Oslo, Background document Commitments to Responsible Use of Antimicrobials in Humans

Transcription

1 Background document Commitments to Responsible Use of Antimicrobials in Humans November 2014, Oslo, Norway Executive summary Antimicrobial resistance is a major concern to public health, threatening the progress made in treatment of infectious diseases as well as advances in modern medicine. The use of antimicrobials is strongly linked to the development of antimicrobial resistance. It is therefore of great importance to find ways to assure responsible use, balancing between minimizing unnecessary use without compromising the health of the individual. The use of antimicrobials in food production and agriculture has further aggravated the problem. There is an urgent need for international multisectoral collaboration, based on a One Health approach to combat antimicrobial resistance. The success of the Global Action Plan is depending on responsible, collaborative efforts at different levels international, regional and national. The action plan aims to develop a shared understanding of the global need to control antimicrobial resistance, and identifying actions to optimize the use of antimicrobial agents in human and veterinarian medicine, to improve the knowledge and understanding of the problem, improve surveillance on resistance and use, promote research and development of new antimicrobials, and finally to develop effective interventions for prevention and control. 1

2 EXECUTIVE SUMMARY... 1 INTRODUCTION... 2 BACKGROUND... 3 The global situation on antimicrobial resistance... 3 Significant gaps in surveillance of antimicrobial resistance and use... 5 The need for standardized methodology for data collection on antibacterial use... 7 NON-HUMAN USE OF ANTIMICROBIALS IN AGRICULTURE, LIVESTOCK, AND FISH FARMS... 7 MALARIA, TUBERCULOSIS, HIV/AIDS... 8 ECONOMIC BURDEN OF ABR/AMR... 9 ACCESS TO ANTIMICROBIALS... 9 INTERVENTIONS TO PROMOTE RESPONSIBLE USE OF ANTIBIOTICS PRESCRIPTION DRUGS AND ANTIBIOTIC STEWARDSHIP PROGRAMS REGULATING OTC SALES AND SELF-MEDICATION Substandard/spurious/falsely-labeled/falsified/counterfeit medical products PUBLIC CAMPAIGNS AND EDUCATION POLICIES TO ADDRESS ANTIBIOTIC RESISTANCE THE NEED TO REGULATE MARKETING INTERVENTIONS TO STRENGTHEN PREVENTION RESEARCH AND DEVELOPMENT OF NEW AND NOVEL ANTIBIOTICS THE NEED FOR A GLOBAL COLLABORATION CONCLUSION REFERENCES: Introduction In May 2014 the Sixty-seventh World Health Assembly adopted resolution WHA67.25 on antimicrobial resistance, requesting the Director-General to develop a draft global action plan to combat antimicrobial resistance (AMR), including antibiotic resistance (ABR). In support of this work Member States, key stakeholders and the Secretariat are convening a number of high-level technical, political and interagency consultations to contribute to the global action plan. The present background document intends to support the consultation on responsible human use and access to antibiotics hosted by Brazil, France, Indonesia, Norway, Senegal, South Africa and Thailand, organized together with the WHO (Oslo, November 2014). The outcome of the consultation will inform revisions of the draft AMR global action plan before its submission to the 68 th World Health Assembly in May

3 Background The concept of AMR is as old as the earliest use of antibiotics (ref Flemings Nobel prize speech). However, during the last three decades the phenomenon has accelerated, while at the same time the development of novel antimicrobials has slowed dramatically. This profoundly threatens the progress in medical treatment and public health, achieved by antimicrobials over the past seven decades. The rapid progression in the global spread of multidrug-resistant bacteria is a threat to low-, middle- and high-income countries alike. The consequences for children, pregnant women, immune compromised people (people living with HIV/AIDS), and other vulnerable groups, will be especially serious. In low-income countries (LIC) vulnerable groups will be faced with the double burden of both limited access to antimicrobials and declining effectiveness of those they can access. Advances in modern medicine will be at risk, as surgical procedures e.g. organ transplantation and hip replacements, as well as treatment of cancer patients undergoing chemotherapy rely on effective antibiotics (1). Another worrisome aspect is the rapid increase in healthcare associated infections (HAI), which is estimated to be twice as prevalent in low- and middle-income countries (LMIC) compared to highincome countries (HIC). This also raises the healthcare costs, often for those who can least afford it. The AMR microbes do not respect geographical borders and are spread by travel, food export/import, contamination of the environment, by husbandry trade and wildlife (animals and migrating birds) (2). Exemplified by the emergence and worldwide spread of carbapenemases among the Enterobacteriaceae family of bacteria (3). The challenges posed by AMR are global, and efforts to control it are in urgent need of international multisectoral collaboration and cooperation. The main driver of AMR is the misuse and overuse of antimicrobials. The following section will outline the global situation on AMR prevalence and consumption of antibiotics, with a focus on ABR. The background document will briefly discuss the association between these, and provide an overview of interventions aimed at improving responsible use of antimicrobials in humans. R&D for new antimicrobials and surveillance, of both AMR and antimicrobial human and non- human use, will be addressed briefly in order to give a more complete view of the problem. The global situation on antimicrobial resistance In June 2014 WHO published the first global report on AMR and surveillance (4).The report focus on a set of nine bacteria antibacterial drug combinations of public health importance, and examines the status on AMR surveillance at country level worldwide, up to 2011 (Table 1 adapted from reference 4). 3

4 Bacteria commonly causing infections in hospitals and in the community Name of bacterium/ Resistance No. out of 194 Member States providing data No. of WHO regions with national reports of 50% resistance or more Escherichia coli/ -vs 3 rd gen. cephalosporins -vs fluoroquinolones Klebsiella pneumoniae/ -vs 3 rd gen. cephalosporins - vs 3 rd carbapenems /6 5/6 6/6 2/6 Staphylococcus aureus/ -vs methicillin MRSA 85 5/6 Bacteria mainly causing infections in the community Name of bacterium/ Resistance No. out of 194 Member States providing data No. of WHO regions with national reports of 25% resistance or more Streptococcus pneumoniae/ -non-susceptible or resistant to 67 6/6 Penicillin Nontyphoidal Salmonella/ -vs fluoroquinolones 68 3/6 Shigella species/ -vs fluoroquinolones 35 2/6 Neisseria gonorrhea/ -vs 3 rd gen. cephalosporins 42 3/6 Table 1: Survey results from the WHO Global Report on Surveillance of Antimicrobial Resistance. The report shows that AMR has spread to all WHO regions, leading to lack of oral treatment options, increasing demand for intravenous treatment, increased health care costs and in worst case no treatment option at all. E.coli and K. pneumoniae, bacteria associated with common infections such as urinary tract infections as well as severe infections such as sepsis, show a high level of resistance to third generation cephalosporins. In these cases patients will have to rely on the access and effectiveness of carbapenems, an expensive last line drug. Of great concern is the emerging K. pneumoniae resistance to carbapenems. Methicillin resistant Staphylococcus aureus (MRSA) is found in more than 50% of available isolates, and penicillin resistant Streptococcus pneumoniae in more than 25% of available isolates. Nontyphoidal Salmonella (NTS) and Shigella species, together causing over 250 million infections globally and more than 1 million deaths, predominantly in the younger populations, shows an increase of resistance towards flouroquinolones leaving oral treatments, such as ciprofloxacin, useless. In 2008 it was estimated that the worlds population experienced 106 million new cases of gonorrhea, with a large proportion showing clear evidence of resistance to previously effective antibiotics. Decreased susceptibility to third-generation cephalosporin means not only that monotherapy is becoming ineffective, but that infected individuals with genital sores will be at higher risk of transmitting HIV, adding to the still raging HIV/AIDS epidemic (5). 4

5 Significant gaps in surveillance of antimicrobial resistance and use Reliable surveillance systems of human and non-human antimicrobial use and resistance are essential to design evidence based strategies to combat AMR. Surveillance of antimicrobial resistance The 2014 WHO report reveals serious limitations related to surveillance. Out of 194 member states, status of surveillance was provided by 129 member states, while only 114 provided actual surveillance data. 22 countries provided data on all nine combinations. The ABR rates presented are a compilation of data from surveillance programmes (often based on a small number of tested isolates of the bacterium, <30) and from scientific journal articles. Interpretation of the report needs to be done with caution since there is no agreed global standard for AMR surveillance. The report is however, despite its weaknesses, the best available indicator of the current global status of AMR and surveillance. This highlights the need for improved documentation and reporting of surveillance data. Today, only two of the WHO regions (PAHO, EURO) have regional surveillance systems. WHO Region AMRO Status of Surveillance ReLAVRA (19 Latin American countries including Canada and the US) SIREVA II (surveillance on pneumonia and meningitis) EURO EARS-NET (28 countries; EU-members+ Norway and Iceland) CAESAR (non EU-members) SEARO Six out of eleven countries have national surveillance systems. Members of the region signed the Jaipur Declaration committing to combat AMR including contribute with information to a regional database WPRO Well-established national surveillance systems in most HIC, no regional surveillance system on AMR EMRO Well-functioning surveillance systems for some specific infections (TB, HIV, malaria), but no regional collaboration on surveillance on AMR AFRO No regional network. Initiatives for national collaborations have been made, but due to lack of resources and strong implementation bodies no regional systems exist Table 2: Status of regional surveillance systems in the WHO regions. Most surveillance data is based in isolates from hospital settings, giving little information about the situation in community settings. It could therefore be argued that available data exaggerates the problem, given that patients in need of hospital care often suffer from severe illness, which does not reflect the situation of outpatient care. To 5

6 further address the prevalence of AMR in the community among healthy individuals, ESBL-E faecal carriage (i.e. people colonized but not infected) has been studied. A present review by Woerther et al. show an evident increase in all regions of the world, developing countries being affected the most (figure 2)(6). Figure 1: Trends in human fecal carriage of extendedspectrum beta-lactamases in the community It is evident that resistant bacteria are well established in hospitals and in the community, and it is of great importance for all countries to collect data from both inpatient and out-patient settings, including people living in rural and urban areas. For instance, it has been shown that children living in rural areas of Vietnam have 22 times higher resistance rates than in urban areas (7). Equally important, is to create parallel surveillance systems for antimicrobial use and resistance in animals and agriculture, exemplified by the Food borne Disease and Zoonoses Network (FWD-Net), collecting ABR data from foodborne bacteria, and the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC), monitoring use of antimicrobials in animals across the EU. Surveillance of antimicrobial use Data on antimicrobial use in humans, animals, food production and agriculture is still not available for most countries. When data is available, it is often collected through surveys and measured by number of packages, which imply that we do not have information of actual pharmacological potency. In many HIC, methodology is in place to perform routine surveillance of human use of antibiotics, but antibiotic surveillance data in the animal and agriculture sector are scarce. The most recent one, by Van Boeckel et al. (8) is based on sales data from retail and hospital pharmacies in 71 countries, derived from the IMS Health MIDAS database. The report shows that global consumption of antibiotics has increased by 36% between 2000 and Six countries or regional groupings (Brazil, Russia, India, China, South Africa and French West Africa) accounted for 76% of the increase in consumption. As pointed out, these countries only stand for a 33% of the total increase of the global population during this period, indicating that the increase in use of antibiotics is driven by other factors than population growth alone. 6

7 Cephalosporins and broad-spectrum penicillins represented 55% of the worldwide consumption in 2010, making them the most frequently used antibiotics. Alarmingly, there was a 45% increase in use of carbapenems and 13% of polymixins, which are two last-resort classes of antibiotics. Drug utilisation research shows a large variation among regions and countries. The reasons for variations are multifactorial; differences in health systems, demographic structure and socioeconomic factors, density of general practitioners and their remuneration incentives, population income, ethnicity, cultural differences, strength of authority control (e.g. regulations of pharmaceutical market, restrictions on prescribing, educational and marketing activities towards prescribers and population, availability of guidelines etc.) (9-11). Antibiotics are also being overused and used inappropriately in HIC with legal restrictions on antibiotic sales in place and available updated guidelines on rational use, which is a significant problem. This is exemplified by physicians treating patients suffering from viral upper respiratory infections with antibiotics. The need for standardized methodology for data collection on antimicrobial use At present there is no common globally established methodology to collect standardized data on the usage of antimicrobial agents for humans and animals, including aquatic species. The IMS data are collected with the purpose of marketing and sales and these data are not available for public use. The ATC/DDD methodology is recommended by the WHO for drug utilisation. Many countries and regional institutions such as OECD health statistics and ECDC present routine data on human antibiotic use using this methodology to evaluate aggregated human drug use in their country/region (12-14). The US do not use the ATC/DDD methodology for routine surveillance in out-patients; instead antibiotic use is measured by prescriptions per 1000 inhabitants (15). In Scandinavia both methodologies are used. A similar methodology for animals, the ATCvet, is linked to the ATC/DDD methodology. AGISAR (WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance) and the ATCvet has been used by the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC), to collect data across the European Union on antibiotic use in animals (including the use in aquatic farming) (ATCvet index and ESVAC) (16, 17). Non-human use of antimicrobials in agriculture, livestock, and fish farms In addition to use of antimicrobials for treatment of active infections in animals, antimicrobials are often used metaphylactic, preventive and/or as growth promoters. In most parts of the world antimicrobial agents are used as growth promoters at low doses in animal feeding-stuff with the purpose to improve productivity. In 1 January 2006 the authorizations of all antimicrobial agents for use as growth promoters were withdrawn in the EU. This is, however, not the case in other regions of the world. For 7

8 example, it is estimated that more than 80% of all antibiotics used in the US is used within the food and agricultural industry (18). This has been formally discouraged by the US FDA in The use of antimicrobials in agriculture outside livestock and pets is poorly described, and the effect on the prevalence and development of AMR is mainly unknown. Malaria, Tuberculosis, HIV/AIDS Tuberculosis, Human Immunodeficiency Virus (HIV), and malaria are some of the worlds leading infectious killers, with the greatest impact in LMIC. WHO estimated 1.5 million deaths caused by HIV/AIDS, and tuberculosis respectively in 2013 (19, 20), and more than deaths caused by malaria in 2012 (21). However, great progress has been made. Since 1990 deaths caused by tuberculosis has decreased by 45% (20). The number of new HIV infections has declined by 19% over the past decade. Antiretroviral therapy for HIV-infected people now reaches 35% of people in need of treatment in LMIC, and deaths related to AIDS decreased by 19 % between 2004 and 2009 (22). Efforts to prevent, treat and eradicate malaria have led to a reduction of mortality by almost 50% since the beginning of the century (21). Strong political commitment and global collaboration on these vertical programs have played a major role in this achievement. However, the progress is threatened by the development of AMR. Approximately 0.5 million cases of multidrug resistant tuberculosis (MDR-TB) were reported last year (20). Drug resistance to antiretroviral therapy is being monitored, and resistance has been detected in three out of five malaria species so far. Due to the increase of resistance related to monotherapies, Artemisinin-based Combination Therapy (ACT) is considered the most effective and safe treatment option. A cause for concern is therefore the development of resistance towards artemisinin, detected and confirmed in a limited area within the Greater Mekong subregion (23). The work to prevent the spread and supply treatment for tuberculosis, HIV/AIDS, and malaria has been through a rapid scale up during the past decade. This is partly due to the success of organizations such as UNAIDS, WHO and CDC to bring these issues to the global health agenda. The Millennium Goals address the need to prevent and treat infectious diseases. However, HIV/AIDS, tuberculosis and malaria are highlighted as three important issues generating strong political commitment and financial support. Valuable lessons can be learned from the work being done to combat tuberculosis, HIV/AIDS, and malaria. The activities of the Green Light Committee (GLC) Initiative is aiming at achieving universal access to prevention, early diagnosis and effective patientcentered treatment for drug resistant tuberculosis, the experiences from the initiative may inform the implementation of the global action plan on AMR. Another example is the Global Plan for Artemisinin Resistance Containment (GPARC) that aims to assure the 8

9 continued effectiveness of artemisinin as a treatment for P. falciparum malaria. One of the key objectives is to increase surveillance of drug efficacy, which was only carried out by 35% of countries endemic for P. falciparum malaria in the period (23). An interesting addition to the GARPC is the emergency mobilization plan, offering global guidance on how to combat artemisinin resistant malaria if it spreads more rapidly than anticipated (23). There are still many uncertainties regarding the full societal effect of AMR and how quickly it will spread. An emergency response plan is therefore an interesting idea. Economic burden of ABR/AMR Attempts have been made to estimate the economic burden of AMR, but due to insufficient surveillance of antibiotic use and resistance there is limited knowledge of the true cost of resistance, especially in LMIC. ABR is related to a direct cost generated by prolonged need for hospital care, longer treatment courses, and more expensive drugs but, ABR also generates an indirect costs (24). In 2013 CDC estimated that 2 million Americans become ill from resistant infections each year out of which die (25). It has been estimated that the yearly cost to the US health system alone lies somewhere between billion US dollars. In the EU it has been estimated that patients die each year due to ABR with an associated cost of 1, 5 billion euros per year (26, 27). The increased cost of AMR in health care in Thailand is estimated to more than million USD in direct costs, and 1.3 billion USD in indirect costs (26). By request of WHO, the World Bank has proposed a study on the current and future global economic impact of AMR. The report aims to provide important information needed to coordinate activities to combat AMR. The report will attempt to develop an analytical model to estimate direct and indirect costs of AMR as a direct outcome. Access to antimicrobials AMR is one of the greatest concerns of public health, and there is an urgent need for interventions to assure responsible use. However, lack of access to essential medicines, antibiotics and vaccines, still cause millions of deaths in primarily LMIC. By improving access in LMIC more than 0,5 million deaths caused by pneumonia and sepsis in newborns could have been prevented (28). Interventions to contain antibiotic consumption, such as regulations, legislations and stewardship programmes, could have considerable implications on access, particularly in low-income settings, and needs to be taken into account when implementing activities to combat AMR. One could argue that lack of access could stall the development of AMR. However, there is a risk that lack-ofaccess-driven use of counterfeits and substandard drugs could result in development of AMR at an even greater scale, than if affordable antibiotics of good quality were available (29). Secondly, this argument strongly contradicts the principle of all 9

10 individuals right to health, which is a basic principle that needs to be respected by the global public health community. In many countries in Sub-Saharan Africa and South-East Asia lack of access to second line antibiotics force prescribers to turn to multiple chemotherapeutic courses using first-line drugs (30), with the risk of driving development of resistance further for these agents. Lack of access has also been showed to be associated with price. A survey comparing pricing, availability and affordability in 36 developing middle-income countries show that availability of generic medicines ranged from 29.4% to 54.4% in the public sector across WHO regions. Generics in the public sector were often more expensive than international reference prices, while prices in the private sector were up to 25 times the international reference price (31). Lack of access drives up prices, and research show that medicine expenditures often constitute the largest out-of pocket cost for households in LMIC. This often leads to patients not completing courses of treatment or to resort to sub-standard medicines, which may drive the selection of resistant organisms. In LMIC 50 % of medicines use has been estimated to be inappropriate (32), This may, however, also be the case in HIC, but the additional development of resistance driven by the use of substandard drugs is not present. Lack of access to medicine often also means lack of access to health care. Improving health care systems is equally important. This includes access to diagnostic capacity, which again will support AMR surveillance. It is estimated that children could be saved each year, if they were given access to diagnostic tests for lower respiratory infections (28). Interventions to promote responsible use of antibiotics A number of interventions are required to promote the responsible use of antimicrobials. These range from implementing antibiotic stewardship programs (APS), dealing with inappropriate prescribing practices, intervening to curtail financial incentives to oversell and overprescribe antibiotics, and dealing with the availability of antibiotics in OTCs in a contextually appropriate manner. Prescription drugs and antibiotic stewardship programs Prescribers and pharmacists often provide patients with antibiotics for reasons other than to treat a specific infection, for example: perceived patient expectations, peer pressure, time constraints, lack of knowledge, lack of diagnostics, incentives and advertising from the pharmaceutical industry, and financial benefits for the prescriber (33). These factors, influenced by the cultural and social context, need to be identified in order to design and implement an effective ASP. ASPs aim at improving antibiotic use, and assure the optimal selection, dosage, and duration of antimicrobial treatment that results in the best clinical outcome for the 10

11 treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance (34). Research on the effects of ASPs in HIC show that HAIs can be reduced by 20-40% (28). There are a number of different ASPs designed to influence different aspects of the prescribing practice. The majority of studies have so far been carried out in hospital settings. However, ASPs have also proven positive effects in outpatient care. Studies evaluating the effects of ASPs are many, and the quality varies greatly. Key messages from this research show that ASPs are likely to be more effective if a combination of different methods is taken into practice rather than only one. Methods to educate prescribers on communication techniques for prudent use are more effective if the prescriber is allowed to reflect on the experience with colleagues (35). A systematic review on interventions to improve antibiotic prescription in upper-, middle- income countries support the conclusion that multifactorial interventions are more effective than single interventions, which by themselves had little to no effect. The review also shows that interventions effectiveness increased, if it targeted one specific infection (36). Two systematic reviews show that ASPs in general are associated with an improved microbial outcome in resistance patterns. However, one review found that it was not possible to recognize specific elements important for success (37), while the other found evidence that restrictive measures had more effect than persuasive measures (38). Both reviews highlight the fact that most research available is of low quality, and that there is a need for well-designed studies. Thailand: Antibiotic Smart Use Program (ASU) Thailand initiated the Antibiotic Smart Use (ASU) Program in 2007 to promote rational use of antibiotics. The ASU Program is a three phase program run by a team of local multidisciplinary members (healthcare personal, local leaders etc.) and organized by partners at the national agencies as well as academics and researchers (i.e. central partners). The local partner designs the strategy, ASP, to be implemented in their unit, while the central partner plays catalytic and supportive roles and facilitates collaboration between local partners. Thailand piloted the program in the province Saraburi, located 200 km from Bangkok with a population of 0, 6 million. The project was introduced in 10 district hospitals and 87 primary health centres. A neighbouring province with similar demographics was selected as the control group. The first phase focused on designing an intervention to reduce prescription of unnecessary use of antibiotics in otherwise healthy patients, suffering from self-determining infections. During phase two, important factors influencing the local prescription practice were identified, as were prescribers poor understanding of antibiotics and disease management, and their perceived pressure from patient s antibiotic expectation. A half day course was then conducted in the 10 district hospitals. Each hospital received a package of materials for patients and prescribers, and financial support to help implementation and evaluation. Evaluation showed a 97% recovery of patients despite not having received antibiotics, and an 18-46% reduction in antibiotic use (27). Phase two focuses on feasibility for ASU scaling up in different contexts and health care units. During this phase decentralization was achieved by training new trainers and encouraging local partners to conduct research and promote good practices. Secondly, efforts were made to integrate ASU practice into national policies. 11

12 The adoption of ASU practice as a pay-for-performance criterion by the National Health Security Office, a major purchaser of health care for Thailand, was an important achievement that prompted nationwide expansion of ASU. Apart from hospitals, ASU has also been implemented in pharmacies and communities. The project has now moved into the third phase, focusing on sustainability. The implementation of the 2011 National Drug Policy (strategies on combating AMR and promoting rational use of medicines) together with civil society movements, such as adoption of Antibiotic Awareness Day as a public campaign in Thailand, has strengthened AMR movement and provides a supportive climate for sustaining ASU practice(26). Research on the impact of ASPs is often conducted in hospital settings. However, the vast majority of antibiotics are being prescribed or sold in outpatient settings. Information is therefore needed to assess the impact of ASPs in community settings. In a randomized trial was conducted in a paediatric primary care program in the US, to assess the impact on prescription practice. An ASP based on clinician education coupled with audit and feedback resulted in a significant decrease in the use of off-guideline antibiotics (39). Due to the lack of health care facilities in many low-resource settings, physicians can t be regarded as the only professionals essential for implementing ASPs. In these settings healthcare can be delivered by nurses alone or, treatment be sought in locations such as pharmacies, local shops and town markets. This means that there is need to engage and include alternative providers of antimicrobials in ASPs if impact on AMR is to be attained. Regulating OTC sales and self-medication Self-medication of antibiotics occurs in many countries, even in countries where antibiotics are classified as prescription-only medicines. This phenomenon is, however, less common in countries with strong regulatory agencies. A systematic review by Morgan DJ, showed that non-prescription use of antimicrobials accounted for % of total use outside of northern Europe and North America (40). In Latin America, regulation and prohibition of OTC sales has been one of the focus points to combat AMR, and OTC sales of antibiotics is now prohibited by law in many countries (41). However, sales data collected from Latin American countries , show an overall increase of consumption. The strategies to combat AMR differ between countries, which makes comparisons of effects of interventions difficult. This is due to differences in both design of interventions, and regulation enforcements. For example, in Chile national regulatory interventions have been combined with mass media attention, awareness campaigns, and involvement of pharmacy staff. While in Colombia, attempts to regulate OTC-sales were implemented only in the capital (42). 12

13 Sales data show a significant decrease (43%) in sales of oral antibiotics in Chile after 1999 (when legislation was reinforced, (27), as well as a decrease in consumption of antibiotics in Colombia, during the entire time frame. A sharp decrease was detected in Colombia in 2005, when regulatory interventions were enforced. As a control Mexico, which had not reinforced legislations at that time, was included in the study. Data from Mexico showed a steady decrease in antibiotic usage (42). As discussed, the positive results seen in Chile could be a result of the combination of regulatory activities, educational activities, and engagement of important stakeholders. However, the decrease of sales in Chile was not long lasting and after two years sales increased (42). Research suggest that successful awareness campaigns need to be run over several years, which could explain the increase of consumption after two years (43). The decrease in Colombia and Mexico could however be a result of other health-care related interventions. The review comment that during the time of data collection, the number of people with household insurance increased in both Colombia and Mexico. This could have led to people seeking medical advice from the public sector instead of the private, and cause a decrease in consumption from the private sector (41). This highlights the need to analyse all sectors of the health-care system to get a full understanding of all factors influencing use, and the need to improve overall health-care systems. Substandard/spurious/falsely-labeled/falsified/counterfeit medical products Due to non-existing or non-functioning regulatory mechanisms, often in combination with lack of access to quality drugs, falsified and substandard medical products have become a large problem in many low-income and lower middle-income countries (44, 45). These products often contain inadequate amounts of active ingredients resulting in suboptimal doses that foster and worsen the development of AMR. Substandard and counterfeit antibacterials, antimalarials and antituberculosis medicines are common in many countries in Africa and Asia especially in the unlicensed markets (45-47). Substandard/spurious/falsely-labelled/falsified/counterfeit (SSFFC) medical products have been shown to promote AMR (48). The issue of SSFFC is, however, complicated due to that fact that these products have emerged partly as a result of the failure to secure global access to affordable health care and medicines. Therefor access needs to be addressed to reduce the use of SSFFCs. A field study aiming to assess the quality of rifampicin and isoniazid from private sector pharmacies in 19 cities in 4 continents, found that 9.1 % did not pass the basic quality testing for level of active pharmaceutical ingredients (API) or disintegration. Looking at the continents separately, Africa had a failure rate of 16.6% (48). 13

14 Rwanda Compared to other African nations, Rwanda has managed to keep a low prevalence of substandard antituberculosis medicine, as well as falsified anti-tuberculosis medicine. This is the result of active strategies to improve quality and strong governmental support to reduce the use of these drugs. In 1990 Rwanda mandated that national manufacturers needed to be WHO approved in order to obtain a drug contract. An intervention based on the knowledge that manufacturers approved by the WHO are five times less likely to fail basic quality control. Since 2011 periodic reviews based on standardized notification forms for poor quality health products, available at all health centres, are being conducted by the National Pharmacovigilance and Medicine Information Center in the Ministry of Health. Guidelines for pharmacovigilance have been adopted and are being implemented by 2400 trained health care workers. Drug testing of anti-tuberculosis medicine is being carried out annually and quarterly from all levels of the health sector, as well as testing of all drug shipments. Patients in need for treatment of tuberculosis have access to free quality assured drugs through the Centers for Diagnosis and Treatment of Tuberculosis (CDTT). And by assuring access, this intervention has allowed strong regulations of sales of anti-tuberculosis medicine, and prohibited antimalarial monotherapy by all private pharmacies not accredited as CDTT. The results of these efforts have led to tuberculosis mortality rates decreasing by 77.1% between 2000 and 2011, and annual malaria deaths decreasing by 85.3% in the years (48). Public campaigns and education Bottom-up approaches, such as awareness campaigns, are likely to be just as important as regulatory interventions to combat AMR. The methods to raise awareness differ depending on a number of factors such as target population and target infection, as well as the cultural and societal view of illness and health care. Public campaigns in HIC in general have a positive effect on use of antibiotics, but multifaceted campaigns have the most impact, especially if the messages are repeated over several years(43). At the colloquium of the International Forum on Antibiotic Resistance in 2002, methods to raise awareness though educational campaigns were discussed in theory and in practice. It was concluded that awareness campaigns are not likely to be successful if they do not focus on the correct end-point; behavior change in the target group and in the society (49). To only focus on education to increase awareness and hope for change is often not sufficient. Evidence suggests that interventions incorporating behavior- change models are more likely to be successful. It is also important that target groups are identified early in the process. A general rule is that interventions that aim to change the behavior in the doctors office need to include both the patient and the physician. Studies show that regardless of the level of knowledge of the patient, the physicians perception of patients demand can lead to unnecessary use. The same is true for patients. If they are not included as a target group, 14

15 it is probable that the patient will seek a second opinion or buy antibiotics OTC if demand is not met. Ideally, the knowledge of the chosen target groups, including socioeconomic and cultural differences, should be researched and combined with facts about the issue, before designing a clear campaign message and strategy (49). The education of physicians and other health-care workers, on how to promote responsible use, also offer the possibility to enforce the implemented interventions. Strengthening health-care workers to take a responsibility to communicate the need for behavior change in the society, could be an important resource to reduce irresponsible use (28). European Antibiotic Awareness Day Inspired by the success on national campaigns in Belgium and France, the EU designed and launched the first regional antibiotic awareness campaign in The campaign takes place on the 18 th of November every year, building on the principle that campaigns are more effective if they run over several of years. The focus of the first European Antibiotic Awareness Day (EAAD) was to reduce unnecessary use primarily in viral upper respiratory infections, and to reach a broad audience (mainly the public and primary health care workers in all European and some non-european country). The first EAAD reached out to 27 EU countries and 5 non-eu countries, reaching the entire continent which has not been done before. Important lessons learned from the first EAAD are that in order to produce campaign material suitable for an entire region, it needs to be based on a clear and rigorous approach, strongly supported by research. This meant that cultural and societal differences can t be taken into consideration. To account for this, nations will have to adjust the campaigns to fit their needs. In addition, it became evident that strong political and stakeholder engagement and support is necessary, to assure region wide coverage. Strong transnational collaborations and organization is crucial. (50) Policies to address antibiotic resistance A range of policies and programmes are required to address increasing AMR worldwide, including increasing country capacity, establishing national plans, and ensuring global coordination. Example of Policy efforts in low- and middle-income countries The Global Antibiotic Resistance Partnership (GARP), initiated under the leadership of the Centre for Disease Dynamics, Economics and Policy, is an initiative seeking to support health systems in LMIC. The aim is to develop sustained local capacity to formulate and promote locally relevant policy related to antibiotic use and resistance in LMIC. Their work is guided by the idea that even though AMR is a global issue, solutions need to be linked to the local context and target behaviour change within the society, strengthened by government support. GARP started working with four countries in 15

16 ; Kenya, India, Vietnam and South Africa. They have since then added Mozambique, Tanzania, Nepal and Uganda (51). Vietnam Due to limited resources to diagnostics tools, high workload, staff shortages, inadequate laboratory quality control, and economic reforms towards a more market-driven economy, Vietnam has struggled against unregulated access to antimicrobials. Regardless of the efforts made to regulate use; including the adoption of laws to make antibiotics available by prescription only, and requiring pharmacies to monitor drug quality and use, irresponsible use have continued to be a problem. Therefore, Vietnam joined GARP in Following the method of GARP, a working-group was formed representing academic communities and, in this case, the government. With the support of GARP, the working-group arranged a stakeholder meeting in Hanoi, 2009, were the plan to conduct a situation analysis was outlined. The purpose of the analysis was to provide information on current AMR patterns and factors influencing use and resistance. The result was presented in a stakeholder, policy workshop in 2011, where the participants were asked to draft policy proposals to control AMR. The recommended policies were used to guide to Ministry of Health in the work to formulate a national action plan. The efforts made, show that there is a strong support for change in Vietnam. However the implemented actions have so far had little effect, regardless of a national action plan. This is probably due to lack of insufficient funding, human resources and financial incentives. It becomes evident that LMIC need continued support to be able to enforce a sustainable solution (7). Example of Policy efforts in high- income countries France France has been one of the countries in Europe with the biggest antibiotic consumption and highest incidence of MRSA during the past decades. In 1998 it was also reported that the annual increase of antibiotic sales from general practices were 2.6 %, making France the number one consumer of outpatient antibiotics in the EU. In a decade, strains of S. pneumonia with reduced susceptibility to penicillin G had increased from 5% to 48%. This situation is by no means unique, however in France; it was enough to evoke change. With strong support by the government, a two-step national consultation was organized in 1999, with the aim to identify strategies to reduce AMR. Expert groups were asked to draw up proposals, and three key objectives were identified; surveillance of resistance and use, control and prevention, and promotion of research on resistance. In the second step the proposals, containing numerous interventions (including regulation, surveillance and education) to be incorporated in a national action plan, were presented to groups of professionals, representing the private and public sector of human and animal health. Finally the proposal was presented to the Ministry of Health as part of a national action plan. After implementing the interventions of the action plan antibiotic consumption has reduces by 23% ( ), MRSA prevalence has reduced from 33% to 26% ( ), a new pneumococcal vaccine has been introduced, and reverse trends has been reported on resistant strains of S. pneumonia (27, 52). 16

17 France strategy to combat AMR builds on the combination of top-down and bottom-up approaches, strengthened by governmental support. It is important to also point out that France, being part of the EU, has access to reasonable well-functioning surveillance system, supplying countries with vital information on development of AMR which is used to advocate for change. The need to regulate marketing Advertising drugs to consumers is a strategy to increase sales. Direct-to-consumer advertising for prescription drugs leads to inappropriate prescribing practice, including prescriptions of more expensive drugs to meet consumer demand (35). Direct to consumer advertising should therefore be prohibited in all countries to reduce the misuse of drugs in general. With the growing threat of entering a post-antibiotic era it is vital that actions to prohibit advertising of antimicrobials are implemented and enforced for any new product that enters the market, as well as for old but still effective products, in order to prolong their effectiveness. Interventions to strengthen prevention According to the WHO 1.1 billion still lack access to safe drinking water, causing almost 90% of all deaths by diarrheal diseases (approximately 1.6 million people)(53). The majority of these could be prevented by improving access to basic hygiene, sanitation, and safe water supply (54). Improving sanitation and access to safe water has also shown to be cost-beneficial (55). The antibiotic use, associated to treat these infections, could be reduced significantly if basic hygiene, sanitation and safe water were provided. Lack of access to basic hygiene, sanitation, and clean water is also one of the major causes of healthcare associated infections (HAI), which has a major influence on global health-care. HAI are associated with increased mortality, complicating the delivery of patient care, increasing the cost of health care, and promotes development of AMR (54). Preventive measures to reduce HAI are therefore recognized as an important component to improve both patient safety and combat AMR worldwide. Drawing from the experience to reduce HAI would add both valuable information and ideas for action when drafting the Global Action Plan on AMR. 17

18 Clean Care is Safer Care- experience from the World Alliance for Patient Safety The World Alliance for Patient Safety was launched in 2004, bringing together stakeholders; including policymakers, representatives from government agencies and health care associations etc., to form a global alliance to increase patient safety. The Alliance identified six action areas, out of which reducing HAI was chosen as the first Global Challenge. Actions to improve hospital practice associated with particular high risk to cause HAI (i.e. hand hygiene, blood products, injection practice, sanitation, waste management, hygiene, clean water, clinical procedures) were identified. Finally, implementation strategies were drafted to implement the action plan and presented to the world as the Clean Care is Safe Care program. Countries taking part in the Clean Care is Safe Care program are encouraged to organize a national Clean Care is Safe Care campaign [Save lives-clean your Hands], formally pledge their commitment to prioritize actions to reduce HAI and to share their knowledge and surveillance data with the Alliance, and finally implementing the WHO Guidelines on Hand Hygiene in Health Care including existing WHO strategies on other high risk hospital practices. Today almost health care facilities are committed to improve hand hygiene, pledges have been given by 130 WHO Member States and autonomous areas to support the initiative, out of which 42 countries are running their own hand hygiene campaign. Research and development of new and novel antibiotics Despite growing concern regarding the effects of AMR, little is happening in the R&D pipeline to bring to market new antibiotics. The World Economic Forum voices a concern in their report Global Risks 2013 (Eights edition), that there is an over-confidence to the markets ability to stimulate the production of new antimicrobials. The lack of incentives is driven by concerns of small or no return on the investments of pharmaceutical companies. The public health community has made it clear that there is a compelling need to safeguard any new antibiotic reaching the market, diminishing the prospect of recapturing the cost of development and production through high sales volumes. This is further underscored by the nature of product itself; antibiotics are only used for short periods of time, often not more than a few days. This can be compared to treatments for chronicle diseases which lead to lifelong consumption, and an ongoing income stream to pharmaceutical manufacturers. Finally, due to bacteria s evolutionary capacity to develop resistance, there is a continuing risk that any new product will become useless within a few years, further limiting the potential returns from investing in new antibiotics. Regardless of the concerns of health care personnel, in the pharmaceutical business marketplace, antibiotics are no more than a product that promises little returns and high risks for any company willing to invest. As a consequence, in 2008, 6 out of 15 major pharmaceutical companies had abandoned their antibiotic discovery programs and 2 had reduced their activities. A study in 2004 showed that only 6 out of 506 drugs in development by 15 of the largest pharmaceutical companies and 7 of the major biotechnology companies were antibiotics (56). 18

19 New initiatives to incentivize pharmaceutical companies to commit to the development of new and innovative antibiotics will need to build on the principle of delinking marketing and sales from investment in research and development. To accomplish this the resources, risks and rewards need to be shared between stakeholders (35). The need for a global collaboration WHO have recognized the following key objectives that need to be addressed by all countries in order to combat AMR; education (of both the public, health care workers etc.), surveillance on both antibiotic use and resistance, responsible antibiotic use in humans, animals and agriculture, research and development, and finally prevention. All objectives being equally important. National action plans should be designed based on a One Health approach and monitored within a results management framework. Due to different settings and circumstances, the effectiveness of strategies will differ between countries and regions. The idea of a one size fits all solution where all countries can follow a list of activities is tempting, but naïve. The AMR challenge is complex and in need of paralleled interventions in highly different contexts to be successful. In order to meet the individual needs of countries and regions, the Global Action Plan has to identify different ways of achieving the same goal, AMR control. Construction of the Global Action Plan on AMR is of great importance as it represents a commitment by all WHO member states to combat AMR. However, it is the implementation of the interventions after the adoption of the Global Action Plan that will determine the outcome. A strong organizational structure needs to be installed to follow-up the implementation of the Global Action Plan, and assure a sustained global commitment, WHO is an important stakeholder and should take the main responsibility for this work. However, their work will need strong collaborating partners, building on experiences of organizations such as UNAIDS in the combat on HIV/AIDS. It has also been suggested to investigate the possibilities of a global framework or treaty on AMR, similar to the WHO Framework Convention on Tobacco Control. Drawing from the experience of the work to prevent the spread of antimalarial resistance, there is a need to discuss an emergency action plan. One way to address this issue is to incorporate implementation of the Global Action Plan through the IHR (2005) framework, into the 8 core capacities. This could potentially allow countries having developed core capacities, to use IHR as a foundation for AMR control. 19