Why We Might Not Be Able to Count on Antibiotics to Stop Infections Anymore
A “superbug” resistant to all known antibiotics has surfaced in the United States for the first time, in a Pennsylvania woman being treated for a urinary tract infection. Microbiologists, who have seen this coming, warn that unless we radically rein in antibiotic use and simultaneously step up research on alternatives, the near future may take us back to a pre-antibiotic pattern of death by infection.
In Europe and North America today, it is almost unthinkable for a child to die from a scratch, or a woman to die of infection after childbirth, or a soldier to die from a shrapnel fragment that nicks an arm. Tragedies like these would have been common occurrences for our ancestors but now are made extraordinarily rare by widespread access to antibiotics.
Antibiotics—antimicrobial compounds that prevent or resolve bacterial infections—are sometimes called miracle drugs. Their discovery revolutionized 20th-century medicine, providing security against everyday infection and enabling lifesaving practices like surgery and chemotherapy. But as we applied this new technology with gusto, the inevitable happened: Bacteria evolved resistance to specific compounds and sometimes entire classes of drugs. In recent decades, resistance has spread rapidly, causing tens of thousands of deaths and billions of dollars of financial losses each year in the United States and the European Union alone.
The rate of new antibiotic development has not kept pace with this growing problem. In fact, the number of new antibiotic agents approved by the FDA has declined steadily over time. Only two new classes of antibiotics have launched in the last 30 years, in contrast to 11 that launched between 1930 and 1970. Most new drugs merely tweak old classes of antibiotics rather than offering novel mechanisms to attack pathogens.
The evidence increasingly points to a desperate need to change the way we rely on traditional antibiotics as a central role in our health care, not to mention addressing the way we use antibiotics in our food system, where drugs are applied to fatten livestock rather than to combat disease.
Stronger Bugs and Fewer Drugs: The Stagnation of Antibiotic Development
A perfect storm of factors has driven most pharmaceutical companies to abandon antibiotic research and development (R&D). The easiest hurdles to overcome may be policy and economic dynamics that inadvertently discourage inquiry. But some hurdles have to do with the nature of scientific inquiry and bacteria themselves.
High risk, low reward. The profit motive of pharmaceutical companies, usually a driver of innovation, works against antibiotic R&D. Antibiotic investments are high-risk/low-reward compared to medicines for chronic illness which get far longer windows of use. To illustrate the challenge, the top cholesterol medication made $12 billion per year under patent protection, whereas the bestselling antibiotic made only $2.5 billion. While the annual sales growth for antivirals and vaccines is 10 percent and 23 percent, respectively, it is only one to two percent for antibiotics. What’s more, resistance means the range of indications for a new antibacterial may shrink as resistance grows.
Factors like these create an unappealing trajectory for investors. Antibiotics are simply not where the money’s at.
Regulatory barriers. One way to shift the risk-reward balance is to update the regulatory environment. Today the new drug approval process unnecessarily inflates costs and uncertainties. In addition, regulatory complexities create an average eight-year gap between when an antibiotic molecule is identified and when it is approved.
Luckily, the fact that these challenges are caused by regulatory agencies means they can be fixed by regulatory agencies.
Market dynamics may be difficult to mitigate directly, but smart policies could make antibiotic development more financially appealing, including tax credits, development grants, and—most tantalizingly—so-called “wild-card” patent extensions, which can be applied to any drug the company markets.
Governments can and should support such measures to reflect the societal savings from a functional antibacterial arsenal. Progress has already been made with the United States’ 2012 Generating Antibiotic Incentives Now (GAIN) provisions, which incentivize companies to develop much-needed antibacterials.
Even so, all the monetary incentives in the world might not fix the scientific problems facing antibiotic development.
Scientific hurdles. Despite technological advances, finding new drugs is getting harder rather than easier. The 1940s to 1960s were the “golden era” of antibiotic discovery, but the last new class of broadly useful antibiotics was discovered in 1986 and every product since then derives from older drugs. Researchers have been forced to return to chemicals previously deemed unworthy of development.
Promising developments. A single cure for the growing epidemic of antibiotic resistant infections seems unlikely, but new therapies offer some solutions, particularly when used together. One tactic is to improve diagnostic capabilities so that we can design drugs to target specific pathogens; such narrow-spectrum antibiotics would create far less selective pressure and therefore enjoy a longer clinical lifetime than existing ones.
Another familiar option is to bolster the immune system, such as with vaccines, which are notably rare for bacteria. Some research targets bacteriophages, viruses that kill specific bacteria, that may be deployed to fight on our side. Bacteriophages have the advantages of effectively attacking dormant and resilient pathogens and leaving the body’s good microbes alone.
An even more innovative alternative seeks to modify bacteria themselves, reducing a pathogen’s virulence or restoring sensitivity to existing antibiotics. The means and genes bacteria use against us are well understood, and new synthetic biology tools like CRISPR may allow us to switch off specific bacterial genes. In one recent study, a DNA modification using CRISPR was delivered into bacteria via bacteriophage.
Finally, by considering dangerous bacteria and their hosts as integrated systems, we can combine complementary antibacterial approaches to create a more robust defense against resistant disease.
These new technologies inspire hope, but for now they remain in early stages of development. Until their promise is borne out, we must safeguard the precious drugs we have.
Farming Superbugs: Antibiotic Misuse in Livestock Production and Policy Solutions
Factors driving the incidence of antibiotic resistance include unnecessary prescriptions in the U.S. and adulterated or incomplete regimens in developing countries where antibiotics may be sold without prescription or oversight.
But a top opportunity for reform is the role of antibiotics in agriculture.
The perfect breeding ground for resistant bacteria. Since the 1950s, continuous sub-therapeutic doses of antibiotics have been administered to livestock to promote growth. Small amounts of drugs delivered daily through food and water reduce the energy animals spend fending off disease and so increase their weight gain per unit of feed.
Such nontherapeutic use is especially common in concentrated animal feeding operations (CAFOs), commonly known as factory farms. These operations often keep tens of thousands of animals in such crowded and unsanitary conditions that ubiquitous antibiotics are deemed necessary to prevent disease. Such sub-therapeutic drug use has expanded so that 60 to 80 percent of all antibiotics produced in the U.S. are for growth promotion. Upwards of 90 percent of antibiotic drugs used in livestock (over 32 million pounds) serve this purpose.
Industrial agriculture creates the perfect conditions for resistance to develop by densely packing host animals and exposing bacteria to constant yet low doses of drugs. In one researcher’s analogy, “CAFOs are comparable to poorly run hospitals, where everyone gets antibiotics, patients lie in unchanged beds, hygiene is nonexistent, infections and re-infections are rife, waste is thrown out the window, and visitors enter and leave at will.”
From livestock to humans. Over time, use of sub-therapeutic antibiotics in agriculture has included every class of antibiotics “clinically important” to human medicine. This unrestrained application leads to dangerous drug-resistant infections in humans. After pathogens develop resistance on farms, they are transmitted to humans through myriad pathways, including food contamination; infection of agricultural workers; and soil, water, and air pollution.
The connection between antibiotic use in agriculture and resistant disease in humans is recognized by health organizations like the WHO, CDC, and FDA and has been confirmed by numerous scientific studies.
European models and promising changes. With this vast array of scientific evidence connecting antibiotic use in agriculture to resistant infections in humans, there can be no question that we must change our food system to protect our drugs. The first step should be to ban the use of antibiotics for growth promotion. Although this move may seem radical, several nations have proved that it can be done without damaging the livestock sector. Bans have existed for specific antibiotics in Europe since the 1960s and the E.U. prohibited the use of any antibiotics for growth promotion in 2006.
So far, the results are encouraging. The U.S. animal husbandry industry has complained that bans would impose a financial burden from increased mortality; however, when Denmark banned all growth promoters it saw a mere one percent increase in the costs of swine production and a negligible change for poultry. The National Research Council estimates that such a ban in the U.S. would raise food expenses by $5-10 per person per year, which is small compared to the massive social and economic burdens of antibiotic-resistant infections.
U.S. late to the game. Unfortunately, the United States has been slow to follow Europe’s lead. Until recently, the FDA included growth promotion under approved uses of antibiotics and the U.S. used more antibiotics per kilo of meat than any other developed nation. Contrived scientific controversy regarding the link between drug use in livestock and resistance in human infections helped maintain the status quo.
Thankfully, the tide is turning: the FDA is currently developing voluntary “judicious use” guidelines for antibiotics in livestock, beginning with a new Veterinary Feed Directive and its Guidance #213 which will be fully implemented by the end of 2016. “Once these changes are fully implemented, it will be illegal to use these medically important antibiotics for production purposes [i.e. growth promotion], period,” explains the FDA blog. “Instead of having unrestricted over-the-counter access, animal producers will need to obtain authorization from a licensed veterinarian to use these medications for therapeutic uses—for prevention, control or treatment of a specifically identified disease.”
The FDA has won commitments from all 25 affected drug companies to change the approved uses of their products and require veterinary oversight. However, any impact depends on the willingness of drug companies to voluntarily police themselves and their customers.
At present, U.S. citizen watchdogs and regulatory agencies including the FDA lack the authority to obtain specific information that would be necessary to enforce a ban on growth promoters. According to Danish researchers, their country’s success was predicated on an understanding of “who is administering what amounts of antibiotic to what animals.”
Under U.S. law, livestock feed formulations are confidential. Another issue of transparency arises because the new guidance allows “medically important antimicrobial drugs that are used on an ongoing basis as a preventive measure.” Roughly 30 percent of such drugs have no specific duration of treatment, creating a loophole through which antibiotic use for growth promotion could continue. “Theoretically, an animal could take the drugs for its entire life, getting growth-promoting benefits under the guise of treating gut illnesses in pigs or liver abscesses in cattle,” Wired author Katie Palmer explains. “And no one has the data that can distinguish one use from the other” (2015).
We must continue to fight for transparency if we are to truly reform our food system and safeguard today’s antibiotics. Only then can we continue saving the lives of scratched children, post-partum women, and all of us who value the freedom to play and work hard.
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The antibacterial arsenal that we have taken for granted for almost a century is being made obsolete by the rapid evolution of our microbial foes. This issue is urgent, and it is global.
We can work to rebuild the dwindling array of life-saving antibacterial drugs by smoothing regulatory processes, strengthening intellectual property rights, adding economic incentives, and building a better knowledge base to screen for new chemicals. Yet there are also inherent limitations to traditional antibiotic development. A few broad-spectrum “miracle drugs” simply cannot remain as the sole or central pillar of antibacterial medicine.
As researchers work to diversify antibacterial tools, we must protect the finite life-saving drugs we already have—first and foremost by adopting and enforcing wise-use practices in animal agriculture. Despite opposition from farm advocates worried about economic costs, Europe’s successful transition suggests that we don’t have to sacrifice modern medicine for cheap burgers. Animal husbandry can thrive, and we can make wise use of today’s antibiotics even as we prepare to fight the bacteria of the future with the weapons of the future.
This article is adapted from a more in-depth examination, “Trading Modern Medicine for Cheap Burgers,” which can be found at the Institute for Ethics and Emerging Technologies. The author would like to thank Molly Nixon, Valerie Tarico and Heather Williams for their scientific and editorial input.