VIEWPOINTS

Seven Ways to Preserve the Miracle of Antibiotics

John G. Bartlett,1 David N. Gilbert,2 and Brad Spellberg3
1

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.

Downloaded from http://cid.oxfordjournals.org/ at Universidade Federal do Rio de Janeiro on April 29, 2013

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.

Antibiotics are a true miracle of modern medicine.

However, in reference to penicillin, the drug he discovered, Fleming gave warning in 1946 [1] that
the public will demand [the drug and] then will
begin an era of abuses. The microbes are educated
to resist penicillin and a host of penicillin-fast organisms is bred out which can be passed to other individuals and perhaps from there to others until they
reach someone who gets a septicemia or a pneumonia which penicillin cannot save. In such a case the
thoughtless person playing with penicillin treatment
is morally responsible for the death of the man who
nally succumbs to infection with the penicillin-resistant organism. I hope the evil can be averted.
Unfortunately, Flemings warning was unheeded, so
this miracle of antibiotics is now endangered owing to
the rapid escalation of antibiotic resistance combined
with the equally rapid decline in discovery and development of new antibiotics.
This is now considered a global health crisis [2],
and the reason is not difcult to understand.

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

Resistance within all microbial classes continues to

grow by natural evolution driven by massive use of
agents that apply selective antimicrobial pressure.
Pharmaceutical development that previously kept us
ahead of resistance is now stalled due to economic and
regulatory barriers. Fifteen of 18 large pharmaceutical
companies have totally left the antibiotic eld, and
there has been no new class of antibiotics for gramnegative bacilli in 4 decades; only 2 drugs with new
microbial targets (linezolid and daptomycin) have
been introduced since 1998 [3]. The pipeline is sparse,
the problem is global, and the prognosis is poor.
It is our impression that the potential for antibiotic
abuse and resistance in the United States is potentially
catastrophic. But it also seems clear that we could do
much better with a bundled program with interventions that have established merit. These are particularly attractive in the era of healthcare reform, which
prioritizes saving lives and saving money, as the cost
and consequences of antibiotic resistance are enormous. What follows is not an in-depth review, but
rather a summary of some major, sometimes humbling, relevant observations (Table 1) [417], with 7
major interventions that collectively address the multitude of contributing factors.
Our proposed antibiotic salvage bundle would
include the following steps:
Establish a US database for antibiotic use and resistance comparable to that of the European Union;
Restrict use of antibiotics in agriculture;

Seven Ways to Preserve Antibiotics

CID 2013:56 (15 May)

1445

Table 1. Compelling Issues From Diverse Sources Indicating

the Magnitude of the Antibiotic Challenge and Opportunities in
the United States

Table 2. Antibiotic Use and Antibiotic Resistance Rates for

Methicillin-Resistant Staphylococcus aureus and CarbapenemaseProducing Klebsiella Bacteremia Isolates

Eighty percent of antibiotics sold in the US are for use in

animals, primarily for growth promotion and infection
prophylaxis, without adequate data supporting efficacy [4].

Pathogen

Country

Antibiotic
Usagea

Rate of
Resistance

Klebsiellab

Greece
The Netherlands

38
11

38%
0.20%

It is estimated that the cost of antibiotic resistance adjusted for

population is 41-fold greater in the US because of greater
frequency of resistance as compared to the EU [6].

MRSAc

Greece

38

51%

The Netherlands

11

1.60%

A pathogen is defined in about 7.6% of US patients

hospitalized with community-acquired pneumonia [7],
compared to up to 89% in other systems using advanced
diagnostic methods [7, 8].

Rates are for 20102011, for intensive care units in the Netherlands [19] and
Greece [20].

It is estimated that use of the bundle to prevent central line

bacteremia could save approximately 18 000 lives and $1.8
billion annually in the US [9].

Bacteremic Klebsiella: rate with carbapenemase-producing strains.

MRSA relative to all S. aureus isolates.

The US accounts for 4.6% of the global population and 46% of

the global antibiotics market [5].

An analysis by the Office of Health Economics in London

calculated that, based on the cost of development and
anticipated return, the current net value of new antibiotics
is $50 million compared to +$1 billion for a neuromuscular
disease [11].
Review of controlled trials for 8 bacterial infections showed that
short courses were therapeutically equivalent to standard
courses [1215].
The risk of nosocomial MRSA bacteremia is approximately 49
times greater with admission to a hospital in the US compared
to hospitals in the Netherlands [16].
A Cochrane meta-analysis suggests that use of procalcitonin
could reduce antibiotic consumption in hospitalized patients with
bacterial infections at diverse anatomical sites by 51% [17].
There have been no new antimicrobial classes for gram-negative
bacilli in the past 40 years, and 15 of the 18 major
pharmaceutical suppliers of antibiotics have now left the
field [3].
Abbreviations: EU, European Union; MRSA, methicillin-resistant Staphylococcus aureus; US, United States.

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.

LESSONS FROM THE EUROPEAN UNION TO

DEFINE AND IMPLEMENT PRIORITIES
The European Union (EU) recognized the impending crisis of
antibiotic resistance and established methods for surveillance

1446

CID 2013:56 (15 May)

Bartlett et al

Daily drug dose per 1000 inhabitants.

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.

Downloaded from http://cid.oxfordjournals.org/ at Universidade Federal do Rio de Janeiro on April 29, 2013

There is a need for more effective consumer education to

counter widespread misconceptions such as Finally, over that
cold. Thank God for Z-Pak (Twitter850 375 followers) [10].

Abbreviation: MRSA, methicillin-resistant Staphylococcus aureus.

ADDRESSING ANTIBIOTIC ABUSE IN FARM

ANIMALS
An astonishing 80% of all antibiotics sold in the United States
are administered to food animals, primarily for growth promotion and infection prophylaxis [4, 22]. There is good evidence that this practice has consequences to human health
and has no clear benet to farmers, although quantitation of
this effect is not possible due to the enormity of the dispersal
area from run-off and other sources of environmental contamination. [23]. The direct effect was noted >35 years ago, with
high rates of antibiotic resistance in the intestinal ora of farm
animals and farmers [18], and more recently with molecular
methods that show that resistant bacteria in farm animals do
reach consumers in meat products [24]. The indirect impact is
supported by observations that up to 90% of antibiotics given
to animals are excreted in urine and stool and then widely
dispersed through fertilizer, surface runoff, and groundwater,
with a profound impact on the environmental microbiome [24].
Country-specic bans on antibiotic abuse in farm animals in
the European Union have been accompanied by signicant declines in antibiotic resistance in humans and animals without
documented harm to humans or animals [23]. The European
Union has recently requested all member states to require antibiotic prescriptions for all antibiotic use in farm animals [11].
Similar restrictions are proposed by the Institute of Medicine
in the United States and by the World Health Organization
[2]. The FDA has recently announced a ban on cephalosporins for growth promotion in certain livestock. A more expansive ban of nearly all antibiotic use for growth promotion is
included in the proposed legislation known as the Preservation
of Antibiotics for Medical Treatment Act (PAMTA; hppt://
www.louise.house.gov/index.php option=com content&id=1315&
ltemid=38). Similarly, new legislation known as the Delivering Antibiotic Transparency in Animals (DATA) Act

(http://waxman.house.gov/press-release/rep-waxman-introducelegislation-monitor-antibiotic-use-animals) would require public

reporting of types and amounts of antibiotics administered to
feed animals, including via feed mills. Both DATA and
PAMTA should be passed.
METHODS TO IMPLEMENT PREVENTION OF
NOSOCOMIAL INFECTIONS
The term implementation as used here refers to the transfer of
scientic advances into practice. The sequence of events for
reducing the frequency of central line bacteremia (CLB) illustrates the concept: National data for CLB in US hospitals in
2002 showed approximately 80 000 cases per year with 28 000
deaths and $45 000 per case in healthcare costs [25]. A 5-step
bundle to prevent CLB was developed and pilot tested to establish efcacy, then tested in a controlled trial in 103 intensive care units in Michigan; the Michigan CLB rates fell from
7.7 to 1.4 per 1000 catheter-days [25]. The CLB prevention
bundle was then adopted as a priority by the US Department
of Health and Human Services (HHS). Blue Cross/Blue Shield
provided nancial rewards for adoption of the bundle; LeapFrog allocated credit; and the Joint Commission on Hospital
Accreditation endorsed the bundle. The CDC then showed the
CLB bundle to be effective in its sentinel hospital network,
leading Dr Arjun Srinivasan, Director of Antibiotic Resistance
at the CDC, to state that if all hospitals in the United States
used the CLB bundle, it would potentially save 18 000 lives
and $1.8 billion annually [9].
The unique feature of this sequence is the efcient transition from a well-validated clinical trial data to broad-scale implementation [26]. The key issue was not the publication to
validate the science, but the endorsement by organizations
that fund and regulate medicine, leading to a policy of nancial penalties to hospitals for failure to reduce CLB rates by
50% [27]. Note that there is now new emphasis to reduce rates
of multiple common nosocomial infections including Clostridium difcileassociated diarrhea, ventilator-associated pneumonia, catheter-associated urinary tract infects, selected
surgical site infections, and MRSA bacteremia [27].
STEWARDSHIP TO IMPROVE HOSPITAL-BASED
ANTIBIOTIC USE
Hospitals are a centerpiece for resistance, reecting the clustering of highly vulnerable patients, extensive use of invasive
procedures, and high rates of antibiotic use. In the United
States, the result is a nosocomial environmental resistome
that is implicated in an estimated excess cost of $18 000
$29 000 per infected patient [28]. The ability to better control
this paradoxical tragedy of the healthcare system is well

Seven Ways to Preserve Antibiotics

CID 2013:56 (15 May)

1447

Downloaded from http://cid.oxfordjournals.org/ at Universidade Federal do Rio de Janeiro on April 29, 2013

europa.eu). The United States has a number of surveillance

systems in place that provide relevant data, but nothing that is
nearly as comprehensive or effective as the EU system. The
Centers for Disease Control and Prevention (CDC) has initiated a plan that addresses some of these issues, but the lack of
incentives from credentialing agencies such as The Joint Commission (a nonprot organization that accredits and certies
healthcare organizations and programs in the United States)
or funding agencies such as the Centers for Medicare and
Medicaid Services are likely to limit use. It seems unacceptable
and embarrassing that the United States at present does not
have the necessary support to implement this plan. The Strategies to Address Antimicrobial Resistance Act was introduced
to Congress nearly 6 years ago to address this need but has
never come to a vote. It should be passed.

illustrated by the strong correlation between antibiotic use and

resistance, reecting the need for stewardship and infection
control measures, as shown by the dramatic differences within
the European Union [19, 20] (Table 2).
Hospital-based antibiotic stewardship programs are critical
to improve antibiotic decisions. A review of 24 reports considered to be of high quality (19962010) showed that stewardship programs achieved signicant reductions in antibiotic use
(11%38% reduction in DDD/1000 patient-days), including
signicant reductions in total antibiotic consumption, duration, and inappropriate use [29]. Hospital-based interventions
with substantial potential or documented benets include the
following:

1448

The intravenous to oral switch that reduces vascular line

sepsis risk and hastens discharge with agents appropriate
for oral use, including uoroquinolones, metronidazole,
clindamycin, linezolid, uconazole, and azithromycin,
will be facilitated.
Intensive care units (ICUs) need to be an area of focused
attention, as shown by a review of 2000 consecutive ICU
patients from a large academic center in which 655 patients (33%) had a nosocomial infection including 169
(26%) who received inappropriate antibiotics with a 4.26fold increase in mortality [29]. A recent report illustrates
the central role of the ICU in a hospital-wide outbreak of
a carbapenemase-producing Klebsiella pneumoniae [30].
A potentially important method to reduce unnecessary
antibiotic exposure is short courses. Multiple controlled
trials including 4 Cochrane Library reviews showed that a
short course was uniformly equivalent to standard duration including 8 days for ventilator-associated pneumonia [12], 7 days for pyelonephritis [13], 10 days for septic
arthritis [14], and 3 days for community-acquired pneumonia (CAP) [15].
Procalcitonin levels reect bacterial replication [17] and
have been extensively tested to facilitate decisions of when
to use or stop antibacterials. A meta-analysis of 7 randomized controlled trials with 1458 patients showed that
procalcitonin-guided decisions reduced total antibiotic
use by 51% without altering outcome [17].
Optimal dosing of antibiotics includes tactics that are
uncommon in practice but improve outcome such as
once-daily aminoglycosides and uoroquinolones or by
prolonged intravenous infusions of -lactams [31]. Increased minimum inhibitory concentrations of MRSA has
forced new dosing recommendations that target trough
levels and require broad-scale reeducation on use of the
most frequently used antibiotic in US hospitals. Colistin is
an example of a drug now in relatively common use
despite limited modern pharmacologic data; recent reviews

CID 2013:56 (15 May)

Bartlett et al

Hence, there is a compelling need for antibiotic stewardship

programs to preserve and properly use existing antibiotics.
Antibiotic stewardship is the common denominator for these
diverse and complex interventions that have established merit,
but implementation of effective stewardship programs is unlikely without incentives from credentialing agencies or
funding agencies, which are currently lacking.
AVOID INAPPROPRIATE ANTIBACTERIAL USE
FOR VIRAL INFECTIONS
Surveys indicate that 40%75% of adults and children who
seek care for viral respiratory tract infections are treated with
antibacterial agents. Consumer demand is cited as an important factor, suggesting that this a combined consumer and
provider education challenge. A 2005 Cochrane review [33] of
39 relevant publications concluded that the only intervention
with effect size sufcient to impact bacterial resistance was
delayed prescription, meaning that antibiotic prescriptions
are to be lled a few days later if symptoms do not improve.
This tactic achieves patient satisfaction and prevents abuse
because viral respiratory tract infections usually improve in
the designated time frame. The Cochrane review noted that lectures, meetings, and printed materials for either consumers or
providers had minimal impact [33], although some combinations have been successful, such as the previously described campaign directed to both consumers and providers in France [21].
DIAGNOSTIC METHODS THAT CAN
TRANSFORM THE MANAGEMENT OF
INFECTIOUS DISEASES
Contemporary clinical microbiology is based on a 150-yearold standard with culture of organisms on seaweed extract (ie,
agar). We are in the midst of a transformation where microbiology diagnostics are based on the detection of the pathogens
unique nucleic acid or biochemical composition. Recently introduced methods can be target-specic, such as polymerase
chain reaction (PCR) methods to detect a single microbe such
as MRSA or to detect 17 respiratory tract viruses or a resistance mechanism [34]. Applications anticipated in the near
future include the PLEX-ID instrument that can detect and
identify >5400 unique microbes within hours and was used to
detect and then follow evolution of the 2009 pandemic H1N1
inuenza strain [35].
Most antibiotic orders are empiric, but molecular diagnostics offer the promise of rapid, even point-of-care, detection of
specic microbes to permit more immediate pathogen-specic

Downloaded from http://cid.oxfordjournals.org/ at Universidade Federal do Rio de Janeiro on April 29, 2013

show substantial erroneous dosing directions in the package

insert [32].

METHODS TO PROMOTE ANTIBIOTIC

DEVELOPMENT
In the United States, the lack of clear, feasible clinical trial
pathways for the regulatory evaluation of candidate antibiotics
has greatly exacerbated the antibiotic market failure. Meanwhile, the European Medicines Agency has recently released a
broad regulatory guidance document that facilitates the feasibility of antibiotic clinical trials [11]. The Infectious Diseases
Society of America has recently proposed a new regulatory
pathway, limited-population antibiotic drug mechanism, to facilitate the development and availability of critically needed
antibiotics, and FDA ofcials have spoken publicly about the
merits of the idea [37]. This would enable substantially
smaller clinical trials, which would be less expensive, take less
time, and address a critical need. In return for approval based
on efcacy in small clinical trials, the antibiotic would receive
a very narrow indication focused only on the high-risk patients for whom benets were shown to outweigh risks.
The FDA may address the regulatory issues that have intimidated antibiotic development, but there is also the reality that
antibiotic development is no longer an economically wise investment. The nancial challenges for antibiotic development
are illustrated by an analysis by the London School of Economics; at discovery, an antibiotic has a net present value
(NPV) of 50 million compared to a +$1 billion estimated
NPV for a new musculoskeletal drug [6]. Contributing factors
are the facts that antibiotics are the only drugs that lose
benet by extensive use, are given in short courses, and are
generally priced at a peak charge of $1000$3000 per course
compared to, for example, cancer chemotherapy at sometimes
>$80 000 or atorvastatin that is often given for decades. In
July 2012, legislation to improve the NPV of antibiotics, called
the Generating Antibiotic Incentives Now (GAIN) Act, was

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.

Seven Ways to Preserve Antibiotics

CID 2013:56 (15 May)

1449

Downloaded from http://cid.oxfordjournals.org/ at Universidade Federal do Rio de Janeiro on April 29, 2013

treatment. This will require substantial prescriber training, but

the need is transparent. In the United States, a recent report
showed that a microbiologic diagnosis was made in only 7.6%
of 17 435 hospitalized patients with CAP [7]. In contrast, investigators at the Karolinska Institutet (Sweden) used PCR to
detect viruses, and semiquantitative PCR for relevant bacteria,
in CAP patients and detected a probable pathogen for 89% of
patients [8]. Another benet of molecular diagnostics is detection of the nucleic acid of heretofore unknown pathogens. The
contents of brain abscesses from 39 patients using 16S ribosomal DNA analysis yielded 76 bacterial species including 23
species that could not be cultured, suggesting potentially important nuances of infectious diseases that have yet to be explored [36]. These data emphasize the need for more research
on the pathogenic role of these uncultivable organisms, as well
as the need for research on what drives resistance.

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.
10. Scanfeld D, Scanfeld V, Larson EL. Dissemination of health information through social networks: Twitter and antibiotics. Am J Infect
Control 2010; 38:1828.
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

21.

1450

CID 2013:56 (15 May)

Bartlett et al

22.
23.

24.
25.

26.

27.

28.

29.
30.

31.
32.
33.

34.

35.

36.

37.

38.

39.
40.

Downloaded from http://cid.oxfordjournals.org/ at Universidade Federal do Rio de Janeiro on April 29, 2013

References

antimicrobial agents and antimicrobial resistance among medically

important bacteria in the Netherlands. SWAB. Available at: http://
www.swab/cms3.nsf/uploads/35ACD 3A546C31716c12578BF002EDC/
$FILE/NethMap2011.pdf. Accessed 4 September 2012.
Miyakis S, Pefanis A, Tsakris A. The challenges of antimicrobial drug
resistance in Greece. Clin Infect Dis 2011; 53:177.
Sabuncu E, David J, Bernede-Bauduin C, et al. Signicant reduction of
antibiotic use in the community after a nationwide campaign in
France, 200207. PLoS Med 2009; 6:e1000084.
Marshall BM, Levy S. Food animals and antibiotics: impacts on
human health. Clin Microbid Rev 2011; 24:71833.
Aarestrup FM, Jensen VF, Emborg HD, Jacobsen E, Wegener HC.
Changes in the use of antimicrobials and the effects on productivity of
swine farms in Denmark. Am J Vet Res 2010; 71:72633.
Wright GD. Antibiotic resistance in the environment: a link to the
clinic. Curr Opin Microbiol 2010; 13:58994.
Pronovost P, Needham D, Berenholtz S. An intervention to decrease
catheter-related bloodstream infections in the ICU. N Engl J Med
2006; 355:272532.
Waters HR, Korn R Jr, Colantuoni E, et al. The business cases for
quality economic analysis of the Michigan Keystone Patient Safety
Program in ICUs. Am J Med Qual 2011; 26:3339.
Srinivasan A, Craig M, Cardo D. The power of policy change, federal
collaboration, and state coordination in healthcare-associated infection
prevention. Clin Infect Dis 2012; 55:42631.
Roberts RR, Hota B, Ahmad I, et al. Hospital and societal costs of
antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis 2009; 49:117584.
Arnold HM, Micek ST, Skrupky LP, Koleff MH. Antibiotic stewardship
in the intensive care unit. Semin Respir Crit Care Med 2011; 12:20629.
Snitkin ES, Zelazny AM, Thomas PJ, et al. Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole gene
sequencing. Sci Transl Med 2012; 4:19.
Drusano GL. Pharmacokinetics and pharmacodynamics of antimicrobials. Clin Infect Dis 2007; 45(suppl 1):S8995.
Bergen PJ, Li J, Nation RL. Dosing of colistin-back to basic PK/PD.
Curr Opin Pharmacol 2011; 11:4649.
Arnold SR, Strauss SE. Interventions to improve antibiotic prescribing
practices in ambulatory care. Cochrane Database Syst Rev 2005; 19:
CD003539.
Caliendo AM. Multiplex PCR and emerging technologies for the detection of respiratory pathogens. Clin Infect Dis 2011; 52(suppl 4):
S32630.
Jeng K, Massire C, Zembower TR, et al. Monitoring seasonal inuenza
A evolution: rapid 2009 pandemic H1N1 surveillance with an reverse
transcription-polymerase chain reaction/electro-spray ionization mass
spectrometry assay. J Clin Virol 2012; 54:3326.
Al Masalma M, Armougom F, Scheld WM, et al. The expansion of
the microbiological spectrum of brain abscesses with use of multiple
16S ribosomal DNA sequencing. Clin Infect Dis 2009; 48:116978.
Promoting Anti-Infective Development and Antimicrobial Stewardship through the US Food and Drug Administration Prescription
Drug User Fee Act (PDUFA). Reauthorization: Before the House
Committee on Energy and Commerces Subcommittee on Health,
2012. Available at: http://www.idsociety.org/uploadedFiles/IDSA/Policy_
and_Advocacy/Current topics_and_Issues/Advancing_Product_Research_
and_Development/Bad_BugsNo_Drugs/Statements/IDSA%20PDUFA%
20GAIN%20Testimony%20030812%20FINAL.pdf. Accessed 13 September 2012.
Spellberg B, Sharma P, Rex JH. The critical impact of time discounting
on economic incentives to overcome the antibiotic market failure. Nat
Rev Drug Discov 2012; 11:168.
Sebelius K. Building a stronger foundation for a new century of treatments and cures. Health Aff (Millwood) 2011; 30:813.
Dolgin E. Trial networks move beyond single-disease strategies. Nat
Med 2011; 17:1525.