Globalization interferes with infectious disease control at the national level (1,5-7). While microbes move freely around the world, unhindered by borders, human responses to infectious diseases are conditioned by jurisdictional boundaries. Therefore, public health responses to infectious diseases must constantly navigate the mazes created by international and national law. Although national law now dominates legal approaches to infectious diseases, the global nature of the emerging infectious disease problem points towards a larger future role for international law.

Especially in federal systems, countries often divide authority for public health among various levels of government. In the United States, for example, states have primary power for public health because the Constitution did not grant the federal government explicit public health powers (8). While the federal government has authority to act in the public health context (9), its statutes and regulations derive from other federal powers. Most U.S. public health law is at the state level. The emerging infectious disease threat points to a larger role not only for international but also for federal law. Federal agencies create networks that allow the state and national governments to cooperate on issues such as antimicrobial resistance, but public health law remains primarily a state domain; therefore, state laws on public health may need to be reevaluated in the context of emerging infectious disease control (10).

The dominant public health strategy against antimicrobial resistance contains improved surveillance of resistant pathogens, as well as rational use and increased research and development of new antimicrobial drugs (1). These elements fit within the larger strategy to address emerging infectious diseases, which stresses surveillance, applied research, prevention and control, and infrastructure development (1).

Antimicrobial drug misuse in both industrialized and developing countries is a problem in connection not only with human treatment, but also with food production (11,45,46). More rational use of antimicrobial drugs in every country—for disease treatment and food production—must be at the core of the response to antimicrobial resistance.

Education has been suggested as the primary tactic for improving antimicrobial drug use (1,16). WHO has recommended "a code of practice for prudent use of antimicrobials in food animal production" (47).

However, the global scope of antimicrobial resistance indicates that an integrated strategy operating at both the national and international legal levels is needed. Such an integrated strategy faces political and legal challenges. Building effective national legal regimes regarding prudent antimicrobial use in many developing countries is unrealistic absent financial, political, and legal support from the international community (46). International legal harmonization of principles for prudent antimicrobial drug use will have to include monitoring and enforcement, as well as financial, technical, and legal assistance by industrialized countries to developing countries.

The international legal strategy needed will be difficult to create. WHO's limited powers to adopt regulations (48) do not seem to extend to creating regulations regarding the use of drugs. WHO has not, for example, proposed revising the International Health Regulations to rationalize the use of antimicrobial drugs. WHO has authority to adopt a convention on the use of antimicrobial drugs (49), but it has not done so (4). As illustrated by its proposal for a code of practice, rather than regulations, for antimicrobial use in food animal production, WHO historically has preferred not to use international legal powers to advance global health. Lessons from international environmental efforts suggest that international law must play a major role in setting international standards for implementation domestically and creating the political, technical, and financial conditions necessary to integrate international and national law (19).

The misuse of antibiotics in food production also raises concerns under international trade law. If antimicrobial drugs routinely used by food producers lose their effectiveness against animal-borne or plant-borne diseases, exports of contaminated food may be restricted by countries applying sanitary and phytosanitary measures (SPS measures) under the World Trade Organization (WTO) and other international trade agreements to keep such food out of their territories as threats to human, animal, or plant health (50). In addition, exports might be disrupted by countries applying SPS measures under international trade agreements against products suspected of containing harmful residues of antimicrobial drugs. The Codex Alimentarius Commission already sets standards for residues from veterinary drugs in food through its Committee on Residues of Veterinary Drugs in Foods, and WHO has recommended that this Codex committee discuss antimicrobial resistance (47). Codex standards have become important in international trade law through the WTO Agreement on the Application of Sanitary and Phytosanitary Measures (SPS Agreement) (50), which uses these standards as a basis for international harmonization of SPS measures. The importance of Codex food safety standards to international trade law was seen in the Beef Hormones Case, in which the WTO held that the European Union violated the SPS Agreement for not providing scientific justification for a beef hormone regulation stricter than the relevant Codex standards (51-53).

The inability of many governments to regulate antimicrobial drug use and the consequent misuse of these drugs raise the possibility that countries might use trade restrictions on food produced with improper use of antimicrobial drugs. In this situation, the food products might have residue levels below those established as maximums by Codex, but the trade restriction is intended to pressure the exporting country to improve regulation of antimicrobial drug use and the process by which the product is made. In the context of environmental protection, trade restrictions seeking to change a production process in another country, rather than to protect against health dangers from a particular product, have been ruled incompatible with international trade law (54-56). Although "relevant processes and production methods" (SPS Agreement, art. 5.2) form part of a risk assessment under the SPS Agreement, the risk must be a specific health risk from the product (e.g., highly inconsistent residue levels created by inadequate antimicrobial regulation) rather than fear of the health consequences of antimicrobial misuse. To avoid losing trade restrictions as part of a general strategy to combat antimicrobial misuse, legitimate trade restrictions against countries that systematically neglect recognized principles and practices for antimicrobial use might be considered; such a move would elevate the status of Codex's Code of Practice for Control of the Use of Veterinary Drugs and Guidelines for the Establishment of a Regulatory Programme for Control of Veterinary Drug Residues in Foods, as the SPS Agreement has elevated the importance of Codex's Maximum Residue Levels for Veterinary Drugs in Foods.

The International Conference on Harmonization, a multilateral effort between the United States, Japan, and the European Union to harmonize pharmaceutical regulatory systems, is another forum for discussing antimicrobial drug resistance. If national regulatory systems begin to grapple with the overuse of antimicrobial drugs, the International Conference on Harmonization might provide a forum to discuss a harmonized approach to more rational drug use in the United States, Japan, and the European Union. As structured, the Conference does not include other countries where overuse of antimicrobial drugs is a serious problem.

National laws for improving antimicrobial drug use face difficulties in industrialized countries; realistic national strategies confront legal and political hurdles. In the United States, state legislatures probably have the power to regulate how physicians prescribe antimicrobial drugs, but any attempt to legislate more rational use of drugs might evoke negative reactions from physicians and their medical associations, who might oppose the government's efforts to interfere with their professional judgment (57). If formal legislative regulation would not prove feasible, an alternative would be self-regulation by the medical and veterinary professions through practice guidelines, for example (57). A peer review process to monitor antimicrobial drug use has also been recommended (1). Managed care organizations may be included in the effort to control misuse of antimicrobial drugs, given their power and economic incentives to curb such misuse by physicians.

Formal regulation of antimicrobial use may be needed, which would involve monitoring and enforcement. In the United States, Congress could regulate use of antimicrobial drugs by monitoring interstate commerce in these products. Congress probably does not have the authority to regulate antimicrobial prescription practices directly; such authority rests with the states. The U.S. Food and Drug Administration (FDA) has authority to restrict the postapproval marketing of new drugs designed for treating serious or life-threatening illnesses and has indicated that these regulations can be used specifically in cases of new antimicrobial drugs (17,58). Restricted distribution is, however, a disincentive to the development of new drugs, and the regulations do not address misuse of existing products. Another regulatory strategy available to the FDA for dealing with resistance in existing products is to modify labeling requirements; modifying labels is, however, somewhat cumbersome (17). Effective regulatory changes in the United States will be jeopardized by the lack of similar changes in other countries.

Perhaps the most powerful U.S. federal strategy would be to make implementation of state policies to curb the misuse of antimicrobial drugs mandatory before states receive federal funds earmarked for public health. Although states might argue that this would encroach on their traditional public health rights and powers, such a federal enactment would be constitutional. In addition, using federal funds to improve antimicrobial use policies nationwide fits with the need for federal political leadership as well as financial and technical assistance. State governments might, therefore, welcome federal money conditioned on implementing policies the money supports. Pharmaceutical companies, worried about the federalization of policies affecting their economic relationships with local and state health-care providers, might oppose these mandates. In addition, federal leadership in this way would also run counter to trends in other areas, such as welfare reform, which are moving responsibilities from the federal to the state level.

In countries where governments subsidize the purchase of antimicrobial drugs, legislative or regulatory changes in these subsidies could lead to a decline in the use of the drugs. When Iceland ended government subsidies of antimicrobial drugs, their use in Iceland declined, while sales kept increasing in other Nordic countries (59). Although Iceland's legislative change was made for political, not medical reasons (59), it illustrates the possible impact of legislative and regulatory controls on the use of antimicrobial drugs.

Improving physicians' awareness of antimicrobial resistance does not address, however, misuse of these drugs by patients (60). MDRTB has developed largely because of improper adherence by patients to TB therapy (10); directly observed therapy was initiated as a result. Because patient misuse of antimicrobial drugs also contributes to the public health crisis, proper completion of antimicrobial therapy must also be addressed.

As the antimicrobial arsenal shrinks, new drug R&D becomes critical (1). Legislation at the domestic level would ensure adequate funding for public sector involvement. For diseases that pose an especially large or complex problem (e.g., malaria), international law can play a role by structuring international cooperation through such institutions as WHO or the World Bank. The recently proposed Multilateral Initiative on Malaria, an international multiagency malaria control program, involves, for example, plans to coordinate R&D on antimalarial products supported by WHO and the World Bank (61-63).

While public involvement and funds are important, the real engine of pharmaceutical development is the private sector. However, pharmaceutical companies have only recently brought new antimicrobial drugs forward for regulatory approval. Critical disincentives continue to constrain private R&D investment in new drugs: intellectual property protection, regulatory approval procedures, and perceived antitrust law limitations on collaborative R&D.

Strategies to address antimicrobial resistance as a public health and legal challenge must consider three levels of interdependence: among the antimicrobial drug surveillance, use, and R&D components of the public health strategy; among the levels of law—national and international; and between the public health and legal aspects of dealing with antimicrobial resistance.

Each element of the public health strategy against antimicrobial resistance affects and depends on the other elements. More rational use of antimicrobial drugs and increased R&D depend on accurate surveillance. Limitations on the use of new drugs negatively affect the incentives pharmaceutical companies have to develop new drugs. Continued misuse of antimicrobial drugs places more pressure on both surveillance and new R&D. The effectiveness of new drugs will have to be measured by accurate surveillance and will continue to be undercut by their misuse. The lack of new R&D will force continued use of existing products, reducing their effective life-span. Thus, any public health strategy addressing antimicrobial resistance must consider all three components.

Because antimicrobial resistance is a global problem, national legal reforms taken in one or a few countries would suffer if other countries did not take similar actions. For example, since drug-resistant pathogens travel easily in today's world, national legal reforms to rationalize antimicrobial use in a few countries might be subverted if such misuse is not curtailed in many other countries. The creation of new international legal duties would likewise be undermined if such duties were not translated into national law. Thus, any legal strategy against antimicrobial resistance must be pursued at both the national and international levels.

Achieving the public health objectives of an antimicrobial resistance strategy involves, at each stage, legal considerations and often calls for legal decisions. National and international law are integral to the public health mission in every country; the interdependence of public health and law forms part of the large multidisciplinary challenge created by the global problem of emerging infectious diseases.

Confronting antimicrobial resistance requires not only a scientific and public health strategy but also a legal strategy. Including law in the developing discourse will broaden and strengthen the strategy for combating antimicrobial resistance.