Evidence-Based Immunology and Infectious Disease

The Economics of Resistant Pathogens and Antibiotic Innovation | Page 2

Published Online: April 23, 2014
Michael R. McKellar, BA; Michael E. Chernew, PhD; and A. Mark Fendrick, MD
Globally, multidrug-resistant (MDR) tuberculosis alone is estimated to infect around 630,000 people.11 While resistant pathogens first appeared almost exclusively in healthcare facilities, there has been a recent increase in community-acquired infections. The rise in resistance not only threatens to increase the numbers of untreatable infections that may lead to serious disability or death, but also threatens to limit the potential of many other medical procedures. Both surgical and nonsurgical procedures that are currently possible due to effective prophylaxis may become no longer possible due to the risk of infection. Finally, the economic costs of resistance are substantial and growing.12

For instance, direct costs of treatment are estimated at $20 billion per year in the United States alone, with indirect costs such as lost wages believed to be underestimated at $35 billion per year. These costs will be even higher as future resistance renders more and more antibiotics ineffective. Overuse is not the only problem with antibiotic prescribing—there are also substantial clinical and economic costs associated with underuse of appropriate antibiotic therapy. Unlike other scenarios in which (in the absence of financial restraints) clinicians provide the most effective treatment, they often prescribe antibiotics that are known to be less effective in order to preserve the potency of alternative, more powerful drugs.13 One study suggests that clinicians avoid using new, more powerful antibiotics in the face of resistant pathogens between 58% and 70% of the time, often citing as their reason that they want to preserve the use of agents that are seen as very effective against resistant pathogens.

Other evidence suggests that cost concerns play a large part in drug choices when treating infectious diseases, with 87% of hospital providers citing cost reduction as a major driver of antibiotic steward programs.14 Regardless of the underlying cause, a large body of research substantiates the belief that when an appropriate antibiotic regimen is delayed or not started, negative clinical consequences, including preventable death, result.15-18 Hesitancy to use the most effective medication due to concern for promoting resistance creates a unique and somewhat paradoxical circumstance, as this restraint reduces the financial incentives for the development of novel agents.

Policies intended to limit use and minimize resistance, such as those restricting the most effective agents to the cases in which less effective agents fail to bring about a cure, are possibly valuable, but they must be balanced with the competing concern of underutilization. The key question is defining the optimal utilization rate. One approach, while hypothetically extreme, would be to ignore the resistance issue and presume that innovation would always develop effective new agents.

This is known as the “private best” scenario, where treatment decisions only reflect the benefit directly to the patient and associated costs of treatment. Another option, which would perhaps qualify as the other extreme, would be to fully incorporate the impact of utilization on resistance, and presume no future innovations. In this case, utilization would be too low because the cost of resistance is overstated if future innovations are ignored. Thus, determining “appropriate use” of antibiotics will always be controversial, since 2 critical variables—the contribution of use to resistance and the development of agents to overcome that resistance—are impossible to precisely estimate.

Since the development of resistance is a reality, we must continually innovate. In fact, the history of antibiotic discovery has mimicked a cat-and-mouse game, with more powerful drugs being developed to treat the very pathogen that a previous antibiotic precipitated. An example of this progression is demonstrated by the development of methicillin-resistant staphylococcus aureus (MRSA), an organism that was effectively treated by vancomycin, until vancomycin-resistant staphylococcus aureus (VRSA) emerged. Now, multidrug-resistant pathogens are rendering even powerful antibiotic combinations ineffective. While it is clear that overuse-related resistance is a serious concern, the documented underuse of the most effective therapy in order to “preserve”

future effectiveness represents another important gap between actual and ideal practice. Combating resistance should clearly involve reducing use in cases where it does not meet the private best standard. Further reductions in use intended to slow resistance must reflect both the impact of reduced use on the individual patient and the impact of reduced use on the incentive to innovate. The social best level of use would incorporate the impact of use on resistance while also adjusting for the potential for future innovation. Fortunately, the discovery of new antibiotics has, for the most part, kept up with resistance—although this need not always be the case.

Existing Regulatory Approaches to Encourage Innovation and Prevent Resistance

During the 1990s, the Institute of Medicine, the Government Accountability Office, and the Office of Technology Assessment all released reports on the growing problem of resistant pathogens, followed in the 2000s by a series of legislative bills attempting to address the concern. More recently, the US GAIN Act attempted to decrease the costs and time of bringing antibiotics that treat serious or life-threatening conditions to market by extending exclusivity and earmarking such antibiotics for expedited US Food and Drug Administration (FDA) review.19,20 Major public health organizations around the world have also attempted to combat the specter of resistance through surveillance, most notably via the SENTRY Antibiotics Surveillance Program.

Global call for greater antibiotic innovation. Many public health agencies around the globe see antibiotic resistance as a major threat to public health. In the United States, the FDA currently cites resistance as a major concern, while a CDC report issued in March 2014 stated that a lethal strain called cabapenem-resistant enterobacteriaceae (CRE) had been on the rise in hospitals.8,21 In November 2013, a Reuters report stated that the last line of antibiotics used to fight CRE was now facing a resistance rate of over 25% in 8 European Union countries.22 The United Kingdom (UK) has ranked antibiotic resistance as a top national health policy concern and released a 5-year strategy to address the issue, which the chief medical officer (the most senior medical advisor at the UK’s National Health Service) is calling a “catastrophic threat.”23

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