Antimicrobial resistance poses one of the biggest threats to public health faced in modern times. If left unchecked, it’s thought that by 2050 the global number of deaths from antimicrobial resistance may be as high as 10 million per year – costing $100 trillion US dollars annually just to manage the effects, according to the 2016 Review on Antimicrobial Resistance.
In this article, we look at the scale of the challenge, and consider the ways in which all international stakeholders – including the pharmaceutical industry, healthcare systems, governments and global population – need to work together in order to avoid these statistics becoming reality.
On the edge of a precipice
Antibiotic resistance is natural selection in action. It arises when infection-causing bacteria survive exposure to a treatment that would normally kill them, allowing drug-resistant strains to spread due to a lack of competition from other bacteria.
The overuse—and misuse—of antibiotics to treat non-bacterial infections, their increased use in agriculture and poor patient adherence to treatment regimens have created the perfect environment for this resistance to emerge.
In fact, the U.S. Centers for Disease Control and Prevention estimates that 70 percent of bacterial infections are already caused by bacterial pathogens that are resistant to at least one antibiotic drug on the market. Most worryingly of all, as reported in Vol. 16 of the Lancet Infectious Disease, even last line of defense antibiotics, such as Colistin, are now ineffective against some strains.
As a result, we risk losing the advances in medicine developed over the last century that we currently take for granted. Life threatening bacterial infections such as pneumonia and tuberculosis could become untreatable, while routine surgical procedures such as caesarean sections and organ transplants that require antibiotics to prevent infection may, in future, become too high risk to perform.
A drug pipeline that’s run dry
Despite the scale and severity of this problem, there exists a significant and well-recognized gap between the demand for new antibiotics and the financial incentives for their development.
The established economic model for pharmaceutical drug products is to recoup the costs of R&D through sales revenues during a period of patent-based exclusivity. However, for antibiotics, this model is problematic for a number of reasons. The need to reserve novel antibiotics and to ensure improved stewardship intrinsically limit sales potential, discouraging investment in their development. Meanwhile, due to financial pressures from an aging population, healthcare payers are increasingly unwilling to pay more for drugs to support the cost of R&D and provide pharmaceutical companies with a competitive return on investment.
As a result, the number of large multinational companies funding basic research in antibiotics has fallen substantially over the past two decades as many have turned their expertise and resources to more profitable ventures.
Incentives for innovation
To address this challenge, many experts believe that a combination of “push” and “pull” strategies towards incentivizing antibiotic drug discovery and development are required, as detailed within The need for a One Health – One Europe – One World Framework.
“Push” approaches, such as increasing access to scientific resources, providing research grants, offering tax incentives and establishing public-private partnerships to reduce the financial risks associated with R&D, could help to overcome the barriers to drug development in the early stages.
“Pull” strategies, on the other hand, reward successful drug development by ensuring future revenue, through monetary prizes, advanced market commitments or patent buyouts. One of the “pull” strategies put forward by the Review on Antimicrobial Resistance is the establishment of a global system of market entry rewards of around one billion USD per drug for treatments in areas of most urgent need.
To incentivize the discovery of new antibiotics and encourage researchers around the world to undertake new research will require significantly increased global funding from a combination of both public and private sources. To ensure that this funding is focused effectively and invested efficiently, the Review on Antimicrobial Resistance has called for the establishment of a Global Innovation Fund to coordinate this.
This body would support early-stage and non-commercial research, helping to form consortia made up of universities, small pharmaceutical companies, CROs, and partner research organizations to take on programs to develop new antibiotics. These partnerships benefit from shared resources and knowledge, helping to make more efficient use of expertise and funding to bring about advances in our understanding of drug targets and new drug molecules more rapidly.
Changing behaviors of all stakeholders
Changing the underlying behavior of stakeholders is essential in order to get on top of this problem. As reported in the International Journal of Infectious Disease and the International Journal of Clinical Pharmacology, one of the most important challenges to overcome lies in improving patient compliance. Studies routinely show poor adherence to antibiotic regimens, with patients often unaware of the real consequences of finishing treatment courses early. Additionally, the relative ease in which antibiotics are available over-the-counter in some regions, combined with incorrect patient self-diagnosis are also significant contributors to the inappropriate and ineffective use of antibiotics, as reported in Vol.11 of the Lancet Infectious Disease.
Better disease prevention, diagnosis and surveillance
Another effective way of slowing down the spread of resistant bacteria is through the prevention of infection in the first place. To do this, there must be global concerted efforts to improve hygiene. Simple measures, such as handwashing, are particularly effective at reducing the spread of infections in hospital settings. In the developing world, greater access to clean water and sanitation will play a critical role in getting on top of this problem.
An additional way in which to reduce the number of infections and lower the demand for therapeutic treatments is through vaccination. However, in low and middle-income countries, numerous bottlenecks around healthcare infrastructure and cost limit the extent to which vaccines can be rolled out. Organizations such as Gavi, the Vaccine Alliance, are tackling these challenges by funding vaccination programs in countries that would otherwise be unable to do so. By pooling the demand for new vaccines for these countries and financing their implementation, the organization helps to attract new vaccine manufacturers into the market and bring costs down.
A further challenge to overcome relates to disease diagnosis. In previous decades, clinicians have arguably been too quick to prescribe antibiotics when the underlying cause of the disease is unclear. This situation often arises as prescribing antibiotics without fully identifying the disease is faster and usually less expensive than running lengthy diagnostic tests. Therefore, more affordable, rapid and reliable diagnostic technologies will be essential to ensure that infections are being treated using the right type of antibiotics, and only in the case of bacterial infections.
Of course, it’s important that we continue to monitor the use and effectiveness of antibiotics, as well as mechanisms for resistance at both national and international levels. Such information is necessary to form health policies, guide responses to health emergencies and identify global, long-term trends.
The issues that have led to the current crisis in antibiotic resistance are both global and multifaceted, and will require international collaboration if they are to be overcome. While changes to the current economic model for antibiotic development are necessary to ensure we have a well-stocked supply of new and effective drugs, it is also essential that we reduce their demand through better stewardship. Only through learning from our mistakes will we ensure that these precious resources are both available and remain effective in future.