Editing Antibiotic (section)

==Resistance==
{{Main|Antimicrobial resistance}}
[[File:Human neutrophil ingesting MRSA.jpg|thumb|left|[[Scanning electron micrograph]] of a human [[neutrophil]] ingesting [[methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']] (MRSA)]]

Antimicrobial resistance (AMR or AR) is a naturally occurring process.<ref name="CDC About Antimicrobial Resistance"/> AMR is driven largely by the misuse and overuse of antimicrobials.<ref name=WHO10October2024/> Yet, at the same time, many people around the world do not have access to essential antimicrobials.<ref name=WHO10October2024/> The emergence of [[List of antibiotic-resistant bacteria|antibiotic-resistant bacteria]] is a common phenomenon mainly caused by the overuse/misuse. It represents a threat to health globally.<ref>{{Cite news |date=26 March 2018 |title=Calls to rein in antibiotic use after study shows 65% increase worldwide |journal=The Guardian |url=https://www.theguardian.com/science/2018/mar/26/calls-to-rein-in-antibiotic-use-after-study-shows-65-increase-worldwide |url-status=live |access-date=28 March 2018 |archive-url=https://web.archive.org/web/20180408063812/https://www.theguardian.com/science/2018/mar/26/calls-to-rein-in-antibiotic-use-after-study-shows-65-increase-worldwide |archive-date=8 April 2018 |vauthors=Sample I}}</ref><ref name=":1">{{Cite journal |last1=Singh |first1=Gagandeep |last2=Rana |first2=Anita |last3=Smriti |date=2024-05-28 |title=Decoding antimicrobial resistance: unraveling molecular mechanisms and targeted strategies |url=https://doi.org/10.1007/s00203-024-03998-2 |journal=Archives of Microbiology |language=en |volume=206 |issue=6 |pages=280 |doi=10.1007/s00203-024-03998-2 |pmid=38805035 |bibcode=2024ArMic.206..280S |issn=1432-072X}}</ref> Each year, nearly 5 million deaths are associated with AMR globally.<ref name=WHO10October2024/>

Emergence of resistance often reflects [[evolution]]ary processes that take place during antibiotic therapy. The antibiotic treatment may [[natural selection|select]] for bacterial strains with physiologically or genetically enhanced capacity to survive high doses of antibiotics. Under certain conditions, it may result in preferential growth of resistant bacteria, while growth of susceptible bacteria is inhibited by the drug.<ref name="Balancing the drug-resistance equation" /> For example, antibacterial selection for strains having previously acquired antibacterial-resistance genes was demonstrated in 1943 by the [[Luria–Delbrück experiment]].<ref name="Mutations of Bacteria from Virus Sensitivity to Virus Resistance" /> Antibiotics such as penicillin and erythromycin, which used to have a high efficacy against many bacterial species and strains, have become less effective, due to the increased resistance of many bacterial strains.<ref name="Voice of America" />

Resistance may take the form of biodegradation of pharmaceuticals, such as sulfamethazine-degrading soil bacteria introduced to sulfamethazine through medicated pig feces.<ref>{{cite journal | vauthors = Topp E, Chapman R, Devers-Lamrani M, Hartmann A, Marti R, Martin-Laurent F, Sabourin L, Scott A, Sumarah M | title = Accelerated Biodegradation of Veterinary Antibiotics in Agricultural Soil following Long-Term Exposure, and Isolation of a Sulfamethazine-degrading sp | journal = Journal of Environmental Quality | volume = 42 | issue = 1 | pages = 173–8 | year = 2013 | pmid = 23673752 | doi = 10.2134/jeq2012.0162 | url = http://www.agr.gc.ca/eng/abstract/?id=27587000000610 | access-date = 22 November 2013 | archive-date = 12 December 2013 | archive-url = https://web.archive.org/web/20131212161710/http://www.agr.gc.ca/eng/abstract/?id=27587000000610 | url-status = live }}</ref>
The survival of bacteria often results from an inheritable resistance,<ref name="Witte2004"/> but the growth of resistance to antibacterials also occurs through [[horizontal gene transfer]]. Horizontal transfer is more likely to happen in locations of frequent antibiotic use.<ref>{{cite book| vauthors = Dyer BD |title=A Field Guide To Bacteria|year=2003|publisher=Cornell University Press|isbn=978-0-8014-8854-2|chapter=Chapter 9, Pathogens|chapter-url=http://www.audible.com/pd/ref=sr_1_1?asin=B002VA8L4Y&qid=1305345229&sr=1-1|url-access=registration|url=https://archive.org/details/fieldguidetobact0000dyer}}</ref>

Antibacterial resistance may impose a biological cost, thereby reducing [[biological fitness|fitness]] of resistant strains, which can limit the spread of antibacterial-resistant bacteria, for example, in the absence of antibacterial compounds. Additional mutations, however, may compensate for this fitness cost and can aid the survival of these bacteria.<ref name="The biological cost of mutational antibiotic resistance: any practical conclusions?"/>

Paleontological data show that both antibiotics and antibiotic resistance are ancient compounds and mechanisms.<ref name="D'Costa2011"/> Useful antibiotic targets are those for which mutations negatively impact bacterial reproduction or viability.<ref name="Gladki2013"/>

Several molecular mechanisms of antibacterial resistance exist. Intrinsic antibacterial resistance may be part of the genetic makeup of bacterial strains.<ref name="Alekshun2007"/><ref>{{cite journal | vauthors = Pawlowski AC, Wang W, Koteva K, Barton HA, McArthur AG, Wright GD | title = A diverse intrinsic antibiotic resistome from a cave bacterium | journal = Nature Communications | volume = 7 | pages = 13803 | date = December 2016 | pmid = 27929110 | pmc = 5155152 | doi = 10.1038/ncomms13803 | bibcode = 2016NatCo...713803P }}</ref> For example, an antibiotic target may be absent from the bacterial [[genome]]. Acquired resistance results from a mutation in the bacterial chromosome or the acquisition of extra-chromosomal DNA.<ref name="Alekshun2007"/> Antibacterial-producing bacteria have evolved resistance mechanisms that have been shown to be similar to, and may have been transferred to, antibacterial-resistant strains.<ref name="Glycopeptide antibiotic resistance genes in glycopeptide-producing organisms"/><ref name="Multidrug Resistance in Bacteria"/> The spread of antibacterial resistance often occurs through vertical transmission of mutations during growth and by genetic recombination of DNA by [[horizontal gene transfer|horizontal genetic exchange]].<ref name="Witte2004"/> For instance, antibacterial resistance genes can be exchanged between different bacterial strains or species via [[plasmids]] that carry these resistance genes.<ref name="Witte2004"/><ref name="Baker2006"/> Plasmids that carry several different resistance genes can confer resistance to multiple antibacterials.<ref name="Baker2006"/> Cross-resistance to several antibacterials may also occur when a resistance mechanism encoded by a single gene conveys resistance to more than one antibacterial compound.<ref name="Baker2006"/>

Antibacterial-resistant strains and species, sometimes referred to as "superbugs", now contribute to the emergence of diseases that were, for a while, well controlled. For example, emergent bacterial strains causing tuberculosis that are resistant to previously effective antibacterial treatments pose many therapeutic challenges. Every year, nearly half a million new cases of [[multidrug-resistant tuberculosis]] (MDR-TB) are estimated to occur worldwide.<ref>[https://web.archive.org/web/20090406170131/http://www.who.int/mediacentre/news/releases/2009/tuberculosis_drug_resistant_20090402/en/index.html "Health ministers to accelerate efforts against drug-resistant TB".] World Health Organization (WHO).</ref> For example, [[NDM-1]] is a newly identified enzyme conveying bacterial resistance to a broad range of [[beta-lactam]] antibacterials.<ref name="Are you ready for a world without antibiotics?"/> The United Kingdom's [[Health Protection Agency]] has stated that "most isolates with NDM-1 enzyme are resistant to all standard intravenous antibiotics for treatment of severe infections."<ref name= "Health Protection Report"/> On 26 May 2016, an [[Escherichia coli|''E. coli'']] "[[antimicrobial resistance|superbug]]" was identified in the United States resistant to [[colistin]], [[drug of last resort|"the last line of defence" antibiotic]].<ref>{{cite journal | vauthors = McGann P, Snesrud E, Maybank R, Corey B, Ong AC, Clifford R, Hinkle M, Whitman T, Lesho E, Schaecher KE | title = Escherichia coli Harboring mcr-1 and blaCTX-M on a Novel IncF Plasmid: First Report of mcr-1 in the United States | journal = Antimicrobial Agents and Chemotherapy | volume = 60 | issue = 7 | pages = 4420–1 | date = July 2016 | pmid = 27230792 | pmc = 4914657 | doi = 10.1128/AAC.01103-16 }}</ref><ref>{{Cite web|url=http://www.scientificamerican.com/article/dangerous-new-antibiotic-resistant-bacteria-reach-u-s/|title=Dangerous New Antibiotic-Resistant Bacteria Reach U.S.|vauthors=Moyer MW|website=Scientific American|date=27 May 2016|access-date=27 May 2016|archive-date=28 July 2020|archive-url=https://web.archive.org/web/20200728063057/https://www.scientificamerican.com/article/dangerous-new-antibiotic-resistant-bacteria-reach-u-s/|url-status=live}}</ref>
In recent years, even anaerobic bacteria, historically considered less concerning in terms of resistance, have demonstrated high rates of antibiotic resistance, particularly ''[[Bacteroides]]'', for which resistance rates to penicillin have been reported to exceed 90%.<ref>{{cite journal | vauthors = Di Bella S, Antonello RM, Sanson G, Maraolo AE, Giacobbe DR, Sepulcri C, Ambretti S, Aschbacher R, Bartolini L, Bernardo M, Bielli A, Busetti M, Carcione D, Camarlinghi G, Carretto E, Cassetti T, Chilleri C, De Rosa FG, Dodaro S, Gargiulo R, Greco F, Knezevich A, Intra J, Lupia T, Concialdi E, Bianco G, Luzzaro F, Mauri C, Morroni G, Mosca A, Pagani E, Parisio EM, Ucciferri C, Vismara C, Luzzati R, Principe L | title = Anaerobic bloodstream infections in Italy (ITANAEROBY): A 5-year retrospective nationwide survey | journal = Anaerobe | volume = 75 | pages = 102583 | date = June 2022 | pmid = 35568274 | doi = 10.1016/j.anaerobe.2022.102583 | hdl = 11368/3020691 | s2cid = 248736289 | hdl-access = free }}</ref>

===Misuse===
[[File:CDC Get Smart poster healthy adult.png|thumb|This poster from the US Centers for Disease Control and Prevention "Get Smart" campaign, intended for use in doctors' offices and other healthcare facilities, warns that antibiotics do not work for viral illnesses such as the common cold.]]

{{Main|Antibiotic misuse}}

Per ''The ICU Book'', "The first rule of antibiotics is to try not to use them, and the second rule is try not to use too many of them."<ref name="Marino"/> Inappropriate antibiotic treatment and overuse of antibiotics have contributed to the emergence of antibiotic-resistant bacteria. However, potential harm from antibiotics extends beyond selection of antimicrobial resistance and their overuse is associated with adverse effects for patients themselves, seen most clearly in [[critically ill]] patients in [[Intensive care unit]]s.<ref name=":0">{{cite journal | vauthors = Arulkumaran N, Routledge M, Schlebusch S, Lipman J, Conway Morris A | title = Antimicrobial-associated harm in critical care: a narrative review | journal = Intensive Care Medicine | volume = 46 | issue = 2 | pages = 225–235 | date = February 2020 | pmid = 31996961 | pmc = 7046486 | doi = 10.1007/s00134-020-05929-3 }}</ref> [[Self-prescribing]] of antibiotics is an example of misuse.<ref name="Larson2007"/> Many antibiotics are frequently prescribed to treat symptoms or diseases that do not respond to antibiotics or that are likely to resolve without treatment. Also, incorrect or suboptimal antibiotics are prescribed for certain bacterial infections.<ref name="pmid15993671"/><ref name="Larson2007"/> The overuse of antibiotics, like penicillin and erythromycin, has been associated with emerging antibiotic resistance since the 1950s.<ref name="Voice of America"/><ref name="Hawkey2008"/> Widespread usage of antibiotics in hospitals has also been associated with increases in bacterial strains and species that no longer respond to treatment with the most common antibiotics.<ref name="Hawkey2008"/>

Common forms of antibiotic misuse include excessive use of [[prophylaxis|prophylactic]] antibiotics in travelers and failure of medical professionals to prescribe the correct dosage of antibiotics on the basis of the patient's weight and history of prior use. Other forms of misuse include failure to take the entire prescribed course of the antibiotic, incorrect dosage and administration, or failure to rest for sufficient recovery. Inappropriate antibiotic treatment, for example, is their prescription to treat viral infections such as the [[common cold]]. One study on [[respiratory tract infection]]s found "physicians were more likely to prescribe antibiotics to patients who appeared to expect them".<ref name="pmid17467120"/> Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescription of antibiotics.<ref name="pmid17509729"/><ref>{{cite journal | vauthors = Coxeter P, Del Mar CB, McGregor L, Beller EM, Hoffmann TC | title = Interventions to facilitate shared decision making to address antibiotic use for acute respiratory infections in primary care | journal = The Cochrane Database of Systematic Reviews | volume = 11 | issue = 11 | pages = CD010907 | date = November 2015 | pmid = 26560888 | pmc = 6464273 | doi = 10.1002/14651858.CD010907.pub2 }}</ref> The lack of rapid point of care diagnostic tests, particularly in resource-limited settings is considered one of the drivers of antibiotic misuse.<ref>{{cite journal | vauthors = Mendelson M, Røttingen JA, Gopinathan U, Hamer DH, Wertheim H, Basnyat B, Butler C, Tomson G, Balasegaram M | title = Maximising access to achieve appropriate human antimicrobial use in low-income and middle-income countries | journal = Lancet | volume = 387 | issue = 10014 | pages = 188–98 | date = January 2016 | pmid = 26603919 | doi = 10.1016/S0140-6736(15)00547-4 | s2cid = 13904240 }}</ref>

Several organizations concerned with antimicrobial resistance are lobbying to eliminate the unnecessary use of antibiotics.<ref name="Larson2007"/> The issues of misuse and overuse of antibiotics have been addressed by the formation of the US Interagency Task Force on Antimicrobial Resistance. This task force aims to actively address antimicrobial resistance, and is coordinated by the US [[Centers for Disease Control and Prevention]], the [[Food and Drug Administration]] (FDA), and the [[National Institutes of Health]], as well as other US agencies.<ref name="pharmguide"/> A non-governmental organization campaign group is ''Keep Antibiotics Working''.<ref name="Keep Antibiotics Working"/> In France, an "Antibiotics are not automatic" government campaign started in 2002 and led to a marked reduction of unnecessary antibiotic prescriptions, especially in children.<ref>{{cite journal | vauthors = Sabuncu E, David J, Bernède-Bauduin C, Pépin S, Leroy M, Boëlle PY, Watier L, Guillemot D | title = Significant reduction of antibiotic use in the community after a nationwide campaign in France, 2002-2007 | journal = PLOS Medicine | volume = 6 | issue = 6 | pages = e1000084 | date = June 2009 | pmid = 19492093 | pmc = 2683932 | doi = 10.1371/journal.pmed.1000084 | df = dmy | veditors = Klugman KP | doi-access = free | title-link = doi }}</ref>

The emergence of antibiotic resistance has prompted restrictions on their use in the UK in 1970 (Swann report 1969), and the European Union has banned the use of antibiotics as growth-promotional agents since 2003.<ref>{{cite web|url=http://www.legaltext.ee/text/en/T80294.htm |title=Regulation (EC) No 1831/2003 of the European Parliament and of the Council |url-status=dead |archive-url=https://web.archive.org/web/20090109031010/http://www.legaltext.ee/text/en/T80294.htm |archive-date=9 January 2009 }}</ref> Moreover, several organizations (including the World Health Organization, the [[National Academy of Sciences]], and the [[U.S. Food and Drug Administration]]) have advocated restricting the amount of antibiotic use in food animal production.<ref>{{cite web |url=http://consumersunion.org/news/the-overuse-of-antibiotics-in-food-animals-threatens-public-health-2/ |access-date=4 July 2016 |title=The Overuse of Antibiotics in Food Animals Threatens Public Health |publisher=Consumer Reports |archive-date=28 June 2016 |archive-url=https://web.archive.org/web/20160628202247/http://consumersunion.org/news/the-overuse-of-antibiotics-in-food-animals-threatens-public-health-2/ |url-status=live }}</ref>{{Unreliable medical source|date=July 2016}} However, commonly there are delays in regulatory and legislative actions to limit the use of antibiotics, attributable partly to resistance against such regulation by industries using or selling antibiotics, and to the time required for research to test causal links between their use and resistance to them. Two federal bills (S.742<ref name="USbill1"/> and H.R. 2562<ref name="USbill2"/>) aimed at phasing out nontherapeutic use of antibiotics in US food animals were proposed, but have not passed.<ref name="USbill1"/><ref name="USbill2"/> These bills were endorsed by public health and medical organizations, including the American Holistic Nurses' Association, the [[American Medical Association]], and the [[American Public Health Association]].<ref>{{cite web |url= http://www.acpm.org/2003051H.pdf |access-date= 12 November 2008 |title=Kee Antibiotics Working|archive-url=https://web.archive.org/web/20090325225525/http://www.acpm.org/2003051H.pdf |archive-date=25 March 2009 |url-status=dead}}</ref><ref>{{cite web | title = The Preservation of Antibiotics for Medical Treatment Act of 2005 (S. 742/H.R. 2562) | publisher = The Institute for Agriculture and Trade Policy | url = https://www.iatp.org/sites/default/files/421_2_72941.pdf | access-date = 4 October 2020 | archive-date = 30 October 2020 | archive-url = https://web.archive.org/web/20201030005409/https://www.iatp.org/sites/default/files/421_2_72941.pdf | url-status = live }}</ref>

Despite pledges by food companies and restaurants to reduce or eliminate meat that comes from animals treated with antibiotics, the purchase of antibiotics for use on farm animals has been increasing every year.<ref>{{cite news|url=https://www.npr.org/sections/thesalt/2016/12/22/506599017/despite-pledges-to-cut-back-farms-are-still-using-antibiotics|title=Despite Pledges To Cut Back, Farms Are Still Using Antibiotics|newspaper=NPR|date=22 December 2016|vauthors=Charles D|access-date=5 April 2018|archive-date=26 July 2020|archive-url=https://web.archive.org/web/20200726054955/https://www.npr.org/sections/thesalt/2016/12/22/506599017/despite-pledges-to-cut-back-farms-are-still-using-antibiotics|url-status=live}}</ref>

There has been extensive use of antibiotics in animal husbandry. In the United States, the question of emergence of antibiotic-resistant bacterial strains due to [[antibiotic use in livestock|use of antibiotics in livestock]] was raised by the US [[Food and Drug Administration]] (FDA) in 1977. 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, which violated FDA regulations.<ref>{{cite news |title=FDA Told to Move on Antibiotic Use in Livestock |url=http://www.medpagetoday.com/PublicHealthPolicy/FDAGeneral/31792 |access-date=24 March 2012 |newspaper=MedPage Today |date=23 March 2012 |vauthors=Gever J |archive-date=27 April 2021 |archive-url=https://web.archive.org/web/20210427031956/https://www.medpagetoday.com/publichealthpolicy/fdageneral/31792 |url-status=live }}</ref>

Studies have shown that [[common misconceptions]] about the effectiveness and necessity of antibiotics to treat common mild illnesses contribute to their overuse.<ref>{{Cite web|url=https://dailytargum.com//article/2021/02/rutgers-study-finds-antibiotic-overuse-is-caused-by-misconceptions-financial|title=Rutgers study finds antibiotic overuse is caused by misconceptions, financial incentives|vauthors=Barnes S|website=The Daily Targum|date=10 February 2021 |access-date=16 February 2021|archive-date=6 December 2021|archive-url=https://web.archive.org/web/20211206103329/https://dailytargum.com/article/2021/02/rutgers-study-finds-antibiotic-overuse-is-caused-by-misconceptions-financial|url-status=live}}</ref><ref>{{cite journal | vauthors = Blaser MJ, Melby MK, Lock M, Nichter M | title = Accounting for variation in and overuse of antibiotics among humans | journal = BioEssays | volume = 43 | issue = 2 | pages = e2000163 | date = February 2021 | pmid = 33410142 | doi = 10.1002/bies.202000163 | url = https://onlinelibrary.wiley.com/doi/abs/10.1002/bies.202000163 | s2cid = 230811912 | access-date = 16 February 2021 | archive-date = 16 February 2021 | archive-url = https://web.archive.org/web/20210216152333/https://onlinelibrary.wiley.com/doi/abs/10.1002/bies.202000163 | url-status = live }}</ref>

Other forms of antibiotic-associated harm include [[anaphylaxis]], [[Adverse drug reaction|drug toxicity]] most notably kidney and liver damage, and super-infections with resistant organisms. Antibiotics are also known to affect [[Mitochondrion|mitochondrial]] function,<ref>{{cite journal | vauthors = Kalghatgi S, Spina CS, Costello JC, Liesa M, Morones-Ramirez JR, Slomovic S, Molina A, Shirihai OS, Collins JJ | title = Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in Mammalian cells | journal = Science Translational Medicine | volume = 5 | issue = 192 | pages = 192ra85 | date = July 2013 | pmid = 23825301 | pmc = 3760005 | doi = 10.1126/scitranslmed.3006055 }}</ref> and this may contribute to the [[bioenergetic failure]] of [[White blood cell|immune cells]] seen in [[sepsis]].<ref>{{cite journal | vauthors = Singer M | title = The role of mitochondrial dysfunction in sepsis-induced multi-organ failure | journal = Virulence | volume = 5 | issue = 1 | pages = 66–72 | date = January 2014 | pmid = 24185508 | pmc = 3916385 | doi = 10.4161/viru.26907 }}</ref> They also alter the [[Microbiome of humans|microbiome]] of the gut, lungs, and skin,<ref>{{cite journal | vauthors = Alagna L, Bandera A, Patruno A, Muscatello A, Citerio G, Gori A | title = Microbiota in ICU, not only a gut problem | journal = Intensive Care Medicine | volume = 45 | issue = 5 | pages = 733–737 | date = May 2019 | pmid = 30671622 | doi = 10.1007/s00134-018-05516-7 | s2cid = 58949829 | doi-access = free | title-link = doi }}</ref> which may be associated with adverse effects such as [[Clostridioides difficile infection|Clostridioides difficile associated diarrhoea]]. Whilst antibiotics can clearly be lifesaving in patients with bacterial infections, their overuse, especially in patients where infections are hard to diagnose, can lead to harm via multiple mechanisms.<ref name=":0" />