Antimicrobial Resistance

in Health & Disease

Mentor : Dr. Sai Krishna

Presented by
Dr. A.Pravalika
Dr. P.Adithya
“ 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
lecture, 1945
Introduction
Antibiotics have revolutionized the practice of
medicine by enabling breakthroughs across the
spectrum of clinical medicine, including safer
childbirth, surgical procedures, organ transplantation,
and myeloablative chemotherapy regimens. However,
antimicrobial resistance (AMR) threatens to impede
and even reverse some of this progress.
Antimicrobial Resistance (AMR) occurs when
microorganisms including bacteria, viruses, fungi, and
parasites become able to adapt and grow in the
presence of medications that once impacted them
 Why does resistance emerge within a
micro-organism?
Through a darwinian selection process microorganisms
have developed robust mechanisms to evade destruction
from many toxic substances.
Most antimicrobial drugs are naturally produced by
microorganisms, including environmental fungi and
saprophytic bacteria, or are synthetic modifications of
them, with only a few drugs (eg, sulphonamides and
fluoroquinolones) being wholly synthetic.
The protective mechanisms that have evolved include
• preventing entry of or exporting the drug,
• producing enzymes that destroy or modify the
antimicrobial,
• or making changes to the antimicrobial target.
Therefore, antimicrobial resistance could be
considered to simply represent the darwinian
competition from natural microorganism derived
antimicrobial molecules.
Functional meta-genomic studies of soil
microorganisms have shown a widespread diversity of
genetic determinants conferring antibiotic resistance,
of which only a fraction have been described in human
pathogens.
One example where a naturally occurring resistance
mechanism has had an effect on human health is the
resistance developed against β-lactam antimicrobial
drugs, in which the enzymes (β-lactamases) that
inactivate these antimicrobial molecules have existed
for millions of years.
 Although de novo mutations can cause new problems
today, naturally occurring resistance factors appear to
predate the antibiotic era.
Permafrost samples from the Yukon revealed the presence
of bacteria with resistance mutations 30 000 years before
the discovery of penicillin.
Resistance factors also were identified in samples drawn
from a cave ecosystem that was isolated for more than 4
million years.
Moreover, phylogenetic analyses of β-lactamases
(enzymes that render penicillin- like antibiotics ineffective)
indicate their emergence 1 billion to 2 billion years ago.
Although naturally occurring resistance factors contribute
to AMR, antibiotic use selects for their emergence;
therefore, human activity plays an important role in the
evolution of AMR.
Emergence of resistance to synthetic antimicrobials
also occurs. This resistance has unfortunately been
widely exemplified in the case of fl uoroquinolones, for
which in Escherichia coli isolated from patients in
Europe, fluoroquinolones resistance is now at 10-40%.
Many resistance mechanism have emerged including
• alteration of target ( A-DNA Gyrase) ,
• increased efflux (export of a drug out of the
microorganism),
• fluoroquinolone inactivation (by an aminoglycoside
N- acetyltransferase), and
• protection of the target by DNA- binding proteins
(known as Qnr)
Why does antimicrobial resistance
emerge at the individual human level?
• A study in India of a cohort of breast fed babies noted
that at 1-day old, 14·3% harboured Enterobacteriaceae
that contained an enzyme that inactivates β-lactam
drugs, an extended-spectrum β-lactamase (ESβL), yet
this increased to 41·5% of babies by day 60.
• The environment, drinking water, and food are probably
the most important means for establishing the normal
(healthy) gut microflora. Antimicrobial- resistant bacteria
have been found in every environment examined so far
including Antarctica, the sea, soil, drinking water, 15 and
various food products.
• This polymicrobial, variably antimicrobial-resistant,
commensal microbiome (microorganisms that are
not causing infection at that body site eg, the
gastrointestinal tract or skin) is established at an
early age
• In a pristine (ie, free from external antimicrobial
selection pressure) ecosystem, antimicrobial-
resistant and non-resistant species coexist in a
stable balance.The human microbiota is no
exception, and commensal microorganism
populations in human beings include species that are
naturally resistant to some antimicrobials.
• Selective pressure is exerted by any condition (eg,
antimicrobial exposure) that allows microorganisms
with inherent resistance or newly acquired mutations or
resistance genes to survive and proliferate.
Antimicrobial use exerts such selective pressure on
commensal human microflora, and pathogens,
increasing the risk of recovery of resistant organisms
from patients.
• Use of antimicrobials in clinical medicine has exposed
the human microbiota to unprecedented high
concentrations of these drugs. In-vivo development of
de-novo resistance within a human individual has been
recorded during treatment courses with a range of
antimicrobials including, worryingly, carbapenems.
Why does resistance emerge at the
population level in humans and
animals?
• 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.
• The role of educating prescribers is crucial in
overcoming antimicrobial misuse or overuse and is
seen to be effective in primary care and secondary
care.
• Additionally, raising awareness of the fundamentals of
antimicrobial use in the general public is equally
essential.
• Confounding factors mean a uniform approach to
understanding resistance cannot be taken. These
factors include
- pathogen–drug interactions,
- pathogen-host interactions,
- mutation rates of the pathogen,
- emergence of successful antimicrobial- resistant
clones,
- the transmission rates of pathogens between
human beings, animals, and the environment,
- cross-resistance, and selection of co-resistance to
unrelated drugs.
• Importantly, at the human population level, public
health factors such as
• rates of vaccine uptake,
• different systems of health care,
• the role of migration and tourism,
• sanitation, and population densities, also
influence the prevalence of resistance
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, varying a 100-fold from 4 mg to 400
mg of antimicrobial per kg of meat produced in
European countries.
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.
Changing context of
health and health care
Misuse and Overuse of Antibiotics
From early days of discovery of antibiotics in the
1940s, Sir Alexander Fleming warned the public about
the high demand for antibiotics in the future which
could lead to their overuse.
15–17 Different surveys across the globe indicate that
many patients firmly believe antibacterial agents
would help with viral diseases like the common cold or
flu.
Furthermore, in many developing countries where
there are deficiencies in proper diagnostic tools,
patient management is predominantly contingent upon
the prescription of medicine, particularly antibiotics.
Administering antibiotics when they are actually not
needed for the treatment is another example of
common misuse of them.
Moreover, many antibiotics are of poor quality and
sold over the counter in the developing countries.
For instance, in India and Vietnam, where there is
insufficient enforcement of regulatory policies on
prescribing medicine, over-the-counter antibiotics are
prevalent. Such availability makes it accessible for
patients to do self-treatment for diseases that do not
necessarily need antibiotics for treatment.
Moreover, antibacterial resistance can develop
because physicians unnecessarily prescribe lengthy
courses of antibiotics.
Financial incentives play an important factor in
overprescribing antibiotics. For example, Chinese
hospitals incentivize physicians to prescribe
antibiotics; as a result, they will receive more money
from pharmaceutical companies.
Another factor contributing to overprescribing
antibiotics by providers is patients’ expectations from
them.Studies have implicated that clinicians consider
the perceived patient request for antibiotics as one of
the major barriers to adhere to standard guidelines for
antibiotic prescriptions. Providers try to avoid the
dissatisfaction of their patients by meeting their
demand for prescribing antibiotics
 Agricultural Use of Antibiotics
Agricultural use of antibiotics is another prominent
contributor to the antimicrobial resistance in
humans.For instance, just in the United States,
approximately 80% of the antibiotics sold are applied to
food that animals eat.
In 2010, 63,200 tons of antibiotics were used in
livestock production worldwide which is significantly
more than human consumption.
In addition to the utilization of antibiotics to treat sick
animals, antibiotics are largely added to healthy animal
feed and drinking water in order to prevent sickness
(prophylaxis) among animals to a large extent, to further
grow herds at subtherapeutic levels, and to elevate feed
efficiency.
For instance, one of the widely used antibiotics in
animal farming worldwide to further promote the
growth of livestock, particularly pigs, is colistin, a
critical last-line antibiotic to treat severe infections in
humans
Increase in Income Levels
An increase in income levels in developing countries
has led to an increase in animal protein consumption
which may require more antibiotics to be added to the
food animals eat.
There has been a stark change in the pattern of anti-
bacterial consumption across the globe within the
past decade. In 2000, the highest antibiotic
consumption rate was in the United States, France,
Spain, New Zealand, and Hong Kong; however, in 2015,
four of the countries with the highest rate of antibiotic
consumption were low-middle income countries such
as Turkey, Tunisia, Algeria, and Romania.
Easy Travel Routes
Studies have suggested that the modern and easy
traveling routes for people, animals, and goods have
also substantially contributed to exposure to resistant
pathogens, human travelers are highly likely to return
colonized and infected to their country.
For instance, Ruppe et al have shown that European
tourists traveling to India who had absolutely no
contact with the Indian health care system still tested
positive for carbapenemase- producing
Enterobacteriaceae (CPE) after they came back from
their trip.
 Primary care for ageing populations
requires antibiotics
Elderly patients often have
implants, catheter infections,
joint replacement surgeries
and chemotherapy whose
associated acute ailments may
require antibiotic treatment.
Older people may be
prescribed long-term
antibiotics to prevent recurring
infections , such as chronic
urinary tract infections in some
elderly women .
Furthermore, elderly patients may take multiple
medications, leading to low adherence to drug
schedules.
In addition to the cumulative effects of long-term
alcohol and tobacco use, low levels of exercise and
poor diet make elderly people more vulnerable to
infection. The resulting high levels of antibiotic use
can increase selection for resistance in this
population.
 People are moving to cities and
creating new health needs
• Dense populations, combined with higher antibiotic
consumption in urban areas, are correlated with
increased resistance.
• Waste management and WASH can be challenging in
large cities, and urban areas have been associated with
many outbreaks of infectious diseases, particularly
those transmitted by the faecal-oral route.
• High population density also increases exposure to
airborne infectious diseases, such as influenza, measles
and TB (71). Primary care must adapt to tackle the
growing challenges of urban life.
• As just one example, urban residents can choose
among many health care providers, and the
increased competition may pressure providers to
keep their clients satisfied by unnecessarily
prescribing antibiotics. Strong regulation is needed
to prevent such effects and their consequences for
AMR.
Commercial health care increases
patients’ costs and antibiotic use
In India, 70% of disease episodes are treated in the
private sector, and in Sri Lanka, more than 40% of out-
of-pocket payments are fees for private medical
practitioners.
Seventy years ago, the Indian health system was 8%
private; today, 80% to 85% of the licensed physicians,
93% of the hospitals and 80% of the outpatient clinics
operate at least in part in the for-profit private sector .
Services at private facilities often fall short of those at
public facilities , which are less likely to prescribe
antibiotics inappropriately .
 Technology is reshaping primary care
• Technological innovations are improving surveillance,
prescribing patterns and public awareness.
• Rapid diagnostic tests would enable physicians to
prescribe specific antibiotics rather than broad-
spectrum antibiotics (76) and to distinguish between
viral and bacterial infections.
• Machine learning has made it possible to track and
classify antibiotic resistance genes from different
sources and to understand patterns in consumption.
This ability to track the origin and spread of
antimicrobial resistance genes will facilitate the
development of AMR control strategies.
• Even in remote regions, mobile applications can
address a range of health needs. BugWise, an
application rolled out in South Africa in late 2017,
gives patients information on their diagnosis, the
appropriate use of antimicrobials and infection
prevention; doctors can enter a patient’s
characteristics and symptoms to obtain guidance on
their diagnosis and the local prevalence of
resistance.
The Internet improves access to
good-quality primary care but also
spreads misinformation
Across the world, educational attainment has risen,
and increasing numbers of people with Internet
access are educating themselves to manage their own
health. Online social networks can help extend public
health awareness (82) but may also promote
misinformation on health issues, such as use of
antibiotics to treat colds and influenza and the
supposed danger of vaccines.
 In France, a seasonal public health campaign to
spread public awareness of viral respiratory infections
and antibiotic resistance led to a 27% reduction in
antibiotic use over five years (85).
Public health messaging through mass media
campaigns (82) has also been successful in reducing
the spread of infections by raising public awareness
about sexual health and increasing condom use.
Growing populations need to be fed
As populations become richer, so do their diets.
Growing demand for animal protein is causing a shift
from traditional mixed farms to large, industrial-scale
farms, which tend to administer antibiotics
extensively both for livestock growth promotion and as
prophylaxis (86).
Antibiotic use in livestock has been linked to the
emergence of resistance, and the transfer of resistant
bacteria has been seen among farm workers, animals
and the environment at poultry and pig farms in
Ethiopia and Denmark.
 Even low concentrations of antibiotics can select for
resistant bacteria of animal origin, which then spread
to humans through the environment, food products and
agricultural workers .
Population growth has put pressure on food resources
and malnutrition is still a problem in the developing
world.
Undernourished people have compromised immune
systems and hence are more vulnerable to infection;
conversely, infection can also cause malnutrition by
impairing nutrient absorption (94).
Bacterial infections, including those that cause
diarrhoea and pneumonia, circulate in malnourished
populations, increasing the burden of resistant and
susceptible disease alike (94).
Food scarcity can lead people to pay less attention to
food safety, and the resulting infections from
contaminated food can both increase antibiotic
consumption and facilitate the spread of AMR.
The high prevalence of bacterial infections in underfed
populations also increases antibiotic consumption.

In short, access to adequate nutrition would reduce

antibiotic use.
Transmission of
Resistance
How does transmission of resistance
occur between micro-organisms?
In addition to selection of antimicrobial resistance
through mutations in genes encoded on a microbe’s
chromosome, new genetic material can also be
exchanged between organisms.
This process can provide the host cell and its progeny
with new genetic material encoding antimicrobial
resistance and can occur through several
mechanisms, of which perhaps the most important is
plasmid transmission .
Antimicrobials influence this, not only by exerting a
selective pressure towards emergence of
antimicrobial resistance, but also by inducing transfer
of resistance determinants between microorganisms.
How does human-human
transmission drive resistance?
In the community, faecal–oral transmission, often
through failures in sanitation, plays an important part,
particularly for resistant Enterobacteriaceae.
Transmission can also occur through sexual
encounters; for Neisseria gonorrhoeae, core groups
have contributed to widespread dissemination of
resistant clones.
Perhaps where the dynamics of transmission are best
understood is in the context of health-care-associated
infections.
Using meticillin-resistant Staphylococcus aureus
(MRSA) as an example, modelling suggests duration of
patient stay and contamination of health-care workers’
hands both contribute to continuing transmission.
During the last 10 years the human microbiota has
acquired antimicrobial resistant Enterobacteriaceae
on an unprecedented scale.In some parts of the world
the carrier rate of ESβL-positive Enterobacteriaceae in
the gut is more than 50% and travel has been clearly
associated with increased risk of gut colonisation with
these organisms.
In a prospective study from the Netherlands, 8·6% of
travellers were colonised with ESβL-producing
Enterobacteriaceae before travel, but 30·5% acquired
gut colonisation during travel, with independent risk
factors being travel to south and east Asia
More recently, and perhaps more worryingly, is the
spread of carbapenem resistance mechanisms across
the world, and between organisms, with New Delhi
metallo-β-lactamase (NDM),15 Klebsiella pneumoniae
carbapenemase,50 and OXA-4851 enzymes being among
those of greatest concern
(fi gure 2).52–54 Travel-related human–human spread has
also been evident for Gram-positive organisms, notably in
the spread of antimicrobial-resistant Streptococcus
pneumoniae from Spain to Iceland
Clinical Outcomes of
AMR
The complex issues of fitness and
reversibility of antimicrobial
resistance
The relationship between antimicrobial resistance and
microbiological fitness differs depending on the
organism, type of antibiotic therapy, and mechanism of
resistance .
In most cases, when mutations leading to resistance are
associated with reduced fitness, compensatory
mutations that result in regained fitness arise.
Resistant strains seen in the clinical setting are largely
those that are able to both survive and effectively spread
in high-density antibiotic environments, such as health
care facilities and day care centers; thus, they are well-
adapted organisms and are usually fitter than a random
selection of strains belonging to the same species.
Does antimicrobial resistance affect
the fitness of micro-organisms?
There is a perception that antimicrobial-resistant
microbes might be less fit (i.e, less able to grow or
cause an infection) than their antimicrobial susceptible
counterparts. This situation would mean that reducing
the burden of resistance might simply be achieved
through removing the selective pressure of
antimicrobials, leading to antimicrobial-resistant
microbes losing out in darwinian competition with the
susceptible strains.
Unfortunately, this is frequently not the case and can
be seen in two important classes of antimicrobials, the
fluoroquinolones and the β- lactams.
Mutations that alter the target of antimicrobials (such
as gyrA, in the case of fluoro-quinolones) can change
bacterial physiology, potentially making them less fit.
Yet compensatory mutations that restore fitness to
wild-type levels might explain, in part, why clinical
isolates resistant to this class of drugs have
proliferated and spread.
As a specific example, mutations detected in a
fluoroquinolone-resistant strain of E coli were
experimentally reconstructed.
Strains with single mutations were less fit than the
parental strain; however, two or more mutations in
combination increased the fitness of the bacterium to
similar or greater levels than that of the antimicrobial-
susceptible strain.
Therefore, once selected, fluoro quinolone-resistant
mutants are able to persist and thrive even in the
absence of fluoroquinolone antimicrobials.
Is emergence of resistance reversible?
Complete eradication of antimicrobial resistance in
populations of microbes after reduced selective
pressure from antimicrobials is not straightforward.
Resistance determinants are easy for microbes to
acquire and might persist at low, but detectable, levels
for many years in the absence of particular
antimicrobials, and in turn, antimicrobial resistant
microbes can persist for many years on human and
animal skin and as faecal flora without any further
exposure or selection pressure.
 Case study of clinical outcomes
Several studies have demonstrated that resistance
frequently leads to a delay in the administration of
microbiologically effective ther-apy, which may be
associated with adverse outcomes. A mismatch between
the empirical therapeutic agent and sub- sequent
susceptibility results for a particular organism is one of
the most significant factors that delays effective therapy.
For example, Lautenbach et al. demonstrated that
patients with extended-spectrum b-lactamase (ESBL)–
producing Klebsiella pneumoniae and Escherichia coli
infections were treated with effective antibiotics a median
of 72 h after infection was suspected; matched control
subjects infected with non–ESBL-pro- ducing strains of K.
pneumoniae and E. coli received appropriate antibiotics a
median of 11.5 h after infection was suspected.
Patients infected with ESBL-producing strains also had
significantly longer hospitalizations and greater hospital
charges than control subjects. In addition, the
emergence of resistance during therapy (which arises
almost invariably to the agent listed) has also been
shown to affect outcomes negatively and significantly.
Infections caused by antimicrobial-resistant organisms
also may require more toxic therapy that can lead to
adverse out- comes. The use of colistin for highly
resistant Pseudomonas or Acinetobacter infections is
associated with a high risk of renal dysfunction .
In addition, some agents used to treat the resistant strain
of an organism are less effective than the agents used to
treat the susceptible strain of the organism—for example,
vancomycin for the treatment of deep-seated methicillin-
resistant
Staphylococcus aureus (MRSA) infections [10]. Finally,
patients infected with organisms that are resistant to all
available anti- microbials often require surgical
MRSA has not been shown to be more virulent than
MSSA [38, 39]. In contrast, there is some evidence to
suggest that community-acquired MRSA is more
virulent than health care–associated MRSA, on the
basis of its shorter doubling time and the higher
proportion of isolates with Panton-Valentine leukocidin
gene and other exotoxin genes .
Given the influence of antimicrobial resistance in the
community on that in hospitals, the increased
virulence of com- munity-acquired MRSA is worthy of
concern and certainly requires further study
Antimicrobial
Resistance :
Implications and Costs
 Patients Perspective
Morbidity and mortality are important consequences of
AMR affecting patients. Compared to non-resistant
forms, resistant bacteria will double the chances of
developing a serious health issue and triple the chances
of death.
United States, 2 million people are affected every year
by AMR and about 23,000 deaths occur as a result. This
number is roughly the same as the European Union
which has an annual mortality rate of 25,000.
Despite the difficulty of obtaining precise mortality
rates, official reports have estimated that about 10
million people will die across the world by 2050 if strong
and effective action against AMR is not taken.
Antimicrobial resistance also sabotages decades of
global fights against many infectious diseases like
tuberculosis, HIV, and malaria
60% of patients with HIV have developed resistance to
HIV medicine particularly in Sub-Saharan
Africa.Plasmodium falciparum, the causative agent of
malaria, has become resistant to anti-malarial
medicines and this trend is predominantly seen in
southeast Asia
Measurements of mortality and length of hospitalization
measure the short-term direct effect of resistance on
the affected patient. However, indirect and long- term
consequences of resistant infections may have
important implications.
For example, a patient with a history of MRSA infection
who presents with a new fever is usually placed in
isolation and empirically treated with vancomycin, even
though he or she may not have MRSA infection.
Other patient-level outcomes that need further
elucidation include the long-term effects of having a
resistant infection on future health, the loss of work and
family time associated with increased hospitalization
time and subsequent recovery, and even the emotional
impact of having a resistant infection.
Antimicrobial resistance also has an effect on patients
who have not had an infection with a resistant organism.
Because of increasing rates of resistance among common
pathogens, broader-spectrum agents are now required for
the empirical therapy of many common bacterial
infections. These agents are usually more expensive, have
more deleterious effects on protective microflora, and,
occasionally, are more toxic or less effective. For
example, third-generation cephalosporins or
fluoroquinolones are recommended for the treatment of
hospitalized patients with community-acquired
pneumonia, exemplifying the loss of use of narrow-
spectrum agents, such as penicillin, for the treatment of
common diseases when rates of resistance at the
population level reach a certain threshold.
Hospital perspective
A number of studies published recently have evaluated the
impact of antibiotic resistance through the assessment of
in-hospital mortality rates and the length of
hospitalization. Fewer studies have examined economic
outcomes. The majority of published studies have shown
an association between antibiotic resistance and adverse
outcomes on the order of a 1.3–2-fold increase in
mortality, morbidity, and cost for patients with resistant
versus susceptible infections.
Limited data exist regarding costs at these sites because
the sources of such information— third-party payers—are
protective of data that they collect, and linking claims
data with microbiology results without breaching patient
confidentiality is difficult.
AMR has disastrous impacts on healthcare costs.
According to the CDC, in the United States alone,
antibiotic resistance could add about $1,400 to the
hospital bill. AMR could cost from $300 billion to more
than $1 trillion annually by 2050 worldwide
Treating patients with resistant infections by using a
combination of regimens may be ineffective; as a result,
compared to other patients, they may need longer
hospitalization stays as well as more intensive care units
(ICUs) and isolation beds in order to prevent the spread of
the infection. Also, nosocomial outbreaks with resistant
pathogens may result in the closure of a wing of a
hospital and the cancellation of elective surgeries,
costing the hospital money.
Furthermore, AMR will challenge performing organ
transplants because they expose the patients to
different infections
Due to AMR, chemotherapy cannot be performed on
patients with cancer.
 Economic perspective
CDC estimated that the cost of antimicrobial resistance
is $55 billion every year in the United States, $20 billion
for health care and about $35 billion for loss of
productivity.
Recent research by the World Bank indicates that
antimicrobial resistance would elevate the rate of poverty
and impact low-income countries compared to the rest of
the world
Furthermore, due to AMR, the gap between the devel-
oping countries and the developed countries will become
more pronounced; as a result, inequity will substantially
increase.
Most of the people who are pushed into extreme
poverty as a result of AMR will be specifically from
low-income countries. This highlights the fact that the
underprivileged population of the world will even-
tually be affected the most because these countries
are more contingent on labor income which will be
reduced if there is a high prevalence of infectious
diseases.
Antimicrobial resistance has a major influence on
labor through the loss of productivity caused by
sickness and premature death. Deaths because of
antimicrobial resistance decrease the workforce,
which in turn negatively impacts the size of the
population as well as the quality of the country’s
human capital
The global trade will also be heavily affected by
antimicrobial resistance if the continuous trends in
AMR still persist. The World Bank report demonstrates
that global exports might decrease significantly by
2050 due to the effects of antimicrobial resistance on
labor-intensive sectors. Thus, it can be concluded that
the undesirable outcomes of AMR on the global
economy are projected to be even more severe than
the global financial recession due to its long-term
impacts on the economy.
Impacts of AMR on livestock output will also be
significant. Just like humans, the effect of AMR on
animals will be due to mortality and morbidity. The
increase in resistance to antimicrobials will make
treatments on animals ineffective and cause the
infections to become more severe.Ultimately, this will
lead to decreased production and trade of livestock,
resulting in elevated prices of protein due to the
decrease in protein sources such as milk, egg, and
meat.
Approaches to optimising
antimicrobial use
Maintain heterogeneity of
antimicrobial agents
Excessively homogeneous antimicrobial use might
contribute to selective pressure. Maintaining
prescribing diversity can be achieved through several
methods.
One such method is drug cycling (replacing an
antimicrobial belonging to one class with one or more
belonging to different classes, sequentially, at the level
of the unit or hospital). However, cycling might only be
useful if implemented before resistance to the
replacement drug has emerged or if resistance to the
first drug imposes a fitness cost.
Another approach is drug mixing (diversification of
antimicrobial prescription at the individual level
allowing for patient variation), which maintains
personalisation of infection treatment. However,
implementing personalised medicine effectively would
require accurate and rapid diagnosis of pathogens,
antimicrobial resistance, and host factors.
Assure and ensure adequate serum
drug concentrations
Subtherapeutic concentrations contribute to poor
treatment responses and exert non-lethal selective
pressures. Unfortunately, suboptimal drug exposures
have many causes:
• use of poor quality drug (falsified, substandard, or
degraded),
• systematic under-dosing (small infants, overweight
adults, infrequent dosing),
• inadequate drug absorption (malnutrition and drug
interactions),
• unusual large apparent volume of distribution
(pregnancy), or
• Particularly rapid clearance.
 Taken individually, populations exposed to sub-
therapeutic concentrations might seem small, but they
represent a high proportion of the patients receiving
antimicrobials in low-income and middle-income
countries.
Optimisation of dosage and guarantee of drug quality
could reduce sub-therapeutic drug exposure and
reduce this modifi able driver of resistance.
Repurposing of withdrawn and
underused antimicrobial drugs
Repurposing previously discovered (often FDA-
approved) pharmacotherapies might provide a
potentially less economically risky pursuit than de-
novo drug discovery.
This approach has already been evident with the
return of colistin and fosfomycin use for multidrug-
resistant Gram-negative infections, repurposing of
older drugs for bacteria such as Acinetobacter
baumannii, and more widespread consideration of
fusidic acid in clinical practice in some countries
since the 1960s.
Incentives advocating new drug discovery, including
mechanisms to accelerate clinical trials, and making
these drugs attractive to industry for production might
also need to be adapted to such repurposed drugs.
 Combination therapy
Combination therapy is use of several antimicrobials to
which the targeted organisms do not show cross-
resistance. This relies on microbial populations
containing singly resistant mutants, but none that are
resistant simultaneously to several drugs. However, the
increasing prevalence of multidrug-resistant strains
needs careful assessment to ensure efficacy of drug
combinations.
This strategy has been successful in preventing or
delaying resistance in tuberculosis, HIV, and malaria.
However, combination therapy successes for the
organisms causing these diseases are not directly
translatable to bacterial infections and have not been
widely recommended so far, often because of the
increased cost, but also from fear of incremental,
unwanted disturbance of the microbiome.
Furthermore, the differentials in half-life of drugs used
in combination should be carefully considered, or
unintentional monotherapy might ensue. In conclusion,
the risk–benefit of combination therapy is unclear and
further work is urgently needed to clarify these issues.
Role of primary health
care in an effective
response to antimicrobial
resistance
Community-based actions are
needed
Community-based approaches, which view people and
communities as owners and advocates of their own
health. For example, a campaign to promote hygiene
distributed educational materials through families
considered to be leaders in the community.
Changes to the labelling of antibiotic medicines can also
raise public awareness and indicate that antibiotics are
protected drugs. In India, the “redline campaign” labelled
antibiotic packaging with a red line, in an effort to
increase public awareness of antibiotic resistance and to
decrease inappropriate use.
Online sales are a problem for regulators because the
Internet is a prohibitively large space to regulate, and
sellers work across borders more easily than do the
regulators charged with protecting the public from
antibiotic misuse and counterfeit and falsified
medications.
Consumers and primary care prescribers should be
made aware of the risks of using uncertified retailers
and encouraged to buy from certified online
pharmacies .
Antimicrobial resistance must also be addressed in the
food chain Reducing antibiotic use in animal husbandry
has financial consequences for farmers, particularly
where hygiene and nutrition for animals are poor.
Nevertheless, primary care providers should be informed
about agricultural use of antimicrobials through specific
training or educational materials.
Raising public awareness of the risks of AMR has already
driven change in antibiotic use where consumers have
expressed their preference for a sustainable and safe
food supply .
Awareness of the role of farming and agriculture in the
emergence of AMR can also prompt better hygiene and
reduced antibiotic use on farms, thereby reducing the
potential for transfer of resistant infections between farm
and community.
 Primary care can reduce
antimicrobial resistance
Primary care facilities should set the example for
community hygiene. Without basic water, sanitation and
hygiene, primary care facilities become points of
exposure to infection, for both patients and staff. Such
facilities can act as the starting point for AMR
transmission in the community and elsewhere.
Hand hygiene stations, sanitary toilets and water
treatment not only improve the quality of care but also
increase the uptake of health care services, encourage
mothers to give birth in facilities, improve staff morale
and become the model for WASH practices in the
community and a staff culture of consistent safe hygiene.
More preservice training on AMR, in addition to
continuing education modules and prescribing
guidelines based on reliable, independent information,
would improve adherence to best practices for
antibiotic prescribing.
Ideally, data on local patterns of antimicrobial use
and consumption should be used to optimize use;
providing feedback to overprescribers on local
prescribing patterns successfully reduced prescribing
in the United Kingdom (109). However, even with good
information, health workers may prescribe antibiotics
unnecessarily if they do not have time to diagnose an
illness and provide follow-up care. Restricting
antibiotic access without addressing fundamental
weaknesses in primary care will not be a long-term
solution to the AMR crisis.
Simple diagnostic tests and other technologies help
control antimicrobial resistance Reducing
underdiagnosis and overtreatment in primary care
through the provision of low-cost rapid diagnostics
could reduce resistance rates (8). However, such tests
for bacterial infections are still not widely available
(110 ) and would require health care workers to be
trained in their use.
Access to primary care facilities has reduced the
frequency of malaria morbidity by up to 66% . The
most effective means of preventing a mild case of
malaria from developing into a severe disease is
through prompt diagnosis and treatment . The
deployment of these simple technologies in primary
care is therefore crucial.
Antibiotic shortages
Maintaining access to antibiotics requires good supply
chain management Antibiotic supply chains are complex.
For some antibiotics, the number of suppliers has
increased, which has made effective management,
regulation and quality assurance more difficult (103). For
example, in some African countries, more than 200
amoxicillin products are registered. In other cases, low
prices have reduced the number of manufacturers and
wholesalers of other essential medicines, creating
vulnerabilities in the supply chain. For example, benzathine
penicillin, usually the first treatment for syphilis, has been
in short supply in 39 countries, including Germany, India
and the United States, since 2015
Antibiotic shortages are particularly common in low-
and middle-income countries, where supply chains
may be weak, pharmaceutical management capacity
poor, procurement systems ineffective and rural
facilities isolated.
In addition, inadequacies in distribution systems may
prevent antibiotic supplies from reaching peripheral
facilities and cause stock-outs, or drugs may degrade
and become less effective because of inadequate
storage. A dependence on only one or a few producers
can make the global supply of certain antibiotics
highly vulnerable to manufacturing process errors and
fluctuations in the availability of active ingredients
(103).
An estimated 7.2% of antibiotics worldwide are falsified
or substandard. Such products may cause as many as 72
430 childhood pneumonia deaths each year . Substandard
drugs may select for resistance if they provide a
subinhibitory dose because the active pharmaceutical
ingredient is insufficient or degraded.
The Internet has provided opportunities for the sale of
substandard and falsified drugs . Infections not managed
with effective treatment are more likely to be transmitted
and spread. Such treatment failures, in the absence of
diagnostic tests, may be attributed to resistance and lead
to the use of second-line antibiotics that should be
conserved for resistant infections .
Conserving antimicrobial
effectiveness should be
part of an integrated
approach to health care
 Strengthening health systems
Primary health care, which emphasises early intervention
and disease prevention, can thereby be an efficient
allocation of limited health care resources. To maximise
the benefits, messaging on AMR needs to be consistent
across programmes, from the management of childhood
illness and maternal care to immunization.
Integrated community case management (iCCM) at the
community level and integrated management of childhood
illness (IMCI) at the facility level have both successfully
used an integrated health systems approach to treat
children with infections.
iCCM provides a simple treatment algorithm for
community health workers treating children with fever,
diarrhoea, coughing, or breathing difficulties.
IMCI offers clinical guidelines to health care facilities, as
well as training and standardised medical practices for
providers , such as criteria for referring a child to a health
care centre and for prescribing antibiotics .
The programmes have reduced mortality rates and costs
for both families and health systems . ICMI has also
reduced antibiotic use even where facilities lack adequate
diagnostics for infections .
Health care workers who have completed IMCI
modules are more likely to prescribe antimicrobials
appropriately, to administer the first dose in the
facility, and to give patients information on proper use.
In many countries, community health workers can
dispense amoxicillin for specific acute childhood
illnesses; in Pakistan, health care workers with iCCM
training who gave oral amoxicillin to children with
severe pneumonia had a lower treatment failure than
those who referred patients to a health facility, in part
because the treatment began sooner (124)
Immunization by Vaccines
Immunization reduces infection, transmission and
antibiotic use Vaccines prevent 2 million to 3 million
deaths from diphtheria, tetanus, pertussis (whooping
cough) and measles each year. An additional 1.5 million
deaths could be avoided if vaccination coverage were
increased . Vaccines can reduce AMR by lowering the
disease burden and thereby reducing both disease
transmission and antibiotic use. Introduction of the first
pneumococcal conjugate vaccine reduced resistant
invasive pneumococcal disease by 57% in the children
vaccinated; it also reduced the disease in adults over 65
years by 49%, even though this population was not
vaccinated .
In Israel, children who had received the pneumococcal
conjugate vaccine used antibiotics for 17% fewer days
than children who had not received it .
The inclusion of pneumococcal conjugate vaccine in
childhood vaccination schedules could reduce the
amount of antibiotics used for pneumonia cases by
47%, the equivalent of 11.4 million antibiotic days
globally.
 Policies, regulations and
monitoring are
needed to control
antimicrobial resistance
Regulation of antibiotics
Policy-makers need to regulate which antibiotics are
available at different tiers of health service so that
increased access does not exacerbate AMR. One way to
balance access and overuse is to promote access to some
antibiotics while reserving others for the treatment of
resistant infections.
In Model List of Essential Medicines, WHO categorized
antibiotics as
1) Access antibiotics, which should be widely available and
quality-assured,
2) Watch antibiotics, which are recommended for a limited
set of specific indications, and
3) Reserve antibiotics, which should be used only as a last
resort. Primary care providers would need reliable supply of
good-quality antibiotics from the access group and then
limit their use of antibiotics in the watch and reserve roups.
Regulation in departments of Food,
agriculture & Animals.
The global action plan published by WHO and endorsed
by the UN Food and Agriculture Organization (FAO) and
the World Organisation for Animal Health (OIE) sets out
the actions needed in each sector and national action
plan.
Ministries of agriculture, fisheries, environment and
others may coordinate their work at the national level;
however, collaboration must extend to local levels.
Countries are being encouraged to phase out the use of
antibiotics as growth promoters and to avoid the
widespread use of those antibiotics that are critical to
human health. Support from the primary health
community and coordination with the agricultural sector
will be essential.
Surveillance & Data collection of AMR
Without maps of resistance and consumption, prescribers
are lost Specific data on resistance and consumption at
the community level are needed to monitor resistance,
inform treatment guidelines and patient treatment , and
understand prescribing patterns.
Moreover, data are needed on total consumption, the
proportion of consultations that result in antibiotics being
prescribed and the proportion of antibiotics prescribed
that are in the “access” group .
The data must then be used by trained community health
care workers to inform treatment. The prevalence and
patterns of resistance seen in primary care could be
different from those seen in tertiary hospitals, where
patients are often treated for recurrent infections that are
more likely to be drug resistant.
Preventing Environmental
Contamination
Environmental contamination is a concern When
microbes are in contact with antimicrobial agents,
resistance can develop. A large proportion of
antibiotics’ active ingredients is excreted in the urine
of humans and animals , and environmental
contamination with antibiotic residues can occur from
pharmaceutical manufacturing or from the effluent of
hospitals or farm animal feed lots. Untreated human
and animal faeces create opportunities for resistance
to develop or be transmitted. Bacterial contamination
of drinking water should always be prevented.
Global & National Action Plans
Action on antimicrobial resistance must involve all
sectors The Global Antibiotic Resistance Partnership
(GARP), set up by the Center for Disease Dynamics,
Economics & Policy (CDDEP) with the support of the
Bill & Melinda Gates Foundation, is an example of the
impact working across the one-health spectrum can
have. GARP has established multisectoral national
level working groups on AMR in 16 low- and middle-
income countries. This has fostered momentum and
advocacy at a grassroots level which has connected
academics directly to policy-makers and enabled
interventions to be country specific.
Global and national action plans emphasize education
WHO’s global action plan on AMR calls on countries to
develop national action plans to manage their response
through health care, food production and the environment
. Primary health care, the most common point of contact
between health services and the public, provides an
opportunity to empower citizens to reduce AMR.
Education is the connection between primary health care
and AMR: educating doctors and patients that antibiotics
are effective only against bacterial infections, educating
farmers and veterinarians not to use antibiotics to
promote growth in livestock, and educating households in
personal hygiene and safe food practices that reduce the
transmission of infection. All these messages can be
delivered by primary health care workers.
 WHO global action plan on
antimicrobial resistance
1. To improve awareness and understanding of
antimicrobial resistance through effective
communication, education and training
2. To strengthen knowledge and the evidence base through
surveillance and research
3. To reduce the incidence of infection through effective
sanitation, hygiene and infection prevention measures
4. To optimize use of antimicrobial medicines in human and
animal health
5. To develop economic case for sustainable investment
that takes account of needs of all countries and to
increase investment in new medicines, diagnostic tools,
vaccines and other interventions
Novel Approaches to
Address Antimicrobial
Resistance
Conclusion
References
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