMENTATION : FUNDAMENTAL Intervention 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, pharmaceuti-

WHO/CDS/CSR/DRS/2001.2 cal 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.

OBIAL RESISTANCE • OBIAL RESISTANCE ● 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.

Implementation: ● Develop a National Strategy and make it a national priority

Who should initiate: ● Ministry of Health ● Other interested parties should contribute (e.g. Professional Societies) ● WHO to assist and contribute

Who should undertake and manage: ● National Intersectoral Task Force appointed by the Ministry of Health

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL ● Sufficient resources should be allocated

Who should evaluate: ● WHO through the Regional Offices

Process Indicators: ● Appointment of the National Intersectoral Task Force ● Allocation of sufficient resources

Outcome Indicators: ● Has a National Strategy been developed?

Intervention 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.

Implementation: ● Establishment by government mandate

Who should initiate: ● Ministry of Health ● Sufficient resources should be allocated

Who should undertake and manage: ● Reference laboratories—accountable to Government Health Depart- ment

Who should evaluate: ● Internal and external, (e.g. international), quality assurance programmes and performance assessments ● National Intersectoral Task Force audit

Process Indicators: ● Evidence of overseeing national resistance surveillance ● Documentation of resistance data

Outcome Indicators: ● 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 INTERVENTIONS—INTERVENTION PRIORITY: FIRST Intervention 1.2 Educate patients on the importance of measures to prevent infection, such as immunization, vector control, use of bednets, etc.

Implementation: ● Develop a National Strategy and make it a national priority

Who should initiate: ● Ministry of Health ● Other interested parties should contribute (e.g. Professional Societies) ● WHO to assist and contribute

Who should undertake and manage: ● National Intersectoral Task Force (e.g. appointed by the Ministry of Health)

IMPLEMENTATION OF THE WHO GLOBAL STRATEGY WHO GLOBAL THE OF IMPLEMENTATION ● Sufficient resources should be allocated

Who should evaluate: ● WHO through the Regional Offices ● Ministry of Health

Process Indicators: ● Appointment of the National Intersectoral Task Force ● Allocation of sufficient resources

Outcome Indicators: ● Has a National Strategy been developed? ● Immunization rates

Intervention 1.3 Educate patients on simple measures that may reduce transmission of infection in the household and community, such as handwashing, food hygiene, etc.

Implementation: ● Develop a National Strategy and make it a national priority

Who should initiate: ● Ministry of Health ● Other interested parties should contribute (e.g. Professional Societies) ● WHO to assist and contribute

Who should undertake and manage: ● National Intersectoral Task Force (e.g. appointed by the Ministry of Health) ● Sufficient resources should be allocated

Who should evaluate: ● WHO through the Regional Offices ● Ministry of Health

Process Indicators: ● Appointment of the National Intersectoral Task Force ● Allocation of sufficient resources

Outcome Indicators ● Has a National Strategy been developed?

Interventions 2.1 and 2.2 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.

Implementation: ● Develop a National Strategy and make it a national priority ● Identify interested organizations and opinion leaders, educators and sources of appropriate information

Who should initiate: ● National Intersectoral Task Force

Who should undertake and manage: ● Organizations delegated by the National Intersectoral Task Force

77 INTERVENTIONS—INTERVENTION PRIORITY: FIRST (continued) Who should evaluate: ● Ministry of Health ● National Intersectoral Task Force ● Professional organizations, universities, delegated organizations

●

WHO/CDS/CSR/DRS/2001.2 Process Indicators: Opinion leaders identified, quantitative and qualitative assessments of educational exposure

Outcome Indicators: ● Levels of knowledge, attitudes and beliefs about antibiotic use, awareness of antimicrobial resistance and disease prevention issues in target populations

OBIAL RESISTANCE • OBIAL RESISTANCE

Intervention 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.

Implementation: ● 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.

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL Who should initiate: ● National Intersectoral Task Force—delegating to suitable interested organizations and opinion leaders

Who should undertake and manage: ● Organizations delegated by the National Intersectoral Task Force

Who should evaluate: ● National Intersectoral Task Force ● Professional organizations, universities and organizations delegated by the National Intersectoral Task Force

Process Indicators: ● Opinion leaders identified ● Curriculum developed and implemented; quantitative and qualitative assessments of educational exposure

Outcome Indicators: ● Levels of knowledge, attitudes and skills regarding management of common infections and containment of antimicrobial resistance

Intervention 2.8 Encourage development and use of guidelines and treatment algorithms to foster appropriate use of antimicrobials.

Implementation: ● 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

Who should initiate: ● National Intersectoral Task Force

Who should undertake and manage: ● Organizations delegated by the National Intersectoral Task Force

Who should evaluate: ● National Intersectoral Task Force ● Organizations delegated by the National Intersectoral Task Force

Process Indicators: ● Production of guidelines and dissemination plan

Outcome Indicators: ● Level of uptake and indicators of appropriate use of antimicrobials among target health care providers

78 INTERVENTIONS—INTERVENTION PRIORITY: FIRST (continued) Intervention 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.

Implementation: ● 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

Who should initiate: ● Hospital management delegating to an infection control committee

IMPLEMENTATION OF THE WHO GLOBAL STRATEGY WHO GLOBAL THE OF IMPLEMENTATION

Who should undertake and manage: ● Infection Control Committee

Who should evaluate: ● National Intersectoral Task Force ● Ideally, external audit by a competent authority delegated by the Na- tional Intersectoral Task Force; in the absence of external evaluation, use benchmarking to other comparable institutions

Process Indicators: ● Infection control strategies, policies, guidelines documented ● Evidence of relevant data collection

Outcome Indicators: ● Data being used to reduce rates of hospital-acquired infection and antimicrobial resistance below an agreed target

Intervention 3.5 Ensure access to microbiology laboratory services that match the level of the hospital, e.g. secondary, tertiary.

Implementation: ● Hospital management, through government if appropriate ● Sufficient resources should be allocated for establishment and maintenance of laboratories

Who should initiate: ● Hospital management—in consultation with appropriately trained staff and learned societies

Who should undertake and manage: ● Microbiologists, or medical/scientific staff adequately trained in microbiology

Who should evaluate: ● 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 Ensure performance and quality assurance of appropriate diagnostic tests, microbial identification, antimicrobial susceptibility tests of key pathogens, and timely and relevant reporting of results.

Implementation: ● Microbiology laboratory

Who should initiate: ● Microbiology laboratory management

Who should undertake and manage: ● Microbiology laboratory management

Who should evaluate: ● An internal and external (national or international) quality assurance programme ● National Laboratory accreditation schemes where they exist

Process Indicators: ● Evidence of participation in quality assurance activities

79 INTERVENTIONS—INTERVENTION PRIORITY: FIRST (continued) Outcome Indicators: ● Performance level in quality assurance activities ● Continuing laboratory accreditation, where accreditation schemes exist

WHO/CDS/CSR/DRS/2001.2 Interventions 5.3 and 5.5 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 OBIAL RESISTANCE • OBIAL RESISTANCE quality, safety and efficacy are granted marketing authorization.

Implementation: ● Ministry of Health establishing and delegating to a Government Drug Regulation Authority

Who should initiate: ● Ministry of Health delegating to a Government Drug Regulation Authority ● National Intersectoral Task Force

Who should undertake and manage: ● Government Drug Regulation Authority ● National Intersectoral Task Force

Who should evaluate: ● Ministry of Health via Government Drug Regulation Authority ● National Intersectoral Task Force

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL Process Indicators: ● 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, prosecu- tions, etc.

Interventions 5.8 and 5.9 5.8 Establish and maintain updated national Standard Treatment Guide- lines (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.

Implementation: ● National Intersectoral Task Force—to establish a suitable Committee consisting of interested organizations, opinion leaders and educators ● Government Drug Regulation Authority

Who should initiate: ● National Intersectoral Task Force—to establish a suitable Committee consisting of interested organizations, opinion leaders and educators ● Government Drug Regulation Authority

Who should undertake and manage: ● Ministry of Health ● National Intersectoral Task Force

Who should evaluate: ● Ministry of Health ● National Intersectoral Task Force

Process Indicators: ● Production of national Standard Treatment Guidelines and EDL ● Plan for implementation and dissemination

Outcome Indicators ● Level of uptake, including indicators of appropriate use of antimicrobials among target health care providers and use of EDLs

80 INTERVENTIONS—INTERVENTION PRIORITY: FIRST (continued) Intervention 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.

Implementation: ● Ministry of Health ● National Intersectoral Task Force—delegating to universities and other training institutions, including suitable interested organizations, opinion leaders and educators

Who should initiate: ● Ministry of Health

IMPLEMENTATION OF THE WHO GLOBAL STRATEGY WHO GLOBAL THE OF IMPLEMENTATION ● National Intersectoral Task Force

Who should undertake and manage: ● Training institutions and organizations delegated by the National Intersectoral Task Force ● Professional bodies responsible for registration of health care professionals

Who should evaluate: ● National Intersectoral Task Force ● Training institutions and organizations delegated by the National Intersectoral Task Force

Process Indicators: ● Curriculum developed and implemented; quantitative and qualitative assessments of educational exposure ● Presence of specific registration requirements for health care professionals

Outcome Indicators: ● 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

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91 258. Swanstrom R, Erona J. Human immunodefi- 260. World Health Organization. Containing antimi- ciency virus type-1 protease inhibitors: therapeu- crobial resistance. Review of the literature and re- tic successes and failures, suppression and port of a WHO workshop on the development of a resistance. Pharmacol Ther, 2000, 86:145–170. global strategy for the containment of antimicrobial resistance. Geneva, Switzerland, 4–5 February 259. Vella S, Palmisano L. Antiretroviral therapy: state 1999. Geneva, 1999. WHO/CDS/CSR/DRS/ of the HAART. Antiviral Res, 2000, 45:1–7. WHO/CDS/CSR/DRS/2001.2 99.2.

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92 Annexes

ANNEX A National Action Plans ANNEX A

Canada: http://www.hc-sc.gc.ca/hpb/lcdc/bid/nosocom/fact1.html

European Union: http://www.earss.rivm.nl/

France: http://www.invs.sante.fr/

Norway: http://odin.dep.no/shd/norsk/publ/handlingsplaner/030005-990326/index-dok000-b-n-a.html

Sweden: http://www.sos.se/FULLTEXT/0000-044/0000-044.htm

United Kingdom: http://www.doh.gov.uk/publications/pointh.htm

USA (Centers for Disease Control and Prevention, Atlanta): http://www.cdc.gov/drugresistance/actionplan/

95 ANNEX B Participation in WHO Consultations

WHO/CDS/CSR/DRS/2001.2

OBIAL RESISTANCE • OBIAL RESISTANCE WHO Global Strategy for the Containment Dr Keith Klugman, The South African Institute for of Antimicrobial Resistance Medical Research, PO Box 1038, Johannesburg 2000, South Africa Workshop to develop the framework document (260) Geneva, 4–5 February 1999 Dr Richard Laing, Associate Professor, Department of International Health, Boston University School of Public Health, 715 Albany St, Boston, MA 02118- List of participants 2526, USA Dr Tasleem Akhtar, Pakistan Medical Research Coun- Dr David Lee, Deputy Director, Drug Management cil, Shahnaki-e-Jamurait Sector G5/2, Islamabad, Program, Management Sciences for Health, Pakistan Arlington, USA Dr Susan Bacheller, Office of Health and Nutrition, Dr Joel Lexchin, 121 Walmer Road, Toronto, Canada USAID/G/PHN/HN/HPSR, Washington, USA Dr Donald E Low, Microbiologist-in-Chief, Mount

WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL Dr Richard Bax, Director and Vice-President, Anti- Sinai Hospital, The Toronto Hospital, Toronto, infective Therapeutic Unit, Clinical Research and Canada Development, SmithKline Beecham Pharmaceuti- Dr Peter Mansfield, Director, MaLAM, Australia cals, Harlow, Essex, UK Dr Shaheen Mehtar, Western Cape, South Africa Dr Tom Bergan, President, International Society of Chemotherapy, Institute of Medical Microbiology, Dr Le Van Phung, Central Biomedical Laboratory, Rikshospitalet (National Hospital), Oslo, Norway Hanoi Medical School, Hanoi, Vietnam Dr Nancy Blum, United States Pharmacopeia, Dr Mair Powell, Medicines Control Agency, Market Rockville, USA Towers, Room 1534, 1 Nine Elms Lane, London, UK Dr Otto Cars, Department of Infectious Diseases, Uppsala University Hospital, Uppsala, Sweden Dr Gro Ramster Wesenberg, Norwegian Medicine Control Authority, Sven Oftedsalsvei 6, Oslo 0950, Dr Keryn Christiansen, Clinical Microbiologist, De- Norway partment of Microbiology & Infectious Diseases, Royal Perth Hospital, Western Australia Dr Dennis Ross-Degnan, DACP, Drug Policy Research Group, Department of Ambulatory Care and Pre- Dr Andres de Francisco, International Health Special- vention, Harvard Medical School, Boston, USA ist, Global Forum for Health Research, c/o World Health Organization, 1211 Geneva 27, Switzerland Dr Budiono Santoso, Department of Clinical Pharma- cology, Faculty of Medicine, Gadjah Mada Uni- Dr David Fidler, Indiana University School of Law, 211 versity Sekip, Yogyakarta, Indonesia South Indiana Avenue, Bloomington IN 47405- 1001, USA Dr Anthony Savelli, Director, Rational Pharmaceuti- cal Management, Management Sciences for Health, Professor Widjoseno Gardjito, Department of Surgery, Arlington, USA Dr Soetomo Hospital, Jalan Professor Dr Moestopo 6–8, Surabaya 60286, Indonesia Dr Ben Schwartz, National Center for Infectious Dis- eases, Centers for Disease Control and Prevention, Dr Judy Gilley, (British Medical Association), Corn- Atlanta, USA wall House Surgery, Cornwall Road, London N3 1LD, UK Dr Wing Hong Seto, Department of Microbiology, Queen Mary Hospital, Hong Kong Dr Neal Halsey, Director of Division of Disease Con- trol, Johns Hopkins University, Baltimore, USA Dr Walter Stamm, Head, Division of Allergy and In- fectious Diseases, University of Washington, Seattle, Professor Pentti Huovinen, Antimicrobial Research USA Laboratories, National Public Health Institute, Turku, Finland Professor Mark Steinhoff, Department of International Health, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, USA

96 Dr J Todd Weber, National Center for Infectious Dis- Dr Marcelo F Galas, Profesional Servicio Anti- eases, Centers for Disease Control and Prevention, microbianos, Instituto Nacional de Enferme-dades Atlanta, USA Infecciosas—ANLIS—”Dr. Carlos G. Malbran”, ANNEX B Buenos Aires, Argentina Dr H Wegener, Danish Zoonosis Centre, National Veterinary Laboratory, Copenhagen, Denmark Dr Manuel Guzmán-Blanco, President of the Commit- tee on Antibiotics of the Sociedad Panamericana Professor M Wierup, Swedish Animal Health Service, de Infectología, (Pan American Society of Infec- Johanneshov, Sweden tious Diseases), Unidad de Microbiología y Enf. Infecciosas, Hospital Vargas, Centro Médico de Caracas, Caracas, Venezuela Representatives from USAID Professor King Holmes, University of Washington, Dr Susan Bacheller Harborview Medical Center, Seattle, USA Dr Anthony Boni Dr Abdulrahman Hassan Ishag, Hospitals Administra- Dr Caryn Miller tion, Department of Curative Medicine, Ministry of Health, Riyadh, Kingdom of Saudi Arabia Professor KK Kafle, Institute of Medicine, TU Teach- WHO Global Strategy for the ing Hospital, Kathmandu, Nepal Containment of Antimicrobial Resistance Dr Adeeba Kamarulzaman, Associate Professor, Head, Prioritization and Implementation Workshop Infectious Diseases Unit, Department of Medicine, Geneva, 12–14 September 2000 University Malaya, Kuala Lumpur, Malaysia Dr Göran Kronvall, Clinical Microbiology—MTC, List of participants Karolinska Hospital, Stockholm, Sweden Dr Samuel Azatyan, Head of the Department of Dr David Lee, Deputy Director, Drug Management Pharmacovigilance and Rational Use of Drugs, Program, Management Services for Health, Armenian Drug and Medical Technology Agency Arlington, USA (ADMTA), Yerevan, Armenia Dra Alina Llop, Directora del Laboratorio Nacional de Dr Luis Bavestrello, Infectious Diseases Specialist and Referencia de Microbiología, Sub-Directora Clinical Pharmacologist, Jefe, Unidad de Instituto Medicina Tropical “Pedro Kouri”, La infectología, Hospital dr. Gustavo Fricke, Viña del Habana, Cuba Mar, Chile Mrs Precious Matsoso, Department of Health, Preto- Dr Mike Bennish, Director, Africa Centre for Health ria, South Africa and Population Studies, Mtubatuba, South Africa Dr Thomas O’Brien, Microbiology Laboratory, Dr Richard E Besser, Respiratory Diseases Branch (C- Brigham and Women’s Hospital, Boston, USA 23), Centers for Disease Control and Prevention, Dr David Ofori Adjei, Director, Nogouchi Memorial Atlanta, USA Institute for Medical Research, University of Dr Christopher C Butler, Senior Lecturer, Department Ghana, Legon, Accra, Ghana of General Practice, University of Wales College of Dr Philip Onyebujo, Department of Health, Pretoria, Medicine, Llanedeyrn Health Centre, Cardiff, UK South Africa Dr John Chalker, Management Services for Health, Associate Professor Neil Paget, Royal Australasian Col- Arlington, USA lege of Physicians, Sydney, Australia Professor Ranjit Roy Chaudhury, National Institute of Dr Ricardo Pérez-Cuevas, Investigador Asociado, Immunology, Shahid Jeet Sing Marg, New Delhi, Unidad de Investigacion Epidemiologica y en India Servicios de Salud CMN Siglo XXI, Instituto Dr Narong Chayakula, Secretary General, Food and Mexicano del Seguro Social, Mexico, Mexico Drug Administration, Ministry of Public Health, Dr Mair Powell, Medical Assessor, Licensing Division, Muang, Nonthaburi, Thailand Department of Health, Medicines Control Agency, Professor Thomas Cherian, Christian Medical College, London, UK Vellore, India Dr Dennis Ross-Degnan, Associate Professor, Drug Mrs Parichard Chirachanakul, Food and Drug Admin- Policy Research Group, Department of Ambula- istration, Ministry of Public Health, Muang, tory Care and Prevention, Harvard Medical School, Nonthaburi, Thailand Boston, USA Dr Scott Fridkin, Medical Epidemiologist, Hospital Professor Sidorenko Sergei, Department of Microbiol- Infections Program (E-55), Centers for Disease ogy, Russia Medical Academy of Postgraduate Control and Prevention, Atlanta, USA Studies, National Research Centre of Antibiotics, Moscow, Russia

97 Dr Richard Smith, Senior Lecturer, Health Economics European Society for Clinical Microbiology and Infectious Dis- Group, School of Health Policy and Practice, Uni- ease (ESCMID) versity of East Anglia, Norwich, UK Peter Schoch, ESCMID Basel, Switzerland Soeparmanto, Dr Sri Astuti S, Kepala Badan Litbang Global Forum for Health Research Kesehatan, Head, National Institute of Health Re- search and Development, Jakarta, Indonesia Andres De Francisco, Senior Public Health Specialist, WHO/CDS/CSR/DRS/2001.2 c/o World Health Organization, Geneva, Switzer- Dr Christian Trigoso, Head of the Bacteriology De- land partment, Instituto de Laboratorio de Salud, La Paz, Bolivia International Association of Medical Laboratory Technolo- gists (IAMLT) Dr Peet Tüll, Medical Director, Division of Commu- Martha A Hjálmarsdóttir, President, Reykjavík, Iceland OBIAL RESISTANCE • OBIAL RESISTANCE nicable Diseases Control, The National Board of Health and Welfare, Stockholm, Sweden International Committee of the Red Cross Associate Professor John Turnidge, Women’s and Chil- Ann Aerts, Head of Health Services, Geneva, Switzer- dren’s Hospital, North Adelaide, Australia land Dr Kris Weerasuriya, Professor of Pharmacology and International Council of Nurses Secretary of the Drug Evaluation Sub-Committee Tesfamicael Ghebrehiwet, ICN Consultant, Nursing (DESC), Ministry of Health, Department of & Health Policy, Geneva, Switzerland Pharmacology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka International Council of Women Pnina Herzog Ph. C.M.R. Pharm.S., President, Jeru- salem , Israel Representatives from WHO Regional Offices International Federation of Infection Control (IFIC) Dr Massimo Ciotti, Communicable Diseases, WHO Anna Hambraeus, Division for Hospital Control, Uni- WHO GLOBAL STRATEGY FOR CONTAINMENT OF ANTIMICR FOR CONTAINMENT STRATEGY WHO GLOBAL Regional Office for Europe, Copenhagen versity Hospital, Uppsala, Sweden Dr Sudarshan Kumari, Regional Advisor, Blood Safety International Federation of Pharmaceutical Manufacturers’ and Clinical Technology, WHO Regional Office Association (IFPMA) for South East Asia, New Delhi, India Peter Hohl, Pharma Research Preclinical Infectious Diseases, F. Hoffmann—La Roche Ltd, Basel, Swit- zerland WHO Meeting on International Aspects of the Containment of Antimicrobial Patricia Hogan, Senior Manager, Pfizer Inc., New York, Resistance USA Geneva, 11–12 January 2001 Tony White, Anti-Infectives Strategic Product Devel- opment, Smithkline Beecham Pharmaceuticals, Harlow, Essex ,UK List of participants International Pharmaceutical Federation (FIP) Alliance for the Prudent Use of Antibiotics (APUA) Diane Gal, FIP Project Coordinator, Den Haag, The Kathleen T Young, Executive Director, Boston, USA Netherlands American International Health Alliance International Society of Chemotherapy Thomas O’Brien, Head, Department of Microbiology, Jean-Claude Pechère, Secrétaire général, Université de Brigham and Women’s Hospital, Boston, USA Génétique et Microbiologie, Université de Geneva James P Smith, Executive Director, Washington, USA CHU, Geneva 4, Switzerland Centers for Disease Control and Prevention (CDC) International Society for Infectious Diseases (ISID) David Bell, Assistant to the Director for Antimicrobial Keryn Christiansen, Co-Chair, ISID Antibiotic Task Resistance, National Center for Infectious Diseases, Force, Department Microbiology and Infectious Atlanta, USA Diseases, Royal Perth Hospital, Perth, Australia Conféderation Mondiale de L’Industrie de la Santé Animale Permanent Mission of Norway to the United Nations Office (COMISA) and other International Organizations at Geneva Anthony J Mudd, Vice President/Secretary General, O Christiansen, Counsellor, Geneva, Switzerland Representative Body of the Worldwide Animal The Wellcome Trust Health Industry, Brussels, Belgium Robert E Howells, Director of Science Programmes, European Commission—Luxembourg London, UK Hartmut Buchow, Euroforum Building, Luxembourg Richard Lane, Head of International Programmes, Lon- don, UK

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

WHO 10 Policy Perspectives on Medicines Containing antimicrobial resistance

April 2005 World Health Organization Geneva

The problem of antimicrobial resistance In many countries, antimicrobials are bought directly from drug outlets without a prescription or advice from ntimicrobial resistance (AMR) is one of the world’s a trained health professional. Amost serious public health problems. Many of the microbes (bacteria, viruses, protozoa) that cause infectious disease no longer respond to common Figure 1 Correlation between penicillin-resistant antimicrobial drugs (antibacterial drugs including antibiotics, antiviral and antiprotozoal drugs). The (non-susceptible) pneumococci and out-patient problem is so serious that unless concerted action is antibiotic use (showing bands with 95% taken worldwide, we run the risk of returning to the confidence intervals) pre-antibiotic era when many more children than now died of infectious diseases and major surgery was 60 impossible due to the risk of infection. The major in- Taiwan, China fectious diseases kill over 11 million people per year. 50 Spain Box 1 shows some AMR prevalence rates, which can vary widely between and within countries, and over France time. 40 USA Greece 30 Portugal Box 1 AMR global prevalence rates 20 Canada Malaria Ireland Luxembourg Iceland enicillin-resistant S.pneumoniae (%) enicillin-resistant S.pneumoniae • chloroquine resistance in 81/92 countries P Austria Belgium Italy Tuberculosis (TB) 10 Germany UK Australia Sweden • 0–17% primary multi-drug resistance Denmark Finland Netherlands Norway HIV/AIDS 0 • 0–25% primary resistance to at least one 0 10 20 30 40 antiretroviral drug Total antibiotic use (DDD/1000 population/day) Gonorrhoea • 5–98% penicillin resistance in Neisseria gonorrhoeae Source: Albrich WC, Monnet DL and Harbarth S, Emerg Infect Dis.; 2004; 10(3):514–7 Pneumonia and bacterial meningitis • 0–70% penicillin resistance in Streptococcus Doctors’ response to AMR has been to switch patients pneumoniae from older antibiotics to newer ones, but new devel- Diarrhoea: shigellosis opment of these is declining as the pharmaceutical • 10–90% ampicillin resistance, industry has shifted from antibiotics to developing 5–95% cotrimoxazole resistance other medicines with potentially larger markets (e.g. Hospital infections for chronic non-infectious illness). Even if new antibi- • 0–70% resistance of Staphylococcus aureus to all penicillins and cephalosporins otics are developed, resistance to them would also develop; so prudent use of antibiotics is essential to maintain their effectiveness for future generations. Source: WHO country data, 2000–03 Serious clinical and financial consequences result Emergence of AMR is a natural phenomenon that from AMR. Morbidity and mortality are increased by follows use of antimicrobials but it is being acceler- delays in administering effective treatment for infec- ated by inappropriate antimicrobial use. Higher tions caused by resistant microorganisms. Prolonged consumption is associated with higher resistance illness and hospitalisation are costly and the use of levels (Fig.1). Estimates suggest that perhaps half drugs other than first-line drugs may increase costs of all antibiotic consumption may be unnecessary. 100-fold (Fig. 2) making them unaffordable for many

Page 1: WHO Policy Perspectives on Medicines — Containing antimicrobial resistance well-established methods exist. Aggregate antimicro- Figure 2 Cost ratio of alternative drugs to first- bial drug consumption data can be used to identify the most expensive and highly used antimicrobials, line antimicrobials for common acute infections 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 80 70 antimicrobial consumption across institutions, regions 60 and countries. Indicators can be used to investigate

50 Alternative drugs antimicrobial use in primary health care, e.g.: 40 30 •% patients prescribed antibiotics; 4th 20 •% of upper respiratory tract cases (usually viral) 3rd 10 Cost ratio to first-line drug 2nd treated with antibiotics; 0 Gonorrhoea Malaria Shigellosis Pneumonia •% of diarrhoeal cases (usually viral) treated with antibiotics; 0.03 0.05 0.06 0.14 Cost per patient with first-line drug (US$) •% cases with infections treated in accordance with clinical guidelines. Source: Adapted from WHO Model Formulary, WHO clinical guidelines and Man- agement Sciences for Health’s 2004 International Drug Price Indicator Guide Focused antimicrobial use evaluation (drug utilization review) can identify problems concerning the use of specific antimicrobials or the treatment of specific governments and patients especially in developing infections, particularly in hospitals. countries. Reasons underlying inappropriate use should be Measuring the problem through investigated intermittently and include diagnostic in- security, prescriber knowledge and habit, unrestricted surveillance availability of antimicrobials, overwork, inappropriate Surveillance is critical to containing the problem of promotion of antimicrobials, profit motives and fear of AMR and requires monitoring over time the magni- litigation. Understanding such reasons allows appro- tude and trends in AMR and antimicrobial use and priate, effective corrective strategies to be chosen. using the data to design interventions and measure their impact. Core national strategies to contain AMR Epidemiological surveillance of antimicrobial Core national strategies to contain AMR are summa- resistance rised below, based on WHO’s Global Strategy for Containment of AMR and Promoting Rational Use of Resistance varies widely with geographical location, Medicines: Core Components. type of community and level of health facility. There- fore local surveillance data should be used to guide clinical management and update clinical guidelines, 1. Mandated multidisciplinary national task educate prescribers and guide infection control force to coordinate policies and strategies to policies. Data should distinguish between hospital contain AMR nosocomial and community-acquired infections and should exclude duplicate isolates from the same Many factors contribute to how antimicrobials patient. are used. Therefore, a multidisciplinary approach is needed to develop, implement and evaluate inter- A national antimicrobial surveillance system should ventions to promote optimal use of antimicrobials and consist of: improve infection control programmes. • national reference microbiology laboratory facilities to coordinate epidemiologically sound surveillance An adequately resourced task force is needed to of AMR in common pathogens in the community, coordinate policy and strategies at national level, in hospitals and other health care facilities; both the public and private health sectors. The form •a network of laboratories, all with adequate inter- of the task force may vary, but it should always involve nal and external quality assurance, that regularly government (ministry of health), the national refer- collect and report relevant resistance data and pro- ence microbiology laboratory, the health professions vide quality microbiological diagnostic services. (doctors, pharmacists, nurses), academia, the national drug regulatory authority, pharmaceutical industry, Surveillance of antimicrobial use consumer groups and NGOs involved in health care. The impact on AMR and use is better if multiple inter- Antimicrobial use should be monitored in terms of ventions are implemented in a coordinated way. the type and degree of irrational use and several Single interventions are likely to have little impact.

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

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

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

Page 5: WHO Policy Perspectives on Medicines — Containing antimicrobial resistance WHO/PSM/2005.1 Original: English

(particularly pigs and poultry) for mass treatment a WHO Consultation. Geneva: WHO; 2002 (WHO/CDS/CSR/ against infectious diseases or for growth promotion. EPH/2002.11). Antimicrobials are also added to water to treat fish World Health Organization. Implementing Antimicrobial Drug diseases and sprayed on to food crops to treat dis- Resistance Surveillance and Containment for HIV, Tuberculo- ease (e.g. fire blight in apples). Most antimicrobials sis and Malaria: An Outline for National Programmes. registered for human use are also registered for Geneva: WHO; 2003 (WHO/CDS/RMD/2003.2). animal use but regulation, such as licensing of pre- World Health Organization. Drug and Therapeutics Committees: scribers, dispensers and outlets, is much less stringently A Practical Guide. Geneva: WHO; 2004 (WHO/EDM/PAR/ applied in the agricultural sector. Although the ma- 2004.1). jority of human AMR results from human use, there is All documents available on http://www.who.int/medicines 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. Contacts in WHO Regional Offices:

Regional Office for Africa: Dr Jean-Marie Trapsida Conclusion Coordinator, Essential Drugs and Medicines Policy A national programme is needed to undertake sur- Tel: +242 8 39258 E-mail: [email protected] veillance of antimicrobial use and resistance and, Regional Office for the Americas: based on this data, to develop, implement and evalu- Dr Jorge A.Z. Bermudez ate strategies to contain AMR. Critical to success are: Essential Medicines, Vaccines and Health Technologies Tel: +1 202 974 3104 E-mail: [email protected] 1. an adequately funded, mandated, multidisciplinary, Regional Office for the Eastern Mediterranean: national task force to coordinate strategies to Dr Zafar Mirza contain AMR; Regional Adviser, Essential Medicines and Biologicals 2. a national reference microbiology laboratory to Tel: +00 202 276 55 61 E-mail: [email protected] coordinate a network of reliable diagnostic Regional Office for Europe: microbiology laboratories; Mr Kees de Joncheere 3. government investment in the health system Pharmaceuticals infrastructure to ensure the controlled availability Tel: +45 3 917 14 32 E-mail: [email protected] of appropriate antimicrobials, and adequately Regional Office for South-East Asia: trained personnel to prescribe and dispense them. Dr Krisantha Weerasuriya Regional Adviser, Essential Drugs and Medicines Policy Tel: +91 11 2337 0804 (ext 26314) Key Documents E-mail: [email protected] Regional Office for the Western Pacific: World Health Organization. How to Investigate Drug Use in Dr Budiono Santoso Health Facilities: Selected Drug Use Indicators. Geneva: Regional Adviser WHO; 1993 (WHO/DAP/93.1). Tel: +63 2 528 9846 E-mail: [email protected] World Health Organization. WHO Global Principles for the Containment of Antimicrobial Resistance in Animals Intended for Food: Report of a WHO Consultation. Geneva: Contacts at WHO Headquarters: WHO; 2000 (WHO/CDS/CSR/APH/2000.4). Medicines Policy and Standards World Health Organization. WHO Global Strategy for Contain- Health Technology and Pharmaceuticals Cluster ment of Antimicrobial Resistance. Geneva: WHO; 2001 WHO Headquarters, Geneva, Switzerland: (WHO/CSR/DRS/2001.2). World Health Organization. Surveillance Standards for Antimicro- Dr Hans V. Hogerzeil bial Resistance. Geneva: WHO; 2001 (WHO/CSR/DRS/2001.5). Director, Medicines Policy and Standards Tel: +41 22 791 3528 E-mail: [email protected] World Health Organization. Infection Control Programmes to Control Antimicrobial Resistance. Geneva: WHO; 2001 Dr Clive Ondari (WHO/CSR/DRS/2001.5). Team Coordinator, Policy, Access and Rational Use Tel: +41 22 791 3676 E-mail: [email protected] World Health Organization. Promoting Rational Use of Medi- cines: Core Components. WHO Policy Perspectives on Dr Lembit Rägo Medicines No.5, Geneva: WHO; 2002 (WHO/EDM/2002.3). Team Coordinator, Quality and Safety: Medicines Tel: +41 22 791 4420 E-mail: [email protected] World Health Organization. Monitoring Antimicrobial Usage in Food Animals for the Protection of Human Health: Report of

© World Health Organization 2005. 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: +41 22 791 2476; fax: +41 22 791 4857; email: [email protected]). 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 therePage 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.

FIFTY-EIGHTH WORLD HEALTH ASSEMBLY WHA58.27

Agenda item 13.10 25 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/2004.7. 2 Document WHO/CDS/CSR/DRS/2001.2. 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 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

= = =

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

ntibiotic use is seen as a critical factor in the emer- public and private mechanisms to improve cost control and gence of resistant bacteria. The impact of irrational increase cost recovery, including user charges, prepayment Ause, including inadequate dosing and poor adher- schemes and insurance. A push for stronger contractual ence to therapy, is potentially just as important as high con- arrangements with private sector providers reflected the sumption.1 At the same time, limited access to antibiotics in prevailing ideological view of the potentially greater quality many parts of the world is contributing to high mortality and efficiency of the private sector. from bacterial infections. Figure 1. Health systems: improving performance. 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 Source: World Health Report 2000. antibiotics and to determine how health system factors influ- The complex issue of antibiotic resistance necessitates a sys- ence human behaviour. The approach is global, but the main tems view, including functions and objectives, where policy focus is on low- and middle-income countries where the makers have the overall role of regulating and prioritising problems are most prominent and where most people live. 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. HEALTH SYSTEMS IN TRANSITION In many low- and middle-income countries, drug distribu- Health sector reforms from the late 1980s were driven main- tion has been taken over almost completely by the private ly by the World Bank, with support from a number of bilat- sector. In Vietnam, market-oriented reforms resulted in the eral aid agencies, and emphasised the need to redefine the number of private pharmacies increasing from none in 1986 relationship between the state, service providers, users and to over 6,000 in 1992; during the same period there was a other health-related organisations.3,4 Privatisation and dereg- sixfold increase in the annual per capita consumption of ulation were promoted and focused on private financial and pharmaceuticals, with antibiotics representing the highest human resources management. Emphasis was laid on mixed proportion of the increase.5,6 Over 50 per cent of the antibi-

A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5–7 MAY 2004 - BACKGROUND DOCUMENT

otics globally is estimated to be bought directly from phar- Public health services may be limited owing to shortages of macies or informal sale outlets without prescriptions,7 under- medicines, materials and trained personnel. 8,11,12 Frequently, lining the increasingly important function of pharmacies or payments are required for people to get attention from the other drug outlets as the first and possibly only contact with staff as health providers have developed their own livelihood health services. strategies to compensate for low incomes.4,13 Lack of drugs results in referral to other dispensary units, possibly far away Secondly, health systems in low-income countries often from the clinic. In actual practice, so-called free services can have problems with lack of human resources, an obstacle that be quite expensive and time-consuming. Private detailers is prominent at present in sub-Saharan Africa.8 Also, few sometimes provide an easily accessible, low-cost alternative countries have systems in place for knowledge transfer and to public or private clinics (Picture 1). The social distance quality control. Consequently, the quality of both services between the actors is less apparent and it is easier for people and medicines varies extensively and problems, including to remain anonymous in cases where privacy is important. false and substandard antibiotics, continue. A third challenge Certain illnesses, such as STIs, are connected with social stig- is the financing of health systems. In industrialised countries matisation and tend to drive people away from regular health financial mechanisms range from general taxation in services, to pharmacies or even to the local market.14 This is Scandinavia to private health insurance in the United States. an unfortunate development as adequate treatment of STIs In most developing countries, including the two largest, demands good knowledge on the part of dispensers, so as to China and India, the financing of health services mainly, limit the spread of highly resistant pathogens as well as including expenditure on drugs, consists of out-of-pocket reducing the spread of HIV. 15 payments from patients.9 In China, reforms have created a situation where prescribing of drugs generates revenues to Picture 1. Indian market place, informal drug vendors 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.

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 unregu- lated contexts, which are often profit-driven. In respect of ‘…whenever I get these symptoms and go to a doctor, he gives me the same diseases where the emerging resistance is most imminent, medicine and charges me 10 rupees. So why not just buy the medicine?’ e.g. respiratory infections, sexually transmitted infections Dua V et al. 1994 (STI) and diarrhoeal diseases, there are also parallel, high levels of self-initiated treatment without health personnel being Antibiotic use is to a great extent influenced also by consulted first. What incentives are driving people to direct cultural preferences and beliefs. Even if the settings are purchase of antibiotics in pharmacies? dramatically different in industrialised and developing coun-

A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5–7 MAY 2004 - BACKGROUND DOCUMENT

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

A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5–7 MAY 2004 - BACKGROUND DOCUMENT

Figure 3. The complexity of factors influencing prescribing 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 Source: Tomson, 1990 the gap between scientific evidence and patient care we need an in-depth understanding of the barriers to and the incen- Unfavourable doctor-patient ratios mean that doctors con- tives for changing behaviour. In general, the focus has been stantly have to deal with an overload of patients. primarily on prescribers working within public health Consequently, no time exists for proper clinical investiga- systems, which we know represent the source of only a small tions and possible other diagnostics, and this time constraint proportion of the drugs delivered to patients worldwide. promotes the use of prescriptions as a means of terminating How do we approach the private sector where irrational use the consultation.14,19 These conditions limit the possibilities is widespread? And how can we reach individuals and influ- for rational prescribing and increase the number of drugs ence their demand for antibiotics? When planning complex prescribed per patient, distorting the value of prescriptions changes in practice, we need to take into account the nature as the correlation to diagnose is low. In a study of public of the intervention, the characteristics of the professionals health centres in Ghana the average number of drugs pre- and patients involved and also the social, organisational, scribed varied from three to nine per patient, including at economic and political contexts. least one or two antibiotics.20 Refusal to prescribe antibiotics, even for non-bacterial diseases, would sometimes be considered highly irrational, INFLUENCING THE PROFESSIONALS according to local cultural criteria.14,19 Along with the poten- To address the growing private sector is a major challenge. tial loss of clientele there is also the fear among prescribers In a study carried out in 68 pharmacies in Hanoi a cluster- that the outcome may be poor or even fatal without antibiotic randomised experiment consisting of a multifaceted inter- treatment. In industrial countries physicians might fear legal vention was applied.21 Treatment of sexually transmitted consequences if they fail to secure adequate treatment in every infections improved tenfold. The adherence to national situation, leading to over-prescribing to relieve the doctor of treatment guidelines in this field has been easier to imple- anxiety. Uncertainty in diagnostics, together with limited ment as the use of a syndromic approach with a combination possibilities to follow up patients’ progress, creates further of several antibiotics actually increased the income for phar- concern over the outcome. This uncertainty leads to ‘overkill’ macists. When the same intervention package was applied in in treatment as the fear of not covering the bacteria causing Bangkok the improvements were less successful, showing the the infection enhances the choice of an antibiotic with a importance of the context when designing an intervention.22 broader spectrum or combinations of several agents. The lack of diagnostic tools makes it difficult for the prescriber to have Attempts to rationalise prescribing practices through only the right arguments to convince the patient and himself that the provision of correct information about antibiotics, their antibiotics are not needed in the individual case. side effects and proper use, with the intention that pre-

A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5–7 MAY 2004 - BACKGROUND DOCUMENT

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

A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5–7 MAY 2004 - BACKGROUND DOCUMENT

CHANGE

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

A MULTIDISCIPLINARY MEETING AT THE DAG HAMMARSKJÖLD FOUNDATION UPPSALA, SWEDEN, 5–7 MAY 2004 - BACKGROUND DOCUMENT

REFERENCES:

1. WHO, WHO Global strategy for containment of antimicrobial 16. Radyowijati A. and Haak H., ‘Determinants of Antimicrobial use in resistance, WHO/CDC/CSR/DRS/2001.2, Geneva, 2001. the developing world’, USAID, Bureau of Global Health, The Child Health Research Project Special Report, 2002. 2. Smith R, Beaglehole R, Woodward D. and Drager N, Global Public Goods for Health, Oxford University Press, 2003. 17. Cederlöf C. and Tomson G, ‘Private pharmacies and the Health Sector Reform in Developing Countries – Professional and Commercial 3. Whitehead M, Dahlgren G. and Evans T, ‘Equity and health sector Highlights’, Journal of Social and Administrative Pharmacy, reforms: can low-income countries escape the medical poverty trap?’ 1995;12(3): 101-111. The Lancet, 2001; 358: 833-836. 18. Dua et al, ‘The use of antimicrobial drugs in Nagpur, India. A window 4. Standing H, ‘An overview of changing agendas in health sector reforms’, on medical care in a developing country’, Social Science and Medicine, Reproductive health matters, 2002;10(20): 19-28. 1994;38(5): 717-724. 5. Chuc et al, ‘Management of childhood acute respiratory infections at 19. Sachs L. and Tomson G., ‘Medicines and culture – a double perspective private pharmacies in Vietnam’, in The Annuals of Pharmacotherapy, on drug utilisation in a developing country’, Social Science and 2001;35: 1283-88. Medicine, 1992;34(3): 307-315. 6. Chalker et al‚ STD management by private pharmacies in Hanoi: 20. Bosu W. K, ‘Survey of antibiotic prescribing pattern in government practise and knowledge of drug sellers’, Sexually Transmitted Infections, health facilities of the Wassa west district of Ghana’, East African 2000;76(4): 299-302. Medical journal, 1997 Mar; 74(3): 138-42. 7. WHO-EMRO, Agenda item 11(a): ‘Antimicrobial resistance and ration- 21. Chuc NT, Larsson M, Do NT, Diwan VK, Tomson GB, Falkenberg T. al use of Antimicrobial agents’, WHO website: ‘Improving private pharmacy practice: a multi-intervention experiment www.int/medicines/organization/par/cd_25th_anniversary/4- in Hanoi, Vietnam’, J Clin Epidemiol. 2002 Nov; 55(11): 1148-55. rational/amr.ppt. Accessed 30 June 2004, 49th Session of the Regional Committee for the Eastern Mediterranean; 30 September–3 October 22. Chalker et al, ‘Effectiveness of a multi-component intervention on 2002, Cairo, Egypt. dispensing practices at private pharmacies in Vietnam and Thailand – A randomised controlled trial’, submitted for publication July 2003, 8. WHO, Shaping the future, World Health Report 2003. IHCAR Karolinska Institutet. 9. Dong et al, ‘Association between health insurance and antibiotics 23. Hadiyono JE, Suryawati S, Danu SS, Sunartono, Santoso B. prescribing in four counties in rural China’, in Health Policy, ‘Interactional group discussion: results of a controlled trial using a 1999;48:29-45. behavioural intervention to reduce the use of injections in public health 10. Mills et al, ’What can be done about the private health sector in low- facilities’, Soc Sci Med. 1996 Apr;42(8):1177-83. income countries?’ Bulletin of the World Health Organization, 24. Santoso B, Suryawati S, Prawaitasari JE, ‘Small group intervention vs 2002;80: 325-330. formal seminar for improving appropriate drug use’, Soc Sci Med. 1996 11. Van der Geest S. and Whyte S. R, The Context of medicines in devel- Apr;42(8):1163-8. Erratum in: Soc Sci Med 1996 Jul;43(1):I. oping countries, Kluwer Academic Publishers, 1988. 25. Grimshaw J. M. and Russell I. T, ‘Effect of clinical guidelines on med- 12. Velásquez G, Madrid Y. and Quick J, ‘Health reform and drug financ- ical practice: a systematic review of rigorous evaluations’ The Lancet, ing: selected topic-health economics and drugs’, DAP series No. 6, 1993;342: 1317–1322. WHO/DAP/98.3, action programme on essential drugs, WHO, Geneva, 26. Little et al, ‘Pragmatic randomised controlled trial of two prescribing 1998. strategies for childhood acute otitis media’, British Medical Journal, 13 Standing H, ‘Health systems: improving performance’, World Health 2001;322: 336-42. Report 2000. 27. Lipsky L. A. and Taylor, C. A, ‘The opinions and experiences of family 14. Whyte S. R, Van Der Geest S. and Hardon A, Social lives of Medicines, physicians regarding direct-to-consumer advertising’, Journal of Family Cambridge University Press, 2002. Practice, 1997;45: 495-499. 15. Gilson L et al, ‘Cost-effectiveness of improved treatment services for 28. Bavestrello L, Cabello A, ‘Impact of Regulatory Measures on Antibiotic sexually transmitted diseases in preventing HIV-1 infection in Mwanza Sales in Chile’, International Conference on Improving Use of Medicines Region, Tanzania’, The Lancet, 1997;350:1805-1809. 2004, Abstract ID: AM003.

7 A fact sheet from ReAct – Action on Antibiotic Resistance, www.reactgroup.org First edition 2007 – Last updated May 2008

Economic aspects of antibiotic resistance

u Resistance to antibiotics results in longer sick leave, or even premature to the loss of all the advantages in an extensive increase in costs to the death. medical care that they have brought patient and family, the hospital, and u However, an even greater econo- about. Advanced surgical procedu- society, due to the need for the use mic burden lies in the future and will res and cancer chemotherapy might of more expensive drugs for second affect generations to come, when the be impossible to perform, resulting line treatment, more tests and much consequences of current use (and in enormous costs, economic as well longer stays in hospital, as well as misuse) of antiobiotics could lead 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 eradica- ble, 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 DEFINITION OF THE PROBLEM as it is imposed on people other balance between the positive effects than the consumer, but also tem- of using antibiotics and the negative n In economic terminology, resistance poral in the sense that when the impact of this use on their temporal is a negative externality. That is, it consequences of resistance have effectiveness. has an undesirable effect on peo- appeared a cost is also borne by the n Resistance has to be included as a ple other than the immediate con- consumer. factor when assessing the relative sumer. costs and benefits of the use of anti- n This is referred to as an external It has to be remembered that: biotics. cost, as it is an undesirable effect n we are looking at containment of (and hence cost) on those other than resistance, not eradication the consumer making the consump- n it is important to assess the opti- tion decision. misation of use of antibiotics over n This external cost is cross-sectional time n in addition to direct costs to the n increased cost of disease surveil- tests to be performed, thus increasing patient, the family and hospital, lance the costs substantially. it is critical to assess social costs n increased costs to firms of absentee- and benefits of antibiotic use and ism strategies to contain resistance (i.e. n possible increase in product prices QUANTITATIVE including positive and negative due to increased costs to firms CONSEQUENCES OF externalities). These strategies will RESISTANCE be wide-ranging and encompass the These consequences, however, relate development of new antibiotics, the only to the direct (and some indirect) There are difficulties in assessing the use of alternative treatments and impacts of resistance itself. Also very exact costs incurred by antibiotic prevention of infectious disease. important is the impact that resistance resistance, one reason being the impact will have on the ability to deliver other of the underlying disease. forms of health care. QUALITATIVE CONSEQUENCES Antibiotics are the cornerstone of By country OF RESISTANCE modern medicine that revolutionized n Cost to US medical care sector of medical care during the last half of the treatment for patients with infec- Treatment failure is the main contribu- previous century. From cradle to grave tions caused by resistant organisms tor to increased costs and can lead to: the role of antibiotics in safeguarding estimated to be $4-7 bn per year. 1, 2 the overall health of human societies n additional investigations such as is pivotal. By institution laboratory tests and X-ray exami- So the costs of antibiotic resistance n Cost to a general hospital of con- nations relate to the loss of these benefits and taining a 5-week outbreak of MRSA n additional or alternative treat- associated treatment possibilities at – approximately £500,000. 3 ments, often much more expensive every stage of human life. Thus, in than drugs used to treat infections order to calculate the full economic By disease caused by sensitive organisms burden of antibiotic resistance we have n Tuberculosis – double the cost n additional side-effects from more to consider the burden of not having of standard treatment ($13,000- toxic treatments, which have to be antibiotics at all, which at the extreme $30,000) 4; multidrug resistant managed would probably collapse the entire tuberculosis, MDRTB – treatment n longer hospital stay modern medical system. cost increased to $180, 000 (CDC n longer time off work The figures below vastly under-rep- estimate).5 n reduced quality of life resent the actual cost of resistance once n Vancomycinresistant enterococci n greater likelihood of death due to it begins to affect these other aspects infections – average extra cost of inadequate or delayed treatment of medical care, such as any surgical $12,766 per case in comparison n increased burden on family of therapy. with controls, due for example to infected individual Besides this alarming future sce- more and longer ICU admissions n increases in private insurance cov- nario antibiotic resistance already has and additional hospitalization days; erage an impact on the care of patients with patients also more often discharged n additional cost for hospital when bacterial infections, which are not yet to long-term facilities, thereby hospital- acquired infection occurs caused by resistant strains. Broader- increasing costs beyond hospitali- and infection control procedures spectrum antibiotics are now being zation. 6 are required prescribed as first-line drugs, when n Infections with ESBL producing n increased overall healthcare expen a certain level of resistance has been Enterobacteriacae – costs and hos- diture, including costs of combating detected in the area. This often means pital charges increased 1.56 and transmission more expensive drugs, greater risk of 1.71 respectively in two studies. 7, 8 side effects, and occasionally more

u ReAct links a wide range of u Our vision is that current and u ReAct believes that anti u ReAct believes that awa individuals, organisations and future generations of people biotics should be used appro reness of ecological balance is networks around the world around the globe should have priately, their use reduced when needed as part of an integral taking concerted action to access to effective treatment of of no benefit and their correct concept of health. respond to antibiotic resistance. bacterial infections. and specific use increased when needed.

2 n Pneumonia caused by penicillin- nonsusceptible Streptococcus pneu- The consequences of current use (and moniae – treatment more expensive misuse) of antiobiotics could lead to the loss than treatment of pneumonia caused by susceptible strains, despite the of all the advantages in medical care that they disease being milder; higher costs have brought about. 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 under- going surgery, the cost of infections reduce transmission are likely to due to resistant gramnegative bacilli n of poor methodological quality appear more cost-effective than was compared with infections due (high risk of bias) strategies to control emergence. to nonresistant strains. The differ- n from developed nations (principally n Micro policies – generally to contain ence in the median hospital cost the USA) transmission – are more likely to was $51,000 and the difference in n not measuring the cost impact of be rigorously evaluated but macro the median cost for antibiotics was ABR policies – generally to contain emer- more than $1,800 per case. 10 n micro (institution) not macro (com- gence – are more likely to be socially munity) optimal in the long-term. n focused on transmission of resist- PERSPECTIVES ance, not emergence Urgent needs n More work to develop and under- The economics of containing This creates a two-fold problem: take macro-economic evaluation. resistance n Assessment of the wider impact of Strategies to contain resistance are n Because of uncertainty, the evalu- resistance on health care delivery, many. In a review, studies of strate- ation of strategies to reduce trans- thus focusing on the wider cost gies that looked at effectiveness and/ mission is easier to undertake than rather than the narrow direct impli- or cost-effectiveness were evaluated.11 evaluation of strategies to control cations of resistance. It was concluded that studies were gen- emergence, and because of discount- erally: ing of future benefits, strategies to

SUGGESTIONS FOR FURTHER READING n Coast J, Smith R, Miller MR. n Cosgrove SE, Carmeli Y. The n Smith RD, Yago M, Millar M, Coast Superbugs: should antimicrobial impact of Antimicrobial Resistance J. Assessing the macroeconomic resistance be included as a cost in on Health and Economic outcomes. impact of a healthcare problem: the economic evaluation? Health Eco- Clinical Infect Dis 2003; 36: 1433- application of computable general nomics, 1996; 5: 217-226. 1437. equilibrium analysis to antimicrobial resistance. Journal of Health n Coast J, Smith RD, Millar MR. n Wilton P, Smith RD, Coast J, Millar Economics, 2005; 24: 1055-1075. An economic perspective on policy M. Strategies to contain the emer- for antimicrobial resistance. Social gence of antimicrobial resistance: n Smith RD, Yago M, Millar M, Coast Science and Medicine, 1998; 46: a systematic review of effectiveness J. A macro-economic approach to 29-38. and cost-effectiveness. Journal of evaluating policies to contain anti- Health Services Research and Pol- microbial resistance: a case study of n Coast J, Smith RD, Karcher AM, icy, 2002; 7(2): 111-117. methicillin-resistant Staphylococ- Wilton P, Millar M. Superbugs II: cus aureus (MRSA). Applied Health How should economic evaluta- Economics and Health Policy, 2006; tion be conducted for interventions 5: 55-65. which aim to reduce antimicrobial resistance? Health Economics, 2002; 11(7): 637-647.

3 REFERENCES

1. American Society for Microbiology. 5. Rajbhandary SS, Marks SM, Bock 9. Einarsson S, Kristjansson M, Kris- Report of the ASM task force on NN. Costs of patients hospitalized tinsson K, Kjartansson G et al. Pneu- antibiotic resistance. Antimicrob. for multidrug-resistant tuberculo- monia caused by Penicillin-non-sus- Agents Chemother 1995 (suppl) sis. Int J Tuberc Lung Dis. 2004; 8: ceptible and Penicillin-susceptibler 1-23. 1012-6. Pneumococci in Adults: A Case- 2. John JF, Fishman NO: Program- 6. Carmeli Y, Elliopoulos G, Mozaffari Control study. Scand. J. Infect. Dis matic role of the Infectious disease E, Samore M: Health and Economic 1998; 30: 253-256. physician in controlling antimicro- Outcomes of Vancomycinresistant 10. Evans H, Lefrak S, Lyman J, Smith bial costs in the hospital Clin. Infect. Enterococci. Arch. Intern. Med. R et al. Cost of Gram-negative Dis 1997; 24: 471-485. 2002; 162: 2223-2228. resistance. Crit Care Med 2007; 35: 3. Cox RA, Conquest C, Mallaghan C 7. Lautenbach E, Patel JB, Bilker 85-95 and Marples RR. A major outbreak WB, Edelstein PH, Fishman NO. 11. Wilton P, Smith RD, Coast J, Mil- of methicillin-resistant Staphyloco- Extended-spectrum beta-lactamase- lar M, Coast J. Assessing the mac- ccus aureus caused by e new phage- producing Escherichia coli and roeconomic impact of a healthcare type (EMRSA-16) Journal of Hospi- Klebsiella pneumoniae: risk factors problem: the application of comput- tal Infection 1995; 29: 87-106. for infection and impact of resist- able general equilibrium analysis to 4. Witon P, Smith RD, Coast J, Millar ance on outcomes. Clin Infect Dis antimicrobial resistance. Journal of M et al. Directly observed treatment 2001; 32(8): 1162-71. Health Economics, 2005; 24: 1055- for multidrug-resistant tuberculo- 8. Schwaber MJ, Navon-Venezia S, 1075. sis: an economic evaluation in the Kaye KS, Ben-Ami R, Schwartz D, United States of America and South Carmeli Y. Clinical and economic Africa. Int. J Tuberc Lung Dis 2001; impact of bacteremia with extended- 5 (12): 1-6 spectrum-beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother 2006; 50(4): 1257-62.

Postal address: Visiting address: Phone: +46 18 471 66 07 ReAct Drottninggatan 4, 3 tr Fax: +46 18 471 6609 Uppsala University Uppsala, Email: [email protected] Box 256 Sweden Web: www.reactgroup.org SE - 751 05 Uppsala Sweden

4 A fact sheet from ReAct – Action on Antibiotic Resistance, www.reactgroup.org First edition May 2007

Decline in Antibacterial Innovation

Despite the increasing risk of antibac- 16 terial resistance, the number of new 15 antibiotics has actually decreased in 14 the past couple of decades. In the four 13 five-year periods between 1983 and 12 2002, the number of new drugs intro- 11 duced has fallen by 56%, from 16 new 10 antibiotics between 1983 and 1987 to 9 7 new antibiotics between 1998 and 8 2002.1 7 6 The R&D pipeline for the near future 5 does not appear to reverse this trend. 4 3 In a study of the pipelines of the 15 2 largest pharmaceutical companies, 1 which were responsible for 93% of 0 antibiotics introduced between 1980 1983-1987 1988-1992 1993-1997 1998-2002 and 2003, there were only 5 antibacterials, or 1.6% of the pipeline for New antibacterial agents approved in the United States, these companies. This contrasts to 1983-2002. Source: Adapted from Spellberg (2004) 5.4% of the pipeline that is dedicated to antiviral drugs.1

Antibacterial, 1.6% Antiviral 5.4%

Rest of Pipeline 93.0%

R&D Pipeline of 15 Largest Pharmaceutical Companies. Source: Data from Spellberg (2004)

 Major Pharmaceutical Companies Exiting the Year Introduced Class of Drug Market At the same time that the number of antibacterials 1935 Sulfonamides in the pipeline is decreasing, a number of major 1941 Penicillins pharmaceuticals have abandoned or sold off their antibiotic units: “Aventis and Roche spun 1944 Aminoglycosides off their anti-infective business. BMS, Eli Lilly, 1945 Cephalosporins Wyeth and Procter & Gamble ended discovery of anti-infectives. GlaxoSmithKline downsized its 1949 Chloramphenicol 2 anti-infective discovery.” 1950 Tetracyclines As of 2004, the antibacterial discovery programs of half of large pharmaceutical companies 1952 Macrolides/ Lincosamides/ Streptogramins in the United States and Japan had been discon- 1956 Glycopeptides tinued or decreased since 1985.2 1957 Rifamycins Lack on Innovative New Drugs 1959 Nitroimidiazoles Combating antibiotic resistance requires more than just new drugs. Resistance to antibiotics 1963 Quinolones frequently leads to resistance to the whole class 1968 Trimethoprim of drugs, thus new classes of drugs are required to treat resistant bacteria, not just new drugs in 2000 Oxazolidinones existing classes. 2003 Lipopeptides 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 1970. No new classes Antibacterial Pipeline by Bacterial Target 4 were discovered in the 1970’s, 80’s or 90’s, and Bacterial Target # of candidates only recently have two new classes become avail- in pipeline able: Oxazolidinones (in 2000) and Lipopeptides Gram +Positive including Methicillin-resistant Staphlo (in 2003).2, 3 coccus aureus (MRSA), Glycopeptide/Vanomycin- A more in-depth analysis of the entire industry intermediate Staphylococcus aureus (GISA/VISA), in 2005 paints a more optimistic picture. White Vanomycin-resistant Enterococci (VRE) 31 found 70 drug candidates in the pipeline ranging from preclinical to pre-registration, 13 of which Respiratory Tract Infections, Multidrug-resistant were in 5 new classes of antibiotics.4 However, of streptococcus pneumoniae (MDRSP) + H.influenzae 16 the 44 candidates whose targets were available, Gram Negative including Extended Spectrum Beta- most target gram-positive bacteria. Lactamase (ESBL), cefotaxime, quinolone-resistant 7

Non-fermenters / Pseudomonas including carbape nem-resistant 5

Anaerobes 1

* Sum does not equal 44 as some drugs have multiple targets

2 Additionally, all the drug candidates for new classes of vation. Some push mechanisms that have been proposed for drugs, when targets were disclosed, targeted only Gram Pos- neglected disease include: itive and RTI bacteria. There are no new class candidates for gram-negative bacteria. n Public compound libraries – provide access to compound The contrast of White’s data with that of Spellberg, which libraries to screen for potential antibacterial activity, was restricted to the 15 largest pharmaceutical companies, reducing R&D costs 7, 8 suggests that smaller companies may be playing a larger role in developing new antibiotics. Of the 36 companies n Patent pooling – the collective management on intellec- that White identifies as ‘current discovers’ of antibacterials, tual property reduces transactional costs and IP barriers only 6 are among Spellberg’s top 15 largest pharmaceutical to innovation 9 companies. While push mechanisms focus on the inputs to R&D, ‘pull’ Little Incentive to Innovate mechanisms focus on the outputs by paying for completed The priority given to an R&D project is determined, in part, projects. Some proposed pull mechanisms have included: by the net present value (NPV) of the drug, which weighs the expenses against the expected revenues in the future.5 The n Advanced Market Commitments – creates a fund which higher the potential revenue of the drug, the higher the NPV establishes an agreement with countries and NGOs to and the resources a company is willing to risk in developing pay a pre-determined per-unit price innovations that a treatment. address a particular need 10 Antibacterials stack very poorly against other therapeu- n Prize Funds – provides a financial reward for new thera- tic classes in terms of NPV: 5 pies addressing a specific health threat 11, 12

Product Development Partnerships. While push and pull Project therapeutic class Risk-adjusted NPV mechanisms manipulate the current system of innova- x $1,000,000 tion, product-development partnerships (PDP) have had an important role in developing the pipeline for neglected Musculoskeletal 1,150 diseases.13 PDPs characteristically leverage the respective Neuroscience 720 expertise of the public and private sectors to create and deliver innovative medicines in neglected diseases. Oncology 300 While there were only 16 new drugs developed between Vaccines 160 1975 and 1999 for tropical diseases and tuberculosis,14 a recent study noted that there are currently 63 drug candidates Injectable antibiotic (Gm+) 100 in the pipeline.13 Fifty percent of the projects were devel- Oral contraceptive 10 oped 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 busi- Several reasons can account for the relatively weak NPV of nesses, which required smaller possible returns on invest- antibacterials: 5, 6 ment, operated under commercial, for-profit models. Drugs with novel mechanisms of action are needed to n Drug discovery for chronic diseases is more favorable combat antibiotic resistance, and PDPs have proven effec- because long-term treatment generates more revenue tive in targeting such “breakthrough” therapies.13 Only 8% than the short-term treatment of antibiotics. of projects developed solely by industry focused on break- n A large number of old antibiotics already exist, result- through therapies, while 49% of PDP projects and 63% of ing in a high level of therapeutic competition for newly industry projects developed in conjunction with PDPs tar- developed drugs. geted breakthrough therapies. 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 time- wise--that are required to bring a new drug to market, increasing the attractiveness of investing in neglected inno-

3 References

1 Spellberg, Brad, et al. “Trends in Anti- 5 Projan, Steve. “Why is Big Pharma 10 As in the proposal for a pneumococ- microbial Drug Development: Impli- Getting Out of Antibacterial Drug Dis- cal vaccine for developing countries. cations for the Future.” Clinical Infec- covery?” Current Opinion in Microbi- Levine, Ruth, Michael Kremer, Alice tious Disease. Vol 38, 1279-1286. ology. Vol 6, pgs 427-430. 2003. and Albright. “Making Markets of May 1, 2004. 6 Charles, Patrick and Lindsay Grayson. Vaccines: Ideas to Action.” Center for 2 Wenzel, Richard. “The Antibiotic Pipe- “The dearth of new antibiotic develop- Global Development. 2005. line- Challenges, Costs, and Values.” ment: why we should be worried and 11 Such as Stiglitz, Joe. “Scrooge and New England Journal of Medicine, what we can do about it.” Medical Intellectual Property Rights.” BMJ Vol 351 (6) 523-526. August 5, 2004. Journal of Australia. 181 (10): 549- 333:1279-80. 2006. 3 Powers, John H. “Antimicrobial Drug 553. 2004. 12 Such as Love, Jamie and Tim Hub- Development Workshop,” Presenta- 7 As in the Special Program on Research bard. “A New Trade Framework for tion co-sponsored by FDA, IDSA, and and Training in Tropical Diseases, Global Healthcare R&D.” PLoS Biol- the International Society of Anti-Infec- www.who.int/tdr ogy. 2(2): e52. 2004. tive Pharmacology. April 15-16, 2004. 8 As in the European Rare Disease Ther- 13 Moran, Mary. “A Breakthrough in As cited in Infectious Disease Society apeutic Initiative, www.erditi.org R&D for Neglected Diseases: New of America, “Bad Bugs, No Drugs,” 9 As in SARS patent pool proposal. Ways to Get the Drugs We Need.” July 2004. PLoS Medicine. Vol 2 (9) 828-832. 4 Simon, James, et al. “Managing severe White, Tony. “New Antibacterials acute respiratory syndrome (SARS) September 2005. Inventory.” EU Intergovernmental intellectual property rights: the pos- 14 Trouiller, Patrice, et al. “Drug develop- Conference on Antibiotic Resistance. sible role of patent pooling.” WHO ment for neglected diseases: a deficient December 9, 2005. Bulletin. 83 (9), 707-710. September market and a public-health failure.” 2005. Lancet 359:2188-94. 2002.

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

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. Executive summary

he world has woken up to hospital-acquired infections. of antibiotics have been discovered in the past thirty years1. MRSA regularly makes the headlines, its incidence Though new research is being done, much of it builds on Tis monitored and massive efforts are made to control existing medicines, and is therefore compromised when tackling its spread. It is important that this concern is not allowed to resistance. obscure an equally worrying reality: the dearth of innovation into new drugs needed to combat resistance. This report is a The consequences, already discernible, are growing numbers of sick wake-up call to those who assume that because we have the and untreatable patients and deaths associated with lack of access to antibiotics we need today, we will have them tomorrow. It is effective antibiotics. The prognosis for five to ten years time is grave. also a reminder that millions of people across the globe do not There are a range of unmet medical needs in the antibiotic even have them today. field that will require different solutions. Treatments are needed for new infections and emerging resistances in developed The Antibiotic Innovation Study was undertaken to find out countries, particularly in the field of Gram negatives. Medicines why there are so few new antibiotics in the pipeline and to ask for community-acquired resistant infections are needed experts and decision-makers in the drug development process in all markets. And new drugs are needed for diseases that what might be done to address this problem. All interviewed predominantly occur in developing countries, such as TB and agree on the need for urgent and concerted action on the part typhoid fever. Innovation for these countries needs to tackle of all stakeholders on the understanding that the prevailing both formulation and presentation of the treatment. market system cannot solve the problem. The study is not an in-depth research project. However, in presenting the views Until now in the pharmaceutical industry’s main markets, of senior experts it identifies important areas of analysis and medical need and the need to make profit for shareholders signals where possible solutions might be found. have been broadly aligned. This is no longer the case and antibiotics now risk becoming subject to the same funding The structure of the pharmaceuticals market does not provide difficulties as the neglected diseases that plague developing the right incentives for sufficient investment in antibiotics to countries. Historically much antibiotic research has been done meet rapidly changing medical need. Only two new classes by Big Pharma, yet smaller (Biotech) companies with reduced

1 See footnote 2

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

RESEARCH LETTERS

We thank all physicians who referred patients to this study and the Sex (age at Time between Site and Outcome (months Cooperative Human Tissue Network (Philadelphia, PA, USA) for onset of onset of AECP type of cancer between diagnosis providing serum samples on 50 controls with solid cancers. AECP,years) and cancer of cancer and death) 1 Yancey KB, Egan CA. Pemphigoid: clinical, histologic, M (62) + 8 years Lung/large cell Deceased (6) immunopathologic, and therapeutic considerations. JAMA 2000; 284: F (85) - 1 monthColon/adeno Alive 350–56. M (51) + 2 months Lung/adeno Deceased (0) 2 Domloge-Hultsch N, Gammon WR, Briggaman RA, Gil SG, Carter F (70) - 8 months Endometrial/adeno Deceased (13) WG, Yancey KB. Epiligrin, the major human keratinocyte integrin M (60) + 6 months Stomach/adeno Deceased (16) ligand, is a target in both an acquired autoimmune and an inherited F (47) + 10 months Stomach/adeno Deceased (11) subepidermal blistering skin disease. J Clin Invest 1992; 90: 1628–33. F (76) + 14 months Colon/adeno Alive 3Lazarova Z, Hsu R, Yee C, Yancey KB. Human anti-laminin 5 F (59) + 12 months Endometrial/adeno Deceased (3) autoantibodies induce subepidermal blisters in an experimental skin F (39) + 11 months Lung/adeno Deceased (21) graft model. J Invest Dermatol 2000; 114: 178–84. M (66) + 1 monthStomach/adeno Deceased (10) 4 Schroeter AL. Pemphigoid and malignancy. Clin Dermatol 1987; 5: Adeno=adenocarcinonia 60–63. 5 Hodge L, Marsden RA, Black MM, Bhogal B, Corbett MF. Bullous Summary data of AECP patients with cancer pemphigoid: the frequency of mucosal involvement and concurrent observed which gave a RR of 7·7 (95% CI: 3·3–15·2). While malignancy related to indirect immunofluorescence findings. Br J Dermatol 1981; 105: 65–69. 0·39 cancers were expected to occur in the latter cohort during their first year of observation, six cancers were Dermatology Branch, Division of Clinical Sciences National Cancer observed which gave a RR of 15·4 (5·7–33·6). IgG antibodies Institute, National Institutes of Health, Bethesda, MD, to laminin 5 were not present in the serum of any controls. 20892–1908, USA (C A Egan MD, Z Lazarova MD, T N Darling MD, C A Patients with AECP had an RR for cancer that was similar Yee BSc, K B Yancey MD) and Cancer Statistics Branch, National to that for malignancy among adults with dermatomyositis; as Cancer Institute, National Institutes of Health, Rockville, MD (T Coté MD) with dermatomyositis, the RR for cancer in these patients was particularly high in the first year of disease. Several older Correspondence to: Dr Conleth A Egan, Dermatology Branch, NCI, reports noted an association between “bullous pemphigoid” Building 10 Room 12N238, National Institutes of Health, Bethesda, and cancer.4 Whereas several studies have dismissed this MD 20892-1908 USA, association, controversy persists and centers on seronegative (email: [email protected]) patients with mucosal involvement.5 This potential association was suggested at a time when AECP was not distinguished from bullous pemphigoid, and when most Variation in antibiotic use in the AECP patients would have been thought to be seronegative (based on the lower sensitivity of assays previously used to European Union detect autoantibodies). Accordingly, it is possible that the Otto Cars, Sigvard Mölstad, Arne Melander suggested association between “bullous pemphigoid” and cancer was based on cohorts including a disproportionate Data on antibiotic use are not publicly available in most number of patients with AECP. European Union countries. We obtained data for non-hospital We considered several potential sources of bias. antibiotic sales for 1997 from the 15 member states and Ascertainment bias could have resulted in the preferential analysed these according to the Anatomic Therapeutic inclusion of patients at high risk of cancer for reasons Chemical classification system, and expressed them as unrelated to the primary risk factor under study (ie AECP). defined daily doses per 1000 people per day. Sales of We thought this bias unlikely since all AECP patients were antibiotics varied more than four-fold: France (36.5), Spain assembled before any suspected association between disease (32.4), Portugal (28.8), and Belgium (26.7) had the highest with cancer. Moreover, patients in this series were not sales, whereas the Netherlands (8.9), Denmark (11.3), watched more closely for cancer. Most cancers developed Sweden (13.5), and Germany (13.6) had the lowest. There after patient enrollment and the relative proportion of was also profound variation in use of different classes of patients with cancer was consistent throughout the study, antibiotics. Detailed knowledge of antibiotic use is necessary (three cancers after enrolment of ten patients, six cancers to implement national strategies for optimum antibiotic use, after enrolment of 21 patients, and ten cancers in the entire and to address the threat posed by resistant microorganisms. cohort of 35). That 80% of patients with AECP who had International efforts are needed to counteract the growing cancer died within 21 months of cancer diagnosis also made problem of antimicrobial resistance.1 Although antibiotic it unlikely that the diagnosis of cancer in this cohort was use at population level is probably an important risk fortuitous and early. The comparison of cancer incidence factor,2 data on antibiotic sales have not been publicly among AECP patients at tertiary care medical centres with available and few international comparisons have been that in the general population could have been an invalid made. We have assessed and compared non-hospital use of comparison; however several studies found the incidence of antibiotics in the 15 member states of the European Union cancer in patients with bullous pemphigoid (or other skin (EU). The term antibiotics encompasses both diseases) at tertiary care medical centers to be approximately semisynthetic derivatives of antibiotics and wholly 10%, well below the 29% incidence that we found. synthetic compounds used as antibacterial agents—eg, We also considered the potential bias introduced by forms sulphonamides, trimethoprim, and fluoroquinolones. of treatment. Drugs commonly used in AECP patients (eg, Data for national sales of antibiotics in 1993 and 1997 glucocorticosteroids or cytotoxic drugs) can increase cancer were purchased from Institute for Medical Statistics risk. However, some patients had relatively mild disease and (IMS), Health Global Services, UK, for 13 of the 15 EU did not require treatment with such drugs. In those receiving countries. This private company gathers data from glucocorticosteroids or cytotoxic drugs, the interval between different sources including manufacturers, wholesalers, the onset of AECP and cancer was so short that it was pharmacies, prescribing doctors, and hospitals, and unlikely that the drugs caused the cancer. Moreover, cancers calculates national estimates. Data from Sweden and identified in AECP patients were solid cancers rather than Denmark were obtained from the National Corporation of lymphomas or leukaemias which are more commonly Swedish Pharmacies and the Danish Medicine Agency, associated with exposure to such drugs. respectively. The National Corporation of Swedish

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For personal use. Only reproduce with permission from The Lancet Publishing Group. RESEARCH LETTERS

Others* Macrolides and lincosamides J01F 35 Quinolones J01M Trimethoprim J01EA Tetracyclines J01A 30 Cephalosporins J01D Penicillinase-resistant penicillins J01CF Narrow-spectrum penicillins J01CE 25 Broad-spectrum penicillins J01CA

10 Defined daily dose per 1000 inhabitants day

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 Therapeutic Chemical J01) only were included in the dispensed in Swedish pharmacies, all of which belong to subsequent analysis. To make comparison easier, the this corporation. Data from Denmark were available only amount of antibiotic (kg) was converted to defined daily for 1997 and included all outpatient sales from community dose (where possible). For antibiotics not given a defined pharmacies. Hospital sales were obtained from nine daily dose by WHO, we used the common daily dose in countries and accounted for 7–15% of total sales in each published work. Where such an estimate was not possible country. Because hospital data was not available from (less than 0·01% of total), we excluded data from analysis. other countries, only non-hospital sales were used in the Oral defined daily dose was used for antibiotics with final analysis. different routes of administration. For antibiotics marketed Swedish and Danish data were obtained as defined daily both alone and in combinations (eg, trimethoprim and dose according to the Anatomic Therapeutic Chemical sulphonamides), amounts of the individual compounds classification system defined by WHO Collaborating were accounted for separately. For antibiotics combined Centre for Drug Statistics Methodology.3 Defined daily with a ␤ lactamase inhibitor, only the amount of the dose is a unit based on the average daily dose used for the antibiotic was included. We could compare publicly main indication of the drug. Sales data from Institute for available data4 and IMS data on total non-hospital Medical Statistics Health were examined and adjusted antibiotic use only in Finland. The two sources differed by according to the Anatomic Therapeutic Chemical less than 11%, and showed a similar distribution of classification. Antibiotics for systemic use (Anatomic 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 3·23 1·53 0·01‡ 1·30 1·81 0·69 1·16 3·65 0·42 13·80 Belgium 10·96 0·21 0·36 2·85 5·09† 0·59 1·95 4·06 0·65 26·72 Denmark 2·39 4·57 0·34 0·02‡ 0·98 0·30‡ 0·22‡ 1·97 0·56 11·35 FInland 3·78 2·30 0·07 2·11 5·50 1·87† 0·52 1·86 1·33† 19·34 France 18·97† 0·31 0·58 3·75 3·38 0·55 1·72 5·98† 1·27 36·51† Germany 2·67 1·59 0·02 0·89 3·26 0·93 0·75 2·54 0·93 13·58 Greece 7·74 0·37 0·02 4·68† 2·69 0·64 1·04 4·50 1·01 22·69 Ireland 8·03 0·87 0·63 1·23 3·50 0·92 0·38 2·50 0·28 18·34 Italy 11·20 0·02‡ 0·02 3·21 0·56‡ 0·87 1·93 5·07 1·11 23·99 Luxembourg 10·58 0·17 0·23 2·86 4·01 0·70 1·61 4·71 0·71 25·58 Portugal 12·08 0·06 0·71 3·28 2·63 1·10 4·04† 3·69 1·24 28·83 Spain 18·01 0·08 0·39 2·48 1·42 0·59 2·48 5·87 1·12 32·44 Sweden 1·36‡ 4·85† 0·99† 0·59 2·97 0·57 1·01 0·97‡ 0·20 13·51 The Netherlands 2·90 0·61 0·16 0·12 2·35 0·57 0·70 1·24 0·31 8·96‡ UK 6·93 0·78 0·68 0·98 3·66 1·12 0·54 3·22 0·13‡ 18·04

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. RESEARCH LETTERS was obtained from Eurostat,5 enabling us to convert sales Western and eastern European data to defined daily dose per 1000 inhabitants per day. Seven countries showed an increase in antibiotic use of trends in testicular cancer mortality less than 4% between 1993 and 1997. Large increases were Fabio Levi, Carlo La Vecchia, Peter Boyle, Franca Lucchini, Eva Negri noted in Italy (34%) and Luxembourg (12%). A reduction in antibiotic use was seen in five countries: Sweden had the Testicular cancer is curable if treated appropriately. We used largest (21%) and Greece the smallest (4%). In 1997, there national mortality data to compare specific death rates from the was a more than four-fold variation between countries in disorder in western and eastern Europe, the USA, and Japan. non-hospital use of antibiotics. France had the highest use, Testicular cancer mortality rates have fallen by about 70% in the and the Netherlands, the lowest (figure, table). USA and western Europe since the 1970s. In eastern Europe, In 11 of the 15 countries, the most commonly used however, death rates from testicular cancer have been declining antibiotic was broad-spectrum penicillin, which varied only since the late 1980s, and at a much slower rate than that between 56% (Spain) and 20% (Germany) of total sales. In recorded elsewhere (about 20%). Consequently, many avoidable Finland the most common drug was a tetracycline (28%), deaths, mainly in young adults, are still occurring in eastern in Austria a macrolide (26%) and in Denmark and Sweden Europe. Available effective treatment strategies for testicular narrow-spectrum penicillins (40% and 36%, respectively). cancer must be implemented in these countries. Total defined daily dose per 1000 inhabitants of all ␤ Testicular cancer is generally curable if appropriate treatment lactam antibiotics (penicillins and cephalosporins) was six is given. Despite a rise in the number of patients with testicular times higher in France (23·0) than in Netherlands (3·6). cancer since the 1970s, mortality rates have fallen in North Cephalosporins were used most in Greece (4·7) and least America1 and western Europe.2 In men aged 45 years and in the Netherlands (0·12). The highest use of tetracyclines younger, mortality rates fell by about a third in the late 1980s was in Finland (5·5). Quinolones were most widely used in by comparison with rates registered in the 1970s—ie, 500 Portugal (4·0) (table). deaths per year in Europe are now prevented.2 The most important finding in this analysis was the great Mortality rates began to decline in the 1980s in Poland, variation in outpatient antibiotic use. The large variation is Czechoslovakia, and East Germany, but at a slower rate than unlikely to be caused by differences in frequency of that recorded in USA and western Europe.3 Trends in bacterial infections. The pronounced differences between testicular cancer rates should, therefore, be monitored Belgium and the Netherlands are noteworthy because of especially carefully in eastern Europe, to identify whether they the close proximity of the countries and their common continue to drop and at what pace. Cancer of the testis is a language. In addition to physicians’ and patients’ attitudes good indicator of progress in adult cancer treatment to antibiotics, historical backgrounds, cultural and social worldwide. Our aim was to do a systematic analysis of trends factors, and disparities in health-care systems might also be in testicular cancer mortality in Europe, the USA, and Japan.2 important factors in determining prescribing patterns. We We derived official death certification numbers from the did not have sufficient data to describe between-country WHO Database, and recoded them according to the Ninth variability of dose regimens, length of treatment, or Revision of the International Classification of Diseases. We availability of antibiotics without prescription. obtained estimates of the resident population from the same These results strengthen the view that antibiotics could WHO database. Age-standardised rates were based on the be used more effectively in many countries. Further world standard population.1,2 analyses of antibiotic use by age-group, setting, and The figure shows trends in certified mortality from testicular indication are required. The threat posed by resistant cancer at age 20–44 years in four broad geographic areas. In microorganisms could be reduced if all countries gathered the European Union (EU) and in six countries of central and data on antibiotic prescriptions. We therefore encourage eastern Europe, peak mortality rates (1·6/100 000 and 1·7/100 EU member states to challenge the IMS data presented in 000, respectively) were reached in the 1970s. Since that date, this study and to do comparable epidemiological studies on mortality rates have fallen in this age group by 67% in the antibiotic prescribing and resistance. European Union. However, in eastern European countries, 1 Wise R, Hart T, Cars O, et al. Antimicrobial resistance is a major after a peak in the late 1970s, the decline in mortality has been threat to public health. BMJ 1998; 317: 609–10. Eastern Europe 2 Melander E, Ekdahl K, Jönsson G, Mölstad S. The frequency of European Union penicillin-resistant pneumococci in children is correlated to the USA 1·8 community-level utilisation of antibiotics. Pediatr Infect Dis J 2000; Japan 19: 1172–77. 1·6 3ATC Index with DDDs. Oslo: WHO Collaborating Centre for Drug Statistics Methodology, 1999. 1·4 4 Nordic Statistics on Medicines. Uppsala: Nordic Council on 1·2 Medicines, 1997. 5 Demographic statistics. Brussels: Eurostat, 1997. 1·0 (ISBN 92-828-0737-1) 0·8 Department of Infectious Diseases, Uppsala University Hospital, 0·6

Uppsala (Prof O Cars MD); STRAMA, Swedish Strategic 000 Rate per 100 0·4 Programme for the Rational Use of Antimicrobial Agents and 0·2 Surveillance of Resistance, Swedish Institute for Infectious Disease Control, Solna, S-171 82, Stockholm, Sweden 0 (O Cars MD, S Mölstad MD, Prof A Melander MD); Unit of Research –74 89 and Development in Primary Health Care, Mjölby, Östergötland –64 –69 –79 –84 – –94 –97 (S Mölstad, MD); NEPI Foundation, Malmö and Stockholm 1960 1965 1970 1975 1980 1985 1990 1995 (S Mölstad MD, Prof A Melander MD); Department of Community Calendar period Medicine, Medical Research Centre, Malmö University Hospital Trends in age-adjusted (world population) death certification (Prof A Melander MD) rates from testicular cancers in men aged 20–44 years Correspondence to: Prof Otto Cars Eastern European countries represented are Bulgaria, Czech Republic, (e-mail: [email protected]) Hungary, Poland, Romania, and Slovakia.

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Computerised clinical *Wenbin Liang, Colin W Binns, 26%. China also has the world’s most decision support in rural Andy H Lee rapid growth rate of resistance (22% [email protected] average growth in a study spanning China School of Public Health, Curtin University of 1994 to 2000).5 Technology, Perth, WA 6102, Australia The faceless threat of antibiotic As you note in your Nov 8 Editorial 1 The Lancet. China unveils plans for health-care resistance is likely to be one of the (p 1608),1 a new draft of the Chinese reform. Lancet 2008; 372: 1608. greatest challenges to global health 2 Ministry of Health of the People’s Republic of

health-care system reform plan China. Percentages of medical professionals by during the 21st century, with a direct was pub lished on Oct 14, 2008. sex, age, qualiﬁ cation and title in 2005. China eﬀ ect on health indicators in low- health statistics yearbook 2007. Beijing: Ministry The government understands that of Health of the People’s Republic of China, 2007. income, middle-income, and high-

Getty Images improving the quality of health care in 3 Wang J, Kushner K, Frey JJ 3rd, Ping Du X, income countries. It is positive that rural areas is vital. Qian N. Primary care reform in the Peoples’ China’s new health system reform Republic of China: implications for training The low quality of the health-care family physicians for the world’s largest suggests a pharmaceutical policy that service in rural areas is largely due to country. Fam Med 2007; 39: 639–43. includes a strategy for rational drug 4 Berner ES, Webster GD, Shugerman AA, et al. the low educational level of many Performance of four computer-based diagnostic use. What happens in China matters physicians in those areas. Data from systems. N Engl J Med 1994; 330: 1792–96. for the world. 2 5 Garg AX, Adhikari NK, McDonald H, et al. the Ministry of Health indicate that, We declare that we have no confl ict of interest. Eff ects of computerized clinical decision in China as a whole, more than 60% support systems on practitioner performance *Andreas Heddini, Otto Cars, of medical practitioners (excluding and patient outcomes: a systematic review. 2005; 293: 1223–38. Sun Qiang, Göran Tomson assistant medical practitioners) have JAMA [email protected] 3 years or fewer of professional training, and around 30% of the whole Centre for Microbiological Preparedness, Swedish Institute for Infectious Disease Control, Nobels väg medical force has only a senior high- Antibiotic resistance in 18, SE-171 82 Solna, Sweden (AH); Action on school level of education. The average China—a major future Antibiotic Resistance, Uppsala University, Uppsala, level of education is even lower in rural Sweden (OC); Center for Health Management and Policy, Shandong University, Jinan, China (SQ); 3 areas. challenge Division of International Health, Department of It would take too long to retrain Public Health Sciences, Karolinska Institutet, most of these doctors to 21st-century Longde Wang and colleagues (Nov 1, Stockholm, Sweden (GT) stan dards. However, with extra fund- p 1697)1 outline the future challenges 1 Wang L, Wang Y, Jin S, et al. Emergence and control of infectious diseases in China. Lancet ing, it might be possible to boost their posed by infectious diseases in the 2008; 372: 1598–605. performance by equipping them with a Chinese context. Infectious diseases 2 Reynolds L, McKee M. Factors infl uencing computerised clinical-decision support remain a major problem in China today antibiotic prescribing in China: an exploratory analysis. Health Policy 2008; system. and Wang and colleagues provide a published online Oct 13. DOI: 10.1016/ Such systems have greatly improved comprehensive review of current and j.healthpol.2008.09.002. 4,5 3 Sun Q, Santoro MA, Meng Q, Liu C, over the past 30 years. A system emerging infectious diseases and Eggleston K. Pharmaceutical policy in China. tailored to rural doctors could work their control. Strikingly, however, Health Aff 2008; 27: 1042–50. as an electronic manual, allowing the increasing threat of antibiotic 4 Zheng Y, Zhou Z. The root causes of the abuse of antibiotics, harm and the rational use of the physi cians to follow diagnostic resistance is only briefl y mentioned. strategy. Hospital Management Forum 2007; algorithms, and providing updated The situation with respect to overuse 123: 23–27 (in Chinese). treatment plans and prevention of antibiotics and antibiotic resistance 5 Zhang R, Eggleston K, Rotimi V, Zeckhauser RJ. Antibiotic resistance as a global threat: 2 guidelines—something that rural in China is severe. Several factors are evidence from China, Kuwait and the United doctors might never have learned involved, including a health system States. Global Health 2006; 2: 6. before. with strong fi nancial incentives for A tailored computerised support sys- drug prescribing.3 Around 75% of tem for rural doctors in China could patients with seasonal infl uenza are Department of Error be deve loped with today’s advanced estimated to be prescribed antibiotics, Clarke SE, Jukes MC, Njagi JK, et al. Eff ect of intermittent preventive treatment of malaria on technology, within a short time, and and the rate of antibiotic prescription health and education in schoolchildren: a cluster- at low cost. China has acknowledged to inpatients is 80%.4 In a study of randomised, double-blind, placebo-controlled problems with its health service, and, resistance patterns of several common trial. Lancet 2008; 372: 127–38—In this Article 5 (July 12), in paragraph four of the Results by leapfrogging ahead to computer- bacteria in China in 1999 and 2001, section (p 134), the second sentence should assisted diagnosis and treatment, the mean prevalence of resistance have read: “The eff ect size was 0·18 (95% CI might be able to overcome some of its among hospital-acquired infections 0·003–0·35) in the counting sounds test and 0·48 (0·09–0·88) in the code present diffi culties. was as high as 41% and that among transmission test.” We declare that we have no confl ict of interest. community-acquired infections was

30 www.thelancet.com Vol 373 January 3, 2009 Perspectives

S t r a m a - a Sw e d i s h w o r k i n g m o d e l f o r containment o f a n t i b i ot i c r e s i s ta n c e

S Mölstad1,2, O Cars3, Johan Struwe ([email protected])3 1. Unit of Research and Development in Primary Care, Jönköping, Sweden 2. Department of Medical and Health Sciences, Linköping University, Linköping, Sweden 3. The Swedish Strategic Programme against Antibiotic Resistance - Strama, Solna, Sweden

The overall aim of Strama (The Swedish Strategic Programme executive working group funded by the government. Detailed Against Antibiotic Resistance) is to preserve the effectiveness of overviews of the efforts to contain antibiotic resistance in Sweden antibiotics in humans and animals. Strama is organised at two and of the systems for the surveillance of antibiotic consumption levels: a network of independent local multidisciplinary groups in and antibiotic resistance have been published [3-5]. each county that provide prescribers with feedback on antibiotic use and resistance and implement guidelines; and a national executive Local Strama groups working group funded by the government. To gain an insight into Strama developed as a network with nodes of independent local antibiotic use, Strama has conducted several large diagnosis- groups coordinated by each county department for communicable prescribing surveys in primary care, in the hospital settings and disease control. The local groups are the drivers of Strama activities. in nursing homes. National antibiotic susceptibility data for These local groups usually comprise specialists in communicable Sweden and mandatory notification show that in recent years the diseases, infectious diseases, clinical microbiology, infection proportion of Streptococcus pneumoniae with decreased sensitivity control, general practice and pharmacy. Paediatricians as well as to penicillin V has stabilised (around 6 %), but the number of ear, nose and throat specialists are common additional members. In notified cases of meticillin-resistantStaphylococcus aureus (MRSA) most counties there is a close link to the local drug and therapeutics has increased and ESBL-producing Enterobacteraceae have turned committee. into an endemic situation. Still, Sweden is among the countries The guiding principle underlying local Strama activities is to with the lowest rates of MRSA (<1 %), S. pneumoniae can still be promote the rational use of antibiotics by providing prescribers with treated with penicillin V and the rate of Escherichia coli-producing feedback on local or individual data on prescription for comparison ESBLs is below 5 %. Strama´s activities have contributed to a with other prescribers and prevailing therapy recommendations. steady decrease in antibiotic use from the mid 1990s until 2004 Local data on antibiotic resistance is provided by the clinical (when total use slowly started to increase again) without measurable microbiology laboratory. Other important activities are to develop negative consequences. Regular collaboration with national and local therapeutic guidelines and to organise courses and lectures regional news media has been one of the key strategies. for local physicians and other health-care workers at different levels of training. While initially focussing on general practice, Background parallel groups targeting hospital care were recently developed in Increasing use of antibiotics and spread of penicillin-resistant an increasing number of counties and regions. pneumococcal clones in the beginning of the 1990s alarmed the There is no formal reporting on either activities or on budgets from medical profession and authorities in Sweden. Strama (The Swedish the local groups to the national level. Data from local projects are Strategic Programme against Antibiotic Resistance) started as an shared and discussed at national meetings at least once annually. informal network between experts and authorities in 1994. In 2000, A problem is that many of the local activities rely on personal Strama, in close cooperation with the National Board of Health and commitment from devoted physicians and that a formal mandate Welfare, prepared a proposal for a national action plan to contain and financial support from the county council is still missing in antibiotic resistance [1]. This proposal was later developed into a many counties. However, the awareness of a need for such targeted governmental bill “Strategy to prevent antibiotic resistance and and mandated activities to contain antibiotic resistance is slowly health-care associated infections” [2], which was passed in 2006. increasing and a growing number of Strama groups (or equivalent Since then Strama has been institutionalised as an independent bodies) are now supported. governmental body with an annual budget of 10 million Swedish crowns from the Ministry of Health and Social Affairs. Recently, a Strama at national level corresponding Strama VL (Veterinary and Food) coordinated by the While the local groups coordinate activities targeting local National Veterinary Institute has been inaugurated. prescribers, the national executive working group is responsible for national coordination of information and meetings, initiating studies The overall aim of Strama’s activities is to preserve the in areas where knowledge gaps have been identified, disseminating effectiveness of antibiotics in humans and animals. Strama is Strama´s results and acting as a node for international collaboration. organised at two levels: local groups in each county and a national The executive working group is supported by a secretariat.

EUROSURVEILLANCE Vol. 13 · Issue 46 · 13 November 2008 · www.eurosurveillance.org 1 Strama has a formal regulatory instruction from the Swedish and packaged with the corresponding veterinary report SVARM [5]. government. The chairman is appointed by the government and Following the increased awareness and the inception of the Strama reports directly to the Ministry of Health and Social affairs. The programme, the total antibiotic sales in general practice in Sweden Strama governance board has members from the Swedish Institute continuously decreased in the 1990s until 2004. In contrast, the for Infectious Disease Control, the National Board of Health and other Nordic countries have either remained at a comparatively Welfare, the National Veterinary Institute, the Medical Products higher level of antibiotic use (Iceland and Finland) or experienced Agency, the Swedish Corporation of Pharmacies (Apoteket AB), the an uninterrupted increasing trend. According to official figures from Swedish Association of Local Authorities and Regions, the Swedish the respective medicine agencies in the Nordic countries, Sweden Reference Group for Antibiotics and the professional societies for has had the lowest antibiotic use since 2003. However, since infectious diseases, infection control and communicable diseases. 2004 a slow rise, mainly attributable to increased prescription of The executive working group has a broad multisectorial composition penicillin to children, has been seen again (Figure 1). including several clinicians and meets at least bimonthly to outline working-directions and priorities and to define areas needing further Drug-prescribing surveys and other studies studies. To learn more about compliance with guidelines in general practice and about antibiotic use in the hospital setting, Strama Although penicillin resistance in S. pneumoniae in the community has initiated and coordinated several large diagnosis- prescribing was the first target of Strama, national activities have continuously surveys. The use of antibiotics in primary care and compliance expanded and today include many additional fields e.g. hospital with the recommendations from the workshops and the quality care, intensive care (“ICU-Strama”) [6-7], nursing homes, day- indicators defined by the General Practitioners Association (SFAM) care centers and clinical trials. ICU-Strama has developed a close have been studied in diagnosis-prescribing surveys conducted in collaboration with the Swedish Intensive Care Registry (SIR) and is 2000, 2002 and 2005 [10-15]. These studies comprised altogether now integrated as a part of its national quality registry. Experiences 15,371 patients with infectious symptoms treated by around 600 from ICU-Strama have been incorporated into the European network general practitioners (GPs). The studies showed high antibiotic care-ICU [8]. prescribing in acute otitis media, acute pharyngotonsillitis and Strama has co-organised several workshops yielding national acute bronchitis, indicating that the current treatment guidelines recommendations for the treatment of various diagnoses for these conditions had not been not fully implemented. For the common in general practice such as acute otitis media, acute treatment of uncomplicated urinary tract infections a shift from pharyngotonsillitis, impetigo, acute sinusitis, urinary tract infections the use of trimethoprim and fluoroquinolones to pivmecillinam and and lower respiratory tract infections. nitrofurantoin is recommended. A restricted use of fluoroquinolones was advocated already in 1996, [16] leading to a decreasing trend The national office supports the local groups, coordinates as clearly documented in the surveys. different activities, supplies national data and manages a national website (www.strama.se). A national meeting with annual updates on scientific and medical aspects of antibiotic resistance, statistics on antibiotic use and resistance as well as results and analysis of performed studies, interventions and educational programmes Figure 1 is held for the members of the local Strama groups and other interested parties. Abstracts and/or presentations are distributed via Antibiotic use in outpatients, methenamine excluded, in defined daily doses (DDD) per 1,000 inhabitants and per day, Sweden, the website for further dissemination as a rule. News, regional and 1978-2007 national data on antibiotic use and resistance are regularly updated as well as treatment guidelines and results from Strama-funded 25 projects. A physician is contracted who regularly distributes relevant news in the field from the medical press and other sources and “Strama News” containing summaries of relevant recent scientific publications is distributed by email to listed subscribers about 20 eight times a year.

Occasionally, a more acute situation unfolds and calls for more 15 extensive actions. This was the case when it became evident that Enterobacteriaceae producing extended-spectrum beta- lactamases (ESBLs) rapidly became increasingly prevalent and caused outbreaks. This prompted Strama to organise a workshop 10 whose findings were then translated into a proposal for a national action plan [9].

Antibiotic utilisation /1,000 inhabitants/day doses daily Defined Strama has taken the responsibility for the regular analysis of antibiotic consumption at national level. A detailed description and analysis of antibiotic consumption and resistance: “SWEDRES 0 - A report on Swedish antimicrobial utilisation and resistance in 1978 1981 1984 1987 1990 1993 1996 1999 2002 2005 human medicine” is published yearly in collaboration with Swedish Institute for Infectious Disease Control (SMI) and is co-produced Source: Apoteket AB

2 EUROSURVEILLANCE Vol. 13 · Issue 46 · 13 November 2008 · www.eurosurveillance.org To address antibiotic use in the hospital setting Strama initiated programme (RSQC surveys) that was further developed into the and coordinated nationwide point prevalence studies in 2003, web-based ResNet (http://130.237.97.245/ResNet/index.jsp). 2004 and 2006. The number of participating hospitals was 54, 49 National antibiotic susceptibility data are presented regularly on and 64 and the number of covered hospitalised patients (proportion the internet. Figure 2 illustrates reporting according to the Swedish of all hospitalised patients in somatic clinics in the respective Communicable Diseases Act. While the proportion of S. pneumoniae years) was 13,536 (60 %), 11,348 (50%) and 17,113 (80 %), with decreased sensitivity to penicillin V has stabilised, the number respectively [17]. Data in these studies were reported by a web- of notified cases of methicillin-resistant Staphylococcus aureus based system and results were likewise available for the participating (MRSA) has increased, ESBL-producing Enterobacteracaeae Strama groups. The studies showed that approximately every third have turned into an endemic situation and, most recently, the hospitalised patient on a given day received antibiotics. While hitherto largest outbreaks of vancomycin-resistant enterococci almost 10 % were given antibiotics to treat a health-care associated (VRE) is ongoing in the Stockholm region. Still, Sweden is among infection, 6-7 % were given surgical or medical prophylaxis and the the countries with the lowest rates of MRSA (still below 1 %), remaining 17-19 % treatment for a community acquired infection. S. pneumoniae can still be treated with penicillin V and the rate The method and protocols used formed the basis for a pan-European of Escherichia coli-producing ESBLs is below 5 %. study coordinated by ESAC [18]. Increasing antibiotic use in the elderly population prompted a Conclusions separate study in 2004 on indications for antibiotic prescribing in Strama’s multidisciplinary and multisectorial programme has 58 nursing homes [19]. developed into a coordinated national effort that has contributed to a decrease in antibiotic use without measurable negative It is important that as a result of the efforts to improve antibiotic consequences. Furthermore, resistance levels are still comparatively use, the reduction in prescriptions does not cause unwanted low in Sweden. Some factors that have paved the way for this negative effects. A survey of hospital admissions recorded in the success have been the utilisation and early involvement of pre- national registry of diagnosis in hospital care, showed no increase existing structures and resources such as the communicable in the number of patients with acute sinusitis, quinsy and acute disease officers, the multi-disciplinary approach, the collaboration mastoiditis despite the reduction in antibiotic prescriptions for with the local drug and therapeutics committees and microbiology children between 1987 and 2003 [20]. Continuous systems for laboratories and the political support at national level. The most such monitoring need to be implemented. Another important task suitable structure for such local nodes will no doubt differ from one for Strama is to encourage studies aimed at preserving the efficacy country to the next and may take some extra resources to identify of existing drugs e.g. through modified dosing regimens or drug and put in place. Particular difficulties can be expected when combinations. trying to collect local data sent to different (remote) microbiology laboratories and to develop mechanisms to aggregate prescriptions Antibiotic resistance from individual prescribers or health-care facilities. Not least, A comparatively widespread practice of culturing clinical regular collaboration with national and regional news media has specimens in combination with well-functioning diagnostic been one of the key strategies. laboratories using harmonised methods (www.srga.org) have formed the basis for the surveillance of antibiotic resistance in Sweden. Recently, however, antibiotic sales seem to have started to Surveillance mainly relies on two major sources: notification of rise again and resistance is increasing in several species. This any resistance according to the Swedish Communicable Diseases must be met by intensified information and education campaigns, Act and since 2002 a combined surveillance and quality control aimed at doctors as well as the general public, on the rational use of antibiotics and the promotion of compliance with basic hygiene in the health-care sector. Examples of areas which call for further attention are antibiotic use in long-term care facilities, Figure 2 among private health-care providers, to treat sexually transmitted Notifications of infections or colonisation with antibiotic-resistant diseases (STIs) and for some chronic conditions such as acne, pathogens notifiable by the Swedish Communicable Disease Act, chronic obstructive pulmonary disease and diabetic foot infections. 1998-2007 To achieve this goal, all local groups should be formally supported

2,500 with a defined mission incorporated in the patient safety and quality work by 2010. 2,000 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 1,500

1,000 References 1. The National Board of Health and Welfare. Swedish plan of action against 500 antibiotic resistance. Stockholm, 2000. Available from: http://soapimg.icecube.

Number of notified cases of Number notified snowfall.se/strama/SPAR,_engelsk_version.pdf

0 2. Swedish Ministry of Health and Social Affairs. Strategy to prevent antibiotic MRSA VRE PNSP ESBL resistance and health-care associated infections. Fact sheet 2008 No.8, May 2006. Stockholm. Available from: http://soapimg.icecube.snowfall.se/strama/ Prop%20Engelsk.pdf MRSA: methicillin-resistant S. aureus since year 2000 VRE: vancomycin-resistant E. feacalis and E. feacium since year 2000 3. Mölstad S , Erntell M , Hanberger H , Melander E , Norman C , Skoog G, et al. PNSP: penicillin-nonsusceptible Streptococcus pneumoniae (minimum inhibitory Sustained reduction of antibiotic use and low bacterial resistance. A 10- year concentration (MIC) for penicillin G ≥ 0.5 mg/L, since 1996) follow-up of the Swedish STRAMA programme. Lancet Infect Dis 8(2):125-32. ESBL: extended spectrum beta-lactamase-producing Enterobacteriaceae, since 2007.

EUROSURVEILLANCE Vol. 13 · Issue 46 · 13 November 2008 · www.eurosurveillance.org 3 4. Struwe J. Fighting antibiotic resistance in Sweden- past, present and future Wien Klin Wochenschr 2008; 120(9-10): 268-79. 5. J Struwe, B Olsson-Liljequist (editors). SWEDRES|2007 – A Report on Swedish Antimicrobial Utilisation and Resistance in Human Medicine. Strama, The Swedish Strategic Programme against Antibiotic Resistance, and the Swedish Institute for Infectious Disease Control. Stockholm, 2007. Available from: http://www.smittskyddsinstitutet.se/upload/Publikationer/swedres-strama- smi-2007.pdf 6. Hanberger H, Burman LG, Cars O, Erlandsson M, Gill H, Nilsson LE, et al. Low antibiotic resistance rates in Staphylococcus aureus, Escherichia coli and Klebsiella spp but not in Enterobacter spp and Pseudomonas aeruginosa: a prospective observational study in 14 Swedish ICUs over a 5- year period. Acta Anaesthiol Scand 2007;51(7):937-41. 7. Hanberger H, Erlandsson M, Burman LG, Cars O, Gill H, Lindgren S, et al. and the ICU-STRAMA Study Group. High antibiotic susceptibility among bacterial pathogens in Swedish ICUs. Report from a nation-wide surveillance program using TA90 as a novel index of susceptibility. Scand J Infect Dis 2004; 36(1):24-30. 8. Hanberger H, Arman D, Gill H, Jindrák V, Kalenic S, Kurcz A, et al. Surveillance of microbial resistance in European Intensive Care Units: a first report from the Care-ICU programme for improved infection control. Intensive Care Med. 2008 Aug 1. [Epub ahead of print]. 9. Strama: ESBL in enteric bacteria. Proposed action plan. November 2007. Stockholm: Strama: Swedish Strategic Programme against Antibiotic Resistance. Available from: http://soapimg.icecube.snowfall.se/strama/Strama%20ESBL%20 eng.pdf 10. Lundborg CS, Olsson E, Mölstad S: Swedish Study Group on Antibiotic Use. Antibiotic prescribing in outpatients-a-1- week diagnosis-prescribing study in 5 counties. Scand J Inf Dis 2002;34(6):442-8. 11. André M, Odenholt I, Schwahn Å, Axelsson I, Eriksson M, Hoffman M, et al. Swedish Study Group on Aantibiotics Use. Upper respiratory tract infections in general practice: diagnosis, antibiotic prescribing, duration of symptoms and use of diagnostic tests. Scand J Inf Dis 2002; 34(12):880-6. 12. Andre M, Eriksson M, Mölstad S, Stalsby-Lundborg C, Jakobsson A, Odenholt I; Swedish Study Group on Antibiotic Use. The management of infections in children in general practice in Sweden: a repeated 1-week diagnosis- prescribing study in 5 counties in 2000 and 2002. Scand J Infect Dis. 2005;37(11-12):863-9. 13. André M, Mölstad S, Stålsby Lundborg C, Odenholt I,. Management of urinary tract infections in primary care: a repeated 1-week diagnosis-prescribing study in 5 counties in Sweden in 2000 and 2002 . Scand J Infect Dis. 2004;36(2):134-8. 14. André M, Eriksson M, Odenholt I. [Treatment of patients with skin and soft tissue infections. Results from the STRAMA survey of diagnoses and prescriptions among general practitioners] Lakartidningen. 2006;103(42):3165-7. Swedish. 15. Andre M, Vernby Å, Odenholt I, Lundborg CS, Axelsson I, 5 Eriksson M, et al. Diagnosis-prescribing surveys in 200, 2002 and 2005 in Swedish general practice: consultations, diagnostics and treatment choices. Scand J Infect Dis 2008;40(8):648-654 16. Cars O, Sandberg T. Restrict the use of fluoroquinolones in UTI [in Swedish]. Information Uppsala: Läkemedelsverket; 1996; 7: 3–4 17. Erntell M, Skoog G, Cars O, Elowson S, Hanberger H, Jorup C et al. The STRAMA-programme (The Swedish Strategic Programme for the Rational use of Antimicrobial agents), Stockholm, Abstract O 404, 18th ECCMID 2008. 18. Erntell M, Ansari F, Goossens H, Davey P. ESAC II Hospital Care Subproject 2005-2007: Patterns of Antibiotic Use in Relation to Diagnose in 19 European Hospitals in 2006, Point Prevalence Study (PPS). 17th European Congress of Clinical Microbiology and Infectious Diseases 2007, O166. 19. Pettersson E, Vernby Å, Mölstad S, Lundborg CS. Infections and antibiotic prescribing in Swedish nursing homes: a cross-sectional study. Scand J Infect Dis 2008;40(5):393-398. 20. Cars O and Olsson Liljequist B, editors. SWEDRES 2005. A report on Swedish antibiotic utilisation and resistance in human medicine. Stockholm: The Swedish Strategic Programme for the Rational Use of Antimicrobial Agents (STRAMA), and the Swedish Institute for Infectious Disease Control. Available from: http://soapimg.icecube.snowfall.se/strama/Swedres%202005.pdf

This article was published on 13 November 2008. Citation style for this article: Mölstad S, Cars O, Struwe J. Strama - a Swedish working model for containment of antibiotic resistance . Euro Surveill. 2008;13(46):pii=19041. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19041

4 EUROSURVEILLANCE Vol. 13 · Issue 46 · 13 November 2008 · www.eurosurveillance.org Review

Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme

S Mölstad, M Erntell, H Hanberger, E Melander, C Norman, G Skoog, C Stålsby Lundborg, A Söderström, E Torell, O Cars

Increasing use of antibiotics and the spread of resistant pneumococcal clones in the early 1990s alarmed the medical Lancet Infect Dis 2008; 8: profession and medical authorities in Sweden. Strama (Swedish Strategic Programme for the Rational Use of 125–32 Antimicrobial Agents and Surveillance of Resistance) was therefore started in 1994 to provide surveillance of antibiotic Unit of Research and use and resistance, and to implement the rational use of antibiotics and development of new knowledge. Between Development in Primary Care, Jönköping, and Department of 1995 and 2004, antibiotic use for outpatients decreased from 15·7 to 12·6 defi ned daily doses per 1000 inhabitants per Medical and Health Sciences, day and from 536 to 410 prescriptions per 1000 inhabitants per year. The reduction was most prominent in children Linköping University, aged 5–14 years (52%) and for macrolides (65%). During this period, the number of hospital admissions for acute Linköping (Prof S Mölstad MD); mastoiditis, rhinosinusitis, and quinsy (peritonsillar abscess) was stable or declining. Although the epidemic spread Department of Communicable Disease Control, County in southern Sweden of penicillin-resistant Streptococcus pneumoniae was curbed, the national frequency increased Hospital, Halmstad from 4% to 6%. Resistance remained low in most other bacterial species during this period. This multidisciplinary, (M Erntell MD); Division of coordinated programme has contributed to the reduction of antibiotic use without measurable negative consequences. Infectious Diseases, Department of Molecular and However, antibiotic resistance in several bacterial species is slowly increasing, which has led to calls for continued Clinical Medicine, University sustained eff orts to preserve the eff ectiveness of available antibiotics. Hospital, Linköping (H Hanberger MD); Department Introduction of several multiresistant pneumococcal clones in the of Clinical Microbiology, Malmö University Hospital, Bacterial resistance to antibiotics, both at the individual early 1990s among young children, especially in day-care Malmö (E Melander MD); and community levels, is an unavoidable side-eff ect of centres in Skåne county in southern Sweden, alarmed Strama, Swedish Institute for consumption of these drugs.1 Antibiotic resistance limits the medical profession and the medical authorities, and Infectious Disease Control, the available treatment options and causes increased prompted coordinated eff orts to prevent further spread Solna (C Norman MD, 4 G Skoog MScPharm, morbidity and mortality as well as increased costs because of these resistant clones. A national organisation, Prof O Cars MD); Department of 2,3 of failure of the empirical therapy. During the past two Strama (the Swedish Strategic Programme for the Public Health Sciences, Division decades, resistance to antibiotics has become a major Rational Use of Antimicrobial Agents and Surveillance of International Health, public-health concern, mainly caused by national and of Resistance), was initiated in 1994 and came into action Stockholm, and Nordic School of Public Health and Apoteket international spread of multiresistant bacterial clones in 1995. The overall aim of Strama is to preserve the AB, Gothenburg and the declining interest from the pharmaceutical eff ectiveness of available antimicrobial agents. Although (Prof C Stålsby Lundborg PhD); industry in research and development of new antibacterial pneumococcal resistance in the community was the fi rst Department of Communicable drugs. target of Strama, the programme has continuously Disease Control, Gothenburg (A Söderström MD); and Sweden has a population of about 9 million, and its expanded, and today comprises activities within many Department of Clinical national health-care insurance system encompasses all fi elds, including primary care, hospital care, nursing Microbiology, Uppsala inhabitants. The 21 county councils have the main University Hospital, Uppsala, Sweden (E Torell MD) responsibility for health care, which is supplied mainly Panel: Members of the national and regional Strama groups by public providers, but also by private providers through Correspondence to: National Strama group Prof Sigvard Mölstad, Unit of contracts with the county councils. Primary and Research and Development in secondary care is organised through each county council, Swedish Institute for Infectious Disease Control Primary Care, Futurum, and regional university hospitals provide tertiary care Medical Products Agency 55185 Jönköping, Sweden. services. All outpatient pharmacies belong to one National Veterinary Institute Tel +46 36 325209; [email protected] parastatal company, Apoteket AB, which has about Swedish Reference Group for Antibiotics 900 pharmacies in the country. The fi nancing of health National Board on Health and Welfare care is mainly public. Approximately 8·3% of gross National Corporation of Swedish Pharmacies national product was spent on health care in 2004, and of Society of County Medical Offi cers for Communicable Disease this approximately 13·4% was spent on drugs. There is Control co-payment for both health care and drugs, with separate Swedish Association of Local Authorities and Regions ceiling costs. On average, about 24% of medicine costs Swedish Board of Agriculture are paid by patients, but the reimbursement is stepwise Regional Strama groups with full co-payment of up to 900 Swedish krona (US$118) Representatives from communicable disease control, general per year. Dental care is not included in health-care practice, infectious diseases, otolaryngology, paediatrics, reimbursement. clinical microbiology, and local pharmacy are always included. In Sweden, antibiotic use increased constantly during In some regional groups additional specialties are included. the 1980s and the beginning of the 1990s. The detection http://infection.thelancet.com Vol 8 February 2008 125 Review

Regional level 18 At least one multidisciplinary Strama group has been

16 formed in each county (panel). These groups, in most cases led by the county medical oﬃ cer for communicable 14 disease control, follow antibiotic use and resistance in their region, and disseminate that knowledge and locally 12 All drugs, excluding methenamine Sulphonamides/trimethoprim (J01E) adapted guidelines on the prevention and treatment of Penicillins (J01C) Quinolones (J01M) infections to professionals in the health-care system. The Tetracylines (J01A) Cephalosporins (J01DA-E) 10 Macrolides and lincosamides (J01F) Others excluding methenamine regional Strama groups work in close collaboration with the regional drug and therapeutics committees. The 8 groups were initially focused on outpatient care, but more recently, special hospital units of Strama have been 6 formed. DDD per 1000 inhabitants per day DDD per 1000 inhabitants 4 Antibiotic use

2 Data on outpatient antibiotic sales has been available in Sweden since 1974 from Apoteket AB (the National 0 Corporation of Swedish Pharmacies) in defi ned daily 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 doses (DDD) per 1000 inhabitants per day, according to Year WHO guidelines,5 and as the number of prescriptions Figure 1: Antibiotic use in outpatients, by type (1987–2004) per 1000 inhabitants per year for diff erent age-groups Methenamine is a urinary antiseptic, with no infl uence on resistance, so was excluded. From Cars et al.6 and geographical areas. All regional Strama groups are DDD=defi ned daily doses. given regional data on antibiotic use by local homes, and day-care centres. Since 2000, Strama has pharmacists. received fi nancial support from the Swedish government. Between 1995 and 2004, total antibiotic use (excluding The aim of this Review is to describe the Strama methenamine, which is a urinary antiseptic) decreased programme and summarise the results of the fi rst by 15% from 17·3 to 14·6 DDD per 1000 inhabitants per 10 years. day, and for outpatient use by 20% from 15·7 to 12·6 DDD per 1000 inhabitants per day (fi gure 1).6 The number of Organisation of Strama prescriptions declined by 23% from 536 to 410 per 1000 National level inhabitants per year. The reduction was most prominent Strama is composed of a national steering group and for macrolides (65%), from 48 to 17 prescriptions per regional Strama groups in every Swedish county 1000 inhabitants per year. The number of prescriptions (panel). The national Strama group includes a broad fell by 37% among children aged 0–4 years, by 52% representation of professional organisations and among children aged 5–14 years, by 23% in those aged relevant authorities. The main objectives of the national 15–64 years, but increased by 12% among those aged group are to coordinate activities for the containment of 65 years and older (fi gure 2). The increased use of antibiotic resistance at the national level. Activities antibiotics among elderly people between 1995 and 1999 include the analysis of trends in antibiotic resistance was partly caused by a change in administrative routines, and consumption, identifi cation of gaps in knowledge, such as the change in use of antibiotics in nursing homes initiation of studies to fi ll these gaps, and priority from hospital use to outpatient use (fi gure 2). setting of areas for interventions. An executive working Approximately half of the prescribed antibiotics were committee, supported by a small secretariat, meets penicillins, of which phenoxymethylpenicillin constituted approximately once a month. Its role is to work out 60–70%.6 yearly action plans, coordinate activities, and support the regional Strama groups. A public website (http:// Indications for antibiotic use www.strama.se) has been available since 1998 with Although the regular dissemination of sales data has regularly updated regional and national data on attracted substantial interest, especially the large and antibiotic use and resistance, treatment guidelines, and unexplained geographical variations in antibiotic use, results from Strama-funded projects. A national such data do not include indications and cannot be used meeting is held annually for the members of the to assess the quality of antibiotic prescribing. Strama has regional Strama groups and other interested parties. At therefore initiated several large surveys on the indications these meetings, updates on scientifi c and medical for antibiotic prescriptions. A diagnosis-prescribing aspects on antibiotic resistance, annual statistics on study in primary care was done by Strama in 2000, and antibiotic use and resistance, and results and analysis repeated in 2002.7–10 These studies comprised about of studies, interventions, and educational programmes 150 general practices (about 600 general practitioners), are discussed. and the total number of patients with infections included

126 http://infection.thelancet.com Vol 8 February 2008 Review

in the studies were 7029 and 5377, respectively. The 1400 studies showed high antibiotic prescribing in acute otitis media, acute pharyngotonsillitis, and acute bronchitis, 0–4 years 5–14 years indicating that the new guidelines for the treatment of 1200 15–64 years acute otitis media and acute pharyngotonsillitis had not ≥65 years been fully implemented. 1000 In uncomplicated urinary tract infections (UTIs), increased use of pivmecillinam and nitrofurantoin has been advocated in favour of trimethoprim and 800 fl uoroquinolones. Increased adherence to these recommendations is indicated in national data on the 600 number of prescriptions of these four antibiotics to women between 2000 and 2005 (Apoteket AB), and data Prescriptions per 1000 inhabitants 400 from the Strama diagnosis-prescribing studies showed similar results.10 To assess hospital antibiotic use, two point-prevalence 200 studies were done with 54 hospitals participating in 2003, and 49 hospitals in 2004.11 The antibiotic treatment of 0 approximately 60% of all admitted patients in Sweden 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 (13 536 and 11 348 patients, respectively) during 1 day was Year assessed.11 Apart from patient-specifi c background data, Figure 2: Antibiotic use in outpatients, by age (1987–2004) such as underlying diagnoses and immunosuppression, Methenamine is a urinary antiseptic, with no infl uence on resistance, so was excluded. From Cars et al.6 the assessment included reasons for antibiotic treatment, whether the antibiotic was prescribed for a Since 1994, each laboratory has collected quantitative community-acquired or hospital-acquired infection or as antibiotic susceptibility data (zone diameters) for defi ned peri-operative prophylaxis, and whether relevant samples antibiotics in at least 100 consecutive clinical isolates of for culture were taken before treatment. According to six bacterial species yearly. The data are entered into an preliminary data from the point-prevalence studies,11 internet-based software program. Hereby, resistance adherence to guidelines on prophylaxis can be improved among clinical isolates of Streptococcus pneumoniae, as well as choice of treatment in UTIs and Staphylococcus aureus, Pseudomonas aeruginosa, community-acquired pneumonia. Data in these studies Haemophilus infl uenzae, Streptococcus pyogenes, and were reported by an internet-based system, and reports Escherichia coli can be followed annually at a national and analysis are likewise available on the internet level.14 reporting system for the participating Strama groups. Infections or colonisation with four diff erent The national trend of increasing antibiotic use in antibiotic-resistant pathogens are notifi able by the elderly people has prompted a separate study on Communicable Disease Act: penicillin-resistant indications for antibiotic prescribing in nursing homes, pneumococci (PRP; minimum inhibitory concentration which was done in 58 nursing homes in 2004.12 for penicillin G ≥0·5 mg/L) since 1996, meticillin-resistant Preliminary data from this study have shown poor S aureus (MRSA), and vancomycin-resistant Enterococcus diagnostic routines and antibiotic overprescribing with faecalis and Enterococcus faecium since 2000. Annual data regard to UTIs. These areas are now subject to diff erent on number and incidence (per 100 000 population) of interventions. these pathogens at a national and county level is available.15 Since 1999, Sweden has participated in the Antibiotic resistance European Antimicrobial Resistance Surveillance System In Sweden, there are 30 clinical microbiological (EARSS). Each participating country collects annual laboratories, with at least one laboratory for each county. quantitative antibiotic susceptibility data on invasive The antimicrobial susceptibility testing methods of clinical isolates of S pneumoniae, E coli, S aureus, Swedish laboratories are well standardised through the E faecalis, and E faecium, and these data are then collated work of the Swedish Reference Group of Antibiotics, and presented on the EARSS website; Swedish national For the EARSS website see methodology subcommittee (SRGA-M), and the data are also presented on the Strama website. http://www.rivm.nl/earss/ 30 laboratories.13 Species-specifi c susceptibility break- Additionally, all regional Strama groups are given For the Strama website see points are used. Validation of susceptibility testing by regional data on resistance by their local microbiological http://www.strama.se histogram analysis is done annually, and internal control laboratories. is done daily or weekly by comparing laboratory-specifi c zone diameters with SRGA-M reference zone distributions Pneumococcal infection of reference strains. The laboratories also test strains from The spread of resistant pneumococci in Skåne county led foreign laboratories as an external control. to the initiation of communicable disease control http://infection.thelancet.com Vol 8 February 2008 127 Review

erythromycin resistance is about 2·5%.6 Between 1997 8 Co-trimoxazole and 2004, the rate of ampicillin-resistant E coli in Penicillin 7 urinary cultures increased from 17% to 24%, and Tetracycline Erythromycin trimethoprim-resistant isolates increased from 8% to 6 15%. 9% of E coli in urinary cultures in 2005 were 5 resistant to ﬂ uoroquinolones, as deﬁ ned by resistance to nalidixic acid.6 4 For S aureus isolated from wound infections in 2005,

Resistance (%) Resistance 3 less than 0·5% were meticillin resistant and 2% were clindamycin resistant. In 2001, a clone of S aureus 2 resistant to fusidic acid spread and became prevalent in 1 many parts of Sweden, leading to 8–10% resistance at the national level. Less than 1% of the invasive S aureus 0 isolates are meticillin resistant.6 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 Year Between 2001 and 2005, high-level aminoglycoside resistance in invasive enterococci was 12–17% in E faecalis Figure 3: Antibiotic resistance of Streptococcus pneumoniae to penicillins, erythromycin, tetracycline, and co-trimoxazole and 6–11% in E faecium. Vancomycin-resistant E faecium 6 For penicillins, all strains with reduced susceptibility are included (minimum has been occasionally reported. inhibitory concentration ≥0·12 mg/L). From Cars et al.6 Intensive care measures against the spread of PRP among children of A national programme in intensive care units (ICUs) preschool age.16 No further epidemic spread to other was started in 1999 to raise awareness of antibiotic counties has been seen, contrary to what was feared,17 resistance and infection control problems among ICU and since 1995, the rates of penicillin-nonsusceptible physicians (ICU-Strama).21 The number of ICUs that pneumococci (PNSP) and PRP in nasopharyngeal took part in the programme has varied over the years cultures have been stable in Skåne.16 However, national with a yearly mean of 28 ICUs between 1999 and 2006. data on pneumococci in nasopharyngeal cultures shows Antibiotic resistance from 14 academic and non-academic slowly increasing rates of PNSP between 1995 and 2004 ICUs, which participated in the ICU-Strama programme (from 4% to 6%),6 despite the decrease in antibiotic use in 1999–2003, showed that 0–1·8% of S aureus isolates among children (fi gure 2 and fi gure 3). Resistance to were meticillin resistant. Similarly, presumptive erythromycin, tetracyclines, and co-trimoxazole also extended-spectrum beta-lactamase phenotype was found increased during this period. The lack of decline in in less than 2·4% of E coli, on the basis of cefotaxime resistance was not expected, but might have been caused susceptibility, except for a peak in 2002 (4·6%). by too short an observation time, continuing spread Cefotaxime resistance was found in 2·6–4·9% of among children, or unknown factors. Thus, once resistant Klebsiella spp. Resistance to cefotaxime among strains have become established in a population, the Enterobacter spp (20–33%) and to imipenem (22–33%) problem may not always be reversible, although some and ciprofl oxacin (5–21%) among P aeruginosa showed studies have indicated a decline in prevalence after no time trend. intervention.16,18,19 In Swedish ICUs, the surveillance programme has By contrast with most other countries in Europe, no shown low prevalences of antibiotic-resistant S aureus increase of antibiotic resistance among invasive (MRSA), E coli, and Klebsiella spp, despite high antibiotic pneumococcal isolates in Sweden has been reported consumption.22 An explanation for the low prevalence of since 2000.20 The frequency of PNSP in invasive isolates resistant E coli, Klebsiella spp, and S aureus was probably has varied between 2·5% and 5·0% and the number of a low entry to the ICUs of epidemic clones of these invasive erythromycin-resistant pneumococci has not organisms because of the low prevalence of these strains increased between 1999 and 2005. in the community. The main cause of the high imipenem and ciprofl oxacin resistance among P aeruginosa was Other bacterial infections probably the high consumption of carbapenems and Beta-lactamase-producing H infl uenzae in naso- quinolones. Experience from other countries and ICUs pharyngeal cultures has remained stable at 10% since show that the situation can change rapidly, and 1995. Beta-lactamase-negative ampicillin-resistant continuous surveillance is therefore necessary to design H infl uenzae is about 3% in nasopharyngeal cultures, interventions in antibiotic policy or hygiene procedures tetracycline resistance is 1%, and resistance to when needed. co-trimoxazole is 10%.6 In S pyogenes from throat cultures, tetracycline resistance increased from 6% in Infection control 1995 to 14–18% in 1998, but has since remained stable. The use of alcohol handrub rather than soap Resistance to clindamycin is rare (<1%) and handwashing has been recommended for disinfection

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Antibiotic prescriptions Mastoiditis 1400 20 0–4 years 5–9 years 1200 10–14 years 15 1000

800 000 inhabitants 10 600

400 5 Prescriptions per 1000 inhabitants 200

0 0

Quinsy Rhinosinusitis 40 40

35 35

25 25 000 inhabitants 000 inhabitants Admissions per 100

20 20

15 15

10 10 Admissions per 100 Admissions per 100

5 5

0 0 7 8 9 8 9 198 198 198 199019911992199319941995199619971998199920002001200220032004 1987198 198 199019911992199319941995199619971998199920002001200220032004 Year Year

Figure 4: Antibiotic prescriptions and hospital admissions for acute mastoiditis, quinsy, and rhinosinusitis for children, by age (1987–2004) From Cars et al.6 of hands between patient contacts in Swedish hospitals rules apply to all patients and staff , including physicians. since the 1970s. Sweden has been one of few countries They include the banning of private clothes and the with less than 1% resistance to meticillin among wearing of fi nger rings, wrist jewellery, and watches at invasive isolates of S aureus. However, recent spread of work. A dress code with short sleeves for all health-care MRSA in a few hospitals in Sweden has underscored workers was introduced, use of alcohol handrub before the need for increasing activities in the fi eld of infection and after every patient, and the use of gowns with every control. Between 1997 and 2000, the largest Swedish close patient contact was recommended. The outbreak of an endemic strain of MRSA (EMRSA-16) introduction of these rules was thought to be one of the occurred at Sahlgrenska University Hospital in main reasons for the successful termination of the Gothenburg. The outbreak was successfully terminated outbreak, and they have since been adopted as standard by use of aggressive infection-control measures and a in most Swedish hospitals. Thus, Strama recently massive high-cost sampling programme.23,24 The main supported a national study on the estimation of lessons learned during this outbreak were that the hand-hygiene compliance rates by measurement of measures taken were cost eff ective and that the alcohol handrub consumption in 44 wards in hospitals previously recommended barrier precautions, nationwide, including ICUs and in surgery and internal implemented when identifying new carriers of MRSA, medicine wards.25 Additionally, Strama initiated the were often introduced too late to be able to curtail the formation of a national expert group on hygiene and outbreak. In an attempt to be one step ahead of MRSA infection control to make an inventory of relevant areas spread, the uniform use of basic hygiene precautions for future actions and interventions in this important was introduced during the outbreak.23 In brief, these fi eld. http://infection.thelancet.com Vol 8 February 2008 129 Review

Indicators for detecting antibiotic guidelines for lower respiratory tract infections are underprescribing needed.7–9 These studies also showed that offi ce tests From the national registry of diagnosis in hospital care were widely used, although not always according to (National Board of Health and Welfare), the number of guidelines. However, there are several reports that the patients with acute sinusitis, quinsy (peritonsillar visit rates for diff erent respiratory tract infections has abscess), and acute mastoiditis was followed for diff erent declined (Mölstad S, unpublished data), which indicate age-groups between 1987 and 2003. According to this larger eff ects than shown in these studies. Therefore registry, hospital admissions for acute mastoiditis, changes in consulting rates will be included among quinsy, and acute rhinosinusitis in children were stable outcome variables in the assessment of future or decreased during this period (fi gure 4).6 Thus, there prescribing studies. were no signs of underprescribing. We also noted a large Few countries can show reliable data on antibiotic reduction in admissions for pneumonia (not shown), consumption before 2000, or a sustainable reduction at a which may have resulted from a reduction in available national level. Declining antibiotic consumption and hospital beds. To fully secure that a further reduction in visiting rates by patients for respiratory tract infections antibiotic use does not increase the number of has been reported from the UK and USA.35–37 Educational complications or give increased durations of illness, campaigns for primary-care clinicians and the public improved systems for surveillance of treatment eff ects have been launched in Wisconsin, USA, and the reports are necessary. have shown a reduction in antibiotic prescribing and number of patients requesting antibiotic treatment.38 In Other activities Belgium, the UK, and France, national campaigns to In 2000, the National Board of Health and Welfare, in reduce antibiotic consumption have taken place with close cooperation with Strama, prepared a national action divergent eff ects.39–42 The long-term outcome of those plan to contain antibiotic resistance in Sweden.26 The eff orts still needs to be shown. objectives of this plan are used in the development of the annual work plans for Strama activities. Benefi ts and limitations New national guidelines were developed for the The Strama project was not designed to be scientifi cally treatment of acute otitis media in 2000, for acute evaluated, but instead to be an ongoing coordinated pharyngotonsillitis and impetigo in 2002, and for acute national eff ort to decrease antibiotic use and spread of sinusitis in 2005. The guidelines for the treatment of resistance. The project lacks a validated control, but UTIs was updated in 2006, and new guidelines for lower antibiotic use has not decreased in the neighbouring respiratory tract infections will be issued in 2008. countries of Denmark, Norway, or Finland.43 We believe that the coordination of diff erent professions and Comparison with other countries and future authorities, and the decentralised organisation with perspectives regional groups for the dissemination and Non-prescribed use of antibiotics is very low in Sweden implementation of guidelines and new knowledge are compared with other European countries.27,28 The survey important factors. Although no coordinated public of hospital admissions for certain infectious diagnoses campaign has been launched in Sweden, as it has in that may be related to below optimum antibiotic use France and Belgium, regular collaboration with news showed that these diagnoses have been stable or media, both national and regional, has been one of the declining, despite the reduction in prescribing to children priories for Strama. Indeed, discussion in the public (fi gure 4); these fi ndings are in agreement with a UK media probably contributed substantially to the study.29 reduction in antibiotic use in the year before Strama Antibiotic use varies between countries, but also with was formally organised (fi gure 1). regard to class of antibiotics, dosage, and treatment Swedish sales data on antibiotic use are highly valid duration.30–32 In the empirical choice of antibiotics, and antibiotics cannot be obtained without a prescription, ecological aspects should be taken into consideration but resistance data reported from micro biological because some antibiotics and regimens have been laboratories can always be questioned despite well shown to be associated with emergence and spread of standardised microbiological methods. However, the resistance.4 For example, the use of macrolides and method to collect resistance data has been identical co-trimoxazole has been related to carriage of PNSP. through the years, and the recommended indications Strama has therefore advocated narrow-spectrum for sampling in primary care have not been widened. penicillin as the drug of choice in most respiratory tract Unfortunately, Strama did not do baseline studies of infections. Although antibiotic use has been knowledge and attitudes of physicians and the general substantially reduced, there are still large seasonal population on antibiotics and resistance, which would variations.33,34 Furthermore, the diagnosis-prescribing have been valuable information for the purpose of studies done in primary care have shown that antibiotic follow-up. A recent qualitative study among doctors has prescribing can be further improved and that new shown that views on resistance vary. Although some

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12 Pettersson E, Vernby Å, Mölstad S, Stålsby Lundborg C. Infections Search strategy and selection criteria in Swedish nursing homes—a cross-sectional study. Scand J Infect Dis (in press). Data for this Review were identifi ed through reference lists of 13 Swedish Reference Group for Antibiotics. Species related relevant papers and the authors own fi les. Additionally, data considerations. http://www.srga.org/foter.htm (accessed Dec 10, were identifi ed by searches of PubMed. English language 2007). 14 Swedish Institute for Infectious Disease Control. ResNet database. papers only were reviewed. No date restrictions were set in http://www4.smittskyddsinstitutet.se/ResNet/index.jsp (accessed these searches. Dec 10, 2007). 15 Swedish Institute for Infectious Disease Control. doctors see resistance as a major problem, some doctors Smittskyddsinstitutet. http://www.smittskyddsinstitutet.se/in- english/statistics/penicillin-resistant-pneumococci-infection-prp/ do not see resistance as either a present or future problem (accessed Jan 2, 2008). (Stålsby Lundborg C, unpublished data). Such information 16 Melander E, Mölstad S, Hansson HB, Persson K. Limited spread of is important for the development and implementation of penicillin-nonsusceptible pneumococci, Skane County, Sweden. Emerg Infect Dis 2004; 10: 1082–87. educational interventions to change prescribing practices. 17 Högberg L, Ekdahl K, Sjöström K, et al. Penicillin-resistant pneumococci in Sweden 1997–2003: increased multi-resistance Conclusions despite stable prevalence and decreased antibiotic use. Microbial Drug Resist 2006; 12: 16–22. In Sweden, Strama has played a major part in the 18 Guillemot D, Varon E, Bernede C, et al. Reduction of antibiotic use reduction of total antibiotic use, in preserving in the community reduces the rate of colonization with penicillin phenoxymethylpenicillin as the drug of choice in most G-nonsusceptible Streptococcus pneumoniae. Clin Infect Dis 2005; 41: 930–38. respiratory tract infections, and may have limited the 19 Seppälä H, Klaukka T, Vuopio-Varkila J, et al. The eff ects of changes spread of multiresistant pneumococcal clones. To reach in the consumption of macrolides antibiotics on erythromycin the long-term aim to preserve the eff ectiveness of resistance in group A streptococci in Finland. Finnish Study Group antibiotics, improved basic hygiene precautions, for Antimicrobial Resistance. N Engl J Med 1997; 337: 441–46. 20 Swedish Institute for Infectious Disease Control. improved antibiotic treatments in terms of choice, Antibiotikaresistens. http://www.smittskyddsinstitutet.se/statistik/ dosage, and length of treatment, and further reductions sok-pa-sjukdomskategori/?c=220 (accessed Jan 2, 2008). in antibiotic use are needed. 21 Hanberger H, Burman LG, Cars O, et al. Low antibiotic resistance rates in S aureus, E coli and Klebsiella spp but not in Enterobacter Confl icts of interest spp and P aeruginosa: a prospective observational study in We declare that we have no confl icts of interest. 14 Swedish ICUs over a fi ve year period. Acta Anaesthiol Scand 2007; 51: 1–5. References 22 Hanberger H, Erlandsson M, Burman LG, et al. High antibiotic 1 Goosens H, Ferech M, Vander Stichele R, Elseviers M, ESAC Project susceptibility among bacterial pathogens in Swedish ICUs. Report Group. Outpatient antibiotic use in Europe and association with from a nation-wide surveillance program using TA90 as a novel resistance: a cross-national database study. Lancet 2005; 365: 579–87. index of susceptibility. Scand J Infect Dis 2004; 36: 24–30. 2 Wise R, Hart T, Cars O, et al. Antimicrobial resistance. Is a major 23 Seeberg S, Larsson L, Welinder-Olsson C, et al. How an outbreak of threat to public health. BMJ 1998; 317: 609–10. MRSA in Gothenburg was eliminated: by strict hygienic routines 3 Levy SB, Marshall B. Antibacterial resistance worldwide: causes, and massive control-culture program. Läkartidningen 2002; challenges and responses. Nat Med 2004; 10: 122–29. 99: 3182–83 (in Swedish). 4 Melander E, Ekdahl K, Jönsson G, Mölstad S. Frequency of 24 Biorholt I, Haglind E. Cost-savings achieved by eradication of penicillin-resistant pneumococci in children is correlated to epidemic methicillin-resistant Staphylococcus aureus (EMRSA)-16 community utilization of antibiotics. Pediatr Infect Dis J 2000; from a large teaching hospital. Eur J Clin Microb Infect Dis 2004; 19: 1172–77. 23: 688–95. 5 World Health Organization Collaborating Centre for Drug Statistics 25 Mannerquist K, Burman LG, Isaksson B, Cars O, Riesenfeld-Orn Methodology. ATC classifi cation index with DDDs 2005. http:// I, Torell E. Estimation of hand hygiene compliance rates by www.whocc.no/atcddd/ (accessed Jan 2, 2008). comparison of actual consumption of hand disinfectants with a 6 Cars O, Olsson Liljequist B, eds. SWEDRES 2005. A report on ward specifi c “gold standard” . Proceedings of the 45th Swedish antibiotic utilisation and resistance in human medicine. Interscience Conference on Antimicrobial Agents and Strama, 2005. http://en.strama.se/dyn//,109,.html (accessed Dec 10, Chemotherapy; Washington, DC, USA; Dec 16–19, 2005. 2007). Abstract K1170. 7 Stålsby Lundborg C, Olsson E, Mölstad S, Swedish Study Group on 26 Swedish National Board of Health and Welfare. Swedish plan of Antibiotic Use. Antibiotic prescribing in outpatients—a one week action against antibiotic resistance. Proposal. June, 2000. http:// diagnosis-prescribing study in fi ve counties. Scand J Infect Dis 2002; soapimg.icecube.snowfall.se/strama/SPAR,_engelsk_version.pdf 34: 442–48. (accessed Dec 10, 2007). 8 André M, Odenholt I, Schwahn Å, et al. Upper respiratory tract 27 Svensson E, Haaijer-Ruskamp F, Stålsby Lundborg C. infections in general practice: diagnosis, antibiotic prescribing, Self-medication with antibiotics in a Swedish general population. duration of symptoms and use of diagnostic tests. Scand J Infect Dis Scand J Infect Dis 2004; 36: 450–52. 2002; 34: 880–86. 28 Grigoryan L, Haaijer-Ruskamp F, Burgerhof J, et al. Self-medication 9 Andre M, Eriksson M, Mölstad S, et al. The management of with antimicrobial drugs in Europe. Emerg Infect Dis 2006; infections in children in general practice in Sweden: a repeated 3: 452–59. 1-week diagnosis-prescribing study in 5 counties in 2000 and 2002. 29 Sharland M, Kendall H, Yeates D, et al. Antibiotic prescribing in Scand J Infect Dis 2005; 37: 863–69. general practice and hospital admissions for peritonsillar abscess, 10 André M, Stålsby Lundborg C, Odenholt I, Mölstad S. mastoiditis, and rheumatic fever in children: time trend analysis. Management of urinary tract infections in primary care: a one BMJ 2005; 331: 328–29. week diagnosis-prescribing study in 5 counties in Sweden. 30 Cars O, Mölstad S, Melander A. Variation in antibiotic use in the Scand J Infect Dis 2004; 36: 134–38. European Union. Lancet 2001; 357: 1851–53. 11 Cars O, Olsson Liljequist B, eds. SWEDRES 2004. A report on 31 Mölstad S, Stålsby Lundborg C, Karlsson A-K, Cars O. 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32 Coenen S, Mölstad S. Preferred antibiotics, dosages and duration of 38 Kiang KM, Kieke BA, Como-Sabetti K, Lynfi eld R, Besser RE, treatment in general practice. A comparison between 10 European Belongia EA. Clinician knowledge and beliefs after state-wide countries. Eur J Gen Pract 2004; 10: 166–68. program to promote appropriate antimicrobial drug use. 33 Ganestam F, Stålsby Lundborg C, Grabowska K, Cars O, Linde A. Emerg Infect Dis 2005; 11: 904–11. Weekly antibiotic prescribing and infl uenza activity in Sweden: 39 Bauraind I, Lopez-Lozano JM, Beyaert A. Association between a study throughout fi ve infl uenza seasons. Scand J Infect Dis 2003; antibiotic sales and public campaign for their appropriate use. 35: 836–42. JAMA 2004; 20: 2468–69. 34 Högberg L, Oke T, Geli P, Lundborg CS, Cars O, Ekdahl K. 40 Parsons S, Morrow S, Underwood M. Did local enhancement of a Reduction in outpatient antibiotic sales for pre-school children: national campaign to reduce high antibiotic prescribing aff ect interrupted time series analysis of weekly antibiotic sales data in public attitudes and prescribing rates. Eur J Gen Pract 2004; Sweden 1992–2002. J Antimicrob Chemother 2005; 56: 208–15. 10: 18–23. 35 Ashworth M, Latinovic R, Charlton J, Cox K, Rowlands G, 41 Sommet A, Sermet C, Boelle PY, Taffl et M, Bernede C, Guillemot D. Gulliford M. Why has antibiotic prescribing for respiratory illness No signifi cant decrease in antibiotic use from 1992 to 2000, in the declined in primary care? A longitudinal study using the General French community. J Antimicrob Chemother 2004; 54: 524–28. Practice Research Database. J Public Health 2004; 26: 268–74. 42 Goosens H, Guillemot D, Ferech M, et al. National campaigns to 36 Majeed A, Wrigley T. Antibiotic prescribing rates in England are improve antibiotic use. Eur J Clin Pharmacol 2006; 62: 373–79. falling. BMJ 2002; 325: 340. 43 Strama. Antibiotic sales statistics. http://en.strama.se/dyn//,96,9. 37 McCaig L, Besser R, Hughes J. Antimicrobial drug prescriptions in html (accessed Dec 10, 2007). ambulatory care settings, United States, 1992–2000. Emerg Infect Dis 2003; 4: 432–37.

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