Module 1: Antimicrobial resistance

PUBLISHED
January 8, 2023

A brief history of antimicrobial resistance (AMR)

Until the 20th Century, influenza and pneumonia, tuberculosis, and enteric infections were
among the top three causes of death. The average life expectancy of an adult in Western
Europe was approximately 50 years, and 2% of children failed to live beyond age 5 because
of premature deaths caused mostly by infectious diseases.

Industrialization and increasing wealth during the 19th century brought improvements in
drinking water and sanitation in many countries, leading to reductions in communicable
enteric infections and improvement in life expectancy Figure 1. By the early 20th century,
vaccines for pertussis, diptheria, yellow fever and tuberculosis were introduced. However,
common bacterial infections remained a serious medical threat. Streptococcal throat
infections were sometimes fatal, ear infections could progress to deafness, mastoiditis or
meningitis. Minor surgeries were associated with risk of life-threatening infections. Maternal
mortality during childbirth approached 2%.

Figure 1: Changes in life expectancy over 500 years.

Antibacterial resistance pre-dates the medical use of antibiotics and is estimated to have
emerged with bacteria on earth approximately 2-2.5 billion years ago. In contrast, the first
humans are believed to have existed around 2 million years ago. The first recorded use of
antimicrobial -like substances was by the early Egyptians, Greeks, and Chinese, who used
natural products with antimicrobial activity for millennia to treat wounds and infections, even
if the causes of these diseases were unknown until the 19th and 20th century. Therefore,
antibiotic resistance was not created by humans and misuse of antibiotic inevitable-it is a
biologic certainty and evolutionary destiny.

The microbiologist and immunologist Paul Ehrlich (1854-1915) (Figure 2) is credited with
the discovery and first medical application of a synthetic antibiotic arsphenamine (Salvarsan)
for the treatment of a bacterial infection-syphilis. He was awarded the Nobel Prize in
Medicine in 1909.
Figure 2: German immunologist Paul Ehrlich (1854-1915). Image: Library of Congress
Yet it was the serendipitous discovery of penicillin in 1928 by Alexander Fleming (Figure 3)
and its subsequent purification of the drug in quantities needed for clinical testing by Drs.
Florey and Chain in the 1930s, that initiated the true start of the modern antibiotic era.
Alexander Fleming was awarded the Nobel Prize in Medicine in 1945.

Interestingly, the term antibiotic was actually coined by Selman Waksman, a biochemist and
microbiologist who discovered the first effective treatment for tuberculosis, streptomycin,
and was awarded the Nobel prize in 1952.

Alexander Fleming was among the first physicians to caution about the risks of resistance to
penicillin if used too little or for a too short of period during treatment. In his Nobel Prize
acceptance speech, Dr. Fleming noted:
Figure 3: Sir Alexander Flemming (1881-1955). Image: Imperial War Museum

“It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them
to concentrations not sufficient to kill them, and the same thing has occasionally happened in
the body. The time may come when penicillin can be bought by anyone in the shops. Then
there is the danger that the ignorant man may easily under-dose himself and by exposing his
microbes to non-lethal quantities of the drug make them resistant.”

-Sir Alexander Fleming, Nobel Prize Lecture, December 11, 1945

By 1947, Fleming’s predictions had come true as the first cases of penicillin resistance were
already being reported. Thus began the modern era’s “arms race” between new antibiotic
discovery and increasing antimicrobial resistance.

Initially, antibiotic discovery seemed to keep pace with resistance as a host of new chemical
classes were developed and introduced in the 1950s-1980’s. For the first half of the century,
the repeated and successful response to emerging resistance was to discover new
antibiotics [1].

Yet by the 1980’s, the discovery of new agents began to slow and this strategy began to
fail Figure 4. The last truly “new” antibiotic class discovered that reached the market was in
1987. Since then, there has been a lack of innovation in the field, and today there are few
novel antibiotic classes in the drug pipeline.

In Module 2 we will examine the scientific challenges and market forces that have made new
antibiotic discovery increasingly difficult and how access to newer antibiotics is limited in
many parts of the world.
Figure 4: Antibiotic discovery timeline. Source: www.reactgroup.org
Once antibiotic resistance develops, it can spread from one colonised patient to another
patient if appropriate hygienic precautions (e.g., hand hygiene, isolation) are not followed.
The risk of resistant bacteria spreading is enhanced in crowded environments, especially
when people in the surrounding area are receiving antibiotics - a common scenario in
hospitals in wards of critically-ill patients.

The consequences of faltering antibiotic discovery are now being felt worldwide as more and
more bacterial infections are becoming harder to treat. Especially worrisome is the lack of
antibiotics against common Gram-negative bacteria (i.e. Escherichia coli, Klebsiella
pneumonia, Pseudomonas aeruginosa, Acinetobacter baumannii) that are increasingly
resistant to all but last-line antibiotics. The rapid global spread of multi- and pan-resistant
bacteria, also known in the lay press as “superbugs,” can cause infections that are not
treatable with existing antibiotics.

How quickly can antibiotics develop resistance?

Click this link to watch a YOUTUBE video of how quickly Escherichia coli and develop
resistance to ciprofloxacin. Another excellent YOUTUBE video from the FRONTLINE
Program: When Antibiotics Don’t Work

Global response to antimicrobial resistance

Recognizing the growing global threat of antibiotic resistance (AMR) on human health but
also the economy and human development, The World Health Organization (WHO) and The
Organisation for Animal Health (OIE) developed in 2001 a Global Plan for Containment of
Antimicrobial Resistance that subsequently led to a Global Action Plan for AMR in 2017 and
more recently a “Call to Action on Antimicrobial Resistance” in 2021. The plan outlines 21
strategies and 5 strategic objectives action plans that should be implemented in member states
to address AMR. These include:

1. Improvements in the awareness and understanding of antimicrobial resistance through

effective communication, education and training
2. Strengthening of knowledge and evidence base of AMR through surveillance and
research
3. Reductions in the incidence of infection through effective sanitation, hygiene and
infection prevention measures
4. Optimization the use of antimicrobial medicines in human and animal health
 5. Development of an economic case for sustainable investment in AMR research that
takes account of the needs of all countries, and increase investment in new medicines,
diagnostic tools, vaccines and other interventions

One aspect of this action plan was the development of Global Antimicrobial Resistance and
Use Surveillance System (GLASS). A link the 2022 report can be here

The WHO also proposed a Priority Pathogen List for research and development of new
antibiotics and established a global antimicrobial use and surveillance program. This list
includes bacterial pathogens that are considered to be be the biggest threat to human health in
addition to Mycobacterium tuberculosis. The WHO list breaks down pathogens into three
groups:

Table 1: WHO priority pathogens

Priority Pathogens included
Acinetobacter baumannii (Carbapenem-resistant)

Critical Pseudomonas aeruginosa (Carbapenem-resistant)

Enterbacterales (3rd generation cephalosporin, carbapenem-resistant)

Enterococcus faecium, vancomycin-resistant

Staphylococcus aureus, methicillin-resistant, vancomycin intermediate and resistant

Helicobacter pylori, clarithromycin-resistant

High
Campylobacter, fluoroquinolone-resistant

Salmonella spp., fluoroquinolone-resistant

Neisseria gonorrhoeae, 3rd generation cephalosporin-resistant, fluoroquinolone-resistant

Streptococcus pneumoniae, penicillin-non-susceptible

Medium Haemophilus influenzae, ampicillin-resistant

Shigella spp., fluoroquinolone-resistant

These pathogens may exhibit multi-drug resistance (MDR), extensive drug resistance (XDR)
or pan-drug resistance (PDR) [2]. Difficult-to-treat resistance (DTR) is a newer definition
used to define isolate resistance patterns that require the use of less-effective or more toxic
“reserve” antibiotics- e.g., Acinetobacter baumanii susceptible only to colistin and
tobramycin [3].

What do these resistance definitions mean?

The resistance definitions used by the WHO have specific meanings.

 MDR-resistance to one agent in at least 3 antibiotic categories

 XDR-resistant except to 2 or fewer antibiotic categories
 PDR-resistant to all agents in all antibiotic categories
 DTR-requires the use of less-effective or more toxic “reserve” antibiotics
Currently, both the WHO and OIE have also developed lists of antibiotics that are considered
of “critical importance” for human and animal medicine. These lists help establish priorities
for antimicrobial resistance surveillance and new drug development.

What are the drivers of antimicrobial resistance?

AMR is a natural phenomenon. Most antimicrobial drugs are naturally produced by micro-
organisms, including environmental fungi and saprophytic bacteria, or are synthetic
modifications of these natural products, with only a few drugs (e.g., sulphonamides and
fluoroquinolones) being wholly synthetic. Yet AMR selection is accelerated by antimicrobial
exposure in health care, agriculture, and the environment. Further transmission is affected by
standards of infection control in healthcare settings, sanitation, access to clean water, access
to assured quality antimicrobials and diagnostics, travel, and migration.

Antimicrobials are among the most commonly prescribed drugs used in human medicine, yet
up to 50% of all antimicrobials prescribed to people are considered unnecessary. This use,
misuse, or overuse of antimicrobial drugs is considered to be a major driving force towards
antimicrobial resistance. Globally, the use of antimicrobials is accelerating worldwide,
particularly in LMICs, as antimicrobials become readily accessible and affordable. The use
of WHO Watch antibiotics increased 90.0% worldwide and 165% in LMICs between 2000
and 2015.

In medicine, the concentration of antibiotic prescribing might be highest in inpatient settings,

with 30–40% of patients on antibiotics in European hospitals. However, the overall
highest quantity of antimicrobial consumption is highest in the community setting.

Yet, more antimicrobials are used in food production than in human beings, with marked
national differences in the number of antimicrobial drugs used in food producing animals as
shown in Figure 5. It has been estimated that 73% of all antibiotic use per by weight is
for food production in animals [4]. Various studies have shown that antimicrobial
resistance has, at least in part, emerged as a result of the selective pressure exerted by
antimicrobial use outside of human medicine, namely in veterinary medicine, food-animal
and fish production, and agriculture. Therefore to effectively AMR, a multifaceted or ONE-
HEALTH approach is required.
Figure 5: Modifiable risk factors that drive antimicrobial resistance. Figure form Homes et
al. [5].

AMR in Low-Middle Income Countries (LMICs)

AMR is a global problem, but its prevalence across the globe varies with antibiotic
consumption, access to clean water and adequate sanitation, vaccination coverage, and access
to quality healthcare. The latest WHO report, based on AMR data from 66 countries,
illustrates an alarming picture of the global status of AMR as an increasing number of
countries are now reporting high rates of resistance among antimicrobials used to treat
common infections.

There are considerable knowledge gaps regarding AMR prevalence in LMICs that lack
clinical and laboratory capacity and surveillance infrastructure. A systematic review of 144
16 studies across Africa lacked AMR data for approximately 40% of the African countries. In
the Asia and Pacific region, South East Asia is estimated to have the highest risk of AMR
emergence and spread, with the highly transferable New Delhi metallo-beta-lactamase-1
(NDM-1) as an example. Furthermore, China and India alone accounted for more than one-
third of the global incidence of 17 multidrug-resistant (MDR) tuberculosis [6].

COVID-19 has focused global attention on the inequitable access to the tools needed to
control the pandemic, with high-income countries (HICs) and low- and middle-income
countries (LMICs) at opposite ends of the scale. In the case of antibiotic resistance, a
pandemic projected to cause four times more deaths per year than occurred from COVID-19
during 2020, inequity between HICs and LMICs is a major challenge [7]:

How is Low-Middle-Income Country (LMIC) defined?

The World Bank defines lower middle income economies as countries where the per capita
gross national income (GNI) falls between $1,026 and $3,955. The countries that are part of
the upper MIC classification with a GNI that falls between $3,956 and $12,475.

Countries currently included: Afghanistan, Albania, Algeria, Angola, Antigua and Barbuda,
Argentina, Armenia, Azerbaijan, Bangladesh, Belarus, Belize, Benin, Bhutan, Bolivia,
Bosnia and Herzegovina, Botswana, Brazil, Burkina Faso, Burundi, Cabo Verde, Cambodia,
Cameroon, Central African Republic, Chad, China (People’s Republic of), Colombia,
Comoros, Democratic Republic of Congo, Congo, Costa Rica, Côte d’Ivoire, Cuba, Djibouti,
Dominica, Dominican Republic, Ecuador, Egypt, El Salvador, Equatorial Guinea, Eritrea,
Eswatini, Ethiopia, Fiji, Gabon, Gambia, Georgia, Ghana, Grenada, Guatemala, Guinea,
Guinea-Bissau, Guyana, Haiti, Honduras, India, Indonesia, Iran, Iraq, Jamaica, Jordan,
Kazakhstan, Kenya, Kiribati, Democratic People’s Republic of Korea, Kosovo, Kyrgyzstan,
Lao People’s Democratic Republic, Lebanon, Lesotho, Liberia, Libya, North Macedonia,
Madagascar, Malawi, Malaysia, Maldives, Mali, Marshall Islands, Mauritania, Mauritius,
Mexico, Micronesia, Moldova, Mongolia, Montenegro, Montserrat, Morocco, Mozambique,
Myanmar, Namibia, Nauru, Nepal, Nicaragua, Niger, Nigeria, Niue, Pakistan, Palau, Panama,
Papua New Guinea, Paraguay, Peru, Philippines, Rwanda, Saint Helena, Samoa, São Tomé
and Príncipe, Senegal, Serbia, Sierra Leone, Solomon Islands, Somalia, South Africa, South,
Sudan, Sri Lanka, Saint Lucia, Saint Vincent and the Grenadines, Sudan, Suriname, Syrian
Arab Republic, Tajikistan, Tanzania, Thailand, Timor-Leste, Togo, Tokelau, Tonga, Tunisia,
Turkey, Turkmenistan, Tuvalu, Uganda, Ukraine, Uzbekistan, Vanuatu, Venezuela, Vietnam,
Wallis and Futuna, West Bank and Gaza Strip, Yemen, Zambia, Zimbabwe

LMICs are particularly susceptible to the emergence and rapid spread of AMR for several
reasons:

 High population density

 Lack of access to clean water, suboptimal sewage systems, poor sanitation
 Poor healthcare infection control practices
 Increasing consumption of antimicrobials in humans
 Availability and distribution of poor-quality (counterfeit) medicines
 Lack of regulation on antimicrobial use in farming, and pharmaceutical industry
pollution

The health and economic impact of AMR is also more severe and longer lasting in LMICs
versus HICs. AMR is generally associated with:

 Increased mortality and health costs

  Antibiotics effective against AMR are more expensive and not affordable for many
patients
 Increasing use of antibiotics with efficacy against AMR leads to higher resistance to
“last-line” antibiotics Figure 6.
 In fact, carbapenem consumption is increasing at a rapid pace in poor economies [8].
 Lack of access to antibiotics in some poorer countries, a driver of mortality
particularly in children under 5 years of age
 Lack of access to newer, expensive antibiotics needed to treat the increasing toll of
MDR and XDR bacterial infections
 Inequity in ability to provide the basic public health interventions that drive many of
the social determinants of infectious diseases in LMICs

Figure 6: Global antibiotic use and resistance in (A) High-income countries versus (B) Low-
income countries. Source: CDDEP [6].
The singular effectiveness of access to clean water, sanitation and hygiene, called WASH, in
preventing the spread of disease is well understood, yet billions of people around the world
still lack access to these necessities [9].

 Currently, 2.1 billion people live without access to safe drinking water and 4.5 billion
people are without access to adequate sanitation.
 Every day, 1300 children under 5 die from preventable diarrhoeal diseases, including
cholera, caused by contaminated water and poor sanitation.
 1 in 3 healthcare facilities lacks soap and water or hand sanitizer where staff provide
patient care. Billions of patients worldwide must rely on these facilities.
 In some countries, up to 90% of women receive routine prophylactic antibiotics
during childbirth, highlighting the conditions under which they are delivering their
babies and what would cause the inevitability of infection

The cumulative lack of WASH adds up to children and adults not only getting unnecessarily
sick—with the associated suffering, medical costs and loss of income or schooling—they are
relying on antibiotics to get better [10]. The challenge here is that WASH is a public works
solution for a public health problem. WASH is not a pill or ‘quick fix’. It requires capital
investment, system strengthening, and behaviour change to ensure that clean water and
functional toilets are available and utilized day-in and day-out. These issues require a
different set of skills than those possessed by medical and public health professionals.

In LMICs, an estimated 670 million people still practice open defaecation in 2017, and only
one in three people have access to safe drinking water, resulting in high rates of diarrheal
disease and equally large amounts of inappropriate antibiotic use [10]. According to WHO
surveys, vaccination, a cornerstone of infection prevention and reducing the need for
antibiotic use, is suboptimal in both HICs and LMICs. In 2019, global third-dose coverage
for childhood pneumococcal vaccination in 149 member states was only 48%, and global
rotavirus vaccine coverage was estimated at 39%. In South Africa, middle-income country,
procures less than 1 million doses of influenza vaccine for its annual influenza season,
despite in excess of 10 million people being identified as high-risk for influenza and
prioritized for vaccination.

Optimizing infection prevention on farms and making improvements to housing conditions

and feed to reduce illness in animals is also critical in food production to offset the need for
antibiotic growth promotion or metaphylaxis in food production animals. While there has
been progress in the reduction of antibiotic use in farms in the EU and other HICs, attention
nor funding for such improvements in LMICs has not even been proposed. “It’s one thing
being told to reduce your antibiotic use in food production, it’s another to have the means to
do so, even for the most committed resource-poor farmer.

As discussed above, the emergence of antimicrobial resistance (AMR) is a complex

phenomenon and is intensified by selective pressure through antibiotic use in humans,
animals, and agriculture. The transmission of AMR to humans occurs from contact with
animals (including food), other humans, and the environment. Transmission is facilitated by
several factors, including high population density, lack of access to clean water, suboptimal
sewage systems, poor sanitation, and poor healthcare infection control practices, all of which
are more common in LMICs. With the increasing consumption of antimicrobials in humans,
lack of regulation on antimicrobial use in farming, and pharmaceutical industry pollution, it
may not be surprising that relatively higher levels of AMR among human pathogens are
being reported from LMICs Figure 7.
Figure 7: Drug resistance index (DRI) across countries. The drug resistance index is a
composite score derived by multiplying the proportion of each antibiotic used to treat a set of
pathogens by the proportion of all isolates that were resistant to that drug. Blue bars represent
high-income countries (HICs) dark blue bars represent low-middle income countries (LMICs)
[6].
In 2022, The Antibiotic Resistance Collaboration published an analysis of mortality rates
associated with antibiotic resistance by country [11]. The authors estimated disability-
adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 23
pathogens and 88 pathogen–drug combinations in 204 countries and territories in 2019. Data
were obtainted from systematic literature reviews, hospital systems, surveillance systems, and
other sources, covering 471 million individual records or isolates and 7585 study-location-
years. Predictive statistical modelling was used to produce estimates of AMR burden for all
locations, including for locations with no data Figure 8.
Figure 8: All-age rate of deaths attributable to and associated with bacterial antimicrobial
resistance by GBD region, 2019 Estimates were aggregated across drugs, accounting for the
co-occurrence of resistance to multiple drugs. Error bars show 95% uncertainty intervals.
GBD=Global Burden of Diseases, Injuries, and Risk Factors Study. Graph in from
reference [11].
These data demonstrate a widening gap in the impact of antimicrobial resistance between
HIC vs. LMICs.

The international focus on awareness, surveillance, infection prevention, stewardship and

research and development (R&D) of new antibiotics may actually be widening the equity gap
by pouring millions of dollars into R&D of new antibiotics and surveillance systems, while
the intervention that could benefit LMICs the most, infection prevention, has received a
relatively few resources.

What are the possible solutions to address resistance inequality?

Recently the COVID-19 pandemic has refocused attention that in infectious diseases The
Access to COVID-19 Tools (ACT)-Accelerator that we will discuss in Model 2 has shown
that financial contributions from HICs to a LMIC-pool can improve equitable access to
diagnostics, therapeutics and vaccines, but it is conceivable that the same model could be
broadened to encompass tools that would support major social change for AMR.

How can the effectiveness of antimicrobials be preserved?

Strategies for the prevention and containment of AMR often focus on:

1. Improvement of infection diagnosis and prescription practices (antimicrobial

stewardship)
2. Reduction of antimicrobial use in agriculture and environmental exposure in general
3. Development of new antimicrobials
4. Access to essential medicines of assured quality
5. Improvement of AMR surveillance

Antimicrobial stewardship is a coordinated program that promotes and focuses on the

appropriate use of antimicrobials and strategies to improve patient outcomes, reduces
antimicrobial resistance, and decrease the spread of infections caused by multidrug-resistant
organisms Figure 9. These programs may be implemented through the use of institution-
specific treatment guidelines and an antibiotic stewardship team (typically infectious diseases
physicians with a clinical pharmacist) who carry out full-time activities to promote and
encourage appropriate antibiotic use.

While these programs have been shown to be successful Figure 10, many gaps remain in the
knowledge of how to optimally design and sustain stewardship programs in the hospital, and
such programs are rarely implemented in community settings where most antibiotic
consumption takes place.
Figure 9: Examples of antimicrobial stewardship efforts
Figure 10: Examples of antimicrobial stewardship outcomes

WHO AWARE Antibiotic Classification

Since 2017, the WHO has published the AWaRe Antibiotic Classification List to support
antibiotic stewardship efforts at local, national and global levels. The classification takes into
account the impact of different antibiotics and antibiotic classes on antimicrobial resistance,
to emphasize the importance of their appropriate use.

Antibiotics are classified into three groups: Access, Watch and Reserve.

 The “Access” group includes antibiotics that have activity against a wide range of
commonly encountered susceptible pathogens while also showing lower resistance
potential than antibiotics in the other groups. Selected Access group antibiotics are
recommended as essential first or second choice empiric treatment options for
infectious syndromes reviewed by the Essential Medicines List (EML) Expert
Committee and are listed as individual medicines on the Model Lists of Essential
Medicines to improve access and promote appropriate use.
 The “Watch” group includes antibiotic classes that have higher resistance potential
and includes most of the highest priority agents among the Critically Important
Antimicrobials for Human Medicine and/or antibiotics that are at relatively high risk
of selection of bacterial resistance. These medicines should be prioritized as key
targets of stewardship programs and monitoring. Selected Watch group antibiotics are
recommended as essential first or second choice empiric treatment options for a
 limited number of specific infectious syndromes and are listed as individual
medicines on the WHO Model Lists of Essential Medicines.
 The “Reserve” group includes includes antibiotics and antibiotic classes that should
be reserved for treatment of confirmed or suspected infections due to multi-drug-
resistant organisms. Reserve group antibiotics should be treated as “last resort”
options.
 Selected Reserve group antibiotics are listed as individual medicines on the WHO
Model Lists of Essential Medicines when they have a favourable risk-benefit profile
and proven activity against “Critical Priority” or “High Priority” pathogens identified
by the WHO Priority Pathogens List1, notably carbapenem resistant
Enterobacteriaceae. These antibiotics should be accessible, but their use should be
tailored to highly specific patients and settings, when all alternatives have failed or are
not suitable. These medicines could be protected and prioritized as key targets of
national and international stewardship programs involving monitoring and utilization
reporting, to preserve their effectiveness.
 Finally, the list includes “not-recommended” antibiotics- fixed-dose combinations
of multiple broad-spectrum antibiotics listed here is not evidence-based, nor
recommended in high-quality international guidelines. WHO does not recommend
their use in clinical practice.

The AWaRe tool is useful for monitoring antibiotic consumption, defining targets and
monitoring the effects of stewardship policies that aim to optimize antibiotic use and curb
antimicrobial resistance. The WHO 13th General Programme of Work 2019–2023 includes a
country-level target of at least 60% of total antibiotic consumption being Access group
antibiotics. Attainment rates of these consumption targets by country is currently reported in
the GLASS surveillance system.

In December 2022, the the WHO published The WHO AWaRe (access, watch, reserve)
antibiotic book. The book provides “concise, evidence-based guidance on how to optimize
use of antibiotics included on WHO’s Model Lists of Essential Medicines. It includes
information on the choice of antibiotic, dose, route of administration, and duration of
treatment for more than 30 of the most common clinical infections in children and adults in
both primary health care and hospital settings.”

Diagnostic stewardship

Inappropriate diagnostic testing can drive unnecessary antibiotic use and is considered an
essential component in stewardship programs. In 2012, The American Board of Internal
Medicine initiated the “Choosing Wisely” campaign design to educate both practitioners and
patients about the importance of avoiding unnecessary diagnostic tests. A link the website can
be found here.

Diagnostic stewardship- Inappropriate diagnostic testing for UTIs

Urine dipsticks (tests strips for leukocyte esterase and nitrates) are frequently used to
“diagnose” urinary tract infections, but are one of the most common drivers for inappropriate
antibiotic prescriptions. Advani recently reviewed the use (and misuse) of this test [12].
The problems of urine dipstick testing were also discussed on the ID:IOTS podcast episode
“Urinalysis paralysis.” The podcast is an entertaining and informative discussion by two UK-
based infectious diseases physicians. A link to the episode can be found here

Case study: A antibiotic stewardship program on a national level in a LMIC

The Antibiotics Smart Use (ASU) program in Thailand was an implementation research
project comprised of three phases:

 Implementation of behavior change interventions

 Examination of the feasibility of scale up; and
 Identification of mechanisms for sustainability

The guiding principle of the ASU program is that antibiotics should not be used to treat non-
bacterial infections. ASU started by trying to reduce unnecessary antibiotic use in patients
with 3 conditions: upper respiratory tract infections, especially common colds with sore
throat; acute diarrhea and simple wounds.

The program focused on simple measures, compatibility with the providers’ values,
advantages with respect to current practice; performing testable interventions, and
transparency.

In the beginning, ASU consisted of a network of researchers from Thailand’s Ministry of

Public Health and pharmacists and doctors from Srinakharinwirot University and
Chulalongkorn University.

 In phase 1 (2007- 2008) they piloted educational and training reforms to improve
prescribing in 10 hospitals and 87 primary health centres in one province. Antibiotic
prescription, provider attitudes of effectiveness and knowledge of antibiotics, non-
prescription rates in case of non-bacterial infections, and patient health and
satisfaction were monitored.
 In phase 2 (2008-2009) the same indicators were then used to scale up the program to
three provinces and two hospital networks, counting to 44 hospitals and 621 primary
health care centres.
 The 3rd phase (2010 – Present) is focusing on long-term sustainability and scale up
of ASU – initially to 22 hospital networks in 15 provinces, and then subsequently
across the entire country.

Phase 1 Phase 2 Phase 3,

Characteristics
(1 year) (1 year, 3 months) transition perio
Test effectiveness of ASU in changing Test feasibility of scaling up Strengthen netwo
Goals
antibiotic prescription behavior ASU model scaling up mecha
3 provinces and 2 networks of 22 hospital netw
Target 1 province
public and private hospitals provinces
Funding
WHO, Thai FDA HSRI, NHSO, Thai FDA DSMDC, Thai F
agencies
Coordinating
Thai FDA Thai FDA DSMDC, Thai F
agencies
Budget US$ 33,000 US$ 73,000 US$ 123,000
 Phase 1 Phase 2 Phase 3,
Characteristics
(1 year) (1 year, 3 months) transition perio
spending
Spillover effect No Yes Yes
The program also had many simple but innovative community health interventions. For
example, holding up a simple concave mirror to consumers trying to buy antibiotics for
treating the common cold and cough was part of a new initiative in Thailand by community
pharmacists to lower consumption of antibiotics Figure 11.

Figure 11: Mirror toolkit for patients to self-assess their sore throat symptoms in Thai
Pharmacies
After completion of Phases 1-2, the following results were noted:

 Positive effects on reducing antibiotic prescribing. Antibiotic use was reduced by 18-
46%
 The percentage of patients who did not receive antibiotics increased by 29.1%,
whereas there was no change in the control groups who were not involved in the ASU
program
  Patient health and satisfaction rates were high, 96%-99.3% of patients surveyed who
did not refeive antibiotics recovered and felt better within 7-10 days after their
medical visits
 Success in scaling up. The number of hospitals adopting ASU increased from 44
hospitals (2008) to more than 600 hospitals (2010).

The ASU project is having an impact beyond the borders of Thailand too and is now seen as a
model for replication in other parts of south-east Asia with interest elicited from as far away
as Africa and Latin America. Read more about the ASU project at react.org

Antimicrobial resistance in Italy

Southern Europe, including Italy, has among the highest rates of resistance for pathogens
included on the WHO Priority Pathogen list. For example, surveillance data from the
European Centres for Disease Control (ECDC) have reported a dramatic increase in
multidrug-resistance (MDR) in Italy since 2009, with now more than one-third of Klebsiella
pneumoniae resistant to previously-considered last-line antibiotics such as
carbapenems Figure 12. An interactive ECDC resistance atlas showing differences in
resistance rates between countries for common antibiotics can be found here. Similarly, the
Italian Antimicrobial Surveillance system (Micronet Resistance Surveillance) has reported:
that for 2021:

 23.8% of Escherichia coli are resistant to 3rd generation cephalosporins

 29.5% of Klebsiella pneumoniae are resistant to carbapenems (including 33.1%
resistant to multiple drug classes)
 16.4% of Pseudomonas aeruginosa are resistant to carbapenems
 86.9% of Acinetobacter spp. are resistant to carbapenems with 78.8% of species
resistant to multiple drug classes
 For the Gram-positive organism Staphylococcus aureus, the percentage of methicillin-
resistant isolates (MRSA) remained stable, around 29.9%%, while a worrying trend
continues to increase in the percentage of Enterococcus faecium isolates resistant to
vancomycin, which in 2020 was equal at 28.2%
 For Streptococcus pneumoniae there was a slight increase in both the percentage of
isolates resistant to penicillin (9.7%).
 Overall, higher antimicrobial resistance rates (around 40%) are observed in ICUs
versus general medical wards for both carbapenem-resistant K. pneumoniae and
methicillin-resistant S. aureus.
Figure 12: Regional differences in carbapenem-resistant Enterobacterales (CRE) bloodstream
infection- 2020 incidence per 100,000 residents in Italy. Source Micronet Resistance
Surveillance Program

The global future of AMR

 Drug-resistant infections already cause at least 700,000 deaths globally a year,
including 230,000 deaths from multidrug-resistant tuberculosis.
 The estimated total number of deaths due to AMR could climb to 10 million
deaths globally per year by 2050 under current projections Figure 13.
 Increasing resistance could lead to an unthinkable future of untreatable infections,
reversing more than a 100 years of medical progress.
o Routine medical procedures or surgery will become more dangerous and
associated with higher complication rates.
o Immunosuppression, cancer chemotherapy and transplantation may carry
unacceptable risk for many patients if infections cannot be effectively
prevented and treated.
 Economic and social progress in many countries will be dramatically impacted by
increasing AMR leading to political and social instability. The initial short-term
economic damage of uncontrolled antimicrobial resistance will be comparable to the
economic shocks experienced during the 2008-2009 global financial crisis and result
in dramatically-increased healthcare expenditures; reductions in food and feed
production, reduced economic output, and increased poverty and inequality. The
economic impact of antimicrobial resistance is predicted to be even greater and longer
lasting on low-and middle-income (LMIC) countries.
Figure 13: Projected deaths due to antimicrobial resistance in 2050. Source: O’Neil Report.

One-Health Perspective of AMR

Because the drivers of antimicrobial resistance lie in humans, animals, plants, food and the
environment, a sustained One Health response is essential to engage and unite all health and
environmental sectors around a shared vision and goals. “One Health” refers to designing and
implementing programmes, policies, legislation and research in a way that enables multiple
groups engaged in human, terrestrial and aquatic animal and plant health, food and feed
production Figure 15 and the environment to communicate and work together to achieve
better public health outcomes.
Figure 14: Rationale for one-health model for addressing AMR. Source: WHO

Antibiotic use in animal food production

Few antimicrobial classes are reserved exclusively for humans Figure 15. The vast majority
of antibiotics are used both in humans and animals, including domestic mammals, birds,
farmed fish and shellfish, honeybees and others.

Figure 15: Dairy farmer administering antibiotics in UK. Source: Financial Times
As noted earlier, 73% of all antibiotic consumption per weight is used for food
production in animals. Critically, two-third of all human infectious diseases that have
emerged or re-emerged in recent decades are zoonotic-i.e. they originated in animals.
Therefore the transmission of antibiotic resistance organisms from the foodchain to humans is
a major health concern.

In horticulture, tetracyclines, streptomycin, and other antimicrobials are used for the
prophylaxis and treatment of bacterial infections that affect plants (e.g., fire blight Erwinea
amylovora).

In veterinary medicine, there are major differences in the way antibiotics are used for
companion animals (e.g., dogs, cats, pet birds, horses) versus food-producing animals.
Antibiotic use in companion animals is broadly similar to humans for the treatment of
infections or in select cases prophylaxis, such as post-surgery. In the case of food animals, if
some animals are infected antibiotics may be administered through feed or water to the entire
group for reasons of practicality or efficiency. Metaphylaxis is a term used to describe
therapeutic/prophylaxis antibiotic treatment at a group level.

The most controversial type of group treatment in food animals is long-term, low-dose mass
antibiotic treatment for purposes of growth promotion Figure 16. This practice has a high
propensity to select for antimicrobial resistance and is driven by economic factors rather than
treatment of clinical infection. The practice was banned by the EU in 2006 but still continues
in some countries such as the United States and China.

Figure 16: Pigs in cages, Quanzhou, China. As the largest consumer of veterinary
antimicrobials, China is critical for combating antimicrobial resistance (AMR). From Van
Boekel et al. [4].
The reported benefits of using antibiotics for growth promotion is controversial and reports of
the beneficial effects in terms of weight gains vary widely widely in the literature (1-10%).
Concerns have been expressed that antimicrobial growth promoters are often used to
compensate for poor hygiene/housing and healthy management [13].

Unfortunately, use of antibiotic for growth promotion has increased dramatically with the
growing demand in meat-based diets. Since 2000, meat production has plateaued in high-
income countries but has grown by 68%, 64%, and 40% in Africa, Asia, and South America,
respectively [4]. The transition to high-protein diets in low- and middle-income countries
(LMICs) has been facilitated by the global expansion of intensive animal production systems,
in which antimicrobials are used routinely to maintain health and productivity.

There are 4 factors that typically determine the health of animals, (e.g., chickens):

1. The genetic stock of the animals

2. Adequate nutrition
3. Hygiene of living conditions
4. Adequate veterinary care

While antibiotics may be able to improve deficiencies in 1 of the 4 areas, if multiple aspects
are missing then antimicrobial resistance is unlikely to improve animal health or growth.
Thus, antimicrobials are often surrogates for good hygiene on farms. Ideally, a key goal to
reduce antibiotic use in animals is to further strengthen the 4 non-antibiotic aspects that are
important to animal health so antibiotic use can be avoided.

Historically, governmental regulations have focused on toxicological dose-response data and

the presence of antimicrobial residues in animal tissue, milk or other edible products
(i.e. eggs) from treated animals - so called minimum residue levels (MRLs) compatible with
acceptable risk in humans. While MRLs are well-understood and enforced with testing
programs and penalties, these programs do not take into account selection of antimicrobial-
resistant pathogens.

The WHO has advocated for the termination of using antimicrobials for growth promotion. A
recent report from the ECDC has suggested some progress in addressing this problem. Using
surveillance data from 2017, the EU/EEA population mean antibiotic consumption in the 29
countries was 130 mg per kg of estimated biomass in humans and 108.3 mg per kg in food-
producing animals Figure 17. This first time since the agencies began publishing the joint
reports in 2011 that antibiotic use in humans has exceeded use in livestock. Consumption of
third- and fourth-generation cephalosporins, fluoroquinolones, and aminopenicillins was
considerably higher in human medicine, while consumption of macrolides was similar, and
consumption of tetracyclines and polymyxins—a last-resort class of antibiotics that includes
colistin—was significantly higher in food-producing animals.

Note
In 2022, new EU legislation will prohibit all forms of routine antibiotic use in farming,
including preventative group treatments and medicated feeding except in extraordinary
circumstances.

Figure 17: Antibiotic use in livestock reported in 2010. Source: Our World in Data.

The impact of animal antibiotic use on human AMR

Case study-cephalosporins

Third generation cephalosporins (ceftotaxime, ceftriaxone) are widely used for serious
infections in humans, including the treatment of urinary tract, abdominal, lung and
bloodstream infections. These antibiotics are classified as “critically-important” for human
health (WHO AGISAR). Ceftiofur, cefpodoxime, and cefoperazone are similar
cephalosporins approved veterinary antibiotics and used predominantly for treating bacterial
infections in food-producing animals including chickens and cattle Figure 18.

Resistance to 3rd generation cephalosporins is mediated by extended-spectrum beta-

lactamases (ESBLs) and AmpC enzymes. ESBL genes are highly mobile and transmitted on
plasmids, transposons and other genetic elements that can spread horizontally (to surrounding
bacteria and different bacterial species) and vertically (to daughter cells through replication).
Consequently, resistance can spread rapidly from patient-to-patient and among different
bacterial species. In recent years, growing resistance to 3rd generation cephalosporins is
common among Escherichia coli and Klebsiella pneumonia has required greater reliance on
the few remaining classes of antimicrobials such as carbapenems.

A number of studies comparing isolates from animals, food and human infections have found
a high genetic similarity or clonal isolates that carry the same ESBL genes and plasmids
colonizing animals used for food production and isolates causing clinical infections in
patients [14].

Ceftiofur is frequently injected in small quantities to hatching eggs or chicks as metaphylaxis

for Escherichia coli infections and/or yolk sac infections [13]. This practice has been shown
to select for cephalosporin resistance in Salmonella enterica serovar Heidelberg- an
important cause of human illness in many countries that is typically associated with
consumption of contaminated poultry products [15].

Figure 18: Chicken farm in the United States of America.** Image source: The Guardian
Studies conducted by the Canadian Integrated Program for Antimicrobial Resistance
Surveillance detected a high degree of temporal correlation in trends of resistance to ceftiofur
and ceftriaxone (a drug of choice for the treatment of severe cases of salmonelloses in
children and pregnant women) among Salmonella Heidelberg from clinical infections in
humans, from poultry samples collected at retail stores, and in E. coli from poultry samples
collected at retail stores [Figure 19][16]. Voluntary termination of ceftiofur metaphylaxis in
hatcheries in the province of Quebec was followed by a precipitous drop in the prevalence of
resistance to ceftiofur; subsequent reintroduction of ceftiofur in a more limited way was
followed by a return to higher levels of resistance.

Figure 19: Ceftiofur resistance in chicken and human Salmonella Heidelberg and chicken *E.
coli
In Japan, voluntary withdrawal of the off-label use of ceftiofur in hatcheries in 2012 was also
associated with significant decrease in broad-spectrum cephalosporin resistance in E.
coli from chickens prepared for cooking. Some other countries (e.g., Denmark) have placed
voluntary restrictions on its use. The label claim for day-old injection of poultry flocks was
withdrawn in Europe, while some countries have banned off-label use of third-generation
cephalosporins, and in other countries there is a requirement that use be restricted to
situations where no other effective approved drugs are available for treatment.

These examples illustrate the danger of using antibiotics from the same class as critical
therapies used to treat human infections for metaphylaxis or treatment in large numbers of
animals. A similar pattern in poultry was also observed with mass medication of poultry
flocks using fluoroquinolones antibiotics and selection of fluoroquinolone-
resistant Campylobacter jejuni infections in humans [17].

Case study: Colistin

Colistin is a member of the polymixin class of antibiotics, which have been used in both
human and veterinary medicine for over 50 years. Until relatively recently, polymixins were
rarely prescribed beyond topical or inhalational therapy in rare cases because of dose-limiting
neurotoxicity and nephrotoxicity of the drugs.
However, use of intravenous colistin has surged in the last decade with the increase in
carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella
pneumoniae. Even as human use has increased, colistin continues to be used in Brazil,
Europe and China a a growth promoting and antibiotic treatment for pigs, poultry and calves.

 In 2014, colistin use in EU member states in animals was higher than humans with a
reported 485 tonnes- 99.7% in oral form or oral medicated feed. In China, with the
world’s largest production of pigs and poultry, an estimated 12,000 tonnes of colistin
was used in the food production industry[18].
 In 2015, Lui and colleagues reported plasmid-mediated colistin-resistance gene, mcr-
1, in Escherichia coli isolates obtained from animals, food and human bloodstream
infections in China [18]. Alarmingly, the resistance gene has also been detected in 5%
of healthy travellers from China in other parts of the world [19].
 The mcr-1 gene has also been detected in isolates obtained from wildlife and surface
water samples, demonstrating environmental contamination [20].
 Additional plasmid-mediated colistin-resistance genes have been reported in many
other bacterial species and countries, including mcr-2 from pigs in Belgium, and mcr-
3,4,5 in other countries [21].
 Colistin illustrates important One-Health Dimensions of AMR that differ from third
generation cephalosporins. Specifically, large volumes of colistin use in animals,
rather than humans, have probably have driven colistin resistance now observed in
humans [22]. Using large quantities of colistin for group treatment or growth
promotion in animals has probably lead to antimicrobial resistance problems in
human health, even through colistin was considered in the past to be less important
because other less toxic treatments were still available.
 In 2017, China banned the use of colistin as a food additive for animals. Colistin is
currently not approved as a food additive in Europe or the United States, but is still be
used in LMICs as a growth promoting agent.

Antimicrobial resistance in animals in LMICs

Many farmers in LMICs are sustenance farmers, and their livelihood is at stake if an animal
becomes ills. Therefore, they may not have the resources for optimally nutritious feed and
housing space/conditions. These challenges, combined with looser regulations on veterinary
drugs, may facilitate the use of antimicrobials in feeding [4].

Figure 20: Global hotspots of antimicrobial resistance in animals.** Data

source resistancebank.org
The largest hotspots of AMR in animals were in Asia and India Figure 20. Asia is home to
56% of the world’s pigs and 54% of the chickens. Other growing hotspots of AMR are found
in central India and Kenya, where resistance to multiple drugs has appeared but not yet
reached 50%.

These data suggest that in areas such as Asia, targeted interventions such as legislative action
and subsidies to improve farm hygiene could reduce the need for antimicrobials in animal
production, thereby preserving important drugs for human medicine and the treatment of sick
animals. In these regions, meat consumption is still low and animal production is gradually
intensifying. Here, there may be a window of opportunity to contain AMR by imposing strict
hygiene standards in newly built farms. This approach could reduce the risk of the spread of
resistant pathogens such as mcr1–carrying E. coli that have emerged in regions where
intensive meat production has been facilitated by enormous quantities of veterinary
antimicrobials.

In Africa, resistance maps reveal the absence of major AMR hotspots, except for the
Johannesburg metropolitan area. This suggests, on the basis of the regions surveyed, that
Africa probably bears proportionately less of the current global burden of AMR than high-
and upper- to middle income countries. Policy-makers coordinating an international response
to AMR might therefore spare Africa from the most aggressive measures, which may
undermine livestock-based economic development and rightfully be perceived as unfair.

Clearly the the transition to sustainable animal production in both HIC and LMICs with
improvements in farm-level biosafety and biosecurity are essential to reduce the future risk of
AMR.

Note
In the 1990s avoparcin, a glycopeptide antimicrobial, was widely used in growth promotion
in pigs and poultry production that was not initially thought to be of public health importance.
Surveillance and research were eventually able to show that avoparcin use in animals
contributed to the selection and wide dissemination of what type of resistance?

Environmental concerns

One health considers possible environmental drivers of AMR in additional to human and
animal health [23]. Many resistance mechanisms such as beta-lactamases are millions of
years old and pre-date antibiotics. Soil and other environmental sources are rich sources of
highly-diverse populations of bacteria and genes.

Antimicrobial resistance to a wide variety of drugs has been demonstrated in environmental

bacteria isolated from the pre-antibiotic era, as well as from various sites (e.g., caves) free of
other sources of exposure to modern antimicrobials. Yet their is abundant evidence that
human has an impact on the resistome- the totality of or resistance genes in the total
environment [24].

Hundreds of thousands of tonnes of antimicrobials are produced annually and find their way
into the environment. Waste from treatment plants and the pharmaceutical industry especially
if inadequately treated, has been show to release high concentrations of antimicrobials into
surface water. Residues and metabolites of antimicrobials are constituents of human sewage,
livestock manure, and aquaculture, along with fecal bacteria and resistance genes. Sewage
treatment and composting of manure reduce concentrations of some but not all antimicrobials
and micro-organisms, which are introduced to soil upon land application of human and
animal bio-solids [25].

In developed countries with good-quality sewage and drinking water treatment, and where
most people have little to no direct contact with food-producing animals, transmission of
bacteria and resistance genes from agricultural sources is largely foodborne, either from
direct contamination of meat and poultry during slaughter and processing, or indirectly from
fruit and vegetables contaminated by manure or irrigation water [26]. In countries with poor
sewage and water treatment, drinking water is likely to be very important in the transmission
of resistant bacteria and/or genes from animals. Poor sanitation also facilitates indirect
person-person water-borne transmission of enteric bacteria among residents as well as
international travellers who return home colonized with resistant bacteria acquired locally.
Through these and other means, including globalized trade in animals and food and long-
distance migratory patterns of wildlife, antimicrobial-resistant bacteria are globally
disseminated.

General measures to address antimicrobial resistance in the wider environment include

improved controls on pollution from industrial, residential, and agricultural sources.
Improved research as well as environmental monitoring and risk assessment are also required
to better understand the role of the environment in the selection and spread of antimicrobial
resistance and to identify more specific measures to address resistance in this sector.

Figure 21: Hotspots of antimicrobial resistance. Figure is from Singer et al. [26]

Cross-border spread of AMR

World airline travel routes in 2014.** Photo credit Jpatokal/Wikimedia (CC BY-SA 2.5)

The COVID-19 pandemic has exposed the limitations of global collaboration and response
within existing global health frameworks, pointing to a clear need for more rules-based global
governance to be able to effectively prevent, prepare and respond to health emergencies in a
more just equitable way. However, valuable lessons from COVID-19 pandemic could
enhance actions against AMR Table 2. Clearly, actions taken by one country have had
substantial consequences for others. governments should significantly bolster global and
national capacity to prevent and respond to global cross-border health threats more broadly.

Table 2: Global successes and shortcomings in the multilateral response to the COVID-19 pandemic. Table i
2021. [27]
Domain Successes Shortcomings
 Many regions and cou
 Sharing of information by researchers learn policy lessons fr
Research
 International research collaborations  Lack of systemic glob
collaboration and
 Public data repositories governance
information sharing
 Duplication of researc

 Multinational initiatives to fund efforts such as

the Coronavirus Global Response and the
 Most funding from na
Coalition for Epidemic Preparedness
 Most vaccine doses se
Innovations
Vaccine discovery countries through bila
 Approval of vaccines and adjuvants
and development  Trade barriers around
 Establishing the principle of equitable vaccine
raw materials
distribution through the COVAX Facility
(despite failures in implementation)

Travel policies  Travel restrictions delayed spread from China  Dissonant COVID-19
in early 2020 policies between high
nations
Table 2: Global successes and shortcomings in the multilateral response to the COVID-19 pandemic. Table i
2021. [27]
Domain Successes Shortcomings
 Restrictions on travel
high COVID-19 incid
contribute little to con
countries

The actions of the EU during the pandemic illustrate the tension between short-term
nationalistic incentives and long-term imperatives for cooperation towards achieving
global public goods such as reducing antimicrobial resistance. The EU has struggled to
balance preferences of individual member-states (and those of their political leaderships),
with the collective interests of all member-states. Such tensions are especially challenging
when health care and health policy issues are involved, given how these have hitherto
remained largely the responsibility of the member-states. In a pandemic, this can lead to
inertia and political indecisiveness at the EU level, with member-states filling the gap with
potentially contradictory or competing decisions.

Looking ahead, it is likely that there will be several changes to the global health architecture,
possibly including a new pandemic treaty and additional international collaborative
mechanisms to promote preparedness and coordinate responses. In the following sections, we
explore what those developments might look like in three key areas.

Summary
The post-COVID-19 world must overcome setbacks from the pandemic to hard-fought
progress in reducing poverty and inequality. Health infrastructure and human resources vital
for fighting AMR have been overburdened and will take many years to recover, particularly
if governments impose austerity measures as they seek to recover from fiscal expansion
during the pandemic.

Decades of funding neglect, combined with continuously increasing global antibiotic

consumption, poor surveillance data, and weak pipelines for new drugs, vaccines and
diagnostics, has left the world vulnerable to a pandemic of resistant and untreatable
infections.

Therefore, strong multilateral collaboration is essential for the world to absorb these shocks
and refocus on the silent but growing pandemic of AMR.

Pandemics are opportunities to re-imagine governance structures and learn from previous
experiences. COVID-19 has shown the importance of multilateral collaboration in diverse
areas, including research and knowledge sharing, discovery, development and distribution of
vaccines and medicines and access to diagnostics and medicines. Action is needed now to
reverse the unthinkable future of untreatable infections.

Lecture Slides
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