An academic-industrial partnership published last January in the prestigious journal Nature the results of the development of antibiotic teixobactin. The reported work is still at an early preclinical stage but it is nevertheless good news. Over the last decades the introduction of new antibiotics has slowed down nearly to a halt and over the same period we have seen a dangerous increase in antibiotic resistant bacteria.
Such is the magnitude of the problem that it has attracted the attention of the U.S. government. Accepting several recommendations presented by the President’s Council of Advisors on Science and Technology (PCAST) in their comprehensive report, the Obama Administration issued last September an Executive Order establishing an interagency Task Force for combating antibiotic resistant bacteria and directing the Secretary of Human and Health Services (HHS) to establish an Advisory Council on this matter. More recently the White House issued a strategic plan to tackle this problem.
Etiology of antibiotic resistance
Infectious diseases have been a major cause of morbidity and mortality from time immemorial. The early discovery of sulfa drugs in the 1930s and then antibiotics in the 1940s significantly aided the fight against these scourges. Following World War II society experienced extraordinary gains in life expectancy and overall quality of life. During that period, marked by optimism, many people presumed victory over infectious diseases. However, overuse of antibiotics and a slowdown of innovation, allowed bacteria to develop resistance at such a pace that some experts now speak of a post-antibiotic era.
The problem is manifold: overuse of antibiotics, slow innovation, and bacterial evolution.
The overuse of antibiotics in both humans and livestock also facilitated the emergence of antibiotic resistant bacteria. Responsibility falls to health care providers who prescribed antibiotics liberally and patients who did not complete their prescribed dosages. Acknowledging this problem, the medical community has been training physicians to avoid pressures to prescribe antibiotics for children (and their parents) with infections that are likely to be viral in origin. Educational efforts are also underway to encourage patients to complete their full course of every prescribed antibiotic and not to halt treatment when symptoms ease. The excessive use of antibiotics in food-producing animals is perhaps less manageable because it affects the bottom line of farm operations. For instance, the FDA reported that even though famers were aware of the risks, antibiotics use in feedstock increased by 16 percent from 2009 to 2012.
The development of antibiotics—perhaps a more adequate term would be anti-bacterial agents—indirectly contributed to the problem by being incremental and by nearly stalling two decades ago. Many revolutionary innovations in antibiotics were introduced in a first period of development that started in the 1940s and lasted about two decades. Building upon scaffolds and mechanisms discovered theretofore, a second period of incremental development followed over three decades, through to 1990s, with roughly three new antibiotics introduced every year. High competition and little differentiations rendered antibiotics less and less profitable and over a third period covering the last 20 years pharmaceutical companies have cut development of new antibiotics down to a trickle.
Current policy initiatives
The PCAST report recommended federal leadership and investment to combat antibiotic-resistant bacteria in three areas: improving surveillance, increasing the longevity of current antibiotics through moderated usage, and picking up the pace of development of new antibiotics and other effective interventions.
To implement this strategy PCAST suggested an oversight structure that includes a Director for National Antibiotic Resistance Policy, an interagency Task Force for Combating Antibiotic Resistance Bacteria, and an Advisory Council to be established by the HHS Secretary. PCAST also recommended increasing federal support from $450 million to $900 million for core activities such as surveillance infrastructure and development of transformative diagnostics and treatments. In addition, it proposed $800 million in funding for the Biomedical Advanced Research and Development Authority to support public-private partnerships for antibiotics development.
The Obama administration took up many of these recommendations and directed their implementation with the aforementioned Executive Order. More recently, it announced a National Strategy for Combating Antibiotic Resistant Bacteria to implement the recommendations of the PCAST report. The national strategy has five pillars: First, slow the emergence and spread of resistant bacteria by decreasing the abusive usage of antibiotics in health care as well as in farm animals; second, establish national surveillance efforts that build surveillance capability across human and animal environments; third, advance development and usage of rapid and innovative diagnostics to provide more accurate care delivery and data collection; forth, seek to accelerate the invention process for new antibiotics, other therapeutics and vaccines across all stages, including basic and applied research and development; finally, emphasize the importance of international collaboration and endorse the World Health Organization Action Plan to address antimicrobial resistance.
Therefore, an important cause of our antibiotic woes seems to be driven by economic logic. On one hand, pharmaceutical companies have by and large abandoned investment in antibiotic development; competition and high substitutability have led to low prices and in their financial calculation, pharmaceutical companies cannot justify new developmental efforts. On the other hand, farmers have found the use of antibiotics highly profitable and thus have no financial incentives to halt their use.
There is nevertheless a mirror explanation of a political character.
The federal government allocates about $30 billion for research in medicine and health through the National Institutes of Health. The government does not seek to crowd out private research investment; rather, the goal is to fund research the private sector would not conduct because the financial return of that research is too uncertain. Economic theory prescribes government intervention to address this kind of market failure. However, it is also government policy to privatize patents to discoveries made with public monies in order to facilitate their transfer from public to private organizations. An unanticipated risk of this policy is the rebalancing of the public research portfolio to accommodate the growing demand for the kind of research that feeds into attractive market niches. The risk is that the more aligned public research and private demand become, the less research attention will be directed to medical needs without great market prospects. The development of new antibiotics seems to be just that kind of neglected medical public need. If antibiotics are unattractive to pharmaceutical companies, antibiotic development should be a research priority for the NIH. We know that it is unlikely that Congress will increase public spending for antibiotic R&D in the proportion suggested by PCAST, but the NIH could step in and rebalance its own portfolio to increase antibiotic research. Either increasing NIH funding for antibiotics or NIH rebalancing its own portfolio, are political decisions that are sure to meet organized resistance even stronger than antibiotic resistance.
The second mirror explanation is that farmers have a well-organized lobby. It is no surprise that the Executive Order gingerly walks over recommendations for the farming sector and avoid any hint at an outright ban of antibiotics use, lest the administration is perceived as heavy-handed. Considering the huge magnitude of the problem, a political solution is warranted. Farmers’ cooperation in addressing this national problem will have to be traded for subsidies and other extra-market incentives that compensate for loss revenues or higher costs. The administration will do well to work out the politics with farmer associations first before they organize in strong opposition to any measure to curb antibiotic use in feedstock.
Addressing this challenge adequately will thus require working out solutions to the economic and political dimensions of this problem. Public-private partnerships, including university-industry collaboration, could prove to be a useful mechanism to balance the two dimensions of the equation. The development of teixobactin mentioned above is a good example of this prescription as it resulted from collaboration between the university of Bonn Germany, Northeastern University, and Novobiotic Pharmaceutical, a start-up in Cambridge Mass.
If the NIH cannot secure an increase in research funding for antibiotics development and cannot rebalance substantially its portfolio, it can at least encourage Cooperative Research and Development Agreements as well as university start-ups devoted to develop new antibiotics. In order to promote public-private and university-industry partnerships, policy coordination is advised. The nascent enterprises will be assisted greatly if the government can help them raise capital connecting them to venture funding networks or implementing a loan guarantees programs specific to antibiotics. It can also allow for an expedited FDA approval which would lessen the regulatory burden. Likewise, farmers may be convinced to discontinue the risky practice if innovation in animal husbandry can effectively replace antibiotic use. Public-private partnerships, particularly through university extension programs, could provide an adequate framework to test alternative methods, scale them up, and subsidize the transition to new sustainable practices that are not financially painful to farmers.
Yikun Chi contributed to this post
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