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Causes::Antimicrobial resistance

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Causes

How antibiotic resistance evolves and spreads

Some bacteria with resistance to antibiotics predate the medical use of antibiotics by humans;<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>{{#invoke:Footnotes|sfn}}{{#invoke:Footnotes|sfn}} however, widespread antibiotic use has caused more bacteria to become resistant, a process called evolutionary pressure.{{#invoke:Footnotes|sfn}}<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

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.<ref name=lid13>The Lancet Infectious Diseases Commission. Antibiotic resistance—the need for global solutions. Lancet Infect Dis 2013;13: 1057–98.</ref>:1060 This may result in emergence of resistance in any remaining bacteria.

Antibiotic use in livestock feed at low doses for growth promotion is an accepted practice in many industrialized countries which leads to resistance.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref><ref name="mathew"/> Releasing large quantities of antibiotics into the environment during pharmaceutical manufacturing by inadequate treatment of wastewater contributes to the likelihood of creating antibiotic-resistant strains.<ref>{{#invoke:citation/CS1|citation |CitationClass=news }}</ref><ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> It is uncertain whether antibacterials in soaps and other products contribute to antibiotic resistance, but they are discouraged for other reasons.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

Human medicine

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.<ref name="Pechère JC 2001 S170–3">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> 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.<ref name=Arn2005>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

Increasing bacterial resistance is linked with the volume of antibiotic prescribed, as well as missing doses when taking antibiotics.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Up to half of antibiotics used in humans are unnecessary and inappropriate.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> For example, a third of people believe that antibiotics are effective for the common cold,<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> and the common cold is the most common reason antibiotics are prescribed<ref>{{#invoke:citation/CS1|citation |CitationClass=book }}</ref> 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.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=book }}</ref>

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 due to fewer complications.<ref name=NPS2013/> Short course regimens exist for community-acquired pneumonia<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> spontaneous bacterial peritonitis,<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> suspected lung infections in ICU patients,<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> in the so-called acute abdomen,<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> middle ear infection, sinusitis and throat infection,<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> and penetrating gut injury.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref><ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> In some situations a short course may not cure the infection as well as a long course.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> A BMJ editorial recommended that antibiotics can often be safely stopped 72 hours after symptoms resolve.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> 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.<ref>Marc Bonten, MD; Eijkman-Winkler Institute for Medical Microbiology, Utrecht, the Netherland | Infectious Diseases, and Inflammation</ref>

Certain antibiotic classes result in resistance more than others. Increased rates of MRSA infections are seen when using glycopeptides, cephalosporins, and quinolones.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref><ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> Cephalosporins, and particularly quinolones and clindamycin, are more likely to produce colonisation with Clostridium difficile{{#invoke:Category handler|main}}[importance?]<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

Factors within the intensive care unit setting such as mechanical ventilation and multiple underlying diseases also appear to contribute to bacterial resistance.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> Poor hand hygiene by hospital staff has been associated with the spread of resistant organisms,<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> and an increase in hand washing compliance results in decreased rates of these organisms.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

The 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.<ref>Farmer, Paul E., Bruce Nizeye, Sara Stulac, and Salmaan Keshavjee. 2006. Structural Violence and Clinical Medicine. PLoS Medicine, 1686–1691. url=?</ref>

Veterinary medicine

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All animals carry bacteria in their intestines. Antibiotics are given to animals. Antibiotics kill most bacteria. But resistant bacteria survive and multiply.

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 health. Rather, it is normal practice to mix antibiotics with livestock food to promote healthier living conditions and to encourage animal growth.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The use of antibiotics in animals is to a large degree involved in the emergence of antibiotic-resistant microorganisms.<ref>The Resistance Phenomenon in Microbes and Infectious Disease Vectors: Implications for Human Health and Strategies for Containment: Workshop Summary. Institute of Medicine (US) Forum on Emerging Infections; Knobler SL, Lemon SM, Najafi M, et al., editors. Washington (DC): National Academies Press (US); 2003.</ref> Antibiotics are used in food with the intention of not only preventing, controlling, and treating diseases, but also to promote growth.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Antibiotic use in animals can be classified into therapeutic, prophylactic, metaphylactic, and growth promotion uses of antibiotics.<ref>Joint FAO/OIE/WHO Expert Workshop on Non-Human Antimicrobial Usage and Antimicrobial Resistance: Scientific assessment at the Wayback Machine (archived 26 September 2004)</ref> 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)
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|CitationClass=journal }}</ref> 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.<ref name=TheRealNews-2014-05-18>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>The Editorial Board of the New York Times, May 10, 2014, The Rise of Antibiotic Resistance</ref> 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 antibiotic resistance.

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.<ref name=TheRealNews-2014-05-18/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Antibiotic Resistance - Linking Human And Animal Health: Improving Food Safety Through a One Health Approach Workshop Summary. Wegener, Henrik C. Washington (DC): National Academies Press (US); 2012.</ref> Studies have shown, however, that, in essence, the overall population levels of bacteria are unchanged; only the mix of bacteria is affected.{{ safesubst:#invoke:Unsubst||date=__DATE__ |$B= {{#invoke:Category handler|main}}{{#invoke:Category handler|main}}[citation needed] }} 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.<ref name="mathew">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref><ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> In particular, poultry feed and water is a common route of administration of drugs, due to higher overall costs when drugs are administered by handling animals individually.

In research studies, occasional animal-to-human spread of drug-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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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 antibiotic-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.<ref name="pmid15151237">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref><ref name="pmid18643826">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

The 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 prohibited.{{ safesubst:#invoke:Unsubst||date=__DATE__ |$B= {{#invoke:Category handler|main}}{{#invoke:Category handler|main}}[citation needed] }} Regarding this matter, the World Organisation for Animal Health has added to the Terrestrial Animal Health Code a series of guidelines with recommendations to its members for the creation and harmonization of national antimicrobial resistance surveillance and monitoring programs,<ref>OIE, Terrestrial Animal Health Code</ref>{{ safesubst:#invoke:Unsubst||$N=Full |date=__DATE__ |$B= {{#invoke:Category handler|main}}[full citation needed] }} monitoring of the quantities of antibiotics used in animal husbandry,<ref>OIE,Terrestrial Animal Health Code</ref>{{ safesubst:#invoke:Unsubst||$N=Full |date=__DATE__ |$B= {{#invoke:Category handler|main}}[full citation needed] }} and recommendations to ensure the proper and prudent use of antibiotic substances. Another guideline is to implement methodologies that help to establish associated risk factors and assess the risk of antibiotic resistance.<ref>OIE,Terrestrial Animal Health Code</ref>{{ safesubst:#invoke:Unsubst||$N=Full |date=__DATE__ |$B= {{#invoke:Category handler|main}}[full citation needed] }}

Natural occurrence

Naturally occurring antibiotic resistance is common.<ref name=Wright10>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> Genes for resistance to antibiotics, like antibiotics themselves, are ancient.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>:457–461The genes that confer resistance are known as the environmental resistome.<ref name=Wright10/> These genes may be transferred from non-disease-causing bacteria to those that do cause disease, leading to clinically significant antibiotic resistance.<ref name=Wright10/> In 1952 it was shown that penicillin-resistant bacteria existed before penicillin treatment;<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and also preexistent bacterial resistance to streptomycin.<ref>Richard William Nelson. Darwin, Then and Now: The Most Amazing Story in the History of Science, iUniverse, 2009, p. 294</ref> 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.<ref>Wayne W. Umbreit, Advances in Applied Microbiology, vol. 11, Academic Press, 1970, p. 80</ref><ref name="pmid4963324">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref><ref name="penicillinase">New Scientist, Jun 8, 1972, p. 546</ref> 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.<ref name="NS">New Scientist, Feb 11, 1989, p. 34</ref> 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.<ref name="penicillinase"/> Search for a penicillinase ancestor has focused on the class of proteins that must be a priori capable of specific combination with penicillin.<ref>Pollock, p. 77</ref> 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.<ref name="NS"/> There is evidence that heavy metals and other pollutants may select for antibiotic-resistant bacteria, generating a constant source of them in small numbers.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref><ref>Abigail A. Salyers, Dixie D. Whitt. Revenge of the microbes: how bacterial resistance is undermining the antibiotic miracle, ASM Press, 2005, 186 pp, no e-book, ISBN 1555812988</ref>:34{{ safesubst:#invoke:Unsubst||$N=Better source |date=__DATE__ |$B= {{#invoke:Category handler|main}}[better source needed] }}


Antimicrobial resistance sections
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