ANTIMICROBIAL RESISTANCE (AMR) is the ability of a microbe to resist
the effects of medication previously used to treat them. This
broader term also covers ANTIBIOTIC RESISTANCE, which applies to
bacteria and antibiotics . Resistance arises through one of three
ways: natural resistance in certain types of bacteria, genetic
mutation , or by one species acquiring resistance from another.
Resistance can appear spontaneously because of random mutations; or
more commonly following gradual buildup over time, and because of
misuse of antibiotics or antimicrobials . Resistant microbes are
increasingly 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); or sometimes superbugs.
Antimicrobial resistance is
on the rise with millions of deaths every year. All classes of
microbes develop resistance: fungi develop antifungal resistance,
viruses develop antiviral resistance, protozoa develop antiprotozoal
resistance, and bacteria develop antibiotic resistance.
Antibiotics should only be used when needed as prescribed by health
professionals. 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. Narrow-spectrum
antibiotics are preferred over broad-spectrum antibiotics when
possible, as effectively and accurately targeting specific organisms
is less likely to cause resistance. Cultures should be taken before
treatment when indicated and treatment potentially changed based on
the susceptibility report. 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, including handwashing and disinfecting between patients,
and should encourage the same of the patient, visitors, and family
Rising drug resistance is caused mainly by improper use of
antimicrobials in humans as well as in animals, and spread of
resistant strains between the two.
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
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
public health." Increasing 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. According to the Centers for Disease Control and
Prevention : "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 each year as a direct result of these
infections." 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).
* 1 Definition
* 2 Causes
* 2.1 Human medicine
* 2.2 Veterinary medicine
* 2.4 Natural occurrence
* 2.5 Environmental
* 3 Prevention
World Health Organization
World Health Organization
* 3.2 Duration of antibiotics
* 3.4 Monitoring
* 3.5 Strategies
* 3.5.1 Vaccines
* 3.5.2 Alternating therapy
* 3.5.3 Development of new drugs
* 3.6 Animal use
* 3.6.1 Europe
* 4 Mechanisms
* 4.1 NDM-1
* 5 Organisms
* 5.1.2 Streptococcus and
* 5.1.5 Carbapenem-resistant Enterobacteriaceae
* 5.1.6 Multidrug-resistant Acinetobacter
* 5.1.7 Drug-resistant
Salmonella and E. coli
* 5.2 Viruses
* 5.3 Fungi
* 5.4 Parasites
* 6 Applications
* 7 Society and culture
* 7.1 Legal frameworks
* 8 See also
* 9 References
* 10 Bibliography
* 10.1 Books
* 10.2 Journals
* 11 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.
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 pressure .
Reasons for the widespread use of antibiotics include:
* 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
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 spread. It
is uncertain whether antibacterials in soaps and other products
contribute to antibiotic resistance, but they are discouraged for
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.
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
BMJ editorial recommended that antibiotics can often be
safely stopped 72 hours after symptoms resolve. 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
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
Clostridium difficile .
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, and an increase in
hand washing compliance results in decreased rates.
This paragraph HAS BEEN NOMINATED TO BE CHECKED FOR ITS NEUTRALITY
. Discussion of this nomination can be found on the talk page .
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Improper use of antibiotics can often be attributed to the presence
of structural violence in particular regions. Socioeconomic factors
such as race and poverty affect accessibility of and adherence to drug
therapy. The efficacy of treatment programs for drug-resistant strains
depends on whether or not programmatic improvements take into account
the effects of structural violence.
The examples and perspective in this section MAY NOT REPRESENT A
WORLDWIDE VIEW OF THE SUBJECT. You may improve this article , discuss
the issue on the talk page , or create a new article , as appropriate.
(November 2015) (Learn how and when to remove this template message )
Antibiotic use in livestock All animals carry
bacteria in their intestines.
Antibiotics are given to animals.
Antibiotics kill most bacteria. But resistant bacteria survive and
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 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.
Eighty percent of antibiotics sold in the
United States are used on
livestock. The majority of these antibiotics are given to animals that
are otherwise healthy. Rather, it is normal practice to mix
antibiotics with livestock food to promote healthier living conditions
and to encourage animal growth. The use of antibiotics in animals is
to a large degree involved in the emergence of antibiotic-resistant
Antibiotics are used in food with the intention of
not only preventing, controlling, and treating diseases, but also to
Antibiotic use in animals can be classified into
therapeutic, prophylactic, metaphylactic, and growth promotion uses of
antibiotics. All four patterns select for bacterial resistance, since
antibiotic resistance is a natural evolutionary process, but the
non-therapeutic uses expose larger number of animals, and therefore of
bacteria, for more extended periods, and at lower doses. They
therefore greatly increase the cross-section for the evolution of
resistance. The origins of antibiotic-resistant Staphylococcus
aureus (CAFO: concentrated animal feeding operations)
Since the last third of the 20th century, antibiotics have been
used extensively in animal husbandry . In 2013, 80% of antibiotics
used in the US were used in animals and only 20% in humans; in 1997
half were used in humans and half in animals. Some antibiotics are
not used and not considered significant for use in humans, because
they either lack efficacy or purpose in humans, such as ionophores in
ruminants, or because the drug has gone out of use in humans. Others
are used in both animals and humans, including penicillin and some
forms of tetracycline. Historically, regulation of antibiotic use in
food animals has been limited to limiting drug residues in meat, egg,
and milk products, rather than by direct concern over the development
of antibiotic resistance. This mirrors the primary concerns in human
medicine, where, in general, researchers and doctors were more
concerned about effective but non-toxic doses of drugs rather than
In 2001, the
Union of Concerned Scientists estimated that greater
than 70% of the antibiotics used in the U.S. are given to food animals
(for example, chickens, pigs, and cattle), in the absence of disease.
The amounts given are termed "sub-therapeutic", i.e., insufficient to
combat disease. Despite no diagnosis of disease, the administration of
these drugs (most of which are not significant to human medicine)
results in decreased mortality and morbidity and increased growth in
the animals so treated. It is theorized that sub-therapeutic dosages
kills some, but not all, of the bacterial organisms in the animal —
likely leaving those that are naturally antibiotic-resistant. Studies
have shown, however, that, in essence, the overall population levels
of bacteria are unchanged; only the mix of bacteria is affected. The
actual mechanism by which sub-therapeutic antibiotic feed additives
serve as growth promoters is thus unclear. Some people have speculated
that animals and fowl may have sub-clinical infections, which would be
cured by low levels of antibiotics in feed, thereby allowing the
creatures to thrive. No convincing evidence has been advanced for this
theory, and the bacterial load in an animal is essentially unchanged
by use of antibiotic feed additives. The mechanism of growth promotion
is therefore probably something other than "killing off the bad bugs".
Antibiotics are used in U.S. animal feed to promote animal
productivity. In particular, poultry feed and water is a common
route of administration of drugs, because of higher overall costs when
drugs are administered by handling animals individually.
In research studies, occasional animal-to-human spread of
antibiotic-resistant organisms has been demonstrated. Resistant
bacteria can be transmitted from animals to humans in three ways: by
consuming animal products (milk, meat, eggs, etc.), from close or
direct contact with animals or other humans, or through the
environment. In the first pathway, food preservation methods can help
eliminate, decrease, or prevent the growth of bacteria in some food
classes. Evidence for the transfer of macrolide-resistant
microorganisms from animals to humans has been scant, and most
evidence shows that pathogens of concern in human populations
originated in humans and are maintained there, with rare cases of
transference to humans.
Play media The
Bacteria on a “Mega-Plate”
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
Staphylococcus aureus , living with
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
Clostridium strains. 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.
Antibiotics have 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. 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,
Antibiotic stewardship programmes appear useful in reducing rates of
WORLD HEALTH ORGANIZATION
In 2014, the WHO stated:
* 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
* Health workers and pharmacists can help tackle resistance by:
* enhancing infection prevention and control;
* only prescribing and dispensing antibiotics when they are truly
* prescribing and dispensing the right antibiotic(s) to treat the
* 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
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.
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. By contrast,
Belgium have high prescribing rates of more than
28 DDD. It is unclear if rapid viral testing affects antibiotic use
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.
ResistanceOpen, an online global map of antimicrobial resistance
HealthMap , 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, by the Center for Disease Dynamics, Economics 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
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.
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.
According to the report, issued in January 2016, the five important
strategies needed for minimising antibiotic resistance are as follows:
Antibiotic stewardship to maintain the value of existing and
* 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
* To avoid the delay in distribution of US$2 billion global
antibiotic resistance innovation fund.
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
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.
Development Of New Drugs
Since the discovery of antibiotics, research and development (R 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
Antibiotic Development 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
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
Biomedical Advanced Research and Development Authority in
Department of Health and Human Services
Department of Health and Human Services announced that it
will spend between $40 million and $200 million in funding for R">
Bacteriophages are used against antibiotic resistant bacteria in
George Eliava Institute ) and in 1 institute in
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.
During 2007, two federal bills (S. 549 and H.R. 962 ) aimed at
phasing out "nontherapeutic" antibiotics in U.S. food animal
production. The Senate bill, introduced by Sen. Edward "Ted" Kennedy ,
died. The House bill, introduced by Rep.
Louise Slaughter , died after
being referred to Committee.
In March 2012, the
United States District Court for the Southern
District of New York , ruling in an action brought by the Natural
Resources Defense Council and others, ordered the FDA to revoke
approvals for the use of antibiotics in livestock that violated FDA
regulations. On April 11, 2012 the FDA announced a voluntary program
to phase out unsupervised use of drugs as feed additives and convert
approved over-the-counter uses for antibiotics to prescription use
only, requiring veterinarian supervision of their use and a
prescription. In December 2013, the FDA announced the commencement
of these steps to phase out the use of antibiotics for the purposes of
promoting livestock growth.
Growing U.S. consumer concern about using antibiotics in animal feed
has led to greater availability of "antibiotic-free" animal products.
For example, chicken producer Perdue removed all human antibiotics
from its feed and launched products labeled “antibiotic free”
under the Harvestland brand in 2007. Consumer response was positive,
and in 2014 Perdue also phased out ionophores from its hatchery and
began using the “antibiotic free” labels on its Harvestland,
Simply Smart, and Perfect Portions products.
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 antimicrobials are:
* 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 worldwide.
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 synthesis.
* 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.
* 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 rate.
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.
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.
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.
NDM-1 is an enzyme that makes bacteria resistant to a broad range of
beta-lactam antibiotics .
NDM-1 was first detected in a
Klebsiella pneumoniae isolate from a
Swedish patient of Indian origin in 2008. It was later detected in
Pakistan , the
United Kingdom , the United States,
Canada and Japan.
According to A Lancet study, NDM-1 (New Delhi
Metallo-beta-lactamase-1) originated in India. The study came to the
conclusion that Indian hospitals are unsafe for treatment as
Nosocomial-infections are common and with the new super-bugs on rise
in India, it can be dangerous.
Methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus
Staphylococcus aureus (colloquially known as "Staph aureus" or a
"Staph infection") is one of the major resistant pathogens. Found on
the mucous membranes and the human skin of around a third of the
population, it is extremely adaptable to antibiotic pressure. It was
one of the earlier bacteria in which penicillin resistance was
found—in 1947, just four years after the drug started being
Methicillin was then the antibiotic of choice, but has
since been replaced by oxacillin because of significant kidney
Methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus (MRSA) was first
detected in Britain in 1961, and is now "quite common" in hospitals.
MRSA was responsible for 37% of fatal cases of sepsis in the UK in
1999, up from 4% in 1991. Half of all S. aureus infections in the US
are resistant to penicillin, methicillin, tetracycline and
This left vancomycin as the only effective agent available at the
time. However, strains with intermediate (4–8 μg/ml) levels of
resistance, termed glycopeptide-intermediate Staphylococcus aureus
(GISA) or vancomycin-intermediate
Staphylococcus aureus (VISA), began
appearing in the late 1990s. The first identified case was in Japan in
1996, and strains have since been found in hospitals in England,
France and the US. The first documented strain with complete (>16
μg/ml) resistance to vancomycin, termed vancomycin-resistant
Staphylococcus aureus (VRSA) appeared in the
United States in 2002.
However, in 2011, a variant of vancomycin has been tested that binds
to the lactate variation and also binds well to the original target,
thus reinstating potent antimicrobial activity.
A new class of antibiotics, oxazolidinones , became available in the
1990s, and the first commercially available oxazolidinone, linezolid ,
is comparable to vancomycin in effectiveness against MRSA. Linezolid
resistance in S. aureus was reported in 2001, but infection rates
have been at consistently low levels and in the
United Kingdom and
Ireland, no resistance was found in staphylococci collected from
bacteremia cases between 2001 and 2006.
Community-acquired MRSA (CA-MRSA) has now emerged as an epidemic that
is responsible for rapidly progressive, fatal diseases, including
necrotizing pneumonia, severe sepsis , and necrotizing fasciitis .
MRSA is the most frequently identified antimicrobial drug-resistant
pathogen in US hospitals. The epidemiology of infections caused by
MRSA is rapidly changing. Since 2000, infections caused by this
organism have emerged in the community. The two MRSA clones in the
United States most closely associated with community outbreaks, USA400
(MW2 strain, ST1 lineage) and
USA300 , often contain Panton-Valentine
leukocidin (PVL) genes and, more frequently, have been associated with
skin and soft tissue infections. Outbreaks of CA-MRSA infections have
been reported in correctional facilities, among athletic teams, among
military recruits, in newborn nurseries, and among men that have sex
with men. CA-MRSA infections now appear endemic in many urban regions
and cause most CA-S. aureus infections.
Streptococcus And Enterococcus
Streptococcus pyogenes (Group A Streptococcus: GAS) infections can
usually be treated with many different antibiotics. Early treatment
may reduce the risk of death from invasive group A streptococcal
disease. However, even the best medical care does not prevent death in
every case. For those with very severe illness, supportive care in an
intensive-care unit may be needed. For persons with necrotizing
fasciitis, surgery often is needed to remove damaged tissue. Strains
of S. pyogenes resistant to macrolide antibiotics have emerged;
however, all strains remain uniformly susceptible to penicillin .
Streptococcus pneumoniae to penicillin and other
beta-lactams is increasing worldwide. The major mechanism of
resistance involves the introduction of mutations in genes encoding
Selective pressure is thought to play an
important role, and use of beta-lactam antibiotics has been implicated
as a risk factor for infection and colonization. S. pneumoniae is
responsible for pneumonia , bacteremia , otitis media , meningitis ,
sinusitis , peritonitis and arthritis .
Enterococcus faecalis and
are associated with nosocomial infections . These strains include:
Enterococcus , vancomycin-resistant Enterococcus
, and linezolid -resistant
Pseudomonas aeruginosa is a highly prevalent opportunistic pathogen .
One of the most worrisome characteristics of P. aeruginosa is its low
antibiotic susceptibility, which is attributable to a concerted action
of multidrug efflux pumps with chromosomally encoded antibiotic
resistance genes (e.g., mexAB-oprM, mexXY) and the low permeability of
the bacterial cellular envelopes.
Pseudomonas aeruginosa has the
ability to produce 4-hydroxy-2-alkylquinolines (HAQs) and it has been
found that HAQs have prooxidant effects, and overexpressing modestly
increased susceptibility to antibiotics. The study experimented with
Pseudomonas aeruginosa biofilms and found that a disruption of
relA and spoT genes produced an inactivation of the Stringent response
(SR) in cells with nutrient limitation, which provides cells be more
susceptible to antibiotics.
Clostridium difficile is a nosocomial pathogen that causes diarrheal
disease worldwide. Diarrhea caused by C. difficile can be
life-threatening. Infections are most frequent in people who have had
recent medical and/or antibiotic treatment. C. difficile infections
commonly occur during hospitalization.
According to a 2015 CDC report, C. difficile caused almost 500,000
infections in the
United States over a year period. Associated with
these infections were an estimated 15,000 deaths. The CDC estimates
that C. difficile infection costs could amount to $3.8 billion over a
C. difficile colitis is most strongly associated with
fluoroquinolones , cephalosporins , carbapenems , and clindamycin .
Some research suggests the overuse of antibiotics in the raising of
livestock is contributing to outbreaks of bacterial infections such as
Antibiotics, especially those with a broad activity spectrum (such as
clindamycin) disrupt normal intestinal flora. This can lead to an
overgrowth of C. difficile, which flourishes under these conditions.
Pseudomembranous colitis can follow, creating generalized inflammation
of the colon and the development of "pseudomembrane", a viscous
collection of inflammatory cells, fibrin, and necrotic cells.
Clindamycin -resistant C. difficile was reported as the causative
agent of large outbreaks of diarrheal disease in hospitals in New
York, Arizona, Florida and Massachusetts between 1989 and 1992.
Geographically dispersed outbreaks of C. difficile strains resistant
to fluoroquinolone antibiotics, such as ciprofloxacin and
levofloxacin, were also reported in North America in 2005.
As of 2013 hard-to-treat or untreatable infections of
carbapenem-resistant Enterobacteriaceae (CRE) were increasing among
patients in medical facilities. CRE are resistant to nearly all
available antibiotics. Almost half of hospital patients who get
bloodstream CRE infections die from the infection.
Acinetobacter is a gram-negative bacteria that causes pneumonia or
bloodstream infections in critically ill patients. Multidrug-resistant
Acinetobacter have become very resistant to antibiotics.
Campylobacter causes diarrhea (often bloody), fever, and abdominal
cramps. Serious complications such as temporary paralysis can also
occur. Physicians rely on ciprofloxacin and azithromycin for treating
patients with severe disease although
Campylobacter is showing
resistance to these antibiotics.
Salmonella And E. Coli
Escherichia coli and
Salmonella can result from the
consumption of contaminated food and water. Both of these bacteria are
well known for causing nosocomial (hospital-linked) infections, and
often, these strains found in hospitals are antibiotic resistant
because of adaptations to wide spread antibiotic use. When both
bacteria are spread, serious health conditions arise. Many people are
hospitalized each year after becoming infected, with some dying as a
result. Since 1993, some strains of E. coli have become resistant to
multiple types of fluoroquinolone antibiotics .
Although mutation alone plays a huge role in the development of
antibiotic resistance, a 2008 study found that high survival rates
after exposure to antibiotics could not be accounted for by mutation
alone. This study focused on the development of resistance in E. coli
to three antibiotic drugs: ampicillin, tetracycline, and nalidixic
acid. The researchers found that some antibiotic resistance in E. coli
developed because of epigenetic inheritance rather than by direct
inheritance of a mutated gene. This was further supported by data
showing that reversion to antibiotic sensitivity was relatively common
as well. This could only be explained by epigenetics.
a type of inheritance in which gene expression is altered rather than
the genetic code itself. There are many modes by which this alteration
of gene expression can occur, including methylation of DNA and histone
modification ; however, the important point is that both inheritance
of random mutations and epigenetic markers can result in the
expression of antibiotic resistance genes.
Resistance to polymyxins first appear in 2011. An easier way for
this resistance to spread, a plasmid known as
MCR-1 was discovered in
On November 5, 2004, the Centers for Disease Control and Prevention
(CDC) reported an increasing number of Acinetobacter baumannii
bloodstream infections in patients at military medical facilities in
which service members injured in the
Kuwait region during
Operation Iraqi Freedom and in
Afghanistan during Operation Enduring
Freedom were treated. Most of these showed multidrug resistance
(MRAB), with a few isolates resistant to all drugs tested.
Klebsiella pneumoniae carbapenemase (KPC )-producing bacteria are a
group of emerging highly drug-resistant Gram-negative bacilli causing
infections associated with significant morbidity and mortality whose
incidence is rapidly increasing in a variety of clinical settings
around the world.
Klebsiella pneumoniae includes numerous mechanisms
for antibiotic resistance, many of which are located on highly mobile
Carbapenem antibiotics (heretofore often the
treatment of last resort for resistant infections) are generally not
effective against KPC-producing organisms.
Tuberculosis is increasing across the globe, especially in developing
countries, over the past few years. TB resistant to antibiotics is
called MDR TB (Multidrug Resistant TB). Globally, MDR TB causes
150,000 deaths annually. The rise of the HIV/AIDS epidemic has
contributed to this.
TB was considered one of the most prevalent diseases, and did not
have a cure until the discovery of
Selman Waksman in
1943. However, the bacteria soon developed resistance. Since then,
drugs such as isoniazid and rifampin have been used. M. tuberculosis
develops resistance to drugs by spontaneous mutations in its genomes.
Resistance to one drug is common, and this is why treatment is usually
done with more than one drug. Extensively Drug-Resistant TB (XDR TB)
is TB that is also resistant to the second line of drugs.
Mycobacterium tuberculosis to isoniazid , rifampin ,
and other common treatments has become an increasingly relevant
clinical challenge. (For more on Drug-Resistant TB, visit the
Multi-drug-resistant tuberculosis page.) Evidence is lacking for
whether these bacteria have plasmids. Also M. tuberculosis lack the
opportunity to interact with other bacteria in order to share
Antibiotic resistance in gonorrhea
Neisseria gonorrhoeae is a sexually transmitted pathogen that causes
gonorrhea , a sexually transmitted disease that can result in
discharge and inflammation at the urethra, cervix, pharynx, or rectum.
It can cause pelvic pain, pain on urination, penile and vaginal
discharge, as well as systemic symptoms. It can also cause severe
reproductive complications. The bacteria was first identified in
1879, although some Biblical scholars believe that references to the
disease can be found as early as Parshat Metzora of the Old Testament
In the 1940s effective treatment with penicillin became available,
but by the 1970s resistant strains predominated. Resistance to
penicillin has developed through two mechanisms: chromasomally
mediated resistance (CMRNG) and penicillinase-mediated resistance
(PPNG). CMRNG involves step wise mutation of penA, which codes for the
penicillin-binding protein (PBP-2); mtr, which encodes an efflux pump
that removes penicillin from the cell; and penB, which encodes the
bacterial cell wall porins . PPNG involves the acquisition of a
plasmid-borne beta-lactamase . N. gonorrheoea has a high affinity for
horizontal gene transfer , and as a result, the existence of any
strain resistant to a given drug could spread easily across strains.
Fluoroquinolones were a useful next-line treatment until resistance
was achieved through efflux pumps and mutations to the gyrA gene,
DNA gyrase . Third-generation cephalosporins have been
used to treat gonorrhoea since 2007, but resistant strains have
emerged. As of 2010, the recommended treatment is a single 250 mg
intramuscular injection of ceftriaxone , sometimes in combination with
azithromycin or doxycycline . However, certain strains of N.
gonorrhoeae can be resistant to antibiotics usually that are normally
used to treat it. These include: cefixime (an oral cephalosporin ),
ceftriaxone (an injectable cephalosporin), azithromycin ,
aminoglycosides , and tetracycline .
Mycoplasma genitalium is a small pathogenic bacterium that lives on
the ciliated epithelial cells of the urinary and genital tracts in
humans. It is still controversial whether or not this bacterium is to
be recognized as a sexually transmitted pathogen. Infection with
Mycoplasma genitalium sometimes produces clinical symptoms, or a
combination of symptoms, but sometimes can be asymptomatic. It causes
inflammation in the urethra (urethritis ) both in men and women, which
is associated with mucopurulent discharge in the urinary tract, and
burning while urinating.
Mycoplasma genitalium infections is becoming
increasingly difficult due to rapidly developing multi-drug
resistance, and diagnosis and treatment is further hampered by the
Mycoplasma genitalium infections are not routinely detected.
Azithromycin is the most common first-line treatment, but the
commonly-used 1 gram single-dose azithromycin treatment can lead to
the bacteria commonly developing resistance to azithromycin. An
alternative five-day treatment with azithromycin showed no development
of antimicrobial resistance. Efficacy of azithromycin against
Mycoplasma genitalium has decreased substantially, which is thought to
occur through SNPs in the 23S rRNA gene. The same SNPs are thought to
be responsible for resistance against josamycin which is prescribed in
Moxifloxacin can be used as a second-line treatment
in case azithromycin is not able to eradicate the infection. However,
resistance against moxifloxacin has been observed since 2007, thought
to be due to parC SNPs .
Tetracyclines , including doxycycline ,
have a low clinical eradication rate for Mycoplasma genitalium
infections. A few cases have been described where doxycycline,
azithromycin and moxifloxacin had all failed, but pristinamycin was
still able to eradicate the infection.
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
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 drug-resistant HIV
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 individuals.
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
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
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".
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Antibiotic resistance is an important tool for genetic engineering .
By constructing a plasmid that contains an antibiotic-resistance gene
as well as the gene being engineered or expressed, a researcher can
ensure that, when bacteria replicate, only the copies that carry the
plasmid survive. This ensures that the gene being manipulated passes
along when the bacteria replicates.
In general, the most commonly used antibiotics in genetic engineering
are "older" antibiotics. These include:
In industry, the use of antibiotic resistance is disfavored, since
maintaining bacterial cultures would require feeding them large
quantities of antibiotics. Instead, the use of auxotrophic bacterial
strains (and function-replacement plasmids) is preferred.
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 "> For instance,
binding global policies could be used to create antimicrobial use
standards, regulate antibiotic marketing, and strengthen global
surveillance systems. Ensuring compliance of involved parties is a
challenge. 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.
Resistance-nodulation-cell division superfamily (RND)
Alliance for the Prudent Use of Antibiotics
* (KPC) antibacterial resistance gene
Drug of last resort
Multidrug-resistant Gram-negative bacteria
New Delhi metallo-beta-lactamase 1
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