A report today from the UK Review on Antimicrobial Resistance (AMR) calls for 10 global interventions to address demand for unnecessary antibiotics and increase investment in new drugs and alternative therapies that come with an estimated $40 billion price tag.
The report, "Tackling Drug-Resistant Infections Globally: Final Report and Recommendations," estimates that annual deaths attributable to antibiotic-resistant infections will rise from the current 700,000 to 10 million by 2050 if action to counter drug resistance is not taken immediately.
The independent AMR report, which was commissioned by the UK government and the Wellcome Trust and chaired by economist Jim O'Neill, PhD, MA, UK treasury secretary, recommends ten interventions to stem demand for antibiotics while encouraging research into treatments and diagnostics that meet crucial medical needs.
The seven recommendations to reduce unnecessary use of antimicrobials are:
- Developing a global public awareness campaign
- Improving sanitation and water quality
- Regulating agricultural antibiotic use
- Heightening surveillance of antimicrobial use and resistant infections
- Investing in rapid diagnostic methods
- Increasing uptake of available vaccines and alternative therapies
- Attracting more professionals to the fields of microbiology and infectious disease
The AMR authors also said that implementing a global innovation fund for treatments that may not be commercially attractive and introducing incentives for investing in new and improved antimicrobials are two steps necessary to increase the supply of effective antibiotics.
The tenth, and overarching, recommendation made by the AMR report calls for the United Nations (UN) and the Group of Twenty (G20) to form a global coalition dedicated to shepherding antibiotic stewardship. The report's authors estimate that all 10 programs will cost $40 billion over the next 10 years, a fraction of the approximately $100 trillion in global production lost because of drug-resistant infections predicted to occur by 2050.
Public awareness, preventive care
Efforts to stem the unnecessary, wasteful, and often harmful use of critical antibiotics require educating the public about proper antimicrobial use, preventing infections for which antibiotics are prescribed, and developing diagnostic tests that can inform tailored pharmaceutical treatment, the authors said.
Public engagement in decreasing demand for antimicrobials should be fostered through a global public awareness campaign, which could be funded by corporate sponsorship at large events, budgeted public health funding in high-income countries, and institutional program support in low- and middle-income nations, the authors said. Public and clinician awareness of proper antibiotic use should be supported by standards for clearly labeling critical drugs and the restriction of over-the-counter and Internet sales of antimicrobial products.
Developing countries currently shoulder much of the burden of growing resistance to antibiotics, and both appropriate and inappropriate drug treatment could be avoided by preventing viral, bacterial, and fungal infections, the experts wrote.
"The basics of public health—clean water, good sanitation and hygiene, infection prevention and control and surveillance—are as critical for reducing the impact of antimicrobial resistance as they are for infectious disease control," said Keiji Fukuda, MD, MPH, the director-general's special representative for AMR at the World Health Organization and report contributor.
Infection control measures in developing countries involve preventing conditions like diarrheal disease, which results in the annual use of nearly 500 million antibiotic courses across four countries (India, Indonesia, Nigeria, and Brazil), a number that improved water quality and sanitation could reduce by 60%, according to the report.
Healthcare-associated infections are one of the major infection control issues facing developed nations, with up to 10% of all hospital inpatients contracting an infection, a rate that rises to 33% of all intensive care unit patients. Across the globe, one key action to prevent infections for which antibiotics are used is simple and frequent hand washing, the authors said.
Agricultural use, environmental runoff
In the United States, more than 70% of antibiotics important to human medical needs are sold for use in animals, the authors said, and the responsibility for addressing this problem must be borne by G20 countries, which produce 80% of global meat products, the report notes.
The authors recommend the development by 2018 of 10-year global targets to reduce antibiotic use in farm animals, along with increased surveillance of antimicrobial use and husbandry practices. Additionally, the agricultural use of last-line antibiotics that treat critical infections in humans must be urgently stopped, and food producers should be required to provide information about antibiotic use in animals to consumers.
Reducing agricultural antimicrobial use will require countries to reduce costs associated with farmers' transitions to more sustainable animal growth and disease prevention practices and to develop standardized lists of antibiotics that should be reserved for human medical use, the authors said. Governments should also develop national surveillance systems to monitor antibiotic consumption and resistance in people and animals.
A related issue involves emissions and water supply pollution caused by manufacturers of active pharmaceutical ingredients. National regulators must set minimum standards for the treatment and release of waste with antimicrobial properties and encourage higher environmental standards in the pharmaceutical industry, the authors said. The AMR report estimates that addressing the growing issue of antibiotics in the water supply will cost $180 million annually to treat 30,000 to 70,000 tons of antimicrobial waste.
Developing underfunded research
A significant issue affecting overprescription of antibiotics for non-bacterial infections or bacterial diseases where antimicrobial treatment is ill-advised is the lack of rapid diagnostic tests. In the United States alone, 27 million of the 40 million people seeking care for respiratory issues each year receive an unnecessary antibiotic prescription, or almost 70%, the authors said.
Development of new diagnostic technology could be spurred in low- and middle-income countries by a commercially viable market stimulus that provides incentives for diagnostic purchases and encourages research into fast and accurate testing methods. Wealthy countries should mandate that all antimicrobial prescriptions are informed by a test result, the authors said.
Though the introduction of new tests would cost $500,000 million to $1 billion per year, the authors said that rapid diagnostics could have results on antibiotic resistance similar to the monumental effects achieved by Gavi, the Vaccine Alliance's enhancement of global vaccine coverage in the early 2000s.
In addition to the benefits offered by rapid and/or point-of-care diagnostics, vaccines and alternative treatment for bacterial infections could be used more widely, the authors said. The AMR report notes that universal coverage of pneumococcal conjugate vaccines could reduce by 47% the amount of antibiotics prescribed for pneumonia caused by Streptococcus pneumoniae.
National agencies should also encourage early-stage research into alternative (non-antibiotic) therapies that target bacterial pathogens. Treatments that show promise include phage therapy (viruses that kill bacteria), lysin enzyme therapy, antibodies that restrict bacteria's pathogenicity, immune stimulation, and peptide treatment, the authors said.
A related issue to improving informed clinical care and treatment involves the global shortage of microbiologists and clinicians specializing in infectious disease. The report found that infectious disease doctors in the United States received lower salaries compared with 24 other physician groups.
If hospitals, laboratories, governments, and private-sector industries want to make headway into tackling antimicrobial resistance, they must reward the professionals focused on antibiotic stewardship and research with higher pay, educational incentives, and prestige, the authors said.
In a commentary today in The Lancet Infectious Diseases, Laura J. V. Piddock, PhD, of the Institute of Microbiology and Infection at the UK's University of Birmingham, writes that professionals entering microbiology and infectious disease research have suffered the effects of underfunding for years, leading to a depletion of expertise in key areas of research. The lack of investment translates into difficulty in moving drugs that treat resistant infections, such as those caused by gram-negative bacteria, from the laboratory to clinical settings.
"The findings of the [AMR] Review team make it eminently clear that globally the antimicrobial-resistance crisis overshadows recent threats by many orders of magnitude," Piddock said.
Increasing the antibiotic supply
Inappropriate and unnecessary antibiotic use contributes significantly to resistance, the experts point out, yet for the many drugs ceasing to treat infections effectively, few exist to take their place. The AMR authors warn that if no new drugs are developed to resistant infections by 2050, we will return to an age where even the most routine healthcare procedures are undertaken at great risk.
Global attention has turned recently to this urgent need, with $375 million for surveillance of drug-resistant infections in low- and middle-income countries dedicated last year by the UK's Fleming Fund, $144 million in total contributed by the United Kingdom and China to kick-start research into new drugs and diagnostics, European initiatives for development of innovative antibiotics, and US efforts from the Biomedical Advanced Research and Development Authority (BARDA).
Despite these ongoing programs, developing new antibiotics and innovative uses for old drugs remains underfunded, commercially unviable, and unattractive to investors, the authors said. Of the $40 billion in annual antibiotic sales globally, only $4.7 billion goes toward patented drugs. To address this issue, the report proposes a global innovation fund to pour $2 billion into early-stage research and development for new antimicrobials over the next 5 years.
In addition to a global fund, the report requests that governments create incentives for development of new drugs, including market entry rewards of about $1 billion per drug, with a focus toward innovative treatments for resistant infections caused by tuberculosis, gonorrhea, and gram-negative bacteria, the authors said. Ideally, manufacturers would be spurred to develop 15 new antibiotics each decade, with at least 4 drugs that target the most medically threatening bacteria.
Global coordination, investment
The authors recommend that the UN and the G20 build a global coalition to devote funding and regulatory attention to the initiatives recommended in the report. They said the most crucial steps are developing a global public awareness campaign, creating market entry rewards for new drugs, stimulating development of better diagnostics, and reducing agricultural use of antibiotics.
"What is certain is that no single country can solve the AMR problem on its own and several of our proposed solutions will require at least a critical mass of countries behind them if they are to make a difference," the authors said.
The $40 billion proposed budget breaks down to $16 billion in research and development funding for new drugs over the next 10 years, $2 billion allocated to a Global Innovation Fund over 5 years, $1 billion to $2 billion dedicated to new diagnostics and vaccines each year, and $40 million to $100 million per year spent on public awareness and education.
Recommended methods for meeting the economic need include imposing a fee on pharmaceutical companies that fail to invest in antibiotic development, taxing antimicrobials, or distributing vouchers to reward innovative research efforts.
Though costs to address growing antimicrobial resistance are steep and interventions represent significant changes to countries' agricultural, medical, and industrial practices, immediate action is necessary, the authors said, adding, "By 2050, the death toll could be a staggering one person every three seconds if antimicrobial resistance is not tackled now."
"Tackling AMR is core to the long-term economic development of countries and our well-being. Solutions to address it must have global access to healthcare at their heart and they must help us to stop wasting medicines that we rely on and yet are exhaustible," the authors said.
AMR Review home page
May 19 AMR Review report (PDF)
May 19 Lancet Infect Dis commentary