Developing an approach to assessing the political feasibility of global collective action and an international agreement on antimicrobial resistance

Background Antimicrobial resistance (AMR) is a global issue. International trade, travel, agricultural practices, and environmental contamination all make it possible for resistant microbes to cross national borders. Global collective action is needed in the form of an international agreement or other mechanism that brings states together at the negotiation table and commits them to adopt or implement policies to limit the spread of resistant microorganisms. This article describes an approach to assessing whether political and stakeholder interests can align to commit to tackling AMR. Methods Two dimensions affecting political feasibility were selected and compared across 82 countries: 1) states’ global influence and 2) self-interest in addressing AMR. World Bank GDP ranking was used as a proxy for global influence, while human antibiotic consumption (10-year percent change) was used as a proxy for self-interest in addressing AMR. We used these data to outline a typology of four country archetypes, and discuss how these archetypes can be used to understand whether a proposed agreement may have sufficient support to be politically feasible. Results Four types of countries exist within our proposed typology: 1) wealthy countries who have the expertise and financial resources to push for global collective action on AMR, 2) wealthy countries who need to act on AMR, 3) countries who require external assistance to act on AMR, and 4) neutral countries who may support action where applicable. Any international agreement will require substantial support from countries of the first type to lead global action, and from countries of the second type who have large increasing antimicrobial consumption levels. A large number of barriers exist that could derail efforts towards global collective action on AMR; issues of capacity, infrastructure, regulation, and stakeholder interests will need to be addressed in coordination with other actors to achieve an agreement on AMR. Conclusions Achieving a global agreement on access, conservation, and innovation – the three pillars of AMR – will not be easy. However, smaller core groups of interested Initiator and Pivotal Countries could develop policy and resolve many issues. If highly influential countries take the lead, agreements could then be scaled up to achieve global action. Electronic supplementary material The online version of this article (doi:10.1186/s41256-016-0020-9) contains supplementary material, which is available to authorized users.


INTRODUCTION
CC0 public domain photo by pixelcreatures To analyze political feasibility, we must consider how countries will act in the face of different proposed international agreements. Predicting how each country will act is a complex process because each country has its own considerations, history with AMR, and global standing. To facilitate our discussion, we describe four simplified types of countries that might be engaged in an AMR agreement: Initiator Countries, Pivotal Countries, Follower Countries and Neutral Countries.

STATE ACTOR TYPOLOGY
Global influence often depends on financial power. Thus, we used the World Bank's 2014 GDP rankings to categorize countries by global influence and designated the top 25% of countries by GDP as the most influential. 12 To categorize countries based on interest in addressing AMR, we looked to antibiotic consumption. We assume that countries that have seen recent large increases in antibiotic consumption have a greater stake in combating AMR than countries with low or stable consumption rates. yet, annual consumption rates, even standardized per capita, obscure underlying trends. For example, low rates of consumption  [15][16][17][18][19] In the USA, for example, the Food and Drug Administration successfully phased out non-treatment uses of medically important antibiotics in agriculture and plans to change OTC status, integrating industry perspectives in the process. [20][21][22] The agricultural industry in South Korea has also taken action. 23

Pivotal Countries
Pivotal Countries are also highly influential with total GDPs falling within the top 25% globally. But these countries also

Initiator Countries
Initiator Countries are both highly influential-their GDPs fall within the top 25% globally-and saw substantial net decreases in human antibiotic consumption between 2000 and 2010. We theorize that these countries could be influential in initiating global action on AMR. Their success in decreasing antibiotic use makes these countries a potential source of expert knowledge on reducing antimicrobial use and AMR.
Further, these countries are most likely to have the resources and capacity to facilitate sustained action on AMR.
Mexico (MEX) is an example of an Initiator Country that has taken steps towards reducing the threat of AMR with some   38 Outside of hospitals, Latvia has one of the lowest rates of antimicrobial use among European Union (EU) countries. 39 Latvia's infection control legislation provides a good basis for improving infection control practices in healthcare. 39 Latvia's success can been used as an example for less wealthy countries to act on AMR; however, with low global influence, Latvia also represents a lower-priority country for recruitment into an AMR agreement.

INFLUENTIAL STAKEHOLDERS
An important first step in analyzing the political feasibility of achieving global agreement on AMR is to identify key stakeholders who are likely to be affected by or play a role in AMR policies. At the international negotiation table, national representatives strive for agreements that promote common goals while remaining true to national priorities. 5 Domestically, key stakeholder groups influence national priorities by lobbying national governments to pursue policies favourable to their groups' interests. 4,5 Where tensions arise between key stakeholder interests and international policies, so can barriers to international agreement. Figure 3 lists the key stakeholders we identified, and summarizes the interests and tensions these stakeholders bring to an AMR agreement. antimicrobial use in animals, 35 as regulations focus primarily on products for export rather than the domestic market. 32 Countries in French West Africa (BEN, BFA, CIV, CMR, COG, GAB, GIN, MLI, SEN, TGO) face many barriers to acting on AMR without support. A lack of knowledge about local conditions is the biggest barrier. There is awareness that some AMR infections-such as MDR-TB-are a concern for the region, yet weak laboratory infrastructure means these countries lack drug resistance surveillance data. 36 Further, the lack of regulations and poor enforcement means that antibioticswhich are often of poor quality-can be dispensed from pharmacies and street vendors. 37 A great deal of capacity building would be required for these countries to take part in global AMR efforts.

Neutral Countries
Neutral Countries are less influential at the global level, and saw net decreases in human antibiotic consumption between 2000 and 2010. These countries might also be a source of expert knowledge, and might already be predisposed to participate in an AMR agreement. Countries in this group present the lowest risk if not initially included in an AMR agreement, because their antibiotic usage has decreased recently and few are major economic players. Latvia (LVA) is an example of a Neutral Country that has been successful at addressing its own AMR issues but that

Agricultural Industry
The agricultural industry relies heavily on antimicrobials, and is a key player in the global discussion on AMR. In 1997, an estimated 50% of all antimicrobials sold globally went to food animal production. 44 By 2030, livestock antibiotic use The pharmaceutical industry's support for an international AMR agreement will likely depend on economic interests.
Antimicrobial R&D offers a poor prospect of financial return. 7,42 Thus, pharmaceutical innovators are more likely to support an AMR agreement that provides appropriate financial incentives to invest in antimicrobial R&D. However, generic drug manufacturers will likely oppose R&D incentives or

International Organizations
International organizations such as the WHO are important actors in global health governance because they can coordinate efforts of other actors and stakeholders. 53 These organizations typically have normative or decisive mandates, and can provide a forum for and authority on specific matters to help establish international agreements. They can also form advocacy partnerships and engage stakeholders who may not otherwise have a voice in policymaking. 52 International organizations are concerned with advancing the interests of their member states. 3 International organizations that propose health standards-such as the WHO-strive for widespread commitment to those standards. However, to establish global standards those organizations must find a position of leadership in an otherwise "crowded and often is expected to increase by 67%, with agricultural use nearly doubling in the BRICS. 45 Using antibiotics of critical importance for human medicine to promote livestock growth and feed efficiency accelerates the development of drug-resistant human pathogens. 46,47 The potential economic impact of an AMR agreement is a major concern for the agricultural industry. The WHO stated that banning antibiotic growth promoters (AGP) is one of the most effective AMR prevention measures. 48

BARRIERS TO INTERNATIONAL AGREEMENT
Barriers to creating an international agreement on AMR Figure 4. Identified Barriers to a Global AMR Agreement

Agenda Setting Barriers
Creating an international AMR agreement requires consistent public and political engagement with the AMR issue. While political goals are often short-term due to election cycles, 34 AMR is a long-term battle that requires long-term funding.
Public engagement with health issues can influence the success of health policies, 4

Barriers to Agenda Setting
which these practices exist in agriculture. 46 Economic and policy evaluations as well as intervention research would provide decision makers with better evidence to support policy decisions.

Agreement Formulation Barriers
A lack of data may also hinder AMR policy formulation.

Agreement Legitimation Barriers
Garnering legal support for an international AMR agreement presents further challenges. A legally binding and enforceable agreement could ensure certain AMR policies are adopted and implemented on a global scale. 76  Nations, and World Organisation for Animal Health to ensure a "one-health" approach. 74 Any new agreement will likely face challenges in harmonizing existing efforts and frameworks while addressing national and regional participation and needs. 80

Agreement Implementation Barriers
To implement an international AMR agreement, actors and stakeholders will need to continue to cooperate at national and international levels. As with policy formulation, the challenge will be to reconcile stakeholder interests as well as international regulatory standards in a manner that

Achieving Agreement on Access
Despite the growing problem of AMR, inadequate access to antibiotics still claims far more lives than antibiotic resistance. 82 A lack of infrastructure, financial constraints, and human resource limitations 83  Achieving agreement on access is also more likely to be feasible if measures are tailored to local needs and capacities.
For example, countries with emerging pharmaceutical markets tend to implement policies that support local drug manufacturers. 87 These countries are therefore likely to oppose, or face barriers to implementing, 88 strict blanket regulatory frameworks. Policies that provide countries with some flexibility to account for local contexts will likely receive broader support.
The high costs associated with certain medicines creates an obstacle to accessing those medicines in many countries. A core group that includes countries such as India-a Pivotal Country with a large stake in the generics market-could be engaged to increase access to affordable generic medications in resource-poor countries. Still, efforts to engage the generic pharmaceutical industry might see limited success in addressing the access problem, because many Follower Countries are reluctant to use generics, in part due to product quality concerns that lead to distrust of off-brand medication. 83 Improving capacity and strengthening regulatory systems among generic manufacturers could help dispel these fears. 83,88 Tensions could arise within the pharmaceutical industry if branded products lose part of their value-added as a result of the influx of quality-assured generics on local markets and have to lower their prices to remain competitive. Drug manufacturers have been known to discontinue drugs in unprofitable markets, 89 which could impact local economies.
Any proposed agreement will need to be adjusted to local market realities and may benefit from engaging participants early on through strategic partnerships with CSOs, existing local entities, and governments to facilitate market access and support more predictable returns. 87 Finally, it is important to note that any agreement that includes measures that impede on countries' authority over health matters will likely be met with great reluctance. However, the value-added of a global agreement on AMR that facilitates and coordinates efforts can be leveraged to increase interest. Key barriers: (1) lack of data on AMR, and (2) global disparities in regulatory frameworks.

Key actors and roles:
While surveillance efforts must be undertaken on a global scale to be effective, engaging key Initiator and Pivotal Countries to strengthen regulatory frameworks on human and animal use of antimicrobials could greatly improve stewardship worldwide.

Summary: Conservation Targeted Commitment to Overcoming a Lack of Regulation
Global gaps in antimicrobial regulations, in both human and animal contexts, present a major barrier to implementing conservation efforts. 96

Achieving Agreement on Innovation
The global AMR response must provide financial incentives

Initiator Countries
Initiator Countries with high interests and investments in pharmaceutical R&D should take the lead on antimicrobial innovation. 107 In fact, select Initiator Countries could tackle antimicrobial innovation alone. 76 High-income countries hold most of the world's innovation capabilities, 83,108 and several Initiator Countries-such as the USA, Japan, and Key barriers: (1) reconciling key pharmaceutical stakeholder interests, (2) distributing costs to spur innovation, and (3) lack of capacity and research infrastructure.

Key actors and roles:
Initiator countries must take the lead on innovation, but Pivotal Country engagement can both help incentivize innovation through sharing of costs and reconcile potentially opposing interests.

Summary: Innovation
France-invest heavily in pharmaceutical R&D. 109 The USA has also identified investment in antimicrobial R&D as a key priority in its national strategy on AMR. 110 Initiator Countries are therefore best positioned to overcome any capacity or research infrastructure barriers associated with kick-starting the antimicrobial pipeline. 40

Pivotal Countries
Supporting pharmaceutical R&D sector interests will be a key concern for Initiator Countries with strong pharmaceutical markets in taking the lead on antimicrobial innovation.
Initiator Countries include most of the top eight developed pharmaceutical markets, where the pharmaceutical R&D sector accounts for nearly 75% of the market share and the provides the largest economic value-added of the pharmaceutical industry. 84,111 Further, industry organizations can provide a powerful platform for members of the R&D sector to lobby national governments for health policies favouring R&D sector interests. 4,112 In light of recent interest from the industry, 43 an innovation agreement that provides a mechanism for fair and sustainable compensation for antimicrobial R&D will likely see little resistance from the R&D sector.
Initiator Countries could receive opposition from the generic pharmaceutical industry if proposed strategies to incentivise innovation appear to limit the generic antimicrobial market in those countries. For example, generic manufacturers have opposed extending patent rights for innovators. 42 The global generic pharmaceutical industry is growing, 108

Funding Barriers
While select Initiator Countries could solve the innovation problem alone, 76 an innovation agreement could leverage support from a broader range of countries to overcome policy formulation barriers of cost distribution and funding.
Key Initiator Countries are more likely to resist leading the innovation response if they perceive they will bear an unfair cost burden. 4 If new antimicrobials must be viewed as a "global public good", then all countries who benefit should contribute to creating that public good. 73  2. National governments, pharmaceutical companies, agriculture groups, civil society, and international organizations will be important stakeholders who must be engaged.
3. Many barriers to an international AMR agreement are likely to arise at different stages of the policy cycle, including agenda setting, agreement formulation, agreement legitimation, and agreement implementation.
4. For the purpose of assessing political feasibility of such an agreement, countries can be categorized into four types based on their global influence and potential interest in addressing AMR.
5. The political feasibility of an international agreement on AMR will depend on engaging a few key influential countries to develop policies that can eventually gain global traction.

Country Typology Analysis
To analyse political feasibility, we must consider how countries will act in the face of different proposed international agreements. Predicting how each country will act is a complex process: each country has its own considerations, history with AMR, and global standing. increased usage greater than 50%, 30-50% increase, 10-29% increase, neutral (less than 10% increase or decrease), 10 to 29% decrease, and 50% or greater decrease. For countries that CDDEP reported as a group we chose to assign the group antibiotic consumption level to each country, and to use their individual GDP rankings. This is not precise but provides an estimate sufficient for our purposes in defining the typology.
This measure gives a long term overview of AMR change at the national level. Whether the country had high or low consumption rates in 2000, a large proportional increase in consumption signals a need to re-examine national priorities, while a decrease indicates successful stewardship efforts.
We plotted these GDP ranking and 10-year percent change in consumption against each other for 82 countries and developed the four types of countries illustrated in Figure 2 of our report.
Data labels use the three letter notations from the World Bank; a full listing of where the 82 countries under consideration fall is presented in Figure A1. Descriptions of the four types are included in the text of this report.
Our typology provides an organizing structure that assists in discussing the similarities of groups of countries. It was not possible to obtain newer data for a large number of countries and we recognize that some countries have made substantial progress more recently. We were also unable to capture animal use of antibiotics as this data is largely unavailable. We incorporate discussions of agricultural antibiotic use into our feasibility analysis to address this aspect of AMR.

Political Feasibility Analysis
Political feasibility has been described as an examination of actors and events in each stage of a policymaking process, and an anticipation of the likely resolution of the policy problem. 114 In defining political feasibility, Webber also outlined the goal of this type of analysis, which "… needs to assess the relative likelihood that a policy proposal or alternative, and a variety of modifications to that alternative, could be adopted and implemented in such a way that the policy problem is Webber's staged approach is valuable because it breaks the policy process into stages that can be individually examined.
However, his approach necessitates having a clearly defined policy proposal as the starting point for a feasibility analysis.
We need to take a more generalist approach to our political feasibility analysis, as we do not have a draft global AMR agreement to use as a starting point. Meltsner has described a different strategy for political feasibility analysis, which is more amenable to our early-stage analysis. Under his system, the analyst identifies actors, their beliefs and motivations, resources, and the sites of their interaction. 115 Our analysis draws on both Meltsner's and Webber's methodologies. We adopt Webber's staged approach to analysis, using the well-known policy-cycle heuristic ( Figure A2). In Part I of our report we identify barriers to an international agreement on AMR and the stage of the policy cycle where those barriers are likely to be problematic. As per Meltsner's methodology, we also identify key actors, their beliefs and motivations (here called interests), and interactions with other stakeholders.
Our barriers analysis centres on the policy-cycle, which breaks the policymaking process into 6 stages. We have chosen to focus on the first four stages: agenda setting, policy formulation, policy legitimation, and policy implementation.
We identified important barriers in our literature review and key informant interviews, and categorized the in barriers by policy stage at which they are most problematic.
To determine the feasibility of policy proposals in Access, Innovation and Conservation, we considered the interlinkages between government priorities and capabilities, global AMR control needs, barriers to policy making, and stakeholder interests. On the basis of these factors we considered the likelihood that agreement on this issue could be achieved. Our analysis centres on rational choice theory: governments are expected to act on AMR in accordance with the best interests of their nation on matters of health and economics. A P P E N D I X Figure A2. The Policy Cycle, adapted from Cairney 116