The evolving threat of antimicrobial resistance Options for action World Health Organization
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ISBN 978 92 4 150318 1 WHO Library Cataloguing-in-Publication Data
The evolving threat of antimicrobial resistance: options for action.
1.Anti-infective agents - adverse effects. 2.Drug resistance, microbial - drug effects. 3.Anti-bacterial agents - administration and dosage. 4.Drug utilization. 5.Health policy. I.World Health Organization. ISBN 978 92 4 150318 1 (NLM classifi cation: QV 250) World Health Organization 2012
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Design by GPS PUBLISHING, France.
This publication has been produced by the WHO Patient Safety Programme as part of its solid commitment topromoting safer care worldwide. It is the result of an international consultation process started in 2008, which gathered input from over 50 international experts in the fi eld of antimicrobial resistance.
Coordinated by WHO, under the auspices of Sir Liam Donaldson, WHO Envoy for Patient Safety, with the leadership and expert advice of David Heymann, Chairman of the Health Protection Agency, UK, and Didier Pittet, Director of the Infection Control Programme, University of Geneva Hospitals, Switzerland, world experts worked for over two years on fi ve main technical areas, which are central to the AMR problem, in order to provide the best evidence and the appraisal of experiences that form the core of this book.
The WHO Patient Safety Programme is indebted to the international experts who contributed to this process.
A full list of contributors is provided at the end of the book. The working group leads and main authors wereFrank M. Aaerestrup, Technical University of Denmark; Awa Aidara-Kane, World Health Organization; Otto Cars and Andreas Heddini, both at Action on Antibiotic Resistance (ReAct), Sweden; Shaoyu Chang and Anthony So, at Duke University, USA; Barry Cookson, at the Health Protection Agency, UK; Petra Gastmeier at Charité University Hospital, Germany; Lindsay Grayson at the University of Melbourne, Australia; Hajo Grundmann, at the National Institute for Public Health and the Environment, The Netherlands; Stuart Levy, from Tufts University School of Medicine, USA; Thomas F O'Brien and John M Stelling, at Brigham and Women's Hospital, USA; and Wing-Hong Seto, from Queen Mary Hospital, Hong Kong SAR, China. The working groups comprised specialists in AMR who together brought their knowledge and understanding of the risks and challenges in the fi ght against AMR and of the most effective interventions to tackle the problem.
Thanks are due to the following WHO Patient Safety Programme staff: Elizabeth Mathai for her lead in harmonizing and editing the contributions of the different experts and Gerald Dziekan who as well as editing, steered and coordinated the development process from consultation to fi nalization. The programme's Coordinator, Itziar Larizgoitia Jauregui, its Director, Najeeb Al-Shorbaji, and Assistant Director-General, Marie-Paule Kieny, provided overall supervision of the project.
Thanks are also due to the WHO technical teams and international experts who developed the 2001 WHO Global Strategy for Containment of Antimicrobial Resistance, and the 2011 World Health Day policy briefs, led by Mario Raviglione, Director of Stop TB, and Hiroki Nakatani, Assistant Director-General, and the Stop TB Team, as well as to those who reviewed the various drafts.
The fi nancial contribution of the Swedish International Development Cooperation Agency (SIDA) throughAction on Antibiotic Resistance (ReAct), Uppsala, Sweden towards design of this publication is gratefully acknowledged.

Antimicrobial resistance (AMR) is not a recent phenomenon, but it is a critical health issue today. Over several decades, to varying degrees, bacteria causing common infections have developed resistance to each new antibiotic, and AMR has evolved to become a worldwide health threat. With a dearth of new antibiotics coming to market, the need for action to avert a developing global crisis in health care is increasingly urgent. In addition to a substantial fi nancial burden that national health-care budgets can ill afford, AMR has economic consequences far beyond the health sector, such as damaging repercussions on international travel and trade resulting from the cross-border spread of resistant infections. The cost of not acting against AMR needs to be considered when deciding resource allocation and assessing interventions. We know how and why AMR develops, what factors favour its emergence and spread, and what measures can be taken to limit it. Why then are we now facing an impending crisis in the treatment of many infections? This book describes the context of the problem, some of the progress made in recent years to tackle it, and what more should be done. Without question, more information and new tools are needed, but available strategies and interventions can go a long way towards minimizing the scale and impact of AMR, and maximizing the effective lifespan of existing antibiotics. Much more could be achieved by better and more widespread application of these measures, and there are many promising opportunities for innovation in this area. Infections which are increasingly resistant to antibiotics together account for a heavy disease burden, often affecting developing countries disproportionately. The use of vast quantities of antibiotics in food-producing animals adds another dimension to a complex situation. Several sectors and services are involved and each, from public health to animal husbandry, has an important role to play in counteracting AMR. Responsibility needs to be shared, and coordination of the separate necessary inputs requires determined leadership, additional resources, and solid commitment at many levels. The World Health Organization (WHO) has long recognized AMR as a growing global health threat, and the World Health Assembly, through several resolutions over two decades, has called upon Member States and the international community to take measures to curtail the emergence and spread of AMR. The WHO Global Strategy for Containment of Antimicrobial Resistance, published in 2001, set out a comprehensive set of recommendations for AMR control which remain valid today. This book examines the experiences with implementing some of those recommendations ten years on, the lessons learnt along the way and the remaining gaps. On World Heath Day 2011, WHO again highlighted AMR and urged countries to commit to a comprehensive fi nanced national plan to combat AMR, engaging all principal stakeholders including civil society.
I am pleased to present this book during the campaign year chosen by WHO for special emphasis on the importance of AMR. It testifi es to the Organization's commitment to promoting and facilitating global action to contain AMR and ensuring that effective antibiotics will be available worldwide in the future. Dr Marie-Paule Kieny
Assistant Director-General
Innovation, Information, Evidence and Research
World Health Organization
WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance Advanced Market Commitment African Network for Drugs and Diagnostics Innovation Asian Network of Surveillance of Resistant Pathogens Alliance for the Prudent Use of Antibiotics Antimicrobial Resistance in the Mediterranean Centers for Disease Control Canadian Integrated Programme for Antimicrobial Resistance Surveillance Clinical and Laboratory Standards Institute Canadian Nosocomial Infection Surveillance Programme Council of Scientifi c and Industrial Research Defi ned Daily Doses Daily Doses per 1000 inhabitants per day Drug Regulatory Agencies Diagnosis Related Group EARS-Net
European Antimicrobial Resistance Surveillance Network European Centre for Disease Prevention and Control Essential Medicines List WHO Regional Offi ce for the Eastern Mediterranean External Quality Assurance ESAC-Net
European Surveillance of Antimicrobial Consumption Network European Committee on Antimicrobial Susceptibility Testing Food and Agriculture Organization Food and Drug Administration Foundation for Innovative New Diagnostics Global Alliance for Vaccines and Immunization Global Foodborne Infections Network Global Laboratory Initiative Good Manufacturing Practice Hazard Analysis and Critical Control Point Health care-Associated Infection Hospitals in Europe Linked for Infection Control through Surveillance Hand Hygiene Culture-change Pilot Programme Immunodefi ciency Virus HIVResNet
Global HIV Drug Resistance Network Human Papilloma Virus Individual Case Safety Reports Integrated Disease Surveillance and Response Innovative Medicines Initiative Intercontinental Marketing Services International Nosocomial Infection Control Consortium Infection Prevention and Control International Surveillance of Reservoirs of Antibiotic Resistance Light Emitting Diode Multidrug-resistant Tuberculosis Ministry of Health Methicillin-resistant Staphylococcus aureus Methicillin-sensitive Staphylococcus aureus Meropenem Yearly Susceptibility Test Information Collection National Antimicrobial Utilization Surveillance Program National Center for Advancing Translational Sciences New Delhi Metallo-beta-lactamase National External Quality Assurance Scheme Nongovernmental National Institutes of Health World Organisation for Animal Health Open Source Drug Discovery Over the Counter Pan American Health Organization Program for Appropriate Technology in Health Polymerase Chain Reaction Product Development Partnerships Point Prevalence Survey Research and Development Action on Antibiotic Resistance Red Latinoamericana de Vigilancia a las Resistencias Antimicrobianas Self-medication with Antibiotics and Resistance Levels in Europe South-East Asia Region Swedish International Development Cooperation Agency Staphylococcus Reference Laboratory Swedish Strategic Programme against Antibiotic Resistance Transatlantic Task Force on Antimicrobial Resistance Research and Training in Tropical Diseases Target Product Profi le Uppsala Monitoring Centre International facility for the purchase of drugs against HIV/AIDS, Malaria and Tuberculosis Vancomycin-resistant World Health Organization WHO Regional Offi ce for the Western Pacifi c Extensively Drug-resistance Tuberculosis Chapter 1 - The evolving threat of antimicrobial resistance - Introduction
Chapter 2 - Surveillance to track antimicrobial use and resistance in bacteria
Chapter 3 - Measures to ensure better use of antibiotics
Chapter 4 - Reducing antimicrobial use in animal husbandry
Chapter 5 - Infection prevention and control in health-care facilities
Chapter 6 - Fostering innovation to combat antimicrobial resistance
Chapter 7 - The way forward: political commitment to enable options for action
Appendix 1: List of 2001 WHO Global Strategy for Containment of Antimicrobial
Resistance recommendations
Appendix 2: List of 2011 WHO World Health Day six-point policy briefs
List of authors, contributors, reviewers and participants in consultation

Chapter 1.
The evolving threat of antimicrobial resistance Chapter 1.
The evolving threat of antimicrobial resistance Bacteria which cause disease react to the antibiotics building up over decades, so that today many used as treatment by becoming resistant to them, common and life-threatening infections are becoming sooner or later. This natural process of adaptation, diffi cult or even impossible to treat, sometimes turning antimicrobial resistance, means that the effective a common infection into a life-threatening one. It is lifespan of antibiotics is limited. Unnecessary use and time to take much stronger action worldwide to avert inappropriate use of antibiotics favours the emergence a situation that entails an ever increasing health and and spread of resistant bacteria. A crisis has been economic burden. The evolving public health threat of antimicrobial parts of the world and some of the progress made resistance (AMR) is driven by both appropriate since the publication of the 2001 strategy. It draws and inappropriate use of anti-infective medicines attention to areas where knowledge is lacking and for human and animal health and food production, where urgent action is still needed. The aim of this book together with inadequate measures to control the is to raise awareness about AMR and stimulate further spread of infections. Recognizing the public health efforts to meet the recommendations outlined in the crisis due to AMR, several nations, international 2001 strategy and in the 2011 WHD policy package. It agencies, and many other organizations worldwide does so by examining the current situation and setting have taken action to counteract it through strategies out what has been done and what more could be done applied in the relevant sectors. Several World Health around the world, in high-, middle- and low-income Assembly resolutions have called for action on specifi c countries. While much of what is summarized here is health aspects related to AMR, and the World Health well known to the scientifi c community, awareness at Organization published its global strategy to contain the political level is also essential, but often lacking. AMR in 2001 .1 On World Health Day (WHD) 2011, in a A specifi c objective is therefore to encourage policy six-point policy package, countries were called upon decision-makers and the global community to commit to (1) commit to a comprehensive, fi nanced national to intensifi ed action against AMR. plan with accountability and civil society engagement, (2) strengthen surveillance and laboratory capacity, (3) The book focuses on fi ve of the most important areas ensure uninterrupted access to essential medicines for the control of antibiotic resistance as recognized of assured quality, (4) regulate and promote rational in the WHO 2001 strategy, which are: surveillance, use of medicines in animal husbandry and to ensure rational use in humans, rational use in animals, proper patient care, (5) enhance infection prevention infection prevention and control, and innovations. and control, and (6) foster innovations and research Political commitment is highlighted as one of the policy and development of new tools.2 actions in the 2011 WHD six-point policy package and is recognized as an indispensable prerequisite for This book describes examples of policy activities and action in the fi ve focus areas of this book. experiences that have addressed AMR in different CHAPTER 1
AMR as a public health concern
Many patients around the world suffer harm due including the artemisinin derivatives, and is a major to AMR because infections – caused by viruses, threat to malaria control.5 The therapeutic effi cacy bacteria, fungi, protozoa or helminths – are no longer of medicines is directly monitored by clinical and susceptible to the common medicines used to treat parasitological outcomes of treatment over at least them. Reports on AMR are most often generated on 28 days. A change of national antimalarial treatment the basis of laboratory results on microbes obtained policy is recommended when the overall treatment from human patients. These reports are used to inform failure rate exceeds 10%. Changes in policy have been decisions on the treatment of individual patients, and necessary in many countries due to the emergence also as evidence for policies at local, national, and of chloroquine resistance, which has become so international levels. Data from around the world confi rm widespread that a combination of medicines including that AMR, including multidrug resistance, is increasing artemisinin (artemisinin-based combination therapy) among many pathogens responsible for infections in is now the recommended fi rst-line treatment for health-care facilities and in the community.3,4 uncomplicated falciparum malaria.5 AMR makes it diffi cult and more expensive to treat Tuberculosis: Resistance is a growing problem in a variety of common infections, causing delays in the treatment of tuberculosis. In 2010, there were an effective treatment, or in worst cases, inability to estimated 290 000 new multidrug-resistant tuberculosis provide appropriate therapy. Many of the medical (MDR-TB) cases detected among the TB cases notifi ed advances in recent years, such as chemotherapy worldwide and about one third of these patients may for cancer treatment and organ transplantation, die annually.6 However, just over 53 000 MDR-TB are dependent on the availability of anti-infective cases (18%) were actually notifi ed globally and many drugs. The predictable consequence of resistance cases were not diagnosed. Diagnostic inadequacies is increased morbidity, prolonged illness, a greater also impede appropriate treatment because in most risk of complications, and higher mortality rates. The cases diagnosis depends on screening tests followed economic burden includes loss of productivity (loss by lengthy laboratory culture techniques. In 2010, it in income, diminished worker productivity, time spent was estimated that 3.4% of all new TB cases were by family) and increased cost of diagnostics and MDR-TB. Even more problematic has been the treatment (consultation, infrastructure, screening, cost emergence of extensively drug-resistant TB (XDR-TB), of equipment, drugs). Both the health and economic which occurs when resistance to second-line drugs consequences of AMR are considerable and costly develops in addition to the resistance associated with but diffi cult to quantify precisely as the available data MDR-TB. By 2011, XDR-TB cases had been confi rmed are incomplete in many countries. The additional in 77 countries.
human burden associated with it (pain, change in daily activities, psychosocial costs) is also signifi cant, but HIV infection: Resistance rates to anti-HIV drug regimens ranging from 10%–20% have been reported even more diffi cult to quantify.
in Europe and the USA. However, rates of transmission Available quantitative evidence on excess harm caused of HIV drug-resistant infections appear to be low to patients through drug resistance comes mainly from (3.7%) in lower/middle income countries despite experiences with malaria, tuberculosis, and to some improvements in access to treatment, according to extent, human immunodefi ciency virus (HIV), which a combined analysis of surveys conducted by WHO are cited below as illustrative examples of the problem. in 20 countries between 2003 and 2009.7 Second-line There is a growing body of evidence that AMR is also treatments are generally effective in patients when the increasingly important in many of the common bacterial fi rst-line therapy has failed, but can only be started diseases, but there are much less systematic data on promptly if virological monitoring is routinely available. its extent and the consequences for patients. To facilitate this, in 2004, WHO developed a Global Strategy for the Prevention and Assessment of HIV Malaria: Resistance to antimalarial medicines has Drug Resistance and has established the HIVResNet, been documented for all classes of antimalarials, a network of over 50 institutions, laboratories and CHAPTER 1
experts, to support capacity-building, surveillance, of the health and economic burdens resulting from and data analysis. In patients infected with HIV, co- resistant infections indicate that the excess mortality infection with AMR bacterial infections (e.g. TB, due to resistant bacterial hospital infections exceeds salmonella) has an adverse effect on HIV disease 25 000 annually (Table 1.1).8 Apart from additional progression and on the spread of HIV infection.
patient morbidity/mortality, the attributable health-care costs and productivity losses are estimated to be Common bacterial infections: AMR is an increasingly at least €1.5 billion each year.8 Estimates from Canada important problem affecting the range of bacterial also show very high excess costs associated with infections occurring in hospitals, other health-care resistant infections.9 facilities, and in the community. Estimates from Europe Table 1.1 Estimated annual burden due to selected antibiotic-resistant bacteria in European
Union Member States, Iceland and Norway, 2007
No. cases of
No. extra
No. extra
Antimicrobial resistant Gram-positive bacteria
Methicillin-resistant Staphylococcus aureus (MRSA) Vancomycin-resistant Enterococcus faecium Antimicrobial resistant Gram-negative bacteria
3rd generation cephalosporin-resistant Escherichia coli 3rd generation cephalosporin-resistant Klebsiella Carbapenem-resistant Pseudomonas aeruginosa * Bloodstream infections, lower respiratory tract infections, skin and soft tissue infections, and urinary tract infections. Numbers in parentheses indicate percentage bloodstream infections.
Source: Adapted from 8 with permission. How AMR affects the overall disease burden is less consequence of AMR in health-care facilities and clear for pathogenic bacteria that cause community- community-associated infections is the need to change acquired infections. Laboratory reports show increasing prescribing practices to newer, more costly medicines resistance among bacteria causing pneumonia, which – some of which are also associated with higher CHAPTER 1
kills about 1.8 million children annually.10 Another rates of adverse reactions. In industrialized countries, THE EVOLVING THREAT OF ANTIMICROBIAL RESISTANCE - INTRODUCTION
approximately 90% of all antibiotics used in humans unknown, the development of treatment guidelines has are prescribed in general practice,11 with antibiotic use become diffi cult for some common infections, and the generally based on national treatment guidelines. With use of second- and third-line medicines adds higher AMR rates increasing and the risk of treatment failure costs to treatment (Figure 1.1).12 Figure 1.1 Escalating costs as recommendations for treatment change
Alternative drugs Cost ratio to first-line drug Cost per patient withfirst-line drug (US$) Source: Reproduced from 12 with permission.
For some bacterial infections including gonorrhoea, spend resources on cheaper fi rst-line therapy that will recommending fi rst-line therapy has proved problematic be ineffective in some of those treated, or switch to from a policy perspective once AMR appears, even more expensive second-line drugs that are associated if only a small proportion of the infecting bacteria are with low rates of resistance and will be effective in most resistant. The dilemma revolves around whether to cases, as described in Box 1.1. CHAPTER 1
Box 1.1 Changing treatment policies for gonorrhoea
Gonorrhoea needs to be treated with an effective fi rst-line antibiotic because subsequent follow-up of patients is often limited. The choice of medicine is rarely based on the results from AMR testing on a case-by-case basis, but usually on treatment algorithms. Resistance appearing in Neisseria gonorrhoea has led to successive changes in recommendations for fi rst-line antibiotic therapy from sulfonamides, penicillins, tetracyclines, and quinolones to cephalosporins.13 Penicillin, which was initially reserved for sulfonamide-resistant gonococcal infections, became the drug of choice for gonococcal urethritis in 1943 (less than 10 years after the introduction of sulfonamides) and remained so until the mid-1970s. From the mid-1980s, fl uoroquinolones became the fi rst-line choice, but by the early 1990s treatment failures due to resistant strains were being reported and this class is no longer recommended as the fi rst choice. Only the third-generation cephalosporins remain an effective fi rst-line treatment for gonorrhoea.14 The Centers for Disease Control and Prevention (CDC) currently recommends a dual therapy using cephalosporin and either azithromycin or doxycycline.15 The evidence for treatment guidelines is often obtained from AMR surveillance data. WHO recommends that an antimicrobial be discontinued for the treatment of gonorrhoea when the proportion of N. gonorrhoea infections resistant to it reaches 5% of isolates in the community.14 Therefore, increasing resistance rates bring about the exclusion of antibiotics from treatment guidelines. Figure 1.2 shows the change in antibiotic choice over time in the United Kingdom (UK) for the treatment of gonorrhoea.16 Figure 1.2 Treatment of gonorrhoea in the UK
Percentage of GRASP GRASP: Gonococcal Resistance to Antimicrobials Surveillance ProgrammeSource: Reproduced from 16 with permission from the Health Protection Agency, UK.
N. gonorrhoea retains resistance to several classes of antibiotics such as tetracycline, penicillin, and quinolones, CHAPTER 1
A change in treatment guidelines is always to newer and more costly antibiotics. High-income countries change their recommendations when the risk of treatment failure is still very low. For example, Japan excluded cefi xime and all other oral extended-spectrum cephalosporins from their treatment guidelines in 2006 because of a few isolates with decreased susceptibility to cefi xime in vitro. Intravenous ceftriaxone is now the fi rst-line therapy in Japan.14 Recent treatment failures with cefi xime have been reported from Australia, Norway, the UK, and the USA. However, treatment failures are likely to be underestimated because of paucity of data from low-income countries with a high burden of sexually-transmitted infections.14 Increasing numbers of strains with decreased susceptibility to ceftriaxone are already being detected17 and treatment failures reported,18 raising serious concerns about the treatment of gonorrhoea in the future. The public health signifi cance is underscored by the fact that treatment of cases is the main strategy for controlling the spread of this infection.
AMR threatens most clinical and public health spread in hospitals and in communities. Several practices in both high income countries and in bacteria which can inactivate carbapenems, and are countries with limited resources – from complex resistant to third-generation cephalosporins, already therapeutic procedures to routine control of common cause signifi cant numbers of health care-associated infectious diseases. and community-onset infections in different parts of the world (Figure 1.3).19 Once resistance has emerged, the resistant bacteria Figure 1.3 Worldwide distribution of different metallo-beta-lactamases
IMP, VIM, SPM, GIM, SIM, AIM, KHM, NDM, DIM: various metallo-beta-lactamasesSource: Reprinted from 19 with permission from Elsevier.
A recent development, and cause for concern, is an The evolution of AMR, and a dearth of new antibiotics apparent shift in the burden of antibiotic resistance in the pipeline, raises the possibility that untreatable which may be occurring between the main classes multi-drug resistant (MDR) infections will become of pathogenic bacteria (from Gram-positive to Gram- more and more common. It is particularly worrisome that once it develops, AMR is either irreversible or negative pathogens); this could further stretch the very slow to reverse, despite the introduction of already limited resources of health services as the AMR containment and stewardship programmes.21 infections due to resistant Gram-negative organisms Consequently, early implementation of interventions will likely outweigh recent achievements in the control to avoid the initial development and/or spread of AMR of Gram-positive pathogens.20 can be considered a key public health policy.
WHO guidance and actions on AMR
The 2001 WHO global strategy1 for the containment resistance and the effectiveness of interventions". It of AMR addresses what to do and how to do it and focuses on resistance to antibacterial drugs, addresses provides a framework of interventions to slow the AMR in general rather than through a disease-emergence and reduce the spread of antimicrobial- specifi c approach, and contains a comprehensive resistant microorganisms wherever anti-infective set of recommendations for interventions. Much medicines are used, through: of the responsibility for implementation lies with individual countries, as governments have a critical reducing the disease burden and spread of role in prioritization and provision of public services, infection; such as information, surveillance, cost-effectiveness analysis, and cross-sector coordination. The strategy improving access to appropriate antimicrobials; acknowledges that containment of AMR will require improving the use of antimicrobials; cant strengthening of health systems in many countries and that the associated costs may strengthening health systems and their be considerable. Consequently on World Health Day 2011, WHO urged national commitment for a enforcing regulation and legislation; comprehensive and fi nanced plan with accountability and civil society engagement.2 encouraging the development of appropriate new drugs and vaccines.
Alliances across countries and continents, such as the transatlantic task force on antimicrobial resistance As stated in the strategy, it was developed with the (TATFAR),22 and the Jaipur declaration by WHO South-recognition that "despite the mass of literature on East Asia Region health ministers to combat AMR23, AMR, there is depressingly little on the true costs of are welcome developments. Examining fi ve domains targeted for AMR containment
Five domains, based on the 2001 global strategy Antimicrobial use in animal husbandry; recommendations,1 which correlate to the six-point Infection prevention and control; policy package, presented on WHD 2011,2 are discussed in more detail in the following chapters: Fostering innovations; Political commitment. Surveillance of antimicrobial resistance and use; CHAPTER 1
To tackle AMR in a comprehensive manner, Rational antimicrobial use and regulation; environmental aspects also need to be considered.24 THE EVOLVING THREAT OF ANTIMICROBIAL RESISTANCE - INTRODUCTION
The presence of resistant bacteria in water, air and soil Antimicrobial use in animal husbandry. A substantial
and the potential impact on the spread of AMR are proportion of total antibiotic use occurs outside the fi eld
being increasingly examined.25-28 Water and soil have of human medicine and is probably a major contributor
also been shown to contain measurable amounts of to the overall problem of emerging AMR. Antimicrobial
antibiotics (derived from contaminated effl uent and use in food-producing animals and in aquaculture very
manure).25, 29 Interventions such as improving water often involves large-scale use for growth promotion
supplies and sanitation could therefore have a major and mass prophylaxis. Resistant pathogens found in
impact on the spread of bacteria and AMR.a Reducing food products can cause infections in humans that
the burden of infections by addressing the social can be diffi cult to treat. Such events may cause a
determinants of health could also help to reduce loss of public confi dence in food safety with important
AMR.b These are important issues which go beyond secondary economic repercussions on the farming
the scope of this book.
sector and the international trade in these products. Unfortunately, regulations and other approaches to Surveillance of antimicrobial resistance and use.
controlling antibiotic use in food-producing animals Data on AMR among local pathogens help defi ne are not consistent worldwide. In countries making the best possible treatment for individual patients. sustained efforts in this area, AMR prevalence among However, the proportion of resistant bacteria can zoonotic bacteria and indicator bacteria in locally vary from one area to another, and in many health produced meat is lower than in imported products,21 facilities there are no local data on resistance demonstrating that the recommended measures can patterns. Experiences from national and international have a measurable impact. surveillance networks on antimicrobial use and
AMR show that data, where available, can be put to Infection prevention and control. AMR bacteria,
multiple uses, including orienting treatment choices, like antibiotic-susceptible bacteria can spread, from
understanding AMR trends, informing public health person to person to the environment, and then back to
policy, identifying priority areas for interventions, and humans. In addition, the genes that encode AMR are
monitoring the impact of interventions to contain often readily transferable from resistant to susceptible
resistance. The lack of adequate surveillance in microorganisms, which can then multiply, spread and
many parts of the world leaves large gaps in existing act as a source of further transfer of resistance genes.
knowledge of the distribution and extent of AMR.
Infection prevention and control activities to limit the spread of resistant bacteria are therefore crucial. There Rational antimicrobial use and regulation. Any
are good examples of effective nationally coordinated use of antibiotics has the potential to stimulate the programmes to limit the spread of specifi c infections development of resistance to it, as this is the natural such as HIV, TB and malaria. response of bacteria to threat. Individual decisions
(by the consumer, the prescriber, or both) to use Fostering innovations. The discovery of penicillin
antimicrobials often ignore the societal perspective of ushered in the "antibiotic era" and the ability to
depleting a "common good" whereby antimicrobial cure infections which were previously often fatal.
use can be compared to the use of a natural resource, However, the antibiotic development pipeline has
such as water. In both cases, individual use and markedly declined over the past few decades and
misuse potentially impact on availability and thus there are now very few effective drugs available to
overall utility for other consumers. Overuse plays an treat recently emerged MDR infections. In a fi eld
important role in the emergence of AMR. Paradoxically, which offers little or no fi nancial incentive to the major
underuse through inappropriate choice, inadequate pharmaceutical companies, innovations are urgently
dosing, poor adherence to treatment, and substandard needed to stimulate the research and the discovery
antimicrobials, also plays an important role in the of antimicrobials and vaccines, and to devise funding
emergence and spread of AMR. One of the main arrangements and partnerships to support research
AMR containment strategies is therefore to increase and development (R&D). In addition, there is a need
appropriate use, and to reduce misuse, of antibiotics.
for new technologies and innovations in other areas CHAPTER 1
such as rapid and point-of-care diagnostic tests actors to implement effective actions. Whether the way and infection prevention and control, which are also forward will be towards a future with a continuing supply critically important for effective control of AMR. of effective antimicrobials, or a return to the pre-antibiotic era, will depend on whether suffi cient leadership, solid Political commitment. The fi nal chapter in this book
looks ahead to the prospects for containment of AMR commitment and coordinated efforts can be brought to
and refl ects on the key role of governments and policy bear on this growing global health threat.
The process for the preparation of this book, led by WHO Patient Safety, started in 2008. The steps in the process were as follows: International expert consultations together with facts gathered from published literature informed the preparation of the initial drafts. An iterative collaboration involved authors and contributors and WHO staff, and included reviews by experts within and outside WHO to assess overall progress in relation to WHO recommendations (2001 global strategy for containment of AMR) particularly of large-scale or scalable interventions being carried out in different parts of the world, focusing on the common bacterial infections. Confl icts of interest were ruled out for all participants in the consultation, as well as for all authors, contributors and reviewers. A framework was developed whereby details of actions related to fi ve major domains could be compiled and reviewed, including methodologies to assess and reduce the AMR burden, implementation of interventions on a large scale, regulation, advocacy and education, cost of acting and not acting, and impact of interventions. These were identifi ed using multiple literature searches of scientifi c and grey literature and input from experts involved in such activities in different parts of the world. Within the scope of the book information and examples of ongoing activities were provided to depict overall progress worldwide. The examples were selected through non-systematic reviews of the literature, by expert groups and WHO staff to illustrate interventions that have had a positive measurable impact. Other examples explain concepts and the lessons to be learnt. Attention was paid to including experiences from different parts of the world and from different relevant subject areas.
The book is based on existing WHO recommendations and does not introduce new recommendations. It aims to raise awareness and encourages relevant authorities and decision-makers in options for action that can be taken to control AMR, based on the WHO global strategy for containment of AMR. The fi nal draft text was submitted for review to a panel of international and WHO experts before fi nalization. CHAPTER 1
Chapter 2.
Surveillance to track antimicrobial use and resistance Chapter 2.
Surveillance to track antimicrobial use and resistance Tracking resistant bacteria and how antibiotics are used is fundamental to local, national and international efforts provides the data needed to measure the degree and to combat AMR. Excellent surveillance is carried out distribution of antimicrobial resistance (AMR), to plan in some countries and regions, but more extensive the strategies and measures needed, and to mobilize geographic coverage and coordination of AMR commitment and resources for action. This surveillance surveillance networks are needed. Effective surveillance is the cornerstone of national successful use of the data to bring about changes and international efforts to control antimicrobial in policies and practice, leading to reductions in resistance. Tracking antibiotic use, and the emergence antimicrobial use, with reduction in AMR in some and spread of resistant strains of bacteria provides cases. Consequences if actions are delayed can also information, insights, and tools needed to guide be understood from such data.
policy and to evaluate measures taken to promote There is a long way to go before effective antimicrobial appropriate antimicrobial use at all levels, from use and resistance surveillance will be established local to global. The crucial role of surveillance worldwide. In resource-poor countries with comparatively was recognized in the 2001 WHO Global Strategy weak health systems, there are constraints related for Containment of AMR, in which surveillance of to infrastructure, trained personnel, networking, and resistance, antimicrobial usage and disease burden coordination. In countries with effective surveillance, are included as major components. Their importance political support and strong health systems appear to be was again highlighted by WHO on the occasion of critical for success.
World Health Day 2011. Surveillance data can be used to improve rational antibiotic use locally and The methods for obtaining data are often problematic, to inform policies and identify priorities for action at especially with regard to data on antimicrobial use. national level, while providing valuable support for Small-scale well-designed studies and surveys, such advocacy at regional and global levels.
as indicator surveys, in different settings can be effective in providing insight into the general situation There are wide variations between regions and and in identifying priority areas for intervention; countries, and within countries, in their capacity to trends may be determined through repetition of these carry out AMR surveillance. Although many countries surveys at specifi c intervals. Data on the burden due have made considerable progress in setting up AMR to AMR, such as treatment failures or extra costs, are surveillance, limitations remain related to fi nancial scarce, especially in community settings. Hospital-and technical resources and methodologies. This based data from high-income countries show that chapter provides examples of such initiatives and the these costs can be considerable.
1. How surveillance helps to contain AMR
Surveillance involves the systematic collection and the need to provide effective antimicrobial therapy to analysis of health-related data, and dissemination to patients today with the need to preserve the usefulness those who will use them in decision-making on public of medicines for future generations. health issues. Ongoing and routine AMR surveillance enables analyses to be made of resistance rates to The information generated through surveillance of antimicrobials among bacteria infecting or colonizing use and of resistance can be seen as complementary. individuals in given locations during defi ned time At the local level, the data are used to formulate periods. The surveillance of antimicrobial use tracks recommendations for rational antibiotic use and standard both how much antimicrobials are being used and treatment guidelines and for ensuring that health-care how they are used by patients and health-care providers comply with recommendations. At subnational providers (i.e. the pattern of use, including the why?, or national levels, data on resistance and use together when?, where? and for what?). The scope of activities inform policy decisions such as development or revision ranges from health facility or local community level to of essential medicines lists, and identify priorities for broader domains at the subnational and national level public health action, such as education campaigns or beyond. Local surveillance units could be linked at or regulatory measures. At regional and global levels, national and international levels to provide national, surveillance data have proved to be invaluable advocacy regional and global surveillance information.
tools in stimulating politicians and health-care providers The ultimate goal of surveillance of antimicrobial use into urgent action, as exemplifi ed in this and other and AMR is to provide the information, insights, and chapters. Conversely, lack of surveillance can lead to tools needed to guide policy on the appropriate use of misdirected and ineffi cient policies, wasting of limited antimicrobials and to inform and evaluate resistance resources, inappropriate therapy and ultimately human containment interventions at local, national and global suffering and death through the inability to provide an levels. Decisions on interventions have to balance effective drug to patients in need. 2. WHO guidance on surveillance to contain AMR
The WHO global strategy for containment of AMR (2001) a prompt fl ow of information from laboratories to includes as a key element a call for the surveillance of prescribers and to national/subnational policy-making resistance, antimicrobial usage and disease burden authorities, and ensuring that the information is used (Appendix 1).1 This call for action was repeated in a appropriately. The importance of local monitoring of resolution adopted by the World Health Assembly antimicrobial use in health-care facilities and in the in 2005 (WHA 58.27) and on World Health Day 2011 community, and linking this to AMR surveillance, is (Appendix 2).2 As has been repeatedly stressed, also recognized. The core actions highlighted on the effective surveillance requires the strengthening of occasion of World Health Day 2011 include engaging laboratory capacity for AMR detection, maintaining in regional and global surveillance networks. 3. The present position regarding these recommendations
Efforts to establish surveillance of antimicrobial use laboratory capacity and weak health systems.30,31-33 and AMR have been made in different parts of the The following sections provide some insights and world, with varying degrees of success, and there are examples on the currently prevailing global status of wide variations between regions and countries, and surveillance for antimicrobial use and AMR, with regard within countries, in their present surveillance capacity to the methodologies for data generation, existing and practice. Systematic surveillance is still lacking surveillance networks, efforts to strengthen laboratory in many hospitals, particularly in countries with poor capacity for surveillance, and using the data obtained. CHAPTER 2
3.1 Methods for surveillance of antimicrobial Bacteria belonging to the normal fl ora of healthy individuals in the general population (e.g use and resistance . nasopharyngeal swabs for pneumococci, or stool for E. coli) have also been The primary data for surveillance are generated in a used for surveillance. This approach enables the large number of different health-care facilities around analysis and comparison of trends in communities, the world. For AMR surveillance, routine diagnostic and measurement of the impact of community-laboratories, often within hospitals, are the primary based interventions, but it also has limitations. Often, source of data. For the surveillance of drug use they focus on only one target bacterium, not fully the situation is less clear-cut as it is not carried out representing the range of bacteria that therapy must within a single clinical discipline. Data on the use of target, hence their direct usefulness for treatment antimicrobials could be obtained from many sources guidelines is limited. Also costs are higher since they such as health-care facilities, pharmacies, and drug include the cost of tests on healthy individuals. procurement/sales services. If data collected in There is general understanding that most laboratories disparate settings are to be reliable and comparable, around the world currently use recommendations for it is necessary to apply quality standards for obtaining testing from the Clinical and Laboratory Standards Institute the data. Although the methods used for AMR (CLSI)a or the European Committee on Antimicrobial determination and quality assurance are now better Susceptibility Testing (EUCAST).b However, the extent standardized worldwide than in 2001, differences still of adherence to these recommendations varies, i n exist. Different principles are used for surveillance, particular in resource-limited settings.34 There are inherent and no single method is applicable in all settings differences between the two sets of recommendations, and throughout the world. Some of these issues are such as the criteria for interpreting the test results. discussed in more detail below.
Monitoring antimicrobial use AMR surveillance Data need to be collected from multiple sources At present, surveillance data are usually by-products and using different methods because consumption of routine diagnostic activities. Laboratory reports of antimicrobials occurs in different types of health originating from routine patient care activities are fi led settings. Surveillance of total use and use patterns in a database for local analysis and surveillance. If the is currently carried out through review of prescription data are based on uniform standard methods of testing, logs, pharmacy databases, drug purchases or sales, or they could be merged with those of other health-care medicines inventories. However, in many countries these facilities for combined analyses, to support multi- data may either not be available at all (not recorded or purpose, multi-centre, multi-level AMR surveillance. not collected) or not obtainable (owned by third parties However, data drawn from routine diagnostic testing such as manufacturers or private pharmacies which have some disadvantages. For example, laboratory have no legal obligation to divulge the information to data are often diffi cult to interpret if not linked to public health authorities). Sales without prescriptions clinical data. Nosocomial pathogens (transmitted or records, and issues such as inability to ascertain within hospitals) may be over-represented if much of whether the patient actually took the medicines that the testing is carried out on inpatients who are more were dispensed, add to the complexity. likely to develop health care-associated infections than patients outside the hospital. These factors may lead Antimicrobial consumption is reported in many ways – to higher apparent rates of AMR, especially for some for example, programmes may report total quantity of bacterial species, when data are drawn from routine use in grams or fi nancial costs, or using standardized diagnostic laboratory tests. Several approaches can measures such as "defi ned daily doses" (DDDs),35 or be used to minimize such biases, but how they are percentage of patients receiving antibiotics. Other applied may vary. alternative measures are also described.36,37 Using CHAPTER 2
http://www.clsi.org/ b http://www.eucast.org/ SURVEILLANCE TO TRACK ANTIMICROBIAL USE AND RESISTANCE
appropriate measurements is important to reach patients in health-care facilities or at dispensing places; appropriate conclusions. For instance, using the focus group discussions; and using "simulated patients". number of consumed packages/inhabitants as a Facilities with electronic medical records could capture measure of antibiotic consumption, does not take into all antimicrobial dispensing records for analysis and consideration possible changes in the number of DDD even link them to microbiology reports. Each approach per package, which may occur over time, and may provides complementary information, and the decision lead to wrong conclusions. to implement one or more depends on policy, needs, and the available resources and expertise.
Total use data also have limitations, mostly as they provide little insight into why antimicrobials are used, Another option is to use point prevalence survey and therefore whether or not their use is appropriate. A formats described by the European Surveillance of number of different strategies may need to be used to Antimicrobial Consumption (ESAC) initiative (Box elucidate why a patient seeks an antimicrobial and why 2.1). This methodology can be applied to any type a provider prescribes a certain antimicrobial, such as: of health-care institution including long-term care detailed, structured questionnaires for patients, health- facilities. Repeated surveys at specifi c time intervals care workers, and/or dispensers; exit interviews with could be used to follow prescribing trends. Box 2.1 ESAC point prevalence survey of antimicrobial use in hospitals
The core action of ESAC* since its establishment has been the collection of quantitative statistics on total antimicrobial use in health care at the national level. This has enabled broad comparisons of total usage of antimicrobials across Europe, but does not directly provide insights into why antimicrobials were prescribed and whether or not their usage was appropriate.
To better understand antimicrobial use practices in hospitals, ESAC coordinated three point prevalence surveys (PPSs) in which a total of 31 European countries involving over 200 hospitals participated. In addition, two PPSs were carried out in nursing homes (>300 institutions). Each participating institution conducted a "snapshot survey" of use. For each patient on antimicrobials, data were collected on the indication for use and the patient's diagnosis. Findings from such surveys confi rm the usability of this method in a large number of facilities at national and regional levels and have permitted hospital doctors and national authorities to develop interventions targeting inappropriate use and to assess their effectiveness. Quantifi able outcome measures and targets for quality improvement are: duration of surgical prophylaxis; proportion of oral versus parenteral use; treatment of some specifi c diseases (e.g. community-acquired pneumonia) excluding certain antibiotics (e.g. quinolones); reason for prescription in notes; and compliance with guidelines.38 * ESAC moved to ECDC in 2011 and is now named ESAC-Net There are important differences between the factors complete and accessible. Data collected locally which infl uence antibiotic use in hospitals and in could potentially feed into national databases that ambulatory care settings and so surveillance of drug can be used to track consumption nationwide and to use in both of these patient populations is useful for participate in regional and global surveillance. the selection of suitable interventions. For example, Canada uses information on prescriptions dispensed WHO recommends the use of simple indicators to by retail pharmacies to understand use in ambulatory follow trends in antimicrobial use, particularly in care,39 while ESAC has attempted to develop quality settings where there is no systematic surveillance, indicators for outpatient antibiotic use.40 However, and provides guidance for local agencies in the starting with surveillance of hospital-based use may identifi cation of defi ciencies and priority areas for be easier logistically, as hospital data are often more intervention.41,42 Indicators which allow identifi cation CHAPTER 2
of use patterns include the percentages of encounters use in other parts of the world could be obtained from with an antibiotic prescribed, pneumonia cases local surveys, and also from other sources such as treated with recommended antibiotics, cases of upper market sources tracking sales. Some examples are respiratory tract infections treated with antibiotics, provided below to illustrate the range and variety of cases of diarrhoea treated with antibiotics, and current data collection efforts.
patients receiving antibiotics without prescription. Local and national surveys using these indicators could prove valuable for monitoring changes over time AMR surveillancein response to the measures taken.43,44 Existing surveillance networks vary widely in scope. They range from networks covering sentinel 3.2 Examples of surveillance of use and laboratories to those that include all patient-care resistance worldwide laboratories. They may be selective for only some bacteria or specimen types, or comprehensive AMR surveillance in the public sector is carried covering all species and specimen types (Table 2.1).45 out in many countries, often linked to multi-centre, Outputs can also vary from summaries to full reports on national or even international networks. Surveillance all isolates. The networking may be local, multi-centre, of antimicrobial use and related networks are present national or international. Features of two international mainly in high-income countries. However, data on surveillance systems are compared in Box 2.2.
Table 2.1 Pathogen-specifi c surveillance networks
Global Foodborne Infections Network (GFN) for foodborne pathogens, e.g. Salmonella and Campylobacter spp Gonococcal Antimicrobial Surveillance Programme (functional in three WHO regions: Western Pacifi c, South-East Asia and the Americas) Sistema Regional de Vacunas (SIREVA) for vaccine-preventable pathogens including S. pneumoniae, H. infl uenzae, and N. meningitidis Laboratory Centre for Disease Control, Canada (LCDC) and PAHO collaborative project on Salmonella and Shigella spp, and Vibrio cholerae Source: Adapted from 45 with permission from Elsevier.
Box 2.2 Description of two International AMR surveillance networks: PAHO and EARS-Net
Over a decade the Pan American Health Organization (PAHO) and the European Antimicrobial Resistance Surveillance Network (EARS-Net), formerly EARSS, have each built an international quality-assured public sector hospital-based AMR surveillance network. The PAHO surveillance system analyses susceptibility data from all isolates at country level and then collates the data from participating countries.c EARS-Net analyses at a central level the susceptibility data from a growing list of species isolated from blood and cerebrospinal fl uid. PAHO data inform and support locally relevant interventions to contain AMR, while EARS-Net benchmarks national AMR and correlates it with antimicrobial consumption at the European level.d CHAPTER 2
A number of regional surveillance initiatives have been are coordinated by WHO regional offi ces, others are launched in all WHO Regions (Table 2.2).45 While some led by other regional agencies.
Table 2.2 AMR Surveillance networks for common bacterial pathogens in the WHO Regions
Years of activity
Organisms under
Integrated Disease Surveillance and 8 epidemic-prone Red Latinoamericana de Vigilancia a las Resistencias Antimicrobianas (Re- Antimicrobial Resistance in the Medi- terranean (ARMed) Regional Programme for Surveillance European Antimicrobial Resistance Surveillance (EARSS) European Antimicrobial Resistance Surveillance Network (EARS-Net) National and regional surveillance Regional Programme for Surveillance AFR: African Region; AMR: Region of the Americas; EMR: Eastern Mediterranean Region; EUR: European Region; SEAR: South-East Asia Region; WPR: Western Pacifi c Region; CSF: Cerebrospinal fl uid.
Source: Adapted from 45 with permission from Elsevier.
In addition to the AMR data from routine clinical contributed data on important resistant bacteria. laboratories, reference laboratories produce more Integrating such data generates additional information detailed information on selected isolates. Some of and could also help in cross-validating clinical these are public health laboratories (e.g. for serotyping laboratory results. salmonella isolates). Privately funded initiatives such as the Asian Network of Surveillance of Resistant Other initiatives such as the International Surveillance Pathogens (ANSORP), the SENTRY Antimicrobial of Reservoirs of Antibiotic Resistance (ISRAR), Surveillance and the Meropenem Yearly Susceptibility coordinated by the Alliance for the Prudent Use of Test Information Collection (MYSTIC) have also Antibiotics (APUA), collect and analyse environmental CHAPTER 2
and veterinary commensal organisms which may National statistics on use in hospital and community serve as reservoirs for AMR. APUA Global Chapters, settings from 34 European countries are collected together with local laboratories in India, the Republic by ESAC, currently coordinated by ECDC (Box 2.5). of Korea, Turkey, Thailand, Viet Nam, Bangladesh, ESAC also runs a web-based point prevalence survey Georgia, and Uganda, collect bacteria from soil, water, consisting of annual snapshots of antimicrobial use for and animals, and carry out preliminary characterization both treatment and prophylaxis in hospitals.46-48 and resistance analyses.e The WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance To understand usage patterns in developing and (AGISAR) attempts to integrate surveillance of transitional countries, WHO has created a database antimicrobial resistance in food-producing animals from 679 studies in 97 countries published between worldwidef (see also Chapter 4).
1990 and 2006 on the use of medicines in primary care.30,49 Inappropriate antibiotic use for upper Monitoring antimicrobial use respiratory infections and diarrhoea over a period of time, as understood from these data, is shown in Figure In many countries data on antimicrobial use in patients 2.1. Such data provide information on antimicrobial seeking care in the public sector may be readily available. use and indicate options for intervention.
Figure 2.1 Antibiotic use for upper respiratory infections and diarrhoea in low- and middle-
income countries (1980s - 2006)
Treatment of acute diarrhoea
% diarrhoea cases % diarrhoea cases treated with antibiotics % diarrhoea cases treated with antidiarrhoeals Treatment of acute respiratory infection
% pneumonia cases treated % upper respiratory tract infections with recommended antibiotics treated with antibiotics % ARI cases treated with cough syrups ARI: Acute Respiratory Infection; ORS: Oral Rehydration Solution.
Source: Reproduced from 49 with permission from World Health Organization.
Sales data collated from different sources are also different countries in the same region over a period of used to assess total antibiotic use (Box 2.3). This time, and for informing policies. type of data has proved valuable in comparing use in Box 2.3 Antimicrobial use data based on sales
(1) Data from retail sales in Latin American countries
Retail sales data from the private sector on oral and injectable antibiotics between 1997 and 2007 were analysed for Argentina, Brazil, Chile, Colombia, Mexico, Peru, Uruguay, and Venezuela. The kilogram sales of each antibiotic were converted into DDD per 1000 inhabitants per day, with the results expressed using 1997 as the reference point. Total antimicrobial use increased in Peru, Venezuela, Uruguay, and Brazil, with the largest relative increases observed in Peru and Venezuela. In Mexico and Colombia the use of some classes of antibiotics decreased, and Argentina and Chile showed major reductions in the use of some antibiotics during the middle of the study period. However, in all countries the use of quinolones increased and there were increases in the use of other categories of antibiotics as well, suggesting a shift in use patterns. The data collected provide a relevant evidence base for policy decisions to improve the use of antimicrobials.50 (2) Use in India based on Intercontinental Marketing Services (IMS) data
IMS data show that in general, expenditure increased in India between 2005 and 2009 for all classes of antimicrobials studied (Figure 2.2).32 Figure 2.2 Antimicrobial use in India (2005 - 2009)
Antibiotic Sales (10 000s of INR)
INR: Indian RupeeSource: Reproduced from 32 with permission from The Center for Disease Dynamics, Economics & Policy.
Many health-care facilities, especially in high-income new initiatives which address how best these routinely countries, routinely collect and archive individual collected data can be used for understanding and patients' illness-related data electronically, for improving antimicrobial use (Box 2.4). purposes such as recording and accounting. There are Box 2.4 Detecting and eliminating bacteria using information technology – DebugIT
The DebugIT project, which receives funding from the European Union's Seventh Framework Programme, aims to
address the challenges of improving antibiotic therapy by making use of data that are already routinely collected and
stored electronically in clinical information systems in hospitals and primary care clinics. Such data sets usually include
information on patients and their illnesses, pathogens and drug treatments. The aim is to acquire new knowledge through
advanced data mining, and to use this knowledge for better decision-making on the management of infectious diseasesg.
There are also reports which identify obvious overuse of been shown to be feasible and benefi cial. Combined antimicrobials causing a signifi cant fi nancial burden for surveillance is contributing to a better understanding of strained public health budgets, and document the positive the relationship between consumption and resistance impact of regulatory and educational campaigns.51,52 and supports important policy changes which modify AMR trends. An initiative of this type involving several countries is described in Box 2.5.
Combined surveillance of use and resistance In countries with functioning health systems, combined surveillance of antibiotic use and resistance has Box 2.5 Surveillance of antimicrobial use and resistance in Europe
Signifi cant improvements in some aspects of antimicrobial use and resistance have been made in several European countries over the past decade. An important element contributing to these achievements has been the collaborative efforts of two EU-funded projects currently managed by ECDC.h European Surveillance of Antimicrobial Consumption Network (ESAC-Net, formerly European Surveillance of Antimicrobial Use, ESAC): ESAC-Net collects data from national statistics on antimicrobial consumption in hospital and community settings from 34 European countries. ESAC-Net has developed and validated protocols for quantitative measurement and qualitative description of antimicrobial use patterns, and has been a forceful advocate with national authorities and the European Commission to improve the use of antimicrobials in Europei.
European Antimicrobial Resistance Surveillance Network (EARS-Net, formerly European Antimicrobial Resistance Surveillance System, EARSS): EARS-Net collects data on seven pathogens of public health importance from blood and cerebrospinal fl uid samples from over 1400 health-care facilities in over 30 European countriesj. ESAC-Net and EARS-Net fi ndings are highlighted each year by the ECDC on European Antibiotic Awareness Day (November 18), an annual campaign targeting national authorities, health-care providers, the media, and the general public to raise awareness of the threat posed by the misuse of antimicrobials and the challenges posed by resistant organismsk.
The southern and eastern Mediterranean antibiotic which could provide evidence in favour of measures resistance and use project (ARMed) was able to gather to reduce the use of antibiotics. data on antimicrobial use, but only from a few hospitals Community-based integrated surveillance of and not at all from community settings.53 However, an resistance and use is limited, especially from low- overall high level of consumption was found in the and middle-income countries, and mostly available region when compared to southern Europe, fi ndings from pilot research (Box 2.6).
Box 2.6 Community-based surveillance of resistance and use: pilot projects
Community-based pilot surveillance projects for antimicrobial resistance and use undertaken in South Africa and India showed that it is feasible to set up such systems and to collect useful data for deciding local policies and targeted interventions. AMR surveillance using E. coli isolated from outpatients was carried out in laboratories attached to large hospitals. Data on antibiotic use were collected from several types of facilities including clinics and pharmacies in the public and private sectors, in defi ned geographical areas. A high level of fl uoroquinolone use for many different infections in the community was seen in India, and high fl uoroquinolone resistance rates were found among E. coli isolates.
Lessons learnt from these projects could inform surveillance initiatives in resource-constrained settings. Issues related to design, methodology, data management, logistics and fi nancing need to be addressed in order to create sustainable surveillance systems and ensure that the data are comparable across sites.34 3.3 Laboratory capacity building for AMR The quality of laboratory test results is without doubt critical to the value of surveillance. This requires that laboratories have in place ongoing quality assurance Laboratory capacity and information technology programmes, such as internal quality control practices at facility levels are imperative for the generation, and participation in external quality assurance (EQA) collation, analysis and sharing of surveillance data.54 programmes. Many countries already have such Competent laboratories are still lacking, particularly systems in operation. Several quality assurance in low-income countries.2 A WHO worldwide survey systems have been set up together with surveillance in 2007 found that overall only 61% of countries that initiatives in the WHO Regions (Table 2.3), some of responded have national level reference laboratories which serve more than one Region.45 for AMR surveillance (55% in low-income, 55% in middle-income, and 84% in high-income countries).43 CHAPTER 2
Table 2.3 Regional external quality assurance programmes for common bacterial pathogens
AFR: External Quality Assurance Programme – WHO Lyon and National Institute for Communicable Diseases, South Africa AMR: Red Latinoamericana de Vigilancia a las Resistencias Antimicrobianas (ReLAVRA) – PAHO and Malbrán Insti-tute, Argentina EMR: External Quality Assurance Programme – WHO Lyon and Bacteriology Central Laboratory, Oman Antimicrobial Resistance in the Mediterranean (ARMed) – National External Quality Assurance Scheme (NEQAS), United Kingdom EUR: National External Quality Assurance Scheme (NEQAS) in collaboration with EARSS/EARS-Net WPR: Royal College of Pathologists of Australia Quality Assurance ProgramsRegional External Quality Assessment Programme – Pacifi c Paramedical Training Center, New Zealand AFR: African Region; AMR: Region of the Americas; EMR: Eastern Mediterranean Region; EUR: European Region; WPR: Western Pacifi c Region.
Source: Adapted from 45 with permission from Elsevier.
Experiences from the regions show that quality surveillance, bring the added benefi t of improving assurance and oversight systems, set up for laboratory functioning as a whole (Box 2.7).
Box 2.7 Regional AMR surveillance network improves quality of testing: PAHO
For over a decade AMRO/PAHO* has developed networks of AMR surveillance laboratories in member countries. The activities include cycles of data entry and inspection, problem detection and notifi cation, profi ciency testing, collegial review and problem solving at annual working meetings, laboratory inspections and recurring reviews to improve test quality as a by-product of the regional AMR surveillance network. The process follows the classic management methods of continuous quality improvement, building on collegiate engagement, interaction and support for widely dispersed laboratory workers.3 *AMRO/PAHO: WHO Regional Offi ce of the Americas/Pan American Health Organization To facilitate analysis of antimicrobial susceptibility use free of charge and is currently used in over 100 test results, WHONETl, a Windows-based database countries to support local, national, and regional software, has been developed and improved surveillance activities in over 1 500 clinical, public since 1989 by the WHO Collaborating Centre for health, veterinary, and food laboratories (Table 2.4). Surveillance of AMR at the Brigham and Women's Box 2.8 explains the application of WHONET to Hospital in Boston, USA. WHONET is available for understand MRSA trends.
Table 2.4 WHONET software use by WHO Region
Number of
WHO Regions
Eastern Mediterranean Region Region of the Americas South-East Asia Region Western Pacifi c Region Source: WHONET. Reproduced with permission.
Users can be linked using web-based programmes. results. The integration of the free outbreak detection Advances in technologies make it possible to improve software SaTScanm into WHONET has enabled user-friendliness and functions such as automatic enhanced detection of both community and hospital-interpretation of data and alerts. Analysed electronic based outbreaks.55,56 Other more sophisticated reports can be issued rapidly, based on entered patient software suitable for these purposes is also available.
Box 2.8 Monitoring MRSA in Malaysia
The Malaysian National Surveillance of Antibiotic Resistance programme was initiated in 1990. Results from routine antibiotic susceptibility tests are collected from 16 major hospitals and analysed using WHONET software. The MRSA rates decreased from 29.5% in 2003 to 22% in 2010.
Figure 2.3 MRSA rates in 16 Malaysian hospitals (2003 - 2010)
Source: Institute for Medical Research, Ministry of Health, Malaysia. Unpublished data, personal communication, 2011. Reproduced with permission.
m www.satscan.org CHAPTER 2
Laboratory capacity strengthening and networking is Laboratory capacity building is also being addressed also being addressed in relation to specifi c infections. in surveillance for foodborne and other enteric The WHO global laboratory networks for MDR/XDR- infections. The Global Foodborne Infections Network TB surveillance and HIV drug resistance surveillance (GFN) is strengthening the capacities of national are successful examples. The Global Laboratory and regional laboratories in the surveillance of major Initiative (GLI) is a network of international partners foodborne pathogens and antimicrobial resistance. dedicated to accelerating and expanding access to Several countries contribute funding and experts for quality-assured laboratory services in response to the the training courses.odiagnostic challenges of TB, notably HIV-associated Some countries with routine surveillance capacities and drug-resistant TB. The GLI provides a focus on TB have also started exploring the use of molecular within the framework of a multi-faceted yet integrated technologies to increase the value of the information approach to laboratory capacity strengthening.n obtained (Box 2.9). Box 2.9 Including molecular testing in surveillance: country examples
Greece has an AMR surveillance networkp which analyses test results on isolates from 40 hospitals, fi les the analysis results on a website and provides results for inclusion in the EARS-Net. It also uses the data to select isolates for molecular studies to identify new problems and targets for intervention (e.g. detection of a hospital cluster of the fi rst Proteus mirabilis isolates to carry the VIM-1 metallo-beta-lactamase).57 Argentina has an AMR surveillance network which analyses test results on isolates from 70 hospitals, sends annual analysis summaries for inclusion in the AMRO/PAHO AMR surveillance reports and has begun to explore detailed collaborative analyses of merged fi les with several other PAHO member countries. An associated laboratory collects selected isolates from the network for additional molecular testing, e.g. of extended-spectrum beta-lactamases.
The Latin American Antimicrobial Resistance Surveillance Network developed horizontal collaborative procedures to ensure support on the identifi cation of emerging resistant mechanisms in Latin America and the Caribbean. It confi rmed the fi rst New Delhi metallo-beta-lactamase (NDM) in Latin America, isolated in a Klebsiella pneumoniae strain. The Staphylococcus Reference Laboratory (SRL) working group is the largest initiative to date.58 It traces clones of S. aureus (MSSA and MRSA) of particular public health importance on a continental scale in Europe. Initiated by EARSS participants, it includes reference and expert laboratories which collect and type isolates from over 400 hospitals in 28 European countries. Results are made available through an interactive geo-toolq.
3.4 Surveillance data used at national and Information is made easily accessible by several international levels agencies which provide frequently updated visuals of AMR rates in defi ned geographic areas and/or Surveillance in itself does not reduce AMR, but the updated reports (e.g. EARS-Net). Some of the most data collected can be used to track the emergence advanced interactive websites provide data in real and spread of resistant strains, promote awareness, time to raise awareness, for advocacy and to stimulate and most importantly provide "information for action" actions (Figure 2.4).
at hospital, national and international levels to reduce or to promote appropriate antimicrobial use. CHAPTER 2
Figure 2.4 Examples of distribution of some AMR pathogens in geographically defi ned areas
The maps at this site depict frequently updated rates of different AMR pathogens over time.
Source: The Center for Disease Dynamics, Economics & Policyr. Accessed 9 January 2012. Reproduced with permission.
AMR data has been used in many countries to assess can also be assessed from such data. Several countries the current situation and to detect trends. in Europe received political and other necessary support to initiate large-scale campaigns to reduce the use of Data on the use of antimicrobials have stimulated national antibiotics and the spread of bacterial pathogens based on level discussions, advocacy and successful actions to the evidence provided by surveillance data. The example improve use (Figure 2.5).59 The impact of interventions of how France turned the tide is detailed in Chapter 3.
Figure 2.5 Total antibiotic use in ambulatory care in 32 countries in 2009
The use of antibiotics in ambulatory care, i.e. outside the hospital, is expressed in defi ned daily doses per 1000 inhabitants per day (DID).
Source: Reproduced and adapted from 59 s with permission from ESAC. CHAPTER 2
Data from integrated surveillance have been used Austria, for example, increasing use of fl uoroquinolones effectively to demonstrate associations between in ambulatory care was accompanied by an increase in antibiotic use and AMR and to infl uence policy. Data resistance to this class of antibiotic, from 7% in 2001 to showing increasing use and increasing resistance exist 25.5% in 2007, among invasive E. coli isolates.60 Total from several high-income countries, and these fi ndings antibiotic use and AMR in a target bacterium in different have stimulated actions to reduce the use of antibiotics. In countries are shown in Figure 2.6.61 Figure 2.6 Antibiotic use and AMR from 1990–2000 in selected countries
S. pneumoniae (%)
Total antibiotic use (DDD/1000 population/day)
DDD: Defi ned Daily Doses Total antibiotic use in outpatients versus prevalence of penicillin-nonsusceptible Streptococcus pneumoniae in 20 industrialized countries. Source: Reproduced from 61 with permission.
Surveillance data have also shown that the impact involved in reversing resistance once it has become of reducing antibiotic use on reduction of resistance established. rates is complex, highlighting the diffi culties CHAPTER 2
Figure 2.7 illustrates that decreasing the use of antibiotics that a nationwide restriction on quinolone use led to an has not always led to a decrease in resistance.62 As a immediate increase in the susceptibility rates of urine more encouraging example, data from Israel showed isolates of E. coli to quinolones. Figure 2.7 Effect of reductions in antibiotic use on the prevalence of AMR in the community
Prescribing reduction Change in resistance Each pair of columns indicates the percentage changes in the prescribing of antimicrobials and the corresponding effect on resistance prevalence. Finland – macrolide use and macrolide resistance, S. pyogenes; Iceland – overall antimicrobial prescribing in children and penicillin resistance, S. pneumoniae; Sweden – trimethoprim use and trimethoprim resistance, E. coli; UK – sulphonamide use and sulphonamide resistance, E. coli; Israel – quinolone use and quinolone resistance, E. coli. Source: Reproduced from 62 with permission from Oxford University Press.
From the mixed experiences documented, a At local health-care facility levels, where surveillance "successful" intervention may be refl ected only in data are used to guide treatment decisions for stable rates of resistance or a diffi cult-to-quantify individual patients, such data have also triggered "decrease in the rate of increase in resistance". actions to improve the use of antibiotics, infection Such fi ndings have stimulated research into many prevention and control, and research. different aspects to gain better understanding of the relationship between antibiotic use and AMR.
4. Harm to patients and society due to AMR
The burden due to AMR infections in hospitals and direct cost of hospitalization for resistant infections in communities may well vary between countries as compared to susceptible infections to be $9–$14 and regions but data collected systematically million. Screening patients on admission to detect to demonstrate this are scarce. Using hospital- carriers of resistant organisms adds another $10 based data collected by the European Surveillance million. To place carriers under precautions to prevent network, attributable mortality and extra costs were spread to other patients adds approximately another calculated using earlier published relative risks. $16 million.9 There is limited information on the impact These calculations indicate that the excess death toll of AMR on community-acquired infections. The impact from selected resistant bacterial hospital infections on hospital and community infections is likely to be exceeded 25 000 per year in that region and that the greater in lower and middle-income countries.
extra health-care costs and productivity losses were at least €1.5 billion per year.8 In outpatients in the Pharmacovigilance could provide an opportunity USA, resistant infections are implicated in more than to capture data on the impact of AMR on individual 63 000 deaths per year.63 Canada estimates excess patients (Box 2.10).
Box 2.10 Pharmacovigilance to detect treatment failure due to AMR
WHO defi nes pharmacovigilance as "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem." The WHO Collaborating Centre for International Drug Monitoring (Uppsala Monitoring Centre, UMC) conducted a pilot study on behalf of the Seventh Framework Programme of the European Commission, to investigate the feasibility of identifying treatment failure due to AMR by using individual case safety reports (ICSRs). In the WHO global ICSR database, VigiBase, terms related to lack of expected therapeutic effect were the ninth most frequently reported adverse reaction. A total of 138 400 such reports were screened for local patterns of disproportionately greater reporting of antimicrobial treatment failure and/or resistance. Observed-to-expected ratios for the number of reports on treatment failure for different antimicrobial active ingredients were computed across a range of database subsets, specifi cally looking for clusters related to country and/or time periods. Such outlying reporting patterns were ranked and the top fi ve investigated in greater detail.
The top outlying reporting patterns refl ected localized hospital outbreaks of AMR infections including one with an index case of multi-resistant Pseudomonas in an outpatient. For two of the case clusters it was stated that the antimicrobial in question was not of poor quality, whereas no such assurance was provided for the other three temporal clusters. More detailed investigation is required to exclude the possibility of substandard/counterfeit products.
This pilot study demonstrates a potential global approach for the detection of impact of AMR, and for detecting possible substandard/counterfeit products (WHO Collaborating Centre for International Drug Monitoring (Uppsala Monitoring Centre, UMC) unpublished data, personal communication, 2011). Since there are many different antibiotics to which information, using a "basket" of resistance and many different pathogens may develop resistance, it is consumption data for different antibiotics. The data on not easy to express the magnitude of AMR in a readily resistance are weighted according to the intensity of comprehensible manner. The concept of a "Drug use for each antibiotic to produce indices that indicate Resistance Index" has recently been suggested as a the magnitude of the resistance problem as a whole CHAPTER 2
means of communicating this complex relationship. and capture trends across time and space.64 The Drug Resistance Index provides aggregate SURVEILLANCE TO TRACK ANTIMICROBIAL USE AND RESISTANCE
5. Gaps and challenges
Surveillance of AMR has advanced considerably diagnostics and development of rapid diagnostic tests
in the past decades, but is still far from fulfi lling the adapted for resource-limited settings would improve
goal of good quality global coverage. For existing surveillance as well as the care of individual patients.
AMR surveillance networks, two factors seem to have
contributed greatly to their success: developments Gaps in data management and networking
in computerized information technology which have capabilities: Sustainable networks at subnational or
reduced the effort involved in participation, and national level are absent in many parts of the world.
support from public health and other leaders which Where networks exist, the capacity to collect, manage
facilitates participation. Some of the continuing gaps and utilize data appropriately may be inadequate.
and challenges are as follows:
Rapid advances in informatics make it necessary to evaluate and continually enhance existing systems. Lack of common defi
nitions for surveillance:
Globally accepted defi nitions for multi-drug resistance Methodological obstacles: Establishing reliable
(MDR) in common bacterial infections, like those that surveillance systems for antimicrobial use is even
exist for TB, may enhance the ability to share, compare more challenging than setting up AMR surveillance
and evaluate resistance information.
networks. Differences that exist in health-seeking behaviour, health-care delivery, availability of records, Lack of geographically representative data: Only a
drug policies and many other differences, make this tiny fraction of the world's AMR test results are utilized a daunting task in most parts of the world. There for surveillance and those often in ways that yield only is no single applicable method for collecting total a fraction of their potential benefi t. Several parts of consumption data or patterns of use from all facilities, the world still do not have capacity to test for AMR in countries or regions worldwide. Several aspects infecting or potentially infecting bacteria. The resulting related to methodology still need to be resolved before lack of data from vast areas in the world minimizes comparable data from different parts of the world can be the benefi ts from surveillance and precludes accurate collected. As for AMR surveillance, in many countries analysis of trends over time. facility level capacity for data collection, management, analyses, feedback and follow-up actions based on Gaps in laboratory capacity: The WHO 2001 results need to be addressed. In addition, unlike AMR,
Strategy and 2011 World Health Day policy package surveillance of antimicrobial use does not belong within both identify strengthening laboratory capacity as a single clinical specialty, and so is often left to the an essential intervention for AMR surveillance. This self-taught interest of pharmacists, pharmacologists involves improving existing laboratories and adding and other professionals. Formal inclusion in a specifi c new ones and also enhancing the ability of staff to discipline could help in capacity-building.
extract, interpret and distribute information from each
test. Many countries still lack competent laboratories Coordination of surveillance networks: There is also
for diagnostic testing. Establishing sustainable and a growing need for network integration and oversight.
quality-assured laboratories with reliable supply Public health agencies will need to take a more active
chains involves consideration by policy-makers and role in organizing and coordinating multi-centre AMR
managers of many elements such as human resources, surveillance networks and their functions, including
laboratory infrastructure, external quality assessment, data analyses and feedback.65 Integrating surveillance
supply systems, standard protocols, and training.
programmes with antibiotic stewardship programmes at facility and national levels is a logical step towards Gaps in diagnostic testing: Where resources are best use of the data collected. One of the earliest
limited, testing for susceptibility to antimicrobials and most lasting benefi ts of launching a surveillance
competes for scarce funding with provision of initiative could be the impetus that it brings to
treatment, and often the costs are met by the patient capacity-building by participating institutions, quality
as an out-of-pocket payment. Even in high-income improvement, and constructive collaboration among
countries, diagnostic tools are currently not always network partners, as experienced in some of the
optimally used. Support for more routine use of examples described above.
Integration of data from animals: Surveillance Other countries are also gathering similar data, as part should ideally incorporate antibiotic use and AMR in of different initiatives. veterinary practice and animal husbandry (see Chapter 4).66 Countries which have national antimicrobial Lack of data on clinical impact: Although there are consumption and AMR databases in both humans examples of surveillance of AMR and antimicrobial and animals may be able to determine the correlation use, there is very little systematic data collection on between total use and AMR at the national level. The clinical impact, such as treatment failures due to AMR, Danish integrated antimicrobial resistance monitoring and this is a major gap. More efforts are needed to and research programmet is an example where develop methodologies and data collection systems summaries and trends from these two sectors are to understand the harm suffered by patients and produced as one easily accessible document. The society as a consequence of AMR.
Canadian Integrated Programme for Antimicrobial Resistance Surveillance (CIPARS) is another example.u CHAPTER 2
Chapter 3.
Measures to ensure better use of antibiotics Chapter 3.
Measures to ensure better use of antibiotics Much of the antimicrobial resistance problem stems be abolished, there would be only limited selective from the misuse of antibiotics, particularly excessive pressure on bacteria to become resistant. Regulations use. If antibiotics were always prescribed appropriately and practical measures are needed to tackle all of these and only when needed, the treatment correctly issues. Political will and leadership are indispensable followed, never used in agriculture or aquaculture, to put the necessary regulations and measures into and if substandard and counterfeit products could practice. The emergence of resistance to antimicrobials is a improved antibiotic use, reduced use and cost consequence of their use. This relationship is evident both savings, and in some cases an impact on AMR has for individual patients and for populations. While antibiotics also been demonstrable. However, the extent to which are essential to cure some infections, signifi cant misuse interventions are implemented and integrated into occurs in most parts of the world, usually in the form health systems varies greatly across countries.
of unnecessary overuse, which increases the selective pressure on bacteria to develop resistance. At a global level, AMR does not have the level of political commitment that is warranted by the actual Many options for action are available to reduce threat, and priorities and capacities of health systems unnecessary use, but putting the measures into practice differ between countries. Tackling inappropriate is often problematic. Political leadership in countries antibiotic use at national level requires a system-wide is needed, but commitment to addressing the issue approach for which the government has the ultimate through policies and regulations may be diffi cult to responsibility. Regulation is needed to ensure the obtain. How to implement the interventions is often quality of medicines and secure the supply chain, unclear – and while reducing unnecessary overuse, and to control the prescription and dispensing of access to these essential medicines for those who need medicines, but the necessary legal and regulatory them has to be ensured. The 2001 WHO Global Strategy framework appears inadequate in many countries. for Containment of AMR provides a number of specifi c Policy leadership and support for actions at facility recommendations based on a strategy that includes level are needed to improve prescribing and to obtain education, supporting treatment decisions through data to inform local policies. Interventions targeting improved diagnostic services and treatment guidelines, dispensers and other sellers are being tested and encouraging restrictions in prescriptions, instituting implemented, but need to be scaled up. A bottom-up prescription audits and feedback, and implementing process involving communities, patients, and health regulations on quality, dispensing and drug promotion.
professionals could prove useful, with education and awareness-raising to engage all stakeholders. This There are encouraging examples from different parts chapter considers the available measures to improve of the world of action to reduce the excessive use of the use of antimicrobials and the gaps and challenges antimicrobials, with successful outcomes including to be met in applying them worldwide.
1. How rational drug use helps to reduce AMR
Antimicrobial resistance is a consequence of real or perceived patients' expectations, drug antimicrobial use, and there is a clear relation between company promotional efforts, or for personal fi nancial use and emergence of resistance at both the individual gain. Commercial outlets may seek to maximize their and population levels. Consumption of antibiotics income by dispensing medicines without prescriptions. correlates with the frequency of resistance at country Consumers may practice self-medication using level, as evidenced by data from the European unnecessary or ineffective antibiotics, or insuffi cient Surveillance of Antimicrobial Consumption (ESAC-Net) quantities of an appropriate antibiotic. and European Antimicrobial Resistance Surveillance Network (EARS-Net).67 The more antibiotics are used, There are many examples and reasons why misuse, particularly when misused, the greater the selective usually overuse, occurs. Upper respiratory tract pressure placed on bacteria to acquire resistance infections, frequent causes of medical consultations, are genes, hence the need to limit the use of these usually caused by viruses and, therefore, do not require medicines to what is necessary and appropriate.
antibiotics. However, antibiotics are frequently prescribed, for instance accounting for 60% of all antibiotic use Rational use of medicines requires that patients in general practice in Eng land.69 Diarrhoeal diseases, receive medications appropriate to their clinical needs, again usually viral in etiology or self-resolving, are often in doses that meet their own individual requirements incorrectly treated with antibiotics. The self-limitation for an adequate period of time, and at the lowest of a viral infection could then be misinterpreted as the cost to them and their community.68 There are at least effect of medication. Misuse also occurs for prophylaxis, two additional factors that need to be considered in for example the inappropriate and excessive use to relation to the rational use of antibiotics: prevent infections following surgery.70 Apart from lack of knowledge, other reasons for antibiotic misuse include • For an antibiotic to be effective it must be of good fi nancial motivation on the part of prescribers, demand quality, and the bacteria causing the infection by patients for a variety of cultural, social and economic need to be susceptible to it. The rational use of reasons, fear of litigation, lack of unbiased information on antibiotics therefore requires information derived medicines, heavy workload with short consultation times from microbiological susceptibility testing and that preclude making a proper diagnosis, and junior assured quality of the antibiotic being used.
prescribers following the poor example of their senior colleagues.
• The use of antibiotics has consequences for both the individual patient and for society. Individual use Overuse of antibiotics is an enormous public health can lead to selection of antibiotic-resistant bacteria problem, and interventions to deal with it have been which may then infect other members of the developed over the last 30 years. This chapter population, causing infections that may be diffi cult discusses options for action and gaps in relation to treat. Antimicrobials are the only class of today's to WHO recommendations to reduce the misuse of medicines for which obsolescence results from use. antibiotics. Often there is no lack of information on Unfortunately, for the fi rst of these factors there is what to do but guidance is missing on how to put often a lack of timely and locally relevant diagnostic the appropriate measures into practice and how to information, and the second is often ignored because the generate the necessary political commitment for their perceived benefi t to an individual patient is considered implementation. As with climate change and other to outweigh the long-term impact on society.
environmental issues, it has to be understood that the results of interventions today may take years to Irrational use includes over-prescription, under- become evident in society, but that both individual prescription, and prescription and dispensing of and collective efforts are crucial now. Bringing unnecessary antibiotic combinations. Physicians about change involves many actors and many may prescribe too many drugs, expensive drugs considerations, and change will have economic or inappropriate drugs because of fear of treatment implications that need to be incorporated into the failure, lack of knowledge of the local AMR situation, relevant budgets.
2. WHO guidance on rational use to contain AMR
The 2001 WHO Global Strategy for Containment of and implementing regulations on quality, dispensing AMR includes many recommendations to promote and promotion of antimicrobials. Including rational rational use of antimicrobials, providing guidance that use as part of the curriculum for professional courses is still valid today for prescribers, dispensers, hospitals and educating patients on antimicrobial use are also and governments (Appendix 1).1 The strategy includes: recommended. The policy briefs published on World educating prescribers and dispensers on appropriate Health Day 20112 reiterated these important measures use of antimicrobials; supporting treatment decisions for reducing irrational use (Appendix 2) and highlighted through improved diagnostic services and treatment the need for stewardship programmes in hospitals, for guidelines; encouraging restrictions in prescriptions engaging professional and civil societies and patient to a selected range of antimicrobials; instituting organizations, and for taking into consideration the prescription audits and feedback; and establishing local factors that drive irrational use in different settings.
3. The present position regarding these recommendations
Because many diverse factors contribute to irrational the time period studied. The use of medicines in the use – including knowledge, perceptions, attitudes public sector was substantially better than in the and behaviour of policy-makers, prescribers, private sector for the prescribing indicators used and manufacturers, dispensers and consumers – there is also for the treatment of acute respiratory infections. no single or simple solution to the problem. Although Low-income settings reported a higher percentage the AMR burden due to misuse is likely to be immense, of patients treated with an antibiotic, suggesting that global data on its magnitude are very limited. overuse may be occurring.43 Scanty data on the antimicrobial use per capita show extreme variations in use between countries Published reports confi rm several large and small-and within countries (Chapter 2). Most available scale efforts to improve antimicrobial use with good information on irrational use is from the public sector, outcomes, but systematic measures integrated into but irrational use could be even more prevalent in the health systems appear to be limited mainly to high private sector due to stronger economic incentives. income countries. The following sections provide And the roles of informal sectors such as traditional some insights into the promotion of rational use. healers also need to be considered. 3.1 A system-wide perspective to promote rational
A WHO Fact Book summarizing results from studies use
on drug use in primary care reported between 1990
and 2006 included 679 studies conducted in 97 An important reason for the relatively low political
countries.49 Less than 70% of bacterial pneumonia priority accorded to AMR at a global level could be the
cases were treated with an appropriate antibiotic, lack of data on the size of the health and economic
but unnecessary overuse was frequent, particularly burden caused by AMR and on the extent of irrational
for viral infections, as exemplifi ed by the high use worldwide. Although the priorities and capacities
proportions of upper respiratory tract infections and of health systems differ in different parts of the world,
diarrhoea cases treated with antibiotics (Chapter tackling the issue of irrational use is complex and
2). Overall the percentage of patients receiving probably requires a system-wide perspective as
antibiotics remained stable at about 40%–50% over depicted in Figure 3.1.71
Figure 3.1 Health systems perspective and structures infl uencing the use of medicines
Legislation (monitoring and enforcement) Financial incentives Health system infrastructure Pharmaceutical policy Source: Compiled from 71. Actions required at different levels of the health system system and drug supply chains can reduce antibiotic have been detailed by professionals working in this consumption, as results from several countries have area.72 Strategies involving different parts of the health shown (Box 3.1). Box 3.1 France – turning the tide against AMR
In the late 1990s, the spread of antibiotic resistance in France became a major public health concern.73 The situation was serious in both general practice and in hospitals. Rapid spread and hyper-endemic occurrence of MRSA was observed in hospitals. In general practice, the rate of S. pneumoniae strains with reduced susceptibility to penicillin G rose sharply from 5% in 1988 to 48% in 1997. During the year 2000, France had the highest outpatient antibiotic consumption per capita in the European Union.
In 1999, an extensive national consultation to defi ne a coordinated scheme for the control of antibiotic resistance was launched by the Réseau National de Santé Publique. This consultative process involved health professionals in human and animal health from the public and private sectors, with experts in the use and the manufacturing of antibiotics and in resistance control. It resulted in proposals for a range of interventions to be incorporated in a national plan of action to control antibiotic resistance. The plan included surveillance of antibiotic consumption and bacterial resistance in humans and animals, control and prevention of AMR spread, and promotion of research on resistance (Table 3.1). In addition, annual public awareness campaigns on the prudent use of antibiotics, continuing education for health professionals, and promotion of rapid testing for S. pyogenes tonsillitis were introduced. CHAPTER 3
As a result of these measures, the consumption of antibiotics was reduced by 23% between 2002 and 2007. At the same time, a 7-valent protein-conjugate pneumococcal vaccine for young children was introduced in 2002. The general decrease in antibiotic consumption combined with the introduction of the new pneumococcal vaccine resulted in reversing trends in penicillin resistance in S. pneumoniae. Additionally, several data sources confi rm a substantial decrease in incidence and prevalence of MRSA. Data from EARS-Net show a decrease in the proportion of MRSA among S. aureus from blood cultures in France, from 33% in 2001 to 26% in 2007.74 Table 3.1 National plan of action to control antibiotic resistance (Ministry of Health, France)
Type of actions
International, national, Regulations, developing tools * hospital, community b. Sentinel network Regulations, developing tools * Experimental, community National, hospital, community National, hospital, community Educating population, health- a. Distribution / hospital care staff training, developing National, hospitaltools * Educating population, health- b. Distribution / community National, community care staff training, regulations Health-care staff training, c. Good practice / hospitals National, hospital regulations, developing tools* Educating population, health- d. Good practice / community care staff training, regulations, National, communitydeveloping tools * * Developing tools (methods and standardization of monitoring, information systems, prescription guides, diagnosis and
therapeutic tests)
** Observatoire National des Préscriptions et Consommations des Médicaments (National Observatory for Prescriptions
and Medicines Consumption)
*** Medicines Committee
Source: Reproduced and adapted from 73 a with permission.
The French national action plan summarized in Box use of antimicrobials and containment of AMR. This 3.1 provides an example of the range of actions that represents a signifi cant challenge in many countries national governments can undertake to improve the with weak regulatory systems. However, even data use of antibiotics and reduce AMR. from European countries with strong regulatory frameworks illustrate the great diversity between and Functioning regulatory systems are considered within countries with more or less similar disease important prerequisites, necessary to support the patterns, in antibiotic prescribing and sales (Figure application of effective strategies for the appropriate 3.2), suggesting that irrational use is still ongoing.59 Figure 3.2 Outpatient use of selected antibiotics in 2009 in 32 countries
Other antimicrobials for systemic use Sulfonamides and trimethoprim Macrolides, lincosamides and streptogramins Cephalosporins and other beta-lactams DDD per 1000 inhabitants and per day Russian Federation DDD: Defi ned Daily DosesSource: Reproduced and adapted from 59 b with permission. CHAPTER 3
The following sections discuss regulations and other the technical nature of the work is highly specialized measures to facilitate rational prescribing from a and different from that of the MoH. However, in most system-wide perspective.
countries there is representation from the MoH in the governing bodies of the DRA, or the DRA remains under the leadership of the MoH. It is essential to avoid Securing the supply of good quality medicines confl icts of interest in the operations of the DRA , as through regulation well as built-in monitoring mechanisms. Ensuring access to good quality medicines and The sale and use of substandard and counterfeit securing the supply chain from manufacturer to end- drugs are common problems, particularly in low- and user form part of a government's responsibility for middle-income countries, although most countries protecting the health of its people. In many parts of the have legislation that prohibits counterfeit drug world, however, the drug supply chain is inadequately manufacturing and selling.77 While substandard drugs and variably secured because regulations related to can be identifi ed through testing, identifi cation of quality, procurement, storage and sales are either counterfeits is often more diffi cult. lacking or insuffi ciently enforced.
Regulating drug promotion: Drug promotion by the
pharmaceutical industry may infl uence prescribing
Ensuring quality: Drug regulation is a process by
which the pertinent authorities, generally at the national behaviour leading to potential misuse. However,
level, assess medicinal products to ensure that they promotional activities and resulting behaviour by
are marketed only if they are effi cacious, safe and of prescribers are diffi cult to quantify. Interventions that
suffi cient quality, and that the information provided counter this infl uence include government regulation,
with respect to them is reliable and complete.75 free and abundant provision of non-commercial
Effective drug regulation should ensure that illegal therapeutic information to health-care professionals
and substandard manufacturing are detected and and the public, and media exposure of abusive
appropriately sanctioned. In many settings, this will promotion.78 The critical monitoring and regulation of
require quality surveillance of marketed products. drug promotional activities is unfortunately not carried
Poor quality products at the point of sale can be due out effectively in many countries. Internet and social
networking sites have become widely used forums for to problems with manufacturing or with the quality the marketing of pharmaceutical products to individual or integrity of the supply chain. For example, many patients worldwide. This new, virtual market has the heat- and moisture-labile antibiotics may become potential to provide novel opportunities for counterfeit degraded if shipped or warehoused under ambient and substandard drug sellers and is likely to create conditions in tropical countries. Many countries new challenges for regulators.79 Enforcement of ethical already have regulatory frameworks in place to ensure codes of conduct for prescribers is a complementary manufacturing of high quality products. However, measure which also appears to be lacking in many weak supervision, incentives to bypass regulations, countries. corruption, and constrained resources may lead to system failures of varying magnitudes. Improving dispensing: Medicines are generally
categorized as controlled substances, prescription-
In almost all countries, governments are responsible for only or over-the-counter (OTC), with antibiotics establishing national Drug Regulatory Agencies (DRA) grouped in the prescription-only category. which are accountable to both the government and the public.76 A ministry of health (MoH) is likely to be aware of In industrialized countries, the dispensing of the need for a broad public policy related to antibiotics, antimicrobials is mainly based on prescriptions from but responsibility for the pharmaceutical industry may qualifi ed medical professionals. This is diffi cult to be with a ministry handling trade, commerce, industry enforce in many middle- and low-income countries for or national development with objectives which may many reasons, including the need to ensure access to be primarily economic and hence not fully aligned medicines when qualifi ed health workers and dispensers with the health-related objectives of the MoH. There are scarce. Therefore OTC sales of antibiotics are CHAPTER 3
is an increasing trend towards drug regulation through common even when there are regulations mandating the autonomous self-fi nancing bodies, mainly because requirement for valid prescriptions. A recent systematic MEASURES TO ENSURE BETTER USE OF ANTIBIOTICS
review of published literature from 1970 to 2009 on even to procure, store and dispense medicines. OTC non-prescription antimicrobials showed that OTC sales sales may also contribute to promoting unreliable drug occurred worldwide and accounted for 19%–100% of quality and pricing. Experience from Chile shows that a antimicrobial use outside northern Europe and North short-term reduction in antimicrobial use based on the America.80 Many dispensers may not be trained or regulation of sales was not sustainable over the long-equipped to diagnose infections, or in some cases term (Box 3.2), for reasons yet to be fully elucidated.
Box 3.2 Chile – Impact of regulation on "prescription only" sales of antibiotics
In the late 1990s in Chile, indiscriminate use of antibiotics increased the incidence of bacterial resistance which led to the use of more expensive antibiotics in the health-care system.81,82 As a part of "The Action Plan to Assure Rational Antibiotic Use", the Ministry of Health intoduced regulatory measures in September 1999. The principal measures were to restrict sales of antibiotics to prescription only, and establish and enforce supervision by regulatory authorities. In addition, posters and leafl ets about the correct use of these drugs were distributed.
Information on antibiotic sales in private community pharmacies from 1996 to 2002 was obtained from the International Marketing System, an auditing system for pharmacy sales. After the introduction of regulation, there was a reduction in defi ned doses/1000 inhabitants/day for the seven antibiotics monitored. Furthermore, the total sales of oral-use antibiotics decreased by 43% from US$ 45.8 million in 1998 to US$ 26.1 million in 2002. However, these reductions were not sustainable in the long-term. Antimicrobial use has increased since 2002, returning to levels close to the baseline in 1997. Regulatory enforcement prohibiting the sale of certain antibiotics without a prescription has not always been successful in reducing their overall consumption.50 The reasons are often unclear, but these experiences may illustrate the need for other interventions, such as those for improving the knowledge and attitudes of consumers and prescribers, to be implemented together with regulations. Improving access to antibiotics: Although over-
The use of left-over drugs for a variety of indications consumption is a key driver of resistance development, is another type of self-medication which is widely paradoxically the limited access to effective treatment practised, including in industrialized countries. The in many low-income countries is also an important "Self-Medication with Antibiotics and Resistance factor for the emergence of resistant bacteria. Using the Levels in Europe" (SAR) project showed consistent wrong antibiotic when the correct one is not available associations between prescribed antibiotic use and not only means that the infection will not be cured, but self-medication from left-overs.83 Regional differences that selection pressure for resistance is unnecessarily were identifi ed, with self-medication higher in eastern applied. Exposing bacteria to drug levels lower than and southern Europe compared to northern and that required to kill them also promotes resistance. western Europe.84 The use of ineffective drugs, inadequate dosing, or no treatment at all also facilitate the spread of pathogens including those with AMR. Facilitating appropriate choice of treatment The availability of, and access to, antiretroviral, Antimicrobial use and AMR surveillance (Chapter 2) antimalarial and anti-TB drugs have in part been provide local data to guide decisions on treatment addressed by initiatives such as the Global Fund for choices. Maintaining an updated essential medicines AIDS, Tuberculosis and Malaria, but there is no similar list and implementing standard treatment guidelines funding or distribution mechanism to cater for the informed by local data should encourage better corresponding needs for effective antibiotics against antimicrobial use and hence improved patient the broad range of common bacterial infections in outcomes. WHO published the fi rst essential drugs list developing countries, or to contain AMR. in 1977, on the principle that some medicines are more CHAPTER 3
useful than others and that essential medicines were in support of these strategies are lacking, effective often inaccessible to many populations. Since then, antimicrobial stewardship will involve a comprehensive the Essential Medicines List (EML) has been updated programme incorporating multiple strategies and regularly and expanded to include new developments. collaboration among various specialties within a given The WHO model EML is to be adapted by countries to health-care institution.85,86 Recent data confi rm that take account of local situations including patterns of such programmes increase appropriate antibiotic antimicrobial susceptibility and the costs of medicines. prescribing, reduce pathogen resistance and improve clinical outcomes of community-acquired pneumonia Antimicrobial stewardship programmes aim to managed within hospitals.87 promote appropriate use of antimicrobials – right choice, duration, dose, and route of administration. A series of measures taken by Australia to promote Several strategies, including prescriber education, rational drug use, including a national EML and formulary restriction, prior approval, streamlining, therapeutic guidelines, are outlined as an example in antibiotic cycling, and computer-assisted programmes Box 3.3. have been proposed. Although rigorous clinical data CHAPTER 3
Box 3.3 Low levels of fl uoroquinolone resistance in Australia
An integrated package of measures to improve antimicrobial use is enforced in Australia. The impact of interventions to guide prudent use is measured using surveillance data in this example. The frequently updated essential drug list and national guidelines on the treatment of most infections and on prophylaxis, aim to guide antimicrobial use within both hospital and community settings. Indications for the use of fl uoroquinolones are limited, and community use is controlled by the Pharmaceutical Benefi t Scheme. Antimicrobial stewardship is implemented as an initiative under the Australian Commission on Safety and Quality in Health Care. In addition, the National Prescribing Service regularly conducts campaigns to reduce unnecessary antibiotic use.
Compared to other countries with existing rational use programmes and low usage of antibiotics, Australia has a higher use of antimicrobials in general but lesser use of fl uoroquinolones, as evidenced by data from the National Antimicrobial Utilization Surveillance Program (NAUSP) annual report 2009–2010 (Figure 3.3). Fluoroquinolone resistance among Gram-negative bacilli remains below 5%, according to the Australian Group on Antimicrobial Resistance 2006 surveillance report, which is lower than resistance rates found in most other countries including those with generally low AMR rates.88 Australia also implements interventions to reduce antibiotic use in animal husbandry and has regulations in place to restrict the use of fl uoroquinolones in this sector.
Figure 3.3 Antibiotic use in Australia (2009–2010) compared to European countries with low use
Imidazole derivatives Fluoroquinolones Aminoglycosides Penicillin -lactamase inhib combs DDDs /1000 OBDs
-lactamase resistant penicillins -lactamase sensitive penicillins NETHMAP SWEDRES
Extended spectrum penicillins NAUSP 2009/2010 includes Australian data fr
P 2009/2010 includes Australian data om July 2009 to June 2010,
from July 2009 to June 2010 DANMAP 2009 rates r
P 2009 rates epr
esent 2009 usage, epresent 2009 usage NETHMAP
2010 rates represent 2008 usage, SWEDRES 2009 rates use numerator data from 2009 and denominator data from 2008.
* Others includes lipopeptides, monobactams, methenamine, nitrofurans, oxazolidinones, polymyxins, rifamycins, short-acting
sulphonamides, streptogramins, steroids, sulphonamide/trimethoprim combinations, trimethoprim. DDD: Defi ned Daily
Doses; OBD: Occupied Bed Day.
Source: Reproduced from 88 with permission.
A number of developing countries have also launched communities and local health services, working hand- coordinated programmes to improve antimicrobial in-hand with a top-down approach providing policy use. The "Antimicrobial Smart Use" project in Thailand, support (Box 3.4).89 for example, is a bottom-up approach, engaging Box 3.4 The Antibiotic Smart Use programme in Thailand
The Antibiotic Smart Use programme aims to improve prescribing of antibiotics in Thailand by targeting both prescribers and patients. Scale up is taking place in phases and there are plans to expand the AMR containment strategy to other sectors. Phase I used multifaceted treatment guidelines and patient education to change prescribing behaviour. In phase II decentralized networks between local and central partners were developed to scale up the programme. Phase III aims at promoting sustainability.
Phase I showed an 18%–46% reduction in antibiotic use and 97% of targeted patients recovered or improved regardless of whether they had taken antibiotics or not. This combined bottom-up and top-down model tried to achieve sustainable promotion of rational use of antibiotics by initiating behaviour change at an individual level and scaling up and sustaining achievements via three strategies: development of collaborative networks, policy advocacy, and forming a social norm. reducing costs by 42% and 24% respectively without any detrimental effects on patients.92 Cost savings Antimicrobial use and the development of resistance from effective antibiotic stewardship schemes for may be infl uenced by the economic behaviour of hospitals is discussed further in section 3.2. Additional individuals and institutions.90 Measures that improve savings of £7300 per 100 000 population could be rational use of drugs have cost implications, which made if national guidelines for antibiotic prescribing need to be weighed against the costs saved by for respiratory tract infections in primary care were reducing unnecessary use and the future costs that implemented, according to a sample calculation.93 would result from not taking action. By extrapolation from a study in a single Chicago hospital,91 the total additional costs in all U.S. hospitals for treating Implementation of policiesresistant versus susceptible infections could be as high as US$ 25–35 billion.
WHO surveys in 2003 and 2007 were carried out to analyse a range of national policy interventions to Substantial savings can be made through rational improve the use of antibiotics, using questionnaires use of antibiotics. For example in the UK, a multi- sent to the ministries of health of all Member States. disciplinary team (including a consultant microbiologist The results from those which responded showed and a clinical pharmacist) promoted rational use of widespread inadequacies in the level of implementation antibiotics in two directorates within one national (Figure 3.4), indicating a need for more comprehensive health service trust. This intervention has succeeded in national strategies.43,44 CHAPTER 3
Figure 3.4 Implementation level of national policies to improve rational drug use
Drug use audit in last 2 years National strategy to contain AMR Antibiotic OTC non-availability Public education on antibiotic use DTCs in > half general hospitals Drug Info Centre for prescribers Obligatory CME for doctors UG doctors trained on EML/STGs STGs updated in last 2 years EML updated in last 2 years Bars represent various national policy interventions. CME: Continued Medical Education, DTC: Drugs and Therapeutics Committee, EML: Essential Medicines List, OTC: Over-the-counter, STG: Standard Treatment Guidelines, UG: UndergraduateSource: Based on 43,44. Reproduced with permission. 3.2 Health care facility-level interventions to strategy for improving antibiotic use in hospitals. The stewardship approach is currently being followed in improve antimicrobial use many health-care facilities in both wealthy and low- A signifi cant proportion of prescriptions for antibiotics income countries. are unnecessary and/or inaccurate with respect It is important to recognize that a physician's ability to to dosage, duration of treatment or the antibiotic prescribe correctly can be compromised by a lack of chosen. Ensuring rational use at health care facility- laboratory diagnostic services or by poor laboratory level requires a coordinated programme of continuous performance, and failure to use the available diagnostic education together with other measures for promoting tests also promotes inappropriate use. appropriate use. In antibiotic stewardship schemes, a multi-disciplinary team supported by the hospital Education of health-care workers is an integral part of administration carries out a range of essential all AMR containment activities. Inclusion of appropriate functions, such as formulary restrictions, audit and use of antibiotics in curricula at both graduate and feedback, education, development and implementation postgraduate levels, as well as continuing education of standard treatment guidelines, and advice and on new developments in the fi eld of antimicrobial planning of treatments.94 Local surveillance data therapy, have been achieved to varying extents in inform many of these activities. Effective antibiotic different countries (Box 3.5). Prescription audit or drug stewardship programmes have consistently shown use evaluation, with feedback to prescribers, have signifi cant cost savings and reduction in antimicrobial been effective in changing behaviour with respect to use, demonstrating that this can be a fi nancially viable the prescription and use of antimicrobials.49 CHAPTER 3
Box 3.5 AMR in the undergraduate medical curriculum of the University of Zambia School of
In 2010, the University of Zambia School of Medicine revised their undergraduate medical curriculum. The topics of AMR and rational use of medicines were inserted prominently. The aim is that graduates enter clinical practice with the right skills and attitudes to be both effective practitioners and committed stewards of AMR containment.95 Political decisions to encourage appropriate for specifi c indications, can have a powerful infl uence prescribing and use of antimicrobials at facility level, in changing national practices, as demonstrated in and encouraging guideline-recommended treatment Sweden (Box 3.6). Box 3.6 A new Swedish government initiative for improving the use of antibiotics
Incentives to encourage rational use at several levels in the health-care system are important. In 2010, the Swedish government announced a strong fi nancial commitment to improve the use of antibiotics. That year, the average use of antibiotics in outpatient care in Sweden was 390 prescriptions per 1000 inhabitants. A new national target was set: a maximum of 250 prescriptions per 1000 inhabitants per year to be reached by 2014. Annual rewards would be shared between those of the 21 county councils that had formed a multidisciplinary working group with a clear mandate to coordinate local activities according to the model proposed by the Swedish Strategic Programme against Antibiotic Resistance (Stramac)96 Participants were to increase the level of compliance with treatment recommendations and reduce the numbers of prescriptions for antibiotics in accordance with annual targets. It is also useful to introduce interventions targeting the implementation of regulations may be relatively dispensers and other sellers, especially in areas where weak (Box 3.7).
Box 3.7 Viet Nam – Improving private pharmacy practice in Hanoi
Following health sector reforms in Viet Nam in the late 1990s, private pharmacies became increasingly important sources of health-care delivery. Major public health problems such as sexually transmitted diseases and acute respiratory infections are treated with antibiotics regularly dispensed without prescriptions, often inappropriately. A study of antimicrobial use was conducted in Hanoi from 1997 to 2000.97 Among a total of 789 private pharmacies in the urban area, 68 were randomly selected and assigned to control or intervention groups. The intervention package consisted of three parts: regulation enforcement with inspection for prescription-only drugs; face-to-face education on pharmacy treatment guidelines; and group meetings of pharmacy staff. After the intervention, practices were monitored using a simulated client method and improvements were identifi ed: there were signifi cant reductions in antibiotic dispensing for acute respiratory infections, and dispensing of cefalexin without prescription decreased from 95% to 56%. Interventions of this type could have a signifi cant impact, considering the high level of utilization of private pharmacy services by those seeking health care in Viet Nam.
3.3 Civil society engagement to reduce the There have been various attempts to educate the misuse of antibiotics general public about the correct use of antibiotics.101 Several clinical trials at the community level, mostly Patient-doctor contacts where patients are expecting in the USA, have shown at least moderate benefi ts of an antibiotic to be prescribed, or where the physician educating patients on the use of antibiotics.102,103 In assumes this expectation, are more likely to result in several countries, public campaigns have been carried the prescription of an antibiotic, as several studies out on a larger scale (Box 3.8). As demonstrated in have shown.98 Thailand, engaging civil society organizations may be an important step to support the process of developing Self-medication, including the use of left-over and/or implementing rational use policies, and in turn antibiotics from previous treatment courses or sharing of unused antibiotics with others, occurs regularly stimulate broader acceptance of recommendations on and has been recognized as one of the contributing rational use.104 A recently published guide to building factors for inappropriate use.84 Societal behaviour also coalitions at local and regional levels to address AMR infl uences self-medication by individuals: migrants aims to help stakeholders organize a collaborative from countries with relatively low antimicrobial effort to address drug resistance locally.105 The priority use moving to a place where self-medication is interventions outlined in the WHO Strategy are coupled practiced more readily, are more likely to carry out with advocacy efforts to achieve the critical mass of self-medication.99 Direct-to-consumer advertising activity needed for a coordinated, multidisciplinary, of medicines, as described earlier, is another factor coalition-based approach to containing drug infl uencing the behaviour of patients.100 Box 3.8 Public education campaigns in high-income countries
In a recent review, a total of 22 public education campaigns to promote a more prudent use of antibiotics at national or regional levels in high-income countries between 1990 and 2007 were identifi ed and the characteristics and outcomes evaluated. The campaigns were distributed in Europe (16), North America (3), Oceania (2), and Israel (1). In the USA, the Get Smart programme included more than 30 different regional campaigns. In most cases, the campaigns were part of a national strategy to reduce antimicrobial use. All campaigns focused mainly on respiratory tract infections and education was mostly symptom-oriented. The intensity of the campaigns varied widely, from simple use of internet distribution channels to expensive mass-media campaigns. Most campaigns that were formally evaluated appeared to reduce antibiotic use. However, the impact on AMR could not be assessed from the data available.101 3.4 International initiatives to infl uence such as the European Commission and the European Centre for Disease Prevention and Control. There are policies, directives and recommendations to facilitate WHO has played a lead role in attempts to improve actions in its Member States and also several activities the use of medicines. In addition to developing the in this direction. Improvement of antimicrobial use is a model EML and carrying out surveys to assess the core element of the European Community strategy to current AMR situation in general, and the specifi c contain AMR.106 role of irrational use as a contributor to resistance development, WHO provides published information The Transatlantic Taskforce on Antimicrobial Resistance and guidance in several areas related to improving (TATFAR) was established by presidential declaration in antimicrobial use. 2009 at the annual summit between the EU presidency and the US president. The purpose of the taskforce is Containing AMR remains an important priority for to identify urgent antimicrobial resistance issues that public health actions and research for many bodies could be better addressed by intensifi ed cooperation CHAPTER 3
between the USA and the EU within key areas including Partnership of the Center for Disease Dynamics, appropriate therapeutic use of antimicrobials in both Economics and Policyf, Strengthening Pharmaceutical medical and veterinary practice.22 Systems project of Management Sciences for Healthg, ReAct – Action on Antibiotic Resistanceh, and the In addition, several agencies and nongovernmental South American Infectious Diseases Initiativei. Many organizations (NGOs) address different aspects of national and international professional societies also rational drug use promotion globally, including the promote rational drug use through their activities and Alliance For Prudent Use of Antibioticsd, the Center for working groups such as the one formalized by the Global Developmente, the Global Antibiotic Resistance International Society of Chemotherapyj.107 4. Gaps and challenges
The main gaps and challenges that need to be Poor awareness at all levels: There is still a need to
addressed in global and national efforts to improve the educate and raise awareness among those involved
use of antimicrobials include the following:
in antimicrobial use worldwide, including policy-makers, regulators, the pharmaceutical industry, Lack of comprehensive strategies:
Despite prescribers, dispensers, consumers and donors, numerous activities and programmes addressing using locally relevant information. Local data on irrational use, many countries have yet to put in place many factors related to irrational use are still lacking coherent and comprehensive strategies to improve in most parts of the world and there is scope for the use of antibiotics. Understanding the current more use of antibiotic stewardship programmes in situation in relation to recommendations made in the hospitals to improve local use. Local factors that 2001 Global Strategy and as part of the 2011 World Health Day policy package, may support the planning may affect prescribing decisions are many and may of adequate sets of interventions. A multidisciplinary, include (to varying degrees) previous education, nationally appointed group could help to engage behaviour of role models, economic incentives, constituents from the different sectors involved, such patients' demands, availability of antibiotics, quality as health care, drug regulation, agriculture and animal of diagnostic tests, drug promotion, availability husbandry, and civil society in taking the process of unbiased information on antibiotics, clinical forward. Political support is essential for such a group guidelines and essential medicines lists, workload of to carry out this complex task.108 prescribers, and supervision. Lack of adequate regulatory frameworks: Many
Insuffi cient education on AMR for professionals:
countries do not have a solid legal and regulatory Both graduate and postgraduate as well as framework to mandate and support the rational use continuing medical education on the appropriate of medicines. Countries with weak regulatory systems use of medicines are defi cient in many countries,44 are hindered with regard to ensuring access to quality leaving many prescribers dependent on the medicines and securing the supply chain. Other relevant pharmaceutical industry for up-to-date information regulatory options include strengthening dispensing on medicines. Face-to-face educational sessions functions, and measures to curb the circulation of as well as distance learning, electronic education substandard and counterfeit drugs as expressed in the and knowledge-sharing methods have tremendous 2001 Global strategy and 2011 WHD policy packages.
potential to improve antimicrobial use. CHAPTER 3
Incentives that encourage overuse: In all situations
Inadequate laboratory testing: Laboratory services
where pharmaceutical sales constitute a direct source for diagnostic testing are not readily available in many of income for hospitals, health centres and individual developing countries, and where they exist there is health-care providers, there may be non-medical wide variation in the quality of testing. Novel diagnostic incentives for prescribing medicines.49,44 Financial tools, especially point-of-care and rapid tests, could incentives that encourage the overuse of antibiotics be expected to have a positive impact on antimicrobial exist in both human and veterinary medical practice use by reducing or eliminating empiric use and helping and in animal husbandry (Chapter 4).
to minimize delays in initiating appropriate treatment. CHAPTER 3
Chapter 4.
Reducing the use of antibiotics in animal husbandry Chapter 4.
Reducing the use of antibiotics in animal husbandry Antibiotics are used widely and in vast quantities to involved and food animals have been shown to carry ensure the health and promote the growth of livestock, resistant human pathogens. Some countries have poultry and fi sh reared for food production. The fact banned the use of antibiotics as growth promoters that greater quantities are used in healthy animals than but the practice remains widespread. Legislation and in unhealthy humans is a cause for serious concern, regulation with enforcement are needed to control the particularly as some of the same antibiotics are use of antibiotics for these purposes in many countries. Antibiotics are used in greater quantities in healthy food- (OIE) have proposed options for actions to be taken producing animals than in the treatment of disease in by national and international authorities. Large-scale human patients. In animal husbandry, antibiotics are interventions are already being instituted in a number used extensively for disease prevention and as growth of countries, mainly aimed at reducing the use of promoters, involving mass administration to many specifi c classes of antimicrobial agents, especially animals at the same time. This practice constitutes those used in human clinical practice. The steps to the main difference between the use of antibiotics in be taken include the introduction and enforcement of animals and in humans. Some of the same antibiotics regulations, methods to promote the prudent use of or classes are in use in food animals and in human antibiotics, and measures to improve animal health so medicine, carrying the risk of emergence and spread that less antibiotic treatment is needed. Several such of resistant bacteria, including those capable of interventions have led to a demonstrable reduction in causing infections in both animals and people. The AMR, though this is not always the case.
importance of food animals as reservoirs of resistant human pathogens is well documented. The spread Important gaps and challenges remain. More of resistance genes from animal bacteria to human information is needed on the prevalence of AMR in bacteria is another potential danger. The problems bacteria of animal origin and its impact on human associated with the use of antibiotics in animal health, on the quantity of antibiotics used for different husbandry, including in livestock, poultry, and fi sh indications and on the classes of antibiotics used. Risk farming, are growing worldwide without clear evidence assessments and risk management are impeded by a of the need for or benefi t from it, leading to increasing lack of data and/or inability to access available data. recognition that urgent action is needed.109 Legislations and regulatory frameworks for the approval of veterinary medicines and for controlling their use There appear to be major differences in the amounts need strengthening in many countries. Capacity to of antimicrobials used per kilogram of meat produced implement interventions varies and the potential impact in high-income countries, which together account of specifi c interventions in different settings is largely for 70% of global meat production. Working groups unknown. This chapter considers the present situation CHAPTER 4
hosted by WHO, the Food and Agriculture Organization and the range of options for action, citing examples of (FAO), and the World Animal Health Organisation experiences with different interventions. REDUCING THE USE OF ANTIBIOTICS IN ANIMAL HUSBANDRY
1. Reducing antimicrobial use in animal husbandry to reduce AMR
As in medical care for people, the introduction of dogs and horses, the use is similar to that in general antimicrobials was a signifi cant milestone in veterinary human medical practice, with individual animal practice. As in humans, these medicines are used treatment being the norm. The main difference for the treatment of infectious diseases in individual between antibiotic use in humans and animals is domestic pets and in farm and food-producing animals seen in the context of food production, where there to ensure animal welfare and global food production. is mass administration of antimicrobials to many The development and spread of AMR is therefore animals at the same time for the purposes of disease also of concern in veterinary medicine. Furthermore, prevention and growth promotion. Such practices resistant bacteria carried by food-producing animals provide favourable conditions for the emergence, can spread to people, mainly via the consumption spread and persistence of AMR bacteria capable of inadequately cooked food, handling of raw food of causing infections not only in animals, but also or by cross-contamination with other foods, but also in people. The antimicrobial agents used for food-through the environment (e.g. contaminated water) producing animals are frequently the same, or and through direct animal contact.
belong to the same classes, as those used in human medicine. The total amount used in animals accounts Use is the main driver for resistance in all of these for well over 50% of total antibiotic use, according to situations. For companion animals such as cats, the available evidence (Figure 4.1).21 Figure 4.1 Annual antibiotic use for human and veterinary practice in Denmark
Antimicrobial growth promoters Prescribed veterinary antimicrobials Prescribed human antibacterials Antimicrobial (tonnes) Source: Reproduced from 21 with permission.
The importance of food animals as reservoirs of fl uoroquinolones; Staphylococcus aureus resistant to AMR bacteria which are pathogenic for humans all beta-lactam-type drugs (i.e. MRSA); enterococci is well documented for zoonotic bacteria such resistant to vancomycin (VRE) and C. diffi cile. as non-typhoidal Salmonella enterica serovars110 There are signifi cant direct and indirect effects of and Campylobacter spp.111 It has been frequently antimicrobial use in animals on AMR in human demonstrated that the use of antimicrobial agents in pathogens, as several lines of evidence have food animals favours the development of resistance indicated. Data are as yet insuffi cient to allow this among bacteria which can then be transmitted to relationship to be fully evaluated, but it is clear that people, and may cause infections and illness. Bacteria action is needed to reduce the use of antibiotics in and resistance to critically important antimicrobial food animals, and to obtain further information on the agents associated with food animals include: impact on AMR. This chapter describes experiences Escherichia coli and Salmonella spp resistant to 3rd and with the implementation of some of the most important 4th generation cephalosporins and to fl uoroquinolones; interventions worldwide, recognizing the differences in Campylobacter spp resistant to macrolides and situations between countries and regions. 2. WHO guidance on reducing antimicrobial use in animal husbandry
The 2001 WHO Global Strategy for Containment 2000 (Box 4.1).109 The recommendations include phasing of AMR includes specifi c recommendations on the out the use in food animals of antimicrobials which are use of antimicrobials in animal husbandry which are used in human medicine, improving their use through based on WHO global principles for the containment regulation, education and guidelines, and monitoring of antimicrobial resistance in animals intended for food, use and resistance in this sector (Appendix1).1 Box 4.1 WHO principles for the containment of AMR in animals intended for food
Introduce pre-licensing safety evaluation of antimicrobials with consideration of potential resistance to human drugs.
Monitor resistance to identify emerging health problems and take timely corrective action to protect human health.
Develop guidelines for veterinarians to reduce the overuse and misuse of antimicrobials in food animals.
Require obligatory prescriptions for all antimicrobials used for disease control in food animals.
In the absence of a public health safety evaluation, terminate or rapidly phase out the use of antimicrobials for growth promotion if they are also used for the treatment of humans.
Create national systems to monitor antimicrobial use in food animals.
The importance of the problem and the urgent need to and training on antimicrobial use in food-producing take action were again stressed during the 2011 World animals, and reducing the need for antimicrobials Health Day. The core actions called for in the WHD through better animal husbandry. The needs for policy briefs include the creation and enforcement national leadership and intersectoral collaboration are CHAPTER 4
of an enabling regulatory framework, strengthening also emphasized (Appendix 2).2 surveillance and monitoring, promoting education REDUCING THE USE OF ANTIBIOTICS IN ANIMAL HUSBANDRY
3. The present position regarding these recommendations
The following sections examine key factors in the global trade in food products of animal origin, the role of antimicrobial use in food animals which numbers of reports documenting resistant bacteria contribute to the growing threat of AMR, and spreading from one country to another through food, national and international actions taken to tackle the and thereby causing infections, are also increasing. problem, illustrated by experiences from different The international spread of resistant pathogens calls parts of the world. for urgent global initiatives to minimize the risk of AMR bacteria developing and spreading from food animals to people, and further within communities 3.1 Increasing recognition of the problem of and hospitals. Working groups hosted by WHO, FAO
AMR through food of animal origin and OIE have reviewed these issues extensively and proposed options for action to be taken by national Extensive and effective monitoring of AMR in and international authorities.109,112-114 animals is carried out in only a very limited number of countries, and frequently these monitoring systems Figure 4.2 is a schematic overview depicting the are not comparable due to differences in methodology. overlap between different reservoirs for some AMR However, AMR among bacteria of animal origin is pathogens. While some are strictly confi ned to the certainly prevalent throughout the world, at varying human reservoir, others have a mainly or partially rates in individual countries and regions. With increasing animal reservoir.66 Figure 4.2 Reservoirs of AMR bacteria causing human infections
P. aeruginosa A. baumannii C. difficile S. pneumoniae H. influenzae Horizontal transfer of resistance genes C. difficile Schematic overview of some of the most important antimicrobial resistant pathogens and the overlap between the different reservoirs. As indicated some pathogens are strictly confi ned within the human reservoir, whereas others have a mainly or partly animal reservoir.
Source: Reproduced from66 with permission CHAPTER 4
The use of fl uoroquinolones (e.g. enrofl oxacin) in food transferred from animals to humans via non-pathogenic animals resulted in the development of ciprofl oxacin- bacteria in food products, and that they could then be resistant Salmonella, Campylobacter and E. coli, which transferred to bacterial pathogens in the human gastro- have caused human infections and spread worldwide intestinal tract. Consistent with this hypothesis is the through travel and food trade. An increasing number presence of similar vancomycin and cephalosporin of studies indicate that a major proportion of resistant resistance genes in both human and animal bacteria.121 E. coli that cause extra-bowel infections in humans may have originated in food animals, especially poultry.115,116 3.2 Antimicrobial use in food production Since 2003, a new variant of MRSA has emerged In modern food production systems, there is widespread and spread among food animals, primarily in pigs, and intensive use of antimicrobial agents. The impact in many countries. The importance of this new farm- of this practice may vary considerably between associated MRSA for human health has not yet been countries and regions, infl uenced by the interaction fully assessed, but it is already a problem for the between human populations (social structure), land control of MRSA in some countries and the prevalence use, contaminated water sources, animal demography appears to be increasing.117 (species, distribution, and density), national policies (production, trade, food security, animal health, etc), C. diffi cile colonizes many food animals and also and national and international trade. The production causes disease in food animals such as piglets, with systems also vary between countries according to an associated high mortality rate118 and has been technological, social, and economic circumstances. found in 4.6%–45% of retail meat samples.119 Since More than 50% of the world's pork production and 2005, in the Netherlands and other countries, there over 70% of poultry meat currently originate from has been an increase in community-acquired human industrialized countries. infections caused by C. diffi cile strain types similar to those found in food animals.120 Community human In general, the quantities and classes of antimicrobials carriage of C. diffi cile is likely to increase the risk of C. used in food animals today are insuffi ciently diffi cile disease, especially among patients who enter documented or controlled worldwide. Monitoring health-care facilities and are treated with antibiotics. of antimicrobial consumption is carried out in only It may also increase the likelihood of C. diffi cile a limited number of countries and, with very few spores contaminating the hospital environment and exceptions, this is restricted to total amounts used, and spreading from person to person. However, the overall not categorized by animal species and antimicrobial contribution of animal C. diffi cile to human disease is classes. Initial crude estimates from different countries not well documented. which do measure antimicrobial use show major As well as selecting for resistant bacteria, the use of differences in the amounts used per kilogram of antimicrobial agents in food animals also selects for meat produced (Figure 4.3). This implies that there is transferable resistance genes. This phenomenon considerable scope for reduction in countries where raises the possibility that resistance genes could be the higher amounts of antimicrobials are in use.122 CHAPTER 4
Figure 4.3 Estimated antimicrobial use to produce one kilogram of meat in different countries
Macrolides and Lincosamides Sulfonamides and Trimethoprim SwitzerlandGermany*Denmark Finland Sweden Norway Amounts in mg of veterinary antibacterial agents sold in 2007 per kg biomass of pig meat, poultry meat and cattle meat produced plus estimated live weight of dairy cattle. *2005 dataSource: Reproduced from 122 with permission from Oxford University Press.
D ata on antimicrobial use are necessary for risk to a large number of animals, oral routes (water and/analysis, interpreting resistance surveillance data, or feed) are used in addition to parenteral injections. and to assess the impact of interventions to promote Prophylaxis and metaphylaxis practices need to be prudent use. Sales data are the usual source of carefully assessed to fi nd an appropriate balance information on antimicrobial use. Data which can between the need to prevent diseases during high-risk have an impact on policies and practice are very often periods and the potential to contribute to AMR. lacking from developing countries, but Kenya is a notable exception where both the total amounts and the classes of antibiotics are monitored: from 1995– 3.3 Actions being taken worldwide 1999, Kenya used on average 14 594 kg of antibiotics Awareness of the risks for human health which can distributed as 7975 kg of tetracyclines, 3104 kg of result from the use of antibiotics in animal husbandry sulfonamides, 955 kg of aminoglycosides, 905 kg of appears to be on the increase, as evidenced by the betalactams, 94 kg of quinolones, 35 kg of macrolides many media reports and scientifi c publications on this and 24 kg of others, including tiamulin.123 topic in recent years, and the large-scale interventions which are being instituted in different parts of the world. Depending on the species of animals, periods of higher risk for infection can be identifi ed. For example, when There are several international networks which animals from different origins are assembled and fi rst coordinate AMR surveillance in human and placed together, physiological stress is at its highest animal populations (see Chapter 2). The WHO- level and there is increased potential for inter-animal Global Foodborne Infections Network (GFN) and transmission of infections. Antimicrobial prophylaxis of the international molecular subtyping network all animals is often carried out to prevent clinical disease for foodborne disease surveillance (PulseNet in such situations. In some countries, mass treatment Internationala) are examples. The WHO Advisory Group is timed to an epidemic (either started or expected), a on Integrated Surveillance of Antimicrobial Resistance practice termed "metaphylaxis". The regulatory status (AGISAR) has developed guidance documents for of such use often resides on the fringe of labelled use global standardization of methods for monitoring AMR for the ‘control' of disease. To facilitate administration and antimicrobial use in food animalsb.
Most interventions are aimed at reducing the use of proposed products, similar to the process followed for specifi c classes of antimicrobial agents in food animals, human use products. For antimicrobials, an evaluation especially those classes which are used in human of the potential impact on human health is also included clinical practice. The measures which have been in many countries. Initially this evaluation focused on implemented include the introduction and enforcement avoiding antimicrobial residues in food products, but of regulations governing the use of antimicrobials, more recently it has been extended to include effects methods to promote the prudent use of antibiotics by on AMR in bacterial populations in slaughter-ready end-users, and measures to improve animal health so animals. The approval process may also include that less antibiotic treatment is needed. consideration as to whether specifi c antimicrobials are of critical importance for human health,124 often with measurable impact on AMR (Box 4.2). WHO has Regulations to restrict the use of antibiotics in categorized antimicrobials which are critically important animals for human use.125 However, current national legislations do not always restrict the use of such critical antibiotics National and international efforts to control AMR in animals. require a fi rm legal and regulatory foundation on which measures can be introduced and enforced. Regulations In many countries, it can be diffi cult to withdraw can contribute at many levels, from licensing to end use approval for an already licensed pharmaceutical of antimicrobials. While regulatory frameworks exist in product. However, it is often possible within the most countries, there are differences in the extent to existing legislation to implement restrictions on the which regulations are implemented. In most countries, approved usages of licensed antimicrobials (Box 4.2). veterinary pharmaceutical products undergo a licensing For example, it is possible to limit off-label / extra-process that assesses the risk/benefi t balance of the label use or to restrict use to individual animals. Box 4.2 Approval and regulations on use of antimicrobials of critical importance
The U.S. Food and Drug Administration successfully withdrew the approval of fl uoroquinolones for use in poultry on 12 September, 2005.126 To achieve the withdrawal, the agency had to demonstrate that the use of enrofl oxacin in poultry causes the development of fl uoroquinolone-resistant Campylobacter in poultry, that these fl uoroquinolone-resistant organisms are transferred to humans, that they may cause the development of fl uoroquinolone-resistant Campylobacter in humans, and that fl uoroquinolone-resistant Campylobacter infections in humans are a health hazard. The process began in 2000, involved the collection and evaluation of thousands of studies, expert testi-mony, an oral hearing, and a complex risk assessment. In Australia, fl uoroquinolones (e.g. ciprofl oxacin), which are antimicrobials of 'critical importance' in human use, have never been approved for use in food production animals. Fluoroquinolone-resistant bacteria are either at very low levels or else non-existent in food animals and resistance is very low in Australian human bacterial isolates in comparison with other countries. Data from the Australian Group on Antimicrobial Resistance 2006 surveillance report show fl uoroquinolone resistance in 2006 to be less than 5% in clinical isolates of Gram-negative bacilli.127 The approval of fl uoroquinolones for use in food animals in 1993 in Denmark saw the rapid emergence of resistance to this class, with 23% of C. coli isolates from pigs found to be resistant during 1995 to 1996. Consequently, in 2002 restrictions were imposed on the veterinary use and prescription of fl uoroquinolones for food-producing animals: fl uoroquinolones could only be used in food-producing animals for the treatment of infections proven by laboratory tests to be resistant to all other antimicrobials, and administered only by injection by a veterinarian, with the use reported to the regional veterinary offi cer. This reduced fl uoroquinolone use in animals in Denmark from 183 kg in 2001 to 49 kg in 2006 and it has remained low since then. Resistance was detected in just 12% of C. coli isolates from pigs tested in 2009.21 CHAPTER 4
Restrictions on the mode of administration could of antimicrobial agents are encouraging. By January be another useful means of limiting use in animals, 2000, the use of all antimicrobials as growth promoters particularly for antimicrobials that are critically important had been prohibited in Denmark. This has resulted for human use, for example, by limiting them to injection- in an overall reduction in resistance among bacteria only. However, this type of restriction is applicable in in animals. The temporal association between the individual animal treatment, but may not always be reduction of macrolide use and the prevalence of AMR feasible for large numbers, for example in poultry fl ocks. among enterococci isolated from pigs in Denmark is Increasing numbers of countries are banning the use shown in Figure 4.4. Resistance will probably never of antibiotics as growth promoters, a very positive return to pre-antibiotic use levels, and so consumption development which has been highlighted in recent of antimicrobials needs to be kept at low levels as media reports. Experiences following cessation of use excessive use could again rapidly drive AMR upwards. Figure 4.4 Macrolide use and resistance among enterococci in pigs, Denmark
% resistant isolates onnes active substanceT Macrolides for pigs Pigs - E. Faecium Pigs - E. Faecalis Source: Reproduced from 21 with permission.
In 1995 a ban of the growth promoter avoparcin (a extra-label manner for routine administration into eggs or glycopeptide) which selects for vancomycin-resistant one day-old chicks in hatcheries, to prevent infections. enterococci (VRE) in Denmark led to a reduction in the Surveillance in the province of Quebec, Canada, prevalence of VRE among animals and in the general demonstrated a marked increase in the prevalence human population. However, VRE has persisted for up of resistance to 3rd generation cephalosporins and to 12 years in poultry farms after the ban and is likely to penicillins among S. enterica serotype Heidelberg persist for many more years. The complex relationship isolates from humans and chickens in early 2005. A between reducing use and the levels of resistance is survey of antimicrobial use in hatcheries in Quebec being explored.128-130 confi rmed that in 2004 all chicken hatcheries switched Experience has shown that any negative effects due to exclusive use of ceftiofur. In early 2005, Quebec to the prohibition of growth promoters are minimal in hatcheries stopped this use voluntarily, after which there the long term, once industry adapts to the changes.131 was a dramatic decline in the prevalence of ceftiofur Apart from prohibitions on the use of antibiotics in food resistance (Figure 4.5). Anecdotal reports indicate that animals, there have also been a number of voluntary the industry has subsequently re-introduced alternating withdrawals. In Canada and the USA, ceftiofur, a 3rd use of ceftiofur with other antimicrobials, and that this generation cephalosporin, may legally be used in an has been followed by a resurgence of resistance.132 CHAPTER 4
Figure 4.5 Cephalosporin resistance after stopping its use in poultry in Quebec, Canada
Voluntary withdrawal of ceftiofur in ovo use Retail chicken E. coli Retail chicken S. Heidelberg Human S. Heidelberg Partial reinstitution of ceftiofur use Prevalence of ceftiofur resistance %
Quarter and year
Source: Reproduced from 132 with permission.
Unfortunately, there are few incentives to encourage them among veterinarians and farmers is likely to voluntary withdrawal of growth promoters and no be helpful. Prudent use guidelines have been issued barriers or sanctions for re-introducing them. in the Netherlands (1986), Denmark (1998), USA (1999/2000), Germany (2000), and in many other Easy access to antimicrobials through sources such countries more recently. However, the infl uence of as online pharmacies, animal feed outlets and pet these guidelines has not been monitored adequately, shops contributes to their overall excessive use and for example the Netherlands is still among the highest makes it increasingly diffi cult to enforce regulations on users of antimicrobials in food animals in Europe.
the use of these products.
Improving animal health to reduce the need for Ideally, sales of an antimicrobial should never involve fi nancial benefi t for the prescriber. Limitations on the The most effective means to reduce the use of sales profi ts obtained by veterinarians in Denmark from antimicrobials and thus prevent AMR is to reduce 1994 to 1995 led to major reductions in the therapeutic the need for antimicrobial treatment. This could use of antimicrobials, especially tetracyclines, without be achieved by improving animal health through any obvious overall harm to animal health.
measures such as immunization against prevalent infections. In Norway, the introduction of effective Prudent use guidelines and education vaccines in farmed salmon and trout in 1987 and improved health management reduced the annual CHAPTER 4
To reduce inappropriate use and promote prudent use of antimicrobials in farmed fi sh by 98% between use, developing treatment guidelines and popularising 1987 and 2004 (Figure 4.6).133 Many countries and REDUCING THE USE OF ANTIBIOTICS IN ANIMAL HUSBANDRY
the EU already have regulations in place to enforce and consumption will change, since most antimicrobial and promote vaccination as a method of reducing agents for growth promotion and prophylaxis are used infections in food animals. However, even if health without any evidence of the need for, or benefi t from, improves, it is not certain that established practices their use. Figure 4.6 Reduction in antimicrobial use after the introduction of vaccination in aquaculture
(tons wfe)
(kg active substance)
1981 1984 1987 1990 1993 1996 1999 2002 Volume of salmon and trout Consumption of antibiotics Wfe: whole fi sh equivalent.
Source: Reproduced from 133 with permission.
Improving hygiene in food production 18 have reached the EU reduction targets in breeding fl ocks of fowl and the decreasing trend in human The FAO/WHO Codex Alimentariusc provides salmonellosis cases is continuing.134 Microbiological recommendations for many aspects of food production criteria for a maximum acceptance level for certain including hygiene, from primary production through to types of AMR Salmonella enterica in food animals fi nal consumption, highlighting the key controls at each have been implemented in Denmark. The impact of stage. It recommends a Hazard Analysis and Critical these interventions has not yet been fully evaluated Control Point (HACCP) approach. Good agriculture practices particularly at the farm level have also been but Denmark has a low rate of domestically-acquired defi ned. The Codex Task Force on Antimicrobial salmonella infections.
Resistance recently developed a risk analysis and management tool to assess the risks to human health Applying advances in data management associated with foodborne antimicrobial resistance. technology In 2006, the EU put in place a programme with specifi c targets for reduction in salmonella contamination. Herd Health and Production Management (HHPM) Based on data from 27 EU Member States in 2009, programmes have been used to improve productivity CHAPTER 4
incrementally, mainly in intensive production based Management Information Systems (MIS) and systems. HHPM monitors the interaction between the databases thus developed could direct attention farm management, herd health and production, to AMR and allow recognition of the contributions of and integrates these components in order to obtain local management, and of environmental and biological optimal results. These programmes use computer- factors, to the development of AMR (Box 4.3). Box 4.3 Computer-based monitoring of antimicrobial use and resistance to improve production
The MIS database used in Costa Rica records both prophylactic use (uterine infusion after artifi cial insemination, dry-off treatment etc), and therapeutic use (disease treatment, mastitis treatment, uterine infusions, etc) of antimicrobial agents in cattle. It includes a module for drugs, which allows the personnel responsible for use to register the drug used. This module enables data gathering for surveillance of antimicrobial use, AMR, and monitors the actions of veterinarians and/or producers. Similar HHPM programmes could be used more widely to monitor AMR at farm level, and correlate the data with environmental and managerial aspects to identify risk factors for AMR.
4. Gaps and challenges
Data on AMR associated with animal husbandry:
countries and within countries. OIE has published a The extent of AMR in foodborne bacteria, and the list of critical antimicrobial agents needed for animal global burden of human infections due to such health136 with an overview of the agents used and bacteria, are unknown. Continuous and updated considered important in different countries. information on foodborne pathogens, their spread and
the status of AMR is necessary to guide risk profi ling, Regulatory provisions: In many countries, the
risk assessment and risk management and to measure legal and regulatory framework to control the use
the impact of interventions. However, very few of antimicrobials in animals could be strengthened.
countries appear to have these monitoring systems in Regulations governing the approval of veterinary
place, and where data are collected, they are often not medicines and restrictions on their use are often
comparable because of methodological differences lacking, or not adequately enforced. Restricting the
(Chapter 2). Regional and national laboratory use in food production animals of antibiotics that are
networks using standard methods would alleviate this "critically important" for human health is recommended
situation.135 There is scope for widening participation by many experts and authorities. Currently, WHO
in existing networks and for strengthening the capacity gives priority to restricting the use of 3rd generation
of the participating laboratories. Databases could cephalosporins and fl uoroquinolones.125 Regulations
also be usefully improved to include phenotypic and could also include provisions for prohibiting for
genotypic features of the bacteria being monitored.
animal use any new drug class developed for human medicine, and of those that are used only in human Data on quantities used: Data on total volumes of medicine (e.g. linezolid, daptomycin, carbapenems,
antimicrobials used and the indications for which they glycopeptides). Regulations also have a potentially are used are also limited. The use of antimicrobials valuable role in supporting compliance with the in animal husbandry is generally not based on international standards for food safety practices in the sound scientifi c principles. Although use for growth production of food of animal origin, developed by the promotion is being reduced in many countries, the FAO/WHO Codex Alimentarius and OIE.
practice is still widespread in many parts of the world.
Correct use for prophylaxis and metaphylaxis is the Data for registration of antimicrobials: It is standard
subject of ongoing debate, and more could be done practice for regulatory agencies to require data on the
to limit antimicrobial use in these areas. The agents effi cacy of a new medicine prior to registration, but used and the modality of use differs widely between these data are rarely available in the public domain. REDUCING THE USE OF ANTIBIOTICS IN ANIMAL HUSBANDRY
This particularly applies to older products that have evaluation of institutional and operational capabilities,
not been subjected to recently-introduced rigorous measure advancement, and propose strategic actions
approval processes. Pharmacovigilance systems for technical cooperation have been developed by the
in place in many countries include the obligation to Pan American Health Organization (PAHO)d.
declare lack of effi cacy, which could be a problem with
drugs that have been in use for a longer period of time. Application of modern technologies: Available
technologies could be better harnessed to analyse Routine, usually qualitative, assessments of risks local situations and risk factors, and for effective
for developing AMR are now incorporated into the communication including the improvement of existing
pre-market authorization process for veterinary communication networks to disseminate already
antimicrobials in some countries. However, these available information. The possibility of developing
assessments are made diffi cult by the complexities of new vaccines, particularly against the infections
the producer-to-consumer continuum and lack of data for which most antibiotics are being used, such as
in several important areas. Positive, albeit modest, gastro-intestinal infections in pigs and calves, mastitis
developments include quantitative risk assessment in cattle and E. coli infections in poultry, could be
for specifi c antimicrobial/organism combinations (e.g. explored. Another possible option is the development
fl uoroquinolone resistance in C. jejuni). Improvements and evaluation of probiotics, which are probably
in methodologies for risk assessment, risk management valuable alternatives to antibiotics in the control of
and risk communication could be benefi cial and gastro-intestinal infections in food animals.
additional guidance in this area from Codex Alimentarius
would be helpful. The application of such guidance Selection of appropriate interventions: Different
at national/regional and international levels could be commodity groups in different settings may require
different interventions. For example an intervention to reduce resistance in 180-day swine system may not be Evaluation of impact: The potential impact of directly applicable to a 42-day broiler chicken system,
different interventions in different settings is still and interventions suited to extensive agriculture are
largely unknown. Measuring impact on food safety, unlikely to be of equivalent effi cacy in intensive settings.
enteric and other zoonotic diseases in people, animal Thus, the choice of interventions could be based on
health, animal productivity, national economy and a process of identifi cation, analysis and prioritization
other indicators at the regional/national level requires of needs and options which could include the
standardized indicators and sustainable capacity for introduction and/or enforcement of regulations on the
monitoring AMR and antimicrobial use. At a local level, use of antimicrobials in animals; measures to improve
the impact could probably be determined by targeted animal health; promotion of prudent antimicrobial use;
research studies, and meta-analyses of such available strengthening hygiene in the food chain; and specifi c
global data could prove useful.
targeted measures in areas with a higher risk of AMR development or serious consequences. Capacity to respond to AMR: National capacity to
respond to problems due to AMR is not uniform at either Capacity building activities including staff training
country or local level. Capacity at farm level is lacking in are still needed in many places. Public education
many countries, for reasons such as a lack of effective on issues related to the use of antibiotics in food-
organizational structure, trained personnel, and suffi cient producing animals may be needed to raise awareness
knowledge about the risks involved. To improve this of the potential harm and unclear benefi t from their
situation, instruments to guide the characterization and use in agriculture and aquaculture.
Chapter 5.
Infection prevention and control in health-care facilities Chapter 5.
Infection prevention and control in health-care facilities As the centres where the most serious illnesses caused by resistant bacteria exert a heavy toll in terms are treated, hospitals are unfortunately also where of illness and mortality, as well as added direct and antibiotic-resistant infections are particularly likely to indirect costs. The key to limiting the risk lies in the develop and spread. Infections acquired in hospitals meticulous application of measures for the prevention and other health-care facilities (nosocomial infections) and control of infection. The hospital environment favours the emergence and Many facilities and countries have progressed well spread of resistant bacteria. In Europe, the death in implementing recommendations on IPC and there toll from health care-associated infections (HAI) have also been several welcome innovations recently caused by multidrug-resistant bacteria is estimated in the fi eld of IPC, as outlined in this chapter. WHO has to exceed 25 000 per year and the death rate may be led and coordinated the development of guidance on higher in other parts of the world. In addition to human core components of IPC, based on evidence-based suffering, the consequences of AMR also result in principles. However, there are considerable differences higher direct and indirect fi nancial costs. within and between countries in the extent to which IPC measures are implemented. Health-care facilities Infection prevention and control (IPC) measures are in some countries lack even the basic elements of IPC. designed to prevent the spread of pathogens, including Situation analyses at national and facility levels would those with AMR, within and between health-care help to defi ne the current status, to set realistic goals facilities, and from facilities to the community, and for the local context, and to develop strategies for also vice versa. This was emphasized in the 2001 progressive improvement.
WHO Global Strategy for Containment of Antimicrobial Resistance and in the 2011 World Health Day policy The gaps and challenges include: lack of data related to briefs. Interventions to bring about system change in HAI and inadequate laboratory capacity in many parts individual health-care facilities involve organizational of the world; lack of uniform standards, data collection structures, human resources, guidelines, protocols and methods and defi nitions; insuffi cient information practices, monitoring and evaluation, infrastructure, on the effectiveness of specifi c interventions and and linking to public health services. In addition the resources needed for effective and sustained to the standard IPC measures, there are specifi c implementation. This chapter examines the situation recommendations concerning AMR pathogens. and options for action to improve it.
1. Infection prevention and control within health-care facilities to contain AMR
Bacteria which develop resistance to antibiotics can and other facilities contributes signifi cantly to the CHAPTER 5
spread in the health-care facility environment and increasing global burden of AMR. Infection prevention beyond. The spread of resistant pathogens in hospitals and control measures are designed to reduce the INFECTION PREVENTION AND CONTROL IN HEALTH-CARE FACILITIES
spread of microorganisms within and between health- (95% CI 36·7–59·1). Methicillin resistance was found care facilities, and from there to the wider community, in more than 50% of S. aureus isolates, a lthough this thereby preventing further infections and antimicrobial varies widely.138 resistance spread. Preventing infections due to resistant bacteria is the ultimate goal of all AMR containment In individual health facilities, several factors may activities.
contribute either to the spread or to the containment of AMR: these include infrastructure of the hospital, There is considerable evidence that resistant policies, protocols and practices, staffi ng numbers, organisms evolve, survive, spread and cause skill-mix and health-care worker behaviour. Other infections within health-care facilities. For example, patient-related factors, such as severity of illness and MRSA was recognized initially in a few hospitals; predisposing medical conditions, would be diffi cult subsequently it became endemic in many health to modify, whereas factors relating to health-care facilities around the world, and some strains are now workers' performance and attitude, work processes also causing infections in the community. The spread and institutional infrastructure can be infl uenced of resistant bacteria is facilitated by the transfer of successfully, provided there is support from local and patients between wards within a hospital and between national political decision-makers. different hospitals (or other facilities), and more widely by travel, including medical tourism.
The long-accepted standard measures to prevent and control infections in health facilities also form the The health and economic burden due to AMR infections essential basis for preventing the spread of AMR, but in hospitals varies between different countries and they may need to be supplemented with additional Europe, the death toll from multidrug- measures. To ensure that standards are implemented resistant bacterial hospital infections is estimated to and maintained, multimodal and multidisciplinary exceed 25 000 per year. Infections due to selected interventions may be needed to bring about a system multidrug-resistant bacteria in the EU are estimated change in individual facilities and in health-care worker to result in extra health-care costs and productivity behaviour. There are also some special considerations losses of at least €1.5 billion each year.8 In the USA, related to resistant pathogens, such as additional health care-associated infections are implicated in isolation standards and specifi c barrier precautions. more than 99 000 deaths per year.137 Although most AMR pathogens colonize far more people than they available data on HAI and AMR infections come from actually infect, and successful IPC strategies need to high-income countries, the burden is likely to be include measures for colonized patients in order to even greater in low-income countries, as reported reduce the development of infections.139,140 in several published studies. Pooled data show the prevalence of HAI in such settings to be 15.5 per 100 IPC can bring added benefi ts through preventing patients (95% CI 12·6–18·9) and the incidence in adult infections, which reduces the need for antibiotic intensive care units as 47.9 per 1000 patient-days therapy and hence reduces antimicrobial use. 2. WHO guidance on infection prevention and control to contain AMR
The importance of IPC is recognized in the 2001 WHO In recent years WHO and many other agencies have Global Strategy for Containment of Antimicrobial focused on the need to identify priorities in IPC and Resistance, which recommends the establishment to stimulate actions to improve the existing situation. of IPC programmes in all hospitals (A ppendix 1).1 Consequently the strategies to enhance IPC were The need for coordination of IPC activities at hospital further elaborated in the World Health Day 2011 policy levels and the education of staff is stressed. briefs (Appendix 2),2 which emphasize the need for IPC in all health facilities, addressing the essential The growing evidence for the spread of AMR infections components such as infrastructure and organizational in health-care facilities, between facilities and across aspects, laboratory support, human resources, borders has revealed many defi ciencies in infection protocols and practices, surveillance, monitoring and CHAPTER 5
prevention and control in facilities around the world. evaluation, and linking these to public health services.
3. The present position regarding these recommendations
Many facilities around the world have made good takes place. Application of the core elements of IPC progress in implementing recommendations on IPC, in each facility is the essential fi rst step in infection but there are still marked differences in the level prevention and control and also in preventing the of implementation within and between countries. spread of resistant microorganisms. As outlined in the The reasons for these differences may include the 2011 World Health Day policy brief (Appendix 2) and degree of commitment, the fi nancial situation, human in the WHO Core components for IPC programmes,141 resource availability, access to materials, as well as several fundamentals need to be addressed, including historical and cultural factors. Since 2005, through infrastructure and design of facilities, organizational the First Global Patient Safety Challenge, WHO has structure, equipment and instruments, staff numbers appealed to Member States to pledge their support and training, protocols and practices. Several nations/for the implementation of measures to reduce hospital subnations around the world, especially in high-income infections in their countries, and thus far at least countries, already meet many of the recommendations 125 have made such pledges, but their progress in and have appropriate practice guidelines and standard implementation is yet to be mappeda. operating procedures in place as relevant for each facility, and these are being implemented meticulously Progress related to the elements needed for IPC in many cases. IPC is also applied increasingly in are summarized in the following sections using the primary and ambulatory care. concepts core elements of IPC (the long-accepted measures such as hand hygiene, environmental The roles, responsibilities and activities of national cleaning, sterilization, disinfection, and others) and authorities in implementing functioning IPC measures where evidence for impact on AMR has programmes at facility levels have been proposed been assessed at least in some studies. by WHO and EU Expert groups (Table 5.1).141-143
National authorities have important leadership roles in
developing policies, recommendations and guidelines,
3.1 Implementing IPC core elements in in making the necessary trained personnel available, in health-care facilities worldwide facilitating implementation in all health-care facilities, and in monitoring progress and providing feedback. Many recommended interventions are to be Protocols and tools are already available from different implemented at the health facility level, but central sources, but choosing those most appropriate and government authorities and policy-makers have modifying them to meet local needs would need a critical role in facilitating and ensuring that this coordination and support from the central authority. CHAPTER 5
Table 5.1 Roles and activities at national and facility levels, as proposed by WHO and EU
expert groups
• Funded and functioning programme to improve IPC in all facilities • A functioning national advisory committee for IPC • National guidelines available for improving IPC specifi cally addressing AMR • A national standard for human resource requirements for improvement of IPC • Oversight on employment of designated IPC personnel, access to accredited microbiology laboratories, facilities for detailed testing and characterisation • Annual reports evaluating surveillance data on HAI and AMR • Offi cial statement on the legal accountability of hospitals for IPC • Control mechanisms to ensure that reimbursement regulations for hospitals are not contradictory to the aim of improving IPC and reducing AMR • IPC indicators included in national health-care quality improvement • Audit of individual facilities, on the basis of indicators, and summary prepared • IPC education in relation to AMR included in medical and nursing curricula • A functioning IPC programme and a multidisciplinary IPC committee Facility
• Local policies and practice protocols available on standard precautions, isolation precautions, screening for resistant organisms • Appropriate facility infrastructure to support and operate IPC and AMR interventions • Regular education programmes on IPC in general and in relation to AMR • An ongoing programme for promotion of IPC methods, e.g. hand hygiene • Monitoring compliance with IPC methods and regular feedback to HCW • Annual progress report issued on AMR pathogens, infections and HAI rates • Access to an accredited microbiology laboratory HAI: Health care-associated Infection, HCW: Health-Care Worker, IPC: Infection Prevention and Control Source: adapted from 141-143 with permission from the World Health Organization and Elsevier. In many parts of the world, implementation of even Overcrowding, inadequate infrastructure, insuffi cient the most basic recommendations poses tremendous trained personnel, limited access to commodities challenges. Differences between countries in the needed for IPC, and limitations in fi nancial resources existence of effective IPC practices within their are all barriers to the implementation of IPC facilities contribute to glaring inequities related to recommendations. With such wide variations in the health-care delivery. These differences extend as far levels of IPC implementation, situation analyses at as IPC measures related to environmental hygiene national and facility levels would help to obtain an and sanitation, which are proven to be important in overview of the current situation, so that realistic goals reducing AMR spread and infections.144 could be set according to the needs and opportunities CHAPTER 5
within the local context, with strategies for progressive Hand hygiene Transmission of resistant pathogens from patient Education of health-care workers in IPC is being to patient via the hands of health-care workers is carried out in many countries with positive effects. a common occurrence, particularly in hospitals. WHO provides guidance on IPC elements to be Hand hygiene therefore remains one of the most included in education programmes for health-care effective, yet simple and cost-effective means for providers in the Patient Safety Curriculum Guide: Multi- reducing the transmission of infections. Several Professional Edition.145 Another positive measure is the reports confi rm that improvement in hand hygiene education of patients on infection prevention, which is greatly reduces the transmission of MRSA and other being undertaken in some countries.146 Many national resistant organisms, and also saves costs and the and international professional societies also play an use of additional resources. Guidelines consistently important role in knowledge sharing and in promoting recommend hand hygiene as an essential method of IPC as part of medical and nursing curricula. controlling the spread of infections including those with AMR .147 The WHO Patient Safety Programme 3.2 Implementation of measures and impact designated the improvement of hand hygiene in all health-care facilities worldwide as the main element on AMR pathogens of the fi rst Global Patient Safety Challenge.b The WHO The measures for which the impact on AMR pathogens Guidelines on Hand Hygiene in Health Care and the has been studied include hand hygiene, contact accompanying tools are examples of resources to precautions, screening measures, readmission promote hand hygiene, measure compliance and alert systems, patient placement, decolonization, document progress in implementing a multimodal education and environmental cleaning. They have strategyc. been used with varying degrees of success to stop The "My Five Moments for Hand Hygiene" concept outbreaks and decrease the disease burden due to proposed under this Challenge helps staff to understand resistant pathogens.139 Evidence for the effectiveness the indications for hand hygiene during routine patient of individual measures to contain AMR is limited, care and is intended to improve compliance. The because studies to determine their comparative multimodal strategy has fi ve components (Figure effectiveness cannot be carried out for ethical and 5.1).148,149 Also under this Challenge, a network of over practical reasons. Most of the evidence for impact of 45 national/subnational campaigns and programmes IPC measures comes from experience with MRSA- promoting hand hygiene in health care is coordinated. related interventions, and to a much lesser extent from While they differ in their scope and range of activities,150 glycopeptide-resistant enterococci. There is relatively the number of participating programmes is increasing little published information on IPC measures specifi c and their scope and coverage are expanding. Large- for Gram-negative resistant organisms, although this scale actions to improve hand hygiene have been situation is changing rapidly.139,140 shown to reduce the numbers of infections with Implementation of a selection of these measures for resistant bacteria (Box 5.1).
AMR reduction is discussed in the following sections.
Figure 5.1 The WHO multimodal strategy for improving hand hygiene
1a. System change –
alcohol-based handrub at point of care
1b. System change – access to safe,
continuous water supply, soap and towels
2. Training and education
3. Evaluation and feedback
4. Reminders in the workplace
5. Institutional safety climate
and planning
Source: Ilustration reproduced from 148 with permission from Elsevier. Remainder reproduced from 149 with permission from the World Health Organization. Box 5.1 Experience from Geneva, Switzerland and Victoria, Australia
The fi rst multimodal intervention was conducted from 1995 to 2000 at the University of Geneva Hospitals, Switzerland. A decrease of almost 50% in health care-associated infections and methicillin-resistant Staphylococcus aureus (MRSA) transmission occured in parallel with a sustained improvement in compliance with hand hygiene. More than 20 000 opportunities for hand hygiene were observed. Although recourse to handwashing with soap and water remained stable, the frequency of hand antisepsis with alcohol-based handrub substantially increased during the study period (p<0·001). The prevalence of overall nosocomial (hospital-acquired) infection decreased from 16·9% to 9·9% (p=0·04), MRSA transmission rates decreased (from 2·16 to 0·93 episodes per 10 000 patient-days; p<0·001), and the consumption of alcohol-based handrub increased from 3·5 to 15·4 L per 1000 patient-days (p<0·001). This multimodal intervention model was used in 2005 by the WHO Global Patient Safety Challenge Clean Care is Safer Care as a basis for the global promotion of hand hygiene.151 In the state of Victoria, Australia, a centrally coordinated, multimodal, multi-site hand hygiene culture-change pilot programme (HHCCP) for reducing rates of MRSA bacteraemia and disease was carried out over a 24-month period (October 2004 to September 2006) in six health-care institutions. Subsequently, the effi cacy of an identical programme implemented throughout Victoria's public hospitals over a 12-month period (between March 2006 and July 2006) was assessed. The mean rate of hand hygiene compliance improved signifi cantly at all pilot programme sites, from 21% at baseline to 48% at 12 months and 47% at 24 months. Mean baseline rates for the number of patients with MRSA bacteraemia and the number of clinical MRSA isolates were 0.05/100 patient days per month and 1.39/100 patient days per month, respectively. These were signifi cantly reduced after 24 months to 0.02/100 patient days per month for bacteraemia (i.e. 65 fewer patients with bacteraemia) and 0.73/100 patient days per month for MRSA isolates (i.e. 716 fewer isolates). Similar fi ndings were noted 12 months after the statewide roll-out, with an increase in mean hand hygiene compliance (from 20% to 53%) and reductions in the rates of MRSA isolates and bacteraemia. 152 CHAPTER 5
Several hospital-based studies also confi rm the at facility levels and estimated at national levels importance of hand hygiene in preventing infections (Box 5.2).153-155 However, poor compliance with hand due to resistant pathogens. The cost-effectiveness hygiene is still a problem in most parts of the world, for of hand hygiene promotion has been demonstrated varying reasons, and continuing efforts are required.
Box 5.2 Cost-effectiveness of hand hygiene promotion
An eight-year study at the University of Geneva Hospitals, Geneva, Switzerland, estimated total costs associated with health care-associated infections (n=37 887) to be SFr 132.6 million (range, SFr 79.6–185.6 million) using conservative cost estimates of an average of SFr 3500 per health care-associated infection. Extra annual costs generated by 260 nosocomial infections equaled the budget for the hand hygiene promotion campaign and showed that the programme was already cost-saving if less than 1% of the reduction in infections was due to improved hand hygiene practices.153 The use of an alcohol-based handrub, together with education and staff performance feedback, reduced the incidence of MRSA infections and expenditures for teicoplanin (an antibiotic used to treat MRSA infections) in hospitals in England. For every £1 spent on the alcohol-based handrub, £9–20 were saved on teicoplanin expenditure.154 An economic analysis of the "cleanyourhands" promotional campaign in England and Wales concluded that the
programme would be cost benefi cial if hospital infection rates were decreased by as little as 0.1%.155
Isolation of AMR infected patients Furthermore, there is confl icting evidence on whether rapid molecular identifi cation methods, such as the The isolation of patients colonized or infected with polymerase chain reaction (PCR), provide better resistant organisms and the application of specifi c results than the conventional screening methods.158 contact precautions are key recommendations that The development and application of screening tests are followed in many facilities.139 Evidence on the is a rapidly evolving fi eld, and interpretation of the effectiveness of different isolation policies and screening published results could be context-dependent.159-161 practices for MRSA indicate that concerted efforts including isolation can reduce MRSA colonization and When screening focuses specifi cally on high-risk infection in hospital inpatients, even when the infection patients (those with previous AMR organism carrier is endemic.156 However, isolation of MRSA patients in status, patients admitted to intensive care units, single rooms is not always feasible in many settings. patients with open wounds, and the room mates Grouping a number of similarly affected patients in the of AMR carriers), there is evidence that screening same bay or part of the ward, with or without their own combined with other measures such as hand hygiene, nursing staff, is an alternative, but more needs to be contact precautions, and staff education can reduce done on monitoring effectiveness and investment in the transmission of resistant pathogens. A policy isolation facilities.157 Guidance is available on personal termed "Search and Destroy" for MRSA, consisting protective equipment,139 but practice is probably far of a range of interventions, including isolating and from satisfactory in many parts of the world.
screening of high-risk patient groups, screening of low-risk groups, strict isolation of carriers, and treatment Screening of patients for AMR bacteria of people carrying MRSA, has been implemented successfully in the Netherlands and several other Screening of all patients for resistant bacteria on European countries. As patients often carry MRSA admission to hospital has produced mixed results. and glycopeptide-resistant enterococci for more than Confl icting results about the effi cacy and cost- a year, computer-based "readmission alert systems" CHAPTER 5
effectiveness of active surveillance by bacterial are used effectively by some hospitals to prevent examination in reducing AMR have been published. delays in recognition of readmitted MRSA carriers.162 INFECTION PREVENTION AND CONTROL IN HEALTH-CARE FACILITIES
3.3 Surveillance of AMR countries. For example, the US Centers for Disease Control and Prevention (CDC) currently supports over Surveillance of AMR enables the identifi cation of 3000 hospitals to report on HAI through its National trends in local endemic patterns and the emergence Healthcare Safety Network.d The "Hospitals in Europe of unusual AMR, such as an increase in numbers, or Linked for Infection Control through Surveillance" the emergence of new resistant strains. Based on this (HELICS) network (subsequently transferred to ECDC) information, antibiotic stewardship programmes in collected, analysed and disseminated data on HAIs.e health-care facilities can help reduce the unnecessary The Canadian Nosocomial Infection Surveillance use of antibiotics. Surveillance systems for AMR Programme (CNISP), initiated in 1994, has 49 sentinel are discussed in detail in Chapter 2 and antibiotic hospitals from nine provinces as participants.f Such stewardship in Chapter 3.
systems are lacking in many low- and middle-income countries. The International Nosocomial Infection Surveillance for HAI and sharing data through Control Consortium (INICC) collects and pools rates networking at national or subnational levels are of HAI and AMR from 36 low- and middle-income integral to health services in many high-income countries (Box 5.3). Box 5.3 The International Nosocomial Infection Control Consortium (INICC) HAI and AMR
Through the analysis and feedback of voluntarily collected surveillance data, INICC promotes evidence-based infection control in hospitals in low- and middle-income countries, and in hospitals without suffi cient experience in HAI surveillance, prevention and control. Regularly updated data serve to show trends in the situation of bacterial resistance related to specifi c types of nosocomial infections.g 163,164 3.4 Innovations in IPC than their laboratory-based predecessors. However, since molecular methods do not necessarily detect In recent years investment in research and resistance in vivo, reliable standard phenotypic tests development to improve IPC practices and antibiotic still have a vital place in diagnosis and screening. stewardship has increased. As a result, there have been several advances including in new diagnostic Advances in molecular methods have made it possible tools, innovative hospital design and engineering, and to trace the sources of outbreaks, by linking infections also new approaches to enable better use of available due to the same bacterial strains or bacteria carrying resources, such as "care bundles" and medical care similar AMR genetic elements. Using such methods, checklists.
several resistance genes and mechanisms are being described, enabling a better understanding of the New methods for detecting pathogens such as epidemiology of AMR, the factors favouring the MRSA, glycopeptide-resistant enterococci and C. emergence of AMR, multiple drug resistances which diffi cile have become available and others are being are genetically linked, the transferability of genes further developed. However, these methods vary carrying AMR, and other aspects. These methods in their sensitivity, specifi city, time to result, and have also provided the evidence for AMR spread within impact in different health-care settings. Near-patient and across hospitals and within regions and across molecular test methods are beginning to appear, and international borders; the account of carbapenemase in the long run they are likely to be more cost effective spread is an example (Chapter 1).19 CHAPTER 5
Interactions with engineering and design experts 3.5 National coordinated IPC programmes and to review health-care infrastructure, devices and equipment have resulted in a number of improvements, such as better antimicrobial delivery systems, new Many countries have national strategies to combat approaches to wound dressing, improved intravenous AMR, and these usually include an IPC component. and urinary catheters and faecal incontinence Some of them are already successful, as summarized devices, better designed isolation cubicles which in Table 5.2. Strategies that have been implemented at can be assembled within a room, improved cleansing national levels include infection reduction target setting, methods and decontamination procedures, alcohol- legislation, accreditation, visits of "improvement based handrub, and innovative product delivery and teams" and various types of inspection and feedback. monitoring devices, all of which should contribute to Penalties for non-compliance are imposed in some reducing the transmission of microorganisms in health- settings and include withholding of patient treatment care facilities. There is still further scope for innovation reimbursements if patients have contracted a HAI, and improving the uptake of effective products.
fi nes, and closure of hospital wards, units or services. CHAPTER 5
Table 5.2 Examples of large-scale campaigns to reduce AMR pathogens in health-care facilities
and/or the community, incorporating IPC interventions
Ministry of Health - Multi-site hygiene culture-change MRSA bacteraemia and the programme number of clinical MRSA isolates - Subsequent statewide roll-out was signifi cantly reduced after 24 and national promotion campaign Belgian Antibiotic Campaigns to decrease antibiotic Compliance with hand hygiene consumption in hospitals and the increased; percentage of resistant Committee (BAPCOC) community (2004), and to improve infections and antibiotic use hand hygiene and prevent HAI (2005, 2007, 2009) Department of Health; - Legislation on HAI and IPC The target to decrease MRSA National Patient - Mandatory reporting of MRSA bacteraemia rate by 50% was Safety Agency; Health bacteraemia rates achieved in 2008.166 Protection Agency - Establishment of reduction C.diffi cile infection was decreased by 54% between 2007/08 and - Chief Executive held responsible for the data- National Hand Hygiene campaign- Many others, e.g. care bundles, visits by improvement teams Ministry of Healthh - Media campaigns to decrease There was a 41% decrease in MRSA infections.168 - Admission screening and (see also Chapter 3) isolation- Reporting on mandatory indicators, beginning in 2004 and reporting of alcohol-based handrub consumption in 2005 Ministry of Health National MRSA monitoring and Percentage of MRSA isolated promotion of the WHO Global decreased from 29.5% in Strategy for the Containment of 2003 to 22% in 2010 (personal Antimicrobial Resistance Source: Compiled and adapted from 152,165-168 CHAPTER 5
There are many other national and international alcohol-based handrub.l China has issued a directive initiatives to reduce infections in hospitals, including whereby one health-care professional profi cient in the following examples. The WHO Regional Offi ce surveillance and infection control is recommended for for the Eastern Mediterranean (EMRO) has initiated every 200 to 250 beds.170a "Patient Safety Friendly Hospital Initiative", with IPC as one of the core elements.i The WHO "African Target setting171 as practised in some countries involves Partnerships for Patient Safety" programme, which selecting at least one resistant indicator organism builds north-south twinning partnerships and south- for mandatory surveillance (e.g. MRSA) based on south knowledge transfer partnerships between the AMR situation in the country. Summarized data hospitals in various African and European countries, for these ‘alert' organisms are monitored over time incorporated hand hygiene improvement as one of its and published periodically, giving political decision-fi rst activities.j The WHO Patient Safety programme makers, the public and the media an opportunity to "Safe Surgery Saves Lives" included IPC aspects as evaluate progress and the impact of any intervention, well as rational use of peri-operative antibiotics in including IPC measures. Such data are also being their Surgical Safety Checklist.k All of these WHO- used by individual health-care facilities for endorsing initiated programmes have led to increased national the quality of service provided. and international efforts to promote IPC. nancing systems with a universal or ceiling budget could, in principle, have strong 3.6 Regulations and incentives related to IPC incentives to reduce HAI-associated costs by investing In a number of countries, adherence to IPC in preventive measures. However, when Germany recommendations is supported by legal provisions introduced a Diagnosis Related Groups (DRG) fi nancing and regulations, and through incentives linked to system in 2001, the AMR situation did not improve. reimbursement of hospital expenses. Many countries The main reason may be that adequate local data on and agencies have included elements of IPC in hospital additional costs for HAI and AMR were not available accreditation protocols. In the USA, hospitals are to allow informed decisions by hospital managers. required to have IPC programmes as a condition for In health-care provision systems which depend, accreditation. France and other European countries even only partially, on fee-for-service reimbursement require all health-care facilities to have an IPC committee mechanisms, there may be little incentive to reduce to defi ne and implement an IPC programme.169 In some the transmission of pathogens in health-care facilities, countries, reporting of HAI is mandatory. In Germany, a as any additional diagnostic procedure or intervention new infection prevention act came into force in 2011. and treatment for a colonized or infected patient Brazil has regulations requiring all facilities to provide generates income for the provider.
4. Gaps and challenges
Inadequate infrastructure and human resources: requires commitment and fi nancing from national/
Defi ciencies in infrastructure and limited access to subnational authorities. Until these major gaps are commodities represent a major barrier to implementing corrected, optimal global IPC will not be achieved.
IPC recommendations in health-care settings in many countries. There are examples of inadequate hospital Lack of suffi ciently trained and dedicated personnel buildings, understaffi ng, inadequate clean water to manage IPC in each health-care facility is another supplies and lack of reliable microbiology support in major barrier in many countries.141 IPC as a clinical many parts of the world. Addressing these defi ciencies discipline has only recently gained visibility and CHAPTER 5
although every health-care worker may have an This could be achieved through a combination of obligation to take steps to prevent infections, often the measures such as ‘care bundle' approaches and overall responsibility for implementing IPC does not interventions targeting human behaviour change. fall clearly within the remit of any one clinical specialty. This may result in a lack of ownership and therefore of Behaviour can be infl uenced by the level of knowledge accountability for IPC within health-care facilities. about an issue and the importance placed on certain interventions. Behaviour change is an area which could Incorporating the principles of IPC in basic medical and benefi t from more research, particularly to understand nursing curricula, and a system for training of experts factors which infl uence and sustain individual and in IPC and AMR, would help meet the education gap. organizational change. The WHO Guidelines on Hand Ongoing education of all health-care personnel and Hygiene in Health Care147 include the evidence for regular audits and feedback to staff help maintain some factors which infl uence the implementation of standards and compliance. hand hygiene recommendations.
Inadequate data on AMR infections: Most of the The assessment of gaps, feasibility and effi cacy of
data on infection rates in hospitals due to resistant interventions, and the stepwise introduction of a series
organisms are from high-income countries. Although of interventions can be facilitated by appropriate tools. a national overview of infection rates is a useful The HARMONY project showed that interactive tools measure and can inform bench-marking, summaries based on a template approach enabled experts on of data from individual facilities are essential to antimicrobial stewardship to review their own policies stimulate local actions. Even well-functioning AMR and processes to facilitate the design of a hospital surveillance systems may not collect data to measure antibiotic policy.172 Similar tools could also help in the magnitude of harm to patients, or the additional assessing existing IPC practices and in elaborating resources needed for managing AMR bacteria HAI. policies. An assessment tool is being developed by Although AMR bacteria, including MRSA and extended- WHO to enable facilities to identify gaps in IPC.
spectrum beta-lactamase-producing strains, are also
transmitted outside hospitals, much less is known Lack of information on costs and cost-
about their transmission in the community.
effectiveness: National budgets allocated to health
care vary, even in high-income countries, and the
The lack of standardized methods and universally situation is worse where resources are limited. Data applicable standards for measuring HAI138, 141 makes on cost-effectiveness in diverse settings are therefore it diffi cult to assess the current situation, and could crucial for policy decision-making. However, there is potentially invalidate comparisons between and within insuffi cient information on health care-associated as facilities or attempts to measure the effectiveness well as societal costs of interventions and the savings of different interventions. Accepted methods mostly due to their impact.
require laboratory support and careful steps to validate the standards and processes used to collect clinical The costs for specifi c interventions may vary considerably, depending on many local factors such as differing material, personnel, and bed costs. To Choosing interventions and implementing quantify the savings resulting from the interventions,
sustainable changes: Choosing and prioritizing the a variety of local issues need to be taken into
most appropriate interventions for an individual facility account, including the pre-intervention burden, the is not always a simple matter. The effectiveness of effectiveness of interventions, potential direct savings specifi c interventions is highly context-dependent, for health-care systems (e.g. shorter hospital stays, and strategies may vary according to the existing fewer readmissions, less need for tests, less use of situation. In highly endemic facilities with limited antimicrobials) as well as savings for social security resources, it may be possible to reduce AMR infection systems and/or increased productivity. rates signifi cantly by the effective introduction of only
a few IPC interventions (e.g. improving hand hygiene, Need for innovations to reduce the transmission
reducing device usage). In settings where basic IPC of pathogens: Both the private and public sectors
measures are already in place, the priority may be to need encouragement to explore new technologies to
ensure sustained compliance with recommendations. reduce the transmission of pathogens and infections
in health-care facilities. "New" products need to be facilities. The credibility of mathematical models tested quickly for feasibility and potential impact in depends on the quality and applicability of the data different health-care settings.
informing them. Additional efforts to gather appropriate data are necessary and consensus in this area needs Mathematical modeling could be applied to estimate to be explored with multi-disciplinary groups. cost–benefi ts of interventions in different settings with differing resource levels and health-care delivery There is also a pressing need for innovative approaches systems. Such models may be useful for determining that are feasible and readily applicable in low-resource the types of interventions best suited for individual settings. CHAPTER 5
Chapter 6.
Fostering innovation to combat antimicrobial resistance Chapter 6.
Fostering innovation to combat antimicrobial resistance With an inexorable increase in antimicrobial-resistant with successful initiatives in scientifi c collaboration, infections, a dearth of new antibiotics in the pipeline funding mechanisms and regulatory provisions. Other and little incentive for industry to invest in research opportunities for innovation exist in all of these areas. and development in this fi eld, innovative approaches An enabling environment for innovation depends on are crucial for the development of new products to support from policy decision-makers. counter the rise of AMR. Innovation is under way, Innovative strategies and technologies are needed being used to spur greater R&D into new technologies. to alleviate the dearth of new antibiotics and other Push incentives that de-link the return on investment products for limiting AMR, ranging from scientifi c to from volume-based sales, such as the public funding fi nancial and regulatory aspects. Various innovative of clinical trials and providing services that help bring approaches are being pursued but more are needed. promising compounds to trials, are being explored. Such Innovation fl ourishes in an enabling environment, and incentives could also reduce the inappropriate use of this chapter examines what can be done to create antibiotics by preventing the need to sell large volumes to conditions that would foster innovation in this fi eld. improve return on investment. Strategies such as pooled procurement and Advanced Market Commitments can While antimicrobial medicines are the mainstay help to create markets that reassure the private sector of treatment for bacterial infections, diagnostics of returns on investment. Target Product Profi les are and vaccines play important complementary roles being used increasingly to help align public health goals by promoting rational use of such medicines and with economic incentives, especially in pharmaceutical preventing infections that would require antimicrobial R&D, to facilitate public sector return on investment. treatment. New products coming on to the market Innovations such as pooling of building blocks of have not kept pace with the increasing needs for knowledge and open access repositories show promise. improvements in antimicrobial treatment. Setting priorities for research and development (R&D) Regulatory requirements have an important role in involves making strategic choices and identifying directing R&D and there is a need for clear guidance to complementary technologies. This chapter considers the industry. Strategic and judicious use of intellectual the current status of innovations, especially in drug property rights, which can be either an incentive or an discovery, and identifi es the main gaps and challenges. obstacle, is discussed. New opportunities could result from supporting greater participation of developing Both scientifi c and fi nancial aspects pose challenges countries in R&D, including small biotechnology fi rms for R&D. Strengthening infrastructure, from specimen and academic institutions. To meet the twin challenges banks for diagnostics to broader compound library of enhanced innovation and affordable end-products, access for drugs, as well as human resources, has there is a need to pilot alternative approaches to facilitated collaborative research. Carefully weighed pharmaceutical R&D, and for concerted action by a CHAPTER 6
fi nancing mechanisms—push and pull incentives— are broad range of stakeholders.
1. The need for innovations in several domains
The increasing health and economic threats posed by reassuring patients that some conditions do not resistant infections call for improved and new products, require antibiotics. Without such tools, patients technology, and ideas to counter AMR. Innovations are may be under-diagnosed, but over-treated. For needed in many different areas, notably in drug discovery, example, an improved diagnostic tool for acute lower vaccine development and diagnostics. Non-antibiotic respiratory infection could theoretically save over therapies such as immuno-modulators and other agents 400 000 unnecessary antibiotic treatments per year may add to advancements in addressing AMR.
in developing countries.173 Diagnostic tools could also assist in the selection of an effective antibiotic Antibiotics, in addition to the treatment of a broad in cases where resistance has rendered fi rst-line range of common infections, ensure the successful treatment ineffective, and in surveillance and infection application of modern medical advances, from prevention and control. organ transplants to cancer chemotherapy. Logically, therefore, for effective treatment, antimicrobials should A spectrum of technologies with applications in many keep a step ahead of resistant pathogens. In reality, domains from health-care delivery systems to food however, a growing range of bacteria are rapidly safety measures, have an impact on the development developing resistance to more and more antibiotics, and spread of AMR. Innovations are needed in these rendering them useless for treating many infections. areas, as well as improvements in technology and Bacteria resistant to almost all known antibiotics have better use of available tools, including in resource- already emerged and are causing infections. Over the constrained settings. The continuing growth in trade past 30 years, only two truly novel classes of antibiotics in animal and agricultural products provides greater have entered the market: the oxazolidinones (linezolid) opportunities for the spread of infectious agents, and cyclic lipopeptides (daptomycin), and resistance and regulatory agencies face increasing challenges has been documented for both of these compounds.
in rapidly detecting pathogens, especially in goods Effective vaccines reduce the prevalence of disease and crossing national borders. Improved diagnostic tools thereby also reduce the need for antibiotics. Several could allow more prompt and sensitive detection of studies have shown signifi cant reduction in resistant pathogenic organisms, including those with AMR, and S. pneumoniae following the introduction of multivalent raise awareness of the globalization of this problem. pneumococcal conjugate vaccines in infants and Innovations in drug formulation can improve patients' children, not only in the vaccinated children but also in the population as a whole (due to reduced transmission adherence to treatment or enhance the effectiveness of infection). This exemplifi es how developments in of antimicrobials. For example, in patients with both vaccines and the strengthening of immunization tuberculosis and HIV infection, the use of fi xed-dose programmes contribute indirectly to the control of AMR.
formulations of multiple antimicrobial components facilitates compliance with the full course of treatment. Rapid point-of-care diagnostic tools for case Innovations to encourage patients' compliance with management of individual patients could play a treatment and optimizing treatment regimens can help valuable role by removing clinical uncertainty and to limit the risk of resistance.
2. WHO guidance on innovations to contain AMR
Encouragement of cooperation between industry, recommendations on fostering innovations address government bodies and academic institutions in aspects such as incentives to advance R&D, fast the search for new drugs and vaccines is one of the tracking market authorization, and partnerships to recommendations in the 2001 WHO Global Strategy promote access to new products (Appendix1).1for Containment of Antimicrobial Resistance. Other CHAPTER 6
A decade later, the global strategy recommendations 2011 WHD policy briefs include improving the use remain valid and on World Health Day 2011, WHO of current diagnostics and antimicrobials, creating renewed the call for global and national commitments incentives for new product development, enabling to develop diagnostics, drugs and vaccines for rapid regulatory processes for new tools, and ensuring infectious diseases. The core actions identifi ed in the equitable access (Appendix 2).2 3. The present position regarding these recommendations
Setting R&D priorities involves consideration of a cost of developing a new drug for treating tuberculosis number of factors which in turn affect progress in at about US$ 76–115 million, including the costs of innovations. These include, as explained below, (i) the failure.175 The much lower PDP estimate indicates that predicted reduction in disease burden; (ii) the expected alternative approaches might usefully be explored, number of treatments averted; (iii) the opportunity particularly for the development of products that would costs for bringing a new technology to market; (iv) offer little fi nancial incentive for the multinationals.
the scientifi c likelihood of achieving a ‘breakthrough' invention; and (v) the likelihood of adapting the product Scientifi c potential for achieving a breakthrough for public health purposes, particularly in resource- invention is often unpredictable. Over a decade limited settings.
of R&D efforts focusing on the high-throughput screening of compounds have yielded disappointing The reduction in the burden of disease could depend on results. Between 1995 and 2001, GlaxoSmithKline the prevalence of the disease, the level of attributable conducted 70 such screening campaigns which morbidity and mortality, and its responsiveness to yielded only fi ve leads, a success rate four-fold lower medical intervention. The effects of a product could than in other therapeutic areas.176 The low yield range from total avoidance of the illness (prevention obtained by high-throughput screening has led to by vaccination) to mitigation of the severity and suggestions that screening of natural products might course of the disease (treatment with drugs). Reliable prove more fruitful. Other opportunities could come diagnostic tests can reduce unnecessary treatment, from recent developments in genome research which which reduces costs, and facilitate the selection of may help bring in the next generation of anti-infective optimal therapy, which is critical when more costly agents. Knowledge of bacterial genomics and protein second-line treatments are needed.
expression has provided novel targets for high-throughput screening against compound libraries and Both the fi nancial costs of R&D and the time from yielded some promising leads, but so far these have laboratory to point-of-care are considerable; they differ not resulted in the successful development of new for diagnostics, drugs and vaccines and also within antibacterial agents for reasons including toxicity. In these categories. Large multinational companies are another approach, some important advances could be likely to view the opportunity costs quite differently made through the modifi cation of existing medicines from small fi rms, product development partnerships, to improve effi cacy and compliance with treatment.
or government-owned pharmaceutical companies. In 2004, a study of 63 projects on drug development for It is important to consider whether technologies are neglected diseases found that half were carried out by likely to be adapted to meet public health needs, multinational companies, on a "no profi t, no loss" basis. particularly in resource-limited settings. Available new The other half were mainly done by smaller companies health technologies are not always used in developing on a commercial basis, motivated by smaller profi ts than countries for reasons such as unaffordable start-multinationals would expect, and in collaboration with up and maintenance costs, lack of infrastructure Product Development Partnerships (PDPs).174 While including water, electricity, refrigeration, and lack of it is estimated to cost over US$ 800 million for a U.S. trained staff. Characteristics of a diagnostic test that multinational pharmaceutical company to bring a new would facilitate its use in developing countries have drug to market, a public-private partnership has put the been proposed (Box 6.1).177 CHAPTER 6
Box 6.1 ASSURED: Characteristics of the ideal diagnostic test for the developing world
Affordable by those at risk of infection
Sensitive (few false-negative results)
Specifi c (few false-positive results)
User-friendly (simple to perform by persons with little training)
Rapid (to enable treatment at fi rst visit) and Robust (does not require refrigerated storage)
Delivered to those who need it
3.1 Overview of the drugs, diagnostics and Drug R&D vaccines pipeline As the number of infections that are treatable with Mapping of the R&D pipeline, both across technologies existing antibacterial drugs progressively decreases, that might combat AMR and across the range of the dearth of new candidate compounds is a matter different pathogens, is far from complete. The distance of much concern. Only two truly novel classes of from laboratory to point-of-care will be shorter or longer antibiotics have been developed over the past 30 years for the development of different products, and this has (Figure 6.1) and both are for the treatment of Gram-to be taken into account in R&D prioritization. The positive bacterial infections, which represent only a R&D pipeline for drugs is perhaps better understood part of the whole spectrum of bacterial pathogens that than for other products. The number of new medicinal are becoming resistant.178 products, including antibiotics, brought successfully to market has not kept pace with the increase in expenditures on pharmaceutical R&D.
Figure 6.1 Discovery of new classes of antibacterial drugs (1930s to 2000s)
Cyclic lipopeptides * Penicillins were the fi rst beta-lactams. This class includes cephalosporins and carbapenems, developed in the 1960s and 1980s, respectively.
Source: Reproduced with data from 178. Modifi ed with permission from Thomson Reuters (Professional) Ltd The future pipeline also appears bleak. Only fi ve (1.6%) development compared to the estimated R&D of the drugs in the R&D pipelines of 15 pharmaceutical investment. The higher the net present value, the companies, which together produced 93% of greater the likely returns on investment. On this basis, antibiotics placed on the market between 1980 and potential returns from a musculoskeletal drug are over 2003, were antibacterials.179 A more comprehensive an order of magnitude greater than those predicted and recent analysis also found disappointingly few for an injectable antibiotic.181 Certain intrinsic features truly novel candidates: of 90 potential systemic of antibacterials affect the net present value, for agents, only four had activity against Gram-negative example an uncomplicated urinary tract infection is bacteria, which are of greater concern than MRSA in usually cured with a short treatment course, whereas some situations, and none had a novel mechanism of anti-hypertensive treatment may be for life. Bacterial action.8 resistance itself contributes to shortening the effective market life-span of an antibiotic. Extrinsic factors that The return on investment on R&D is likely to be infl uence the net present value include differences in relatively low for antibiotics. Compared to many disease burden between developed and developing other medicines, particularly those prescribed for countries, the level of therapeutic competition, and the long-term use, antibiotics have a smaller commercial limits on reimbursement. In 2009, 60% of the US$ 1.3 market. Antibiotics for primarily hospital-based use billion global sales of meropenem, a broad spectrum command a higher average price and have greater antibacterial drug, were in industrialized countries, market growth prospects than those for community including the USA, Europe, and Japan. In contrast, less use, which currently accounts for over 60% of total than a fi fth of the estimated global sales of fi rst-line TB antibiotic sales.180 drugs – a smaller market in the range of US$ 261–418 million – were from high-income countries. Beyond CHAPTER 6
The net present value of a drug candidate is used these calculations on returns, gains for a company's to estimate the expected returns from a drug under reputation, the opportunity to enter into emerging FOSTERING INNOVATION TO COMBAT ANTIMICROBIAL RESISTANCE
markets, and collaboration with PDPs which help opportunity costs and therefore differing incentives with the regulatory systems of developing countries, that could be used to take candidates through the could also infl uence a company's prioritization of pipeline. A company with a diverse portfolio of drug R&D projects. Public health needs could enter candidates is positioned differently to consider trade- this equation in the form of policy interventions to offs in investing in a musculoskeletal drug compared to diminish the fi nancial risks associated with R&D, an antibacterial drug. In contrast, a smaller company's or as enhancements in the likelihood of returns on future may depend on the success of a single drug. Rescuing and repurposing existing drugs could entail The prominent role played by smaller fi rms (Box lower R&D costs, and picking up drugs shelved for 6.2) raises important issues such as differences in other reasons could also prove useful (e.g. Cubicin®). Box 6.2 The potential role of small companies in antibiotic R&D
In November 2003, Cubicin® (daptomycin) produced by Cubist Pharmaceuticals Inc was approved in the USA. Daptomycin is the fi rst of a new class of antibiotics, the lipopeptides. Administered in the hospital setting, this drug targets S. aureus, including MRSA, and other Gram-positive bacteria causing complicated infections. Eli Lilly fi rst discovered daptomycin, but discontinued its development because of concerns over toxicity when administered in high dose therapy. Licensed from Eli Lilly in 1997, daptomycin was then successfully developed by Cubist.
Several factors may have contributed to this success of a small company. It targets the smaller hospital market, where the prescriber is more clearly identifi able, and therefore only a small workforce is needed to promote the drug. Secondly, the rise of hospital infections with MRSA led to a growing market potential for antibiotics with MRSA as the target. Also, concern over the dearth of new-class antibiotics may have helped with the regulatory process of the U.S. Food and Drug Administration (FDA).182 The pharmaceutical market is mature and prospects to point-of-use is shorter, and typically the R&D costs for further growth are limited. Market penetration are lower, than for drug development. But with a lower by generic products is high and newly developed net present value, diagnostic products command a antimicrobials are likely to face competition from the smaller share of investment and returns. Innovations large numbers of those already approved and widely are needed to increase the use of existing diagnostics, used. While R&D programmes may favour broad- as well as for the development of new technologies.
spectrum antimicrobials, public health authorities could seek to limit their use in order to counter the Lessons can be drawn from experience in international development of resistance. Discouraging the use of a coordinated actions to improve TB diagnostics and newly developed antimicrobial for fi rst-line treatment their utilization. Of the billion-dollar worldwide market is usual practice, and in many cases this measure has for TB diagnostics, one third is outside the established a negative impact on sales. market economies.185 Sputum microscopy remains the mainstay of TB diagnostics in resource-limited Diagnostics R&D settings. By expanding reference laboratory capacity and facilitating the roll-out of new diagnostic tools The pipeline for new diagnostics differs from that that can be deployed in more peripheral settings, of drugs in several key respects. The global market WHO and the Stop TB Partnership Global Laboratory for diagnostics in 2008 was US$ 41 billion, most of Initiative (GLI) hope to improve the effi cacy and reach which related to infectious diseases.183 In contrast, the of TB diagnostic tools.186 Recently, WHO revised its worldwide market for medicines in the same year was policy guidance to include new technologies for TB US$ 758 billion (Figure 6.2).184 For diagnostics, the time diagnosis, such as molecular line probe assays and required for the development process from laboratory fl uorescent light emitting diode (LED) microscopy. CHAPTER 6
WHO also endorsed Xpert® MTB/RIF, a new rapid test of the value of this market. Several new vaccines, for diagnosing TB and identifying TB with rifampicin such as those against S. pneumoniae, rotavirus, resistance, which was developed by Cepheid with and human papilloma virus (HPV), have been support from the Foundation for Innovative New successful both clinically and in markets. Wyeth's Diagnostics (FIND). Obviating the need for lengthy Prevenar® (pneumococcal septavalent conjugate in vitro culture, the results can be obtained in under vaccine), an antibacterial vaccine, reached an annual two hours.187 In exchange for support for R&D, FIND sales record of US$ 2.7 billion in 2008.189 Recently, has secured concessionary pricing of these tests in 10-valent and 13-valent pneumococcal vaccines resource-limited settings. The Xpert system also from GlaxoSmithKline and Pfi zer respectively have opens up opportunities to add on other diagnostic been licensed. Information on many activities that are tests to the instrument, e.g. for sexually transmitted taking place in vaccine development can be accessed diseases. through the WHO web pages.a The development of new diagnostic tests relies on Nevertheless, the track record still reveals signifi cant the availability of biospecimens that are needed scientifi c challenges facing the development of new to evaluate these tools. For tuberculosis, an open- vaccines. A recent update of R&D efforts on anti- access collection of over 41 000 samples from adult staphylococcal vaccines and immunoglobulins shows patients in 13 countries has been assembled in a TB much enthusiasm for attacking the pathogen with Specimen and Strain Bank by the Special Programme toxin-based or virulence factor-based interventions. for Research and Training in Tropical Diseases (TDR). However, 5 out of 7 projects have so far failed or Responding to concerns over the quality of tests, been terminated. A wide range of R&D cost estimates FIND, TDR, and the WHO Regional Offi ce for the for new vaccine development exists, and these vary Western Pacifi c (WPRO) supported an evaluation of considerably by disease area and vaccine complexity. rapid diagnostic tests for malaria. Such evaluations The recently approved meningococcal conjugate are much needed and enable purchasing decisions to vaccine adapted to strains endemic in sub-Saharan be based on test performance as well as price.
Africa received a seed grant of US$ 70 million from the Gates Foundation and additional funding as the Vaccines R&D programme has begun to scale up for distribution and delivery. The Roll Back Malaria Initiative, on the other The worldwide market for vaccines was estimated at hand, estimates the R&D costs at approximately US$ 24 billion in 2008.188 Five multinational companies US$ 800 million per new malaria vaccine. Thus, – GlaxoSmithKline, Merck & Co, Novartis, Sanofi signifi cant fi nancial resources are always needed to Aventis, Wyeth (now part of Pfi zer) – account for 85% bring new vaccine candidates to market. CHAPTER 6
Figure 6.2 Global markets of medicines, diagnostics, and vaccines in 2008 (US$ billion)
Source: Data obtained from 183 3.2 Creating an enabling environment for of forecasted demand, increase purchase volumes, and provide an opportunity to harmonize regulatory R&D and innovations to improve access and quality issues among purchasing agents. The dearth of diagnostics, drugs and vaccines for Pooled procurement could also exert monopsony neglected diseases in the developing world has (consolidation of purchasing power) infl uence, which triggered a renewed look at alternative approaches can shape how the products perform and how they in many areas to improve product development and are priced and marketed.
access to available products. Creating an enabling As an example, the WHO's procurement service for environment could be a critical factor in stimulating diagnostics evaluates diagnostic test kits prior to their innovation, particularly where paying markets are inclusion in the Bulk Procurement Scheme. Reviewed small and resources limited. annually, test kits have to meet certain standards of performance. Negotiating with manufacturers, Clear market signals to stimulate and streamline WHO has secured assay tests at half the open market price under the Bulk Procurement Scheme. This procurement service started in 1990 to assist Member States in accessing high quality HIV test kits Market signals on both the demand and supply sides at reasonable cost, but now covers diagnostics for a could potentially enlist greater public and private range of conditions, from malaria to hepatitis B and sector engagement in R&D. Improving the demand C. In 2007 the service procured 13 million test kits for side signal could be an option not only to improve priority diseases, making substantial savings for 45 procurement and quality of products, but also to Member States, mostly low-income countries, which stimulate development to meet demand. Pooling the procured test kits under this arrangement.b procurement needs of many purchasers could enable suppliers to more easily foresee the likely demand in a Established in 2000, the Global Alliance for Vaccines market. Such efforts could also ensure greater stability and Immunization (GAVI) is a public-private partnership CHAPTER 6
which works with procurement partners and seeks involve disease-endemic countries in R&D, especially to ensure access for low and lower-middle income upstream in the drug discovery and pre-clinical countries to new and underutilized vaccines. GAVI phases. Launched in October 2008, the African prioritizes its investments in a portfolio of vaccines on Network for Drugs and Diagnostics Innovation (ANDI) the basis of various factors, from vaccine readiness seeks to promote and sustain the R&D innovation for and cost, to cases and deaths averted. Using drugs and diagnostics in disease-endemic settings. Advance Market Commitments (AMC) as a strategy, ANDI hopes to strengthen south-south research ties GAVI guaranteed a viable market to pneumococcal and to facilitate the creation of partnerships between vaccine manufacturers provided they could develop a the public and private sectors.192 vaccine meeting a predefi ned Target Product Profi le (TPP). Following this, WHO developed a TPP for Creating a trusted platform for testing and evaluating pneumococcal conjugate vaccine candidates where diagnostics could help respond to the lack of a vaccine product must meet 13 required attributes, capacity in many parts of the world. TDR obtains including serotype formulation, projected public health clinical samples from disease-endemic countries impact, safety, and suitability for use in developing for its specimen banks for TB and malaria, and country health systems.190 With support from GAVI, has carried out series of evaluations on diagnostic the Pneumococcal Global Serotype Project created tests for visceral leishmaniasis, malaria, sexually metrics that assess whether a pneumococcal vaccine transmitted infections, and CD4 counts for HIV/AIDS. matches regional serotype coverage. By examining commercially available diagnostic tests using predefi ned criteria, these evaluations TPP could also be an effective instrument in the help set standards for quality diagnostic tests and product development process and for R&D funding provide guidance for international and national level agencies and product development partnerships. In procurement.
this context, a TPP can provide a clear description of where R&D might meet an important public health need. The U.S. FDA uses TPP as a basis for communication Policies to create an enabling environmentbetween pharmaceutical companies and the agency's Of the various factors central to an enabling staff as well as with review panels.191 TPP could also environment for pharmaceutical innovation, three are be used to solicit inputs for decisions, from various probably particularly noteworthy for antibiotic R&D: stakeholders including sponsors, research personnel, (i) potential regulatory impediments to bringing health health-care workers, patients, regulatory agencies, technologies to market; (ii) strategic use of intellectual and policy-makers in disease-endemic countries. TPP property rights that might help relieve upstream could therefore be a useful approach to bring new bottlenecks in R&D, such as access to compound health technologies for combating AMR to market.
libraries; and (iii) open innovation, including open source drug discovery. These aspects are discussed Capacity strengthening at various levels to below.
enhance innovation Regulatory issues potentially shape the enabling environment for innovation, particularly for drugs. Strengthening infrastructure for R&D, including the Since 1964, antimicrobials have had among the training of research scientists, may be needed in highest rates of regulatory agency approval and many areas of the world for each stage of product shortest approval times for any therapeutic class. development across health technologies and also for Therefore regulatory restrictions would not appear to the roll-out of new products. Antimicrobial R&D efforts be the principal factor preventing antimicrobial R&D. could take a lesson from the WHO Stop TB strategy to ensure that key infrastructure and a trained workforce However, providing clear guidance on the regulatory are available in developing countries. process would benefi t companies submitting products for registration. Regulatory reforms could also be While pharmaceutical companies in industrialized envisaged to decrease the costs of clinical trials or CHAPTER 6
countries are increasingly conducting clinical trials reduce the time required for conducting them. Options in developing countries, more needs to be done to could include the review of sample size requirements, FOSTERING INNOVATION TO COMBAT ANTIMICROBIAL RESISTANCE
a fast track process for approvals, and providing market exclusivity on antibiotics to lowering intellectual incentives such as FDA priority vouchers or extended property barriers to enable greater scientifi c exchange. market exclusivity, as explained below. But as a pull mechanism, intellectual property based incentives fail to de-link recouping R&D expenses from The sample sizes for clinical trials infl uence not only volume-based sales, and so such approaches could the cost, but also the time for recruiting and enrolling encourage inappropriate marketing and irrational use patients and are dependent on the study design. of antibiotics. Careful consideration is required before Debate about the most appropriate trial design is adopting such policies into practice. still ongoing. Regulatory authorities understandably seek to avoid repeating the circumstances that led to Extending market exclusivity on a drug increases the the withdrawal of telithromycin, an antibiotic for the potential for returns on R&D investment. However, treatment of community-acquired respiratory tract delaying the entry of generic products into the market infections, after 53 cases of hepatotoxicity, including may result in monopoly pricing and so availability based deaths, were reported. In an effort to abide by earlier on price. The U.S. Orphan Drug Act approach provides agreements with industry sponsors, the U.S. FDA had an extended market exclusivity period of seven approved telithromycin solely on the basis of non- years. The judicious application of this to antibiotics inferiority trials.193 was proposed in the 2001 WHO Global Strategy for Containment of AMR (Appendix1). In September Recently the USA adopted the FDA Priority Review Voucher programme. In exchange for conducting R&D 2008, the U.S. Congress extended the market on treatments for neglected diseases and bringing the exclusivity to three years for "older" antibacterial product through the regulatory process, a company drugs approved for a new indication, and to fi ve years receives a voucher that entitles it to receive priority for a previously unapproved "older" antibacterial drug. review for another product. The benefi t of reducing With such measures already in place, the potential for the time for the FDA to act on a new drug application incremental gain from this approach may be limited. gives the voucher value, and some have estimated Intellectual property rights could also impede the voucher's value at potentially more than US$ 100 innovation and affordable access. A proliferation million per product.194 The fi rst successful applicant of patenting can create a situation where "multiple to the programme was Novartis, which received FDA owners each have a right to exclude others from a approval of Coartem®, but this was a drug added to scarce resource, while no one has an effective privilege the WHO Essential Medicines List in 2002 and already of use".197 For example, multiple building blocks of widely available in developing countries. However, the knowledge are required to develop a vaccine or to FDA priority voucher programme has been criticized adapt it to microbial strains endemic in developing on grounds that the voucher's value is not calibrated countries. An analysis of the patent holdings around to the usefulness of the drug developed, and that there ten key malarial antigens found that there were 167 are no assurances that what the industry gains from patent families, held by 75 different assignees.198 the voucher will result in more affordable products or Royalty stacking from these multiple components can even more research.195 A recent study has also raised add signifi cant cost to the fi nal product: for example, concerns about safety problems associated with accelerated regulatory deadlines.
Merck & Co pays 24%–26% royalties on worldwide sales of its cervical cancer vaccine, Gardasil®, to Another innovative approach could be to involve GlaxoSmithKline and other patent holders.199 regulatory agencies to encourage co-development of diagnostics with drugs, whereby the recruitment of Patent holdings may also present obstacles to the patients with treatment-resistant infection might be assembly of composite inventions, such as fi xed-dose made considerably more effi cient.
combination drugs for HIV/AIDS or malaria, or infl ate their combined cost. For example, in 2003 Abbott Intellectual property rights policies can have an raised the price of Norvir® (ritonavir) by 400%. This important infl uence on R&D. While judicious application price increase pushed the price of non-Abbott drug of some policies could enhance the incentive for R&D, combinations for HIV/AIDS upwards while Kaletra®, some approaches could prove to be obstacles. Policy Abbott's combination, remained at the same price proposals to encourage R&D range from extending and captured a larger market share – although still CHAPTER 6
remaining out of affordable reach for many in the initiatives could provide models for antibacterial developing world.200 compound libraries, thus lowering the entry barrier for academic research institutions and smaller fi rms to UNITAID recently launched the ‘Medicines Patent pursue these drug candidates.
Pool',201 to enable effective cross-licensing and production of fi xed-dose combination AIDS drugs, Open Source Drug Discovery is another option for particularly for second-line therapy and pediatric enabling innovation. Building on bioinformatics tools formulations. If applied to antibiotics, pooling of and web-based platforms, open source models create patents could lower transaction costs and so allow opportunities for scientists across organizations, decision-makers to target upstream (knowledge disciplines and borders to collaborate and share building blocks) or downstream (e.g. fi xed-dose information freely. Examples include the sharing combinations) innovations. of genetic sequencing data, as encouraged by the Other modes of pooling building blocks of knowledge, Bermuda Rules under the Human Genome Project, from data to compound libraries, could also help to and innovation platforms such as the Indian Council accelerate R&D not only for neglected diseases, but on Scientifi c and Industrial Research's Open Source also for health technologies to combat AMR. The U.S. Drug Discovery initiative for Tuberculosis (Box 6.3), National Institutes of Health (NIH) Molecular Libraries demonstrating the vibrant potential of online scientifi c Initiative pools compounds in a public repository. The collaboration. However, there are complexities related European Rare Disease Therapeutic Initiative and the to regulations, the need for collaboration beyond TDR programme have sought alternative approaches virtual interaction (e.g. access to laboratory facilities), to tap into proprietary compound libraries. These and a potentially complicated patent situation.
Box 6.3 Open Source Drug Discovery
Launched in 2008, the Open Source Drug Discovery (OSDD) project of India's Council of Scientifi c and Industrial Research (CSIR) is an on-line collaborative platform for projects on Mycobacterium tuberculosis, from gene sequencing to new drug development. Committed to an open source philosophy, the project requires those joining its efforts to grant back additions and modifi cations to the OSDD community under a "click-wrap license." A click-wrap license is an on-line agreement made by the user upon accepting the general conditions by clicking through. In the space of only a few years, the project has prioritized a potential drug target for TB, and enlisted hundreds of volunteers in re-annotating the TB genome within a span of four months. To date, more than 4500 participants from 130 countries are engaged in various work packages, including in silico screening, in vivo target validation, and lead molecules identifi cation. As part of the initiative, CSIR has involved multiple universities, where local infrastructure will be upgraded and students will conduct experiments related to this initiative. This initiative is still at an early stage in its development, but it represents an important advance over previous open source efforts in biomedical R&D. Financing innovation form of public sector or philanthropic funding of different stages of R&D. Two types of fi nancing options are explored in this section: (i) push mechanisms that pay for inputs of With a pledge of UK£91 million during a fi ve year period, R&D and thereby lower the risks of R&D investments the Wellcome Trust's Seeding Drug Discovery Initiative and (ii) pull mechanisms that pay for outputs of R&D attempts to advance R&D of novel small molecule and thereby offer greater assurance of a return on the drug candidates. Several projects funded under this investment or a paying market.
initiative relate to AMR, for example GlaxoSmithKline (i) Push mechanisms: Lowering the risks of R&D received UK£4 million to develop compounds for the
could entice more fi rms to pursue R&D for health treatment of Gram-negative bacteria. From 2008, the technologies to combat AMR. These could take the Innovative Medicines Initiative (IMI), a joint European FOSTERING INNOVATION TO COMBAT ANTIMICROBIAL RESISTANCE
Commission-pharma industry initiativec, is channeling and overall there is still a gap in PDPs addressing €2 billion over fi ve years into developing new drugs in these broader needs.
fi ve disease areas, including infectious diseases. (ii) Pull mechanisms: Pull mechanisms lower the risks
The U.S. NIH has also announced plans to create of market entry through a guaranteed purchase of the the National Center for Advancing Translational product. Pull mechanisms can take various forms Sciences (NCATS). NCATS will focus on "accelerating such as third party payer, government reimbursement, the development and delivery of new, more effective or awarding prizes. therapeutics." The Center will consolidate and build upon some already promising initiatives, complementing Prizes provide rewards after results are produced. This academic and private sector R&D efforts.
has the advantage of knowing with some certainty the results for which the public sector might pay, but there The increased public funding of clinical trials might also are also disadvantages that must be addressed in the lower the barriers to bringing a new antibacterial drug design of the prize. Given the "winner-takes-all" nature to the market. In return, companies could be asked for of some prizes, competitors may not be willing to share disclosure of clinical trial data and for assurances of their fi ndings or the building blocks of knowledge on the affordable pricing and rational use of their products.202 way to winning the prize, although incentives built into the design of the prize competition could mitigate these The Meningitis Vaccine Project has adapted the shortcomings. However, the prospective competitors for meningococcal conjugate vaccine to strains endemic a prize have to be suffi ciently resourced – a potentially in sub-Saharan Africa with support from a US$ 70 million signifi cant barrier – to complete the race to the fi nish Gates Foundation grant. The transfer of conjugate line. Prizes might also need to be complemented vaccine technology, which is also part of the project, builds capacity in a developing country. The by push mechanisms and other incentives that help Netherlands Vaccine Institute, through its work on lower the barrier to entry. If prizes can de-link fi nancial an international technology platform for infl uenza incentives from the subsequent volume of sales of the viruses in collaboration with WHO, has shown that product, this would realign economic incentives to another push approach might be to provide expertise encourage rational use of drugs better than incentives and training for vaccine production to multiple based on patent or market exclusivity.203manufacturers in low- and middle-income countries.d Perhaps a more recognizably traditional use of prizes Other product development partnerships (PDPs) serve is the one recently offered by the Global Alliance for by mobilizing public and private sector resources TB Drug Development to stimulate simpler and safer for R&D, connecting needed inputs, and negotiating methods for making a phase II trial of a TB drug arrangements where private sector expertise or candidate (PA-824). For prizes of US$ 20 000, 27 scale-up is required. The number of PDPs across the entities submitted proposals, and two won awards spectrum of health technologies has proliferated. FIND for their unique ideas that will be further tested by a has made signifi cant strides in advancing diagnostics contract research organization. Spurred by a proposal for TB and in negotiating concessionary prices for from Knowledge Ecology International and Médecins such tests. PATH has worked on a broad range of sans Frontières, momentum has built to consider diagnosticse specifi cally targeting low-resource how a prize might stimulate innovation of a low-cost, settings; its efforts have been important in building point-of-care, rapid diagnostic test for tuberculosis. local R&D and manufacturing capacity for diagnostics The X Prize Foundation has received a planning grant in developing countries. By lowering the risk–return from the Gates Foundation to develop an X Prize for ratio, PATH has also engaged the private sector to diagnosing tuberculosis in the developing world.204 help ensure a more sustainable delivery of products. In April 2009, Bangladesh, Barbados, Bolivia and But there remain unmet needs for antibacterial drug Suriname submitted a proposal for establishing a prize and diagnostic development for a range of diseases, fund for developing a low-cost, rapid diagnostic test c http://www.imi.europa.eu/d http://www.fl usecure.eu/e http://www.path.org/dxcenter/HomePage.php CHAPTER 6
for tuberculosis for consideration by the WHO Expert its impact as a pull mechanism for products in earlier Working Group on R&D Financing.205 stages of development cannot be judged. Secondly, there are questions regarding which companies might Another pull mechanism is the Advanced Market participate in the AMC, and particularly whether there Commitment (AMC). Conceived as a fi nancial incentive is room for the participation of manufacturers from to encourage companies to bring their products through disease-endemic countries who may not be ready to the fi nal stages to market, the AMC guarantees supply vaccines – on this issue GAVI kept the door the initial sale price of the vaccines developed to open by awarding funds to manufacturers in tranches. meet the TPP. Piloting this approach through GAVI, Thirdly, some have questioned whether the AMC fi ve countries (Canada, Italy, Norway, the Russian subsidy price plus the retail price of US$ 7.00 for Federation, and the United Kingdom) and the Gates the initial doses purchased was higher than what the Foundation contributed a total of US$ 1.5 billion to public could afford. GAVI plans an evaluation of the bring to market a late-stage pneumococcal conjugate AMC, which should inform the design of future AMCs. vaccine adapted to developing countries. With limited available evidence, the relative strengths This pilot AMC project raises important issues that and shortcomings of these different approaches are yet deserve resolution before replicating it for other to be fully defi ned. Both push and pull mechanisms, and pharmaceutical products. The pilot project focused on also the strategic use of public and philanthropic funding, a vaccine already entering phase III clinical trials, hence could leverage additional private sector resources. 4. Gaps and challenges
The main gaps and challenges involved in combating explored to ensure funding for R&D. This support can be antimicrobial resistance include the following: tied to ensuring fair returns to the public, such as through lower prices and improved rational use, and help de-link Concerted action by stakeholders: Any government,
return on investment from volume-based sales. UN agency, product development partnership, or NGO
is unlikely to be successful in stimulating R&D if acting Involvement of developing countries in R&D:
in isolation. Policies and actions to create an enabling Initiatives to encourage and support institutions in environment for innovations in technologies and drugs developing countries, including small biotechnology to combat AMR require the concerted effort of various fi rms and academic institutions, might bring new key stakeholders in both the public and private sectors.
contributors to pharmaceutical innovation. They would face lower opportunity costs and be committed to Identifying gaps and setting priorities: Although
numerous efforts are already being made to stimulate scaling up products affordably. Specimen banks
innovation, there are still many gaps in R&D across to facilitate diagnostics development, training in
a range of health technologies for products targeting different aspects of R&D from medicinal chemistry to
AMR containment. A priority-setting approach for Good Manufacturing Practice (GMP), and technical
R&D for health technologies that might, separately assistance with the regulatory process are potential
or in synergy, help combat AMR, could prove useful. measures to build local infrastructure, so that disease-
Developing TPPs could help to organize and give endemic countries can also participate in innovation.
focus to R&D. The co-development of diagnostics
with drugs might accelerate clinical trial recruitment Access to information: Obstacles in the diagnostics
R&D pipeline also include defi ciencies in the pooled as well as lower R&D costs.
knowledge of advances in biomarker research, the Alternative funding mechanisms: More could be lack of access to clinical trial data, and other important
done to improve funding mechanisms targeting R&D scientifi c information. Broader access to compound
(push mechanisms) complemented by selected pull libraries and research inputs, such as through open
mechanisms coordinated and aligned around TPPs. access repositories and open source collaboration, Several options, including public co-fi nancing, could be could lower the barrier to entry and enhance innovation. FOSTERING INNOVATION TO COMBAT ANTIMICROBIAL RESISTANCE
Chapter 7.
The way forward: political commitment to enable options for action Chapter 7.
The way forward: political commitment to enable options for action The global health crisis due to antimicrobial resistance and practical measures that work are well known and concerns us all. It is a question of whether or not there could be applied more widely. Mobilizing the necessary will be effective antibiotics to treat many important expertise and resources to mount a concerted effort to life-threatening infections in the future. AMR can be prevent and control AMR will depend on the commitment minimized, and despite knowledge gaps, the strategies of policy decision-makers across the world. The development of resistance by a growing number urgency – "no action today, no cure tomorrow" – and of pathogens to a growing number of antibiotics is call for political commitment and intensifi ed efforts to a public health problem which has been steadily apply the array of measures needed to alleviate the increasing for several decades. It has now reached a problem.206 By setting out the main facets of the AMR scale and distribution which led WHO to recognize AMR situation – what drives it, what can be done about it as a global public health crisis. AMR is both a medical – illustrated by practical experiences from around the and an economic problem, with consequences felt world, this book seeks to encourage greater national worldwide, including in lower-income countries where and international efforts and further initiatives to the burden of infectious diseases is generally greater counter AMR. and the availability, accessibility and affordability of medicines more limited. The preceding chapters of Experts agree that the recommendations made by this book have examined the main contributing factors WHO in the 2001 Global Strategy remain largely valid to the AMR problem and the strategies and measures 10 years later, but their implementation is still far from needed to deal with them, highlighting the importance universal or complete. To add impetus to national of governments in creating the enabling environment and international efforts, WHO has repeatedly called necessary to implement effective actions. Looking for action through a series of World Health Assembly ahead, the overriding message from past experience resolutionsa. All of these resolutions urged concerted is that AMR can be contained, if not totally prevented, efforts to tackle AMR at global level as a matter of and that a concerted effort could ensure that it will urgency. The WHO regional offi ces have also sought not constitute a signifi cant public health threat in the to stimulate action through several regional resolutions long term. and scientifi c forums.
The urgency of the AMR situation is now well recognized International and national actions to address AMR by most policy-makers, scientists, and professionals have shown what can be done, often with good in relevant domains, and by civil society including results, but usually these efforts have been limited in patients' advocacy groups. Combating antimicrobial scope and lacking coordination. The reasons behind resistance was chosen by WHO as the theme for World the lack of general worldwide determination to tackle Health Day 2011, to draw international attention to the AMR perhaps include a widespread assumption that a 1998 «WHA 51.17 Emerging and other communicable diseases: antimicrobial resistance»; 2001 «WHA 54.11 WHO medicines strategy»; 2001 «WHA 54.14 Global health security: epidemic alert and response»; 2005 «WHA 58.27 Improving the containment CHAPTER 7
of antimicrobial resistance»; 2007 «WHA 60.16 Rational use of medicines»; 2007 «WHA 60.20 Better medicines for children» (http://apps.who.int/gb and http://apps.who.int/gb/archive/).
scientifi c advancement will eventually resolve the Interventions, such as those focussing on hospitals, problem by bringing in an endless supply of new and pharmacies, medical and veterinary practices, are potent anti-infective medicines. But the reality is that ongoing in many countries, but very few countries have there are only very few new antibiotics on the horizon, nationally funded and coordinated comprehensive and this is not a priority for pharmaceutical companies, activities. These are mostly high-income countries with and so the effective lifespan of existing antibiotics stronger management and infrastructure capabilities, must be prolonged by preventing and controlling AMR. which have progressed further in designing, As discussed in this book, there is broad international implementing and sustaining AMR interventions and in consensus on the key areas for action and the specifi c networking and data collection. But where commitment, measures that need to be taken. As part of the six- including from the political level exists, some less point policy recommendations, the call to action wealthy countries are also making important progress on WHD 2011 highlights political commitment as a and showing the way for others. Strengthening health prerequisite for a comprehensive and coordinated systems in countries where these are weaker is an issue multi-stakeholder effort against AMR. This book for most public health initiatives, including national recognizes and stresses the crucial role of political efforts to limit the development and spread of AMR. This commitment to lead and support concerted action would enable the countries to participate in, and benefi t in all relevant domains, for the benefi t of populations fully from, global efforts to deal with the problem. The worldwide. Decisions on interventions have to balance commitment of policy decision-makers will be essential the need to provide effective antimicrobial therapy to to ensure leadership and support for these efforts.
patients today with the need to preserve the usefulness of medicines for future generations.
Although most of the large-scale actions described in this book have a ‘top down' approach instated A number of strategies and measures have been with government support, there are other successful implemented successfully, and not only in the examples where activities were initiated by a few wealthier countries, as shown by examples cited in motivated individuals and groups, and which were this book. All of those require some level of political later developed stepwise to a nationwide scale. This commitment, leadership and support. Sustaining and is probably a useful model to follow, particularly building upon these gains requires assured fi nancial, where resources for large-scale national actions are human resources and infrastructure capabilities, as is not suffi cient at the outset. It requires leadership true for most health programmes in many countries. and support from the political level fostering multi- A range of interventions are needed, but not all of stakeholder engagement and empowerment for action. them are necessary or relevant in all countries or To fi ll knowledge gaps regarding implementation, it settings. As local circumstances and current AMR is important to incorporate mechanisms to monitor statuses differ widely between and within countries, a and evaluate the impact, resource requirements and country-focused situation analysis would be a logical sustainability of the measures taken. initial step towards setting up a comprehensive anti-AMR programme. Prioritizing national strategies, The role of WHO is to facilitate action worldwide measures and resources is essential and to this through stimulating political commitment, advocating end, partnerships and closer collaboration could be for action, shaping collaborations between different fostered between policy-makers, academia, and stakeholders, facilitating development of evidence- appropriate professionals, managers, and interest based guidance, norms and standards, and tools groups. More collaboration is needed between for countries to implement specifi c interventions and disciplines within sectors as well. In the health sector, evaluations. WHO support is critical for strengthening for example, between those involved in promoting global surveillance strategies and networks, and in the rational use of medicines and those in infection defi ning an AMR research agenda.
prevention and control. In producing this book, WHO seeks to stimulate thinking and policy action in this Although there is more to be learnt about the impact of direction, by discussing the range of key issues and AMR on individuals, societies and countries, the need actions in one document, probably for the fi rst time, for additional information should not delay national to assist policy decision-makers, and raise awareness or international anti-AMR initiatives, of which there among all stakeholders concerned by AMR. are plenty of successful examples. And many more CHAPTER 7
opportunities for innovation could be exploited in areas could lead to apathy and inaction, with people feeling spanning the spectrum from scientifi c discovery, R&D that their own individual effort is not worth making. for new products, fi nancing mechanisms, regulatory On the contrary, efforts at all levels are essential aspects, to marketing and service provision. Some and advocacy is needed to convince and encourage very promising developments have already accrued people, from patients to policy-makers, to make their from recent innovations in these areas.
special contribution, and to be part of the solution rather than part of the problem. Leadership by Because AMR is a complex problem with many governments is, therefore, crucial to motivate, support diverse contributing factors, tackling it effectively has and sustain these efforts, if the way forward is to be to involve many individuals and groups in society. the way towards long-term availability of effective This may be perceived as a discouraging reality that antimicrobial medicines.
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Appendix 1
List of 2001 WHO Global Strategy for Containment of Antimicrobial Resistance recommendations
1. PATIENTS AND THE GENERAL COMMUNITY 1.1 Educate patients and the general community on the appropriate use of antimicrobials.
1.2 Educate patients on the importance of measures to prevent infection, such as immunization, vector control, use of bednets, etc.
1.3 Educate patients on simple measures that may reduce transmission of infection in the household and community, such as handwashing, food hygiene, etc.
1.4 Encourage appropriate and informed health care seeking behaviour.
1.5 Educate patients on suitable alternatives to antimicrobials for relief of symptoms and discourage patient self-initiation of treatment, except in specifi c circumstances.
2. PRESCRIBERS AND DISPENSERS 2.1 Educate all groups of prescribers and dispensers (including drug sellers) on the importance of appropriate antimicrobial use and containment of antimicrobial resistance.
2.2 Educate all groups of prescribers on disease prevention (including immunization) and infection control issues.
2.3 Promote targeted undergraduate and postgraduate educational programmes on the accurate diagnosis and management of common infections for all health care workers, veterinarians, prescribers and dispensers.
2.4 Encourage prescribers and dispensers to educate patients on antimicrobial use and the importance of adherence to prescribed treatments.
2.5 Educate all groups of prescribers and dispensers on factors that may strongly infl uence their prescribing habits, such as economic incentives, promotional activities and inducements by the pharmaceutical industry.
Management, guidelines and formularies
2.6 Improve antimicrobial use by supervision and support of clinical practices, especially diagnostic and treatment strategies.
2.7 Audit prescribing and dispensing practices and utilize peer group or external standard comparisons to provide feedback and endorsement of appropriate antimicrobial prescribing.
2.8 Encourage development and use of guidelines and treatment algorithms to foster appropriate use of antimicrobials.
2.9 Empower formulary managers to limit antimicrobial use to the prescription of an appropriate range of selected antimicrobials.
2.10 Link professional registration requirements for prescribers and dispensers to requirements for training and continuing education.
3.1 Establish infection control programmes, based on current best practice, with the responsibility for effective management of antimicrobial resistance in hospitals and ensure that all hospitals have access to such a programme.
3.2 Establish effective hospital therapeutics committees with the responsibility for overseeing antimicrobial use in hospitals.
3.3 Develop and regularly update guidelines for antimicrobial treatment and prophylaxis, and hospital antimicrobial formularies.
3.4 Monitor antimicrobial usage, including the quantity and patterns of use, and feedback results to prescribers.
3.5 Ensure access to microbiology laboratory services that match the level of the hospital, e.g. secondary, tertiary.
3.6 Ensure performance and quality assurance of appropriate diagnostic tests, microbial identifi cation, antimicrobial susceptibility tests of key pathogens, and timely and relevant reporting of results.
3.7 Ensure that laboratory data are recorded, preferably on a database, and are used to produce clinically- and epidemiologically-useful surveillance reports of resistance patterns among common pathogens and infections in a timely manner with feedback to prescribers and to the infection control programme.
Interactions with the pharmaceutical industry
3.8 Control and monitor pharmaceutical company promotional activities within the hospital environment and ensure that such activities have educational benefi t.
4. USE OF ANTIMICROBIALS IN FOOD-PRODUCING ANIMALS 4.1 Require obligatory prescriptions for all antimicrobials used for disease control in foodanimals.
4.2 In the absence of a public health safety evaluation, terminate or rapidly phase out the use of antimicrobials for growth promotion if they are also used for treatment of humans.
4.3 Create national systems to monitor antimicrobial usage in food animals.
4.4 Introduce pre-licensing safety evaluation of antimicrobials with consideration of potential resistance to human drugs.
4.5 Monitor resistance to identify emerging health problems and take timely corrective actions to protect human health.
4.6 Develop guidelines for veterinarians to reduce overuse and misuse of antimicrobials in food animals.
5. NATIONAL GOVERNMENTS AND HEALTH SYSTEMS Advocacy and intersectoral action
5.1 Make the containment of antimicrobial resistance a national priority.
— Create a national intersectoral task force (membership to include health care professionals, veterinarians, agriculturalists, pharmaceutical manufacturers, government, media representatives, consumers and other interested parties) to raise awareness about antimicrobial resistance, organize data collection and oversee local task forces. For practical purposes such a task force may need to be a government task force which receives input from multiple sectors.
— Allocate resources to promote the implementation of interventions to contain resistance. These interventions should include the appropriate utilization of antimicrobial drugs, the control and prevention of infection, and research activities.
— Develop indicators to monitor and evaluate the impact of the antimicrobial resistance containment strategy.
5.2 Establish an effective registration scheme for dispensing outlets.
5.3 Limit the availability of antimicrobials to prescription-only status, except in special circumstances when they may be dispensed on the advice of a trained health care professional.
5.4 Link prescription-only status to regulations regarding the sale, supply, dispensing and allowable promotional activities of antimicrobial agents; institute mechanisms to facilitate compliance by practitioners and systems to monitor compliance.
5.5 Ensure that only antimicrobials meeting international standards of quality, safety and effi cacy are granted marketing authorization.
5.6 Introduce legal requirements for manufacturers to collect and report data on antimicrobial distribution (including import/export).
5.7 Create economic incentives for appropriate use of antimicrobials.
Policies and guidelines
5.8 Establish and maintain updated national Standard Treatment Guidelines (STGs) and encourage their implementation.
5.9 Establish an Essential Drugs List (EDL) consistent with national STGs and ensure the accessibility and quality of these drugs.
5.10 Enhance immunization coverage and other disease preventive measures, thereby reducing the need for antimicrobials.
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.
5.12 Ensure that prescribers have access to approved prescribing literature on individual drugs.
Surveillance of resistance, antimicrobial usage and disease burden
5.13 Designate or develop reference microbiology laboratory facilities to coordinate effective epidemiologically sound surveillance of antimicrobial resistance among common pathogens in the community, hospitals and other health care facilities. The standard of these laboratory facilities should be at least at the level of recommendation 3.6.
5.14 Adapt and apply WHO model systems for antimicrobial resistance surveillance and ensure data fl ow to the national intersectoral task force, to authorities responsible for the national STGs and drug policy, and to prescribers.
5.15 Establish systems for monitoring antimicrobial use in hospitals and the community, and link these fi ndings to resistance and disease surveillance data.
5.16 Establish surveillance for key infectious diseases and syndromes according to country priorities, and link this information to other surveillance data.
6. DRUG AND VACCINE DEVELOPMENT 6.1 Encourage cooperation between industry, government bodies and academic institutions in the search for new drugs and vaccines.
6.2 Encourage drug development programmes which seek to optimize treatment regimens with regard to safety, effi cacy and the risk of selecting for resistant organisms.
6.3 Provide incentives for industry to invest in the research and development of new antimicrobials.
6.4 Consider establishing or utilizing fast-track marketing authorization for safe new agents.
6.5 Consider using an orphan drug scheme where available and applicable.
6.6 Make available time-limited exclusivity for new formulations and/or indications for use of antimicrobials.
6.7 Align intellectual property rights to provide suitable patent protection for new antimicrobial agents and vaccines.
6.8 Seek innovative partnerships with the pharmaceutical industry to improve access to newer essential drugs.
7. PHARMACEUTICAL PROMOTION 7.1 Introduce requirements for pharmaceutical companies to comply with national or international codes of practice on promotional activities.
7.2 Ensure that national or internationally codes of practice cover direct-to-consumer advertising, including advertising the Internet.
7.3 Institute systems for monitoring compliance with legislation on promotional activities.
7.4 Identify and eliminate economic incentives that encourage inappropriate antimicrobial use.
7.5 Make prescribers aware that promotion in accordance with the datasheet may not necessarily constitute appropriate antimicrobial use.
8. INTERNATIONAL ASPECTS OF CONTAINING ANTIMICROBIAL RESISTANCE 8.1 Encourage collaboration between governments, non-governmental organizations, professional societies and international agencies to recognize the importance of antimicrobial resistance, to present consistent, simple and accurate messages regarding the importance of antimicrobial use, antimicrobial resistance and its containment, and to implement strategies to contain resistance.
8.2 Consider the information derived from the surveillance of antimicrobial use and antimicrobial resistance, including the containment thereof, as global public goods for health to which all governments should contribute.
8.3 Encourage governments, non-governmental organizations, professional societies and international agencies to support the establishment of networks, with trained staff and adequate infrastructures, which can undertake epidemiologically valid surveillance of antimicrobial resistance and antimicrobial use to provide information for the optimal containment of resistance.
8.4 Support drug donations in line with the UN interagency guidelines*.
8.5 Encourage the establishment of international inspection teams qualifi ed to conduct valid assessments of pharmaceutical manufacturing plants.
8.6 Support an international approach to the control of counterfeit antimicrobials in line with the WHO guidelines**.
8.7 Encourage innovative approaches to incentives for the development of new pharmaceutical products and vaccines for neglected diseases.
8.8 Establish an international database of potential research funding agencies with an interest in antimicrobial resistance.
8.9 Establish new, and reinforce existing, programmes for researchers to improve the design, preparation and conduct of research to contain antimicrobial resistance.
* Interagency guidelines. Guidelines for Drug Donations, revised 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 Organization, 1999. WHO/EDM/QSM/99.1.
Appendix 2
2011 World Health Day six point policy brief
1. Commit to a comprehensive, fi nanced national plan with accountability and civil society a. Provide stewardship and coordinationb. Cost plans and mobilize resourcesc. Build Partnerships with civil society 2. Strengthen surveillance and laboratory capacity a. Establish AMR surveillance and monitoring systemsb. Build laboratory capacity for rapid and reliable diagnostic testingc. Engage in regional and global surveillance networks 3. Ensure uninterrupted access to essential medicines of assured quality a. Reinforce the system for supply of essential medicinesb. Assure the quality of drugs according to international standards 4. Regulate and promote rational use of medicines, including in animal husbandry, and ensure proper patient care a. Promote and enforce standard treatment guidelinesb. Enforce prescription-only use of antimicrobialsc. Promote education on antimicrobial medicines and their used. Reduce antimicrobial use in food-producing animals (i) Provide national leadership and promote intersectoral collaboration(ii) Create and enforce an enabling regulatory framework(iii) Strengthen surveillance and monitoring(iv) Promote education and training on antimicrobial use in food-producing animals(v) Reduce the need for antimicrobials through better animal husbandry e. Work to reduce fi nancial incentives that encourage irrational use of medicines 5. Enhance infection prevention and control a. Ensure availability of IPC programmes across the spectrum of health care, that include core elementsb. Foster basic IPC standards in congregate settingsc. Promote standards IPC measures and provide education on IPC in the community setting 6. Foster innovations and research and development for new tools a. Improve the use of current diagnostics and antimicrobialsb. Create incentives for new product developmentc. Enable rapid regulatory processes for new tools and equitable access List of authors,
contributors and

List of Authors, contributors and reviewers
(listed in alphabetic order in each section) Chapter 1. The evolving threat of antimicrobial resistance
Authors: M. Lindsay Grayson, University of Melbourne, Australia; David Heymann, Health Protection Agency, UK;
Didier Pittet, Hôpitaux Universitaires de Genève, Switzerland.
Chapter 2. Surveillance to track antimicrobial use and resistance
Authors: Hajo Grundmann, National Institute for Public Health and the Environment, The Netherlands; Thomas F.
O'Brien, Brigham and Women's Hospital, USA; John M. Stelling, Brigham and Women's Hospital, USA.
Contributors: Luis Bavestrello Fernández, Centro Médico Clinica Reñaca, Chile; John Chalker, Management Sciences for Health, USA; Marcelo Galas, Instituto Nacional de Enfermedades Infecciosas, Argentina; Herman Goossens, University of Antwerp, Belgium; Elizabeth Mathai, World Health Organization, Switzerland; Sachiko Satake, Gunma University, Japan.
Chapter 3. Measures to ensure better use of antibiotics
Authors: Otto Cars, Action on Antibiotic Resistance (ReAct), Sweden; Andreas Heddini, Action on Antibiotic Resistance
(ReAct), Sweden; Stuart Levy; Tufts University School of Medicine, USA.
Contributors: Inge Gyssens, Radboud University Nijmegen Medical Centre, The Netherlands; Stephan Harbarth, Hôpitaux Universitaires de Genève, Switzerland; Kathleen Holloway, WHO Regional Offi ce for South-East Asia, India; Keith P. Klugman, Emory University, USA; David Ofori-Adjei, Centre for Tropical Clinical Pharmacology and Therapeutics, Ghana; Iruka Okeke, Haverford College, USA; Eva M.A. Ombaka, Business Network International (BNI) Tanzania Pwani, United Republic of Tanzania; Chitr Sitthi-Amorn, Chulalongkorn University, Thailand.
Chapter 4. Reducing Antimicrobial use in Animal Husbandry
Authors: Frank M. Aaerestrup, Technical University of Denmark, Denmark; Awa Aidara-Kane, World Health
Organization, Switzerland.
Contributors: Peter Collignon, Canberra Hospital, Australia; Ran Lu, Chinese Center for Disease Control and Prevention, People's Republic of China; Scott McEwen, University of Guelph, Canada; Eric Mitema, University of Nairobi, Kenya; Gérard Moulin, Agence Nationale du Médicament Vétérinaire (ANMV), France; Enrique Perez-Gutierrez, World Health Organization, Republic of Panama; H. Morgan Scott; Kansas State University College of Veterinary Medicine, USA. Chapter 5. Prevention and control of infection in the health care facilities
Authors: Barry Cookson, Health Protection Agency, UK; Petra Gastmeier, Charité University Hospital, Germany; Wing-
Hong Seto, Queen Mary Hospital, Hong Kong SAR, People's Republic of China.
Contributors: Benedetta Allegranzi, World Health Organization, Switzerland; Hu Bijie, Zhongshan Hospital of Fudan University, People's Republic of China; Ian Gould, Aberdeen Royal Infi rmary, UK; Victor Lim, International Medical University, Malaysia; Ralf-Peter Vonberg, Institute for Medical Microbiology and Hospital Epidemiology, Germany. Chapter 6. Fostering Innovation to Combat Antimicrobial Resistance
Authors: Shaoyu Chang, Duke University, USA; Anthony So; Duke University, USA.
Contributors: Robert A. Bonomo, Case Western Reserve University, USA; Kelly Chibale, University of Cape Town, South Africa; Ramanan Laxminarayan, Center for Disease Dynamics, Economics and Policy, USA; Evan Lee, Foundation for Innovative New Diagnostics (FIND), Switzerland; Rohit Malpani, Oxfam America, USA; Piero Olliaro, UNICEF/UNDP/World Bank/WHO Special Programme on Research and Training in Tropical Diseases, Switzerland; Rosanna Peeling, The London School of Hygiene and Tropical Medicine, UK; Nina Schwalbe, Global Alliance for Vaccines and Immunization, Switzerland; Els Torreele, Open Society Foundations, USA; Bernhard H. Weigl; PATH, USA.
Chapter 7. The way forward: political commitment to enable options for action
Authors: Gerald Dziekan, Itziar Larizgoitia Jauregui, and Elizabeth Mathai, World Health Organization, Switzerland .
Alix Beith, Center for Disease Dynamics, Economics & Policy, USA; John Conly, University of Calgary/Alberta Health
Services, Canada; Gabriel Levy Hara, Maimónides University, Argentina; David Heymann, Health Protection Agency,
UK; Po-Ren Hsueh, National Taiwan University, Taiwan, People's Republic of China; Mohan P. Joshi, Strengthening
Pharmaceutical Systems, USA; Niyada Kiatying-Angsulee, Chulalongkorn University, Thailand; Anke Meiburg,
Ecumenical Pharmaceutical Network (EPN), Kenya; Lindsay Nicolle, University of Manitoba, Canada; Arturo Quizhpe
Peralta, University of Cuenca, Ecuador; Didier Pittet, Hôpitaux Universitaires de Genève, Switzerland; Victor Rosenthal,
International Nosocomial Infection Control Consortium (INICC), Argentina; Gunnar Skov Simonsen, University Hospital
of North Norway, Norway; Arjun Srinivasan, Centers for Disease Control and Prevention (CDC), USA; Evelina Tacconnelli,
Università Cattolica del Sacro Cuore, Italy; Linda Tollefson Food and Drug Administration, USA; as well as all authors.
World Health Organization Headquarters, Switzerland
Susanne Carai, Yves Chartier, Daniel Chemtob, Sergey Romualdovich Eremin, Dennis Falzon, Martin Friede, Tauhidul
Islam, Ernesto Jaramillo, Douglas Macpherson, Paul Nunn, Charles Penn, Carmem Lucia Pessoa Da Silva, Mario
Raviglione, Douglas Wares, Diana Weil, Matteo Zignol.
World Health Organization Regional Offi ces
WHO Western Pacifi c Region: Henk Jan Bekedam, Eva-Maria Christophel, Catharina van Weezenbeek.
WHO Region of the Americas: Jose Luis Castro, Jorge Matheu, Pilar Ramon Pardo.
Consultation process participants Frank M. Aaerestrup, Denmark; Awa Aidara-Kane, WHO; Benedetta Allegranzi, WHO; Luis Bavestrello Fernandez, Chile; Sepideh Bagheri Nejad, WHO; Silvia Bertagnolio, WHO; Hu Bijie, People's Republic of China; Robert A. Bonomo, USA; Andrea Bosman, WHO; Samir Brahmachari, India; Jean Carlet, France; Yehuda Carmeli, Israel; Otto Cars, Sweden; John Chalker, USA; Shaoyu Chang, USA; May Chu, WHO; Sébastien Cognat, WHO; Peter Collignon, Australia; Barry Cookson, UK; Sara E. Cosgrove, USA; Sarah Deeny, UK; Sir Liam Donaldson, UK; Gerald Dziekan, WHO; Sittana S. Elshafi e, Qatar; Dennis Falzon, WHO; Christophe Fraser, UK; Martin Friede, WHO; Marcelo Galas, Argentina; Petra Gastmeier, Germany; Hellen Gelband, USA; Herman Goossens, Belgium; Ian Gould, UK; Felix Greaves, WHO; Hajo Grundmann, The Netherlands; Inge Gyssens, The Netherlands; Valentina Hafner, WHO; Julie Hall, WHO; Stephan Harbarth, Switzerland; Andreas Heddini, Sweden; Ole Heuer, Sweden; David Heymann, UK; William Hanage, UK; Kathleen Holloway, WHO; Ernesto Jaramillo, WHO; Edward Kelley, WHO, Iain Kennedy, WHO; Keith Klugman, USA; Paul Lalvani, USA; Angela Lashoher, WHO; Itziar Larizgoitia Jauregui, WHO; Ramanan Laxminarayan, USA; Evan Lee, Switzerland; Stuart Levy, USA; Victor Lim, Malaysia; Knut Lonnroth, WHO; Ran Lu, People's Republic of China; Elizabeth Mathai, WHO; Colin Mathers, WHO; Scott McEwen, Canada; Eric Mitema, Kenya; Gérard Moulin, France; Doris Murgditchian, WHO; Nabila N'Metwalli, WHO; Lai King Ng, WHO; David Ofori-Adjei, Ghana; Iruka Okeke, USA; Eva M.A. Ombaka, United Republic of Tanzania; Fernando Otaiza, WHO; Enrique Perez-Gutierrez, Republic of Panama; Carmem Pessoa da Silva, WHO; Pauline Philip, WHO; Didier Pittet, Switzerland; Rose Pray, WHO; John Rainford, WHO; Pilar Ramon Pardo, PAHO/WHO; Cathy Roth, WHO; Matthew Samore, USA; Sachiko Satake, Japan; Fabio Scano, WHO; Nina Schwalbe, Switzerland; H. Morgan Scott, USA; Wing-Hong Seto, Hong Kong SAR, People's Republic of China; Marcus Shepheard, UK; Chitr Sitthi-Amorn, Thailand; Ian Smith, WHO; Anthony So, USA; Sri Suryawati, Indonesia; John Stelling, USA; Vivian Tang, WHO; Wayne Van Gemert, WHO, Ralf-Peter Vonberg, Germany; Mohammad Youssef, WHO; Matteo Zignol, WHO.
Book editing and project management Editing: Lindsay Martinez, Switzerland.
Project management: Gerald Dziekan, Itziar Larizgoitia Jauregui, Elizabeth Mathai, with the support of Katthyana Aparicio, Armorel Duncan, Margaret Kahuthia and Laura Pearson, WHO, Switzerland. The evolving threat of antimicrobial resistance Options for action World Health Organization
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E DEL LAMBRUSCO 20/21 - 27/28 dell'Amministrazione insieme e senza paura sono Fabio Franceschini, Vostro nuovo Sindaco dal 26 maggio scorso. Partiamo con qualche dato personale. Portate pazienza ma non tutti mi conoscono bene e prometto che questa sarà la prima e ultima volta che vi assillerò con sciocchezze personali. Dunque, sono nato il 17 marzo 1963 a Modena, dal 1994 sono sposato con Mariella ed ho


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