Bacterial Resistance: What Can Policy Do To Help?

October 25, 2017

Recently, the research and development of new antibiotics has plummeted due to small cumulative profits . The overuse of antibiotics is the driving force behind the emergence of antimicrobial resistance. The potential repercussions from this include significantly greater health care expenses due to the increased difficulty of treatment and surgeries and infections becoming life-threatening once again. Now the main question is if a combination of federal initiatives and research-based solutions will be enough to mitigate the effects.

By Aishwarya Saluja and Sima Parekh

The discovery of antibiotics was a groundbreaking event in fighting and preventing bacterial infections. These drugs kill bacteria by blocking protein synthesis or interfering with cell wall production [1]. However, since the golden age of antibiotic discovery, the 1950s to 1970, research and development of new antibiotics has plummeted [2]. This dramatic decline can be attributed to big pharmaceutical companies dropping their antibiotic programs and shifting focus to more profitable drugs that require long term patient use. Antibiotics are hard to find and develop, leading to poor commercial returns, and the sector has therefore become increasingly underfunded. In a dangerous parallel, antibiotic resistance is becoming more prevalent. According to the CDC, at least two million illnesses and 23,000 deaths are caused by antibiotic-resistant bacteria in the U.S. alone [3].

(Image: Cumulative profits from antibiotics research. Source: Review on Antimicrobial Resistance)

(Image: Cumulative profits from antibiotics research. Source: Review on Antimicrobial Resistance)

Causes of Resistance Development

The overuse of antibiotics has turned out to be the driving force for the evolution of resistance. Epidemiological studies have demonstrated “a direct relationship between antibiotic consumption and the emergence and dissemination of resistant bacterial strains.” [4] Patients who take antibiotics unnecessarily when treating viral illness unwittingly foster resistance in their microbes. Much of the misuse of antimicrobials is associated with the lack of rapid diagnostics that can pinpoint the exact nature of the diseases causing microbes. Doctors and prescribers, unsure of the kind of disease affecting their human or animal patient but still needing to provide treatment to them, rely on treatment with broad-spectrum drugs that may or may not cure the patient but still expose microbes to a variety of drugs, and therefore increases the likelihood of resistance developing to them.[5]. According to data collected by the Centers for Disease Control and Prevention and presented in the Journal of the American Medical Association (JAMA), at least 30% of antibiotic regimens prescribed in the United States are unnecessary [6]. In addition, some countries and the Internet allow antibiotic purchase without a doctor’s prescription, leading to cavalier use [7]. Finally, poor drug quality assurance programs can force patients and providers to use sub-optimal concentrations of antibiotics, further increasing the risk of resistance development [8].

(Image: Causes of Antibiotic Resistance. Source: World Health Organization)

(Image: Causes of Antibiotic Resistance. Source: World Health Organization)

Antibiotic resistance has been reported since the initial discovery of penicillin but “the size and cost of [antibacterial resistance] trials [are] a huge financial disincentive for big drug companies and a huge barrier to small ones.” [9] Trials can cost between $70 to $120 million dollars because not many patients carry drug resistant bacteria and these small patient pools mean that each patient can cost approximately $1 million dollars. [10] The scientific community has been discussing the issue of drug resistance for 20 years and still has not seen the momentum needed to address the issue. [11]

(Image: Antimicrobrial R&D is not attractive to venture capitalists. Source: Review on Antimicrobial Resistance)

(Image: Antimicrobrial R&D is not attractive to venture capitalists. Source: Review on Antimicrobial Resistance)

Federal Initiatives to Combat the Resistance

The need to research and combat antibiotic resistance is dire and therefore incentives must be introduced to entice companies to invest in antibiotic research and development. The government understands the urgency of combating resistance and in 2015 the White House released The National Action Plan for Combating Antibiotic-Resistant Bacteria (CARB), aiming to reduce inappropriate outpatient antibiotic use by at least half by 2020 (or 15% of overall antibiotic prescriptions). Other goals of CARB include strengthening the “One-Health” approach to integrate public health, veterinary services, and environmental surveillance in order to improve detection and control of resistance [12].

Resistance is not limited to medical settings or the human body. Farm animals are commonly fed antibiotics to enable them to grow faster and bigger [13]. Many of these drugs pass from the animals into soil and water sources where exposed bacteria become increasingly resistant. The resistant bacteria are then transmitted to humans through ingestion of infected meat or contact with infected animals and run off water[14]. The National Resources Defense Council has been pushing food companies to reduce to use of antibiotic drugs in their supply chains and publicized the issue to force major food companies to better their production methods. The organization made great strides in 2015 when it passed the nation’s first law to collect information about and curb farm antibiotic use in the state of California; it is currently working to push the U.S. Food and Drug Administration to make this a countrywide mandate [15].

To incentivize further study , the government could reissue the 1997 Pediatric Exclusivity Provision (PEP) for anti-antibiotic resistance research and development in a new form. PEP granted pharmaceutical companies an extra six months of patent life for a drug in exchange for carrying out FDA-requested pediatric studies. Before 1997, few drugs were tested on patients younger than 16 and the FDA wanted to encourage more adolescent clinical trials [16]. PEP proved that the market-entry reward method is effective to stimulate companies to increase their pediatric drug development research. Even though new antibiotic drug discovery may have limited sales potentials, the longer patent life increases the financial payoff.

The Economic Impact

The economic impact of antibiotic resistance is a major reason for concern. The estimated annual cost, direct and indirect, of antimicrobial resistance is estimated to be $55 billion in the U.S. [17] One study projects that by 2050, approximately 10 million lives will be at risk and a cumulative $100 trillion of economic output will be at risk due to the projected increase of antimicrobial resistant infections [18]. Net economic impact of resistance is defined as the attributable cost of treatment of an infection due to a resistant isolate (the treatment cost) minus the cost of preventing such infections [19]. There are three main factors contributing to the overall economic cost: costs to the hospitals, hospital charges to the infected patient, resource utilization to control the infection and prevent further spreading, and overall system-wide health care costs [20]. Hospital costs include operating costs, and the cost of drugs, tests, and general patient care activities. However, patients will often be overcharged if larger insurance companies, Medicare, and Medicaid do not cover the entire bill, due to the extended care required by a more resistant pathogen. Generally, patients infected with an antimicrobial resistant organism experience increased treatment failure with subsequent use of more expensive treatments, extra investigations, longer hospital stays, longer time off work and most importantly, premature death [21]. Further, hospitals will often negotiate discounts with larger payers like Medicare or private firms like Aetna. In order to ensure all costs are reimbursed, patients often get exacerbated bills to offset the risk of these more strenuous treatments against the discounted payments, particularly when the patient’s coverage is limited. There is also the opportunity cost of diverting funds to replace outdated, ineffective antibiotics to produce new antibiotics instead of funding other public health programs [22]. One must also consider the effects of externalities when evaluating the economic impact of antimicrobial resistance. For example, antimicrobial usage has a positive effect on society due to decreased morbidity from sub-clinical infections and decreased spread of microbes between patients. However, negative externalities occur due to the loss of antimicrobial effectiveness, which can then lead to further overconsumption of antimicrobials since patients and providers do not feel the direct impact of this externality. [23]. Policy strategies to combat this revolved around greater regulation and taxation.

Research-Based Solutions

There are ways to combat bacterial resistance without needing to create new lines of antibiotics. Although bacteria are harmless on their own, in large groups the organisms secrete toxic molecules called virulence factors [24]. As Carmen Drahl’s 2014 study suggested, if scientists can interfere with quorum sensing, bacterial communication systems, they can manipulate bacteria into thinking they are alone and prevent the release of these disease-causing factors. Her experiment compared two strains of Pseudomonas aeruginosa, a notoriously antibiotic-resistant pathogen. One had its quorum-sensing system genetically inactivated and the antibacterial resistant microbes failed to replicate [25]. They can also starve bacteria of metals they need to survive. Certain bacteria can use minerals as energy sources and break down the matter through metabolism. Through a process called bioleaching, these microorganisms squeeze out metal ores or concentrates combined with sulfur [26]. Furthermore, decreasing infection rates, mostly through efforts of improved sanitation, would obviate the need for antibiotic use, and inherently decrease resistance rates. This model can be implemented through improved clean water and sanitation access in poorer countries and improved prescribing practices and systemic care in wealthier nations. Public policy should favor actions by world health organizations to promote alternative actions like vaccine administration, which would decrease infection rates and lead to lower antibiotic use rates. The overuse of antimicrobials is also related to high rates of infection and the dependence on antimicrobials as curative treatments, reducing the focus afforded to preventive care that might prevent an infection in the first place [27].

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