The discovery of anti-infective agents such as antibiotics, antifungals, antivirals, and antibacterials in the 1930s and 1940s represents a transformative moment in human history. They have made an invaluable contribution to the prevention and treatment of infectious diseases. Since their introduction, anti-infectives have revolutionized healthcare and saved millions of lives. Unfortunately, over time, bacterium inevitably develops resistance to existing drugs, making infections difficult if not impossible to treat.
Drug-resistant infections and related morbidity and mortality are on the rise in the United States and around the world. The World Health Organization has identified antimicrobial resistance as one of the three greatest threats to human health. The Institute of Medicine, Center for Disease Control and Prevention, National Institutes of Health, and the Food and Drug Administration all warn that drug-resistant bacteria are a serious public health threat, especially considering there are few novel drugs in the pipeline to combat them. Current data documents the impending disaster due to the confluence of decreasing investment in antibacterial drug research and development associated with the rapid rise of resistance to the current drugs on the market.
While antibiotic resistance is not an entirely new phenomenon, it is turning into a health care disaster. National surveillance data and independent studies show that drug-resistant, disease-causing bacteria have multiplied and spread at alarming rates in recent decades. University of California medical professor Stuart H. Cohen, MD recently told the Wall Street Journal “[The resistance problem] has probably been smoldering for years, but recently it’s almost like a switch got triggered.”
Over 1.7 million Americans acquire bacterial infections in U.S. hospitals each year, and more than 99,000 die as a result of these infections, according to Center for Disease Control estimates. About 70% of the bacteria that cause these infections have developed resistance to at least one anti-microbial drug. Shockingly, resistant, hospital-acquired infections cause more deaths per annum than AIDS, traffic accidents, or influenza. In addition to the burden on human health, infections caused by resistant bacteria result in an additional $5 billion in healthcare costs annually because of a greater severity of infection that requires longer and more complex treatments.
The over-prescription and overuse of antibiotics has produced an increasingly widespread number of resistant microbes. Current global trends, including urbanization and global travel and trade, have increased the demand for antibiotic misuse. One area where it is both feasible and logical to limit antibiotic overuse is in production of food animals. In North America and Europe, an estimated 50% of all antibiotics are used in food-producing animals and poultry. Much of this is not for treating sick animals but rather for preventing disease and promoting growth. As a result, a large number of animals are regularly exposed to sub-therapeutic concentrations of antibiotics, with disastrous results. Additionally, through evolution and natural selection, bacteria have mutated existing genes or acquired new genes from other organisms to become more robust species that are just as virulent but are now also resistant to commonly used antimicrobials.
While resistance to available antimicrobials is rapidly rising, investment in antimicrobial drug research and development is steadily declining. Among the 13 major pharmaceutical companies only 5 maintain antimicrobial discovery programs. Subsequently, only 3 new antimicrobial compounds are in advanced clinical development. The reasons for declining investment in the research and development of antimicrobials are multifaceted; however, several unique challenges have been identified. Research and development is both time-consuming and expensive, requiring more than 10 years and costing between $800 million and $1.7 billion to bring a new drug to the marketplace. Unlike most new drugs, even narrow-spectrum antimicrobials are often used to treat various types of infection. This results in increased costs because of the requirement for clinical trials for each indication, with enrollment of large numbers of patients to ensure the drug’s safety and to document its effectiveness against specific microbial pathogens. Furthermore, because there are no rapid diagnostic tests for many resistant pathogens, it can be difficult and costly to find suitable patients to enroll in clinical trials.
Typical market forces also play a role in the lack of pharmaceutical companies investing in antimicrobial discovery and development. Infections tend to be acute conditions and antimicrobials are fast acting and effective. Therefore, antimicrobials do not generally enjoy a large sustained market share as is common with drugs that chronic, long-term conditions such as diabetes or hypertension. Secondly, the long-term market potential of antimicrobials is limited by the inevitable development of resistant microbial strains.
Legislative action is necessary to stem the tide of pharmaceutical company departures from antimicrobial research and development and to stimulate the involvement of non-active companies. Primarily, policymakers must focus on adopting incentives to bolster investment in the discovery of new drugs, or the public health threat will become even more catastrophic.
What is needed is a multidimensional approach that incorporates marketplace, clinical, and economic incentives simultaneously to stimulate private sector investment and innovation with mechanisms to support current products as well as encourage the development of new ones. Current antimicrobials could be supported through the extension of patents, market exclusivity, or data exclusivity. Drug development could be spurred through changes in clinical trial and review and approval guidelines. The accelerated publication of updated guidelines for anti-infective clinical trials would provide much needed clarity and ensure the relevance of current guidelines, which would encourage innovative clinical trial designs that lead to a better understanding of drug effectiveness against resistant microbial pathogens. Additionally, antimicrobials against targeted pathogens could receive priority or accelerated review with a goal date of 6 months.
Incentives such as tax credits equal to 50% for research and development of novel antimicrobials and tax credits equal to 20% available for investment in property used for antimicrobial research and development would provide economic assistance to companies that develop and produce antimicrobials. Funding could also be provided through clinical trial grants that would assist small manufacturers in conducting clinical trials. Grants could also be provided for the development of antimicrobials in an area of critical public health need but limited commercial potential.
Without decisive action, drug resistance can only get worse. Government-sponsored research and refinement of existing regulations and policies can help to address the overall problem of antibiotic resistance, and help reduce the cost of drug discovery and development. However, the key focus needs to be on industry action. Policymakers must enact legislation that creates incentives for pharmaceutical and biotechnology companies to remain active in the discovery of new antimicrobial drugs. New drugs are desperately needed to fight the bacteria that have become increasingly resistant to antibiotics. It is not possible to predict when an epidemic of drug-resistant bacteria will occur—but we do know it will happen.
Sam K. Theodosopoulos is an undergraduate at The George Washington University where he is a member of the College Republicans and the editor of the GW Young Americas Foundation blog.
