Policy ForumGlobal Health

Achieving global targets for antimicrobial resistance

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Science  26 Aug 2016:
Vol. 353, Issue 6302, pp. 874-875
DOI: 10.1126/science.aaf9286

After decades of neglect, antimicrobial resistance (AMR) has captured the attention and concern of the public health community and global leaders. In September 2016, a high-level meeting of the United Nations General Assembly (UNGA) will discuss how countries can cooperate to preserve global access to effective antimicrobials. This will be only the fourth health issue (and the first One Health issue, integrating human, animal, and environmental health) to bring together heads of state at the UNGA for a rare opportunity to set a global agenda to combat the crisis. We believe that (i) setting targets for reducing drug-resistant infections, (ii) adequate financing for global action, and (iii) defining the global health architecture to address AMR should be elements of a UN plan.

The costs of antibiotic treatment and mortality due to resistance are increasing worldwide (1). The greatest burden occurs in low- and middle-income countries (LMICs), especially among the young: An estimated 214,000 neonatal sepsis deaths are attributable to resistant pathogens each year (2). But high-income countries are not immune: An estimated 23,000 people in the United States and 25,000 in Europe die each year from resistant pathogens (1, 2). That said, lack of access and delayed access to antibiotics kill more people than AMR. The challenges of expanding appropriate access to antimicrobials while restricting inappropriate access require changes to financing and delivering health care.

Targets and Surveillance

Use of antibiotics is the most important driver of selection for resistance and loss of effectiveness. Use is increasing globally, driven by rising incomes and increasing access, and varies in human and animal sectors across countries, depending on prevailing medical, veterinary, and regulatory practices.

We propose that no country consume more than the current median global level [8.54 defined daily doses (DDDs) per capita per year] (see the figure). We estimate that this would lower overall human use by 17.5% globally [see (3); see supplementary materials (SM)]. Reducing use is accomplished by improving public health and sanitation. In low-income countries, antibiotics are used to compensate for the lack of public health infrastructure (e.g., vaccination coverage and infection control). A target linked to UN Sustainable Development Goals 3 (on health) and 6 (on water and sanitation) for public health would reduce reliance on antibiotics.

Reductions could be achieved through public campaigns, aimed at physicians and patients, to discourage inappropriate antibiotic use (4), particularly in response to seasonal influenza (3). Although LMICs face a higher burden of infectious disease, per capita consumption of antimicrobials in most LMICs is well below our target, thus, it need not compromise legitimate uses.

There is potential for reducing consumption in the animal sector. We propose global phasing out of the use of antimicrobial growth promoters; a deadline of 5 years would be appropriate, given the urgency of the problem. This could avert much of the projected 67% increase in use for farm animals between 2010 and 2030 (3). Although this would incur some cost to agricultural sectors, even in China (the largest consumer of antibiotics in agriculture), that cost is likely on the order of $3 billion a year, a small fraction of the country's burden of AMR (5). The costs of improving biosafety and biosecurity in farming operations to phase out antimicrobial growth promoters would be largely offset by lowering the risk of infection and cost of antimicrobials. We envision a process similar to that in the European Union where there was declared intent to phase out subtherapeutic use, followed by regulatory changes. Globally, this could work through a multilateral process, as with global movements to phase out, e.g., asbestos or chlorofluorocarbons.

National-level restrictions on antibiotic effluents from pharmaceutical manufacturing, agricultural operations, and hospital waste that contribute to buildup of resistance genes in the soil and water are an urgent priority.

Targets for reductions in antibiotic consumption should be accompanied by targets to reduce levels of a drug-resistance index (e.g., the proportion of infections that are resistant), based on a weighted-average of resistance of the eight World Health Organization (WHO) priority pathogens to first-line antibiotics, nationally, regionally, and globally within 5 years (6). We do not specify the scale of reduction—the immediate priority is to prevent increases—but recommend review in 2021 to consider more stringent targets. The strategies chosen would reflect health system context and priorities of individual countries.

Existing surveillance programs for AMR can contribute to target monitoring at the national level (7), e.g., the Global Antimicrobial Resistance Surveillance System and ResistanceMap (8). Surveillance should involve the livestock sector and the wider environment and should track access and use, as well as indicators, such as water, sanitation, and vaccination coverage. Data on AMR must be translated into epidemiologically sound estimates of public health burden; such estimates require information on treatment rates and failures (2) not routinely collected.

Surveillance cannot be the sole responsibility of individual countries; it is a global good and should be financed accordingly. Initiatives such as the Fleming Fund and the Global Health Security Agenda provide opportunities to strengthen surveillance in countries with poor public health architecture. Not all surveillance elements need to be replicated at a national level; integrating local activities into multinational networks may be efficient, with appropriate structures for data-sharing, analysis, and communication.

Global Financing

Substantial funds have been committed in the United States and Europe to tackle AMR, but success will be limited without globalscale investments. The need to incentivize development of new vaccines, diagnostics, novel therapies, and stewardship methods, as well as traditional antibiotics, to ensure availability of the “antibiotic umbrella” has been recognized (9). Vaccines face high development costs and uncertain markets; however, the Gavi Vaccine Alliance financing mechanism has been successful in bringing new vaccines into wide use.

Antimic robial sales vary by country

Data from 75 countries. The five countries with highest total antibiotic sales for human use and the five with highest per capita sales are identified. See SM.

GRAPHIC: N. CARY/SCIENCE

Development and deployment of diagnostics are more difficult. Knowledge of the underlying pathogen and its drug sensitivity would improve antibiotic use, but new diagnostics are needed. Diagnostics must be rapid and sufficiently inexpensive if they are to be used before the decision to begin antibiotic treatment. The Longitude, Horizon, and National Institute of Allergy and Infectious Diseases (NIH) prizes for innovative diagnostics stipulate that winners demonstrate the feasibility of deploying globally.

New alternatives to traditional antibiotics are needed. Multiple noncompound approaches that target bacteria or the host have been proposed (10). Antibiotics can interact to synergize, antagonize, or suppress each other's effects (11); interactions modify the evolution of resistance. Financial stimuli for antibiotic development must address the lack of incentives for appropriate use (12) and should enable sustainable access, when clinically appropriate. Initiatives are being implemented to improve the development pipeline for new antibiotics (e.g., the Generating Antibiotics Incentives Now in the United States and the Innovative Medicines Initiative in Europe) but cannot be long-term solutions because resistance develops quickly to new antibiotics. Initiatives like the Affordable Medicines Facility—Malaria, that aimed to conserve the effectiveness of antimalarial drugs, involved a high-level subsidy (aimed at manufacturers, not retailers) and were found to be successful at increasing sales of quality-assured artemisinin combinations and reducing the use of monotherapies that contribute to drug resistance (13, 14). Scaling from the size of response relative to Gross Domestic Product in the European Union and United States (which allocates ∼$1 billion annually to AMR), we anticipate that a global fund of at least $5 billion annually will be needed.

Global Architecture

The global response to HIV/AIDS, effective in curtailing that epidemic, was accelerated by the 2001 UNGA on HIV/AIDS (15). A clear set of actions tied to targets, financing, institutional commitment to cross-sectoral coordination at the national level, international monitoring and accountability, and civil society participation should also now be reflected in a UNGA plan for AMR. A global architecture must transcend the individual animal and human domains (16). Proposed approaches include ones similar to the Intergovernmental Panel on Climate Change, or the Montreal Protocol (17).

The current tripartite arrangement among WHO, the Food and Agricultural Organization (FAO), and World Organization for Animal Health (OIE) offers promise but is unlikely to be sustainable given their other priorities. We recommend a new High-Level Coordinating Mechanism (HLCM) under the UN Secretary General because (i) access to effective antimicrobials transcends the remit of WHO, involving animal health and the environment; (ii) nonstate actors play an important role; and (iii) significant new funding is needed for research and development.

The HLCM, consisting of WHO, FAO, OIE, the World Bank, relevant UN agencies and other international organizations, major multisectoral stakeholders, and global experts, reports to the UN Secretary General and should coordinate support for development, implementation, and monitoring of national plans and relevant actions. It can raise awareness and financing if leadership is given seniority within the UN system. A new HLCM would allow a more inclusive governing body (e.g., with nonstate actor voting rights), and engagement with civil society, patient groups, and the private sector.

Financing would likely come through a replenishment process, such as used by the Global Fund and the Gavi Alliance through World Bank Trust Funds (18); an organization solicits multiyear donor commitments on a regular schedule (e.g., every 3 years), rather than every year. Buy-in of countries across the world, particularly the Group of 77, and funders, such as the Bill and Melinda Gates Foundation, would be essential.

Antibiotic resistance threatens decades of progress in medicine, food security, and public health. Global collective action rooted in national responses is needed. The UNGA high-level meeting could help shift world opinion, build consensus around core feasible goals, and integrate solutions into policy approaches by UN member states, international organizations, and philanthropies.

References

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