Microbiolspec - ARBA 0009 2017

Antimicrobial Resistance:
a One Health Perspective

SCOTT A. MCEWEN1 and PETER J. COLLIGNON2
1
Department of Population Medicine, University of Guelph, Guelph, Canada N1G 2W1;
2
Infectious Diseases and Microbiology, Canberra Hospital, Canberra,
Australia and Medical School, Australian National University, Acton, Australia
ABSTRACT One Health is the collaborative effort of multiple INTRODUCTION

health science professions to attain optimal health for people,
Antimicrobial resistance is a global public health crisis
domestic animals, wildlife, plants, and our environment.
The drivers of antimicrobial resistance include antimicrobial
that threatens our ability to successfully treat bacterial
use and abuse in human, animal, and environmental sectors infections (1, 2). Microbiologists and infectious disease
and the spread of resistant bacteria and resistance determinants specialists have long recognized the problem—the dis-
within and between these sectors and around the globe. coverer of penicillin Sir Alexander Fleming himself drew
Most of the classes of antimicrobials used to treat bacterial attention to the threat of resistance from underdosing
infections in humans are also used in animals. Given the (3)—but realization of the vast scale of the resistant
important and interdependent human, animal, and environ- threat is only now reaching wider audiences. Many in-
mental dimensions of antimicrobial resistance, it is logical to
fectious agents that could once be successfully treated
take a One Health approach when addressing this problem.
This includes taking steps to preserve the continued with any one of several drug classes have acquired re-
effectiveness of existing antimicrobials by eliminating their sistance to most, and in some cases, virtually all of these
inappropriate use and by limiting the spread of infection. drugs (4, 5). The threat is most acute for antibiotics and
Major concerns in the animal health and agriculture sectors are synthetic antibacterial antimicrobial agents, the focus
Downloaded from https://journals.asm.org/journal/spectrum on 17 April 2023 by 200.37.80.186.

mass medication of animals with antimicrobials that are critically of this paper, but also threatened are antifungals, anti-
important for humans, such as third-generation cephalosporins parasitics, and antivirals (6). How did we get from the
and fluoroquinolones, and the long-term, in-feed use of
point where antimicrobials were truly “wonder drugs”
medically important antimicrobials, such as colistin, tetracyclines,
and macrolides, for growth promotion. In the human sector
that could be relied upon to cure a wide range of life-
it is essential to prevent infections, reduce over-prescribing of threatening infections to the point today, where resis-
antimicrobials, improve sanitation, and improve hygiene and tance to most antimicrobials is widely prevalent and the
infection control. Pollution from inadequate treatment of supply of new classes of drugs has dwindled to a trickle?
industrial, residential, and farm waste is expanding the resistome The complete answer is not simple, nor unfortunately, is
in the environment. Numerous countries and several
international agencies have included a One Health approach
within their action plans to address antimicrobial resistance. Received: 2 January 2017, Accepted: 3 January 2018,
Necessary actions include improvements in antimicrobial use Published: 29 March 2018
regulation and policy, surveillance, stewardship, infection Editors: Frank Møller Aarestrup, Technical University of Denmark,
Lyngby, Denmark; Stefan Schwarz, Freie Universität Berlin, Berlin,
control, sanitation, animal husbandry, and alternatives to Germany; Jianzhong Shen, China Agricultural University, Beijing,
antimicrobials. WHO recently has launched new guidelines on China, and Lina Cavaco, Statens Serum Institute, Copenhagen,
the use of medically important antimicrobials in food-producing Denmark
animals, recommending that farmers and the food industry stop Citation: McEwen, Collignon PJ. 2017. Antimicrobial resistance: a
using antimicrobials routinely to promote growth and prevent one health perspective. Microbiol Spectrum 6(2):ARBA-0009-2017.
doi:10.1128/microbiolspec.ARBA-0009-2017.
disease in healthy animals. These guidelines aim to help preserve
Correspondence: Scott A. McEwen, [email protected]
the effectiveness of antimicrobials that are important for human
© 2018 American Society for Microbiology. All rights reserved.
medicine by reducing their use in animals.
ASMscience.org/MicrobiolSpectrum 1
McEwen and Collignon
the solution. One thing seems certain: that overuse of Similarly, actions taken (or not taken) to contain anti-
these precious drugs in multiple sectors (human, animal, microbial resistance in one sector affect other sectors (13,
agriculture) is the main problem and one that must be 14). Antimicrobial resistance is an ecological problem
addressed (4, 7). that is characterized by complex interactions involving
Through the process of Darwinian selection, micro- diverse microbial populations affecting the health of hu-
organisms faced with antimicrobial selection pressure mans, animals, and the environment. It makes sense to
enhance their fitness by acquiring and expressing resis- address the resistance problem by taking this complexity
tance genes and then share those genes with other bac- and ecological nature into account using a coordinated,
teria. Thus, antimicrobial use and overuse are important multisectoral approach, such as One Health (6, 15–19).
drivers of the resistance phenomenon; the other main One Health is defined as “the collaborative effort
drivers are factors that promote the spread of resistant of multiple health science professions, together with
bacteria and their genes locally and globally (8). These their related disciplines and institutions—working lo-
include poor infection control, environmental contami- cally, nationally, and globally—to attain optimal health
nation, and geographical movement of infected humans for people, domestic animals, wildlife, plants, and our
and animals (9, 10). Wherever antimicrobials are used, environment” (20). The origins of One Health are cen-
there are reservoirs of resistance, including within hu- turies old and are based on the mutual dependency of
mans and the local environments of hospitals and the humans and animals and the recognition that they share
community, as well as in animals and the farm and not only the same environment, but also many infectious
aquaculture environments, but also in water, soil, wild- diseases (19). It has been estimated that as many as 75%
life, and many other ecological niches, due to pollution of human infectious diseases that have emerged or re-
by sewage, pharmaceutical industry waste, and manure emerged in recent decades are zoonotic; that is, they
runoff from farms (Fig. 1) (10, 11). Bacteria and their originated in animals (21). Rudolf Virchow and William
genes move relatively easily within and between humans, Osler were medical pioneers that recognized the impor-
animals, and the environment. Microbial adaptations tance of a comparative approach to medical investiga-
to antimicrobial use and other selection pressures within tion, and veterinarian Calvin Schwabe coined the term
any one sector are reflected in any other sector (8, 12). “One Medicine” to denote the many commonalities in
FIGURE 1 Diagrammatic representation of the routes of transmission of antimicrobial

resistance between farm animals, the wider environment, and humans. Reprinted from
Science (12) with permission of the publisher.
2 ASMscience.org/MicrobiolSpectrum
Antimicrobial Resistance: a One Health Perspective
human and animal medicine and in recognition that differences in the ways that antimicrobials are used in
most veterinary activities benefit human health, either companion animals (e.g., dogs, cats, pet birds, horses)
directly or indirectly (19, 22). One Health goes further, compared to food-producing animals. Antimicrobial use
embracing the health of the environment as well as hu- practices in companion animals are broadly similar to
man and animal health, and promotes the view that those in humans; that is, the drugs are mostly adminis-
with the ever-increasing human population growth that tered on an individual animal basis for the treatment
is accompanied by climate change, increasing pollution, of clinical infection, with some use for prophylaxis in
and depletion of the earth’s resources, health disciplines individual animals, such as postsurgery (29, 30). In the
and others must work together to provide for the future case of food animals, however, when some animals in a
health and well-being of humans, animals, and the en- group are clinically infected and in need of antimicrobial
vironment (19, 20). therapy, for reasons of practicality and efficiency, the
In this chapter, we take a One Health perspective on drugs are frequently administered through feed or water
the problem of antimicrobial resistance by showing its to the entire group (e.g., pens of pigs, flocks of broilers),
multisectoral and interrelated nature, highlighting im- even when the majority of the animals are not displaying
portant risks to the health of humans and animals, and signs of infection (in effect, prophylaxis). This is, how-
describing One Health approaches to the containment of ever, now defined inappropriately by many in the animal
antimicrobial resistance, particularly at the international health sector as “therapeutic” use. In addition, there is
level. We then offer some reflections on challenges facing use in food animals similar to what happens in people,
the One Health approach in reconciling the sometimes- when antimicrobials are used to treat individual clini-
conflicting interests that deter some measures to add- cally sick animals (e.g., dairy cows with mastitis) (23).
ressing antimicrobial resistance. At the outset, we state “Metaphylaxis” is a term used variously to describe
our belief that human health and well-being are the therapeutic and/or prophylactic treatment at the group
most important considerations for preserving the con- level, usually in the context of mass administration of
tinued effectiveness of antimicrobials, even within a therapeutic doses of an antimicrobial to a group of
One Health perspective, but that it is also in the greater, animals at high risk of infection, e.g., administration
long-term interest of humankind to adequately care for of an injectable antimicrobial to groups of calves upon
animals and the environment. arrival at a feedlot because of a high risk of bovine res-
piratory disease (23, 31). Antimicrobial prophylaxis in
groups of people is uncommon and is usually limited
USE OF ANTIMICROBIALS IN HUMANS, to the management of serious, highly communicable in-
ANIMALS, AND PLANTS fections such as meningococcal disease. Even in those

A few antimicrobial classes are reserved more or less ex- cases, for example, meningococcal disease in a child at
clusively for humans, in particular those used to treat school, antimicrobials are recommended to be limited to
tuberculosis (e.g., isoniazid) or other infections for which those with prolonged and close contact (usually those in
animals are typically not treated (e.g., cattle with bovine the same household) and not to be given to all pupils in
tuberculosis are usually destroyed rather than treated). same school or classroom (32).
A few others are limited to veterinary use (e.g., flavo- Many in industry justify group-level treatments as
phospholipols, ionophores), mainly because of toxicity therapeutic when clinical infections are observed in at
to humans. However, the great majority of antimicrobial least some of the animals in the pen or flock, or pro-
classes are used in both humans and animals, including phylactic when there are no sick animals present, but
domestic mammals, birds, farmed fish and shellfish, they are at high risk of clinical bacterial infection due
honey bees, and others (23–27). In horticulture, tetra- to exposure to infectious agents (e.g., mixing of animals
cyclines, streptomycin, and some other antimicrobials from different sources), unsanitary or crowded condi-
are sometimes used for the treatment and prophylaxis tions, or other factors (e.g., age, stress of transport) (31).
of bacterial infections of fruit, such as apples and pears The most controversial type of group treatment in
(e.g., “fire blight” caused by Erwinia amylovora) (28). food animals is long-term, low-dose mass medication
In people, antimicrobials are mostly used for the treat- for purposes of growth promotion. The controversy is
ment of clinical infections in individual patients, but rooted partially in the propensity of this practice to select
there is also limited prophylactic use in individuals (e.g., for antimicrobial resistance and partially in its justifi-
postsurgery) or in groups (e.g., prevention of meningo- cation on economic grounds, rather than for treatment
coccal disease). In veterinary medicine there are notable of clinical infection. Antimicrobial growth promoters
are important contributors to antimicrobial resistance animals, as well as the challenges that arise from com-
because they are administered to entire groups of ani- peting interests and imbalances of risk and benefit in
mals, usually for prolonged periods of time and often at various sectors. The first case, which focuses on the
subtherapeutic doses—conditions which favor the se- third-generation cephalosporins, illustrates One Health
lection and spread of resistant bacteria within and be- issues concerning an antimicrobial intended mainly for
tween groups of animals, as well as to humans through therapeutic purposes in animals, but in some important
food or other environmental pathways (33). The period situations it is also used prophylactically. The second
of exposure is usually greater than 2 weeks and often is case features colistin, which illustrates One Health con-
for almost the entire life of an animal, e.g., in chickens siderations arising from an older class of antimicro-
for 36 days. It is imprudent to extensively use antimi- bial that has long been used in animals for therapeutic,
crobials for economic reasons alone when it is clear that prophylactic, and in some countries, growth promotion
such use selects for resistance to antimicrobials of im- purposes, but quite recently has gained importance to
portance to human and animal health (6, 27, 34, 35) and human health.
also may have relatively little or no economic benefits
(35, 36). Based on experimental studies, mostly con- Third-Generation Cephalosporins
ducted decades ago, the purported production benefits Third-generation cephalosporins are broad-spectrum
of antimicrobial growth promoters range widely (1 to beta-lactam antimicrobials that are widely used in hu-
10%), but surveillance and animal production data from mans and animals. Cefotaxime, ceftriaxone, and several
Europe suggest that benefits in animals reared in good other members of the class are used for a wide variety
conditions are probably quite small and may now be of frequently serious infections of humans, particularly
nonexistent. In the past, benefits were derived mainly in hospital settings, e.g., urinary tract, abdominal, lung,
from the disease prophylaxis properties of the antimi- and bloodstream infections due to Escherichia coli,
crobials used, rather than enhancement of feed efficiency Klebsiella pneumoniae, and other bacteria, but also in
or other production effect (35). Some large poultry cor- community settings, e.g., Neisseria gonorrhoeae (42).
porations are now marketing chicken raised without Because of their important role in the therapy of many
antimicrobials administered at the hatchery or farm bacterial infections where resistance has become a major
levels (36). problem, third-generation cephalosporins have been clas-
Concerns are expressed that antimicrobial growth sified as “critically important” for human health (42).
promoters are used to compensate for poor hygiene and Ceftiofur is the principal third-generation cephalo-
housing and as a replacement for proper animal health sporin for veterinary use; others include cefpodoxime,
management (14, 34, 35). For these reasons, the World cefoperazone, and cefovecin. Ceftiofur is approved in

Health Organization (WHO) advocates for the termi- many countries for the treatment of several bacterial
nation of the use of antimicrobials for growth promo- infections, predominantly in food-producing animals.
tion (6, 34, 37), and the practice has been banned in It is limited to parenteral administration, so treatment
Europe and elsewhere and phased out in some other usually is administered to individual animals, either
countries, such as the United States and Canada (38– singly or in groups (43). Depending on the species, it is
40). Recently, the World Organization for Animal used to treat pneumonia, arthritis, polyserositis, septi-
Health (OIE) reported that 41% of 146 countries re- cemia, metritis, meningitis, and infections of other body
porting on antimicrobial use in animals allow the use systems (44). However, it is also sometimes used in mass
of antimicrobial growth promoters. This represents a therapy (metaphylaxis or prophylaxis). This can be
reduction from 51% of 151 reporting countries in 2012 either under an approved label claim (e.g., injection of
(41). Among the drugs allowed are several categorized feedlot cattle for control of bovine respiratory disease)
by WHO as critically important to humans, for example, or off-label (e.g., injection of hatching eggs or day-old
colistin, fluoroquinolones, and macrolides (42). chicks for prevention of E. coli infections). Factors that
favor the use of ceftiofur include its broad-spectrum
activity, clinical efficacy, zero withdrawal time of milk
ONE HEALTH ANTIMICROBIAL from treated lactating dairy animals (due to its high
RESISTANCE CASE STUDIES maximum residual level [MRL]), and availability of a
The following two case studies illustrate some of the long-acting preparation (43, 44).
antimicrobial resistance problems that arise from the use In Europe, where high-quality data on antimicrobial
of the same classes of antimicrobials in humans and consumption in animals are available, approximately
14 tonnes of third- and fourth-generation cephalospo- horizontal dissemination of the responsible genes in a
rins were used in 2014, mainly in food animals (25). This variety of bacterial species from humans, animals, and
represented about 0.16% of total antimicrobial con- the environment (43, 50). Several studies conducted in
sumption in animals in Europe. In the United States, Europe and the United States have attempted to deter-
total consumption of all cephalosporins (not just third- mine the relatedness of ESBL-bearing E. coli from hu-
generation) in animals was approximately 32.3 tonnes mans, animals (particularly poultry), and food (50–52).
in 2015 (45). In some studies, there was only limited relatedness of
In many countries, cephalosporins are commonly ESBL-containing E. coli isolates (53), but other studies
used in humans. For example, in Europe, as a percent- comparing isolates from animals, food, and human
age of total defined daily dose per 1,000 inhabitants per infections have found higher similarity in ESBL genes in
day for systemic use, cephalosporins accounted for a plasmids as well as some similar clones (53–55). This
range of 0.2% (Denmark) to 23.5% (Malta) in 2012; a includes studies using whole-genome sequencing. One
total of 101 tonnes of third-generation cephalosporins group failed to demonstrate evidence for recent clonal
for use in Europe were consumed overall in humans transmission of cephalosporin-resistant E. coli strains
(26). In the United States, approximately 82 tonnes of from poultry to humans but instead found evidence that
third-generation cephalosporins for use in humans were cephalosporin resistance genes are mainly disseminated
consumed in 2011 (46). Among countries that report in animals and humans via distinct plasmids (50). If one
antimicrobial consumption data, quantities of third- considers the large numbers of different E. coli clones
generation cephalosporins used in humans are greater likely to be present in food animals, plus the wide dis-
than in animals. tribution of foods and their ingestion by people, it is
Resistance to the third-generation cephalosporins is not surprising that “clonal” transmission is only rarely
mediated by extended-spectrum beta-lactamases (ESBLs) detected compared to plasmid distribution and exchange.
and AmpC beta-lactamases (43). ESBL genes are highly However, it is still unclear to what extent beta-lactamase-
mobile and are transmitted on plasmids, transposons, bearing E. coli strains from animals are directly respon-
and other genetic elements. AmpC beta-lactamases were sible for human infections. Given the high human disease
originally reported to be chromosomal but have also burden from these organisms, however, even if this was
been identified on plasmids and shown to have spread only a small fraction, it is still very important.
horizontally among Enterobacteriaceae (43). Unfortu- The critical importance of third-generation cephalo-
nately, in many countries resistance to third-generation sporins to human health and serious concerns about the
cephalosporins is common among E. coli and K. pneu- ease with which resistance emerges and spreads, both
moniae from severe human infections (47, 48), placing clonally and horizontally, have focused considerable at-

greater reliance on the few remaining classes of avail- tention on their use in animals, particularly with regard
able antimicrobials, such as carbapenems. Resistance to mass medication of ceftiofur to groups of animals (26,
to these drugs is accompanied by serious public health 33, 43). As mentioned above, the requirement for par-
consequences; a systematic review conducted by the enteral administration places practical limits on mass
WHO reported that patients with third-generation medication to certain situations, such as injection of
cephalosporin-resistant E. coli infections had a 2-fold steers on arrival at the feedlot or routine injection of
increase in all-cause mortality, bacterium-attributable pigs. However, one such mass exposure application that
mortality, and 30-day mortality compared with suscep- is now severely restricted in many countries has been
tible infections (1). Resistance has also been reported convincingly shown to provide powerful selection pres-
in Salmonella, particularly mediated by CMY-2 AmpC sure for resistance in E. coli and Salmonella. It involves
beta-lactamase genes, and these are frequently colocated administration of ceftiofur to eggs or day-old chicks at
with genes encoding resistance to other classes of anti- the hatchery using highly automated equipment that in-
microbials, including tetracyclines, aminoglycosides, jects small quantities of the drug to the many thousands
and sulfonamides. As a consequence, coselection of beta- of hatching eggs or chicks intended for treated flocks
lactam resistance in Enterobacteriaceae (including ceph- (56, 57). The main reason for this treatment is prophy-
alosporin resistance) by use of other antimicrobials in laxis against E. coli infections and/or yolk sac infections.
animals, including tetracyclines administered in feed, has This practice has been shown to select for cephalosporin
been reported (49). resistance in Salmonella enterica serovar Heidelberg, an
Much of the spread of E. coli with ESBL and other important cause of human illness in many countries that
beta-lactamases is thought to be clonal, but there is also is typically associated with consumption of contami-
nated poultry products (58). Surveillance conducted ban on the use of ceftiofur and other critically important
by the Canadian Integrated Program for Antimicrobial antimicrobials for disease prophylaxis (Chicken Farmers
Resistance Surveillance detected a high degree of tem- of Canada, http://www.chickenfarmers.ca/what-we-do
poral correlation in trends of resistance to ceftiofur (and /antibiotics/faq/). In Japan, voluntary withdrawal of the
ceftriaxone, a drug of choice for the treatment of severe off-label use of ceftiofur in hatcheries in 2012 was also
cases of salmonellosis in children and pregnant women) followed by a significant decrease in broad-spectrum
among Salmonella Heidelberg from clinical infections in cephalosporin resistance in E. coli from broilers (59).
humans, from poultry samples collected at retail stores, Some other countries (e.g., Denmark) have also placed
and in E. coli from poultry samples collected at retail voluntary restrictions on its use (60). The label claim for
stores (56) (Fig. 2). Voluntary termination of this use day-old injection of poultry flocks was withdrawn in
of ceftiofur in hatcheries in the province of Quebec Europe, while some countries banned off-label use of
was followed by a precipitous drop in the prevalence third-generation cephalosporins (e.g., the United States)
of resistance to ceftiofur; subsequent reintroduction of (43, 61), and in other countries there is a requirement
its use, apparently in a more limited way, was followed that use be restricted to situations where no other ef-
by a return to higher levels of resistance (57). fective approved drugs are available for treatment (62).
In recognition of the resultant human health risks, in From the One Health antimicrobial resistance per-
2014, the Canadian poultry industry placed a voluntary spective, the third-generation cephalosporins are good
FIGURE 2 Ceftiofur resistance in chicken and human Salmonella Heidelberg and chicken
E. coli. Reprinted from the Public Health Agency of Canada (56) with permission of the
publisher.
examples of antimicrobials that are considered critically be used rarely, if at all, in animals, and only when sup-
important for both human and animal health (Table 1) porting laboratory data demonstrate that no suitable
and for which the main concerns for selection and alternatives of less human health importance are avail-
spread of resistance from animals to humans derive from able (37). Their use as mass medications should be re-
their use as mass medications in large numbers of ani- stricted.
mals, for either therapy or prophylaxis. In this regard,
there are parallels with fluoroquinolones, another class Colistin
of critically important antimicrobials, to which resis- Colistin is a member of the polymixin class of anti-
tance among Campylobacter jejuni isolates emerged fol- microbials, which have been used in both human and
lowing mass medication of poultry flocks (63–65). In veterinary medicine for over 50 years (67). Polymixins,
Australia, where fluoroquinolones were never approved which cause nephrotoxicity and neurotoxicity in people
in food animals, fluoroquinolone-resistant strains in (68), were until recently mainly limited to topical use
food animals remain very rare (66). in humans and treatment of infections in cystic fibrosis
Given the critical importance of these two classes patients (by inhalation as colistimethate sodium). Colistin
of antimicrobials to human medicine and the clear evi- is gaining importance as a drug of last resort for paren-
dence that treatment of entire groups of animals se- teral use in the treatment of multiresistant Gram-negative
lects for resistance in important pathogens that spread infections including carbapenem-resistant Pseudomonas
from animals to humans (57, 65), third- and fourth- aeruginosa, Acinetobacter baumannii, K. pneumoniae,
generation cephalosporins and fluoroquinolones should and E. coli, mainly in intensive care units in certain
TABLE 1 Classification of importance of antimicrobial classes for human health and animal health
Category Human health (WHO) (42) Animal health (OIE) (162)

Critically important Aminoglycosides Aminoglycosides
Ansamycins Amphenicols
Carbapenems and other penems Cephalosporins (3rd and 4th generation)
Cephalosporins (3rd and 4th generation) Macrolides
Phosphonic acid derivatives Penicillins (natural, aminopenicillins, aminopenicillins
Glycopeptides with beta-lactamase inhibitor, antistaphylococcal)
Glycylcyclines Fluoroquinolones
Lipopeptides Sulfonamides
Macrolides and ketolides Diaminopyrimidines
Monobactams Tetracyclines
Oxazolidinones

Penicillins (natural, aminopenicillins, and antipseudomonal)
Polymyxins
Quinolones
Drugs used solely to treat tuberculosis or
other mycobacterial diseases
Highly important Amidinopenicillins Ansamycin—rifamycins
Amphenicols Cephalosporins (1st and 2nd generation)
Cephalosporins (1st and 2nd generation) and cephamycins Ionophores
Lincosamides Lincosamides
Penicillins (antistaphylococcal) Phosphonic acid
Pleuromutilins Pleuromutilins
Pseudomonic acids Polymyxins (including bacitracin and other polypeptides)
Riminofenazines 1st-generation quinolones (flumequin, miloxacin,
Steroid antibacterials nalidixic acid, oxolinic acid)
Streptogramins
Sulfonamides, dihydrofolate reductase inhibitors,
and combinations
Tetracyclines
Important Aminocyclitols Aminocoumarin
Cyclic polypeptides Arsenical
Nitrofurantoins Bicyclomycin
Nitroimidazoles Fusidic acid
Orthosomycins
Quinoxalines
Streptogramins
Thiostrepton
countries (69–71). Where approved for use in food ani- floxacin or ceftriaxone. Multidrug resistance was less
mals (e.g., Brazil, Europe, China), most colistin is ad- common among Salmonella isolates with phenotypic
ministered orally to entire groups of pigs, poultry, and colistin resistance (67).
in some cases calves, for treatment and prophylaxis of Until very recently it was thought that acquired co-
diarrhea due to Gram-negative infections (67, 71, 72). In listin resistance was limited to chromosomal mutation
some countries colistin is also used for growth promotion and was essentially nontransferable (67). In November
(41). Other claims for polymixins exist, including mastitis 2015, however, Liu et al. (72) reported a transferable
in cows, systemic endotoxemia in horses, and skin and plasmid-mediated colistin resistance gene, mcr-1, in
eye infections in companion animals, but the quantities E. coli isolates obtained from animals, food, and hu-
used for these purposes are small (67). In countries where man bloodstream infections from China. Spread of
colistin is approved for use in food animals and for the gene by conjugation has been shown in K. pneumo-
which antimicrobial consumption data are available, the niae, Enterobacter aerogenes, other Enterobacter spp.,
quantities consumed for animal production vastly exceed and P. aeruginosa (72). Aided by the rapid application
those used in humans. In Europe, for example, colistin of whole-genome sequencing techniques to strain col-
use in humans is quite low overall, at 0.012 defined daily lections around the world, retrospective analyses have
doses per 1,000 inhabitants per day in 2014, although revealed the mcr-1 gene in several bacterial species iso-
there is considerable between-country variation, and lated from human, animal, and environmental samples
there has been an increase in recent years (73). Animal in numerous countries (76–79), and the gene was found
use of colistin in Europe also varies widely, for example, in about 5% of healthy travelers (80). The earliest
from 0 mg/population correction unit (PCU) (Finland, identification of the gene thus far was in E. coli from
Iceland, and Norway) to 34 mg/PCU (Spain) in 2013 poultry collected in the 1980s in China (81). In Europe,
(67). In 2013, total consumption in animals in Europe the mcr-1 gene is still relatively uncommon; for exam-
was 495 tonnes—99.7% in oral form (e.g., for oral so- ple, Doumith et al. reported that within large United
lution, medicated feed premix, and oral powder) (67). Kingdom databases, mcr-1 was detected in 15 of 24,000
Liu et al. reported that in China, with the world’s largest (0.0625%) isolates of Salmonella spp., E. coli, Klebsiella
production of pigs and poultry, an estimated 12,000 spp., Enterobacter spp., and Campylobacter spp., from
tonnes of colistin was used in food animal production human and food samples collected between 2012 and
(72). 2015 (82). The mcr-1 gene has also been detected in iso-
Until recently, limited data on colistin resistance lates obtained from wildlife and surface water samples,
were available, partly because of technical difficulties demonstrating environmental contamination (83). Now
in phenotypic susceptibility testing (67, 74), and it was even more plasmid-mediated colistin resistance genes

not included in panels for routine resistance surveil- have been reported. This started with a novel mcr-2 gene
lance in Gram-negative bacteria from animals, food, the in E. coli from pigs in Belgium (84), and mcr-3, mcr-4,
environment, and humans. Mandatory monitoring for and mcr-5 genes have been reported in many other
colistin resistance in Salmonella and E. coli from animals bacterial species and in many countries (85).
and some foods was initiated in Europe in 2014 (75), Colistin illustrates some important One Health di-
when it was reported that 0.9% of 4,037 E. coli isolates mensions of antimicrobial resistance that differ from
from broilers and 7.4% of 1,663 E. coli isolates from those of the third-generation cephalosporins. These re-
fattening turkeys demonstrated phenotypic colistin re- late, in particular, to the history and patterns of colistin
sistance (>2 mg/liter.) (67). Resistance was also found use in humans and animals and to the subsequent emer-
in 8.3% of isolates from broilers, 4.4% from broiler gence of resistance to the polymyxin class of antimi-
meat, 2% from turkeys, and 27.7% from turkey meat; a crobials, probably driven by large volumes of colistin
large proportion of resistant isolates were S. enterica used in animals rather than by use in humans. As men-
serovar Enteritidis (but this may represent a type of in- tioned above, for many years the toxicity and avail-
trinsic resistance rather than resistance by an acquired ability of other safer and more effective antimicrobials
chromosomal or plasmid-mediated mechanism [75]). limited colistin to mainly topical uses in people. How-
Multidrug resistance was common; among 162 colistin- ever, with the emergence of multidrug resistance in
resistant E. coli isolates from poultry or poultry meat, many Gram-negative bacteria, there has been increasing
91.4% were resistant to three or more other antimicro- need for this drug to treat severe, life-threatening in-
bials; 120 (74.1%) of the isolates were also resistant fections in humans in some countries. The colistin case
(using epidemiological cutoff values) to either cipro- demonstrates (once again) that using large quantities of
antimicrobials for group treatments or growth promo- to determine the concentrations of antimicrobial residue
tion in animals can lead to significant antimicrobial re- in foods (so-called maximum residue levels, or MRLs)
sistance problems for human health, even if the drug that are compatible with acceptable levels of risk in
class is initially believed to be less important, because the exposed humans (91). This enables the establishment
relative importance of antimicrobials to human health of a “withdrawal time,” the time from administra-
changes. The European Medicines Agency (EMA) has tion of a drug until residues in foods from animals are
recommended an overall reduction of the use of poly- reliably below the MRL for that drug. Regulations
mixins in animals, with national targets of 5 mg/PCU requiring avoidance of above-MRL (i.e., unsafe) and
and 1 or below 1 mg/PCU for countries with previous potentially chemically toxic concentrations of antimi-
high and moderate use, respectively (67). crobial residues were widely established many years ago
This closely parallels the experience of the 1990s with and are enforced with testing programs and penalties
avoparcin, a glycopeptide antimicrobial growth pro- (31). For decades, veterinarians and farmers adminis-
moter used widely in pig and poultry production that tering therapeutic antimicrobials to animals have been
was initially thought not to be of public health impor- well aware of the need to adhere to withdrawal times
tance. However, another glycopeptide, vancomycin, was to maintain product quality. This is a simple concept
critically important in the treatment of life-threatening that was straightforward in application, easily commu-
methicillin resistant Staphylococcus aureus (MRSA) nicated and enforced, and did not really interfere with
and for enterococcal infections of humans (the latter the veterinarian’s access to antimicrobials, so long as
especially in penicillin-allergic patients) (86). Surveil- the withdrawal times and other label requirements were
lance and research eventually were able to show that followed. On the other hand, this does not take into
avoparcin use in animals contributed to the selection and account antimicrobial resistance. The dynamics of anti-
widespread dissemination of vancomycin-resistant en- microbial resistance are not nearly as predictable, and
terococci and glycopeptide resistance genes in entero- microbiological risks cannot so easily be assessed, man-
cocci from animals, food, humans, and the environment aged, and communicated in such a simple, straightfor-
(87). There should be no need to repeat this lesson; ward manner as drug toxicity (33, 92, 93), and this has
antimicrobials, even if at some times regarded as only plagued the timely development and implementation
of minor importance to human health (e.g., colistin), of One Health approaches to address antimicrobial re-
should not be administered to groups of animals for sistance in animals.
routine disease prophylaxis or growth promotion. Concerns about the human health antimicrobial re-
sistance risks from antimicrobial use in animals initially
focused on administration of antimicrobials in animal
HISTORY OF ONE HEALTH DIMENSIONS

feeds, particularly those administered without veterinary
OF ANTIMICROBIAL RESISTANCE prescription for growth promotion (88). In 1968, the
The history of efforts to address the One Health di- Swann Committee recommended separate regulation
mensions of antimicrobial use in food animals is in of “feed antibiotics” and “therapeutic antibiotics,” such
some ways a study of country-by-country variation in that the latter should be available for use in animals only
the application of the available scientific evidence to under veterinary prescription (94). These recommenda-
antimicrobial policy (for more detail see reference 88). tions were soon adopted in the United Kingdom and
Public health concerns about antimicrobial use in ani- elsewhere in Europe, and as a consequence, the use of
mals have since the 1950s focused on both micro- penicillins, tetracyclines, sulfonamides, and other anti-
biological and toxicological effects (89, 90). While the microbials with therapeutic applications in humans and
latter are largely beyond the scope of this article, it can animals became no longer available over-the-counter in
be argued that the generally successful approaches that Europe for use as growth promoters (95). However, the
quickly evolved to assess and manage the toxicological United States, Canada, and many other countries did not
risks have made it more difficult to address the more follow the European example of distinctly separating
challenging microbiological risks from antimicrobial antimicrobials for food animals into those for veterinary
resistance. It is fairly straightforward, using pharma- use and those for feed additives.
cokinetics and pharmacodynamics, to predict rates of Concerns about antimicrobial feed additives were not
depletion of antimicrobial residues in edible products limited to Europe; since 1969, several U.S. organizations
(meat, milk, eggs) from treated animals and, along with (e.g. National Academy of Sciences, Food and Drug Ad-
toxicological dose-response data from animal studies, ministration ([FDA], Office of Technology Assessment)
have deliberated on the use of antimicrobial drugs in serovar Typhimurium DT104 (34, 102). As mentioned
animals, particularly in feeds (96–100), but early attempts previously, avoparcin was a glycopeptide antimicrobial
to withdraw approval for “subtherapeutic” (growth- that was used as a feed additive in Europe, Australia,
promotion) administration of antimicrobials from animal and many other countries and that selected for resistance
feeds were met with arguments that there was inadequate to vancomycin, another glycopeptide (34, 103). At the
epidemiological evidence that the resultant antimicrobial- same time, increasing concerns about resistance to the
resistant bacteria are commonly transmitted to humans fluoroquinolone class among important human patho-
and cause serious illness (98). In 1987, the FDA asked the gens focused attention on the use of these drugs in ani-
National Academy of Sciences Institute of Medicine to mals, particularly in poultry, where they were typically
review the human health consequences and risk associ- administered in water at the flock level (102). Endtz and
ated with including subtherapeutic levels of penicillin coworkers demonstrated convincingly that fluoroquino-
and tetracyclines in animal feed (101). The Institute of lone resistance among C. jejuni isolated from poultry
Medicine committee concluded that there was insufficient and clinical infections of humans emerged soon after
direct evidence to establish conclusively the presence of a veterinary use of the drugs was introduced (63). In the
human health hazard from such use, but the committee United States, an application to approve fluoroquino-
found a substantial body of indirect evidence, particularly lone use in poultry was met with concern that it would
for Salmonella. They developed a quantitative risk as- compromise the effectiveness of the drug class for the
sessment model, the first in this field, using data from treatment of human infections. The FDA eventually ap-
epidemiological surveillance and published literature, proved the application, but to address resistance con-
and concluded that the estimated annual number of fatal cerns restricted off-label use of the drug in food animals
antimicrobial-resistant salmonellosis cases in the United and established the U.S. National Antimicrobial Re-
States due to subtherapeutic use of penicillin and tetra- sistance Monitoring program in 1996 to improve food
cycline was most likely about 40 but ranged from 1 to chain surveillance of antimicrobial resistance of human
400. They went on to use the risk assessment model to health concern. Within a short time, surveillance and
identify the fraction of these cases attributable to anti- research confirmed that fluoroquinolone use in poultry
microbial uses in livestock feed and estimated that these did indeed adversely affect human health by selecting
“excess deaths” were in the range of 6 per year in the for resistance to this class of drugs in C. jejuni, and the
United States (101). Unfortunately, the assembled indirect FDA withdrew its approval of its use in poultry, but this
evidence and formal quantitative risk assessment findings required a prolonged legal process (65).
were apparently insufficient for U.S. regulatory purposes, In 1986, Sweden was the first European country
since the FDA proposal to withdraw “subtherapeutic” to ban antimicrobial growth promoters in food animals

(low-dose, long-term administration) use of penicillin and (34). Denmark, through a combination of voluntary
tetracycline from animal feeds was not implemented (98). industry initiatives and regulatory action, terminated
It is remarkable that the finding of excess deaths could the use of avoparcin in 1995 and then other antimicro-
be considered acceptable from a regulatory perspective. bial growth promoters by 1999 (35). Subsequently,
After another 3 decades of evidence gathering, and with the European Union terminated the use of all antimi-
greater societal and stakeholder acceptance that some- crobial growth promoters as of January 1, 2006. The
thing must be done about growth promoters, the FDA European Union has continued to permit therapeutic
recently introduced guidance for the voluntary removal of use of approved antimicrobials in animals, including
claims for growth promotion and other “production fluoroquinolones and some other critically important
uses” of medically important antimicrobials in the United antimicrobials for humans, with some restrictions, for
States (40). The choice of a voluntary approach may at example, that third-generation cephalosporins should
least in part reflect the previous difficulties with forced not be used in poultry (104).
withdrawals where the burden of proof is placed on the The history of some of these major attempts to ad-
regulator. dress One Health antimicrobial resistance issues reveals
The 1990s saw a resurgence in concerns about anti- remarkable differences between countries in the speed
microbial resistance in the human, agricultural, and and efficiency with which they made major regulatory
veterinary sectors. In particular, growth promoter use changes to the availability of antimicrobials for use in
of avoparcin and therapeutic use of fluoroquinolones animals on the basis of concerns about human health.
featured prominently in these concerns, along with the This is especially the case for drugs that had been on the
emergence and spread of multiple-resistant S. enterica market for years. Globally, Europe and the United States
have been the dominant centers of regulatory activity, of antimicrobial-resistant Salmonella contamination of
with some other countries more or less following suit, meat and poultry products (33) and may also be re-
particularly with U.S. approaches. Broadly speaking, sponsible for fruit and vegetable contamination through
European countries have been more nimble in moving fecal contamination of the environment (108). Salmo-
forward with major regulatory changes to antimicrobial nella resistance to any medically important antimicro-
availability (e.g., implementation of the Swann recom- bial is a public health concern, but particularly to those
mendations and, later, the outright ban on antimicro- critically important to human health, such as cephalo-
bial growth promoters), and this may reflect a greater sporins and fluoroquinolones (33, 34, 57), for which
willingness in Europe to exercise precaution in favor therapeutic options can be limited. Therapy in some
of public health when making antimicrobial policy. The groups (e.g., children and pregnant women) can be very
United States, while quite ready to exercise precaution restricted because of issues of toxicity with many anti-
in some stages of the drug licensing process (e.g., pre- biotics. Beta-lactams such as third-generation cephalo-
approval human safety evaluation), has been hampered sporins often may be the only therapy available to treat
by demands for higher levels of proof of adverse effects serious infections.
on human health (by legislatures and industry groups) to Concerns have been expressed that fluoroquinolone
justify revoking specific drug authorizations for animals use in food animals is linked to quinolone resistance in
(e.g., subtherapeutic uses of penicillin and tetracycline in Salmonella (34, 102, 109, 110). Surveillance data com-
livestock feed and fluoroquinolone for the treatment of piled by WHO indicate that rates of fluoroquinolone
poultry). resistance in nontyphoidal Salmonella vary widely by
geographical region. For example, rates are relatively
low in Europe (2 to 3%), higher in the Eastern Medi-
RISKS TO PUBLIC HEALTH terranean region (up to 40 to 50%), and wide-ranging
AND ANIMAL HEALTH in the Americas (0 to 96%) (1). Many Salmonella
Antimicrobial resistance is harmful to health because it strains are also resistant to antimicrobials that have long
reduces the effectiveness of antimicrobial therapy and been used as growth promoters in many countries (e.g.,
tends to increase the severity, incidence, and cost of in- Canada, the United States), including tetracyclines,
fection (4, 105). Antimicrobial use in humans has been penicillins, and sulfonamides (34, 107). Antimicrobial
associated with resistance in numerous important hu- resistance in some of the more virulent Salmonella
man pathogens affecting various body systems (2), and serovars (e.g., Heidelberg, Newport, Typhimurium) has
there is now considerable evidence that antimicrobial been associated with more severe infections in humans
use in animals is an important contributor to antimi- (33, 101, 105, 111). Resistance to other critically im-

crobial resistance among pathogens of humans, in par- portant antimicrobials continues to emerge in Salmo-
ticular, common enteric pathogens such as Salmonella nella; for example, a carbapenem-resistant strain of
spp., Campylobacter spp., Enterococcus spp., and E. Salmonella was identified on a pig farm that routinely
coli and in some cases other bacteria that can also be administered prophylactic cephalosporin (ceftiofur) to
zoonotic, e.g., S. aureus (7, 14, 23, 33, 34). There is also piglets (112).
increasing concern that exposure of bacteria to heavy C. jejuni infections are among the most common
metals and biocides (e.g., disinfectants, antiseptics) in food- and waterborne infections in many countries, and
animals and environmental niches may coselect for re- while antimicrobial treatment is typically not indicated
sistance to antimicrobials (106). in uncomplicated cases, because they are usually self-
Nontyphoidal Salmonella is among the most common limiting, resistance to some antimicrobials, e.g., fluoro-
bacteria isolated from foodborne infections of humans. quinolones, has been associated with greater severity,
It has been estimated that globally, there are around including longer duration of infection (105, 113). As
94 million cases, including 155,000 deaths, of nonty- mentioned above, fluoroquinolone resistance is associ-
phoidal Salmonella gastroenteritis each year (1). Ani- ated with the use of this drug in animals, especially in
mals are the most important reservoirs of nontyphoidal poultry, where it is typically administered as a mass
Salmonella for humans, and resistance has been associ- medication in drinking water (63, 64). In Australia,
ated with antimicrobial use in animals, along with other where fluoroquinolones have never been licensed for use
management factors such as mixing of animals from in poultry but are widely used in humans, quinolone
different sources and transport (33, 94, 101, 107). Fecal resistance among C. jejuni isolates from human in-
shedding by carrier animals is an important source fections remains very low (66). Macrolides are widely
used in animals, and in many countries they are ad- risks including by using newer methodologies such
ministered in feed to groups of animals and in some cases as whole-genome sequencing (123). WHO has also re-
as growth promoters, and such uses have been associ- ported wide-ranging rates of E. coli resistance to third-
ated with macrolide resistance in Campylobacter (33, generation cephalosporins, for example, up to 48% in
40). the Americas and 70% in Africa and South-East Asia
E. coli is an important pathogen of both humans and (1). A systematic review of the health burden from third-
animals. In humans, E. coli is a common cause of serious generation cephalosporin resistance (including ESBL)
bacterial infections, including enteritis, urinary tract in- in E. coli infections relative to susceptible infections re-
fection, and sepsis. For example, reported rates of blood- vealed a significant 2-fold increase in all-cause mortality,
stream E. coli infections in developed countries ranged bacterium-attributable mortality, and 30-day mortality.
between 30 and 50 episodes per 100,000 population Patients with fluoroquinolone-resistant E. coli infections
annually in the past (114, 115). Currently in England, experienced a significant 2-fold increase in all-cause
the rate is about 64 cases per 100,000 per year and mortality and 30-day mortality (1).
rising. A large and increasing proportion is antimicro- MRSA is an important pathogen of humans in both
bial resistant (116). These higher rates are also being community and hospital settings, causing skin, wound,
seen in countries with good surveillance systems in place, bloodstream, and other types of infection (1, 124, 125).
e.g., Denmark (60). Serious staphylococcal infections in people are common:
In animals, E. coli is responsible for enteritis, various about 10 to 30 per 100,000 inhabitants per year (126).
extra-intestinal infections such as mastitis in lactating WHO reports that beta-lactam resistance (i.e., MRSA)
animals, and septicemia. In poultry, E. coli causes cel- is a global problem, with rates of resistance of up to
lulitis, salpingitis, synovitis, and omphalitis (yolk sac 80 to 100% in Africa, up to 90% in the Americas, and
infections) (117). Some E. coli strains appear to be up to 60% in Europe (1). Systematic review of the health
species-specific pathogens, while others are capable burden of MRSA relative to methicillin-susceptible
of infecting multiple species, including humans. Many S. aureus showed that patients with predominantly
E. coli strains appear to behave as commensals of the gut healthcare-associated MRSA infections experienced a
of animals and humans but may be opportunistic path- significant increase in all-cause mortality, bacterium-
ogens as well as donors of resistance genetic elements attributable mortality, and intensive care unit mortality
for pathogenic E. coli or other species of bacteria (51, and septic shock (1). Community acquired MRSA bac-
118). Although antimicrobial resistance is a rapidly in- teremia has increased with time, and the disease is
creasing problem in E. coli infections of both animals associated with more necrotizing pneumonia and cuta-
and humans, the problem is better documented for neous abscesses, although with less endovascular infec-

isolates from human infections, where resistance is ex- tion compared to more sensitive strains of S. aureus.
tensive, particularly in developing countries (1, 119). Unlike healthcare-associated infections, patients with
Humans are regularly exposed to antimicrobial-resistant community-acquired MRSA bacteremia did not have
E. coli through foods and inadequately treated drinking higher mortality than did patients with more sensitive
water (120, 121). Resistance to third-generation cepha- strains of S. aureus (127).
losporins, fluoroquinolones, and/or carbapenems is S. aureus and other staphylococci are also recognized
increasing in many regions, particularly in developing pathogens of animals; for example, they are responsible
countries (1, 119). Travelers from developed coun- for cases of mastitis in cattle and skin infections in pigs
tries are at risk of acquiring multiresistant E. coli from and companion animals (128, 129). MRSA was until
other people or contaminated food and/or water (114, recently relatively rare in animals, but strains pathogenic
121, 122). There are now serious problems with ESBL to humans have emerged in several animal species (129–
E. coli in both developing and developed countries, 132). Transmission to humans is currently thought to
and foods from animals, poultry in particular, have be mainly through contact with carrier animals (132).
been implicated as sources for humans (50, 53, 55), al- The predominant strain isolated from animals, sequence
though the magnitude of the contribution from food type 398, while pathogenic to humans, is not considered
animals is uncertain. WHO is attempting to improve this a major epidemic strain (128, 129). Antimicrobial use
situation by the establishment and expansion of inte- in livestock, as well as lapses in biosecurity within and
grated surveillance of antimicrobial resistance in food- between farms and international trade in animals, food,
borne bacteria using the application of a One Health or other products are factors contributing to the spread
approach, which will help establish links and calculate of this pathogen in animals (129, 133).
ONE HEALTH CONSIDERATIONS nure or irrigation water (33, 65, 108). In countries with
FROM THE ENVIRONMENT poor sewage and water treatment, drinking water is
Antimicrobial resistance in other pathogens as well as likely to be very important in the transmission of resis-
gut commensals and bacteria in other ecological niches tant bacteria and/or genes from animals (114, 134, 139).
can also be driven by antimicrobial use in animals and Poor sanitation also facilitates indirect person-person
humans. One Health includes consideration of the en- waterborne transmission of enteric bacteria among re-
vironment as well as human and animal health (19, sidents as well as international travelers who return
134). The ecological nature of antimicrobial resistance is home colonized with resistant bacteria acquired locally
a reflection and consequence of the interconnectedness (119, 145). Through these and other means, including
and incredible diversity of life on the planet (18). Many globalized trade in animals and food and long-distance
pathogenic bacteria, the antimicrobials that we use to migratory patterns of wildlife, antimicrobial-resistant
treat them, and genes that confer resistance have en- bacteria are globally disseminated.
vironmental origins (e.g., soil) (8, 16, 135). Some im- General measures to address antimicrobial resistance
portant resistance genes, such as beta-lactamases, are in the wider environment include improved controls on
millions of years old (135, 136). Soil and other envi- pollution from industrial, residential, and agricultural
ronmental matrices are rich sources of highly diverse sources. Improved research as well as environmental
populations of bacteria and their genes (135, 137). An- monitoring and risk assessment are required to better
timicrobial resistance to a wide variety of drugs has understand the role of the environment in the selection
been demonstrated in environmental bacteria isolated and spread of antimicrobial resistance and to identify
from the preantibiotic era, as well as from various sites more specific measures to address resistance in this sec-
(e.g., caves) free of other sources of exposure to modern tor (11, 14, 116, 119, 135, 146).
antimicrobials (8, 134, 136, 138). Despite having an-
cient origins, there is abundant evidence that human
activity has an impact on the resistome, which is the ONE HEALTH STRATEGIES TO ADDRESS
totality of resistance genes in the wider environment ANTIMICROBIAL RESISTANCE
(135, 137, 138). Hundreds of thousands of tonnes of WHO and other international agencies (e.g., Food and
antimicrobials are produced annually and find their way Agriculture Organization [FAO], OIE), along with many
into the environment (14, 24). Waste from treatment individual countries, have developed comprehensive
plants and the pharmaceutical industry, particularly if action plans to address the antimicrobial resistance crisis
inadequately treated, has been shown to release high (6, 147–153). The WHO Global Action Plan seeks to
concentrations of antimicrobials into surface water (14, address five major objectives, discussed in the following

15, 139, 140). Residues and metabolites of antimicro- subsections. The WHO Global Action Plan embraces
bials are constituents of human sewage, livestock ma- a One Health approach to address antimicrobial resis-
nure, and aquaculture, along with fecal bacteria and tance, and it calls on member countries to do the same
resistance genes (137, 141–143). Sewage treatment and when developing their own action plans (6).
composting of manure reduce concentrations of some
but not all antimicrobials and microorganisms, which Improve Awareness and Understanding of
are introduced to soil upon land application of human Antimicrobial Resistance through Effective
and animal biosolids (144). Communication, Education, and Training
Various environmental pathways are important Antimicrobial resistance is a rapidly evolving, highly
routes of human exposure to resistant bacteria and their complex topic, not least its One Health dimensions,
genes from animal and plant reservoirs (14, 112) and which feature various forms of antimicrobial use within
provide opportunities for better regulations to control human, animal, and environmental sectors, accompa-
antimicrobial resistance (Fig. 3). In developed countries nied by selection of antimicrobial resistance among
with good-quality sewage and drinking water treatment, bacteria in a wide variety of niches and with serious
and where most people have little to no direct contact consequences to the health of humans and animals. At
with food-producing animals, transmission of bacteria the most basic level, everyone should understand the
and resistance genes from agricultural sources is largely principles of basic hygiene to prevent the spread of
foodborne, either from direct contamination of meat infections, understand the need to follow the antimi-
and poultry during slaughter and processing, or indi- crobial prescriber’s instructions for treatment, and have
rectly from fruit and vegetables contaminated by ma- a basic appreciation of the risks to themselves and others

FIGURE 3 Schematics of the hotspots and drivers of antimicrobial resistance. The envi-
ronmental compartments that are currently monitored or regulated by the Environmental
Agency (EA; England) are denoted by an asterisk in red. WDF, Water Framework Directive.
Reprinted from Frontiers in Microbiology (140) with permission of the publisher.
associated with antimicrobial use, in addition to the raise animals, fruits, and vegetables with no or minimal
benefits (4, 6). This applies to antimicrobial use in use of antimicrobials and ideally use them only for the
humans as well as animals. While all can benefit from a treatment of clinically ill individual animals. They also
more in-depth understanding of the One Health dimen- need to know how to reduce the need for antimicrobial
sions of antimicrobial resistance, those with particular treatment by improving overall levels of husbandry and
need include companion animal owners, farmers, vet- minimizing overcrowded, unsanitary, and stressful con-
erinarians, and others involved in food production and ditions that promote the spread of disease in populations
the wider food industry. The depth of understanding of animals and plants (154, 155). Veterinarians who
that these groups require varies. Animal owners should prescribe antimicrobials and advise farmers on disease
understand that some bacterial infections are shared by prevention obviously require a deeper understanding of
animals and humans and that they should follow vet- the One Health dimensions of antimicrobial resistance.
erinary advice on antimicrobial use and prevention of Veterinarians should possess the knowledge, attitudes,
disease transmission. Farmers should understand how to and behaviors that characterize good antimicrobial
stewardship, thereby protecting the health and welfare prevent them (1, 6). There are many gaps in our un-
of their patients, the economic interests of their clients, derstanding of the complex biology that characterizes
as well as the health of the wider community (147, 153– the One Health dimensions of resistance, but many ad-
155). Human health professionals would also benefit vances have been made in recent years that support
from a good understanding of the One Health aspects of evidence-based interventions to address antimicrobial
antimicrobial resistance and a better understanding and resistance (4, 7, 136).
implementation of the mechanisms that help control the Surveillance of antimicrobial resistance and anti-
spread of pathogens, including resistant bacteria, e.g., by microbial use in both human and nonhuman sectors is
infection control, improved hygiene, improved sanita- necessary to estimate the extent, patterns, and health
tion, etc. All health professionals should have a good burden of resistance at the national, regional, and in-
understanding of the modifiable drivers of antimicrobial ternational levels (123, 156). Such surveillance should
resistance (Fig. 4) and be motivated to reduce their im- be able to detect emerging trends in antimicrobial re-
pact on antimicrobial resistance selection and spread. sistance of clinical significance to humans and animals
Opportunities to enhance awareness and understand- (1, 26, 56). Surveillance should inform educational
ing of One Health dimensions of antimicrobial resistance efforts to minimize antimicrobial resistance, as well as
include the health promotion and health protection antimicrobial use policies and antimicrobial steward-
programs offered by pubic health and animal health ship programs (4, 6, 7). Surveillance is also needed to
organizations, consumer information campaigns (public, measure the effectiveness of interventions and other
animal owners), farmer outreach activities, veterinary measures that are taken to control antimicrobial resis-
consultations, farm industry publications (farmers), vet- tance (17, 157). One Health surveillance of antimicro-
erinary curricula, and professional development pro- bial resistance should include sampling of appropriate
grams (veterinarians, physicians). bacteria from specimens collected in various human,
animal, and environmental settings including hospi-
Strengthen the Knowledge and Evidence tals, extended-care and community settings, veterinary
Base through Surveillance and Research clinics, farms, food, and the environment (e.g., wildlife,
Surveillance and research are essential because they soil, water) (17, 123, 155). Surveillance of antimicrobial
identify antimicrobial resistance problems and how to use should also be conducted in human, veterinary, and
FIGURE 4 Role of modifiable drivers for antimicrobial

resistance: a conceptual framework. Reprinted from
Lancet (8) with permission of the publisher.
agricultural settings and should provide estimates of to which they are effective in limiting the spread of
antimicrobial consumption in humans and animal spe- antimicrobial resistance, particularly in nonpathogenic
cies at the national level along with suitable denomina- bacteria, is rarely if ever evaluated. Nevertheless, to
tors (e.g., population size, numbers of animals, PCUs) reduce the need for antimicrobial use in animals,
to enable comparisons among countries (17, 60, 123). whether for treatment or prophylaxis, it is important
To provide information that is useful for assessing and to adopt health management measures to prevent dis-
guiding prescribing practices and antimicrobial use be- ease in animals, particularly those responsible for the
haviors, antimicrobial use monitoring should also take largest quantities of medically important antimicrobials
place at the level of prescribing (e.g., hospitals, commu- (e.g., Streptococcus suis infections and diarrhea in pigs,
nity, veterinary clinic, farm) (60, 123, 158). Surveillance pneumonia in calves, E. coli infections in broilers, mas-
data should be analyzed, interpreted, and presented in an titis in dairy cows) (31, 155).
integrated fashion across sectors, and reports should be To reduce human exposure to the spread of anti-
timely in order to be useful to relevant stakeholders (60). microbial resistance from environmental sources and
WHO has provided guidance on harmonized, integrated pathways, it is also important to implement measures
surveillance of antimicrobial resistance and antimicro- to improve the safety of food and drinking water, par-
bial use to assist developed and developing countries in ticularly in underdeveloped countries, and to control
implementing their own national surveillance programs environmental pollution from the pharmaceutical in-
and to contribute to improved global surveillance activ- dustry (118, 135, 140). Foodborne pathogen reduction
ities which are essential for better coordination of inter- programs at the farm, slaughter, and further processing
national efforts to contain antimicrobial use (123). levels are important for controlling the spread of enteric
Targeted research is essential to demonstrate how re- bacteria such as Salmonella and Campylobacter to hu-
sistance develops and spreads within and between eco- mans (154). Likewise, measures to improve the micro-
logical niches and species of bacteria, including pathogens biological quality of drinking water (from source water
as well as enteric commensals and environmental bacte- protection through to disinfection) as well as proper
ria (4, 11, 33). To reduce antimicrobial use in animals, sewage treatment are important to reduce exposure to
additional research is needed for suitable cost-effective bacteria from environmental sources, as well as to re-
alternatives to antimicrobials for disease prevention and duce indirect human-human transmission of enteric
enhancement of growth and production efficiency (7, 14, bacteria (both susceptible and resistant) (16, 114).
15). Additional research is also needed to support anti-
microbial stewardship such as improved diagnostic tools, Optimize the Use of Antimicrobial Medicines
ways to improve antimicrobial prescribing and utilization in Human and Animal Health

behaviors, and better vaccines (4–6). A One Health approach to improved antimicrobial
stewardship involves a range of regulatory, voluntary,
Reduce the Incidence of Infection and other means to preserve the effectiveness of anti-
through Effective Sanitation, Hygiene, microbials in human, animal, and agricultural settings
and Infection Prevention Measures (4). This approach should include interventions to pro-
Infection control in healthcare settings, particularly mote judicious use of antimicrobials, as well as moni-
hospitals, is a well-recognized and important means toring of antimicrobial utilization and mechanisms for
to limit the spread of antimicrobial resistance in hu- continued improvement of prescribing and utilization (7,
mans (16, 118). In veterinary clinics, however, formal 147, 160). A One Health approach to stewardship re-
infection control programs are underutilized (159, 160). quires some alignment of activities in the various sectors
At the farm level, infection control in the form of bio- (human, veterinary, agriculture) to achieve the overall
security and other disease control programs is important goal of preserving antimicrobial effectiveness for both
in most food animal industries, particularly for inten- humans and animals (6, 160). This involves finding a
sive production in the poultry and swine sectors (7, way of balancing the sometimes-competing interests
23). Some animal disease control programs are applied that exist in the different sectors, and this can be con-
at the national level, particularly to prevent the intro- tentious. Typically, human health interests predominate,
duction of exotic animal pathogens to the national herd, but animal health and welfare are also important con-
while others are applied at the farm level (147, 154, siderations (37). In our view, economic interests are
155). These programs usually target production-limiting subordinate to health considerations. From the One
animal pathogens or specific zoonoses, and the extent Health perspective, antimicrobial stewardship programs
should seek to ensure that antimicrobials are reserved fluoroquinolones, and macrolides are found in the crit-
for the treatment of clinical infections in humans and ically important category of antimicrobials on both lists
animals that occur despite the existence of good infec- (Table 1). Some individual countries (e.g., Canada,
tion control and other programs designed to minimize United States) and the European Union have developed
the need for treatment (147, 155, 160). Overall, there is their own approaches to categorizing antimicrobial
greater emphasis on national regulatory interventions classes with respect to importance to human health (62).
to control antimicrobial resistance in the veterinary/ It would be useful to harmonize the criteria used in these
agricultural sectors than in human medicine (160). This different classifications of antimicrobials with respect to
is a reflection of the importance that society places on human health and to make progress in reconciling the
the health of humans relative to other interests, and with overlap in the human and animal lists (163).
it, a more frequent need in the veterinary/agricultural There are several ways to incorporate this antimi-
sectors for mandatory controls and restrictions that crobial classification into antimicrobial risk manage-
are best applied at a systems level, rather than relying ment strategies. One example is to eliminate the growth
on voluntary measures at the prescriber or user level. promotion uses of medically important antimicrobials
Regulatory approval of antimicrobials for use in animals (i.e., classes within the critically important, highly im-
normally depends on the demonstration that such use is portant, and important categories of the WHO list) (34,
safe for humans (through exposure to residues in food 37, 155). This strategy has been used in the European
and selection of antimicrobial resistance) as well as being Union and Korea and is being implemented in other
safe for animals and efficacious (31, 40, 62). Examples countries (e.g., Canada, United States) (38, 39). Another
of regulatory interventions taken to address antimicro- way is to completely restrict the use in animals of certain
bial resistance include the ban on the use of antimicro- microbials that are critically important in humans. For
bial growth promoters in food-producing animals in the example, in the European Union carbapenems, glyco-
European Union, restriction of the extra-label use of peptides, monobactams, and some other classes are not
fluoroquinolones and third-generation cephalosporin in licensed for use in food animal species, nor may they be
animals in the United States, and the prescription-only used off-label in these species, and in companion ani-
availability of antimicrobials for veterinary use in many mals they may be used only in exceptional circumstances
countries (7, 35, 61). (38, 62). It is also possible to utilize categorization in
Drug classification is an important tool for addressing schemes involving treatment cascades or formularies
antimicrobial resistance. From the One Health perspec- (e.g., first-line, second-line, etc. choices). For example,
tive, the most important classification schemes are those the European Union stipulates that in consideration
that categorize antimicrobials with respect to their im- of their importance to human health, third- and fourth-
generation cephalosporins and fluoroquinolones should

portance to human and animal health (Table 1). Begin-
ning in 2005 and then updated at regular intervals, be used only when there are no alternative antimicro-
WHO has developed a scheme to classify antimicrobials bials authorized for the target species and indications
used in humans into three categories: critically impor- (38, 62). Another application of antimicrobial classifi-
tant, highly important, and important (42, 161). The cation is the promotion of antimicrobial stewardship
purpose of the classification is to guide risk management by industry. For example, the McDonald’s corporation,
strategies to prevent and control antimicrobial resistance Perdue, Tyson Foods, and other major food companies
from food animal production. Two criteria are used for have adopted antimicrobial use policies that require
classification, and additional criteria are used to priori- suppliers to restrict food animal use of antimicrobials
tize those antimicrobial classes in the critically important classified by WHO as critically important for human
category. Examples of the highest-priority classes are medicine (36, 164, 165).
quinolones and third- and fourth-generation cephalo-
sporins (42, 161).
The OIE has developed a system of classification of Develop the Economic Case for Sustainable
antimicrobials of importance to animal health (162). Investment that Takes Account of the Needs
The list was first adopted by the OIE in 2007 and then of All Countries and Increase Investment
updated in 2013 and 2015. It was based on information in New Medicines, Diagnostic Tools,
obtained from a survey of OIE member countries. There Vaccines, and Other Interventions
is considerable overlap of the WHO and OIE lists; for While this particular objective of the WHO Global Ac-
example, third- and fourth-generation cephalosporins, tion Plan is aimed largely at the human health sector,
there is also a need for investments in the animal health Codex Alimentarius is a set of international food
sector that reduce the need for antimicrobials, such as standards administered under the auspices of the FAO
additional vaccines and other nonantimicrobial disease and WHO. In 2001, in recognition of the importance
control strategies. of antimicrobials to human health as well as animal
health, Codex recommended that the FAO, OIE, and
WHO jointly address antimicrobial resistance issues.
CURRENT ROLES OF INTERNATIONAL One outcome was a series of joint FAO/WHO/OIE
ORGANIZATIONS IN ONE HEALTH ASPECTS expert workshops on nonhuman antimicrobial usage
OF ANTIMICROBIAL RESISTANCE and antimicrobial resistance that implicitly took a One
Several international organizations have made impor- Health perspective (33, 154, 163, 169).
tant One Health contributions to the containment of The 29th session of the Codex Alimentarius Com-
antimicrobial resistance. Since the early 1990s, WHO mission established the Ad Hoc Intergovernmental Task
has undertaken several expert, multidisciplinary, multi- Force on Antimicrobial Resistance with a mandate to
sectoral consultations and advisory groups, compiled propose guidelines for risk analysis of foodborne anti-
considerable objective evidence of and scientific opinion microbial resistance (170). These guidelines are most
about the human health impacts of antimicrobial use applicable to national public health agencies that regu-
in animals, and formulated wide-ranging recommen- late the nonhuman use of antimicrobials (92). There is
dations applicable to all stakeholders (e.g., regulatory a focus on foodborne antimicrobial resistance (to the
authorities, pharmaceutical industry, animal production exclusion of nonhuman sectors, such as companion
industry, veterinarians, farmers, public health, con- animals and the environment) because Codex is a food
sumers) (155). The first was the 1997 report Medical standards organization. This undertaking built on pre-
Impact of the Use of Antimicrobials in Food Animals vious work on risk assessment and management of
(34), which was quickly followed by numerous others foodborne chemical and microbiological hazards con-
(6, 35, 102, 155). The need to consider the human health ducted by Codex, as well as the OIE and VICH (Inter-
importance of antimicrobials when managing antimi- national Cooperation on Harmonization of Technical
crobial resistance in animals led to the previously men- Requirements for Registration of Veterinary Medicinal
tioned work by WHO to categorize antimicrobial classes Products). The resulting Guidelines for Risk Analysis of
according to their relative importance in human medi- Foodborne Antimicrobial Resistance (CAC/GL 77-2011)
cine (42, 161). Furthermore, since 2008, the WHO provide a methodology for evidence-based decision-
Advisory Group on Integrated Surveillance of Antimi- making and policy formation on One Health dimensions
crobial Resistance has issued six reports that include of antimicrobial resistance and will be particularly im-
scientific information, guidelines for integrated surveil-

portant if antimicrobial resistance control becomes an
lance of antimicrobial resistance and antimicrobial use, international trade issue (170).
and recommendations in support of global efforts to On the international front, the European Union has
contain antimicrobial resistance, particularly in the de- been very active in One Health antimicrobial resistance
veloping world (37, 123, 166). WHO recently launched activities, particularly with regard to the regulation of
new guidelines on the use of medically important anti- antimicrobials for veterinary use and in the integrated
microbials in food-producing animals, recommending surveillance of antimicrobial resistance and antimicro-
that farmers and the food industry stop using antimi- bial use (17, 25, 26, 38, 43, 67, 104, 110, 124, 171–
crobials routinely to promote growth and prevent dis- 173). The European action plan to address antimicro-
ease in healthy animals. The purpose of the guidelines is bial resistance declared the need for a One Health ap-
to preserve the effectiveness of antimicrobials that are proach to address antimicrobial resistance, in view of the
important for human health by reducing their excessive interconnection between animal health, human health,
use in animals (37). and ecosystems (147). In many ways, the European ap-
The OIE has contributed technical guidance on anti- proach is a model for other regions/countries to follow
microbial resistance and antimicrobial use monitoring, because it is relatively proactive, thorough, consistent
antimicrobial resistance risk analysis, and the prudent with international standards, policy oriented, and well
use of antimicrobials in veterinary medicine and aqua- communicated through abundant publicly available in-
culture (167, 168). As mentioned previously, the OIE formation on antimicrobial use policies and the scientific
also developed a list of critically important antimicro- information on which they are based. European agen-
bials for animal health (162). cies with important responsibilities in this One Health
approach include the EMA, the European Center for antimicrobial use data from Europe, including analyses
Disease Control (ECDC), and the European Food Stan- of statistical associations between antimicrobial resis-
dards Agency (EFSA). The Committee for Medicinal tance and antimicrobial use data across sectors (26,
Products for Veterinary Use of the EMA regulates vet- 171). While recognizing the limitations in the data, the
erinary drugs across the European Union and has ar- analyses demonstrated positive ecologic (national level)
ticulated a strategy to address antimicrobial resistance associations between consumption of antimicrobials and
concerns that includes periodic re-evaluation of mar- resistance in bacteria to corresponding antimicrobials in
keting authorizations, public release of decisions, pro- both humans and animals. There were also some posi-
motion of alternatives to antimicrobials, advice, and tive associations between antimicrobial consumption in
reflection papers (172). An example of the latter is the animals and resistance in bacteria from humans. These
recent review of colistin use in human and veterinary findings reinforce the need for many countries to reduce
medicine in Europe that addresses resistance mecha- the overall consumption of antimicrobials in both the
nisms, evidence of the selection and spread of colistin human and animal sectors (26).
resistance, a profiling of the risks to public health from
the use of colistin in animals, and risk management
options, including those rejected and those recom- ONGOING ONE HEALTH CHALLENGES IN
mended with full discussion of the rationale (67). ADDRESSING ANTIMICROBIAL RESISTANCE
Monitoring of veterinary antimicrobial use from coun- The need for a One Health approach to address anti-
tries within the European Union and European Economic microbial resistance is now firmly established at the in-
Area (EEA) has been conducted since 2009 under the ternational level and is included in the action plans of
ESVAC (European Surveillance of Veterinary Antimi- many countries around the world (6, 147–153). This is
crobial Consumption) project (17, 25). ESVAC has been fostering communication among sectors that for too
instrumental in developing national-level antimicrobial long operated in isolation and offers the potential for
use data collection methodologies for the veterinary sec- greater coordination and understanding across sectors.
tor, technical units of measurement, and approaches for Other positive developments include the establishment
the collection of antimicrobial consumption data by ani- of integrated antimicrobial resistance and antimicrobial
mal species. ESVAC publishes annual reports on sales use surveillance systems in many countries, explicit
of veterinary antimicrobial agents in European Union/ consideration of antimicrobial resistance issues in the
European Economic Area countries (25). Monitoring of regulation of veterinary use of antimicrobials, a trend
antimicrobial use in the human health sector, conducted toward more countries terminating the use of medically
by the ECDC through ESAC-Net, has been in place since important antimicrobials as growth promoters, and

2001 and focuses on consumption in the community and actions by some major food industries to use their buy-
hospital sectors. Certain ESAC projects studied anti- ing power to limit the use of medically important anti-
microbial consumption in the community and hospital microbials in food animals. However, despite these
sectors. The ESAC has also conducted point-prevalence positive signs, the available data indicate that globally,
surveys of antimicrobial prescribing in hospitals and in antimicrobial use is still far too excessive in both the
long-term care facilities and developed indicators of ap- human and animal sectors and antimicrobial resistance
propriate antimicrobial prescribing in primary care. The among important pathogens continues to increase at
ESAC data were used to explain the variation of anti- alarming rates (2, 4, 16, 24). Much more progress is
biotic resistance in Europe and to assess the impact of needed in addressing these issues in the human and
interventions in the community (72). animal sectors on a global basis, in both developed and
Surveillance of antimicrobial resistance in Europe is developing countries.
conducted by the ECDC (bacteria from human infec- There are many challenges to improving antimicro-
tions) and EFSA (bacteria from animals and food). The bial stewardship in humans and animals (155, 160).
ECDC and EFSA publish annual summaries of anti- These include a lack of adequate motivation for change
microbial resistance (as well as zoonotic infections and and awareness of the need for all prescribers and users
food-borne outbreaks) for individual member states to be good antimicrobial stewards, a lack of oversight
within the European Union (75). The ECDC, EFSA, and and controls on antimicrobial availability in many coun-
EMA have also published Joint Interagency Antimicro- tries, and pressures on prescribers from patients and
bial Consumption and Resistance Analysis integrated animal owners to use antimicrobials even when they
reports and analyses of antimicrobial resistance and are unnecessary (4, 7, 154). Reflection on the history of
antimicrobial use shows, not surprisingly, that we have and the relatively limited uptake of animal treatment
been very quick to adopt uses for these drugs but ex- guidelines and formularies in most countries (147,
ceedingly slow to cut back on use when it is harmful to 155, 123, 174). To address antimicrobial resistance on
the wider community. In the veterinary/agricultural sec- a global scale, it is important that all countries have the
tors, most antimicrobials were authorized for use before basic regulatory, infrastructure, oversight, and enforce-
there was any systematic evaluation of the potential ad- ment capabilities to control antimicrobial availability
verse effects on antimicrobial resistance. Like pesticides, and use as laid out by international guidelines, such as
improved genetics of animals and crops, and advances in those from WHO and OIE (147, 155, 123). Related to
animal nutrition, large-scale use of antimicrobials was this is the need for good antimicrobial consumption
widely adopted during the post-WWII intensification data from all countries. Antimicrobial consumption is
and scaling-up of agriculture and is still considered in an essential indicator of resistance selection pressure
many circles as necessary for efficient food production. and, when adjusted for population size, allows for com-
In some countries, agricultural interests and veterinary parison between countries, regions, hospitals, veterinary
medical organizations have been too slow to accept clinics, farms, etc. This can be a powerful tool for im-
the scientific evidence of harm to public health from proving antimicrobial stewardship, as has been shown
excessive antimicrobial use in animal production and to in countries that are using it (60, 158). When collected
make the changes needed to raise animals humanely regularly at the level of prescriber or use (e.g., farm),
with reduced use of antimicrobials. Notwithstanding these data can be used to evaluate and improve stew-
the tremendous new insights provided by antimicrobial ardship and to set benchmarks and reduction targets.
resistance research and surveillance, and major improve-
ments in antimicrobial resistance risk analysis meth-
odologies, there will always be uncertainties and data CONCLUSION
gaps in a subject as complex as antimicrobial resistance. History has shown that it is not feasible to neatly sepa-
Improvements in our ability to analyze bacteria and their rate antimicrobial classes into those exclusively for use
genes using whole-genome sequencing and metageno- in humans or animals, with the exception of new anti-
mics in animals, people, and the environment, along microbial classes. These should probably be reserved for
with metadata analysis and phylogenetic studies should use in humans as long as few or no alternatives are avail-
allow us to make better links and understand with more able. The majority of classes, however, will be available
precision the ways they multiply and spread. More for use in both sectors, and the challenge for One Health
importantly, it will help us better track how antimicro- is to ensure that the use of these drugs is optimal overall.
bial resistance genes that have long been in existence This is likely to be achieved when antimicrobials used in

spread and recirculate in plants, insects, animals, people, both sectors are used for therapy, only rarely for pro-
soil, and water. This will help us better understand what phylaxis, and never for growth promotion and when we
is driving the development and the spread of antimi- better control the types and amounts of antimicrobials
crobial resistance and better manage it. plus the numbers of resistant bacteria that we allow to be
Nevertheless, given the highly unpredictable nature placed into the environment.
of antimicrobial resistance, and the propensity of resis-
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Antimicrobial Resistance:

a One Health Perspective

ABSTRACT One Health is the collaborative eﬀort of multiple INTRODUCTION

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FIGURE 1 Diagrammatic representation of the routes of transmission of antimicrobial

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Category Human health (WHO) (42) Animal health (OIE) (162)

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FIGURE 4 Role of modiﬁable drivers for antimicrobial

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