In my last piece, I may have given the impression that in spite of early successes we are in full retreat from superbugs. The simple existence of Totally Drug Resistant Tuberculosis (TDR-TB) is certainly the stuff of Hollywood-style nightmares. Unfortunately, as I described previously, there are obstacles standing in the way of the development of new ways of fighting back against the threat of antibiotic resistance. These obstacles, the scientific difficulty of discovering new bacterial targets to attack and the regulatory burden faced by those that choose to try, have left us in a position of antibiotic research being a very financially unattractive proposition. While it might seem very easy to dwell on the dark side, there are pockets of people organizing with new and varied methods of striking back.
One approach being promoted by The Pew Charitable Trusts along with many others is the Limited Population Antibacterial Drug (LPAD) mechanism for approval, which would entail smaller clinical trials with the condition that successful drugs would only be available for limited populations of patients that met very specific criteria for treatment. While this framework may well result in new antibiotics appearing more quickly on the market than the traditional pathway, the limited opportunities for commercialization will mean that pharmaceutical companies will only find this an attractive proposition if they can increase the prices charged to reflect this. In an environment of ever increasing healthcare costs, charging more for life-saving drugs will mean that while the LPAD mechanism will no doubt be a very useful new weapon in our arsenal for fighting antibiotic resistance, it is unlikely to be the only weapon we will need. Any successful strategy in the evolutionary war we are engaged in with pathogenic bacteria will require a diversity of approaches.
Fortunately, there is already such a diversification of methods to stockpile our arsenal. Another of these methods aims to directly tackle the significant financial cost that pharmaceutical companies face for the research and development of new antibiotics. A 2011 study from the London School of Economics estimated that a new antibiotic could be expected to LOSE a company an average of $50 million. Little wonder they are less and less enthusiastic about pursuing such research. A possible solution is being implemented by the Biomedical Advanced Research and Development Authority (BARDA). BARDA is part of the Office of the Assistant Secretary for Preparedness and Response, which was set up in the wake of Hurricane Katrina to improve the federal response to disasters and sudden public health emergencies. BARDA's interest in antibiotics is primarily directed at agents that could be used in bio-terrorism attacks, such as anthrax or tularemia. Who better to take on the escalation of weaponry in our "war" against infectious disease?
BARDA employ a mechanism termed "cost sharing," which entails awarding contracts to develop antimicrobial agents. As an example, in September 2011, Glaxo Smith Kline (GSK) was awarded a contract to develop the snappily titled "GSK2251052" for $38 million over two years with the option to extend for another two years and up to $94 million. These arrangements are even more attractive to the contractors given that the company involved would retain any intellectual property (IP) that resulted, although BARDA would retain the first option for licensing. Whether this option is worth exercising will entirely depend on the new drugs that are developed fitting in to the mission of BARDA. Bearing in mind the estimated loss of $50 million per drug, it is easy to see why Robin Robinson, director of BARDA, reports an increase in interest from the pharmaceutical sector for this pathway. However, commercial interest is no guarantee of success. Development of GSK2251052 by GSK was terminated in October 2012 due to the discovery during phase two clinical trials of resistance to the new drug. The appearance of resistance at such an early stage only provides further evidence for new antibiotics only selecting for pre-existing resistance already present in bacterial populations, despite the fact that these newly developed drugs may be quite distinct from those used previously. That resistance already exists is entirely consistent with the context of a conflict nearly as old as life itself and only serves to further highlight the enormity of the task we face when devising new weapons against pathogens that would do us harm.
At this point "cost-sharing" looks a lot like a public subsidy of the pharmaceutical industry, which begs the question: Why not also pay for this work to be done by the National Institutes of Health (NIH) or some other similar agency? The agency doing the work would still retain the IP and thus control over the use of any drugs that result. There is a clear medical need for new antibiotics but the market on its own would seem to have little incentive to participate.
Under these circumstances, should we view development of new antibiotics as a matter of a public cost to protect public health?
The alternative would seem to be accepting a huge increase in the cost of antibiotics which raises all sorts of questions about how they will be paid for and by whom. The pharmaceutical industry certainly has a huge depth and breadth of experience in developing new drugs so it seems unwise to not include them as much as possible.
What will most likely be required is a combination of approaches as to how we are to keep ahead of this constant, ongoing war that we have stumbled into. Certainly more weapons in the form of antibiotics will be needed. At the same time, perhaps greater efforts should be made in diplomacy by taking advantage of our knowledge of the human microbiome, that has evolved to have as much interest in our continued survival as we do. In future posts, I will cover some of our efforts in "coalition building" in this conflict, including fecal transplants being used for Clostridium dificile infections to greater effect than antibiotics.
While we need to stockpile our arsenal of weapons, we must also have an eye to more peaceful arbitration. "Walk softly and carry a big stick," as Teddy Roosevelt is credited with saying.