Antimicrobial resistance (AMR or AR) is the ability of a microbe to
resist the effects of medication previously used to treat
them. The term includes the more specific antibiotic
resistance (AR or ABR), which applies only to bacteria becoming
resistant to antibiotics. Resistant microbes are more difficult to
treat, requiring alternative medications or higher doses, both of
which may be more expensive or more toxic. Microbes resistant to
multiple antimicrobials are called multidrug resistant (MDR); those
extensively drug resistant (XDR) or totally drug resistant (TDR) are
sometimes called "superbugs".
Resistance arises through one of three mechanisms: natural resistance
in certain types of bacteria, genetic mutation, or by one species
acquiring resistance from another. All classes of microbes can
develop resistance: fungi develop antifungal resistance, viruses
develop antiviral resistance, protozoa develop antiprotozoal
resistance, and bacteria develop antibiotic resistance. Resistance can
appear spontaneously because of random mutations.
Preventive measures include only using antibiotics when needed,
thereby stopping misuse of antibiotics or antimicrobials.
Narrow-spectrum antibiotics are preferred over broad-spectrum
antibiotics when possible, as effectively and accurately targeting
specific organisms is less likely to cause resistance. For people
who take these medications at home, education about proper use is
essential. Health care providers can minimize spread of resistant
infections by use of proper sanitation and hygiene, including
handwashing and disinfecting between patients, and should encourage
the same of the patient, visitors, and family members.
Rising drug resistance is caused mainly by use of antimicrobials in
humans and other animals, and spread of resistant strains between the
Antibiotics increase selective pressure in bacterial
populations, causing vulnerable bacteria to die; this increases the
percentage of resistant bacteria which continue growing. With
resistance to antibiotics becoming more common there is greater need
for alternative treatments. Calls for new antibiotic therapies have
been issued, but new drug development is becoming rarer.
Antimicrobial resistance is on the rise globally, predominantly due to
greater access to drugs in low and middle income countries.
Estimates are that 700,000 to several million deaths result per
year. Each year in the United States, at least 2 million
people become infected with bacteria that are resistant to antibiotics
and at least 23,000 people die as a result. There are public calls
for global collective action to address the threat include proposals
for international treaties on antimicrobial resistance. Worldwide
antibiotic resistance is not fully mapped, but poorer countries with
weak healthcare systems are more affected.
3.1 Human medicine
3.2 Veterinary medicine
3.3 Natural occurrence
3.4 Environmental pollution
4.1 Duration of antibiotics
4.2 Monitoring and mapping
4.3 Limiting antibiotic use
4.3.1 At the hospital level
4.3.2 At the level of GP
4.3.3 At the individual level
4.3.4 Country examples
4.4 Water, sanitation, hygiene
4.5 Management in animal use
4.5.2 United States
4.6 Global action plans and awareness
Antibiotic Awareness Week
5 Mechanisms and organisms
7 Society and culture
7.1 Legal frameworks
8 Further research
8.2 Alternating therapy
8.3 Development of new drugs
8.4 Phage therapy
9 See also
12 External links
Diagram showing the difference between non-resistant bacteria and drug
resistant bacteria. Non-resistant bacteria multiply, and upon drug
treatment, the bacteria die. Drug resistant bacteria multiply as well,
but upon drug treatment, the bacteria continue to spread.
The WHO defines antimicrobial resistance as a microorganism's
resistance to an antimicrobial drug that was once able to treat an
infection by that microorganism. A person cannot become resistant
to antibiotics. Resistance is a property of the microbe, not a person
or other organism infected by a microbe.
World Health Organization
World Health Organization (WHO) report released April 2014 stated,
"this serious threat is no longer a prediction for the future, it is
happening right now in every region of the world and has the potential
to affect anyone, of any age, in any country. Antibiotic
resistance—when bacteria change so antibiotics no longer work in
people who need them to treat infections—is now a major threat to
How antibiotic resistance evolves and spreads
Bacteria with resistance to antibiotics predate medical use of
antibiotics by humans. However, widespread antibiotic use has
made more bacteria resistant through the process of evolutionary
Reasons for the widespread use of antibiotics in human medicine
increasing global availability over time since the 1950s
uncontrolled sale in many low or middle income countries, where they
can be obtained over the counter without a prescription, potentially
resulting in antibiotics being used when not indicated.:1060 This
may result in emergence of resistance in any remaining bacteria.
Other causes include:
Antibiotic use in livestock feed at low doses for growth promotion is
an accepted practice in many industrialized countries and is known to
lead to increased levels of resistance.
Releasing large quantities of antibiotics into the environment during
pharmaceutical manufacturing through inadequate wastewater treatment
increases the risk that antibiotic-resistant strains will develop and
It is uncertain whether antibacterials in soaps and other products
contribute to antibiotic resistance, but antibacterial soaps are
discouraged for other reasons.
Deaths attributable to antimicrobial resistance every year compared to
other major causes of death.
Increasing bacterial resistance is linked with the volume of
antibiotic prescribed, as well as missing doses when taking
antibiotics. Inappropriate prescribing of antibiotics has been
attributed to a number of causes, including people insisting on
antibiotics, physicians prescribing them as they feel they do not have
time to explain why they are not necessary, and physicians not knowing
when to prescribe antibiotics or being overly cautious for medical
and/or legal reasons. Lower antibiotic concentration contributes
to the increase of AMR by introducing more mutations that support
bacterial growth in higher antibiotic concentration.
For example, sub-inhibitory concentration have induced genetic
mutation in bacteria such as Pseudomonas aeruginosa and Bacteroides
Up to half of antibiotics used in humans are unnecessary and
inappropriate. For example, a third of people believe that
antibiotics are effective for the common cold, and the common cold
is the most common reason antibiotics are prescribed even though
antibiotics are useless against viruses. A single regimen of
antibiotics even in compliant individuals leads to a greater risk of
resistant organisms to that antibiotic in the person for a month to
possibly a year.
Antibiotic resistance increases with duration of treatment. Therefore,
as long as an effective minimum is kept, shorter courses of
antibiotics are likely to decrease rates of resistance, reduce cost,
and have better outcomes with fewer complications. Short course
regimens exist for community-acquired pneumonia spontaneous
bacterial peritonitis, suspected lung infections in intense care
wards, so-called acute abdomen, middle ear infections,
sinusitis and throat infections, and penetrating gut
injuries. In some situations a short course may not cure the
infection as well as a long course. A
BMJ editorial recommended
that antibiotics can often be safely stopped 72 hours after
Because individuals may feel better before the infection is
eradicated, doctors must provide instructions to them so they know
when it is safe to stop taking a prescription. Some researchers
advocate doctors' using a very short course of antibiotics,
reevaluating the patient after a few days, and stopping treatment if
there are no clinical signs of infection.
Certain antibiotic classes result in resistance more than others.
Increased rates of MRSA infections are seen when using glycopeptides,
cephalosporins, and quinolone antibiotics. Cephalosporins, and
particularly quinolones and clindamycin, are more likely to produce
Factors within the intensive care unit setting such as mechanical
ventilation and multiple underlying diseases also appear to contribute
to bacterial resistance. Poor hand hygiene by hospital staff has
been associated with the spread of resistant organisms.
Antibiotic use in livestock
All animals carry bacteria in their intestines.
Antibiotics are given
Antibiotics kill most bacteria. But resistant bacteria
survive and multiply.
World Health Organization
World Health Organization concluded that inappropriate use of
antibiotics in animal husbandry is an underlying contributor to the
emergence and spread of antibiotic-resistant germs, and that the use
of antibiotics as growth promoters in animal feeds should be
World Organisation for Animal Health
World Organisation for Animal Health has added to
the Terrestrial Animal Health Code a series of guidelines with
recommendations to its members for the creation and harmonization of
national antimicrobial resistance surveillance and monitoring
programs, monitoring of the quantities of antibiotics used in
animal husbandry, and recommendations to ensure the proper and
prudent use of antibiotic substances. Another guideline is to
implement methodologies that help to establish associated risk factors
and assess the risk of antibiotic resistance.
Naturally occurring antibiotic resistance is common. Genes for
resistance to antibiotics, like antibiotics themselves, are
ancient. The genes that confer resistance are known as the
environmental resistome. These genes may be transferred from
non-disease-causing bacteria to those that do cause disease, leading
to clinically significant antibiotic resistance.
In 1952 it was shown that penicillin-resistant bacteria existed before
penicillin treatment; and also preexistent bacterial resistance to
streptomycin. In 1962, the presence of penicillinase was detected
in dormant endospores of Bacillus licheniformis, revived from dried
soil on the roots of plants, preserved since 1689 in the British
Museum. Six strains of Clostridium, found in the bowels of
William Braine and John Hartnell (members of the Franklin Expedition)
showed resistance to cefoxitin and clindamycin.
Penicillinase may have emerged as a defense mechanism for bacteria in
their habitats, such as the case of penicillinase-rich Staphylococcus
aureus, living with penicillin-producing Trichophyton; however, this
may be circumstantial. Search for a penicillinase ancestor has
focused on the class of proteins that must be a priori capable of
specific combination with penicillin. The resistance to cefoxitin
and clindamycin in turn was attributed to Braine's and Hartnell's
contact with microorganisms that naturally produce them or random
mutation in the chromosomes of
There is evidence that heavy metals and other pollutants may select
for antibiotic-resistant bacteria, generating a constant source of
them in small numbers.
Antibiotic resistance is a growing problem among humans and wildlife
in terrestrial or aquatic environments. In this respect, the spread
and contamination of the environment, especially through "hot spots"
such as hospital wastewater and untreated urban wastewater, is a
growing and serious public health problem.
been polluting the environment since their introduction through human
waste (medication, farming), animals, and the pharmaceutical
industry. Along with antibiotic waste, resistant bacteria follow,
thus introducing antibiotic-resistant bacteria into the environment.
Already in 2011, mapping of sewage and water supply samples in New
Delhi showed widespread and uncontrolled infection as indicated by the
presence of NDM-1-positive enteric bacteria.
While 70 to 80 percent of diarrhea is caused by viral pathogens, for
which antibiotics are not effective, around 40 percent of these cases
are nevertheless attempted to be treated with antibiotics. In some
areas even over 80 percent of cases are attempted to be treated with
As bacteria replicate quickly, the resistant bacteria that enter the
environment replicate their resistance genes as they continue to
divide. In addition, bacteria carrying resistance genes have the
ability to spread those genes to other species via horizontal gene
transfer. Therefore, even if the specific antibiotic is no longer
introduced into the environment, antibiotic-resistance genes will
persist through the bacteria that have since replicated without
Antibiotic resistance is widespread in marine
vertebrates, and they may be important reservoirs of
antibiotic-resistant bacteria in the marine environment.
Mission Critical: Preventing
Antibiotic Resistance (CDC report,
There have been increasing public calls for global collective action
to address the threat, including a proposal for international treaty
on antimicrobial resistance. Further detail and attention is still
needed in order to recognize and measure trends in resistance on the
international level; the idea of a global tracking system has been
suggested but implementation has yet to occur. A system of this nature
would provide insight to areas of high resistance as well as
information necessary for evaluation of programs and other changes
made to fight or reverse antibiotic resistance.
Five important strategies needed for minimising antibiotic resistance
are as follows:
Antibiotic stewardship to maintain the value of existing and future
The timing of prescription to use the effective antibiotics sooner
rather than later
To develop and approve ten new antibiotics by 2020
Development of a molecular method for detecting antibiotic resistance
To avoid the delay in distribution of US$2 billion global antibiotic
resistance innovation fund.
Duration of antibiotics
Antibiotic treatment duration should be based on the infection and
other health problems a person may have. For many infections once a
person has improved there is little evidence that stopping treatment
causes more resistance. Some therefore feel that stopping early may
be reasonable in some cases. Other infections, however, do require
long courses regardless of whether a person feels better.
Monitoring and mapping
There are multiple national and international monitoring programs for
drug-resistant threats, including methicillin-resistant Staphylococcus
aureus (MRSA), vancomycin-resistant S. aureus (VRSA), extended
spectrum beta-lactamase (ESBL), vancomycin-resistant Enterococcus
(VRE), multidrug-resistant A. baumannii (MRAB).
ResistanceOpen is an online global map of antimicrobial resistance
HealthMap which displays aggregated data on antimicrobial
resistance from publicly available and user submitted data.
The website can display data for a 25-mile radius from a location.
Users may submit data from antibiograms for individual hospitals or
laboratories. European data is from the EARS-Net (European
Antimicrobial Resistance Surveillance Network), part of the ECDC.
ResistanceMap is a website by the Center for Disease Dynamics,
Economics & Policy and provides data on antimicrobial resistance
on a global level.
Limiting antibiotic use
Antibiotic stewardship programmes appear useful in reducing rates of
Excessive antibiotic use has become one of the top contributors to the
development of antibiotic resistance. Since the beginning of the
antibiotic era, antibiotics have been used to treat a wide range of
disease. Overuse of antibiotics has become the primary cause of
rising levels of antibiotic resistance. The main problem is that
doctors are willing to prescribe antibiotics to ill-informed
individuals who believe that antibiotics can cure nearly all
illnesses, including viral infections like the common cold. In an
analysis of drug prescriptions, 36% of individuals with a cold or an
upper respiratory infection (both viral in origin) were given
prescriptions for antibiotics. These prescriptions accomplished
nothing other than increasing the risk of further evolution of
antibiotic resistant bacteria.
At the hospital level
Antimicrobial stewardship teams in hospitals are encouraging optimal
use of antimicrobials. The goals of antimicrobial stewardship are
to help practitioners pick the right drug at the right dose and
duration of therapy while preventing misuse and minimizing the
development of resistance. Stewardship may reduce the length of stay
by an average of slightly over 1 day while not increasing the risk of
At the level of GP
Given the volume of care provided in primary care (General Practice),
recent strategies have focused on reducing unnecessary antibiotic
prescribing in this setting. Simple interventions, such as written
information explaining the futility of antibiotics for common
infections such as upper respiratory tract infections, have been shown
to reduce antibiotic prescribing.
The prescriber should closely adhere to the five rights of drug
administration: the right patient, the right drug, the right dose, the
right route, and the right time.
Cultures should be taken before treatment when indicated and treatment
potentially changed based on the susceptibility report.
About a third of antibiotic prescriptions written in outpatient
settings in the United States were not appropriate in 2010 and 2011.
Doctors in the U.S. wrote 506 annual antibiotic scripts for every
1,000 people, with 353 being medically necessary.
Health workers and pharmacists can help tackle resistance by:
enhancing infection prevention and control; only prescribing and
dispensing antibiotics when they are truly needed; prescribing and
dispensing the right antibiotic(s) to treat the illness.
At the individual level
People can help tackle resistance by using antibiotics only when
prescribed by a doctor; completing the full prescription, even if they
feel better; never sharing antibiotics with others or using leftover
Netherlands has the lowest rate of antibiotic prescribing in the
OECD, at a rate of 11.4 defined daily doses (DDD) per 1,000 people per
day in 2011.
Sweden also have lower prescribing rates, with Sweden's
rate having been declining since 2007.
Belgium have high prescribing rates of more than 28
Water, sanitation, hygiene
Infectious disease control through improved water, sanitation and
hygiene (WASH) infrastructure needs to be placed at the center of the
antimicrobial resistance (AMR) agenda. The spread of infectious
diseases caused by inadequate
WASH standards is a major driver of
antibiotic demand in developing countries. Growing usage of
antibiotics together with persistent infectious disease levels have
led to a dangerous cycle in which reliance on antimicrobials increases
while the efficacy of drugs diminishes. The proper use of
infrastructure for water, sanitation and hygiene (WASH) can result in
a 47–72 percent decrease of diarrhea cases treated with antibiotics
depending on the type of intervention and its effectiveness. A
reduction of the diarrhea disease burden through improved
infrastructure would result in large decreases in the number of
diarrhea cases treated with antibiotics. This was estimated as ranging
from 5 million in Brazil to up to 590 million in India by the year
2030. The strong link between increased consumption and resistance
indicates that this will directly mitigate the accelerating spread of
Sanitation and water for all by 2030 is Goal Number 6 of the
Sustainable Development Goals.
An increase in hand washing compliance by hospital staff results in
decreased rates of resistant organisms.
Management in animal use
Antibiotic use in livestock § Concerns about
In 1997, European Union health ministers voted to ban avoparcin and
four additional antibiotics used to promote animal growth in 1999.
In 2006 a ban on the use of antibiotics in European feed, with the
exception of two antibiotics in poultry feeds, became effective.
In Scandinavia, there is evidence that the ban has led to a lower
prevalence of antibiotic resistance in (nonhazardous) animal bacterial
populations. As of 2004, several European countries established a
decline of antimicrobial resistance in humans through limiting the
usage antimicrobials in agriculture and food industries without
jeopardizing animal health or economic cost.
United States Department of Agriculture
United States Department of Agriculture (USDA) and the Food and
Drug Administration (FDA) collect data on antibiotic use in humans and
in a more limited fashion in animals. The FDA first determined in
1977 that there is evidence of emergence of antibiotic-resistant
bacterial strains in livestock. The long-established practice of
permitting OTC sales of antibiotics (including penicillin and other
drugs) to lay animal owners for administration to their own animals
nonetheless continued in all states. In 2000, the FDA announced their
intention to revoke approval of fluoroquinolone use in poultry
production because of substantial evidence linking it to the emergence
Campylobacter infections in humans. Legal
challenges from the food animal and pharmaceutical industries delayed
the final decision to do so until 2006. Fluroquinolones have been
banned from extra-label use in food animals in the USA since 2007.
However, they remain widely used in companion and exotic animals.
Global action plans and awareness
A global action plan to tackle the growing problem of resistance to
antibiotics and other antimicrobial medicines was endorsed at the
Sixty-eighth World Health Assembly in May 2015. One of the key
objectives of the plan is to improve awareness and understanding of
antimicrobial resistance through effective communication, education
and training. React based in
Sweden has produced informative material
on AMR for the general public.
Videos are being produced for the general public to generate interest
Antibiotic Awareness Week
World Health Organization
World Health Organization has promoted the first World Antibiotic
Awareness Week running from 16–22 November 2015. The aim of the week
is to increase global awareness of antibiotic resistance. It also
wants to promote the correct usage of antibiotics across all fields in
order to prevent further instances of antibiotic resistance.
Antibiotic Awareness Week has been held every November since
2015. For 2017, the Food and Agriculture Organization of the United
Nations (FAO), the
World Health Organization
World Health Organization (WHO) and the World
Organisation for Animal Health (OIE) are together calling for
responsible use of antibiotics in humans and animals to reduce the
emergence of antibiotic resistance.
Mechanisms and organisms
Diagram depicting antibiotic resistance through alteration of the
antibiotic's target site, modeled after MRSA's resistance to
penicillin. Beta-lactam antibiotics permanently inactivate PBP
enzymes, which are essential for bacterial life, by permanently
binding to their active sites. MRSA, however, expresses a PBP that
does not allow the antibiotic into its active site.
The four main mechanisms by which microorganisms exhibit resistance to
Drug inactivation or modification: for example, enzymatic deactivation
of penicillin G in some penicillin-resistant bacteria through the
production of β-lactamases. The emergence of carbapenem-resistant
Gram-negative pathogens poses a serious threat to public health
Klebsiella pneumoniae carbapenemases (KPCs) and
carbapenemases of the oxacillinase-48 (OXA-48) type have been reported
worldwide. New Delhi metallo-β-lactamase (NDM) carbapenemases were
originally identified in
Sweden in 2008 and have spread worldwide
rapidly. Most commonly, the protective enzymes produced by the
bacterial cell will add an acetyl or phosphate group to a specific
site on the antibiotic, which will reduce its ability to bind to the
bacterial ribosomes and disrupt protein synthesis.
Alteration of target- or binding site: for example, alteration of
PBP—the binding target site of penicillins—in MRSA and other
penicillin-resistant bacteria. Another protective mechanism found
among bacterial species is ribosomal protection proteins. These
proteins protect the bacterial cell from antibiotics that target the
cell’s ribosomes to inhibit protein synthesis. The mechanism
involves the binding of the ribosomal protection proteins to the
ribosomes of the bacterial cell, which in turn changes its
conformational shape. This allows the ribosomes to continue
synthesizing proteins essential to the cell while preventing
antibiotics from binding to the ribosome to inhibit protein
Alteration of metabolic pathway: for example, some
sulfonamide-resistant bacteria do not require para-aminobenzoic acid
(PABA), an important precursor for the synthesis of folic acid and
nucleic acids in bacteria inhibited by sulfonamides, instead, like
mammalian cells, they turn to using preformed folic acid.[citation
Reduced drug accumulation: by decreasing drug permeability or
increasing active efflux (pumping out) of the drugs across the cell
surface These pumps within the cellular membrane of certain
bacterial species are used to pump antibiotics out of the cell before
they are able to do any damage. They are often activated by a specific
substrate associated with an antibiotic. as in fluoroquinolone
A number of mechanisms used by common antibiotics to deal with
bacteria and ways by which bacteria become resistant to them.
Antibiotic resistance can be a result of horizontal gene
transfer, and also of unlinked point mutations in the pathogen
genome at a rate of about 1 in 108 per chromosomal replication.
Mutations are rare but the fact that bacteria reproduce at such a high
rate allows for the effect to be significant. A mutation may produce a
change in the binding site of the antibiotic, which may allow the site
to continue proper functioning in the presence of the antibiotic or
prevent the binding of the antibiotic to the site altogether.
Antibiotic action against a pathogen can be seen as an environmental
pressure. Those bacteria with a mutation that allows them to survive
will reproduce, pass the trait to their offspring, which leads to the
microevolution of a fully resistant colony. Chromosomal mutations
providing antibiotic resistance benefit the bacteria but also confer a
cost of fitness. For example, a ribosomal mutation may protect a
bacterial cell by changing the binding site of an antibiotic but will
also slow protein synthesis. manifesting, in slower growth
In Gram-negative bacteria, plasmid-mediated resistance genes produce
proteins that can bind to DNA gyrase, protecting it from the action of
quinolones. Finally, mutations at key sites in
DNA gyrase or
topoisomerase IV can decrease their binding affinity to quinolones,
decreasing the drug's effectiveness.
Klebsiella pneumoniae, the bacterium in which NDM-1 was first
Further information: List of antibiotic resistant bacteria
Bacteria can develop antibiotic resistance. Recent
findings show no necessity of large populations of bacteria for the
appearance of antibiotic resistance. Small populations of E. coli in
an antibiotic gradient can become resistant. Any heterogeneous
environment with respect to nutrient and antibiotic gradients may
facilitate antibiotic resistance in small bacterial populations.
Researchers hypothesize that the mechanism of resistance development
is based on four SNP mutations in the genome of E. coli produced by
the gradient of antibiotic.
Antibiotic resistance can be introduced artificially into a
microorganism through laboratory protocols, sometimes used as a
selectable marker to examine the mechanisms of gene transfer or to
identify individuals that absorbed a piece of DNA that included the
resistance gene and another gene of interest.
New Delhi metallo-beta-lactamase 1
New Delhi metallo-beta-lactamase 1 (NDM-1) is an enzyme that
makes bacteria resistant to a broad range of beta-lactam antibiotics.
The most common bacteria that make this enzyme are gram-negative such
Escherichia coli and Klebsiella pneumoniae, but the gene for NDM-1
can spread from one strain of bacteria to another by horizontal gene
Specific antiviral drugs are used to treat some viral infections.
These drugs prevent viruses from reproducing by inhibiting essential
stages of the virus's replication cycle in infected cells. Antivirals
are used to treat HIV, hepatitis B, hepatitis C, influenza, herpes
viruses including varicella zoster virus, cytomegalovirus and
Epstein-Barr virus. With each virus, some strains have become
resistant to the administered drugs.
HIV antivirals is problematic, and even multi-drug
resistant strains have evolved. Resistant strains of the HIV
virus emerge rapidly if only one antiviral drug is used. Using
three or more drugs together has helped to control this problem, but
new drugs are needed because of the continuing emergence of
Infections by fungi are a cause of high morbidity and mortality in
immunocompromised persons, such as those with HIV/AIDS, tuberculosis
or receiving chemotherapy. The fungi candida, Cryptococcus
Aspergillus fumigatus cause most of these infections
and antifungal resistance occurs in all of them. Multidrug
resistance in fungi is increasing because of the widespread use of
antifungal drugs to treat infections in immunocompromised
Of particular note, Fluconazole-resistant Candida species have been
highlighted as a growing problem by the CDC. More than 20 Candida
species of Candida can cause
Candidiasis infection, the most common of
which is Candida albicans. Candida yeasts normally inhabit the skin
and mucous membranes without causing infection. However, overgrowth of
Candida can lead to Candidiasis. Some Candida strains are becoming
resistant to first-line and second-line antifungal agents such as
azoles and echinocandins.
The protozoan parasites that cause the diseases malaria,
trypanosomiasis, toxoplasmosis, cryptosporidiosis and leishmaniasis
are important human pathogens.
Malarial parasites that are resistant to the drugs that are currently
available to infections are common and this has led to increased
efforts to develop new drugs. Resistance to recently developed
drugs such as artemisinin has also been reported. The problem of drug
resistance in malaria has driven efforts to develop vaccines.
Trypanosomes are parasitic protozoa that cause African trypanosomiasis
Chagas disease (American trypanosomiasis). There are no
vaccines to prevent these infections so drugs such as pentamidine and
suramin, benznidazole and nifurtimox and used to treat infections.
These drugs are effective but infections caused by resistant parasites
have been reported.
Leishmaniasis is caused by protozoa and is an important public health
problem worldwide, especially in sub-tropical and tropical countries.
Drug resistance has "become a major concern".
The phenomenon of antimicrobial resistance caused by overuse of
antibiotics was predicted already by
Alexander Fleming who said "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 nonlethal quantities of the
drug make them resistant."
Society and culture
For the fiscal year 2016 budget, President Obama has suggested to
nearly double the amount of federal funding to "combat and prevent"
antibiotic resistance to more than $1.2 billion. Many
international funding agencies like USAID, DFID, SIDA and Bill &
Melinda Gates Foundation has pledged money for developing strategies
to counter antimicrobial resistance.
Since the mid-1980s pharmaceutical companies have invested in
medications for cancer or chronic disease that have greater potential
to make money and have "de-emphasized or dropped development of
antibiotics". On January 20, 2016 at the
World Economic Forum
World Economic Forum in
Davos, Switzerland, more than "80 pharmaceutical and diagnostic
companies" from around the world called for 'transformational
commercial models' at a global level to spur research and development
on antibiotics and on the "enhanced use of diagnostic tests that can
rapidly identify the infecting organism".
Some global health scholars have argued that a global, legal framework
is needed to prevent and control antimicrobial
resistance.[page needed][page needed] For
instance, binding global policies could be used to create
antimicrobial use standards, regulate antibiotic marketing, and
strengthen global surveillance
systems.[page needed][page needed] Ensuring
compliance of involved parties is a challenge.[page needed]
Global antimicrobial resistance policies could take lessons from the
environmental sector by adopting strategies that have made
international environmental agreements successful in the past such as:
sanctions for non-compliance, assistance for implementation, majority
vote decision-making rules, an independent scientific panel, and
specific commitments.[page needed]
On March 27, 2015, the
White House released a comprehensive plan to
address the increasing need for agencies to combat the rise of
antibiotic-resistant bacteria. The Task Force for Combating
Bacteria developed The National Action Plan for
Bacteria with the intent of providing a
roadmap to guide the US in the antibiotic resistance challenge and
with hopes of saving many lives. This plan outlines steps taken by the
Federal government over the next five years needed in order to prevent
and contain outbreaks of antibiotic-resistant infections; maintain the
efficacy of antibiotics already on the market; and to help to develop
future diagnostics, antibiotics, and vaccines.
The Action Plan was developed around five goals with focuses on
strengthening health care, public health veterinary medicine,
agriculture, food safety and research, and manufacturing. These goals,
as listed by the White House, are as follows:
Slow the Emergence of Resistant
Bacteria and Prevent the Spread of
Strengthen National One-Health Surveillance Efforts to Combat
Advance Development and use of Rapid and Innovative Diagnostic Tests
for Identification and Characterization of Resistant Bacteria
Accelerate Basic and Applied Research and Development for New
Antibiotics, Other Therapeutics, and Vaccines
Improve International Collaboration and Capacities for Antibiotic
Resistance Prevention, Surveillance, Control and
The following are goals set to meet by 2020:
Establishment of antimicrobial programs within acute care hospital
Reduction of inappropriate antibiotic prescription and use by at least
50% in outpatient settings and 20% inpatient settings
Establishment of State
Antibiotic Resistance (AR) Prevention Programs
in all 50 states
Elimination of the use of medically important antibiotics for growth
promotion in food-producing animals.
According to WHO policymakers can help tackle resistance by
strengthening resistance tracking and laboratory capacity; regulating
and promoting appropriate use of medicines. Policymakers and
industry can help tackle resistance by: fostering innovation and
research and development of new tools; promoting cooperation and
information sharing among all stakeholders.
It is unclear if rapid viral testing affects antibiotic use in
Microorganisms do not develop resistance to vaccines because a vaccine
enhances the body's immune system, whereas an antibiotic operates
separately from the body's normal defenses. Furthermore, if the use of
vaccines increase, there is evidence that antibiotic resistant strains
of pathogens will decrease; the need for antibiotics will naturally
decrease as vaccines prevent infection before it occurs. However,
new strains that escape immunity induced by vaccines may evolve; for
example, an updated influenza vaccine is needed each year.
While theoretically promising, antistaphylococcal vaccines have shown
limited efficacy, because of immunological variation between
Staphylococcus species, and the limited duration of effectiveness of
the antibodies produced. Development and testing of more effective
vaccines is underway.
Alternating therapy is a proposed method in which two or three
antibiotics are taken in a rotation versus taking just one antibiotic
such that bacteria resistant to one antibiotic are killed when the
next antibiotic is taken. Studies have found that this method reduces
the rate at which antibiotic resistant bacteria emerge in vitro
relative to a single drug for the entire duration.
Studies have found that bacteria that evolve antibiotic resistance
towards one group of antibiotic may become more sensitive others.
This phenomona can be utilized to select against resistant bacteria
using an approach termed collateral sensitivity cycling, which
has recently been found to be relevant in developing treatment
strategies for chronic infections caused by Pseudomonas
Development of new drugs
Since the discovery of antibiotics, research and development (R&D)
efforts have provided new drugs in time to treat bacteria that became
resistant to older antibiotics, but in the 2000s there has been
concern that development has slowed enough that seriously ill people
may run out of treatment options. Another concern is that doctors
may become reluctant to perform routine surgeries because of the
increased risk of harmful infection. Backup treatments can have
serious side-effects; for example, treatment of multi-drug-resistant
tuberculosis can cause deafness or psychological disability. The
potential crisis at hand is the result of a marked decrease in
industry R&D. Poor financial investment in antibiotic
research has exacerbated the situation. The pharmaceutical
industry has little incentive to invest in antibiotics because of the
high risk and because the potential financial returns are less likely
to cover the cost of development than for other pharmaceuticals.
In 2011, Pfizer, one of the last major pharmaceutical companies
developing new antibiotics, shut down its primary research effort,
citing poor shareholder returns relative to drugs for chronic
illnesses. However, small and medium-sized pharmaceutical
companies are still active in antibiotic drug research.
In the United States, drug companies and the administration of
Barack Obama have been proposing changing the standards by
which the FDA approves antibiotics targeted at resistant
organisms. On 12 December 2013, the
to Advance Patient Treatment (ADAPT) Act of 2013 was introduced in the
U.S. Congress. The ADAPT Act aims to fast-track the drug development
in order to combat the growing public health threat of 'superbugs'.
Under this Act, the FDA can approve antibiotics and antifungals needed
for life-threatening infections based on data from smaller clinical
Centers for Disease Control and Prevention
Centers for Disease Control and Prevention (CDC) will
reinforce the monitoring of the use of antibiotics that treat serious
and life-threatening infections and the emerging resistance, and make
the data publicly available. The FDA antibiotics labeling process,
'Susceptibility Test Interpretive Criteria for Microbial Organisms' or
'breakpoints' is also streamlined to allow the most up-to-date and
cutting-edge data available to healthcare professionals under the new
On 18 September 2014 Obama signed an executive order to implement
the recommendations proposed in a report by the President's
Council of Advisors on Science and Technology (PCAST) which outlines
strategies to stream-line clinical trials and speed up the R&D of
new antibiotics. Among the proposals:
Create a 'robust, standing national clinical trials network for
antibiotic testing' which will promptly enroll patients once
identified to be suffering from dangerous bacterial infections. The
network will allow testing multiple new agents from different
companies simultaneously for their safety and efficacy.
Establish a '
Special Medical Use (SMU)' pathway for FDA to approve new
antimicrobial agents for use in limited patient populations, shorten
the approval timeline for new drug so patients with severe infections
could benefit as quickly as possible.
Provide economic incentives, especially for development of new classes
of antibiotics, to offset the steep R&D costs which drive away the
industry to develop antibiotics.
The executive order also included a $20 million prize to encourage the
development of diagnostic tests to identify highly resistant bacterial
National Institutes of Health
National Institutes of Health plans to fund a new research
network on the issue up to $62 million from 2013 to 2019.
Using authority created by the Pandemic and All Hazards Preparedness
Act of 2006, the Biomedical Advanced Research and Development
Authority in the U.S. Department of Health and Human Services
announced that it will spend between $40 million and
$200 million in funding for R&D on new antibiotic drugs under
development by GlaxoSmithKline.
One major cause of antibiotic resistance is the increased pumping
activity of microbial ABC transporters, which diminishes the effective
drug concentration inside the microbial cell. ABC transporter
inhibitors that can be used in combination with current antimicrobials
are being tested in clinical trials and are available for therapeutic
regimens.[undue weight? – discuss]
Main article: Phage therapy
Phage therapy is the therapeutic use of bacteriophages to treat
pathogenic bacterial infections.
Phage therapy has many potential
applications in human medicine as well as dentistry, veterinary
science, and agriculture.
Bacteriophages are much more specific than antibiotics. They are
typically harmless not only to the host organism, but also to other
beneficial bacteria, such as the gut flora, reducing the chances of
Bacteriophages are used against antibiotic resistant bacteria in
Georgia (George Eliava Institute) and in one institute in Wrocław,
Alliance for the Prudent Use of Antibiotics
Drug of last resort
(KPC) antibacterial resistance gene
Multidrug-resistant Gram-negative bacteria
Resistance-nodulation-cell division superfamily
Resistance-nodulation-cell division superfamily (RND)
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