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Johns Hopkins University School of Medicine, Baltimore, Maryland; 2Department of Medical Education, Providence Portland Medical Center, Portland,
Oregon; and 3Liu Vaccine Center, Torrance, California
Keywords.
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Antibiotic resistance is a well-acknowledged crisis with no clearly dened comprehensive, national corrective
plan. We propose a number of interventions that, collectively, could make a large difference. These include
collection of data to inform decisions, efforts to reduce antibiotic abuse in people and animals, great emphasis on antibiotic stewardship, performance incentives, optimal use of newer diagnostics, better support for
clinical and basic resistance-related research, and novel methods to foster new antibiotic development.
antibiotic resistance; antibiotic salvage; European Union, stewardship; molecular diagnostics.
Received 9 November 2012; accepted 29 January 2013; electronically published 12 February 2013.
Correspondence: John G. Bartlett, MD, Division of Infectious Diseases, Johns
Hopkins University School of Medicine, 1830 E Monument St, Rm 447, Baltimore,
MD 21205 (jb@jhmi.edu).
Clinical Infectious Diseases 2013;56(10):144550
The Author 2013. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/cid/cit070
1445
Pathogen
Country
Antibiotic
Usagea
Rate of
Resistance
Klebsiellab
Greece
The Netherlands
38
11
38%
0.20%
MRSAc
Greece
38
51%
The Netherlands
11
1.60%
Rates are for 20102011, for intensive care units in the Netherlands [19] and
Greece [20].
Prevent selected nosocomial infections using an established systematic implementation plan based on
precedent;
Aggressively promote antibiotic stewardship;
Promote use of new diagnostics with emphasis on pointof-care molecular methods;
Reduce the Food and Drug Administration (FDA) antibiotic barrier; and
Facilitate publicprivate partnerships for antibiotic
development.
1446
Bartlett et al
on antibiotic use and resistance more than 15 years ago. Antibiotic use is reported as daily drug dose (DDD) per 1000 inhabitants per day according to pharmacy records, and
resistance data are reported by sentinel laboratories using standard methods. The result is a living record of country-specic
data for antibiotic consumption and resistance proles by microbial species, drug, and date for 26 countries [18]. The
United States has no comparable data system, but the European Union record suggests we should.
The correlation between antibiotic consumption and resistance is illustrated by comparing data for methicillin-resistant
Staphylococcus aureus (MRSA) and carbapenemase-producing
Klebsiella for the Netherlands versus Greece, 2 countries that are
at the low versus high end, respectively, of per capita antibiotic
use in the EU database (Table 2) [19, 20]. The difference is expected, but the magnitude is dramatic. The obvious result is the
relative safety and limited need for new antibiotics in hospitals
in the Netherlands, presumably reecting policies and practices
that foster prudent antibiotic use and infection control [16, 19].
An example of the use of EU data is France, which had
high rates of multidrug-resistant Streptococcus pneumoniae in
2002 and also had the highest rate of antibiotic use in the European Union (36.5 DDD/1000 inhabitants) [21]. This led to
an ambitious nationwide program directed to both providers
and consumers. The results showed a 26% nationwide decrease in antibiotic prescriptions during the study period [21],
and a follow-up report of the global antibiotic market showed
that France is the country with the greatest reduction in antibiotic prescriptions in the worlda decrease of 21% from
2000 to 2009 [5].
The European Union systematically assesses antibiotic
usage and resistance data to guide interventions to effect systematic change [11, 18, 19] and accomplishes this despite great
diversity in resources, language, and politics (http://www.ema.
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Bartlett et al
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signed into law as part of the FDA Safety and Innovation Act.
GAIN is an important rst step, but careful analyses concluded that these incentives are not strong enough to substantively
alter the NPV of antibiotics, so more is needed [38].
Publicprivate partnerships (PPPs) are an alternative potentially important resource to address the antibiotic market
failure. US HHS Secretary Kathleen Sebelius has written that
PPPs are considered critical to overcome the chokepoints in
our medical pipelines [39]. PPPs may consist of nonprot
corporations funded by both public and private revenues, such
as the Global Alliance for TB Drug Development. The Global
Alliance recently successfully developed a novel drug for tuberculosis (PA-824, a nitroimidazole) through phase II clinical
trials in partnership with Novartis, academic centers, and the
National Institute for Allergy and Infectious Diseases (NIAID).
PPPs may also consist of government grants, contracts, or investments in for-prot drug development, akin to the model by
which the Department of Defense offsets research and development costs for new military technologies. The US government
has established such PPP programs, for example, at the Biomedical Advanced Research and Development Authority (BARDA).
BARDA has already awarded contracts totaling well over $150
million to facilitate development of candidate antibiotics such as
PT 434 and GSK 225152 that have activity against highly resistant gram-negative bacilli. Another example is the development
by the NIAID of a Clinical Research Network on Antibacterial
Resistance slated to start in 2014 [40]. This network of collaborating clinical centers modeled after the AIDS Clinical Trial
Group could be the foundation of national data for antibiotic
resistance, antibiotic usage, antibiotic stewardship, and infection
prevention, as well as antibiotic trials. This new program is
welcome, although, given the magnitude of the resistance
problem, the level of National Institutes of Health funding for
this network and the related resistance issues are concerning.
In summary, bacterial resistance now threatens the extraordinary health benets achieved with antibiotics. Resistance is a
global crisis reecting the extensive use of these drugs and the
failure of pharmaceutical companies to address the challenge.
This review presents a bundle of methods to address the antibiotic resistance issue with 3 emphasis areas: to identify priorities, reduce antibiotic consumption, and stimulate new
product development. Nearly all recommendations have a scientic foundation, precedent, and demonstrated impact.
Note
Potential conicts of interest. J. G. B. has received payment for consultation or honoraria from Epocrates, Medscape, and Medicine. B. S. has
received institutional grant support from Cubist, Pzer, Eisai, and BristolMyers Squibb, and has received payment for consultation or honoraria
from GlaxoSmithKline, Pzer, Basilea, The Medicines Company, Achaogen, Eisai, Meiji, Polymedix, Cardeas, Afnium, and Adenium. D. G.
reports no potential conicts.
1449
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All authors have submitted the ICMJE Form for Disclosure of Potential
Conicts of Interest. Conicts that the editors consider relevant to the
content of the manuscript have been disclosed.
20.
1. Fleming A. Penicillins nder assays its future. New York Times 1945; 21.
2. The evolving threat of antimicrobial resistance: options for action.
Geneva, Switzerland: World Health Organization, 2012. ISBN:
9789241503181.
3. Infectious Diseases Society of America. The 1020 Initiative: pursuing
a global commitment to develop 10 new antibacterial drugs by 2020.
Clin Infect Dis 2010; 50:1081.
4. US Food and Drug Administration. 2010 summary report on antimicrobials sold or distributed for use in food producing animals, 2011.
Available at: http://www.fda.gov/downloads/ForIndustry/UserFees/
AnimalDrugUserFeeActADUFA/M277657.pdf. Accessed 17 February
2012.
5. Hamad B. The antibiotics market. Nat Rev Drug Discov 2010; 9:675.
6. Sharma P, Towse A. New drugs to tackle antimicrobial resistance:
analysis of EU policy options. London: Ofce of Health Economics.
Available at: http://www.ohe./org/publications/article/new-drugs-totackle-2012 resistance-5.cfm. Accessed 5 July 2012.
7. Bartlett JG. Diagnostic tests for agents of community-acquired pneumonia. Clin Infect Dis 2011; 52(suppl 4):S296304.
8. Johansson N, Kalin M, Tiveljung-Lindell A, Giske CG, Hedlund J. Etiology of community-acquired pneumonia: increased microbiological
yield with new diagnostic methods. Clin Infect Dis 2010; 50:2029.
9. Centers for Disease Control and Prevention . Vital signs: central line
associated blood stream infectionsUnited States, 2001, 2008, and
2009. MMWR Morb Mortal Wkly Rep 2011; 60:2438.
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11. Watson R. Europe launches 12 point plan to tackle antimicrobial resistance. BMJ 2011; 343:d7528.
12. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs. 15 days of
antibiotic therapy for ventilator-associated pneumonia in adults: a
randomized trial. JAMA 2003; 209:258898.
13. Sandberg T, Skoog G, Hermansson AB, et al. Ciprooxacin for 7 days
versus 14 days for women with acute pyelonephritis: a randomized,
open-label and double blind placebo controlled, non-inferiority trial.
Lancet 2012; 380:484.
14. Peltola H, Pkknen M, Kallio MJ, Osteomyelitis-Septic Arthritis
Study Group. Short-versus long term antimicrobial treatment for
acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culture-positive cases. Pediatr Infect Dis J 2010;
29:11238.
15. el Moussaoui R, de Borgie CA, van den Broek P, et al. Effectiveness of
discontinuing antibiotic treatment after three days versus eight days in
mild to moderate-severe community acquired pneumonia: randomized, double blind study. BMJ 2006; 332:1355.
16. van Cleef B, Kluytmans J, Bentheu B, et al. Cross border comparison
of MRSA bacteremia between the Netherlands and North RhineWestphalia (Germany): a cross sectional study. PloS One 2012; 7:
e42787.
17. Tang H, Huang T, Jing J, Shen H, Cui W. Effect of procalcitoninguided treatment in patients with infections: a systematic review and
meta-analysis. Infection 2009; 37:497507.
18. Ansari F, Molana H, Goossens H, Davey P. ESAC II Hospital Care
Study Group. Development of standardized methods for analysis of
changes in antibacterial use in hospitals from 18 European countries:
the European Surveillance of Antimicrobial Consumption (ESAC) longitudinal survey, 200006. J Antimicrob Chemother 2010; 65:268591.
19. National Institute for Public Health and the Environment; Ministry of
Health, Welfare and Sport. NETHMAP 2011: consumption of
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