Antibiotic Resistance. Because of overuse and misuse, some antibiotics are losing effectiveness against highly resistant bacteria.
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h e a lt h p o l ic y b r i e f w w w. h e a lt h a f fa i r s .o r g 1
Health Policy Brief m ay 2 1 , 2 0 1 5
Antibiotic Resistance. Because of overuse
and misuse, some antibiotics are losing
effectiveness against highly resistant
bacteria.
declining, limited, or zero effectiveness. This
what’s the issue? policy brief primarily focuses on the dimin-
Many of the world’s diseases are caused by ishing effectiveness of many drugs specifically
microorganisms such as bacteria, fungi, vi- in fighting bacteria, referred to here as “anti-
ruses, and parasites. While there are a num- biotic resistance.”
ber of drugs designed to treat these infections,
resistant strains are emerging at a rate that is With so many agencies involved in the regu-
currently outpacing the development of effec- lation and use of antibiotics, comprehensive
tive new drugs. Methicillin-resistant Staphy- solutions must focus on creating a coordinat-
lococcus aureus (MRSA) alone kills more than ed plan that touches on aspects of research
19,000 Americans every year—more than em- and development as well as enhanced infec-
physema, HIV/AIDS, Parkinson’s disease, and tion prevention and control, and stewardship
homicide combined. Despite this public health to ensure the proper use of these drugs across
need, pharmaceutical companies do not have different settings.
strong economic incentives to develop new an-
tibiotic drugs. This brief provides an overview of antibiotic
resistance, including a summary of its cur-
Unless new drugs are developed—together rent impact, the factors that contribute to its
with measures taken to slow the emergence spread, and the policy recommendations put
of new drug-resistant microbes—previously in place by federal and global public health
treatable infections will become major public agencies. It also reviews the debate around
health concerns, posing grave threats to in- the regulation of antibiotic use in agriculture
fected individuals and increasing the risk of and examines new developments in policy and
spreading to others. In recent years, several research associated with multidrug-resistant
global and national public health organiza- bacterial diseases and their underlying causes.
tions have highlighted the growing number
of multidrug-resistant microbes as a major what’s the background?
public health priority.
According to the Centers for Disease Control
©2015 Project HOPE– The commonly used term “antimicrobial and Prevention (CDC), at least two million ill-
The People-to-People
resistance” applies to any microbe—bacteria, nesses and 23,000 deaths are caused by anti-
Health Foundation Inc.
10.1377/hpb2015.6 fungus, or virus—against which drugs have biotic-resistant bacteria in the United States
alone. In 2013 there were about 480,000 newh e a lt h p o l ic y b r i e f a n t i b i o t ic r e sis ta n c e 2
global cases of multidrug-resistant tubercu- in the workforce could theoretically become
losis. According to the World Health Organi- too risky to undertake at all.
zation (WHO), gonorrhea may soon become
untreatable as more than ten countries have One issue that makes antibiotic resistance
reported strains that are resistant to all cur- difficult to combat is that drug-resistant mi-
rently available forms of antibiotic treatment, crobes are everywhere. According to the
and no new drugs have been approved. If WHO, in all regions of the world there are
trends persist and resistance continues to rise, high proportions of antibiotic resistance in
some reports estimate that by 2050 there will bacteria that cause common infections in the
“The more be ten million antimicrobial resistance–relat-
ed deaths worldwide, costing the world up to
urinary tract, lungs, and bloodstream; and a
high percentage of hospital-acquired infec-
antibiotics are US$100 trillion. tions are caused by highly resistant or multi-
used, the more drug-resistant bacteria. In fact, most deaths
opportunities To some degree, antibiotic resistance is un- related to antibiotic resistance are attributable
avoidable. The development of resistance is to infections acquired in health care settings
bacteria have to an evolutionary inevitability, even where an- such as hospitals and nursing homes.
evolve to defeat timicrobials are used properly and sparingly.
them.” All microbes have the potential to mutate and Another frequently cited factor in the emer-
render drugs ineffective. Once a few have mu- gence of multidrug-resistant strains of bacte-
tated, they spread when antibiotics wipe out ria is the misuse of antibiotics. For example
the susceptible bacteria, leaving a niche for when patients fail to complete their drug regi-
the resistant ones to occupy. mens at home, they may allow some bacteria to
survive the treatment and develop resistance
Antibiotic-resistant infections typically oc- in the process. In other circumstances, anti-
cur in health care–related settings, such as biotics may be prescribed when they are not
hospitals and nursing homes, where infec- medically necessary. This can allow other-
tions can spread quickly between patients wise harmless bacteria to develop resistance,
with compromised immune systems. Patients which may then be transferred to other more
who use certain medical devices, such as ven- dangerous bacteria.
tilators and catheters, are at a higher risk for
infection, according to the CDC. Agricultural Use
Overuse and Misuse While these practices may contribute to
the spread of resistant microbes, human con-
The more antibiotics are used, the more op- sumption only makes up about 20 percent of
portunities bacteria have to evolve to defeat antibiotic sales in the United States. The vast
them. The overuse of antibiotics—the CDC es- majority of antibiotics is used agriculturally
timates that up to 50 percent of antibiotics are in beef, poultry, pork, and fish farms to pre-
unnecessary or inappropriate as prescribed— vent infection and promote growth among the
in medicine and agriculture has led to a slew animals.
of so-called superbugs.
While it is unclear whether the larger volume
The potential impact of widespread anti- of antibiotics used in agriculture compared
biotic resistance is far reaching within the to hospitals translates to a greater contribu-
health care system. When first-line and then tion to the emergence of multidrug-resistant
second-line antibiotic treatment options strains of bacteria, the use of the drugs in food
are limited by resistance or are unavailable, production has garnered a significant amount
health care providers are forced to use antibi- of attention in media and policy spheres.
otics that may be less effective and more toxic
and that may require resources such as lon- According to an investigative report by the
ger hospital stays—driving up both morbidity news outlet Reuters, antibiotics are given as
rates and health care costs. standard practice during most of the life of
chickens, not just when the birds are sick. In
Without new therapies to treat or prevent every instance of antibiotic use identified, the
infections, lifesaving procedures such as or- doses were at the low levels that scientists say
gan transplants, chemotherapy, dialysis, and are especially conducive to the development of
caesarian sections will become more danger- drug-resistant strains.
ous; and non-lifesaving surgeries, such as hip
operations, that allow people to live active Many of the antibiotics used agriculturally
lives for longer and may enable them to stay belong to categories considered medically im-h e a lt h p o l ic y b r i e f a n t i b i o t ic r e sis ta n c e 3
portant to humans (such as penicillin and tet- • To enhance infection prevention and con-
racyclines). Despite this evidence, the United trol; and
States (in sharp contrast to Europe, which has
a long history of restricting antibiotic use in • To foster innovations and research and de-
animals) has been slow to pass any binding velopment for new tools.
legislation limiting the agricultural use of
critical antibiotics. In 2012, as part of the Food and Drug Ad-
ministration Safety and Innovation Act,
President Barack Obama signed into law the
what’s the policy?
23,000
Generating Antibiotic Incentives Now (GAIN)
Combating antibiotic resistance will require Act of 2011. These provisions added a five-year
coordination on behalf of a complex web of extension to the exclusivity period during
stakeholders. The National Institutes of Health which antibiotics that treat serious or life-
funds research, including studies that per- threatening infections could be sold without
deaths tain to the development of new antimicrobial generic competition. The intention of the act
products. The Food and Drug Administration was to increase the potential for profits from
According to the CDC, at least
two million illnesses and 23,000 (FDA) approves them for marketing and sale. new antibiotics—giving drug companies more
deaths are caused by antibiotic- The Department of Agriculture and the FDA time to recoup their investment costs and en-
resistant bacteria in the United have roles overseeing their agricultural use. courage the development of new antibiotics.
States alone.
The CDC, in addition to its role in surveil- In 2014 the WHO published its first global
lance, prevention, and control, tracks diseases report on surveillance of antimicrobial resis-
and engages in public education campaigns to tance, with data provided by 114 countries.
inform doctors and patients how the drugs The WHO has already initiated a collaboration
should be used in humans. The Biomedical with partners across many sectors to identify
Advanced Research and Development Author- strategies and actions to mitigate antimicro-
ity engages the drug development industry in bial resistance. Those partners have included
an integrated, systematic approach to devel- the World Organisation for Animal Health and
oping and procuring drugs in tackling public the Food and Agriculture Organization of the
health emergencies. The Department of De- United Nations to promote best practices to
fense (DOD) and the Department of Veterans avoid the emergence and spread of antibacte-
Affairs (VA) determine appropriate use and rial resistance, including optimal use of anti-
monitoring in military patient populations. biotics in both humans and animals.
And the State Department determines the US
trade policy on prescription drugs. In January 2014 President Obama again
mentioned antibiotic resistance—this time in
In recent years, several global and federal his State of the Union address. In March 2014
health agencies have attempted to call atten- he announced he would add $30 million to the
tion to the issue of antibiotic resistance and, budget to fund monitoring and research into
more broadly, antimicrobial resistance. In 2011 drug-resistant bacteria. Then in September
the theme of World Health Day was “Antimi- 2014 he issued an executive order on com-
crobial resistance: no action today, no cure to- bating antibiotic-resistant bacteria. In it, he
morrow.” The initiative resulted in a six-point called for the establishment of a “task force for
policy package designed to assist countries combating antibiotic-resistant bacteria...to be
with tools to combat antimicrobial resistance. co-chaired by the secretaries of Defense, Ag-
In summary, the points were as follows: riculture, and [Health and Human Services]”
with the mission of creating a five-year Nation-
• To commit to a comprehensive, financed al Action Plan that would include goals, mile-
national plan with accountability and civil so- stones, and metrics for measuring progress.
ciety engagement;
In March 2015 President Obama urged Con-
• To strengthen surveillance and laboratory gress to double the federal funding available
capacity; for antibiotic resistance surveillance and pre-
vention, bringing the total to more than $1.2
• To ensure uninterrupted access to essen- million. The same month, the White House re-
tial medicines of assured quality; leased the National Action Plan for Combating
Antibiotic-Resistant Bacteria that had been
• To regulate and promote rational use of promised the previous fall. The plan detailed
medicines, including in animal husbandry, five goals: slowing the emergence of drug-
and ensure proper patient care; resistant bacteria, strengthening nationalh e a lt h p o l ic y b r i e f a n t i b i o t ic r e sis ta n c e 4
surveillance efforts, improving rapid diagnos- biotics would be a major blow to the indus-
tic tests for resistant strains of bacteria, pro- try, resulting in sicker animals and inferior
moting research, and fostering collaboration. consumer products. PAMTA was introduced
to Congress in 2007, 2009, 2011, and 2013. It
Under each goal, the action plan lays out key was referred to committee multiple times but
milestones for the next one, three, and five was never heard in the House Committee on
years. For example, the plan calls for routine Energy and Commerce.
reporting of antibiotic use and resistance data
by 95 percent of Medicare-eligible hospitals, The FDA does provide voluntary guidelines
as well as by DOD and VA health care facilities, that will have the effect of regulating anti-
“In general, new by 2020. Over the same time period, the CDC biotic use by producers of poultry, swine, beef
antibiotics are and the FDA will create the repository and da- cattle, and other livestock. The use of medi-
less profitable tabase for resistant bacterial strains and, in cally important antibiotics (as determined by
compared to conjunction with the DOD, will provide them
to diagnostic test manufacturers and research
the FDA) for growth promotion is scheduled
to be phased out by December 2016. The FDA
other types of laboratories, as needed. Using these new sys- says it also inspects the mills where animal
drugs.” tems, the task force has called for the reduc- feed is made but does not examine the feed
tion of inappropriate antibiotic use over the tickets—documents that show why the drugs
next five years by 50 percent in outpatient set- are administered.
tings and by 20 percent in inpatient settings.
In June 2014 the FDA released a progress re-
port on its strategy to promote the judicious
what’s the debate? use of antibiotics in food-producing animals.
Antibiotic Use in Animals According to the report, all twenty-six drug
manufacturers affected by the FDA’s volun-
One portion of the debate surrounding an- tary guidelines agreed to fully engage in the
tibiotic resistance has to do with its implica- strategy by modifying labels so that medically
tions for animal husbandry. The WHO, the important antimicrobials will not be used to
American Medical Association, the Infectious promote growth. At the same time, they will
Disease Society of America, the Consumers incorporate the oversight of a veterinarian for
Union, the Union of Concerned Scientists, and the remaining therapeutic uses of such drugs.
about 450 other organizations support legis-
lation that would eliminate routine antibiotic Additionally, in November 2014 the Pew
use in animal feed and water. Charitable Trusts reviewed the labels of all
287 antibiotic products identified as being af-
Historically, policy attempts to regulate the fected by the guidance and found that eighty-
use of antibiotics in animal feed have not been three of the labels had overlapping growth
successful. In 2007 Rep. Louise Slaughter (D- promotion and prevention dosages.
NY) proposed a bill called the Preservation
of Antibiotics for Medical Treatment Act, or In April 2015 Tyson Foods, the largest poul-
PAMTA, which would require drug manufac- try producer in the United States, announced
turers to prove that the non-therapeutic use of that it would eliminate the use of human anti-
their antibiotics wouldn’t contribute to anti- biotics in its flocks by September 2017.
biotic resistance. This bill would have phased
out the nontherapeutic use of antibiotics in New Drug Development
animal feed and water, prohibit the use of an-
tibiotics in animals that aren’t sick, and make Another major branch of the debate has fo-
it illegal to routinely give animals antibiotics cused on what the government’s role should
for disease prevention. be in incentivizing the development of new
antibacterial drugs. In general, the direction
The bill was supported by medical and sci- of new pharmaceutical research by private
entific experts and opposed by meat industry corporations is driven, at least in part, by the
stakeholders, including the National Beef expectation of return-on-investment. Compa-
Packing Company, the National Pork Produc- nies make money on drugs when they are used
ers Council, the Animal Health Institute, the in high volume, sold at a high price, or both.
American Veterinary Medical Association, the Developing new antibiotics—while medically
National Chicken Council, the National Tur- necessary—does not necessarily lend itself to
key Federation, the Food Marketing Institute, any of these money-making scenarios.
and several major pharmaceutical companies.
The companies argued that phasing out anti-h e a lt h p o l ic y b r i e f a n t i b i o t ic r e sis ta n c e 5
Antibiotics are widely used but have histori- ulation. The medications would need to be la-
cally been fairly inexpensive. In recent years beled clearly for physicians so that they could
US antibiotic prescriptions per capita have effectively weigh the medications’ risks and
declined compared to all prescription drugs benefits as they pertain to particular patients.
(see Exhibit 1). In 2013 antibiotics accounted
for 6.4 percent of all US prescriptions but only Additionally, provisions in the GAIN Act
2.6 percent by value. This discrepancy, paired referenced above help stimulate the develop-
with the medical need for new antibiotics, has ment of new antibiotics. Under the act, certain
prompted some advocates to push for govern- antibacterial or antifungal drugs intended to
ment intervention in the drug approval proc- treat serious or life-threatening infections can
ess specific to antibiotic development. Some be designated as Qualified Infectious Disease
policy makers have suggested allowing for Products (QIDPs), which receive priority re-
higher reimbursement from insurance com- view and are eligible for fast-track designation.
panies as a way to incentivize new treatments.
The act also incentivized new drug devel-
Another approach would be to alter the drug opment by giving drug companies five more
development pathway for antibiotics that ad- years of market exclusivity without generic
dressed an unmet medical need. For drugs competition. As of September 2014 the FDA
that qualify, this could reduce cost barriers to had granted fifty-nine QIDP designations for
get new products to market. In 2013 the FDA thirty-nine different molecules. In February
held a public hearing on a potential pathway 2015 the FDA approved Avycaz, the fifth new
to expedite the approval of critical new drugs, antibacterial drug with the QIDP designation.
including antibiotics needed to treat serious
or life-threatening infections with few or no The GAIN Act has increased drug company
satisfactory treatment options. This Limited interest in developing antibiotics, but some
Population Antibacterial Drug (LPAD) ap- critics say it’s still not enough. In a February
proval pathway would evaluate these drugs 2015 op-ed published in the New York Times,
using smaller trials than traditional drug de- oncologist and University of Pennsylvania
velopment programs. vice provost Ezekiel J. Emanuel suggested
that the US government partner with other
The streamlined LPAD pathway, while po- countries to offer a US$2 billion prize to the
tentially innovative, may come at some cost. first five companies or academic institutions
There would be some uncertainty about poten- to develop and get regulatory approval for a
tial risks based on smaller trials that are less new class of antibiotics. He reasoned that the
able to identify and predict infrequent adverse payment would provide a beneficial return for
events in any statistically significant way. This companies, as well as provide cost savings for
is less of a concern with a limited population the health care system, which he estimated
of patients with serious or life-threatening in- spends about US$20 billion per year on costs
fections and unmet medical needs, but these related to antibiotic resistance.
risks would be of more concern if the drugs
were to be used in a more general patient pop- A recent report released from the UK’s Re-
view on Antimicrobial Resistance (AMR)
exhibit 1 looks specifically at ways to encourage and
improve the development of new antibiotic
Per Capita US Prescriptions, Antibiotic and Total, 2009–13 drugs. The report recommends creating a
global AMR Innovation Fund to boost invest-
1.00 ment in early-stage research and “de-link” a
drug’s profit from its volume in sales.
0.95 13.5
Antibiotic Rx per capita
Other Policy Proposals
Total US Rx per capita
0.90 Antibiotic Rx
Within health care settings and medical
0.85 13.0
practices, efforts to stem antibiotic resistance
Total US Rx
0.80
have focused on more judicious prescribing
policies and infection control. In 2013 the CDC
0.75 12.5 estimated that four out of five Americans are
prescribed antibiotics each year. Part of this
2009 2010 2011 2012 2013
is as a result of physicians’ prescribing anti-
source Kevin Outterson, John H. Powers, Gregory W. Daniel, and Mark B. McClellan, “Repairing the
Broken Market for Antibiotic Innovation,” Health Affairs 34, no. 2 (2015):277–85.h e a lt h p o l ic y b r i e f a n t i b i o t ic r e sis ta n c e 6
biotics defensively, even if their patients most teixobactin that targets polymers that build
likely will not benefit from them. the bacterial cell wall. The drug’s pathway—
examined in mice but not yet in humans—is
Options for curbing this practice have in- similar to vancomycin, another antibiotic of-
cluded incentive payments and feedback sys- ten used as a last-resort treatment for resistant
tems, but these programs can be expensive strains of bacteria such as MRSA. In their pa-
and have had limited success. One technique per, the researchers highlighted how the tech-
that has shown some promise is to educate pa- nology used for this discovery might help lead
tients about the proper use and prescription of to additional drug discoveries.
50
antibiotics. A 2014 study found that a simply
worded poster placed in exam rooms helped While it is tempting to assume that a po-
% of reduce unnecessary antibiotic prescriptions
for respiratory infections during flu season
tential new human antibiotic means that the
pharmaceutical industry’s interest in develop-
antibiotics by approximately 20 percent. ing new antibacterial drugs will spring back
into gear, it’s important to consider that the
The CDC estimates that up to It is not just prescription drugs that have failure rate for antibiotics from early discov-
50 percent of antibiotics are come under stricter scrutiny. In May 2015 ery stage to actual drug approval is 97 percent.
unnecessary or inappropriate as the FDA proposed a rule that would require In general, new antibiotics are less profitable
prescribed. companies that manufacture hand sanitiz- compared to other types of drugs, as their use
ers used in hospital settings to submit new is tightly controlled by hospitals trying to pre-
studies looking at key safety issues, including vent the emergence of new resistant strains,
possible hormonal effects and contributions and yet drug companies are not able to com-
to antibiotic-resistant bacteria. Products that pensate for slow adoption by charging more
could not be proven safe and effective by 2018 because they’d have to compete with inexpen-
would have to be reformulated or removed sive generic antibiotics. In 2011, for example,
from the market. Pfizer, one of the few drug companies to work
on developing new antibiotics, closed its re-
search lab in Connecticut.
what’s next?
There are several potential directions for For health care facilities, life science re-
new antimicrobial drug research and devel- searchers, federal agencies, and local health
opment. Better diagnostic tools could affect officials to meet many of the specific goals
the way antibiotic resistance is detected, di- outlined in the Obama administration’s re-
agnosed, and reported. More rapid tests could cent National Action Plan, they will require
help to prevent overprescription of antibiotics additional resources. To that end, President
and assist with global surveillance measures Obama’s fiscal year 2016 budget proposes to
already emerging as a result of policy goals. nearly double the amount of federal funding
for combating and preventing antibiotic re-
There are also potential developments sistance to more than $1.2 billion. Congress,
for new drugs. Researchers at Northeastern however, is unlikely to support and enact the
University recently published a paper in Na- president’s full budget request. n
ture about a potential new antibiotic calledh e a lt h p o l ic y b r i e f a n t i b i o t ic r e sis ta n c e 7
About Health Policy Briefs
resources
Written by
Teresa Chin
Consulting Editor Antibiotic Resistance Project, GAIN: How a New Law Timothy F. Landers, Bevin Cohen, Thomas E.
Is Stimulating the Development of Antibiotics (Philadel- Wittum, and Elaine L. Larson, “A Review of Antibi-
Editorial review by phia, PA: Pew Charitable Trusts, November 7, 2013). otic Use in Food Animals: Perspective, Policy, and Po-
Robert Guidos
tential,” Public Health Reports 127, no. 1 (2012): 4–22.
Senior Advisor to the Director
Antibiotic Resistance Project, Gaps in FDA’s Antibiot-
Center for Drug Evaluation and Research
ics Policy (Philadelphia, PA: Pew Charitable Trusts, Losee L. Ling, Tanja Schneider, Aaron J. Peoples,
Food and Drug Administration
November 30, 2014). et al., “A New Antibiotic Kills Pathogens without De-
Kevin Outterson tectable Resistance,” Nature 517 (2015): 455–9.
Professor of Law and N. Neal Pike Scholar Carol Cogliani, Herman Goossens, and Christina
in Health and Disability Law Greko, “Restricting Antimicrobial Use in Food Ani- Review on Antimicrobial Resistance, Antimicrobial
Boston University mals: Lessons from Europe,” Microbe 6, no. 6 (2011): Resistance: Tackling a Crisis for the Health and Wealth
Associate Fellow, Chatham House 274–9. of Nations (London, UK: Review on Antimicrobial
Editor in Chief, Journal of Law, Resistance, December 2014).
Medicine and Ethics Nadine Czekalski, Tom Berthold, Serena Caucci,
Andrea Egli, and Helmut Bürgmann, “Increased Lev- Brad Spellberg, Martin Blaser, Robert J. Guidos,
Rachel Zetts
els of Multiresistant Bacteria and Resistance Genes et al., “Combating Antimicrobial Resistance: Policy
Senior Associate, Antibiotic Resistance
after Wastewater Treatment and Their Dissemina- Recommendations to Save Lives,” Clinical Infectious
Project
Pew Charitable Trusts tion into Lake Geneva, Switzerland,” Frontiers in Diseases 52, Suppl 5 (2011): S397–428.
Microbiology 3 (2012):106.
Rob Lott The White House, Executive Order—Combating An-
Deputy Editor Michael A. Jahne, Shane W. Rogers, Ivan P. Rambler, tibiotic-Resistant Bacteria (Washington, DC: White
Health Affairs Edith Holder, and Gina Hayes, “Hierarchal Cluster- House Press Office, September 18, 2014).
ing Yields Insight into Multidrug-Resistant Bacteria
Tracy Gnadinger Isolated from a Cattle Feedlot Wastewater Treatment World Health Organization, Antimicrobial Resistance
Assistant Editor System,” Environmental Monitoring and Assessment (Geneva, Switzerland: World Health Organization,
Health Affairs updated April 2015).
187, no. 1 (2015): 4168.
Health Policy Briefs are produced under
a partnership of Health Affairs and the
Robert Wood Johnson Foundation.
Cite as:
“Health Policy Brief: Antibiotic
Resistance,” Health Affairs,
May 21, 2015.
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