Two major ways that modern medicine saves lives are through antibiotic treatment of severe infections and the performance of medical and surgical procedures under the protection of antibiotics. Yet we have not kept pace with the ability of many pathogens to develop resistance to antibiotics that are legacies of the golden era of antibiotic discovery, the 1930s to 1960s. We call that period “golden” because success seemed routine then; we call it an “era” because it ended. When industry scientists shifted from making variants of old drugs to pursuing fundamentally new drugs with activity against resistant pathogens, they generally failed. Persistent, costly failure to discover novel antibiotics that would be destined for short-term use even if they survived the regulatory approval process led industry to change its focus to drugs whose long-term use prevents or mitigates noninfectious diseases. As people in wealthier regions run out of effective antibiotics, they come to share the lot of people in poorer regions who can't afford them to begin with.1

At least some clinical isolates of many pathogenic bacterial species — Mycobacterium tuberculosis, Neisseria gonorrhoeae, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and species of enterobacter, salmonella, and shigella — are now resistant to most antibiotics. The problem seems out of control. Yet there are reasons for optimism: progress has recently been made on 4 of 10 key challenges to ensuring that antibiotics retain an effective role in medicine.2

Recognition. Alexander Fleming and Howard Walter Florey sounded the first warning about antibiotic resistance when they accepted the 1945 Nobel Prize for the discovery of penicillin. Physicians and scientists have expanded and expounded the message ever since, but it has recently begun to resonate with the public, the press, and leaders in business and government.2

In the past decade, various key organizations, including the Infectious Diseases Society of America, the Centers for Disease Control and Prevention, the World Health Organization (WHO), and the World Economic Forum, have made antibiotic resistance the focus of highly visible reports, conferences, and actions. This year, the activity seems to have accelerated. In April, the WHO declared that the problem “threatens the achievements of modern medicine. A post-antibiotic era — in which common infections and minor injuries can kill — is a very real possibility for the 21st century.” In May, the World Health Assembly commissioned the WHO to deliver a global action plan on antimicrobial resistance. In June, the British public voted to dedicate a government-sponsored £10 million Longitude Prize to the best solution to the resistance problem. And in September, the U.S. President's Council of Advisors on Science and Technology released a report on antibiotic resistance linked to an executive order from President Barack Obama, who directed the National Security Council to work with a governmental task force and a nongovernmental advisory council to develop a national action plan by February 2015. Among other goals, the plan will propose implementation of antibiotic stewardship in health care facilities and the community; development of rapid, point-of-care diagnostics; recruitment of academic and industry partners to increase the pipeline of antibiotics, vaccines, and alternative approaches; and international collaboration for prevention, surveillance, and control of antibiotic resistance.

Partnership. Innovative experiments in public–private partnership are under way for antibiotic-drug discovery. In 2012, the Bill and Melinda Gates Foundation expanded its Tuberculosis Drug Accelerator program to include multiple drug companies, academic institutions, a foundation, and a government laboratory. Participants pool efforts, assays, and compounds, aiming to identify, validate, and inhibit new targets with new drugs. In 2013, the U.S. Biomedical Advanced Research and Development Authority began funding antibiotic research in industry, and the European Commission and the European Federation of Pharmaceutical Industries and Associations launched a partnership for antibiotic discovery.

Return. The retreat of most major pharmaceutical companies from antibiotic research has resulted in little competition in the development of novel antibiotics in a market that is currently worth more than $40 billion annually for drugs that are starting to fail. Several small companies seeking to fill the gap have had new antibiotics approved, and the world's fourth-largest drug company recently announced its return to the effort. However, major disincentives remain, including the difficulty of conducting large clinical trials to compare drugs in patients with antibiotic-resistant infections.

Prevention. Antibiotics' growing lack of effectiveness has spurred a resurgence in infection surveillance and control practices; renewed efforts in vaccination; and increased attention to deficiencies in sanitation. Nonetheless, much remains to be learned about how to prevent acquisition and transmission of resistance.

Despite progress on these fronts, securing a long-term ability to treat bacterial infections requires addressing six more daunting challenges.3

Leadership. We believe that sound solutions will require a global organization with the authority, leadership, and resources to oversee collaboration of the health, security, economic, and development sectors; maintain global surveillance of antibiotic resistance; and manage rewards for developing and conserving antibiotics.

Rewards. Unless monetary rewards are delinked from drug sales,4,5 few companies will invest in high-risk programs to develop drugs whose use must be restricted and which will probably ultimately lose their clinical utility. Sales-based compensation has also supported rampant profiteering through drug dilution, substandard manufacture, and counterfeiting, which foster resistance and undermine treatment. Moreover, if rewards derive from price and price reflects value, the prices of new, lifesaving antibiotics will preclude access by the poor. Instead, a new antimicrobial oversight agency could administer a fund that rewards antibiotic developers in proportion to the estimated quality-adjusted life-years saved — creating an incentive to expand medically indicated access by keeping prices close to the cost of production and distribution. At the same time, continuing payouts to originators as long as drugs have clinical utility would minimize the adverse effect of conservation on profitability.

Access. The ideal economic model would enable us to provide access to lifesaving antibiotics to all who need them while restricting overuse that contributes not only to resistance, but perhaps also to epidemic obesity, asthma, and other disorders. A global fund could solicit contributions in proportion to countries' gross domestic product, but in the short term, equitable access might require wealthier countries to subsidize appropriate antibiotic use in poorer countries.

Conservation through prioritization of medical use. The current practice of applying the most antibiotic tonnage to growth promotion in food animals and plants is incompatible with an expectation that antibiotics will cure life-threatening infections. We believe that governments worldwide should impose restraints like those in force in the European Union, which have not reduced food production.

Conservation through prescription tailored to diagnosis. Ideally, technological advances in point-of-care diagnostics would enable prescribers to avoid dispensing antibiotics for viral infections and fevers of unknown origin. Better diagnostics could allow prescriptions to be tailored narrowly to a pathogen's susceptibilities. Adoption of such technology would require physician education, suitable reimbursement, and documentation of outcomes.

Conservation through controlled access. In wealthier countries, all health care facilities should institute antibiotic-stewardship programs. In poorer countries, despite the need to expand access to effective antibiotics, there's also an urgent need to reduce inappropriate use fostered by misaligned financial incentives for providers and by over-the-counter access. Given the ease with which antibiotic resistance spreads, we all share an interest in helping poorer countries build sufficient infrastructure to allow medical personnel to distinguish among pathogens before antibiotics are prescribed.

These issues concern everyone. Military leaders don't want their personnel devastated by infections associated with wounds or close quarters. Drug-company leaders realize that the public expects their firms to produce life-saving medicines and blames them when they don't — an attitude shared in countries whose developing economies offer companies their best prospects for growth. But physicians may care about this problem most passionately, for they must tell more and more families that there is no hope. Doctors can act not just individually and medically, but also collectively and civically, to persuade elected officials to respond to expert panels' recommendations and national leaders' directives with the legislation, appropriation, regulation, enforcement, and cooperation needed to ensure access to these life-saving drugs.