Combating the Threat of Antibiotic Resistance: The Pressing Need for New Solutions
By: Mark Chee, Karishma Popli, Erin Brown, Anthony Hung, Preet Patel, and Rachel Milner
In the United States alone, the Center for Disease Control (CDC) estimates that over 2
million people are infected with antibiotic resistant bacteria and 23,000 die as a result (1). The
antibiotics that since their invention have saved millions of lives throughout the world,
increased life expectancy, and facilitated vast improvements in health often do not work.
Antibiotics of last-resort, which are only used after all other treatment options have failed, are
becoming increasingly ineffective against these infections.
Especially troubling is the fact that no new classes of antibiotics have been approved by
the FDA since 1987 (2). Worse yet, an EMA-ECDC-ReAct study found that of the antibiotics in
the research and development (R&D) pipeline targeting Gram-negative infections, none had a
novel mechanism of action, making it unlikely that they would show activity against this
important category of antibiotic resistant bacteria (3). This barren R&D pipeline is the result of
decreased investment in antibiotics compared to new, more profitable drugs for chronic
disease.
Although legislation in the U.S. has attempted to simulate antibiotic development, they
have failed to incentivize the development of antibiotics that address unmet patient needs. The
Generating Antibiotic Incentives Now (GAIN) Act of 2012 extended monopoly protections for
drugs granted “qualified infectious disease product” (QIDP) status. Pharmaceutical companies
received an accelerated review of new drug applications and five years of market exclusivity for
a broad range of antibiotics that did not need to show added benefits over existing treatment.
Of the four QIDPs that were approved by the FDA last year, three treated acute skin infections
caused by susceptible bacteria for which effective drugs already existed (4). This increase in
therapeutic competition caused by the influx of new drugs that treat the same infections as
existing drugs may in fact exacerbate the problem of antibiotic R&D by decreasing the financial
incentive for pharmaceutical companies to develop new drugs. According to a study of FDA
approved drugs from 1980-2009, the withdrawal rate of antibiotics from the market (43%) is
already more than three times higher than non-antibiotics (13%). Many of these withdrawn
drugs appear just not to be effective enough to compete with existing regimens (5).
While previous legislation fails to incentivize truly novel antibiotics, the 21st Century
Cures draft legislation being proposed in the U.S. House of Representatives actively seeks to
further speed the drug approval process at the cost of patient safety. This proposal, which
would affect all drugs not just antibiotics, would replace phase III clinical trials with “smaller”
datasets with alternative endpoints, animal or mathematical models, or findings in test tubes.
AIDS activists, who had at one time advocated for faster FDA drug approval, have criticized this
draft legislation for dismantling the regulatory safeguards that help ensure patient safety (6).
Yet against the background of the dark and looming post antibiotic era, there remains
hope in the form of the recently discovered antibiotic Teixobactin (7). In laboratory tests,
Teixobactin has shown efficacy against a broad range of infections by preventing bacteria from
synthesizing their outer coats. So far, no bacterial resistance has been observed. More
importantly was the novel process used to discover Teixobactin, one that may herald a new
generation of antibiotics. In the past, most antibiotics developed in the laboratory were first
identified through studying compounds produced by cultured bacteria harvested from the wild,
where a fierce battle for survival constantly occurs between microorganisms that produce
antibiotics as weapons against each other. Scientists at North Eastern University discovered
Teixobactin by turning this dogma on its head, using a newly developed platform called iChip to
sample environmental factors released by bacteria directly in the soil, allowing them to
discover molecules produced by bacteria that currently cannot be cultivated in the laboratory
(7).
While Teixobactin has not been FDA approved and is still years away from use in human
populations, many issues will determine true impact of this discovery. First, after Teixobactin is
brought to market, it will only be truly useful in combating the rising tide of resistant pathogens
if it is reasonably priced in both the U.S. and abroad. Furthermore, Teixobactin and other novel
antibiotics must be conserved and used appropriately to avoid the onset of resistance. Lastly,
the potential of iChip to discover future antibiotics may be severely limited if it used
proprietarily, preventing other laboratories from using the technology to discover more novel
drugs.
However, Teixobactin still represents an example of the type of scientific innovation
needed to combat the growing threat of antibiotic resistance. For this to occur, we need
legislation that incentivizes the development of novel drugs like Teixobactin rather than me-too
drugs and regulatory processes that ensure that compounds discovered through technologies
like iChip are safe and effective in patients before being brought to market. Antibiotic
resistance will be one of the pressing issues of our time, but our policies must still put patients
first.
References
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7.
Centers for Disease Control and Prevention (CDC), Antibiotic Resistance Threats in the
United States, 2013. 2013, CDC: Atlanta, GA.
World Economic Forum, Global Risks 2013. 2013, World Economic Forum: Geneva,
Switzerland.
Freire-Moran, L., et al., Critical shortage of new antibiotics in development against
multidrug-resistant bacteria—Time to react is now. Drug Resistance Updates, 2011.
14(2): p. 118-124.
Doshi, P., Speeding new antibiotics to market: a fake fix? Vol. 350. 2015.
Outterson, K., et al., Approval and withdrawal of new antibiotics and other antiinfectives
in the U.S., 1980-2009. J Law Med Ethics, 2013. 41(3): p. 688-96.
Gonsalves, G. and D. Zuckerman, Commentary: Will 20th century patient safeguards be
reversed in the 21st century? Vol. 350. 2015.
Ling, L.L., et al., A new antibiotic kills pathogens without detectable resistance. Nature,
2015. 517(7535): p. 455-459.