Antimicrobial Resistance: formulation of the response in the global health context

Rafael Almeida da Silva Beatriz Nascimento Lins de Oliveira Luiza Pinheiro Alves da Silva Maria Auxiliadora Oliveira Gabriela Costa Chaves About the authors

ABSTRACT

Antimicrobial Resistance (AMR) has proved to be a major public health problem at the global level. This paper examined the formulation of the response to AMR negotiated through the World Health Organization (WHO) by its Member States. Related WHO reports and resolutions from 1998 to 2019 were analysed. The findings indicate that, from 2014 on, more robust conditions were established for approval of a Global Action Plan on AMR, encompassing the concept of One Health and involving other international entities (FAO, OIE, WTO and Unep). Content analysis and various analytical frameworks, considering two economic sectors (the livestock and pharmaceutical industries), proved relevant to illustrating the complexity of the issue, reinforcing its global importance and acknowledging the extent of antibiotic use in animals and the gaps in technological innovation. As the WHO is not only an important agent for mobilizing the response to AMR at the global level, but – despite a context of de-funding – has guaranteed a budget for action in this area, it is concluded that the public health perspective should prevail in the response to AMR.

KEYWORDS
Global health; Drug resistance, microbial; One Health; Livestock industry; Orphan drug production

Introduction

Antimicrobial Resistance (AMR) is currently considered to be a major global public health problem. It is estimated that approximately four million people acquire health care-related infections annually in the European Union (EU) and that some 37,000 die as a result of resistant infections acquired in hospital environments. Most (67.6%) of these deaths are caused by multi-antibiotic-resistant bacteria11 European Center for Disease Prevention and Control. Antimicrobial Resistance and Health Care associated infection programme [internet]. [União Europeia]: ECDC; [acesso em 2020 set 18]. Disponível em: https://ecdc.europa.eu/en.
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The World Health Organization (WHO) describes AMR as the ability of microorganisms (bacteria, fungi, viruses, and parasites) to change when exposed to antimicrobial drugs and to resist such drugs, leaving them ineffective22 World Health Organization. Antimicrobial Resistance fact sheets- What is antimicrobial resistance? [internet]. [Genebra]: WHO. [acesso em 2017 set 10]. Disponível em: https://www.who.int/features/qa/75/en/.
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. Often, however, the term is exemplified by the case of antibiotics used in bacterial infections.

AMR occurs as a result of the natural interaction among microorganisms in the environment33 Munita JM, Arias CA. Mechanisms of Antibiotic Resistance. In: Virulence Mechanisms of Bacterial Pathogens. Microbiol Spectr. 2016; 4(2):481-511., but its increasing incidence may result from a series factors, such as high consumption and improper use of antimicrobial drugs; populations’ lack of information; overuse of antimicrobial drugs in agriculture and livestock production; and environmental pollution caused by discharge of pharmaceutical waste into soil or water. The problem is aggravated by a lack or insufficiency of regulation; a lack of oversight of antimicrobial drug consumption by government institutions; and a lack of innovative antimicrobial drugs as a result of low investment in Research and Development (R&D)44 Kaae S, Malaj A, Hoxha I. Antibiotic knowledge, attitudes and behaviours of Albanian health care professionals and patients-a qualitative interview study. J Pharm Policy Pract. 2017; 10(1):13.

5 Pavyde E, Veikutis V, Maciuliene A, et al. Public Knowledge, Beliefs and Behavior on Antibiotic Use and Self- Medication in Lithuania. Int J Environ Res Public Health. 2015; 2(6):7002-7016.

6 Michael CA, Dominey-Howe D, Labbate M. The antimicrobial resistance crisis: causes, consequences, and management. Frontiers in public health. 2014; 2:145.

7 Roca I, Akova M, Baquero F, et al. The global threat of antimicrobial resistance: science for intervention. New microbes and new infections. 2015; 6:22-29.

8 Brasil. Decreto-lei nº 8448, de 6 de maio de 2015. Regulação da Fiscalização dos Produtos de Uso Veterinário [internet]. Diário Oficial da União. 6 Maio 2015. [acesso em 2017 nov 15]. Disponível em: http://www.planalto.gov.br/.
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-99 Davis MA, Hancock DD, Besser TE. Multiresistant clones of Salmonella enterica: The importance of dissemination. The Journal of laboratory and clinical medicine. 2002; 140(3):135-141..

Improper and excessive use of antimicrobial drugs in agriculture and livestock contributes to increasing incidence of AMR in humans. These medicine are used in the livestock industry to treat and prevent infections, as well as to promote animal growth, bringing selective pressure to bear on microorganisms to become resistant. Transmission to humans can occur directly, by contact, or indirectly, on consuming food products and from pollution caused by agricultural biological waste77 Roca I, Akova M, Baquero F, et al. The global threat of antimicrobial resistance: science for intervention. New microbes and new infections. 2015; 6:22-29..

Despite the seriousness of AMR, few new antibiotics have been developed in the past 40 years. Traditional market incentives have not been – and are unlikely to be – able to bridge this gap in innovation, especially in a context where use of these medicines is being restricted1010 United Nations. Report of the United Nations Secretary-General's High-Level Panel on Access to medicine [internet]. [Nova York]; [2016]. [acesso em 2018 set 20]. Disponível em: http://apps.who.int/medicinedocs/en/m/abstract/Js23068en/.
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At the international level, in 2015, the WHO Member States adopted the Global Action Plan on Antimicrobial Resistance (Resolution WHA68.7) at the World Health Assembly (WHA)1111 World Health Organization. Draft global action plan on antimicrobial resistance [internet]. [Genebra]: WHO; [2015]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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. This plan was based on the One Health concept, which assumes that human, animal and environmental health are interrelated and proposes that different fields of knowledge integrate with each other to address health problems1212 Boqvist S, Soderqvist K, Vagsholm I. Food safety challenges and One Health within Europe. Acta Veterinaria Scandinavica. 2018, 60(1):1-13.,1313 Ministério da Saúde. Resistência antimicrobiana: enfoque multilateral e resposta brasileira. In: Saúde e Política Externa: os 20 anos da Assessoria de Assuntos Internacionais de Saúde (1998-2018). [internet]. [Brasília, DF]: MS; [2018]. [acesso em 2020 maio 20]. Disponível em: www.saude.gov.br.
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Given the complexity and multi-causality of AMR, responses to it involve regulatory networks at various stages in the chain of antimicrobial drug production, use and trade, with implications for various economic sectors, such as the livestock and pharmaceutical industries. Considering the multiple dimensions of the response required by AMR, as well as the different actors in society and the economy directly involved and affected, this paper examines the formulation of the AMR response negotiated at the WHO by its Member States. Its working assumption is that the fronts on which it is considered important to take action to tackle AMR have broadened over the years, posing the need to involve other multilateral bodies and actors.

Methodology

This study falls within the policy analysis field, because it acknowledges the role of proposal formulation in a multilateral arena such as the WHO. The WHO belongs to the United Nations (UN) system and is characteristically member-driven, that is, directed by the decisions of its Member States. By negotiating and approving resolutions in the WHA, the Member States mandate the work of the WHO and agree on country guidelines on the various issues negotiated1414 World Health Organization. Governance [internet]. [Genebra]: WHO; [data desconhecida]. [acesso em 2019 jan 20]. Disponível em: https://www.who.int/about/governance.
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. Although the resolutions approved in the WHA are not binding, they do have the potential to guide policies, plans and programmes at the national level.

The reports and resolutions approved are important sources for examining the main arguments agreed among the countries on the subject of AMR. In this study, these arguments are themselves considered to constitute formulations of responses to AMR, which can in turn influence the formulation of national-level responses. In addition to reports and resolutions, this study examined other documents (chart 1), such as WHO budgets, spanning the 22-year period from 1998 to 2019.

Chart 1
List of documents examined

The study used a triangulation among multiple theoretical frames of reference, including the policy cycle concept proposed by Howlett & Ramesh (2009) (as in Mattos et al.)4545 Mattos RA, Baptista, TWF. Caminhos para análise das políticas de saúde. Porto Alegre: Rede UNIDA; 2015., involving five distinct phases: agenda setting, policy formulation, decision process, policy implementation and policy evaluation. Although related to national-level policymaking, some of these phases – formulation and implementation – can be of use in analysing the role of international processes and, subsequently, their influence on policy formulation at the national level. Accordingly, this study is considered to be an endeavour to recognise the international dimension in national-level public policymaking.

The global health governance proposal described by Frenk & Moon4646 Frenk J, Moon S. Governance challenges in global health. New England Journal of Medicine. 2013; 368(10):936-942. is considered in analysing the architecture established in the process conducted at the WHO on the issue in question. The analysis of the institutional dimension offered by Sell4747 Sell SK. The quest for global governance in intellectual property and public health: Structural, discursive, and institutional dimensions. Temp. L. Rev. 2004; 77:363. also proved relevant to appraising issues of global governance (chart 2).

Chart 2
The institutional dimension as proposed by Sell and the global health functions as proposed by Frenk & Moon

The document analysis, based on the proposal by Minayo et al.4848 Minayo CSM, Deslandes FS, Gomes R. Pesquisa social: Teoria, método e criatividade. Petrópolis: Vozes; 2009., at first considered three categories (general aspects of AMR, pharmaceutical innovation and agriculture and livestock). After reading the documents, the categories were reorganised, making the results easier to interpret and synthesise. These were: formulation of the response to AMR; the new formulation of the response to AMR and developments from it; and global health system governance and functions applied to the case of AMR.

As the analysis was based on documents that were the outcome of negotiations, the study is recognised to be limited as regards any possibility of identifying tensions among countries on sensitive aspects of the subject over the course of the negotiating process. The ‘formulation process’ was considered to be the development, over time, of content included in the AMR response, as well as the involvement of other multilateral institutions.

Results and discussion

Formulation of the response to tackle AMR

The period from 1998 to 2013 was identified to be when the response to AMR was formulated in the WHO: when the issue was acknowledged to be a public health problem and discussions were held on the action to be taken to deal with the problem. It was possible to organise this period into the three distinct phases described below (figure 1).

Figure 1
Timeline of AMR response formulation

*Biennial budget.

**International-level response.

World Health Organization (WHO), World Animal Health Organization (OIE), United Nations Food and Agriculture Organization (FAO), United Nations Organization (UN), United Nations Environment Programme (Unep). Global Antibiotic Research and Development Partnership (GARDP), List of antibiotics by level of resistance (AWare Classification).

Period from 1998 to 2001: the problem recognition and first formulation of the response to AMR

AMR appeared on the WHO agenda for the first time in 1998, when discussion of a Report1515 World Health Organization. Report of regional interest adopted by the fifty-first World Health Assembly [internet]. [Genebra]: WHO; [1998]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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resulted in the approval of Resolution WHA51.171616 World Health Organization. Resolution and decision of fifty-first Assembly [internet]. [Genebra]: WHO; [1998]. [acesso em 2017 ago 10]. Disponível em: http://apps.who.int/gb/archive/.
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. In the two-year period 1998-1999, the organisation approved a specific budget of about US$23 million for this issue1717 World Health Organization. Financial Report and Audited Financial Statements for the period 1 January 1998- 31 December 1999. [internet]. [Genebra]: WHO; [1998]. [acesso em 2020 maio 20]. Disponível em: http://apps.who.int/gb/archive/.
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That Resolution mentioned that using antimicrobial drugs in humans or animals, whatever the amount or purpose, fostered selective pressure on bacteria to become resistant to such medicines, which favours the spread of AMR1616 World Health Organization. Resolution and decision of fifty-first Assembly [internet]. [Genebra]: WHO; [1998]. [acesso em 2017 ago 10]. Disponível em: http://apps.who.int/gb/archive/.
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. Responsibility for the problem was acknowledged to lie with both human and veterinary medicine, because medicines are also used in animal production and agriculture1515 World Health Organization. Report of regional interest adopted by the fifty-first World Health Assembly [internet]. [Genebra]: WHO; [1998]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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. It was recommended that governments develop strategies to reduce antibiotic consumption in humans and in animal production1515 World Health Organization. Report of regional interest adopted by the fifty-first World Health Assembly [internet]. [Genebra]: WHO; [1998]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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,1616 World Health Organization. Resolution and decision of fifty-first Assembly [internet]. [Genebra]: WHO; [1998]. [acesso em 2017 ago 10]. Disponível em: http://apps.who.int/gb/archive/.
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One possible reason why the subject entered onto the WHO agenda in 1998 was that, in that year, the European Union (EU) had embarked on a process of reviewing of its community rules on the use of antibiotics in animal production4949 Castanon JIR. History of the use of antibiotic as growth promoters in European poultry feeds. Poultry Science. 2007; 86(11):2466-2471.. Castanon4949 Castanon JIR. History of the use of antibiotic as growth promoters in European poultry feeds. Poultry Science. 2007; 86(11):2466-2471. reported that Sweden was the first European country to ban the use of antibiotic growth promoters, and its entry into the EU in 1995 brought the issue into the bloc’s discussions. Also in 1995, Germany and Denmark banned certain therapeutic classes of antibiotic for animal use, further helping to raise the issue within the EU. In the late 1990s, EU rules were altered to tighten restrictions on the use of antibiotics as animal growth promoters4949 Castanon JIR. History of the use of antibiotic as growth promoters in European poultry feeds. Poultry Science. 2007; 86(11):2466-2471..

As regards innovation, the Resolution asserted that antimicrobial drug-resistant infections are made harder to treat by the lack of effective agents for some cases and by the prohibitive prices of new generation antimicrobial drugs1515 World Health Organization. Report of regional interest adopted by the fifty-first World Health Assembly [internet]. [Genebra]: WHO; [1998]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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. Many countries were unable to afford innovative medicines, while existing antimicrobial drugs were being prescribed irrationally. The solutions proposed included strengthening patent laws. That Resolution made no provision for recommendations to countries as regards the innovation gap. It merely recommended that the WHO collaborate in knowledge sharing among the public sector, academia and industry, and encourage promotion of R&D in the area1717 World Health Organization. Financial Report and Audited Financial Statements for the period 1 January 1998- 31 December 1999. [internet]. [Genebra]: WHO; [1998]. [acesso em 2020 maio 20]. Disponível em: http://apps.who.int/gb/archive/.
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In 2001, the WHO published the Global Strategy for Containment of Antimicrobial Resistance (WHO/CDS/CSR/DRS/2001.2)1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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, proposing a series of interventions to retard the emergence and reduce the dissemination of microorganisms resistant to antimicrobial drugs.

With regard to animal production, the document addressed the relation between the food production system and the spread of AMR. World population growth had driven mounting demand for foods from animal sources and, in order to meet that need, animal production had shifted to an intensive model, thus creating an environment favourable to the spread of infectious diseases among animals. This, in turn, led to antibiotics’ being used to treat and prevent diseases and also to promote animal growth1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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The WHO recognised the relationship between antibiotic use in animal production and AMR in humans in the light of evidence that antibiotic-resistant bacterial strains had appeared in humans after antibiotics were introduced into production of foods from animal sources. France, Germany, Ireland, the Netherlands, Russia and other countries had reported that certain strains had become less susceptible to antibiotics after their use was permitted in animal production1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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Recognising that AMR is a complex, multifactor problem, the 2001 document1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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outlined an inter-sector strategy resting on collaboration among various sectors of society (doctors, veterinary doctors, pharmacists and other health professionals, agricultural and livestock producers, the pharmaceutical industry, civil society, governments and other interested parties)1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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. That document also proposed legislation to control the consumption of antibiotics in animal production; for instance, making veterinary prescription mandatory for the dispensing of antibiotics1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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Regarding technological innovation, the 2001 document repeated that the risk of there being no effective therapies in coming years resulted from a gap to innovate in antimicrobial drugs. The gap was justified by the lengthy, expensive R&D activities involved and by the fact that restrictions on the use of new medicines, indicated as the therapeutic option of last resort, could have adverse impact on sales. The document acknowledged that firms should recover their R&D expenditures and gain profit from the product. Accordingly, new antimicrobial drugs and vaccines should be developed in order to avert the future impact of resistance, but that incentives were necessary for private R&D in this field1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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The Global Strategy of 20011818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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warned of the existence of biases in cost-effectiveness studies, which favoured new antimicrobial agents, because older ones unprotected by patents were not attractive, and that studies of the cost or clinical impact of AMR were lacking. Added to this, access to new medicines was unequal, because it was limited in less-developed countries, and solutions were required for resource-limited settings. Greater interaction among industry, government and academia was cited as one possible solution in this context1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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.

It proposed that international research and cooperation networks be set up to work on harmonizing regulatory requirements, and specifically mentioned interaction with industry through innovative incentives for investment in antimicrobial drug R&D. The suggestions mentioned included a regulatory fast track or application of a policy similar to that in place for orphan diseases; time-limited exclusivity; and appropriate patent protection. Action to combat AMR should be taken at the global level, framed by the concept of “global public goods for health”1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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, and coordinated in such a way as to avoid duplicating efforts. It was also suggested to establish an international database of funding sources for research in the field, thus creating a single gateway for projects, developing new programmes and strengthening existing ones1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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PERIOD FROM 2002 TO 2005: LITTLE DISCUSSION ON THE ISSUE

Between 2002 and 2004, the topic of AMR was not addressed at the WHA, probably in view of the 2001 Global Strategy and the expectation that Member States would be drawing up their own action plans. In 2005, AMR was mentioned again at the WHA, but matters relating to antibiotic use in agriculture and livestock production were not discussed2020 World Health Organization. Report of regional interest adopted by the fifty-eight Assembly [internet]. [Genebra]: WHO; [2005]. [acesso em 2017 ago 20]. Disponível em: http://apps.who.int/gb/archive/.
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,2121 World Health Organization. Resolution and decision of fifty-eight Assembly [internet]. [Genebra]: WHO; [2005]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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On innovation, Report A58/142020 World Health Organization. Report of regional interest adopted by the fifty-eight Assembly [internet]. [Genebra]: WHO; [2005]. [acesso em 2017 ago 20]. Disponível em: http://apps.who.int/gb/archive/.
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once again stressed the high prices of antimicrobial drugs when launched onto the market and proposed solutions to the problem, such as prices being lowered by the industry and using generic alternatives. Nonetheless, Resolution WHA58.272121 World Health Organization. Resolution and decision of fifty-eight Assembly [internet]. [Genebra]: WHO; [2005]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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of the same year contained no action in this respect.

The mention of competition with generic medicines to address high prices marked a shift from solutions put forward in previous documents, which had pointed to reinforcing the intellectual property system. That shift in orientation is likely to have reflected the process – underway in the WHO as well – on the subject of public health, innovation and intellectual property, triggered chiefly by the approval in 2003 of Resolution WHA56.275050 World Health Organization. Resolution and decision of fifty - sixth Assembly [internet]. [Genebra]: WHO; 2003. [acesso em 2019 maio 20]. Disponível em: http://apps.who.int/gb/archive/.
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, which set up the Commission on Intellectual Property Rights, Innovation and Public Health (CIPIH)5050 World Health Organization. Resolution and decision of fifty - sixth Assembly [internet]. [Genebra]: WHO; 2003. [acesso em 2019 maio 20]. Disponível em: http://apps.who.int/gb/archive/.
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.

PERIOD FROM 2006 TO 2013: LITTLE VISIBILITY FOR AMR ON THE WORLD HEALTH ASSEMBLY AGENDA

Few documents on the subject of AMR were found to have been issued in the WHO from 2006 to 2013. Meanwhile, between 2003 and 2012, the subject of public health, innovation and intellectual property gained prominence in the wake of developments from the 2006 CIPIH report5151 World Health Organization. Report of the Commission on Intellectual Property Rights, Innovation and Public Health [internet]. [Genebra]: WHO; [2016]. [acesso em 2019 jan 10]. Disponível em: https://www.who.int/intellectualproperty/report/en/.
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and approval in 2008 of the Global Strategy and Plan of Action on Public Health, Innovation and Intellectual Property5252 World Health Organization. The Global Strategy and Plan of Action on Public Health, Innovation and Intellectual Property [internet]. [Genebra]: WHO; [2008]. [acesso em 2019 jan 10]. Disponível em: https://www.who.int/phi/implementation/phi_globstat_action/en/.
https://www.who.int/phi/implementation/p...
and the 2012 report of the Consultative Expert Working Group on R&D: Financing and Coordination (CEWG)5353 World Health Organization. Research and Development. Report of the Expert Working group [internet]. [Genebra]: WHO; [2010]. [acesso em 2019 jan 10]. Disponível em: http://apps.who.int/gb/archive/.
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,5454 World Health Organization. Consultative Expert Working group on Research and Development: Financing and Coordination [internet]. [Genebra]: WHO; [2012]. [acesso em 2019 maio 20]. Disponível em: http://apps.who.int/gb/archive/.
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. The latter sought proposals of new funding sources and innovative funding mechanisms to encourage R&D to meet health needs that affected developing countries disproportionately.

In the eight years during which the issue of AMR was not addressed explicitly at WHA meetings, advances were observed in implementation of a global strategy for AMR, such as the development of integrated epidemiological surveillance systems on the African continent and in Latin American countries and the implementation of strategies to address the problem in regions including the Eastern Mediterranean, Southeast Asia, the EU and the Western Pacific5050 World Health Organization. Resolution and decision of fifty - sixth Assembly [internet]. [Genebra]: WHO; 2003. [acesso em 2019 maio 20]. Disponível em: http://apps.who.int/gb/archive/.
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.

Although the Plan of Action on AMR approved in 2001 was in place, the WHO considered it not to have been widely accepted by countries5050 World Health Organization. Resolution and decision of fifty - sixth Assembly [internet]. [Genebra]: WHO; 2003. [acesso em 2019 maio 20]. Disponível em: http://apps.who.int/gb/archive/.
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. In 2014, of the 92 Member States present, only 29 had developed national strategies, 20% of them developing countries. Accordingly, in 2013, the WHO Director-General set up a strategic and technical consultative committee on AMR, which met for the first time that same year and concluded that it was necessary to renew and expand the global strategy to contain AMR5050 World Health Organization. Resolution and decision of fifty - sixth Assembly [internet]. [Genebra]: WHO; 2003. [acesso em 2019 maio 20]. Disponível em: http://apps.who.int/gb/archive/.
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,5151 World Health Organization. Report of the Commission on Intellectual Property Rights, Innovation and Public Health [internet]. [Genebra]: WHO; [2016]. [acesso em 2019 jan 10]. Disponível em: https://www.who.int/intellectualproperty/report/en/.
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.

Reformulation of the AMR response and related developments

PERIOD FROM 2014 TO 2019: FORMULATION OF THE AMR RESPONSE AND AN IMPLEMETATION PLAN.

In 2014, AMR returned to the WHO agenda in more robust form and with a view to engaging other global actors. Report A67/392424 World Health Organization. Report of Sixty-Seventh World Health Assembly. [internet]. [Genebra]: WHO; [2014]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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and Resolution WHA67.252525 World Health Organization. Resolution and decision of Sixty-Seventh World Health Assembly [internet]. [Genebra]: WHO; [2014]. [acesso em 2017 ago 20]. Disponível em: http://apps.who.int/gb/archive/.
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were approved

Two changes proposed in 2014 stand out in relation to the plan approved in 2001. The first was the adoption of the One Health concept as a guiding principle for formulation of a global plan of action on AMR. The WHO regarded the concept as allowing a coherent, comprehensive and integrated approach at the global, regional and national levels, involving different actors and sectors, such as human and veterinary medicine, agriculture, environment and consumers.

The second change was the establishment of a Global Task Force on Antimicrobial Resistance based on tripartite collaboration among the United Nations Food and Agriculture Organization (FAO), the World Animal Health Organization (OIE) and the WHO2424 World Health Organization. Report of Sixty-Seventh World Health Assembly. [internet]. [Genebra]: WHO; [2014]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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,2525 World Health Organization. Resolution and decision of Sixty-Seventh World Health Assembly [internet]. [Genebra]: WHO; [2014]. [acesso em 2017 ago 20]. Disponível em: http://apps.who.int/gb/archive/.
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.

In that context, the WHO Director-General called for a Global Plan to be drawn up to assist the Assembly with its decisions and assure that all countries, especially developing countries, were able to respond to AMR2424 World Health Organization. Report of Sixty-Seventh World Health Assembly. [internet]. [Genebra]: WHO; [2014]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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,2525 World Health Organization. Resolution and decision of Sixty-Seventh World Health Assembly [internet]. [Genebra]: WHO; [2014]. [acesso em 2017 ago 20]. Disponível em: http://apps.who.int/gb/archive/.
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. That document was then drafted in collaboration among the three organisations mentioned earlier.

The draft approved in 20142626 World Health Organization. Draft global action plan on antimicrobial resistance. [Internet]. [Genebra]: WHO; [2014]. [acesso em 2017 ago 20]. Disponível em: http://apps.who.int/gb/archive/.
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outlined the priority areas for AMR response action, with quantifiable targets and goals and implementation plans specifying roles and responsibilities of the actors involved. It also provided for indicators to enable progress to be monitored, measured and replicated.

The 2014 Report (A67/39)2424 World Health Organization. Report of Sixty-Seventh World Health Assembly. [internet]. [Genebra]: WHO; [2014]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
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broadened its view of the innovation problem to include the lack of innovation in diagnostics. The report mentioned the insufficiency of investment in R&D for AMR-related technologies, whether preventive (vaccines), treatment-related (antimicrobial drugs) or diagnostic. It stressed the need for incentives for innovation in the field, associated with sustainable new models to support R&D in the long term and recommended that the WHO partner with industry. That year’s Resolution (WHA67.25)2525 World Health Organization. Resolution and decision of Sixty-Seventh World Health Assembly [internet]. [Genebra]: WHO; [2014]. [acesso em 2017 ago 20]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
cited limited development of new antimicrobial agents, and mentioned the CEWG Report and the R&D Observatory. It recommended that countries encourage new collaborative and financing models for innovation. The need to finance R&D and Innovation (RD&I) in this field was mentioned both in recommendations to the countries and in the WHO mandate2525 World Health Organization. Resolution and decision of Sixty-Seventh World Health Assembly [internet]. [Genebra]: WHO; [2014]. [acesso em 2017 ago 20]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
.

This gap in technological innovation is a central item in discussions of AMR. Beginning in 2003, the issue of public health, innovation and intellectual property began to gain prominence in the WHO, and arguments and actions relating to this public health issue can be seen as included into documents issued from 2014 onwards.

In 2015, the 68th WHA reaffirmed the importance of the tripartite collaboration (WHO/FAO/OIE) and mentioned the institutions’ common interest in tackling AMR3232 World Health Organization. Report of sixty-eight World Health Assembly [internet]. [Genebra]: WHO; [2015]. [acesso em 2017 ago 2017]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
. That year the Tripartite developed a new Global Action Plan on AMR1111 World Health Organization. Draft global action plan on antimicrobial resistance [internet]. [Genebra]: WHO; [2015]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
and a meeting was convened with the Secretary-General to hold a high-level meeting on AMR in 20163333 World Health Organization. Resolution and decision of sixty-eight Assembly [internet]. [Genebra]: WHO; [2015]. [acesso em 2017 ago 2017]. Disponível em: http://apps.who.int/gb/archive/.
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.

The Resolution approved that same year (WHA68.7) requested all Member States to adapt the Global Action Plan on AMR to their national priorities. It also stipulated that, by the 70th WHA, in 2017, all country plans should be aligned with the WHO plan1111 World Health Organization. Draft global action plan on antimicrobial resistance [internet]. [Genebra]: WHO; [2015]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
and with the standards and guidelines laid down by other international bodies, such as the Codex Alimentarius Commission, FAO and OIE3333 World Health Organization. Resolution and decision of sixty-eight Assembly [internet]. [Genebra]: WHO; [2015]. [acesso em 2017 ago 2017]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
.

In 2016, the WHO published Report A70/123535 World Health Organization. Global action plan on antimicrobial resistance. Options for establishing a global development and stewardship framework to support the development, control, distribution and appropriate use of new antimicrobial medicines, diagnostic tools, vaccines and other interventions [internet]. [Genebra]: WHO; [2016]. [acesso em 2017 ago 20]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
, as well as a Global Framework for Development and Stewardship to Combat Antimicrobial Resistance, produced jointly by the WHO, FAO and OIE. The Framework pointed to the need to support the development, control, distribution and appropriate use of new antimicrobial drugs, diagnostic tools, vaccines and other interventions, with a view to promoting affordable access to existing and new antimicrobial medicines and diagnostic tools, taking into account the needs of all countries and in line with the Global Action Plan on Antimicrobial Resistance3535 World Health Organization. Global action plan on antimicrobial resistance. Options for establishing a global development and stewardship framework to support the development, control, distribution and appropriate use of new antimicrobial medicines, diagnostic tools, vaccines and other interventions [internet]. [Genebra]: WHO; [2016]. [acesso em 2017 ago 20]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
.

In 2016, AMR became an issue beyond the health arena with the UN’s approval of the Political Declaration of the High-Level Meeting of the General Assembly on Antimicrobial Resistance. The document reaffirmed that the Global Plan of Action on AMR should be drawn up by the WHO in collaboration with the FAO, OIE and UN, and represent the commitment of Heads of State and Government to developing a multi-sector action plan in line with the One Health concept3636 United Nations Organization. Political Declaration of the High- Level Meeting of General Assembly on Antimicrobial Resistance [internet]. [Genebra]: UN; [2016]. [acesso em 2017 set 20]. Disponível em: https://digitallibrary.un.org/record/842813.
https://digitallibrary.un.org/record/842...
.

That document mentioned that AMR posed a challenge to attainment of the Sustainable Development Goals set in Agenda 2030. It also instituted the Interagency Coordination Group (IACG) on AMR. The Group was co-chaired by the WHO and the UN Secretariat, with the participation of other institutions of the UN system, international organisations, civil society and private sector representatives and experts in a number of AMR-related fields. Its main aim was to produce a report to assist decision-making on AMR at the 73rd WHA3636 United Nations Organization. Political Declaration of the High- Level Meeting of General Assembly on Antimicrobial Resistance [internet]. [Genebra]: UN; [2016]. [acesso em 2017 set 20]. Disponível em: https://digitallibrary.un.org/record/842813.
https://digitallibrary.un.org/record/842...
. In 2019, the Group published the report ‘No time to wait: securing the future from drug-resistant infections’4444 United Nations. No time to wait: securing the future from drug-resistant infections. Report to the Secretary - General of the United Nations. [internet]. [Genebra]: UN; [2019]. [acesso em 2020 maio 20]. Disponível em: http://apps.who.int/.
http://apps.who.int/...
.

Unlike previous years, in 2016 and 2017 no Resolution was approved on AMR at the WHA, because the Global Plan of Action on AMR had been approved in 2015. In 2018, the Tripartite signed a collaboration agreement with the United Nations Environment Programme (UNEP) (figure 1) to tackle AMR at a multi-sector (human-animal-environment) interface4040 World Health Organization. Memorandum of Understanding between The United Nations Food and Agriculture Organization and The World Organisation for Animal Health and The World Health Organizations. [internet]. [Genebra]: WHO; [2018]. [acesso em 2020 maio 20]. Disponível em: https://www.who.int/antimicrobial-resistance/publications/tripartite-work-plan/en/.
https://www.who.int/antimicrobial-resist...
.

At each WHA after 2015, countries were updated as to the status of Member States’ adoption of the Global Action Plan. In 2017, 67 countries had developed their plans to address the problem3838 World Health Organization. Report of seventieth World Health Assembly. Antimicrobian Resistance [internet]. [Genebra]: WHO; [2017]. [acesso em 2020 maio 20]. Disponível em: http://apps.who.int/gb/archive/.
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; by 2019, 117 countries had done so. However, only half of these – among them Brazil – had set up a multi-sector committee with representatives of various fields1313 Ministério da Saúde. Resistência antimicrobiana: enfoque multilateral e resposta brasileira. In: Saúde e Política Externa: os 20 anos da Assessoria de Assuntos Internacionais de Saúde (1998-2018). [internet]. [Brasília, DF]: MS; [2018]. [acesso em 2020 maio 20]. Disponível em: www.saude.gov.br.
www.saude.gov.br...
. The number of countries still developing their plans remained at 62 from 20173838 World Health Organization. Report of seventieth World Health Assembly. Antimicrobian Resistance [internet]. [Genebra]: WHO; [2017]. [acesso em 2020 maio 20]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
to 20194242 World Health Organization. Follow-up to the high-level meetings of the United Nations General Assembly on health-related issues. [internet]. [Genebra]: WHO; [2019]. [acesso em 2020 maio 20]. Disponível em: https://apps.who.int/.
https://apps.who.int/...
.

At the 2019 WHA, the countries reaffirmed their commitment to continue increasing their efforts to adopt the Global Plan of Action on AMR at the national level4343 World Health Organization. Resolution and decisions of Seventy-Second World Health Assembly. Antimicrobial resistance. [internet]. [Genebra]: WHO; [2019]. [acesso em 2020 maio 20]. Disponível em: https://apps.who.int/.
https://apps.who.int/...
. The Resolution addressed the question of the rational use of antibiotics in humans and animals, and mentioned the clinical guidelines for using antibiotics that are important to human health4343 World Health Organization. Resolution and decisions of Seventy-Second World Health Assembly. Antimicrobial resistance. [internet]. [Genebra]: WHO; [2019]. [acesso em 2020 maio 20]. Disponível em: https://apps.who.int/.
https://apps.who.int/...
(the ‘AWaRE’ Classification). As regards RD&I, it was agreed that the countries would support voluntary technology transfer to prevent and control AMR4343 World Health Organization. Resolution and decisions of Seventy-Second World Health Assembly. Antimicrobial resistance. [internet]. [Genebra]: WHO; [2019]. [acesso em 2020 maio 20]. Disponível em: https://apps.who.int/.
https://apps.who.int/...
.

Other initiatives led by the WHO during this period included setting up the Global Antibiotic Research and Development Partnership (GARDP) in 2016, publication of a list of resistant pathogens and approval of guidelines and best practices for animal production in 2017 (figure 1 and chart 3).

Chart 3
Examples of 'global public goods'5555 Drugs for Neglected Diseases Initiative. Global Antibiotic Research & Development Partnership (GARDP) [internet]. [Genebra]. [acesso em 2019 set 10]. Disponível em: https://www.dndi.org/achievements/gardp/.
https://www.dndi.org/achievements/gardp/...
in the AMR field

The WHO approved specific budgets for AMR for the two-year periods 2016-2017 and 2018-2019 of US$19 million and US$42 million, respectively. What is striking is that the budget for 2018-2019 is roughly double those approved for 2016-2017 and 1998-1999 (about US$23 million). That fact indicates that, despite the structural crisis in WHO funding5858 Ventura D, Perez F. Crise e reforma da organização mundial de saúde. Lua Nova. 2014; 92:45-77., funds were earmarked for AMR. It also points to greater breadth and commitment in the 2015 plan as compared with 2001.

Global health system governance and functions applied to the case of AMR

Drawing on the concept of Global Governance for Health4646 Frenk J, Moon S. Governance challenges in global health. New England Journal of Medicine. 2013; 368(10):936-942., the document analysis in this study found that the WHO recognised AMR as a global health problem, because no country alone could contain its advance, which overrides national borders and involves diverse sectors of society1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
.

It is evident that, over the whole course of formulation of the Global Plan of Action on AMR at the WHO, the issue of international cooperation to support developing countries and least-developed countries (LDCs) to formulate their plans to tackle AMR. Inequality among Member States was recognised as an important issue and, for that reason, international cooperation served as a tool for supporting LDCs by developing epidemiological surveillance laboratories and programmes and training personnel1111 World Health Organization. Draft global action plan on antimicrobial resistance [internet]. [Genebra]: WHO; [2015]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
,1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
.

Both the 2001 Global Strategy1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
and the 2015 Global Action Plan1818 World Health Organization. Global strategy for containment of antimicrobial resistance [internet]. [Genebra]: WHO; [2001]. [acesso em 2017 ago 17]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
reinforced the importance of epidemiological surveillance as one of the structural components of the response to AMR. It was recommended that each Member State develop a national system to monitor antibiotic consumption in humans and animals and the incidence of AMR. Also as regards epidemiological surveillance, the platform of the Global Antimicrobial Resistance Surveillance System (Glass) was inaugurated in 2015. This initiative was designed to collect and analyse country-level information on AMR so as to produce evidence to guide national, regional and global action to tackle AMR. By 2019, 105 countries claimed to have their own surveillance systems; 67 shared their findings and 48 input crude data to the GLASS initiative4242 World Health Organization. Follow-up to the high-level meetings of the United Nations General Assembly on health-related issues. [internet]. [Genebra]: WHO; [2019]. [acesso em 2020 maio 20]. Disponível em: https://apps.who.int/.
https://apps.who.int/...
.

The Global Plan of Action on AMR, as well as the guidelines and initiatives on antibiotic use in agriculture and livestock, and research, development and innovation in new antimicrobial drugs (chart 3), are all regarded as examples of ‘global public goods’4646 Frenk J, Moon S. Governance challenges in global health. New England Journal of Medicine. 2013; 368(10):936-942. in the AMR context.

Global health is thus the outcome of the policymaking process in a diversity of institutional spaces4646 Frenk J, Moon S. Governance challenges in global health. New England Journal of Medicine. 2013; 368(10):936-942.. Considering the concept of institutional dimension proposed by Sell4747 Sell SK. The quest for global governance in intellectual property and public health: Structural, discursive, and institutional dimensions. Temp. L. Rev. 2004; 77:363., the document analysis found that a number of multilateral institutions participated in the process of formulating the plan to tackle AMR, including the WHO, FAO, OIE, UN, World Trade Organization (WTO) and later the UNEP (figure 2). This gives greater grounds for claiming that development of the AMR response plan was the outcome of meshing among organisations with different perspectives.

Figure 2
Diagram of the institutional dimension of global health in the case of AMR

*The United Nations System comprises specialised agencies and institutional programmes.

United Nations Environment Programme (Unep), United Nations Food and Agriculture Organization (FAO), United Nations Organization (UN), World Health Organization (WHO), World Trade Organization (WTO), World Animal Health Organization (OIE).

Illustrating that interrelationship, it can be seen that three of the four sub-functions of Stewardship were applied there4646 Frenk J, Moon S. Governance challenges in global health. New England Journal of Medicine. 2013; 368(10):936-942.: cross- sector health advocacy; negotiation and consensus building; and setting rules to manage the dimensions of health across sectors.

The Resolution of the 68th WHA states that the WHO partnered with the UN in order to join forces in search of efficient mechanisms with which to implement the Global Action Plan for all nations, considering the needs of developing countries3333 World Health Organization. Resolution and decision of sixty-eight Assembly [internet]. [Genebra]: WHO; [2015]. [acesso em 2017 ago 2017]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
. With regard to AMR, the WHO was found to have collaborated with other multilateral organisations so as to further the interests of global health in other institutions that were not responsible for health-related issues, but which could influence the global health field.

As regards negotiating and consensus building on the use of antibiotics in agriculture and livestock, no mention was found of any ban on the use antibiotics as growth promoters in animal production, probably because this was an issue of tension and dissent among countries. At the national level, some countries took different positions on the issue on the basis of various arguments. EU countries banned growth promoters as of 20065959 Kahn LW. One health and the politic of antimicrobial resistance. John Hopkins University Press; 2016. and recently (2018)6060 European Parliament: veterinary medicine: another step in fighting antibiotic resistance. [internet]. [acesso em 2020 maio 10]. Disponível em: https://www.europarl.europa.eu/news/en/headlines/society/20181018STO16580/veterinary-medicines-fighting-antibiotic-resistance.
https://www.europarl.europa.eu/news/en/h...
restricted the preventive use of antibiotics in animal production6060 European Parliament: veterinary medicine: another step in fighting antibiotic resistance. [internet]. [acesso em 2020 maio 10]. Disponível em: https://www.europarl.europa.eu/news/en/headlines/society/20181018STO16580/veterinary-medicines-fighting-antibiotic-resistance.
https://www.europarl.europa.eu/news/en/h...
. Meanwhile, some developing countries, such as Brazil, permit the use of growth promoters88 Brasil. Decreto-lei nº 8448, de 6 de maio de 2015. Regulação da Fiscalização dos Produtos de Uso Veterinário [internet]. Diário Oficial da União. 6 Maio 2015. [acesso em 2017 nov 15]. Disponível em: http://www.planalto.gov.br/.
http://www.planalto.gov.br/...
,1313 Ministério da Saúde. Resistência antimicrobiana: enfoque multilateral e resposta brasileira. In: Saúde e Política Externa: os 20 anos da Assessoria de Assuntos Internacionais de Saúde (1998-2018). [internet]. [Brasília, DF]: MS; [2018]. [acesso em 2020 maio 20]. Disponível em: www.saude.gov.br.
www.saude.gov.br...
.

The 2014 Resolution mentions that the partnership among the WHO, FAO and OIE was set up to manage conflicts of interest, with a view to support the drafting Global Action Plan on AMR2525 World Health Organization. Resolution and decision of Sixty-Seventh World Health Assembly [internet]. [Genebra]: WHO; [2014]. [acesso em 2017 ago 20]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
.

On the option between ‘banning’ or ‘not banning’ the use of growth promoters, the IACG reached a compromise in which it recommended that certain antibiotics classified as critically important to human health should gradually be phased out4444 United Nations. No time to wait: securing the future from drug-resistant infections. Report to the Secretary - General of the United Nations. [internet]. [Genebra]: UN; [2019]. [acesso em 2020 maio 20]. Disponível em: http://apps.who.int/.
http://apps.who.int/...
of animal use. The report considered that initiative to be a first step towards the rational use of antibiotics in animal production4444 United Nations. No time to wait: securing the future from drug-resistant infections. Report to the Secretary - General of the United Nations. [internet]. [Genebra]: UN; [2019]. [acesso em 2020 maio 20]. Disponível em: http://apps.who.int/.
http://apps.who.int/...
. Accordingly, the establishment of the FAO/WHO/OIE taskforce is believed to have been fundamental in building consensus on the use of antibiotics for promoting growth.

In addition to consensus building, the actors are considering settting new rules or instruments to manage AMR-related issues. The 2016 Report mentioned the legal status of the standards, guidelines and codes of practice of the Codex Alimentarius and OIE enjoyed under WTO agreements3434 World Health Organization. Report of sixty-nine World Health Assembly. Antimicrobial Resistance [internet]. [Genebra]: WHO; [2016]. [acesso em 2017 ago 2017]. Disponível em: http://apps.who.int/gb/archive/.
http://apps.who.int/gb/archive/...
.

The Stewardship sub-function ‘setting rules to manage the dimensions of health across sectors’ is exemplified in the IACG report by the process still under way among countries with regard to adopting binding and non-binding instruments for measures on AMR4444 United Nations. No time to wait: securing the future from drug-resistant infections. Report to the Secretary - General of the United Nations. [internet]. [Genebra]: UN; [2019]. [acesso em 2020 maio 20]. Disponível em: http://apps.who.int/.
http://apps.who.int/...
.

Conclusions

This study examined the formulation of the response to AMR in the WHO. The findings indicate that, although the issue has been on the agenda since 1998, and a plan to address AMR was approved in 2001, few advances can be seen as regards adoption by WHO Member States. In 2014, when the One Health concept was endorsed, conditions were created for adhesion by other international institutions (FAO, OIE and WTO) and for approval of the Global Plan of Action on AMR.

Given the complexity and comprehensiveness of the factors relating to AMR, it was to be expected that design of a global response to the problem would be immersed in that complexity, particularly because not only do public health needs affect sensitive economic sectors – the agriculture and livestock and pharmaceutical industries – but they also reinforce asymmetries among countries. In that light, it was fundamental to triangulate among multiple analytical frames of reference so as to permit a broader understanding of the study object, underscoring its global importance and recognising the dimension of antibiotic use in animals and the gap in technological innovation.

Besides being an important mobilising agent for the response to AMR at the global level, the WHO has also assured a budget for actions on this issue even in a context of defunding. It is thus concluded that the public health perspective should prevail in the response to AMR. It remains to be analysed how far-reaching will be national-level adoption of the proposals approved multilaterally to curtail the spread of AMR and, at the same time, assure that therapeutic options involving existing and new antimicrobial drugs continue to be available to those who need them.

  • Financial support: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes)

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Publication Dates

  • Publication in this collection
    16 Nov 2020
  • Date of issue
    Jul-Sep 2020

History

  • Received
    11 Dec 2019
  • Accepted
    08 June 2020
Centro Brasileiro de Estudos de Saúde RJ - Brazil
E-mail: revista@saudeemdebate.org.br