Perspective

The NEW ENGLAND JOURNAL of MEDICINE

n engl j med nejm.org 1
T
wo major ways that modern medicine saves lives
are through antibiotic treatment of severe infec-
tions and the performance of medical and surgical
procedures under the protection of antibiotics. Yet
we have not kept pace with the
ability of many pathogens to de-
velop resistance to antibiotics
that are legacies of the golden era
of antibiotic discovery, the 1930s
to 1960s. We call that period
golden because success seemed
routine then; we call it an era
because it ended. When industry
scientists shifted from making
variants of old drugs to pursuing
fundamentally new drugs with
activity against resistant patho-
gens, they generally failed. Per-
sistent, costly failure to discover
novel antibiotics that would be
destined for short-term use even
if they survived the regulatory
approval process led industry to
change its focus to drugs whose
long-term use prevents or miti-
gates noninfectious diseases. As
people in wealthier regions run
out of effective antibiotics, they
come to share the lot of people
in poorer regions who cant af-
ford them to begin with.
1
At least some clinical isolates
of many pathogenic bacterial spe-
cies Mycobacterium tuberculosis,
Neisseria gonorrhoeae, Enterococcus
faecium, Staphylococcus aureus, Kleb-
siella pneumoniae, Acinetobacter bau-
mannii, Pseudomonas aeruginosa, and
species of enterobacter, salmo-
nella, and shigella are now
resistant to most antibiotics. The
problem seems out of control.
Yet there are reasons for opti-
mism: progress has recently been
made on 4 of 10 key challenges to
ensuring that antibiotics retain an
effective role in medicine.
2
Recognition. Alexander Fleming
and Howard Walter Florey sound-
ed the first warning about anti-
biotic resistance when they ac-
cepted the 1945 Nobel Prize for
the discovery of penicillin.
Physicians and scientists have ex-
panded and expounded the mes-
sage ever since, but it has recently
begun to resonate with the pub-
lic, the press, and leaders in busi-
ness and government.
2
In the past decade, various key
organizations, including the Infec-
tious Diseases Society of America,
the Centers for Disease Control
and Prevention, the World Health
Organization (WHO), and the
World Economic Forum, have
made antibiotic resistance the fo-
cus of highly visible reports, con-
ferences, and actions. This year,
the activity seems to have accel-
Antibiotic Resistance Problems, Progress, and Prospects
Carl Nathan, M.D., and Otto Cars, M.D., Ph.D.
The New England Journal of Medicine
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PERSPECTI VE
n engl j med nejm.org 2
erated. In April, the WHO de-
clared that the problem threat-
ens the achievements of modern
medicine. A post-antibiotic era
in which common infections
and minor injuries can kill is
a very real possibility for the 21st
century. In May, the World
Health Assembly commissioned
the WHO to deliver a global ac-
tion plan on antimicrobial resis-
tance. In June, the British public
voted to dedicate a government-
sponsored 10 million Longitude
Prize to the best solution to the
resistance problem. And in Sep-
tember, the U.S. Presidents
Council of Advisors on Science
and Technology released a report
on antibiotic resistance linked to
an executive order from President
Barack Obama, who directed the
National Security Council to
work with a governmental task
force and a nongovernmental ad-
visory council to develop a na-
tional action plan by February
2015. Among other goals, the
plan will propose implementa-
tion of antibiotic stewardship in
health care facilities and the com-
munity; development of rapid,
point-of-care diagnostics; recruit-
ment of academic and industry
partners to increase the pipeline
of antibiotics, vaccines, and alter-
native approaches; and interna-
tional collaboration for prevention,
surveillance, and control of anti-
biotic resistance.
Partnership. Innovative experi-
ments in publicprivate partner-
ship are under way for antibiotic-
drug discovery. In 2012, the Bill
and Melinda Gates Foundation
expanded its Tuberculosis Drug
Accelerator program to include
multiple drug companies, aca-
demic institutions, a foundation,
and a government laboratory.
Participants pool efforts, assays,
and compounds, aiming to iden-
tify, validate, and inhibit new
targets with new drugs. In 2013,
the U.S. Biomedical Advanced
Research and Development Au-
thority began funding antibiotic
research in industry, and the
European Commission and the
European Federation of Pharma-
ceutical Industries and Associa-
tions launched a partnership for
antibiotic discovery.
Return. The retreat of most
major pharmaceutical companies
from antibiotic research has re-
sulted in little competition in the
development of novel antibiotics
in a market that is currently
worth more than $40 billion an-
nually for drugs that are starting
to fail. Several small companies
seeking to fill the gap have had
new antibiotics approved, and the
worlds fourth-largest drug com-
pany recently announced its re-
turn to the effort. However, ma-
jor disincentives remain, including
the difficulty of conducting large
clinical trials to compare drugs in
patients with antibiotic-resistant
infections.
Prevention. Antibiotics growing
lack of effectiveness has spurred
a resurgence in infection surveil-
lance and control practices; re-
newed efforts in vaccination; and
increased attention to deficiencies
in sanitation. Nonetheless, much
remains to be learned about how
to prevent acquisition and trans-
mission of resistance.
Despite progress on these
fronts, securing a long-term abil-
ity to treat bacterial infections
requires addressing six more
daunting challenges.
3
Leadership. We believe that
sound solutions will require a
global organization with the au-
thority, leadership, and resources
to oversee collaboration of the
health, security, economic, and
development sectors; maintain
global surveillance of antibiotic
resistance; and manage rewards
for developing and conserving
antibiotics.
Rewards. Unless monetary re-
wards are delinked from drug
sales,
4,5
few companies will in-
vest in high-risk programs to de-
velop drugs whose use must be
restricted and which will proba-
bly ultimately lose their clinical
utility. Sales-based compensation
has also supported rampant prof-
iteering through drug dilution,
substandard manufacture, and
counterfeiting, which foster resis-
tance and undermine treatment.
Moreover, if rewards derive from
price and price reflects value, the
prices of new, lifesaving anti-
biotics will preclude access by the
poor. Instead, a new antimicro-
bial oversight agency could admin-
ister a fund that rewards anti-
biotic developers in proportion
to the estimated quality-adjusted
life-years saved creating an in-
centive to expand medically indi-
cated access by keeping prices
close to the cost of production
and distribution. At the same time,
continuing payouts to originators
as long as drugs have clinical
utility would minimize the adverse
effect of conservation on profit-
ability.
Access. The ideal economic mod-
el would enable us to provide ac-
cess to lifesaving antibiotics to
all who need them while restrict-
ing overuse that contributes not
only to resistance, but perhaps
also to epidemic obesity, asthma,
and other disorders. A global fund
could solicit contributions in pro-
portion to countries gross do-
mestic product, but in the short
term, equitable access might re-
quire wealthier countries to sub-
sidize appropriate antibiotic use
in poorer countries.
Conservation through prioritization
of medical use. The current practice
of applying the most antibiotic
tonnage to growth promotion in
Antibiotic Resistance
The New England Journal of Medicine
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PERSPECTI VE
3
food animals and plants is in-
compatible with an expectation
that antibiotics will cure life-
threatening infections. We be-
lieve that governments worldwide
should impose restraints like
those in force in the European
Union, which have not reduced
food production.
Conservation through prescription
tailored to diagnosis. Ideally, tech-
nological advances in point-of-
care diagnostics would enable
prescribers to avoid dispensing
antibiotics for viral infections and
fevers of unknown origin. Better
diagnostics could allow prescrip-
tions to be tailored narrowly to a
pathogens susceptibilities. Adop-
tion of such technology would
require physician education, suit-
able reimbursement, and docu-
mentation of outcomes.
Conservation through controlled
access. In wealthier countries, all
health care facilities should insti-
tute antibiotic-stewardship pro-
grams. In poorer countries, de-
spite the need to expand access
to effective antibiotics, theres
also an urgent need to reduce in-
appropriate use fostered by mis-
aligned financial incentives for
providers and by over-the-counter
access. Given the ease with which
antibiotic resistance spreads, we
all share an interest in helping
poorer countries build sufficient
infrastructure to allow medical
personnel to distinguish among
pathogens before antibiotics are
prescribed.
These issues concern every-
one. Military leaders dont want
their personnel devastated by in-
fections associated with wounds
or close quarters. Drug-company
leaders realize that the public ex-
pects their firms to produce life-
saving medicines and blames
them when they dont an atti-
tude shared in countries whose
developing economies offer com-
panies their best prospects for
growth. But physicians may care
about this problem most pas-
sionately, for they must tell more
and more families that there is
no hope. Doctors can act not just
individually and medically, but
also collectively and civically, to
persuade elected officials to re-
spond to expert panels recom-
mendations and national leaders
directives with the legislation, ap-
propriation, regulation, enforce-
ment, and cooperation needed to
ensure access to these life-saving
drugs.
Disclosure forms provided by the authors
are available with the full text of this article
at NEJM.org.
From the Department of Microbiology and
Immunology, Weill Cornell Medical College,
New York (C.N.); and the Department of
Medical Sciences, Uppsala University,
Uppsala, Sweden (O.C.).
This article was published on October 1,
2014, at NEJM.org.
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2. Cars O. Securing access to effective anti-
biotics for current and future generations:
whose responsibility? Ups J Med Sci 2014;
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3. Nathan C. Fresh approaches to anti-infec-
tive therapies. Sci Transl Med 2012;4:140sr2.
4. Nathan C. Aligning pharmaceutical inno-
vation with medical need. Nat Med 2007;
13:304-8.
5. So AD, Ruiz-Esparza Q, Gupta N, Cars O.
3Rs for innovating novel antibiotics: sharing
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e1782.
DOI: 10.1056/NEJMp1408040
Copyright 2014 Massachusetts Medical Society.
Antibiotic Resistance
The New England Journal of Medicine
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Copyright 2014 Massachusetts Medical Society. All rights reserved.