Overview

The Ongoing Threat of Antimicrobial Resistance

a,b, c,d
Richard R. Watkins, MD, MS *, Robert A. Bonomo, MD

KEYWORDS
 Antimicrobial resistance  Antibiotics  Public health

KEY POINTS
 The effectiveness of antibiotics continues to erode because of the relentless spread of
antimicrobial resistance (AMR).
 Public and private foundations, professional organizations, and international health
agencies recognize the threat posed by AMR and have issued calls for action.
 One of the main drivers of AMR is overprescription of antibiotics, both in human and in vet-
erinary medicine.
 The One Health concept is a response from a broad group of stakeholders to counter the
global health threat posed by AMR.

INTRODUCTION

The discovery and clinical implementation of antibiotics in the twentieth century is one
of the greatest achievements in modern medicine. These “miracle drugs” treat infec-
tions ranging from minor to life threatening, enable surgeons to perform complex pro-
cedures in challenging anatomic locations, allow organ transplantation to be feasible,
and empower oncologists to give higher doses of curative chemotherapy for cancer,
thereby increasing the chance for remission. Unfortunately, the global dissemination
of antimicrobial resistance (AMR) threatens to undo all these advances and lead us
back to the “preantibiotic era.” Moreover, the global economic cost of AMR is stag-
gering and estimated to result in a loss of $3 trillion in gross domestic product
annually.1
According to a recent Centers for Disease Control and Prevention (CDC) report,
approximately 2.8 million infections from antibiotic-resistant bacteria occur annually

a
Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH, USA;
b
Department of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA; c Medical
Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH,
USA; d Case VA Center for Antimicrobial Resistance and Epidemiology (Case VA-CARES), Case
Western Reserve University, Cleveland, OH, USA
* Corresponding author. Division of Infectious Diseases, Cleveland Clinic Akron General, Akron,
OH.
E-mail address: WatkinR2@ccf.org

Infect Dis Clin N Am - (2020) -–-

https://doi.org/10.1016/j.idc.2020.04.002 id.theclinics.com
0891-5520/20/ª 2020 Elsevier Inc. All rights reserved.
2 Watkins & Bonomo

in the United States, resulting in more than 35,000 deaths.2 Moreover, these infections
have a higher risk for hospitalization and complications.3 AMR is an inevitable evolu-
tionary outcome because all organisms develop genetic mutations to avoid lethal se-
lective pressure. As long as antibiotics are used against human pathogens, these
bacteria will continue to develop and use resistance mechanisms.4 At present, more
than 70% of pathogenic bacteria are resistant to at least 1 antibiotic.5 Notably, a sur-
vey of infectious diseases physicians in the United States found that 60% had encoun-
tered a bacterial infection resistant to available drugs in the previous year.6
AMR is a complicated process that is driven by multiple factors (Box 1). Despite the
global spread of AMR, regulatory approval of new antibiotics has declined 90% during
the past 30 years in the United States.7 In addition to the high cost of antibiotic
research and development, the rapid evolution of AMR has meant diminished market
returns for the pharmaceutical industry.8 For example, the 4 antibiotics (ceftazidime-
avibactam, meropenem-vaborbactam, plazomicin, and eravacycline) approved since
2015 that target carbapenem-resistant Enterobacteriales (CRE) compete against each
other for market share, which has led to disappointing sales.9 The present economic
incentives in place to sustainably develop new antibiotics may be failing, and new
models that incentivize long-term growth and development are needed.
After many years out of the mainstream, the serious threat posed by AMR has been
increasingly recognized by the media and governmental organizations. In September
2014, the White House proposed the National Strategy for Combating Antibiotic-
Resistant Bacteria, wherein President Obama charged Congress with designing a
research agenda to combat AMR on multiple fronts.10
The CDC has prepared a list of AMR bacteria in the United States that are of most
concern (Box 2). Of these threats, the widespread dissemination of AMR gram-
negative bacilli (GNB) is arguably the most worrisome at present. Limited treatment
options, the ease of plasmid-mediated transfer of resistance genes among GNB,
the widespread distribution of Enterobacteriales (formally Enterobacteriaceae) as
part of the human microbiome, the asymptomatic colonization present in certain indi-
viduals, and higher mortality associated with CRE compared with susceptible strains

Box 1
Factors that promote antimicrobial resistance

 Bacterial population density in health care facilities; allows transfer of bacteria within a
community and enables resistance to emerge
 Inadequate adherence to best infection control practices
 Increase of high-risk patient populations (eg, chemotherapy, dialysis, and transplant patients
and patients residing in long-term care facilities)
 Antibiotic overuse in agriculture
 Global travel and tourism (including medical tourism)
 Poor sanitation and contaminated water systems; can lead to the spread of resistant bacteria
in sewage
 Improper antibiotic prescribing in human medicine (eg, for viral infections or for
inappropriately long courses of therapy)
 Overprescription of broad-spectrum antibiotics; can exert selective pressure on commensal
bacteria
 Paucity of rapid diagnostic tests to guide proper antibiotic prescribing
 Lack of approved vaccines for drug-resistant pathogens
 The Ongoing Threat of Antimicrobial Resistance 3

Box 2
Antibiotic-resistant bacteria of concern in the United States

Urgent threat level

Carbapenem-resistant Enterobacteriaceae
Candida auris
Clostridioides difficile
Carbapenem-resistant Acinetobacter
Drug-resistant N gonorrhoeae
Serious threat level
Drug-resistant Campylobacter
Drug-resistant Candida
ESBL-producing Enterobacteriaceae
Vancomycin-resistant Enterococcus
Multidrug-resistant P aeruginosa
Drug-resistant Salmonella serotype Typhi
Drug-resistant nontyphoidal Salmonella
Drug-resistant Shigella
Methicillin-resistant S aureus
Drug-resistant Streptococcus pneumoniae
Drug-resistant tuberculosis
Concerning threat level
Erythromycin-resistant group A Streptococcus
Clindamycin-resistant group B Streptococcus
Watch list
Azole-resistant Aspergillus fumigatus
Drug-resistant Mycoplasma genitalium
Drug-resistant Bordetella pertussis

Adapted from Centers for Disease Control and Prevention. Antibiotic resistance threats in the
United States, 2019. Report available at https://www.cdc.gov/drugresistance/pdf/threats-
report/2019-ar-threats-report-508.pdf. Accessed December 3, 2019.

can be insurmountable challenges.11 Moreover, risk factors are increasingly identified

for acquiring AMR-GNB and include recent antibiotic usage, residence in extended
care facilities, admission to an intensive care unit (ICU), possessing an indwelling de-
vice or wounds, poor functional status, organ or stem cell transplantation, receipt of
immunomodulatory therapies, and travel to an endemic area.12
Of the drug classes to which AMR can emerge, the most problematic is against the
b-lactams. These drugs (penicillins, cephalosporins, monobactams, and carbape-
nems) are among the most time-honored, safest, and most potent of antibiotics.
b-Lactam resistance in GNB is primarily mediated through b-lactamase genes (bla)
that are frequently encoded on plasmids and other mobile genetic elements. b-Lacta-
mases are classified into 4 main groups based on their amino acid sequences (classes
A, B, C, and D).13 Class A includes extended-spectrum b-lactamases (ESBLs) and
Klebsiella pneumoniae carbapenemase enzymes; class B enzymes are the metallo-
b-lactamases (of which New Delhi metallo-b-lactamase [NDM] is a prime example);
class C enzymes are the chromosomal and plasmid encoded cephalosporinases;
and class D enzymes are oxacillinases. Class D b-lactamases are among the most
diverse and complex families possessing many carbapenem hydrolyzing variants (car-
bapenem hydrolyzing class D). It is notable that Acinetobacter baumannii, although at
1 time considered a "less-virulent” pathogen compared with K pneumoniae and Pseu-
domonas aeruginosa, plays a significant role in spreading broad-spectrum resistance
genes and many bla variants of every major class to other gram-negative organisms.14
4 Watkins & Bonomo

EVOLUTION OF ANTIBIOTIC RESISTANCE

The first effective antimicrobial agent, sulfonamide, was introduced into clinical
practice in 1935. Within 2 years, sulfonamide resistance was reported, and the
same AMR mechanisms are still present more than 80 years later.15 One useful way
to understand the basic mechanisms of AMR is through the “bullet-and-target”
concept, whereby the sites of drug activity (the target) can be changed by enzymatic
modification, transformed by genomic mutations, and bypassed metabolically (eg,
sulfonamide resistance); the antibiotic (the bullet) can undergo enzymatic inactivation
and degradation (eg, b-lactamases), reduced access into the cell (eg, porin loss), and
increased removal from the cell (eg, efflux pumps).16,17 Emerging evidence suggests
that resistance mechanisms in Mycobacterium tuberculosis (MTb), one of the oldest
and most widespread human pathogens, are induced by mutations caused by subin-
hibitory concentrations of antibiotics.18 Indeed, the sole source of resistance to anti-
MTb drugs is by mutation of the target genes. To illustrate, patients infected with MTb
who previously received quinolone antibiotics developed resistance to this antibiotic
class as well as to first-line anti-MTb drugs.19 These data highlight the phenomenon
of “collateral damage” by showing a strong and direct correlation between the use
of antibiotics and resistance.
One important example of contemporary evolution in resistance phenotypes is
Salmonella typhi. In the early twentieth century, the preantibiotic era, typhoid fever
exacted a 20% mortality, which was significantly reduced with the introduction of
effective therapy. Fluoroquinolones became the agents of choice in the 1990s, but
1 lineage of Salmonella with reduced susceptibility has widely disseminated.20 Unfor-
tunately, efforts to develop novel therapies against S typhi are minimal.21 Thus, we are
on the verge of widespread resistance with few effective alternatives for typhoid fever,
raising the possibility of a return to the preantibiotic era for this disease.22 Two other
notable examples are (i) the evolution of penicillin resistance in Neisseria gonorrhea
whereby alterations in penicillin-binding proteins accelerated the development of
resistance to penicillin; and (ii) the discovery of ESBLs whereby single point mutations
in b-lactamase genes undermined the impact of expanded-spectrum cephalosporins
(eg, ceftazidime).
Although AMR has traditionally been identified as a hospital-acquired problem, the
impact from the environment is increasingly recognized. Certain environmental com-
partments (eg, municipal wastewater systems, pharmaceutical manufacturing efflu-
ents, and agricultural waste products) are characterized by extremely high
concentrations of bacteria coupled with subtherapeutic concentrations of antibiotics,
leading to the discharge of AMR bacteria and AMR genes into the wider environ-
ment.23 For example, river sediment downstream from a waste water treatment plant
had 10 novel combinations of cephalosporin-resistance genes as well as an
imipenem-resistant Escherichia coli.24 Uncertainty exists as to whether AMR genes
that are acquired by both clinically relevant bacteria and nonpathogenic ones in the
environment originate from the same sources. Furthermore, the role of environmental
bacteria in spreading AMR genes to nosocomial pathogens is unknown. Investigating
these conundrums should be a priority because of the global scale of AMR.

ANTIBIOTICS AND AGRICULTURE

The use of antibiotics in agriculture is becoming increasingly scrutinized. More than 13

million kilograms of antibiotics are used annually in agriculture in the United States,
approximately 80% of the antibiotics consumed in the country.25 Most of this usage
is not for treating disease in animals (livestock), but for growth promotion and disease
 The Ongoing Threat of Antimicrobial Resistance 5

prevention, usually at subtherapeutic concentrations. Chang and colleagues26 have

suggested the following 3 mechanisms by which AMR in agriculture could threaten
human health:
1. A human is infected by a resistant pathogen through contact with livestock or
through ingestion of bacteria from contaminated food or water;
2. A human becomes colonized by resistant bacteria through one of these means and
then spreads it to another person who subsequently becomes ill;
3. Resistance genes arising in agriculture are spread to humans through horizontal
gene transfer, and the resulting resistant strains are selected by antibiotic use in
people.
Evidence suggests several strains of pathogens that infect humans have originated
from animals, including stains of AMR Campylobacter spp,27 Salmonella spp,28
methicillin-resistant Staphylococcus aureus (MRSA),29 vancomycin-resistant Entero-
coccus (VRE),30 ESBL-producing Enterobacteriales,31 and CRE.32 The transfer of
resistance determinants from animals to humans, however, is difficult to trace, and
the role of these animal reservoirs in clinical AMR remains enigmatic.
Given the link between AMR and antibiotic use in farm animals, a possible solution is
to ban antibiotics except when livestock are ill. The European Union banned all
nontherapeutic antibiotics in animals in 2006, and the Food and Drug Administration
issued a policy in 2012 asking farmers to voluntarily decrease their use of antibiotics.
Theoretically, antibiotic selection pressure should be reduced by a ban, leading to
less-resistant organisms in the environment. Avoparcin, a vancomycin analogue,
was banned as a feed additive in Taiwan in 2000, and a nationwide surveillance study
found the frequency of VRE in chicken farms decreased in association with this legis-
lation.33 Despite a paucity of definitive data, a better argument for restricting antibi-
otics in agriculture may be to reduce the prevalence of resistant pathogens and,
thereby, lower the chances for horizontal transfer of resistance genes.
Significant challenges exist for banning antibiotics in agriculture in the United
States. Given the wide geographic distribution of farms, regulatory oversight would
likely be difficult to enforce. Also, it would be problematic to clearly know what the an-
tibiotics were being used for, such as treating sick animals versus prophylaxis against
infections. One proposal is to implement an antibiotic user fee. According to Hollis and
Ahmed,25 a user fee would be easier to administer because it could be collected at the
manufacturing stage, would discourage low-value uses of antibiotics, would generate
revenues that could help pay for new antibiotic development by the pharmaceutical
industry or support antimicrobial stewardship efforts, and could encourage govern-
ments to collaborate, such as signing treaties to collect revenue generated by the
user fees. Finally, a “One Health” approach has been advocated as a way to engage
multiple sectors and stakeholders (eg, human health, animal health, agriculture, and
the environment) to address AMR on multiple fronts.34

SOCIETAL BURDEN OF ANTIBIOTIC RESISTANCE

The economic impact of AMR is enormous. Overall, AMR is estimated to cost

$55 billion in the United States annually.35 Furthermore, an infection by an
ESBL-producing E coli or Klebsiella spp can increase hospitalization costs by
$16,450 and add an additional 9.7 days to the length of stay.36
Novel AMR genes disproportionately originate in lower-income countries, with
downstream impact on the originating country and in those outside the region.20
For example, NDM-1 was first identified in a strain of K pneumoniae from a patient
6 Watkins & Bonomo

in Sweden who had returned from India.37 Regarding the health impact of AMR, the
World Health Organization (WHO) reported a significant increase in all-cause mortality
and 30-day mortality from infections caused by third-generation cephalosporin-resis-
tant (including ESBL) and fluoroquinolone-resistant E coli as well as expanded-
spectrum cephalosporin (eg, ceftazidime and cefepime) -resistant and carbapenem-
resistant K pneumoniae.38 MRSA infections lead to significant increases in all-cause
mortality, bacterium-attributable mortality, ICU mortality, septic shock, length of
stay, and a 2-fold risk increase for discharge to long-term care compared with
methicillin-sensitive S aureus.39 Thus, the management of MRSA imposes important
economic costs to health care organizations, although there is a scarcity of definitive
evidence available to allow for a comprehensive evaluation of the economic burden.

WHAT CAN BE DONE TO AVOID A POSTANTIBIOTIC ERA?

Although identifying and developing new drugs or vaccines are an important solution
to the AMR problem, the development of therapeutics is a costly and complicated
endeavor. In addition to novel antibiotics in development, early preliminary data ob-
tained by using phage cocktails against Acinetobacter spp seem promising.40 A
phage-derived enzyme with highly potent lytic activity has been shown to improve
therapy against MRSA.41 Monoclonal vaccines have also been tested, but their clinical
applications are still in the early stages (eg, P aeruginosa monoclonal vaccine under
development by Medimmune). Therefore, alternative strategies are necessary,
particularly in low-income countries.
An important and effective way to limit the spread of AMR is to reduce the con-
sumption of antibiotics. In 2004, Bergman and colleagues42 showed that regional
macrolide use was closely associated with erythromycin resistance in Streptococcus
pyogenes. Reducing antibiotics use is one of the central tenets of antibiotic steward-
ship, now universally recognized as beneficial.43 For example, a stewardship program
from a Swedish university hospital decreased antibiotic usage by 27% without any
negative impact on patient outcomes, primarily by limiting broad-spectrum agents.44
On a wider scale, antibiotic prescribing nationally in the United States has improved,
with a 5% decrease from 2011 to 2016.45 However, reducing antibiotic consumption
alone is not a panacea for stopping AMR, which requires a multifaceted approach.
The World Alliance Against Antibiotic Resistance has put forward a declaration that
includes 10 proposals for tackling AMR.46 Several of them (eg, more rapid diagnostic
tests, antibiotic stewardship, and surveillance networks) are not new ideas, but none-
theless are widely recognized as beneficial. Therefore, the value of the declaration is
that it convincingly and authoritatively conveys the recommendations through a global
perspective. One important concept in the document that deserves emphasis is the
pressing need for an improved national surveillance mechanism in the United States.
Currently there are several public databases and global surveillance projects,
including Antimicrobial Resistance: Global Report on Surveillance, from the WHO;
the European Antimicrobial Resistance Interactive Database; the Surveillance
Network database in the United States and Australia; and the Global Study for Moni-
toring Antimicrobial Resistance Trends. In 2002, this last study began to monitor
in vitro resistance of GNB in intraabdominal infections and more recently has focused
on resistance to carbapenems and ESBLs.47 Efforts to improve and coordinate
microbiological information with clinical outcomes among these various programs
are truly necessary.
Despite increasing media attention, the general public largely remains unaware of
the threat posed by AMR. Of concern, a recent global survey conducted by the
 The Ongoing Threat of Antimicrobial Resistance 7

WHO found that even in countries where national antibiotic awareness programs had
been conducted, there was still widespread belief that antibiotics were effective
against viral illnesses.48 Certainly better educational efforts are needed.
Another disconcerting finding from the report was the widespread practice of anti-
biotics available without a prescription.48 This ill-informed practice undoubtedly leads
to overconsumption, especially among commonly used drugs in low-income settings
(eg, fluoroquinolones to treat viral illnesses where typhoid fever is endemic). Changing
antibiotics to prescription status will require strong government action, which is also
necessary to make improvements in infrastructure and to provide better access to
health care providers and laboratory facilities.
The role of the microbiome in the spread and control of AMR is increasingly recog-
nized. Many commensal bacterial species, which were previously considered rela-
tively harmless residents of the human gut, are now seen as disease-causing
organisms.49 Indeed, the microbiome is host to a vast reservoir of antibiotic resistance
genes (ARG), which vary because of a multitude of factors, including diet, antibiotic
use, country of residence, and occupation. For example, Yang and colleagues50
showed residents of China have a higher relative abundance of ARG in the gut,
followed by Americans and Europeans. Although antibiotics clearly affect the micro-
biome, the confounding effects of illness and aging make investigating their role a
challenge.51
Finally, fecal microbiota transplant (FMT) has been shown to decrease ARG and
potential pathogens, along with changing the function and composition of the micro-
biome.52 Although promising, the potential benefits of FMT must be carefully weighed
against the risks, which can include bacteremia or death, as described in a recent
report.53

SUMMARY

AMR can only be tackled through a comprehensive approach that includes drug dis-
covery and development, sustainable antibiotic usage policies, and disease-
prevention strategies, like improving sanitation in low-income countries, infection-
control practices in hospitals, and better diagnostic testing. Whether novel vaccines
or phage therapy can be used to treat specific AMR bacteria remains to be seen,
although there appears to be some promise in the use of phages against A baumanii,
P aeruginosa, and Mycobacteria. Most of the political will and necessary resources
must come from high-income countries. AMR is a complicated existential threat to hu-
manity that requires a coordinated effort across a multitude of organizations and po-
litical boundaries.

REFERENCES

1. Naylor NR, Atun R, Zhu N, et al. Estimating the burden of antimicrobial resistance:
a systematic literature review. Antimicrob Resist Infect Control 2018;7:58.
2. CDC. Antibiotic resistance threats in the United States, 2019. Atlanta (GA): U.S.
Department of Health and Human Services, CDC; 2019. Available at: https://
www.cdc.gov/drugresistance/Biggest-Threats.html. Accessed December 3,
2019.
3. Livermore D. Current epidemiology and growing resistance of gram-negative
pathogens. Korean J Intern Med 2012;27:128–42.
4. National Institute of Allergy and Infectious Diseases. NIAID’s antibacterial resis-
tance program: current status and future directions. 2014. Available at: http://
8 Watkins & Bonomo

www.niaid.nih.gov/topics/antimicrobialResistance/documents/
arstrategicplan2014.pdf. Accessed December 3, 2019.
5. Katz ML, Mueller LV, Polyakov M, et al. Where have all the antibiotic patents
gone? Nat Biotechnol 2006;24:1529–31.
6. Hersh AL, Newland JG, Beekmann SE, et al. Unmet medical need in infectious
diseases. Clin Infect Dis 2012;54:1677–8.
7. Shlaes DM, Sahm D, Opiela C, et al. The FDA reboot of antibiotic development.
Antimicrob Agents Chemother 2013;57:4605–7.
8. Payne DJ, Gwynn MD, Holmes DJ, et al. Drugs for bad bugs: confronting the
challenges of antibiotic discovery. Nat Rev Drug Discov 2007;6:29–40.
9. Nielsen TB, Brass EP, Gilbert DN, et al. Sustainable discovery and development
of antibiotics–is a nonprofit approach the future? N Engl J Med 2019;38:503–5.
10. Obama B. National strategy for combating antibiotic-resistant bacteria. Washing-
ton, DC: White House; 2014. p. 1–33.
11. Vasoo S, Barreto JN, Tosh PK. Emerging issues in gram-negative bacterial resis-
tance: an update for the practicing clinician. Mayo Clin Proc 2015;90:395–403.
12. Tzouvelekis LS, Markogiannakis A, Psichogiou M, et al. Carbapenemases in
Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global
dimensions. Clin Microbiol Rev 2012;25:682–707.
13. Hall BG, Barlow M. Revised Ambler classification of beta-lactamases.
J Antimicrob Chemother 2005;55:1050–1.
14. Potron A, Poirel L, Nordmann P. Emerging broad-spectrum resistance to Pseudo-
monas aeruginosa and Acinetobacter baumannii: mechanisms and epidemi-
ology. Int J Antimicrob Agents 2015;45(6):568–85.
15. Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol
Biol Rev 2010;77:417–33.
16. Aminov RI. A brief history of the antibiotic era: lessons learned and challenges for
the future. Front Microbiol 2010;1:134.
17. Tang SS, Apisarnthanarak A, Hsu LY. Mechanisms of b-lactam antimicrobial resis-
tance and epidemiology of major community- and healthcare-associated multi-
drug-resistant bacteria. Adv Drug Deliv Rev 2014;78:3–13.
18. Fonseca JD, Knight GM, McHugh TD. The complex evolution of antibiotic resis-
tance in Mycobacterium tuberculosis. Int J Infect Dis 2015;32:94–100.
19. Deutschendorf C, Goldani LZ, Santos RP. Previous use of quinolones: a surrogate
marker for first line anti-tuberculosis drugs resistance in HIV-infected patients?
Braz J Infect Dis 2012;16:142–5.
20. Kariuki S, Revathi G, Kiiru J, et al. Typhoid in Kenya is associated with a dominant
multidrug-resistant Salmonella enterica serovar Typhi haplotype that is also wide-
spread in Southeast Asia. J Clin Microbiol 2010;48:2171–6.
21. Baker S. A return to the pre-antimicrobial era? Science 2015;347:1064–6.
22. Koirala KD, Thanh DP, Thapa SD, et al. Highly resistant Salmonella enterica sero-
var Typhi with a novel gyrA mutation raises questions about the long-term efficacy
of older fluoroquinolones for treating typhoid fever. Antimicrob Agents Chemother
2012;56:2761–2.
23. Berendonk TU, Manaia CM, Merlin C, et al. Tackling antibiotic resistance: the
environmental framework. Nat Rev Microbiol 2015;13:310–7.
24. Amos GCA, Hawkey PM, Gaze WH, et al. Waste water effluent contributes to the
dissemination of CTX-M-15 in the natural environment. J Antimicrob Chemother
2014;69:1785–91.
25. Hollis A, Ahmed Z. Preserving antibiotics, rationally. N Engl J Med 2013;369:
2474–6.
 The Ongoing Threat of Antimicrobial Resistance 9

26. Chang Q, Wang W, Regev-Yochay G, et al. Antibiotics in agriculture and the risk
to human health: how worried should we be? Evol Appl 2015;8:240–7.
27. Travers K, Barza M. Morbidity of infections caused by antimicrobial-resistant bac-
teria. Clin Infect Dis 2002;34(Suppl 3):S131–4.
28. Brunelle BW, Bearson BL, Bearson SM. Chloramphenicol and tetracycline
decrease motility and increase invasion and attachment gene expression in spe-
cific isolates of multi-drug resistant Salmonella enterica serovar Typhimurium.
Front Microbiol 2015;5:801.
29. Van der Mee-Marquet N, Francois P, Domelier-Valentin AS, et al. Emergence of
unusual bloodstream infections associated with pig-borne-like Staphylococcus
aureus ST398 in France. Clin Infect Dis 2011;52:152–3.
30. Lebreton F, van Schaik W, McGuire AM, et al. Emergence of epidemic multi-drug-
resistant Enterococcus faecium from animal and commensal strains. MBio 2013;4
[pii:e00534-13].
31. Reich F, Atanassova V, Klein G. Extended-spectrum b-lactamase- and AmpC-
producing enterobacteria in healthy broiler chickens, Germany. Emerg Infect
Dis 2013;19:1253–9.
32. Wang Y, Wu C, Zhang Q, et al. Identification of New Delhi metallo-b-lactamase 1
in Acinetobacter lwoffii of food animal origin. PLoS One 2012;7:e37152.
33. Lauderdale TL1, Shiau YR, Wang HY, et al. Effect of banning vancomycin
analogue avoparcin on vancomycin-resistant enterococci in chicken farms in
Taiwan. Environ Microbiol 2007;9:819–23.
34. Cabrera-Pardo JR, Lood R, Udekwu K, et al. A One Health–One World initiative to
control antibiotic resistance: a Chile-Sweden collaboration. One Health 2019;
14(8):100100.
35. Smith R, Coast J. The true cost of antimicrobial resistance. BMJ 2013;346:f1493.
36. Lee SY, Kotapati S, Kuti JL, et al. Impact of extended-spectrum beta-lactamase-
producing Escherichia coli and Klebsiella species on clinical outcomes and hos-
pital costs: a matched cohort study. Infect Control Hosp Epidemiol 2006;27:
1226–32.
37. Walsh TR, Weeks J, Livermore DM, et al. Dissemination of NDM-1 positive bacte-
ria in the New Delhi environment and its implications for human health: an envi-
ronmental point prevalence study. Lancet Infect Dis 2011;11:355–62.
38. World Health Organization. Antimicrobial resistance: global report on surveil-
lance. Geneva (Switzerland): WHO; 2014.
39. Antonanzas F, Lozano C, Torres C. Economic features of antibiotic resistance: the
case of methicillin-resistant Staphylococcus aureus. Pharmacoeconomics 2015;
33:285–325.
40. LaVergne S, Hamilton T, Biswas B, et al. Phage therapy for a multidrug-resistant
Acinetobacter baumannii craniectomy site infection. Open Forum Infect Dis 2018;
5:ofy064.
41. Fujiki J, Nakamura T, Furusawa T, et al. Characterization of the lytic capability of a
LysK-like endolysin, Lys-phiSA012, derived from a polyvalent Staphylococcus
aureus bacteriophage. Pharmaceuticals (Basel) 2018;11(1) [pii:E25].
42. Bergman M, Huikko S, Pihlajamäki M, et al. Effect of macrolide consumption on
erythromycin resistance in Streptococcus pyogenes in Finland in 1997-2001.
Clin Infect Dis 2004;38:1251–6.
43. Livermore DM. Of stewardship, motherhood and apple pie. Int J Antimicrob
Agents 2014;43:319–22.
44. Nilholm H, Holmstrand L, Ahl J, et al. An audit-based, infectious disease
specialist-guided antimicrobial stewardship program profoundly reduced
10 Watkins & Bonomo

antibiotic use without negatively affecting patient outcomes. Open Forum Infect
Dis 2015;2(2):ofv042.
45. CDC. Antibiotic use in the United States, 2018 update; progress and opportu-
nities. Atlanta (GA): US Department of Health and Human Services, CDC; 2019.
46. Claret J. The World Alliance Against Antibiotic Resistance: consensus for a decla-
ration. Clin Infect Dis 2015;60(12):1837–41.
47. Morrissey I, Hackel M, Badal R, et al. A review of ten years of study for monitoring
antimicrobial resistance trends (SMART) from 2002 to 2011. Pharmaceuticals
(Basel) 2013;6:1335–46.
48. World Health Organization. Worldwide country situation analysis: response to
antimicrobial resistance. Geneva (Switzerland): WHO; 2015.
49. Sommer MOA, Dantas G, Church GM. Functional characterization of the anti-
biotic resistance reservoir in the human microflora. Science 2009;325:1128–31.
50. Yang Z, Guo Z, Qiu C, et al. Preliminary analysis showed country-specific gut re-
sistome based on 1,267 feces samples. Gene 2016;581:178–82.
51. Relman DA, Lipsitch M. Microbiome as a tool and a target in the effort to address
antimicrobial resistance. Proc Natl Acad Sci U S A 2018;115:12902–10.
52. Hourigan SK, Ahn M, Gibson KM, et al. Fecal transplant in children with Clostri-
dioides difficile gives sustained reduction in antimicrobial resistance and poten-
tial pathogen burden. Open Forum Infect Dis 2019;6:ofz379.
53. DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-resistant E. coli bacteremia trans-
mitted by fecal microbiota transplant. N Engl J Med 2019;381:2043–50.