Keeping Pace: Protecting Our Troops and Our Population by Incentivizing Antimicrobial Research and Development

Washington, DC | October 4, 2011

George Platsis, BBA, MBA, MA-DEM
Sean Kavanagh, BA, MS (Candidate, May 2012)

Review by:

Dr. George Jackowski, Ph.D.

Disclaimer: The opinions presented in this paper are those of the authors and do not imply endorsement by any United States government agency or any other organizations the authors may be affiliated with.

In the past century, the American medical community has made leaps and bounds in preventative care. Vaccines have helped to eradicate killer diseases, such as small pox and tetanus, and have made great efforts to stop or slow the spread of others, such as hepatitis A and B. Likewise, many modern antibiotics over the last 70 years, have helped fight off an overwhelming majority of infections that once plagued America. Indeed, the life-expectancy of Americans has increased dramatically due to these advancements and improvements. Vigorous research programs, and the steadfast determination of medical scientists to develop safe and effective medicines, are evident in the American healthcare system, with their results ranking among the greatest scientific contributions to humanity.

But by no means should one consider this battle to be over. We must not forget that a resurgence and adaptation of these pathogens can come back to haunt us at any time, and with history as our teacher, such a situation is virtually inevitable. There are many diseases that we have “eradicated”, yet in reality, they still exist in one form or another (such as in a laboratory or incubated in another species). The fact that these diseases have not been present in our ecosystem for one, two, or even three generations, also means that the general population possesses no natural antibodies to these “eradicated” diseases. If pathogens resurface or adapt (helped by emerging enzymes and proteins that cause genetic mutation), their affect would compound an already dangerous threat. Given these realities, our troops, and our citizens, are being affected. Approximately 1.7 million patients in the United States get an infection in hospital each year, where about 99,000 of will die as a result of these infections (National Institutes of Health); this is an issue that must be addressed.

Understanding the Pharmaceutical Industry in the 21st Century

The pharmaceutical industry has undergone a massive wave of consolidation over the last ten plus years, giving rise to the increased threat of antibiotic-resistant diseases. The threat is largely a function of decreased research and development in the antimicrobial fields as these pathogens evolve and mutate. The decrease of research and development, in part, can be attributed to the currently available, inexpensive, and generic antibiotics that have varying degrees of effectiveness (Mossialos, Morel, Edwards, Bereson, Gemmill-Toyama, & Brogam, 2010).

A contributing factor as well is that antibiotics do not appear to be profitable relative to drugs used for longer periods of time. One estimate suggests that the risk-adjusted net present value for antibiotics is a factor of 100, compared with 300 for an anticancer drug, 720 for a neurological drug, and 1150 for a musculoskeletal drug (Projan, 2003). But there are more factors that need to be considered in order to illustrate a more holistic picture of the current landscape. They include (Shales, 2007):

• - A lack of pipeline products in many companies
• - The rapid rising costs of clinical development (which increases pressure on eventual return on investment)
• - The perception of a relatively flat demand for antibiotic market (even though empirical evidence shows infectious bacterial diseases are largely on the rise)
• - The perceived hostile regulatory environment
• - The massive consolidation of the pharmaceutical industry, particularly between the years of 1980-2003

Accordingly, as of 2007, only half (6 of the 12) of the existing large pharmaceutical companies are involved in antimicrobial research, versus 18 back in 1980 (Shales, 2007). Moreover, as both the hospital and community settings see an increase to bacterial resistance, the current state of insufficient investment in new antibiotic treatments becomes an ever-growing public health concern (Mossialos, Morel, Edwards, Bereson, Gemmill-Toyama, & Brogam, 2010).

A Complex Challenge

In essence, our diminished investment in this field has seriously crippled our capacity to be resilient against both current and emerging threats. Given the complexity of the 21st Century, the threats we face on account of these issues are not only ones of public health, but ones that transcend to economy and national security. Inasmuch, action must be taken by the government to help invigorate research and development in antimicrobial research, particularly when seventy percent of the bacteria causing these types of infections are resistant to at least one drug commonly used to treat these infections (National Institutes of Health).

The current realities provide no incentive for the pharmaceutical industry to undertake antimicrobial research and development. This is not a function of their unwillingness, but rather, it is a function of regulatory constraints and no protection on return-on-investment, specifically in the form of exclusivity to qualifying products. Put simply, the current realities do not allow pharmaceutical companies to make antimicrobial research and development investments a priority. The current system prevents for their investment to ever be recouped, even as professionals and researchers have suggested, time and time again, that incentives appeal to both small and large pharmaceutical companies and have proven results (Mossialos, Morel, Edwards, Bereson, Gemmill-Toyama, & Brogam, 2010).

The short-term harm is that our soldiers are paying the price for this, along with American citizens back home in American hospitals, a place where some of these infectious diseases thrive in their spread (Peleng, Seifart, & Paterson, 2008). For example, some of the most common nosocomial infections currently occurring in the United States are caused by: Staphylococci, E. Coli, Klebisiella, and Acinetocabtor (National Institutes of Health) , infections that are running rampant among troops.

The long-term harm is that this is a situation that threatens American economic strength and national security. Not only would incentivizing the process help, but more predictable procedures in the regulatory process, particularly from the Food and Drug Administration, would have a net-net-net benefit of minimizing the impact of this emerging and re-emerging threat we face, both in the battle zones and on the home front.

We owe it to our soldiers to provide them with the best immediate care, and, we owe it to our citizenry to protect them from this serious threat over the long-term. Some proposals, such as The Generating Antibiotic Incentives Now Act of 2011 (H.R. 2182), introduced on June 15, 2011 in Congress, and known as the GAIN Act, are good first steps, but they are exactly that: first steps. It is a difficult task to craft regulatory policy recommendations that address the challenges we are facing, but it is a challenge that we must face head on.

A compounding issue that arises is that no government agency truly wants to take the lead in this field (or at least has shown the willingness to take on an honest and forthright lead). It has been shown or demonstrated that none of the agencies have specific competencies or the desire to take the lead in coordinating such an effort. The paradox here is that legislators want to know which agency will take the lead. Therefore, the endless cyclical maze and confusion between the legislative and executive branches begins, and, never seems to end (Shales, 2007).

A Lay of the Land

For just over half a century we have enjoyed the benefits of antibiotics. In so many ways, they revolutionized how the medical field operated. Moreover, their benefits are both short- and long-term and cross into so many sectors of our country. Indeed, from a military perspective, their use in the Second World War provided a strategic advantage to the Allied troops. Yet these pathogens, like all living organisms, adapt. And they are adapting quite successfully, making antibiotic-resistant diseases affect all facets of our life. This is evident as we have seen the progression from the use of penicillin to methicillin in treatment, and now we our armaments being depleted with the increase of methicillin-resistant Staphylococcus aureus (also known as MRSA), a human pathogen that causes life threatening infections of skin, bone, heart, and other vital organs (National Institutes of Health).

Today’s reality also suggests that we face certain strains of these organisms that are resistant to all known antibiotics (Peleng, Seifart, & Paterson, 2008). Given the realities of the 21st Century, such as increased global travel, the transmission of these diseases has gone up exponentially. Cross-contamination from local national patients cared for in deployed US hospitals has been postulated as a source of some of these multidrug-resistant infectious diseases (Sutter, et al., 2011) and simply as a function of global business and tourist travel, the following holds true: if a highly-infectious disease is in London, it will be in Shanghai, Sydney, New York City, Johannesburg, and so on, within 24-48 hours. It is certainly within the realm of possibility as well that these leisurely travelers carry these infectious diseases asymptomatically (Sutter, et al., 2011).

Another reality of the 21st Century of course includes military operations throughout the world. We are seeing increased cases of infectious diseases in our troops, with high extremity (Davis, Moran, C. Kenneth, & Gray, 2005), and apart from the health impact that exists, there is another very important reality: the economic cost. Antibiotic-resistant infectious diseases alone cost the US healthcare system $20 billion annually (Roberts, 2009) and this number does not even take into account related costs (such as lost work hours at home, increased costs to replace injured soldiers in the battle zone, and general all-round drops in productivity across the board). And when accounting for effects to: household income, tax revenues, and national savings, this figure balloons up to $34 billion by some estimates (Mossialos, Morel, Edwards, Bereson, Gemmill-Toyama, & Brogam, 2010). Logic suggests, and research has proven (Peleng, Seifart, & Paterson, 2008), that longer hospital stays, on account of acquired infectious diseases, increase health costs. Moreover, many of the patients that have been infected, particularly in the war zone, are requiring ongoing management even after discharge (Tribble, et al., 2011), increasing the economic costs even more. Infectious diseases know no borders, making this is a global issue. Modernized countries, all over the world, are susceptible and recent results from the United Kingdom showing the implications of antibiotic resistant-related costs help illustrate the economic impact even more. Antibiotic resistant-related costs led to decreases of: 0.3% in household income, 0.35% in tax revenue, and 2% in national savings (Mossialos, Morel, Edwards, Bereson, Gemmill-Toyama, & Brogam, 2010).

There is a simple reality: keeping people alive costs money, and, this cost is considerably higher if they are military personnel. The faster military personnel can recover, and get back to duty, means a lower cost, holistically, on the state and the taxpayer, in both the short- and long-term. The net effect of this of course is that it ultimately represents a risk to our national security. Our national security is a function of our economic health; it has always been, and, it will always continue to be. Inasmuch, as we let this serious issue exasperate, not only are we risking the immediate health of individual lives, but the economic impacts increase the risk against the security of our nation.

As identified above by recognizing there as associated costs, there are the secondary and tertiary effects of the infectious disease spread that lead to productivity challenges due to lost man-hours and the global transmission of infectious diseases. Unfortunately, many of these issues are not normally considered or factored into any decision-making process. But they should be. While currently some of these infectious diseases target only the most critically ill, such as those with breaches in the skin or susceptible airways (Peleng, Seifart, & Paterson, 2008), the spread of infectious disease to front-line workers is a reality that must be dealt with, be it here at home in the United States or in the battle zone as this emerging threat grows. These frightening and real scenarios (Whitman, et al., 2008) not only pose a threat to military personnel overseas, which experience field contaminations due to the pathogen’s ability to spread quickly (Scott, et al., 2007), but also pose threats to the general populace back home in the United States.

And this is where the ultimate threat lies: not only are our soldiers being harmed by these pathogens, but they are making their way back to the general populace. Enzymes, such as NDM-1, and proteins, which act as a type of “bacterial Kevlar”, have been extremely successful in their ability to survive in the hospital-setting environment, and, in their ability to rapidly acquire resistance to antibiotics (Chen, et al., 2011). These reasons alone justify the call to incentivize research that address antimicrobial issues and aim to combat the threats our military forces, and general population, face. The calls by public health officials in the mid-to-late 20th Century that that declared the end of infectious diseases was approaching was not only presumptuous and ambitious, but proven, empirically, that they were dead wrong.

The diverging reality of: emergence of multidrug-resistant bacteria versus decreased antimicrobial innovation is setting us up for disaster. Put simply, the fact that antimicrobial research has dwindled, primarily due to its lack of profitability, while antibiotic-resistance increases, compounds the threats we face from the contexts of: health, economic strength, and national security. With globalization still on the rise, and migration and international trade showing no conclusive evidence of slowing down, no country can ever truly isolate itself from this threat. This is the context we currently live in.

Emerging and Re-Emerging Threats

Much like humans adapt, so do bacteria. These single- and multi-celled organisms often possess the capability to become antibiotic-resistant in one form or another. Antimicrobial resistant pathogens are spreading throughout the United States, Canada, Australia, Austria, Colombia, Denmark, Germany, Italy, Switzerland, and even Hawaii (Tenover & Goering, 2009), which is essentially to say: these pathogens are spreading all over the world. Moreover, we are seeing these infectious diseases in the war zones, such as Afghanistan and Iraq (Hospenthal, et al., 2011) and these microorganisms survive for prolonged periods in the hospital environment (Peleng, Seifart, & Paterson, 2008).

Yet, we are also beginning to see that antibiotic-resistance may become a bigger concern than previously thought to be. The long-time prevailing thought was that antibiotic-resistance was a function of antibiotic overuse (which is true and scientifically proven), but, we are also beginning to see new emerging threats in the field. New research shows these drug-resistant pathogens are present not only due to antibiotic overuse, but antibiotic-resistance may be naturally-occurring and has been around for quite some time. That is not to say this reality is new to the environment, but it is new to us.

What some characterize as a “ticking genetic time-bomb” (Ubelacker, 2011) are recent results that show antibiotic-resistance also being a naturally-occurring phenomenon that predates modern humanity (D'Costa, et al., 2011). Ancient DNA, dating back some 30,000 years, conclusively shows that antibiotic-resistant genes existed in soil bacteria, deep-rooted even in continental North America. This extremely noteworthy discovery reinforces that this problem is even bigger than we thought. What it means is that we a very real threat on our hands, that has only been compounded by new discoveries, due to our neglect of this reality.

The Effect on Military Operations

The incident rate of multidrug-resistant organisms* in current US military operations is staggering this reality has been affecting troops overseas (Scott, et al., 2007) with devastating effects and have complicated the care of the personnel wounded in combat (Sutter, et al., 2011). Infectious complications are the primary causes of morbidity and are a leading cause of mortality in patients who survive the first few days after injury (Murray, et al., 2011). Between the years of 2005-2009, deployed hospitals and receiving military centers received 21,272 patients where 18,560 were screened multidrug-resistant organism colonization (Hospenthal, et al., 2011). In just the first year of the study, 6% were found to be colonized with Acinetobacter (commonly dubbed as “Iraqibacter”), E. coli, or Klebsiella; all infectious diseases.

A. baumannii has been documented in countries all over the world, both developed and undeveloped, including, but not limited to: the United States (Tenover & Goering, 2009), Canada (McCraken, et al., 2009), the United Kingdom (Chen, et al., 2011), China (Chen, et al., 2011), Pakistan (Perry, et al., 2011), and numerous outbreaks in South America (Peleng, Seifart, & Paterson, 2008). It is an emerging infection that is becoming one of the hardest to combat because it is a multidrug-resistant infection that is difficult to detect and control (Maragakis & Perl, 2008). Its clinical significance is that in the last 15 years it has been able to propel itself, with remarkable ability, to be antibiotic resistant (Peleng, Seifart, & Paterson, 2008).

Moreover, because its ability to adapt and spread, it is one of the organisms currently threatening the antibiotic era (Peleng, Seifart, & Paterson, 2008), particularly as it has the ability to survive in dry temperatures (Davis, Moran, C. Kenneth, & Gray, 2005), a condition that increases the risk of hospital-environment spread. An even larger concern surrounding A. baunmannii is that it can cross between species, making animals both susceptible, and reservoirs, for such diseases (Endimiami, et al., 2011). And it is worth noting that A. baumannii is not normally associated with skin and soft-tissue infections, but recently, it has been noted that soldiers with gunshot wounds, received in battle in Iraq and Afghanistan, are susceptible to infections of this kind (Sebeny, Riddle, & Petersen, 2008) and complications are even beginning to arise if it affects the central nervous system (Peleng, Seifart, & Paterson, 2008).

While particular emphasis has been placed on acinetobactor in this report, one should not discount the prevalence of E. Coli and Klebsiella. Trends have been showing that over the last five years the prevalence of acinetobactor in troops to be falling, yet the threat still exists as E. Coli (Hospenthal, et al., 2011) and Klebsiellab seem to be taking over (Hospenthal, et al., 2011) and on the rise (Sutter, et al., 2011).

Barriers to Innovation and the GAIN Act

The current business model for antibiotic research and development is out-dated. In most cases, antibiotic treatments lasts only a few days, making antimicrobial research a hard sell for pharmaceutical companies which make the lion’s share of their profits on long-term treatments and often end up investing in medicines that require lifelong use. The net result is that pharmaceutical companies and stay away from any research that would result in short-term use because of its low profitability. Current pricing and reimbursement policies do not prioritize drugs according to their ability to reduce morbidity or mortality (Mossialos, Morel, Edwards, Bereson, Gemmill-Toyama, & Brogam, 2010). For example, cancer and central nervous-system related drugs attain much higher prices despite sometimes offering only a few months of additional life (Outterman, 2005), yet the proper treatment for an infectious disease may save the life of somebody that goes on to live decades.

Even the most philanthropic of companies will look long and hard at undertaking projects that show little-to-no protected return-on-investment, particularly as research and business costs continue to soar. Yet drug-resistant enzymes that help bacteria adapt are making a global resurgence (Tenover & Goering, 2009) and continually find new ways to beat our current pool of antibiotics. As identified, the combination of weak research and development practice in this field, and the sudden increase of drug resistant pathogens, has a wide range of negative effects, such as leaving localized field hospitals open to exposure from these deadly infections.

Given that antibiotic resistance is a global issue, the ideal scheme would be to have an incentive program that was initiated at the global level; unfortunately that will not happen given the difficulty in garnering support on such a wide scale (Mossialos, Morel, Edwards, Bereson, Gemmill-Toyama, & Brogam, 2010). Inasmuch, it will rest on the “big players” such as the United States, the European Union, Canada, and Australia to take the lead on this matter. Accordingly, work and research is needed to keep pace with a number of evolving infections that are successfully fighting off modern antibiotics. The Generating Antibiotic Incentives Now Act (GAIN Act), is an important first step that offers a comprehensive and financially sound action plan that will reinvigorate antibiotic research and development in the United States.

Given economic hardships and general global austerity, grants taken from public purse are difficult to justify, and as mentioned, incentivizing research has a proven track record of benefits, for both small and large pharmaceutical companies. The GAIN Act accounts for the tumultuous budgetary constraints by offering economic incentives. First, it provides a mechanism to protect intellectual property, allowing pharmaceutical companies to recover costs and generate profits over time. Thus, developing an antibiotic for resistant pathogens, as defined in an exclusivity period, would give the company the necessary extension to recover costs and generate a profit. This is not a new idea, as the bioterror legislation proposed by Lieberman and Hatch several years included this sort of incentive. This legislation was dead on arrival to Senate as it was strongly opposed by the generics industry and many consumer groups which claimed it would exacerbate the drug price situation in the United States (Shales, 2007).

Secondly, the GAIN Act offers tax incentives, creating a direct method of putting these dollars right back into research and development. It is noteworthy that the GAIN Act also offers some regulatory latitude in order to fast-track and give priority-review to new products, thus making the approval process for new medicines slightly more predictable allowing for ready-for-use drug therapy that is needed today.

The GAIN Act is an instrument of support that will serve not only our troops, but also the entire civilian population of the United States. As such, leadership in Washington should support this piece of legislation wholeheartedly as a first step, but keeping in mind it is just that: a first step. The regulatory impediments are still high and the more difficult the lawmakers make it for the pharmaceutical companies to invest in antimicrobial research and development, particularly when little-to-no incentives are offered, the more we expose our troops, and our homeland, to increased risk.

Moreover, this is not a new issue, but one that has been creeping up on us and must be addressed. The Infectious Disease Society of America has published numerous works that make the strong case for such research. Accordingly, the linkage between pending legislation on biodefense and the development of new antibacterial drugs for resistant pathogens has also been made (Shales, 2007). What this all suggests is that while this is an issue that must be addressed there are solutions available in the current system and legislation. What this ultimate leads to is a question of political will.

Bacterial Reality

In summary, these pathogens are severe contributing factors to the deaths of our troops and are making their way into civilian hospitals, even back here at home, given their virulence and resistance. Military operations, along with global and leisurely travel are contributing factors that cannot be ignored, especially when so many in living Western countries are now opting for selective medical care in different countries where these infections are prevalent (Sutter, et al., 2011), particularly as they look to save on medical costs. The short-term cost to the patient may be reduced, but the long-term cost to the state will certainly increase. Even under the best of circumstances (permanent, noncombat hospitals), the control of outbreaks of these types of infectious diseases is difficult (Scott, et al., 2007).

At the highest of prices, we have empirical evidence from the war zone that shows this is an issue that cannot be ignored (Tribble, et al., 2011). Many researchers, doctors, and military personnel have stated that protecting our wounded troops from these infectious diseases is a must (Sutter, et al., 2011), that new control strategies are need (Scott, et al., 2007), and even more say the increased and new antimicrobial research and development is needed (Davis, Moran, C. Kenneth, & Gray, 2005), (Peleng, Seifart, & Paterson, 2008), particularly when protecting against the secondary resistance these organisms are showing. Coupled with the facts that there are increased economic costs and the accepted rationale that antibiotic-resistance was due to antibiotic overuse (which has now been proven can also be naturally-occurring, dating back to before humanity’s time), we have a serious issue on our hands that cannot be ignored.

The current “well of antibiotics” that we have used to combat these superbugs is drying up (and the case can actually be made that is has already dried up). “Last ditch efforts” or “silver bullets” such as Colistin are even losing their effect on certain strains. Even “antibiotic cocktails” (a mixture of medicines) are proving to be ineffective. Yet, there is a very real crisis that is looming, contributing to the death of soldiers in the field and civilians back home, and little is being done about it. So much time, effort, and resources are put into saving a wounded soldier’s life, yet once they reach a stage of recovery, they become infected with one of these antibiotic resistant diseases, setting their recovery back considerably, resulting in them becoming violently ill and even dying.

Tens of thousands of people are dying annually, with hundreds of thousands more being hospitalized, all on account of the antimicrobial research that is NOT being undertaken. The research and development of these therapies takes years to develop and the longer we remain inactive, the larger threat we face.

Because of who they are, and what this country has asked of them in fighting two wars, our men and women in uniform deserve the very best of all our resources; this most certainly includes medical treatment. On his first trip to Afghanistan, newly appointed Secretary of Defense Leon Panetta told troops:

“You deserve no less. You're putting your lives on the line. Many have given their lives on this mission. The least we can do is to say to them that we will support them every step of the way.” (Panetta, 2011)

In closing, it is without doubt and crucial that future research and development in the antimicrobial field be undertaken in order to minimize adverse effects and help minimize, and even prevent, the emergence of future types of resistance. Given the current realities, the incentivizing of the process, through: tax incentives, protection of intellectual property, and a more predictable regulatory process, will surely increase research and development which will ultimately: help our men and women in the forces, improve the health care system, reduce the economic burden on the taxpayer, and provide for increased national security.

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