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TACKLING

ANTIBIOTIC
RESISTANCE:
WHAT DO WE
KNOW

AND

WHAT

DO WE NEED TO
KNOW?
RAMANAN
L AXMINARAYAN

By now, anyone who has not heard that


our antibiotics no longer work as well as
they used to probably has not picked up a
newspaper or magazine in years. Why?
you may ask. Rewind to when antibiotics
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diseases just 72 years ago. They were
miracle drugs that were able to travel
through the body and kill living bacterial
cells while leaving human cells unharmed.
Even back then, Alexander Fleming, who
discovered penicillin as a result of an
experiment gone bad, predicted that, over
time, the constant selection pressure created
by the use of penicillin and other antibiotics
would give rise to new strains that would
be untreatable with the use of antibiotics.
Resistance had emerged even before he had
collected on his Nobel Prize and has been
increasing ever since.

CULTURES Vol 2, Issue 2 Page 51

Changing behavior is our best


bet to reduce the threat of
resistance. A recent Lancet
Infectious Diseases study showed
that, in a set of six premier U.S.
hospitals, one-third of antibiotic
prescriptions were given in
instances where there was no
sign of infection. Campaigns have
been shown to work in reducing
the demand for antibiotics.
Annual mass media campaigns
in Belgium reduced antibiotic
prescriptions by 36% between
1999 to 2000 and 2006 to 2007.
It is unclear whether such
campaigns could work in low- and
middle-income countries and if
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the campaigns have come to an
end. However, behavior change
problems have been encountered
Scanning electron micrograph
before in contexts as varied as
of methicillin-resistant
smoking in public places, drunk
Staphylococcus aureus
surrounded by debris (above)
driving, and driving without
and killing and escaping from a
wearing a seatbelt. Those were
human white blood cell (below).
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in which to change behavior, but,
in each instance, change was accomplished through
a lengthy process of social education. In the case of
antibiotic use, we have gaps in our understanding of
how to nudge doctors to prescribe less and patients to
demand fewer antibiotics.
The actual level of resistance is highly variable across
time and geography. Much of what we know about
resistance levels around the world comes from tertiary
hospitals that are likely to cater to the sickest patients
and therefore present the greatest level of resistance.
If we inadvertently convey an incorrect message
that most antibiotics are no longer working, we run
the risk of physicians prescribing unnecessary
antibiotics to reduce the chance that a patient does
Page 52 Across the Divide Laxminarayan

not fail treatment with the more readily available first- and
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the treatment of resistance, without inadvertently making the
problem worse by pushing doctors and patients into using
unnecessarily powerful antibiotics.
A third unknown relates to how to price antibiotics. If priced too high,
they become inaccessible to those who need them. If priced too low,
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price of antibiotics has to be considered in arriving at a socially
optimal policy for antibiotic pricing.

TOP: Images from Flemings original penicillin article in 1929.


BOTTOM: Laxminarayan gives a TED Talk in September 2014.

CULTURES Vol 2, Issue 2 Page 53

The CDC conservatively


estimates that at least
23,000 people died of
drug-resistant infections
last year in the U.S.
alone. Meanwhile, few
companies are in the
antibiotics business,
having moved onto
chronic diseases where
there is much more
money to be made.
RAMANAN L AXMINARAYAN

A fourth unknown relates to the focus on new drug


development. Although all agree that new antibiotic
classes are needed, there is much that could be done
by way of innovation involving combination therapies,
such as amoxicillin-clavulanate, that target both essential
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could repurpose old drugs to optimize dosing levels and
the duration and route of administration and leverage
pharmacokinetics and pharmacodynamics to identify
promising combination drug therapies.
For example, optimizing the dosing
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the 1950s, can reduce toxicity and
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Today,
bacterial
infections
like
pneumonia and gonorrhea, which
could be treated with penicillin for
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that cost hundreds of dollars. The
CHECK OUT
CDC conservatively estimates that
at least 23,000 people died of drugRAMANAN
resistant infections last year in the
L AXMINARAYAN
U.S. alone. Meanwhile, few companies
GIVING A TED TALK
are in the antibiotics business, having
THE COMING CRISIS
moved onto chronic diseases where
IN ANTIBIOTICS IN
there is much more money to be
SEPTEMBER 2014.
made. But that does not make sense.
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Shouldnt pharmaceutical companies
be interested in selling antibiotics in a
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world with more resistance and where
people are dying of infectious diseases?
After all, if payers or individuals would
pay tens of thousands of dollars for a new cancer drug
that extends life by two months, they should be able to
pay a few hundred dollars for a new antibiotic that can
extend life by decades? Turns out that few payers would
approve such an expensive antibiotic because of fear
that it would be overused and bankrupt them. The most
expensive antibiotic that Medicare will pay for is Synercid
at a cost of $236 per injection. In comparison, the most
expensive cancer drugs cost over $50,000 per month
and extend life by just a few months. Another issue is
CULTURES Vol 2, Issue 2 Page 55

that only a trained oncologist can prescribe anticancer drugs, but


any GP (general practitioner) can prescribe antibiotics. It is the
medicine that most doctors think they know how to use but that
few appreciate the value of.
It is unclear why we should expect new antibiotics to be cheap. After
all, we have exhausted the lowest hanging fruit of antibiotics that were
easily, even serendipitously discovered. Inevitably, newer antibiotics
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way that oil costs a lot more money now than thirty years ago. This,
by itself, is not a bad thing. Just as
the rising price of oil is a signal to
us that we should not count on
oil lasting forever, the rising price
of new antibiotics is a signal that
we should be more careful about
how we use the drugs we have.
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antibiotics, but the same is true for
expensive gene therapy or cancer
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ensuring that no one dies because
of a lack of access to medicines that
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In 2014, the federal Biomedical
Advanced
Research
and
Development Authority (BARDA)
agreed to pay GlaxoSmithKline
$200 million for work on new
antibiotics, with no guarantee of
success. It is unclear if this either
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solves the problem of a depleted
the discovery of penicillin in 1929.
pipeline
or
of
incentivizing
conservation. Even if there were a new antibiotic as a result of the
process, what incentive would anyone have for conserving the ones
we have if we thought the government was going to step in each time
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oil wells to keep the price of oil low. So why would we make that
argument in the case of antibiotics? Instead, the government should
Page 56 Across the Divide Laxminarayan

aim to make sure that reimbursement through Medicare and


Medicaid is appropriate to the cost of new antibiotics, make sure
that those new drugs are used appropriately when taxpayers pay
for them, and get out of the way.
Despite these unknowns, we know enough to slow down the rate
at which antibiotic resistance has emerged and spread. Lack of
evidence should not be a reason to improve how antibiotics are
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these gaps in our understanding is a clear need.

RAMANAN L AXMINARAYAN
Ramanan Laxminarayan is director and senior fellow at the Center
for Disease Dynamics, Economics & Policy, and senior research
scholar and lecturer at Princeton University. Through his work on
the Extending the Cure Project in the United States and the Global
Antibiotic Resistance Partnership, he has worked to improve the
understanding of drug resistance as a problem of managing a
shared global resource. Laxminarayan is a series editor of the
Disease Control Priorities in Developing Countries, 3rd edition.
Laxminarayan has worked with the World Health Organization
(WHO) and the World Bank on evaluating malaria treatment policy,
vaccination strategies, the economic burden of tuberculosis, and
control of noncommunicable diseases. He has served on a number
of advisory committees at WHO, the Centers for Disease Control and
Prevention, and the Institute of Medicine. In 2003 to 2004, he served
on the National Academy of Science/Institute of
Medicine Committee on the Economics of
Antimalarial Drugs and subsequently
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Medicines Facility for malaria, a
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resistance and improve access to
antimalarial drugs. In 2012, he created
the Immunization Technical Support
Unit in India, which has been credited with
helping to rapidly improve immunization
coverage in that country.

CULTURES Vol 2, Issue 2 Page 57