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Array ( [0] => {{short description|Antimicrobial substance active against bacteria}} [1] => {{cs1 config|name-list-style=vanc|display-authors=6}} [2] => {{Redirect|Antibacterial}} [3] => {{about|treatment of bacterial infection|anti-tumor antibiotics|Chemotherapy#Cytotoxic antibiotics}} [4] => {{Use dmy dates|date=January 2020}} [5] => {{Infobox drug class [6] => | Name = [7] => | Image = Staphylococcus aureus (AB Test).jpg [8] => | Alt = [9] => | Caption = Testing the susceptibility of ''[[Staphylococcus aureus]]'' to antibiotics by the [[Kirby-Bauer antibiotic testing|Kirby-Bauer disk diffusion method]] – antibiotics diffuse from antibiotic-containing disks and inhibit growth of ''S. aureus'', resulting in a zone of inhibition. [10] => | Pronounce = [11] => | Synonyms = [12] => [13] => | Use = [14] => | ATC_prefix = [15] => | Mode_of_action = [16] => | Mechanism_of_action = [17] => | Biological_target = [18] => | Chemical_class = [19] => [20] => | Drugs.com = [21] => | Consumer_Reports = [22] => | medicinenet = [23] => | rxlist = [24] => [25] => | MeshID = [26] => }} [27] => [28] => An '''antibiotic''' is a type of [[antimicrobial]] substance active against [[bacteria]]. It is the most important type of antibacterial agent for fighting [[pathogenic bacteria|bacterial infections]], and antibiotic [[medication]]s are widely used in the [[therapy|treatment]] and [[antibiotic prophylaxis|prevention]] of such infections.{{cite web |url=https://www.nhs.uk/conditions/Antibiotics-penicillins/Pages/Introduction.aspx |title=Antibiotics |publisher=NHS |date=5 June 2014 |access-date=17 January 2015 |archive-date=18 January 2015 |archive-url=https://web.archive.org/web/20150118023314/http://www.nhs.uk/conditions/antibiotics-penicillins/pages/introduction.aspx |url-status=live }}{{cite web |url=http://ecdc.europa.eu/en/eaad/antibiotics/Pages/factsExperts.aspx |title=Factsheet for experts |publisher=European Centre for Disease Prevention and Control |access-date=21 December 2014 |archive-url=https://web.archive.org/web/20141221183712/http://ecdc.europa.eu/en/eaad/antibiotics/Pages/factsExperts.aspx |archive-date=21 December 2014 |url-status=dead }} They may either [[bactericide|kill]] or [[bacteriostatic agent|inhibit the growth]] of bacteria. A limited number of antibiotics also possess [[antiprotozoal]] activity.For example, [[metronidazole]]: {{cite web|title=Metronidazole|url=https://www.drugs.com/monograph/metronidazole.html|publisher=The American Society of Health-System Pharmacists|access-date=31 July 2015|archive-date=6 September 2015|archive-url=https://web.archive.org/web/20150906002140/http://www.drugs.com/monograph/metronidazole.html|url-status=live}}{{cite book|title=Chemical Analysis of Antibiotic Residues in Food.|date=2012|publisher=John Wiley & Sons, Inc.|isbn=978-1-4496-1459-1|pages=[https://archive.org/details/antibioticssimpl0002gall/page/1 1–60]|url=https://archive.org/details/antibioticssimpl0002gall/page/1}} Antibiotics are not effective against [[virus]]es such as the ones which cause the [[common cold]] or [[influenza]];{{Cite web|title=Why antibiotics can't be used to treat your cold or flu|url=https://www.health.qld.gov.au/news-events/news/antibiotics-viruses-cold-flu|date=2017-05-06|website=www.health.qld.gov.au|language=en-AU|access-date=2020-05-13|archive-date=9 August 2020|archive-url=https://web.archive.org/web/20200809150646/https://www.health.qld.gov.au/news-events/news/antibiotics-viruses-cold-flu|url-status=live}} drugs which inhibit growth of viruses are termed [[antiviral drug]]s or antivirals rather than antibiotics. They are also not effective against [[fungi]]; drugs which inhibit growth of fungi are called [[antifungal drug]]s. [29] => [30] => Sometimes, the term ''antibiotic''—literally "opposing life", from the [[Greek language|Greek]] roots ἀντι ''anti'', "against" and βίος ''bios'', "life"—is broadly used to refer to any substance used against [[microbe]]s, but in the usual medical usage, antibiotics (such as [[penicillin]]) are those produced naturally (by one [[microorganism]] fighting another), whereas non-antibiotic antibacterials (such as [[sulfonamide]]s and [[antiseptic]]s) are [[total synthesis|fully synthetic]]. However, both classes have the same goal of killing or preventing the growth of microorganisms, and both are included in [[antimicrobial chemotherapy]]. "Antibacterials" include [[bactericide]]s, [[bacteriostatic]]s, [[antibacterial soap]]s, and chemical [[disinfectant]]s, whereas antibiotics are an important class of antibacterials used more specifically in medicine{{cite web |url=http://www.tufts.edu/med/apua/about_issue/agents.shtml#1 |title=General Background: Antibiotic Agents |work=Alliance for the Prudent Use of Antibiotics |access-date=21 December 2014 |archive-url=https://web.archive.org/web/20141214195917/http://www.tufts.edu/med/apua/about_issue/agents.shtml#1 |archive-date=14 December 2014 |url-status=dead }} and [[antibiotic use in livestock|sometimes in livestock feed]]. [31] => [32] => Antibiotics have been used since ancient times. Many civilizations used topical application of moldy bread, with many references to its beneficial effects arising from ancient Egypt, [[Nubia]], [[China]], [[Serbia]], Greece, and Rome.{{Cite journal | vauthors = Gould K |date= March 2016 |title=Antibiotics: from prehistory to the present day |journal=Journal of Antimicrobial Chemotherapy |volume=71 |issue=3 |pages=572–575 |doi=10.1093/jac/dkv484 |pmid=26851273 |issn=0305-7453|doi-access=free }} The first person to directly document the use of molds to treat infections was [[John Parkinson (botanist)|John Parkinson]] (1567–1650). Antibiotics revolutionized medicine in the 20th century. Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany with [[Paul Ehrlich]] in the late 1880s. [[Alexander Fleming]] (1881–1955) discovered modern day [[penicillin]] in 1928, the widespread use of which proved significantly beneficial during wartime. The first [[sulfonamide (medicine)|sulfonamide]] and the first [[wikt:systemic|systemically]] active antibacterial drug, [[Prontosil]], was developed by a research team led by [[Gerhard Domagk]] in 1932 or 1933 at the [[Bayer]] Laboratories of the [[IG Farben]] conglomerate in Germany.{{cite journal | vauthors = Aminov RI | title = A brief history of the antibiotic era: lessons learned and challenges for the future | journal = Frontiers in Microbiology | volume = 1 | pages = 134 | year = 2010 | pmid = 21687759 | pmc = 3109405 | doi = 10.3389/fmicb.2010.00134 | doi-access = free }} However, the effectiveness and easy access to antibiotics have also led to their [[antibiotic misuse|overuse]]{{cite journal | vauthors = Laxminarayan R, Duse A, Wattal C, Zaidi AK, Wertheim HF, Sumpradit N, Vlieghe E, Hara GL, Gould IM, Goossens H, Greko C, So AD, Bigdeli M, Tomson G, Woodhouse W, Ombaka E, Peralta AQ, Qamar FN, Mir F, Kariuki S, Bhutta ZA, Coates A, Bergstrom R, Wright GD, Brown ED, Cars O | title = Antibiotic resistance-the need for global solutions | journal = The Lancet. Infectious Diseases | volume = 13 | issue = 12 | pages = 1057–98 | date = December 2013 | pmid = 24252483 | doi = 10.1016/S1473-3099(13)70318-9 | url = http://dspace.ucuenca.edu.ec/handle/123456789/22122 | hdl-access = free | hdl = 10161/8996 | s2cid = 19489131 | access-date = 25 August 2020 | archive-date = 10 June 2020 | archive-url = https://web.archive.org/web/20200610091542/http://dspace.ucuenca.edu.ec/handle/123456789/22122 | url-status = live }} and some bacteria have evolved [[antibiotic resistance|resistance]] to them.{{cite web|vauthors=Brooks M|title=Public Confused About Antibiotic Resistance, WHO Says|url=http://www.medscape.com/viewarticle/854564|website=Medscape Multispeciality|access-date=21 November 2015|date=16 November 2015|archive-date=20 November 2015|archive-url=https://web.archive.org/web/20151120032454/http://www.medscape.com/viewarticle/854564|url-status=live}}{{cite journal | vauthors = Gould K | title = Antibiotics: from prehistory to the present day | journal = The Journal of Antimicrobial Chemotherapy | volume = 71 | issue = 3 | pages = 572–5 | date = March 2016 | pmid = 26851273 | doi = 10.1093/jac/dkv484 | doi-access = free }}{{Cite book|title= Antibiotics: Targets, Mechanisms and Resistance|url= https://books.google.com/books?id=3SZrAAAAQBAJ|publisher= John Wiley & Sons|date= 4 December 2013|isbn= 978-3-527-33305-9| vauthors = Gualerzi CO, Brandi L, Fabbretti A, Pon CL |pages= 1}} The [[World Health Organization]] has classified [[antimicrobial resistance]] as a widespread "serious threat [that] 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".{{cite book |url=http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf?ua=1 |title=Antimicrobial resistance: global report on surveillance |publisher=The World Health Organization |date=April 2014 |access-date=13 June 2016 |isbn=978-92-4-156474-8 |archive-date=6 June 2016 |archive-url=https://web.archive.org/web/20160606181615/http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf?ua=1 |url-status=live }} Global deaths attributable to antimicrobial resistance numbered 1.27 million in 2019.{{cite journal | title = Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis | language = English | journal = Lancet | volume = 399 | issue = 10325 | pages = 629–655 | date = February 2022 | pmid = 35065702 | pmc = 8841637 | doi = 10.1016/S0140-6736(21)02724-0 | vauthors = Murray CJ, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar G, Gray A, Han C, Bisignano C, Rao P, Wool E, Johnson SC, Browne AJ, Chipeta MG, Fell F, Hackett S, Haines-Woodhouse G, Kashef Hamadani BH, Kumaran EA, McManigal B, Achalapong S, Agarwal R, Akech S, Albertson S, Amuasi J, Andrews J, Aravkin A, Ashley E, Babin F, Bailey F, Baker S }} [33] => [34] => ==Etymology== [35] => [36] => The term 'antibiosis', meaning "against life", was introduced by the French bacteriologist [[Jean Paul Vuillemin]] as a descriptive name of the phenomenon exhibited by these early antibacterial drugs.{{cite book|title=Applied Microbiology|vauthors=Saxena S|publisher=Springer India|year=2015|isbn=978-81-322-2258-3|pages=83–120|chapter=Chapter 8: Microbes in Production of Fine Chemicals (Antibiotics, Drugs, Vitamins, and Amino Acids)|doi=10.1007/978-81-322-2259-0|s2cid=36527513}}{{cite journal | vauthors = Foster W, Raoult A | title = Early descriptions of antibiosis | journal = The Journal of the Royal College of General Practitioners | volume = 24 | issue = 149 | pages = 889–894 | date = December 1974 | pmid = 4618289 | pmc = 2157443 }} Antibiosis was first described in 1877 in bacteria when [[Louis Pasteur]] and [[Robert Koch]] observed that an airborne bacillus could inhibit the growth of ''[[Bacillus anthracis]]''.{{cite journal|vauthors=Landsberg H|year=1949|title=Prelude to the discovery of penicillin|journal=Isis|volume=40|issue=3|pages=225–7|doi=10.1086/349043|s2cid=143223535}} These drugs were later renamed antibiotics by [[Selman Waksman]], an American microbiologist, in 1947.{{cite journal | vauthors = Waksman SA | title = What is an antibiotic or an antibiotic substance? | journal = Mycologia | volume = 39 | issue = 5 | pages = 565–569 | date = 1947 | pmid = 20264541 | doi = 10.1080/00275514.1947.12017635 }} [37] => [38] => The term ''antibiotic'' was first used in 1942 by [[Selman Waksman]] and his collaborators in journal articles to describe any substance produced by a microorganism that is [[wikt:antagonism|antagonistic]] to the growth of other microorganisms in high dilution. This definition excluded substances that kill bacteria but that are not produced by microorganisms (such as [[gastric juices]] and [[hydrogen peroxide]]). It also excluded [[chemical synthesis|synthetic]] antibacterial compounds such as the [[sulfonamide (medicine)|sulfonamides]]. In current usage, the term "antibiotic" is applied to any medication that kills bacteria or inhibits their growth, regardless of whether that medication is produced by a microorganism or not.{{Cite book|url=https://archive.org/details/antimicrobialdru0000scho|title=The Antimicrobial Drugs|vauthors=Scholar EM, Pratt WB|publisher=Oxford University Press, US|year=2000|isbn=978-0-19-512529-0|pages=[https://archive.org/details/antimicrobialdru0000scho/page/3 3]|url-access=registration}}{{cite journal|vauthors=Davies J, Davies D|date=September 2010|title=Origins and evolution of antibiotic resistance|journal=Microbiology and Molecular Biology Reviews|volume=74|issue=3|pages=417–33|doi=10.1128/MMBR.00016-10|pmc=2937522|pmid=20805405}} [39] => [40] => The term "antibiotic" derives from ''anti'' + βιωτικός (''biōtikos''), "fit for life, lively",{{cite book|title=A Greek-English Lexicon|veditors=Liddell HG, Scott R|chapter=βιωτικός|chapter-url=https://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.04.0057%3Aentry%3Dbiwtiko%2Fs|via=[[Perseus Project]]|access-date=20 February 2021|archive-date=25 April 2023|archive-url=https://web.archive.org/web/20230425182154/https://www.perseus.tufts.edu/hopper/text?doc=Perseus:text:1999.04.0057:entry%3Dbiwtiko/s|url-status=live}} which comes from βίωσις (''biōsis''), "way of life",{{cite book|title=A Greek-English Lexicon|veditors=Liddell HG, Scott R|chapter=βίωσις|chapter-url=https://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.04.0057%3Aentry%3Dbi%2Fwsis|via=[[Perseus Project]]|access-date=20 February 2021|archive-date=25 February 2021|archive-url=https://web.archive.org/web/20210225214659/http://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.04.0057%3Aentry%3Dbi%2Fwsis|url-status=live}} and that from βίος (''bios''), "life".{{cite book|title=A Greek-English Lexicon|veditors=Liddell HG, Scott R|chapter=βίος|chapter-url=https://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.04.0057%3Aentry%3Dbi%2Fos1|via=[[Perseus Project]]|access-date=20 February 2021|archive-date=27 February 2021|archive-url=https://web.archive.org/web/20210227060426/http://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.04.0057%3Aentry%3Dbi%2Fos1|url-status=live}} The term "antibacterial" derives from [[Greek language|Greek]] ἀντί (''anti''), "against"{{cite book|title=A Greek-English Lexicon|veditors=Liddell HG, Scott R|chapter=ἀντί|chapter-url=https://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.04.0057%3Aentry%3Da%29nti%2F|via=[[Perseus Project]]|access-date=20 February 2021|archive-date=10 October 2012|archive-url=https://web.archive.org/web/20121010011324/http://www.perseus.tufts.edu/hopper/text?doc=Perseus:text:1999.04.0057:entry=a)nti%2F|url-status=live}} + βακτήριον (''baktērion''), diminutive of βακτηρία (''baktēria''), "staff, cane",{{cite book|title=A Greek-English Lexicon|veditors=Liddell HG, Scott R|chapter=βακτηρία|chapter-url=https://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.04.0057%3Aentry%3Dbakthri%2Fa|via=[[Perseus Project]]|access-date=20 February 2021|archive-date=24 February 2021|archive-url=https://web.archive.org/web/20210224153634/http://www.perseus.tufts.edu/hopper/text?doc=Perseus:text:1999.04.0057:entry=bakthri/a|url-status=live}} because the first bacteria to be discovered were rod-shaped.[http://oxforddictionaries.com/definition/bacterium?q=bacterial#bacterium__2 bacterial] {{Webarchive|url=https://web.archive.org/web/20210827221846/https://languages.oup.com/#bacterium__2 |date=27 August 2021 }}, on Oxford Dictionaries [41] => [42] => ==Usage== [43] => ===Medical uses=== [44] => Antibiotics are used to treat or prevent bacterial infections,{{cite book|title=Antibiotics Simplified.|date=2011|publisher=Jones & Bartlett Publishers|isbn=978-1-4496-1459-1|pages=15–17|url=https://books.google.com/books?id=vIRgA57q414C&q=Antibiotics|access-date=28 April 2024|archive-date=2 January 2024|archive-url=https://web.archive.org/web/20240102114230/https://books.google.com/books?id=vIRgA57q414C&q=Antibiotics#v=snippet&q=Antibiotics&f=false|url-status=live}} and sometimes [[protozoan infection]]s. ([[Metronidazole]] is effective against a number of [[parasitic disease]]s). When an infection is suspected of being responsible for an illness but the responsible pathogen has not been identified, an [[empiric therapy]] is adopted.{{cite journal | vauthors = Leekha S, Terrell CL, Edson RS | title = General principles of antimicrobial therapy | journal = Mayo Clinic Proceedings | volume = 86 | issue = 2 | pages = 156–67 | date = February 2011 | pmid = 21282489 | pmc = 3031442 | doi = 10.4065/mcp.2010.0639 }} This involves the administration of a [[broad-spectrum antibiotic]] based on the signs and symptoms presented and is initiated pending laboratory results that can take several days. [45] => [46] => When the responsible pathogenic microorganism is already known or has been identified, [[therapy#Definitive therapy|definitive therapy]] can be started. This will usually involve the use of a narrow-spectrum antibiotic. The choice of antibiotic given will also be based on its cost. Identification is critically important as it can reduce the cost and toxicity of the antibiotic therapy and also reduce the possibility of the emergence of antimicrobial resistance. To avoid surgery, antibiotics may be given for non-complicated acute [[appendicitis]].{{cite journal | vauthors = Rollins KE, Varadhan KK, Neal KR, Lobo DN | title = Antibiotics Versus Appendicectomy for the Treatment of Uncomplicated Acute Appendicitis: An Updated Meta-Analysis of Randomised Controlled Trials | journal = World Journal of Surgery | volume = 40 | issue = 10 | pages = 2305–18 | date = October 2016 | pmid = 27199000 | doi = 10.1007/s00268-016-3561-7 | s2cid = 4802473 }} [47] => [48] => Antibiotics may be given as a [[preventive healthcare|preventive measure]] and this is usually limited to at-risk populations such as those with a [[immunodeficiency|weakened immune system]] (particularly in [[HIV]] cases to prevent [[pneumonia]]), those taking [[immunosuppressive drug]]s, [[cancer]] patients, and those having [[surgery]]. Their use in surgical procedures is to help prevent infection of [[surgical incision|incisions]]. They have an important role in [[dental antibiotic prophylaxis]] where their use may prevent [[bacteremia]] and consequent [[infective endocarditis]]. Antibiotics are also used to prevent infection in cases of [[neutropenia]] particularly cancer-related.{{cite journal | vauthors = Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley DK, Kuderer NM, Langston AA, Marr KA, Rolston KV, Ramsey SD | title = Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline | journal = Journal of Clinical Oncology | volume = 31 | issue = 6 | pages = 794–810 | date = February 2013 | pmid = 23319691 | doi = 10.1200/JCO.2012.45.8661 }}{{cite journal | vauthors = Bow EJ | title = Infection in neutropenic patients with cancer | journal = Critical Care Clinics | volume = 29 | issue = 3 | pages = 411–41 | date = July 2013 | pmid = 23830647 | doi = 10.1016/j.ccc.2013.03.002 }} [49] => [50] => The use of antibiotics for secondary prevention of coronary heart disease is not supported by current scientific evidence, and may actually increase cardiovascular mortality, all-cause mortality and the occurrence of stroke.{{cite journal | vauthors = Sethi NJ, Safi S, Korang SK, Hróbjartsson A, Skoog M, Gluud C, Jakobsen JC | title = Antibiotics for secondary prevention of coronary heart disease | journal = The Cochrane Database of Systematic Reviews | volume = 2 | issue = 5 | pages = CD003610 | date = February 2021 | pmid = 33704780 | pmc = 8094925 | doi = 10.1002/14651858.CD003610.pub4 | collaboration = Cochrane Heart Group }} [51] => [52] => ===Routes of administration=== [53] => There are many different [[routes of administration]] for antibiotic treatment. Antibiotics are usually [[oral administration|taken by mouth]]. In more severe cases, particularly deep-seated [[systemic disease|systemic infections]], antibiotics can be given [[intravenous therapy|intravenously]] or by injection. Where the site of infection is easily accessed, antibiotics may be given [[routes of administration#Topical|topically]] in the form of [[eye drop]]s onto the [[conjunctiva]] for [[conjunctivitis]] or [[ear drop]]s for ear infections and acute cases of [[otitis externa|swimmer's ear]]. Topical use is also one of the treatment options for some skin conditions including [[acne vulgaris|acne]] and [[cellulitis]].{{cite journal | vauthors = Pangilinan R, Tice A, Tillotson G | title = Topical antibiotic treatment for uncomplicated skin and skin structure infections: review of the literature | journal = Expert Review of Anti-Infective Therapy | volume = 7 | issue = 8 | pages = 957–65 | date = October 2009 | pmid = 19803705 | doi = 10.1586/eri.09.74 | s2cid = 207217730 }} Advantages of topical application include achieving high and sustained concentration of antibiotic at the site of infection; reducing the potential for systemic absorption and toxicity, and total volumes of antibiotic required are reduced, thereby also reducing the risk of antibiotic misuse.{{cite journal | vauthors = Lipsky BA, Hoey C | title = Topical antimicrobial therapy for treating chronic wounds | journal = Clinical Infectious Diseases | volume = 49 | issue = 10 | pages = 1541–9 | date = November 2009 | pmid = 19842981 | doi = 10.1086/644732 | doi-access = free }} Topical antibiotics applied over certain types of surgical wounds have been reported to reduce the risk of surgical site infections.{{cite journal | vauthors = Heal CF, Banks JL, Lepper PD, Kontopantelis E, van Driel ML | title = Topical antibiotics for preventing surgical site infection in wounds healing by primary intention | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 11 | pages = CD011426 | date = November 2016 | pmid = 27819748 | pmc = 6465080 | doi = 10.1002/14651858.CD011426.pub2 }} However, there are certain general causes for concern with topical administration of antibiotics. Some systemic absorption of the antibiotic may occur; the quantity of antibiotic applied is difficult to accurately dose, and there is also the possibility of local [[hypersensitivity]] reactions or [[contact dermatitis]] occurring. It is recommended to administer antibiotics as soon as possible, especially in life-threatening infections. Many emergency departments stock antibiotics for this purpose.{{cite journal | vauthors = Hung KK, Lam RP, Lo RS, Tenney JW, Yang ML, Tai MC, Graham CA | title = Cross-sectional study on emergency department management of sepsis | journal = Hong Kong Medical Journal = Xianggang Yi Xue Za Zhi | volume = 24 | issue = 6 | pages = 571–578 | date = December 2018 | pmid = 30429360 | doi = 10.12809/hkmj177149 | doi-access = free }} [54] => [55] => ===Global consumption=== [56] => Antibiotic consumption varies widely between countries. The [[WHO]] report on surveillance of antibiotic consumption published in 2018 analysed 2015 data from 65 countries. As measured in defined daily doses per 1,000 inhabitants per day. Mongolia had the highest consumption with a rate of 64.4. Burundi had the lowest at 4.4. [[Amoxicillin]] and [[amoxicillin/clavulanic acid]] were the most frequently consumed.{{cite news |title=UK antibiotic consumption twice that of the Netherlands, WHO report finds |url=https://www.pharmaceutical-journal.com/20205732.article |access-date=22 December 2018 |publisher=Pharmaceutical Journal |date=14 November 2018 |archive-date=22 December 2018 |archive-url=https://web.archive.org/web/20181222221210/https://www.pharmaceutical-journal.com/20205732.article |url-status=dead }} [57] => [58] => ==Side effects== [59] => [[File:Choosing Wisely antibiotics poster small English.pdf|thumb|right|Health advocacy messages such as this one encourage patients to talk with their doctor about safety in using antibiotics.]] [60] => Antibiotics are screened for any negative effects before their approval for clinical use, and are usually considered safe and well tolerated. However, some antibiotics have been associated with a wide extent of adverse [[side effect]]s ranging from mild to very severe depending on the type of antibiotic used, the microbes targeted, and the individual patient.{{cite journal | vauthors = Slama TG, Amin A, Brunton SA, File TM, Milkovich G, Rodvold KA, Sahm DF, Varon J, Weiland D | title = A clinician's guide to the appropriate and accurate use of antibiotics: the Council for Appropriate and Rational Antibiotic Therapy (CARAT) criteria | journal = The American Journal of Medicine | volume = 118 | issue = 7A | pages = 1S–6S | date = July 2005 | pmid = 15993671 | doi = 10.1016/j.amjmed.2005.05.007 | collaboration = Council for Appropriate Rational Antibiotic Therapy (CARAT) | doi-access = free }} Side effects may reflect the pharmacological or toxicological properties of the antibiotic or may involve hypersensitivity or [[allergy|allergic]] reactions. Adverse effects range from fever and nausea to major allergic reactions, including [[photodermatitis]] and [[anaphylaxis]].{{cite web |title=Antibiotics – Side effects |website=NHS Choices |publisher=National Health Service (NHS), UK |url=http://www.nhs.uk/Conditions/Antibiotics-penicillins/Pages/Side-effects.aspx |date=6 May 2014 |access-date=6 February 2016 |archive-date=7 February 2016 |archive-url=https://web.archive.org/web/20160207044627/http://www.nhs.uk/Conditions/Antibiotics-penicillins/Pages/Side-effects.aspx |url-status=live }} [61] => [62] => Common side effects of oral antibiotics include [[diarrhea]], resulting from disruption of the species composition in the [[intestinal flora]], resulting, for example, in overgrowth of pathogenic bacteria, such as ''[[Clostridium difficile (bacteria)|Clostridium difficile]]''.{{cite web|title=Antibiotic-Associated Diarrhea – All you should know|access-date=28 December 2014|url=http://www.bestnaturalremedies.net/antibiotic-associated-diarrhea|archive-date=25 April 2015|archive-url=https://web.archive.org/web/20150425102547/http://www.bestnaturalremedies.net/antibiotic-associated-diarrhea|url-status=dead}} Taking [[probiotics]] during the course of antibiotic treatment can help prevent antibiotic-associated diarrhea.{{cite journal | vauthors = Rodgers B, Kirley K, Mounsey A | title = PURLs: prescribing an antibiotic? Pair it with probiotics | journal = The Journal of Family Practice | volume = 62 | issue = 3 | pages = 148–50 | date = March 2013 | pmid = 23520586 | pmc = 3601687 }} Antibacterials can also affect the [[vaginal flora]], and may lead to overgrowth of [[yeast]] species of the genus ''[[Candida (genus)|Candida]]'' in the vulvo-vaginal area. Additional side effects can result from [[drug interaction|interaction]] with other drugs, such as the possibility of [[tendon]] damage from the administration of a [[quinolone antibiotic]] with a systemic [[corticosteroid]].{{cite journal | vauthors = Lewis T, Cook J | title = Fluoroquinolones and tendinopathy: a guide for athletes and sports clinicians and a systematic review of the literature | journal = Journal of Athletic Training | volume = 49 | issue = 3 | pages = 422–7 | date = 1 January 2014 | pmid = 24762232 | pmc = 4080593 | doi = 10.4085/1062-6050-49.2.09 }} [63] => [64] => Some antibiotics may also damage the [[mitochondrion]], a bacteria-derived organelle found in eukaryotic, including human, cells.{{Citation needed|date=January 2022}} Mitochondrial damage cause [[oxidative stress]] in cells and has been suggested as a mechanism for side effects from [[fluoroquinolone]]s.{{cite journal | vauthors = Marchant J | title = When antibiotics turn toxic | journal = Nature | volume = 555 | issue = 7697 | pages = 431–433 | date = March 2018 | pmid = 29565407 | doi = 10.1038/d41586-018-03267-5 | doi-access = free | bibcode = 2018Natur.555..431M }} They are also known to affect [[chloroplast]]s.{{cite journal | vauthors = Wang X, Ryu D, Houtkooper RH, Auwerx J | title = Antibiotic use and abuse: a threat to mitochondria and chloroplasts with impact on research, health, and environment | journal = BioEssays | volume = 37 | issue = 10 | pages = 1045–53 | date = October 2015 | pmid = 26347282 | pmc = 4698130 | doi = 10.1002/bies.201500071 }} [65] => [66] => == Interactions == [67] => [68] => ===Birth control pills=== [69] => There are few well-controlled studies on whether antibiotic use increases the risk of [[oral contraceptive pill|oral contraceptive]] failure.{{cite journal | vauthors = Anderson KC, Schwartz MD, Lieu SO | title = Antibiotics and OC effectiveness | journal = JAAPA | volume = 26 | issue = 1 | pages = 11 | date = January 2013 | pmid = 23355994 | doi = 10.1097/01720610-201301000-00002 }} The majority of studies indicate antibiotics do not interfere with [[combined oral contraceptive pill|birth control pills]], such as clinical studies that suggest the failure rate of contraceptive pills caused by antibiotics is very low (about 1%). Situations that may increase the risk of oral contraceptive failure include [[compliance (medicine)|non-compliance]] (missing taking the pill), vomiting, or diarrhea. Gastrointestinal disorders or interpatient variability in oral contraceptive absorption affecting [[ethinylestradiol]] [[serum (blood)|serum levels]] in the blood. Women with [[Irregular menstruation|menstrual irregularities]] may be at higher risk of failure and should be advised to use [[contraception|backup contraception]] during antibiotic treatment and for one week after its completion. If patient-specific risk factors for reduced oral contraceptive efficacy are suspected, backup contraception is recommended. [70] => [71] => In cases where antibiotics have been suggested to affect the efficiency of birth control pills, such as for the broad-spectrum antibiotic [[rifampicin]], these cases may be due to an increase in the activities of hepatic liver enzymes' causing increased breakdown of the pill's active ingredients. Effects on the [[gut flora|intestinal flora]], which might result in reduced absorption of [[estrogen]]s in the colon, have also been suggested, but such suggestions have been inconclusive and controversial. Clinicians have recommended that extra contraceptive measures be applied during therapies using antibiotics that are suspected to interact with oral [[contraceptive]]s. More studies on the possible interactions between antibiotics and birth control pills (oral contraceptives) are required as well as careful assessment of patient-specific risk factors for potential oral contractive pill failure prior to dismissing the need for backup contraception. [72] => [73] => ===Alcohol=== [74] => Interactions between alcohol and certain antibiotics may occur and may cause side effects and decreased effectiveness of antibiotic therapy. While moderate alcohol consumption is unlikely to interfere with many common antibiotics, there are specific types of antibiotics with which alcohol consumption may cause serious side effects. Therefore, potential risks of side effects and effectiveness depend on the type of antibiotic administered.{{cite journal | vauthors = Moore AA, Whiteman EJ, Ward KT | title = Risks of combined alcohol/medication use in older adults | journal = The American Journal of Geriatric Pharmacotherapy | volume = 5 | issue = 1 | pages = 64–74 | date = March 2007 | pmid = 17608249 | pmc = 4063202 | doi = 10.1016/j.amjopharm.2007.03.006 }} [75] => [76] => Antibiotics such as [[metronidazole]], [[tinidazole]], [[cephamandole]], [[latamoxef]], [[cefoperazone]], [[cefmenoxime]], and [[furazolidone]], cause a [[disulfiram]]-like chemical reaction with alcohol by inhibiting its breakdown by [[acetaldehyde dehydrogenase]], which may result in vomiting, nausea, and shortness of breath. In addition, the efficacy of doxycycline and [[erythromycin]] succinate may be reduced by alcohol consumption.{{cite book | vauthors = Stockley IH |year= 2002 |title= Stockley's Drug Interactions |edition= 6th |location= London |publisher= Pharmaceutical Press}}{{page needed|date=December 2013}} Other effects of alcohol on antibiotic activity include altered activity of the liver enzymes that break down the antibiotic compound. [77] => [78] => ==Pharmacodynamics== [79] => {{Main|Antimicrobial pharmacodynamics}} [80] => The successful outcome of antimicrobial therapy with antibacterial compounds depends on several factors. These include [[immune system|host defense mechanisms]], the location of infection, and the pharmacokinetic and pharmacodynamic properties of the antibacterial. The bactericidal activity of antibacterials may depend on the bacterial growth phase, and it often requires ongoing metabolic activity and division of bacterial cells. These findings are based on laboratory studies, and in clinical settings have also been shown to eliminate bacterial infection.{{cite book |vauthors=Pelczar MJ, Chan EC, Krieg NR |year=2010 |contribution=Host-Parasite Interaction; Nonspecific Host Resistance |title=Microbiology Concepts and Applications |edition=6th |publisher=McGraw-Hill |location=New York |pages=478–479}} Since the activity of antibacterials depends frequently on its concentration, ''in vitro'' characterization of antibacterial activity commonly includes the determination of the [[minimum inhibitory concentration]] and minimum bactericidal concentration of an antibacterial. [81] => To predict clinical outcome, the antimicrobial activity of an antibacterial is usually combined with its [[pharmacokinetics|pharmacokinetic]] profile, and several pharmacological parameters are used as markers of drug efficacy.{{cite journal | vauthors = Dalhoff A, Ambrose PG, Mouton JW | title = A long journey from minimum inhibitory concentration testing to clinically predictive breakpoints: deterministic and probabilistic approaches in deriving breakpoints | journal = Infection | volume = 37 | issue = 4 | pages = 296–305 | date = August 2009 | pmid = 19629383 | doi = 10.1007/s15010-009-7108-9 | s2cid = 20538901 }} [82] => [83] => ===Combination therapy=== [84] => [85] => In important infectious diseases, including tuberculosis, [[combination therapy]] (i.e., the concurrent application of two or more antibiotics) has been used to delay or prevent the emergence of resistance. In acute bacterial infections, antibiotics as part of combination therapy are prescribed for their [[drug synergy|synergistic]] effects to improve treatment outcome as the combined effect of both antibiotics is better than their individual effect.{{cite journal | vauthors = Ocampo PS, Lázár V, Papp B, Arnoldini M, Abel zur Wiesch P, Busa-Fekete R, Fekete G, Pál C, Ackermann M, Bonhoeffer S | title = Antagonism between bacteriostatic and bactericidal antibiotics is prevalent | journal = Antimicrobial Agents and Chemotherapy | volume = 58 | issue = 8 | pages = 4573–82 | date = August 2014 | pmid = 24867991 | pmc = 4135978 | doi = 10.1128/AAC.02463-14 }}{{cite journal | vauthors = Bollenbach T | title = Antimicrobial interactions: mechanisms and implications for drug discovery and resistance evolution | journal = Current Opinion in Microbiology | volume = 27 | pages = 1–9 | date = October 2015 | pmid = 26042389 | doi = 10.1016/j.mib.2015.05.008 | doi-access = free }} [[Fosfomycin]] has the highest number of synergistic combinations among antibiotics and is almost always used as a partner drug.{{cite journal | vauthors = Antonello RM, Principe L, Maraolo AE, Viaggi V, Pol R, Fabbiani M, Montagnani F, Lovecchio A, Luzzati R, Di Bella S | title = Fosfomycin as Partner Drug for Systemic Infection Management. A Systematic Review of Its Synergistic Properties from In Vitro and In Vivo Studies | journal = Antibiotics | volume = 9 | issue = 8 | pages = 500 | date = August 2020 | pmid = 32785114 | pmc = 7460049 | doi = 10.3390/antibiotics9080500 | doi-access = free }} [[Methicillin-resistant Staphylococcus aureus|Methicillin-resistant ''Staphylococcus aureus'']] infections may be treated with a combination therapy of [[fusidic acid]] and rifampicin. Antibiotics used in combination may also be antagonistic and the combined effects of the two antibiotics may be less than if one of the antibiotics was given as a [[monotherapy]]. For example, [[chloramphenicol]] and [[tetracyclines]] are antagonists to [[penicillin]]s. However, this can vary depending on the species of bacteria.{{cite web |url=http://medical-dictionary.thefreedictionary.com/antibiotic+antagonism |title=antagonism |access-date=25 August 2014 |archive-date=26 August 2014 |archive-url=https://web.archive.org/web/20140826115751/http://medical-dictionary.thefreedictionary.com/antibiotic+antagonism |url-status=live }} In general, combinations of a bacteriostatic antibiotic and bactericidal antibiotic are antagonistic. [86] => [87] => In addition to combining one antibiotic with another, antibiotics are sometimes co-administered with resistance-modifying agents. For example, [[β-lactam antibiotics]] may be used in combination with [[beta-lactamase inhibitor|β-lactamase inhibitor]]s, such as [[clavulanic acid]] or [[sulbactam]], when a patient is infected with a [[Beta-lactamase|β-lactamase]]-producing strain of bacteria.{{cite journal | vauthors = Drawz SM, Bonomo RA | title = Three decades of beta-lactamase inhibitors | journal = Clinical Microbiology Reviews | volume = 23 | issue = 1 | pages = 160–201 | date = January 2010 | pmid = 20065329 | pmc = 2806661 | doi = 10.1128/CMR.00037-09 }} [88] => [89] => ==Classes== [90] => {{Main|List of antibiotics}} [91] => [92] => [93] => File:Antibiotics action.svg|Molecular targets of antibiotics on the bacteria cell [94] => File:Protein synthesis inhibitors antibiotic.png|Protein synthesis inhibitors (antibiotics) [95] => [96] => [97] => Antibiotics are commonly classified based on their [[mechanism of action]], [[chemical structure]], or spectrum of activity. Most target bacterial functions or growth processes. Those that target the bacterial cell wall ([[penicillin]]s and [[cephalosporin]]s) or the cell membrane ([[polymyxin]]s), or interfere with essential bacterial enzymes ([[rifamycin]]s, [[lipiarmycin]]s, [[quinolone antibiotic|quinolones]], and [[sulfonamide (medicine)|sulfonamides]]) have [[bactericide|bactericidal]] activities, killing the bacteria. [[Protein synthesis inhibitor]]s ([[macrolide]]s, [[lincosamides]], and [[tetracycline]]s) are usually [[bacteriostatic]], inhibiting further growth (with the exception of bactericidal [[aminoglycoside]]s). Further categorization is based on their target specificity. "Narrow-spectrum" antibiotics target specific types of bacteria, such as [[gram-negative]] or [[gram-positive]], whereas [[broad-spectrum antibiotics]] affect a wide range of bacteria. Following a 40-year break in discovering classes of antibacterial compounds, four new classes of antibiotics were introduced to clinical use in the late 2000s and early 2010s: cyclic [[lipopeptide]]s (such as [[daptomycin]]), [[glycylcyclines]] (such as [[tigecycline]]), [[oxazolidinone]]s (such as [[linezolid]]), and [[lipiarmycin]]s (such as [[fidaxomicin]]).{{cite book |vauthors= Cunha BA |title= Antibiotic Essentials |year= 2009 |publisher= Jones & Bartlett Learning |isbn= 978-0-7637-7219-2 |page= 180}}{{cite journal | vauthors = Srivastava A, Talaue M, Liu S, Degen D, Ebright RY, Sineva E, Chakraborty A, Druzhinin SY, Chatterjee S, Mukhopadhyay J, Ebright YW, Zozula A, Shen J, Sengupta S, Niedfeldt RR, Xin C, Kaneko T, Irschik H, Jansen R, Donadio S, Connell N, Ebright RH | title = New target for inhibition of bacterial RNA polymerase: 'switch region' | journal = Current Opinion in Microbiology | volume = 14 | issue = 5 | pages = 532–43 | date = October 2011 | pmid = 21862392 | pmc = 3196380 | doi = 10.1016/j.mib.2011.07.030 }} [98] => [99] => ==Production== [100] => {{Main|Production of antibiotics}} [101] => With advances in [[medicinal chemistry]], most modern antibacterials are [[semisynthetic]] modifications of various natural compounds.{{cite journal | vauthors = von Nussbaum F, Brands M, Hinzen B, Weigand S, Häbich D | title = Antibacterial natural products in medicinal chemistry--exodus or revival? | journal = Angewandte Chemie | volume = 45 | issue = 31 | pages = 5072–129 | date = August 2006 | pmid = 16881035 | doi = 10.1002/anie.200600350 }} These include, for example, the [[beta-lactam antibiotics]], which include the [[penicillin]]s (produced by fungi in the genus ''[[Penicillium]]''), the [[cephalosporin]]s, and the [[carbapenem]]s. Compounds that are still isolated from living organisms are the [[aminoglycoside]]s, whereas other antibacterials—for example, the [[Sulfonamide (medicine)|sulfonamides]], the [[quinolone antibiotic|quinolones]], and the [[oxazolidinone]]s—are produced solely by [[chemical synthesis]]. Many antibacterial compounds are relatively [[small molecule]]s with a [[molecular weight]] of less than 1000 [[dalton (unit)|daltons]].{{cite book |url=https://books.google.com/books?id=av5SHPiHVcsC&q=oral%20drug%20molecular%20weight%20distribution%20antibiotics&pg=PA800 |title=Antibiotic Discovery and Development |vauthors=Dougherty TJ, Pucci MJ |publisher=Springer |year=2011 |page=800 |isbn=978-1-4614-1400-1 |access-date=28 April 2024 |archive-date=2 January 2024 |archive-url=https://web.archive.org/web/20240102114324/https://books.google.com/books?id=av5SHPiHVcsC&q=oral%20drug%20molecular%20weight%20distribution%20antibiotics&pg=PA800#v=snippet&q=oral%20drug%20molecular%20weight%20distribution%20antibiotics&f=false |url-status=live }} [102] => [103] => Since the first pioneering efforts of [[Howard Florey]] and [[Ernst Boris Chain|Chain]] in 1939, the importance of antibiotics, including antibacterials, to [[medicine]] has led to intense research into producing antibacterials at large scales. Following screening of antibacterials against a wide range of [[bacteria]], production of the active compounds is carried out using [[industrial fermentation|fermentation]], usually in strongly [[wikt:aerobic|aerobic]] conditions.{{cite journal | vauthors = Fedorenko V, Genilloud O, Horbal L, Marcone GL, Marinelli F, Paitan Y, Ron EZ | title = Antibacterial Discovery and Development: From Gene to Product and Back | journal = BioMed Research International | volume = 2015 | pages = 591349 | date = 2015 | pmid = 26339625 | pmc = 4538407 | doi = 10.1155/2015/591349 | doi-access = free }} [104] => [105] => ==Resistance== [106] => {{Main|Antibiotic resistance}} [107] => [[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)]] [108] => [109] => The emergence of [[antibiotic-resistant bacteria]] is a common phenomenon mainly caused by the overuse/misuse. It represents a threat to health globally.{{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}} [110] => [111] => 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. For example, antibacterial selection for strains having previously acquired antibacterial-resistance genes was demonstrated in 1943 by the [[Luria–Delbrück experiment]]. 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. [112] => [113] => Resistance may take the form of biodegradation of pharmaceuticals, such as sulfamethazine-degrading soil bacteria introduced to sulfamethazine through medicated pig feces.{{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 }} [114] => The survival of bacteria often results from an inheritable resistance, 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.{{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}} [115] => [116] => 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. [117] => [118] => Paleontological data show that both antibiotics and antibiotic resistance are ancient compounds and mechanisms. Useful antibiotic targets are those for which mutations negatively impact bacterial reproduction or viability. [119] => [120] => Several molecular mechanisms of antibacterial resistance exist. Intrinsic antibacterial resistance may be part of the genetic makeup of bacterial strains.{{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 }} 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. Antibacterial-producing bacteria have evolved resistance mechanisms that have been shown to be similar to, and may have been transferred to, antibacterial-resistant strains. 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]]. For instance, antibacterial resistance genes can be exchanged between different bacterial strains or species via [[plasmids]] that carry these resistance genes. Plasmids that carry several different resistance genes can confer resistance to multiple antibacterials. 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. [121] => [122] => 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.[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). For example, [[NDM-1]] is a newly identified enzyme conveying bacterial resistance to a broad range of [[beta-lactam]] antibacterials. 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." 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]].{{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 }}{{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}} [123] => 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%.{{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 }} [124] => [125] => ===Misuse=== [126] => [[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.]] [127] => [128] => {{Main|Antibiotic misuse}} [129] => [130] => 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." 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.{{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 }} [[Self-prescribing]] of antibiotics is an example of misuse. 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. The overuse of antibiotics, like penicillin and erythromycin, has been associated with emerging antibiotic resistance since the 1950s. 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. [131] => [132] => 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". Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescription of antibiotics.{{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 }} The lack of rapid point of care diagnostic tests, particularly in resource-limited settings is considered one of the drivers of antibiotic misuse.{{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 }} [133] => [134] => Several organizations concerned with antimicrobial resistance are lobbying to eliminate the unnecessary use of antibiotics. 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. A non-governmental organization campaign group is ''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.{{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 }} [135] => [136] => 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.{{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 }} 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.{{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 }}{{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 and H.R. 2562) aimed at phasing out nontherapeutic use of antibiotics in US food animals were proposed, but have not passed. 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]].{{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}}{{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 }} [137] => [138] => 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.{{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}} [139] => [140] => 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.{{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 }} [141] => [142] => Studies have shown that [[common misconceptions]] about the effectiveness and necessity of antibiotics to treat common mild illnesses contribute to their overuse.{{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|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}}{{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 }} [143] => [144] => 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,{{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 }} and this may contribute to the [[bioenergetic failure]] of [[White blood cell|immune cells]] seen in [[sepsis]].{{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 }} They also alter the [[Microbiome of humans|microbiome]] of the gut, lungs and skin,{{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 }} which may be associated with adverse effects such as [[Clostridioides difficile infection|Clostridium 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. [145] => [146] => ==History== [147] => {{For timeline|Timeline of antibiotics}} [148] => [149] => Before the early 20th century, treatments for infections were based primarily on [[folk medicine|medicinal folklore]]. Mixtures with antimicrobial properties that were used in treatments of infections were described over 2,000 years ago. Many ancient cultures, including the [[Ancient Egyptian medicine|ancient Egyptians]] and [[Ancient Greek medicine|ancient Greeks]], used specially selected [[Mold (fungus)|mold]] and plant materials to treat [[infection]]s. [[Nubian people|Nubian]] mummies studied in the 1990s were found to contain significant levels of [[tetracycline]]. The beer brewed at that time was conjectured to have been the source.{{cite journal | vauthors = Armelagos, George | date = 2000 | title = Take Two Beers and Call Me in 1,600 Years: Use of Tetracycline by Nubians and Ancient Egyptians | journal = Natural History | issue = 5; May | pages = 50–53 | url = https://ay14-15.moodle.wisc.edu/prod/pluginfile.php/59948/mod_resource/content/0/Take_two_Beers.pdf | access-date = March 13, 2017 }}{{Dead link|date=October 2022 |bot=InternetArchiveBot |fix-attempted=yes }} [150] => [151] => The use of antibiotics in modern medicine began with the discovery of synthetic antibiotics derived from dyes.{{cite journal | vauthors = Williams KJ | title = The introduction of 'chemotherapy' using arsphenamine - the first magic bullet | journal = Journal of the Royal Society of Medicine | volume = 102 | issue = 8 | pages = 343–348 | date = August 2009 | pmid = 19679737 | pmc = 2726818 | doi = 10.1258/jrsm.2009.09k036 }}{{cite book | vauthors = Goodman LS, Gilman A |author-link1=Louis S. Goodman |author-link2=Alfred Gilman, Sr. |title=The Pharmacological Basis of Therapeutics |publisher=Macmillan |location=New York |year=1941|title-link=The Pharmacological Basis of Therapeutics }}Various [[Essential oil]]s have been shown to have anti-microbial properties.{{cite journal | vauthors = Chouhan S, Sharma K, Guleria S | title = Antimicrobial Activity of Some Essential Oils-Present Status and Future Perspectives | journal = Medicines | volume = 4 | issue = 3 | pages = 58 | date = August 2017 | pmid = 28930272 | pmc = 5622393 | doi = 10.3390/medicines4030058 | doi-access = free }} Along with this, the plants from which these oils have been derived from can be used as niche anti-microbial agents.{{cite journal | vauthors = Cowan MM | title = Plant products as antimicrobial agents | journal = Clinical Microbiology Reviews | volume = 12 | issue = 4 | pages = 564–582 | date = October 1999 | pmid = 10515903 | pmc = 88925 | doi = 10.1128/CMR.12.4.564 }} [152] => [153] => ===Synthetic antibiotics derived from dyes=== [154] => [[File:Salvarsan-montage.png|thumb|right|upright=0.9|Arsphenamine, also known as salvarsan, discovered in 1907 by Paul Ehrlich.]] [155] => Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany with [[Paul Ehrlich]] in the late 1880s. Ehrlich noted certain dyes would colour human, animal, or bacterial cells, whereas others did not. He then proposed the idea that it might be possible to create chemicals that would act as a selective drug that would bind to and kill bacteria without harming the human host. After screening hundreds of dyes against various organisms, in 1907, he discovered a medicinally useful drug, the first synthetic antibacterial [[Organoarsenic chemistry|organoarsenic compound]] [[salvarsan]], now called arsphenamine. [156] => [[File:Paul Ehrlich and Sahachiro Hata.jpg|thumb|left|[[Paul Ehrlich]] and [[Sahachiro Hata]] ]] [157] => This heralded the era of antibacterial treatment that was begun with the discovery of a series of arsenic-derived synthetic antibiotics by both [[Alfred Bertheim]] and Ehrlich in 1907. Ehrlich and Bertheim had experimented with various chemicals derived from dyes to treat [[trypanosomiasis]] in mice and [[spirochaeta]] infection in rabbits. While their early compounds were too toxic, Ehrlich and [[Sahachiro Hata]], a Japanese bacteriologist working with Ehrlich in the quest for a drug to treat [[syphilis]], achieved success with the 606th compound in their series of experiments. In 1910, Ehrlich and Hata announced their discovery, which they called drug "606", at the Congress for Internal Medicine at [[Wiesbaden]].{{cite journal|vauthors=Frith J|title=Arsenic – the "Poison of Kings" and the "Saviour of Syphilis"|journal=Journal of Military and Veterans' Health|volume=21|issue=4|url=http://jmvh.org/article/arsenic-the-poison-of-kings-and-the-saviour-of-syphilis/|access-date=31 January 2017|archive-date=26 February 2017|archive-url=https://web.archive.org/web/20170226102745/http://jmvh.org/article/arsenic-the-poison-of-kings-and-the-saviour-of-syphilis/|url-status=live}} The [[Hoechst AG|Hoechst]] company began to market the compound toward the end of 1910 under the name Salvarsan, now known as [[arsphenamine]]. The drug was used to treat syphilis in the first half of the 20th century. In 1908, Ehrlich received the [[Nobel Prize in Physiology or Medicine]] for his contributions to [[immunology]].{{cite web|url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1908/ehrlich-bio.html|title=The Nobel Prize in Physiology or Medicine 1908|website=NobelPrize.org|access-date=13 June 2017|archive-date=14 August 2018|archive-url=https://web.archive.org/web/20180814214526/https://www.nobelprize.org/nobel_prizes/medicine/laureates/1908/ehrlich-bio.html|url-status=live}} Hata was nominated for the [[Nobel Prize in Chemistry]] in 1911 and for the Nobel Prize in Physiology or Medicine in 1912 and 1913.{{cite web|url=https://www.nobelprize.org/nomination/archive/show_people.php?id=3941|title=Nomination Archive|date=April 2020|website=NobelPrize.org|access-date=13 June 2017|archive-date=26 July 2020|archive-url=https://web.archive.org/web/20200726053416/https://www.nobelprize.org/nomination/archive/show_people.php?id=3941|url-status=live}} [158] => [159] => The first [[sulfonamide (medicine)|sulfonamide]] and the first [[wikt:systemic|systemically]] active antibacterial drug, [[Prontosil]], was developed by a research team led by [[Gerhard Domagk]] in 1932 or 1933 at the [[Bayer]] Laboratories of the [[IG Farben]] conglomerate in Germany, for which Domagk received the 1939 Nobel Prize in Physiology or Medicine.{{cite web |url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1939/press.html |title=Physiology or Medicine 1939 – Presentation Speech |publisher=Nobel Foundation |access-date=14 January 2015 |archive-date=14 January 2015 |archive-url=https://web.archive.org/web/20150114032532/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1939/press.html |url-status=live }} Sulfanilamide, the active drug of Prontosil, was not patentable as it had already been in use in the dye industry for some years. Prontosil had a relatively broad effect against [[Gram-positive]] [[coccus|cocci]], but not against [[Enterobacteriaceae|enterobacteria]]. Research was stimulated apace by its success. The discovery and development of this sulfonamide [[drug]] opened the era of antibacterials.{{cite journal | vauthors = Wright PM, Seiple IB, Myers AG | title = The evolving role of chemical synthesis in antibacterial drug discovery | journal = Angewandte Chemie | volume = 53 | issue = 34 | pages = 8840–69 | date = August 2014 | pmid = 24990531 | pmc = 4536949 | doi = 10.1002/anie.201310843 }}{{cite journal | vauthors = Aminov RI | title = A brief history of the antibiotic era: lessons learned and challenges for the future | journal = Frontiers in Microbiology | volume = 1 | pages = 134 | date = 1 January 2010 | pmid = 21687759 | pmc = 3109405 | doi = 10.3389/fmicb.2010.00134 | doi-access = free }} [160] => [161] => ===Penicillin and other natural antibiotics=== [162] => {{See also|History of penicillin}} [163] => [[File:Penicillin core.svg|thumb|upright=0.75|[[Penicillin]], discovered by [[Alexander Fleming]] in 1928]] [164] => Observations about the growth of some microorganisms inhibiting the growth of other microorganisms have been reported since the late 19th century. These observations of antibiosis between microorganisms led to the discovery of natural antibacterials. [[Louis Pasteur]] observed, "if we could intervene in the antagonism observed between some bacteria, it would offer perhaps the greatest hopes for therapeutics". [165] => [166] => In 1874, physician Sir [[William Roberts (physician)|William Roberts]] noted that cultures of the mould ''[[Penicillium glaucum]]'' that is used in the making of some types of [[blue cheese]] did not display bacterial contamination.{{cite journal | vauthors = Foster W, Raoult A | title = Early descriptions of antibiosis | journal = The Journal of the Royal College of General Practitioners | volume = 24 | issue = 149 | pages = 889–94 | date = December 1974 | pmid = 4618289 | pmc = 2157443 | quote = the first scientific observations of the antagonistic actions of various micro-organisms were made ... by William Roberts of Manchester (1874) and John Tyndall of London (1876). }} [167] => [168] => In 1895 [[Vincenzo Tiberio]], Italian physician, published a paper on the antibacterial power of some extracts of mold.{{Cite journal |vauthors=Bucci R, Gallì P |date=11 May 2012 |title=Public Health History Corner Vincenzo Tiberio: a misunderstood researcher |url=http://ijphjournal.it/article/view/5688 |journal=Italian Journal of Public Health |volume=8 |issue=4 |access-date=30 September 2017 |archive-date=20 September 2018 |archive-url=https://web.archive.org/web/20180920160850/https://ijphjournal.it/article/view/5688 |url-status=dead }} [169] => [170] => In 1897, doctoral student [[Ernest Duchesne]] submitted a dissertation, "{{lang|fr|Contribution à l'étude de la concurrence vitale chez les micro-organismes: antagonisme entre les moisissures et les microbes}}" (Contribution to the study of vital competition in micro-organisms: antagonism between moulds and microbes),{{cite book | vauthors = Duchesne E | translator = Witty M |title= Duchesne's Antagonism between molds and bacteria, an English Colloquial Translation| isbn= 978-1-5498-1696-3|date= 23 September 2017 | publisher = Independently Published }} the first known scholarly work to consider the therapeutic capabilities of moulds resulting from their anti-microbial activity. In his thesis, Duchesne proposed that bacteria and moulds engage in a perpetual battle for survival. Duchesne observed that ''[[Escherichia coli|E. coli]]'' was eliminated by ''Penicillium glaucum'' when they were both grown in the same culture. He also observed that when he [[inoculation|inoculated]] laboratory animals with lethal doses of [[typhoid]] bacilli together with ''Penicillium glaucum'', the animals did not contract typhoid. Duchesne's army service after getting his degree prevented him from doing any further research.{{cite book|vauthors=Straand J, Gradmann C, Simonsen GS, Lindbæk M|title=International Encyclopedia of Public Health: Antibiotic Development and Resistance|date=2008|publisher=Academic Press|pages=200|url=http://www.sciencedirect.com/topics/page/Arsphenamine|access-date=31 January 2017|archive-date=4 October 2016|archive-url=https://web.archive.org/web/20161004031024/http://www.sciencedirect.com/topics/page/Arsphenamine|url-status=live}} Duchesne died of [[tuberculosis]], a disease now treated by antibiotics. [171] => [172] => In 1928, Sir [[Alexander Fleming]] postulated the existence of [[penicillin]], a molecule produced by certain moulds that kills or stops the growth of certain kinds of bacteria. Fleming was working on a culture of [[pathogen|disease-causing]] bacteria when he noticed the [[spore]]s of a green mold, ''[[Penicillium rubens]]'',{{cite journal |vauthors=Pathak A, Nowell RW, Wilson CG, Ryan MJ, Barraclough TG|date=September 2020 |title=Comparative genomics of Alexander Fleming's original ''Penicillium'' isolate (IMI 15378) reveals sequence divergence of penicillin synthesis genes|journal=Scientific Reports|volume=10 |issue=1 |pages=Article 15705 |doi=10.1038/s41598-020-72584-5|pmid=32973216|pmc=7515868|bibcode=2020NatSR..1015705P }} in one of his [[agar plate|culture plates]]. He observed that the presence of the mould killed or prevented the growth of the bacteria.{{cite journal | vauthors = Tan SY, Tatsumura Y | title = Alexander Fleming (1881-1955): Discoverer of penicillin | journal = Singapore Medical Journal | volume = 56 | issue = 7 | pages = 366–7 | date = July 2015 | pmid = 26243971 | pmc = 4520913 | doi = 10.11622/smedj.2015105 }} Fleming postulated that the mould must secrete an antibacterial substance, which he named penicillin in 1928. Fleming believed that its antibacterial properties could be exploited for chemotherapy. He initially characterised some of its biological properties, and attempted to use a crude preparation to treat some infections, but he was unable to pursue its further development without the aid of trained chemists. [173] => [174] => [[Ernst Chain]], [[Howard Florey]] and [[Edward Abraham]] succeeded in purifying the first penicillin, [[penicillin G]], in 1942, but it did not become widely available outside the Allied military before 1945. Later, [[Norman Heatley]] developed the back extraction technique for efficiently purifying penicillin in bulk. The chemical structure of penicillin was first proposed by Abraham in 1942{{Cite journal|vauthors=Jones DS, Jones JH|date=1 December 2014|title=Sir Edward Penley Abraham CBE. 10 June 1913 – 9 May 1999|url=http://rsbm.royalsocietypublishing.org/content/60/5.1|journal=Biographical Memoirs of Fellows of the Royal Society|language=en|volume=60|pages=5–22|doi=10.1098/rsbm.2014.0002|issn=0080-4606|doi-access=free|access-date=10 May 2017|archive-date=26 November 2023|archive-url=https://web.archive.org/web/20231126055623/http://rsbm.royalsocietypublishing.org/content/60/5.1|url-status=live}} and then later confirmed by [[Dorothy Crowfoot Hodgkin]] in 1945. Purified penicillin displayed potent antibacterial activity against a wide range of bacteria and had low toxicity in humans. Furthermore, its activity was not inhibited by biological constituents such as pus, unlike the synthetic [[sulfonamides]]. (see below) The development of penicillin led to renewed interest in the search for antibiotic compounds with similar efficacy and safety. For their successful development of penicillin, which Fleming had accidentally discovered but could not develop himself, as a therapeutic drug, Chain and Florey shared the 1945 [[Nobel Prize in Medicine]] with Fleming.{{cite web |url=https://www.nobelprize.org/prizes/medicine/1945/summary/ |access-date=13 January 2018 |title=The Nobel Prize in Physiology or Medicine 1945 |publisher=The Nobel Prize Organization |archive-date=23 May 2020 |archive-url=https://web.archive.org/web/20200523072137/https://www.nobelprize.org/prizes/medicine/1945/summary/ |url-status=live }} [175] => [176] => Florey credited [[René Dubos]] with pioneering the approach of deliberately and systematically searching for antibacterial compounds, which had led to the discovery of gramicidin and had revived Florey's research in penicillin. In 1939, coinciding with the start of [[World War II]], Dubos had reported the discovery of the first naturally derived antibiotic, [[tyrothricin]], a compound of 20% [[gramicidin]] and 80% [[tyrocidine]], from ''Bacillus brevis''. It was one of the first commercially manufactured antibiotics and was very effective in treating wounds and ulcers during World War II. Gramicidin, however, could not be used systemically because of toxicity. Tyrocidine also proved too toxic for systemic usage. Research results obtained during that period were not shared between the [[Axis powers|Axis]] and the [[Allied powers of World War II|Allied powers]] during World War II and limited access during the [[Cold War]].{{cite journal | vauthors = Capocci M | title = Cold drugs. Circulation, production and intelligence of antibiotics in post-WWII years | journal = Medicina Nei Secoli | volume = 26 | issue = 2 | pages = 401–21 | date = 1 January 2014 | pmid = 26054208 }} [177] => [178] => ===Late 20th century=== [179] => During the mid-20th century, the number of new antibiotic substances introduced for medical use increased significantly. From 1935 to 1968, 12 new classes were launched. However, after this, the number of new classes dropped markedly, with only two new classes introduced between 1969 and 2003.{{cite journal | vauthors = Conly J, Johnston B | title = Where are all the new antibiotics? The new antibiotic paradox | journal = The Canadian Journal of Infectious Diseases & Medical Microbiology | volume = 16 | issue = 3 | pages = 159–60 | date = May 2005 | pmid = 18159536 | pmc = 2095020 | doi = 10.1155/2005/892058 | doi-access = free }} [180] => [181] => ==Antibiotic pipeline== [182] => Both the WHO and the [[Infectious Disease Society of America]] report that the weak antibiotic pipeline does not match bacteria's increasing ability to develop resistance.Antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline, including tuberculosis. Geneva: World Health Organization; 2017 (WHO/EMP/IAU/2017.12). Licence: CC BY-NC-SA 3.0 IGO.{{cite journal | vauthors = Boucher HW, Talbot GH, Benjamin DK, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D | title = 10 x '20 Progress--development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America | journal = Clinical Infectious Diseases | volume = 56 | issue = 12 | pages = 1685–94 | date = June 2013 | pmid = 23599308 | pmc = 3707426 | doi = 10.1093/cid/cit152 }} The Infectious Disease Society of America report noted that the number of new antibiotics approved for marketing per year had been declining and identified seven antibiotics against the [[Gram-negative bacilli]] currently in [[phases of clinical research#Phase II|phase 2]] or [[phases of clinical research#Phase III|phase 3]] clinical trials. However, these drugs did not address the entire spectrum of resistance of Gram-negative bacilli.{{cite news |title=Drug pipeline for worst superbugs 'on life support': report |vauthors=Steenhuysen J |url=http://in.reuters.com/article/us-antibiotics-superbugs-idINBRE93H05520130418 |work=Reuters |date=18 April 2013 |access-date=23 June 2013 |archive-date=25 December 2015 |archive-url=https://web.archive.org/web/20151225054947/http://in.reuters.com/article/us-antibiotics-superbugs-idINBRE93H05520130418 |url-status=dead }}{{cite journal | vauthors = Boucher HW, Talbot GH, Benjamin DK, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D | title = 10 x '20 Progress--development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America | journal = Clinical Infectious Diseases | volume = 56 | issue = 12 | pages = 1685–94 | date = June 2013 | pmid = 23599308 | pmc = 3707426 | doi = 10.1093/cid/cit152 | others = Infectious Diseases Society of America }} According to the WHO fifty one new therapeutic entities - antibiotics (including combinations), are in phase 1-3 clinical trials as of May 2017. Antibiotics targeting multidrug-resistant Gram-positive pathogens remains a high priority.{{cite journal | vauthors = Liu J, Bedell TA, West JG, Sorensen EJ | title = Design and Synthesis of Molecular Scaffolds with Anti-infective Activity | journal = Tetrahedron | volume = 72 | issue = 25 | pages = 3579–3592 | date = June 2016 | pmid = 27284210 | pmc = 4894353 | doi = 10.1016/j.tet.2016.01.044 }} [183] => [184] => A few antibiotics have received marketing authorization in the last seven years. The cephalosporin ceftaroline and the lipoglycopeptides oritavancin and telavancin have been approved for the treatment of acute bacterial skin and skin structure infection and community-acquired bacterial pneumonia.{{cite journal | vauthors = Fernandes P, Martens E | title = Antibiotics in late clinical development | journal = Biochemical Pharmacology | volume = 133 | pages = 152–163 | date = June 2017 | pmid = 27687641 | doi = 10.1016/j.bcp.2016.09.025 | doi-access = free }} The lipoglycopeptide dalbavancin and the oxazolidinone tedizolid has also been approved for use for the treatment of acute bacterial skin and skin structure infection. The first in a new class of narrow spectrum [[macrocycle|macrocyclic]] antibiotics, fidaxomicin, has been approved for the treatment of ''C. difficile'' colitis. New cephalosporin-lactamase inhibitor combinations also approved include ceftazidime-avibactam and ceftolozane-avibactam for complicated urinary tract infection and intra-abdominal infection. [185] => [186] => {{Columns-list|colwidth=30em| [187] => * [[Ceftolozane]]/[[tazobactam]] (CXA-201; CXA-101/tazobactam): [[Antipseudomonal]] [[cephalosporin]]/[[β-lactamase]] inhibitor combination (cell wall synthesis inhibitor). FDA approved on 19 December 2014. [188] => * [[Ceftazidime]]/[[avibactam]] (ceftazidime/NXL104): antipseudomonal cephalosporin/β-lactamase inhibitor combination (cell wall synthesis inhibitor).{{cite journal | vauthors = Butler MS, Paterson DL | title = Antibiotics in the clinical pipeline in October 2019 | journal = The Journal of Antibiotics | volume = 73 | issue = 6 | pages = 329–364 | date = June 2020 | pmid = 32152527 | pmc = 7223789 | doi = 10.1038/s41429-020-0291-8 }} FDA approved on 25 February 2015. [189] => * [[Ceftaroline]]/avibactam (CPT-avibactam; ceftaroline/NXL104): Anti-[[MRSA]] cephalosporin/ β-lactamase inhibitor combination (cell wall synthesis inhibitor). [190] => * [[Cefiderocol]]: [[cephalosporin]] siderophore. FDA approved on 14 November 2019. [191] => * [[Imipenem]]/relebactam: [[carbapenem]]/ β-lactamase inhibitor combination (cell wall synthesis inhibitor). FDA approved on 16 July 2019. [192] => * [[Meropenem/vaborbactam]]: [[carbapenem]]/ β-lactamase inhibitor combination (cell wall synthesis inhibitor). FDA approved on 29 August 2017. [193] => * [[Delafloxacin]]: [[quinolone]] (inhibitor of DNA synthesis). FDA approved on 19 June 2017. [194] => * [[Plazomicin]] (ACHN-490): semi-synthetic [[aminoglycoside]] derivative ([[protein synthesis inhibitor]]). FDA approved 25 June 2018. [195] => * [[Eravacycline]] (TP-434): synthetic [[tetracycline]] derivative (protein synthesis inhibitor targeting bacterial ribosomes). FDA approved on 27 August 2018. [196] => * [[Omadacycline]]: semi-synthetic [[tetracycline]] derivative (protein synthesis inhibitor targeting bacterial ribosomes). FDA approved on 2 October 2018. [197] => * [[Lefamulin]]: pleuromutilin antibiotic. FDA approved on 19 August 2019. [198] => * [[Brilacidin]] (PMX-30063): peptide defense protein mimetic (cell membrane disruption). In phase 2. [199] => * [[Zosurabalpin]] (RG-6006): lipopolysaccharide transport inhibitor. In phase 1.{{cite journal |last1=Zampaloni |first1=C |last2=Mattei |first2=P |last3=Bleicher |first3=K |last4=Winther |first4=L |last5=Thäte |first5=C |last6=Bucher |first6=C |last7=Adam |first7=JM |last8=Alanine |first8=A |last9=Amrein |first9=KE |last10=Baidin |first10=V |last11=Bieniossek |first11=C |last12=Bissantz |first12=C |last13=Boess |first13=F |last14=Cantrill |first14=C |last15=Clairfeuille |first15=T |last16=Dey |first16=F |last17=Di Giorgio |first17=P |last18=du Castel |first18=P |last19=Dylus |first19=D |last20=Dzygiel |first20=P |last21=Felici |first21=A |last22=García-Alcalde |first22=F |last23=Haldimann |first23=A |last24=Leipner |first24=M |last25=Leyn |first25=S |last26=Louvel |first26=S |last27=Misson |first27=P |last28=Osterman |first28=A |last29=Pahil |first29=K |last30=Rigo |first30=S |last31=Schäublin |first31=A |last32=Scharf |first32=S |last33=Schmitz |first33=P |last34=Stoll |first34=T |last35=Trauner |first35=A |last36=Zoffmann |first36=S |last37=Kahne |first37=D |last38=Young |first38=JAT |last39=Lobritz |first39=MA |last40=Bradley |first40=KA |title=A novel antibiotic class targeting the lipopolysaccharide transporter. |journal=Nature |date=3 January 2024 |volume=625 |issue=7995 |pages=566–571 |doi=10.1038/s41586-023-06873-0 |pmid=38172634|doi-access=free |pmc=10794144 |bibcode=2024Natur.625..566Z }}{{cite journal |last1=Pahil |first1=KS |last2=Gilman |first2=MSA |last3=Baidin |first3=V |last4=Clairfeuille |first4=T |last5=Mattei |first5=P |last6=Bieniossek |first6=C |last7=Dey |first7=F |last8=Muri |first8=D |last9=Baettig |first9=R |last10=Lobritz |first10=M |last11=Bradley |first11=K |last12=Kruse |first12=AC |last13=Kahne |first13=D |title=A new antibiotic traps lipopolysaccharide in its intermembrane transporter. |journal=Nature |date=3 January 2024 |volume=625 |issue=7995 |pages=572–577 |doi=10.1038/s41586-023-06799-7 |pmid=38172635|doi-access=free |pmc=10794137 |bibcode=2024Natur.625..572P }}}} [200] => [201] => Possible improvements include clarification of clinical trial regulations by FDA. Furthermore, appropriate economic incentives could persuade pharmaceutical companies to invest in this endeavor. In the US, the [[Antibiotic Development to Advance Patient Treatment]] (ADAPT) Act was introduced with the aim of fast tracking the [[drug development]] of antibiotics to combat the growing threat of 'superbugs'. Under this Act, FDA can approve antibiotics and antifungals treating life-threatening infections based on smaller clinical trials. The [[Centers for Disease Control and Prevention|CDC]] will monitor the use of antibiotics and the emerging resistance, and publish the data. The FDA antibiotics labeling process, 'Susceptibility Test Interpretive Criteria for Microbial Organisms' or 'breakpoints', will provide accurate data to healthcare professionals.{{cite web|url=http://assets.fiercemarkets.net/public/lifesciences/HR3742.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://assets.fiercemarkets.net/public/lifesciences/HR3742.pdf |archive-date=2022-10-09 |url-status=live|title=Antibiotic Development to Advance Patient Treatment Act of 2013|publisher=US Congress|date=12 December 2013}} According to Allan Coukell, senior director for health programs at The Pew Charitable Trusts, "By allowing drug developers to rely on smaller datasets, and clarifying FDA's authority to tolerate a higher level of uncertainty for these drugs when making a risk/benefit calculation, ADAPT would make the clinical trials more feasible."{{cite news|vauthors=Clarke T|title=U.S. Congress urged to pass bill to speed development of antibiotics|url=https://www.reuters.com/article/us-usa-congress-antibiotics-idUSKBN0HE25W20140919|agency=Reuters|access-date=19 September 2014|newspaper=Reuters|date=19 September 2014|archive-date=9 December 2015|archive-url=https://web.archive.org/web/20151209012151/http://www.reuters.com/article/us-usa-congress-antibiotics-idUSKBN0HE25W20140919|url-status=live}} [202] => [203] => === Replenishing the antibiotic pipeline and developing other new therapies === [204] => Because antibiotic-resistant bacterial strains continue to emerge and spread, there is a constant need to develop new antibacterial treatments. Current strategies include traditional chemistry-based approaches such as [[natural product]]-based [[drug discovery]],{{cite journal | vauthors = Moloney MG | title = Natural Products as a Source for Novel Antibiotics | journal = Trends in Pharmacological Sciences | volume = 37 | issue = 8 | pages = 689–701 | date = August 2016 | pmid = 27267698 | doi = 10.1016/j.tips.2016.05.001 | s2cid = 3537191 | url = https://ora.ox.ac.uk/objects/uuid:53d851f3-3719-4ac3-aa5a-b70ac82e4115 | access-date = 25 August 2020 | archive-date = 27 July 2021 | archive-url = https://web.archive.org/web/20210727100821/https://ora.ox.ac.uk/objects/uuid:53d851f3-3719-4ac3-aa5a-b70ac82e4115 | url-status = live }}{{cite journal | vauthors = Cushnie TP, Cushnie B, Echeverría J, Fowsantear W, Thammawat S, Dodgson JL, Law S, Clow SM | title = Bioprospecting for Antibacterial Drugs: a Multidisciplinary Perspective on Natural Product Source Material, Bioassay Selection and Avoidable Pitfalls | journal = Pharmaceutical Research | volume = 37 | issue = 7 | pages = 125 | date = June 2020 | pmid = 32529587 | doi = 10.1007/s11095-020-02849-1 | url = https://zenodo.org/record/3909383 | s2cid = 219590658 | access-date = 17 September 2020 | archive-date = 2 December 2020 | archive-url = https://web.archive.org/web/20201202010902/https://zenodo.org/record/3909383 | url-status = live }} newer chemistry-based approaches such as [[drug design]],{{cite journal | vauthors = Mashalidis EH, Lee SY | title = Structures of Bacterial MraY and Human GPT Provide Insights into Rational Antibiotic Design | journal = Journal of Molecular Biology | volume = 432 | issue = 18 | pages = 4946–4963 | date = August 2020 | pmid = 32199982 | doi = 10.1016/j.jmb.2020.03.017 | pmc = 8351759 }}{{cite journal | vauthors = Xia J, Feng B, Wen G, Xue W, Ma G, Zhang H, Wu S | title = Bacterial Lipoprotein Biosynthetic Pathway as a Potential Target for Structure-based Design of Antibacterial Agents | journal = Current Medicinal Chemistry | volume = 27 | issue = 7 | pages = 1132–1150 | date = July 2020 | pmid = 30360704 | doi = 10.2174/0929867325666181008143411 | s2cid = 53097836 }} traditional biology-based approaches such as [[immunoglobulin therapy]], and experimental biology-based approaches such as [[phage therapy]],{{cite journal | vauthors = Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM | title = Phage treatment of human infections | journal = Bacteriophage | volume = 1 | issue = 2 | pages = 66–85 | date = March 2011 | pmid = 22334863 | pmc = 3278644 | doi = 10.4161/bact.1.2.15845 }}{{cite journal | vauthors = Czaplewski L, Bax R, Clokie M, Dawson M, Fairhead H, Fischetti VA, Foster S, Gilmore BF, Hancock RE, Harper D, Henderson IR, Hilpert K, Jones BV, Kadioglu A, Knowles D, Ólafsdóttir S, Payne D, Projan S, Shaunak S, Silverman J, Thomas CM, Trust TJ, Warn P, Rex JH | title = Alternatives to antibiotics-a pipeline portfolio review | journal = The Lancet. Infectious Diseases | volume = 16 | issue = 2 | pages = 239–51 | date = February 2016 | pmid = 26795692 | doi = 10.1016/S1473-3099(15)00466-1 | s2cid = 21677232 | url = http://eprints.brighton.ac.uk/14828/1/Alternatives%20to%20Antibiotics%20-%20a%20pipeline%20portfolio%20review.pdf | access-date = 22 November 2018 | archive-date = 17 August 2019 | archive-url = https://web.archive.org/web/20190817222112/http://eprints.brighton.ac.uk/14828/1/Alternatives%20to%20Antibiotics%20-%20a%20pipeline%20portfolio%20review.pdf | url-status = live }} [[fecal microbiota transplant]]s,{{cite journal | vauthors = Moayyedi P, Yuan Y, Baharith H, Ford AC | title = Faecal microbiota transplantation for ''Clostridium difficile''-associated diarrhoea: a systematic review of randomised controlled trials | journal = The Medical Journal of Australia | volume = 207 | issue = 4 | pages = 166–172 | date = August 2017 | pmid = 28814204 | doi = 10.5694/mja17.00295 | s2cid = 24780848 }} [[antisense RNA]]-based treatments, and [[CRISPR|CRISPR-Cas9]]-based treatments.{{cite journal | vauthors = Ghosh C, Sarkar P, Issa R, Haldar J | title = Alternatives to Conventional Antibiotics in the Era of Antimicrobial Resistance | journal = Trends in Microbiology | volume = 27 | issue = 4 | pages = 323–338 | date = April 2019 | pmid = 30683453 | doi = 10.1016/j.tim.2018.12.010 | s2cid = 59274650}}{{cite journal | vauthors = Vrancianu CO, Gheorghe I, Czobor IB, Chifiriuc MC | title = Antibiotic Resistance Profiles, Molecular Mechanisms and Innovative Treatment Strategies of ''Acinetobacter baumannii'' | journal = Microorganisms | volume = 8 | issue = 6 | pages = Article 935 | date = June 2020 | pmid = 32575913 | pmc = 7355832 | doi = 10.3390/microorganisms8060935 | doi-access = free }} [205] => [206] => ==== Natural product-based antibiotic discovery ==== [207] => {{See also|Bioprospecting}} [208] => {{multiple image|perrow = 2|total_width=275| image1 = Streptomyces sp 01.png| image2 = Acremonium falciforme PHIL 4167 lores.jpg| image3 = Hydrastis.jpg| image4 = Agelas tubulata cropped.jpg|footer = Bacteria, fungi, plants, animals and other organisms are being screened in the search for new antibiotics.}} [209] => Most of the antibiotics in current use are [[natural product]]s or natural product derivatives,{{cite journal | vauthors = Hutchings MI, Truman AW, Wilkinson B | title = Antibiotics: past, present and future | journal = Current Opinion in Microbiology | volume = 51 | pages = 72–80 | date = October 2019 | pmid = 31733401 | doi = 10.1016/j.mib.2019.10.008 | doi-access = free }} and [[bacteria]]l,{{cite journal | vauthors = Holmes NA, Devine R, Qin Z, Seipke RF, Wilkinson B, Hutchings MI | title = Complete genome sequence of Streptomyces formicae KY5, the formicamycin producer | journal = Journal of Biotechnology | volume = 265 | pages = 116–118 | date = January 2018 | pmid = 29191667 | doi = 10.1016/j.jbiotec.2017.11.011 | doi-access = free }}{{Cite web|url=http://ww3.hutchingslab.uk/?sub1=6f4e1dc8-2273-11ed-9fdf-59bd5baf79e5|title=hutchingslab Resources and Information.|website=ww3.hutchingslab.uk|access-date=22 August 2022|archive-date=7 April 2023|archive-url=https://web.archive.org/web/20230407153239/http://ww3.hutchingslab.uk/?sub1=6f4e1dc8-2273-11ed-9fdf-59bd5baf79e5|url-status=dead}} [[fungal]],{{cite journal | vauthors = Bills GF, Gloer JB, An Z | title = Coprophilous fungi: antibiotic discovery and functions in an underexplored arena of microbial defensive mutualism | journal = Current Opinion in Microbiology | volume = 16 | issue = 5 | pages = 549–65 | date = October 2013 | pmid = 23978412 | doi = 10.1016/j.mib.2013.08.001 }} [[plant]]{{cite journal | vauthors = Kenny CR, Furey A, Lucey B | title = A post-antibiotic era looms: can plant natural product research fill the void? | journal = British Journal of Biomedical Science | volume = 72 | issue = 4 | pages = 191–200 | year = 2015 | pmid = 26738402 | doi = 10.1080/09674845.2015.11665752 | s2cid = 41282022 }}{{cite journal | vauthors = Al-Habib A, Al-Saleh E, Safer AM, Afzal M | title = Bactericidal effect of grape seed extract on methicillin-resistant Staphylococcus aureus (MRSA) | journal = The Journal of Toxicological Sciences | volume = 35 | issue = 3 | pages = 357–64 | date = June 2010 | pmid = 20519844 | doi = 10.2131/jts.35.357 | doi-access = free }}{{cite journal | vauthors = Smullen J, Koutsou GA, Foster HA, Zumbé A, Storey DM | title = The antibacterial activity of plant extracts containing polyphenols against Streptococcus mutans | journal = Caries Research | volume = 41 | issue = 5 | pages = 342–9 | year = 2007 | pmid = 17713333 | doi = 10.1159/000104791 | s2cid = 44317367 }}{{cite journal | vauthors = Monte J, Abreu AC, Borges A, Simões LC, Simões M | title = Antimicrobial Activity of Selected Phytochemicals against Escherichia coli and Staphylococcus aureus and Their Biofilms | journal = Pathogens | volume = 3 | issue = 2 | pages = 473–98 | date = June 2014 | pmid = 25437810 | pmc = 4243457 | doi = 10.3390/pathogens3020473 | doi-access = free }} and [[animal]]{{cite journal | vauthors = Tanaka N, Kusama T, Kashiwada Y, Kobayashi J | title = Bromopyrrole Alkaloids from Okinawan Marine Sponges Agelas spp | journal = Chemical & Pharmaceutical Bulletin | volume = 64 | issue = 7 | pages = 691–4 | date = April 2016 | pmid = 27373625 | doi = 10.1248/cpb.c16-00245 | doi-access = free }} extracts are being screened in the search for new antibiotics. Organisms may be selected for testing based on [[ecological]], [[ethnomedical]], [[genomic]], or [[historical]] rationales. [[Medicinal plants]], for example, are screened on the basis that they are used by traditional healers to prevent or cure infection and may therefore contain antibacterial compounds.{{cite journal | vauthors = Cowan MM | title = Plant products as antimicrobial agents | journal = Clinical Microbiology Reviews | volume = 12 | issue = 4 | pages = 564–82 | date = October 1999 | pmid = 10515903 | pmc = 88925 | doi = 10.1128/CMR.12.4.564 }} Also, soil bacteria are screened on the basis that, historically, they have been a very rich source of antibiotics (with 70 to 80% of antibiotics in current use derived from the [[actinomycetes]]).{{cite journal | vauthors = Mahajan GB, Balachandran L | title = Sources of antibiotics: Hot springs | journal = Biochemical Pharmacology | volume = 134 | pages = 35–41 | date = June 2017 | pmid = 27890726 | doi = 10.1016/j.bcp.2016.11.021 }} [210] => [211] => In addition to screening natural products for direct antibacterial activity, they are sometimes screened for the ability to suppress [[antimicrobial resistance|antibiotic resistance]] and [[antibiotic tolerance]].{{cite journal | vauthors = Abreu AC, McBain AJ, Simões M | title = Plants as sources of new antimicrobials and resistance-modifying agents | journal = Natural Product Reports | volume = 29 | issue = 9 | pages = 1007–21 | date = September 2012 | pmid = 22786554 | doi = 10.1039/c2np20035j }} For example, some [[secondary metabolites]] inhibit [[drug efflux]] pumps, thereby increasing the concentration of antibiotic able to reach its cellular target and decreasing bacterial resistance to the antibiotic.{{cite journal | vauthors = Marquez B | title = Bacterial efflux systems and efflux pumps inhibitors | journal = Biochimie | volume = 87 | issue = 12 | pages = 1137–47 | date = December 2005 | pmid = 15951096 | doi = 10.1016/j.biochi.2005.04.012 }} Natural products known to inhibit bacterial efflux pumps include the [[alkaloid]] [[lysergol]],{{cite journal | vauthors = Cushnie TP, Cushnie B, Lamb AJ | title = Alkaloids: an overview of their antibacterial, antibiotic-enhancing and antivirulence activities | journal = International Journal of Antimicrobial Agents | volume = 44 | issue = 5 | pages = 377–86 | date = November 2014 | pmid = 25130096 | doi = 10.1016/j.ijantimicag.2014.06.001 | s2cid = 205171789 | url = https://zenodo.org/record/1004771 | access-date = 19 July 2019 | archive-date = 18 August 2020 | archive-url = https://web.archive.org/web/20200818103721/https://zenodo.org/record/1004771 | url-status = live }} the [[carotenoid]]s [[capsanthin]] and [[capsorubin]],{{cite journal | vauthors = Molnár J, Engi H, Hohmann J, Molnár P, Deli J, Wesolowska O, Michalak K, Wang Q | title = Reversal of multidrug resistance by natural substances from plants | journal = Current Topics in Medicinal Chemistry | volume = 10 | issue = 17 | pages = 1757–68 | year = 2010 | pmid = 20645919 | doi = 10.2174/156802610792928103 }} and the [[flavonoid]]s [[rotenone]] and [[chrysin]]. Other natural products, this time [[primary metabolite]]s rather than secondary metabolites, have been shown to eradicate antibiotic tolerance. For example, [[glucose]], [[mannitol]], and [[fructose]] reduce antibiotic tolerance in ''[[Escherichia coli]]'' and ''[[Staphylococcus aureus]]'', rendering them more susceptible to killing by [[aminoglycoside]] antibiotics.{{cite journal | vauthors = Allison KR, Brynildsen MP, Collins JJ | title = Metabolite-enabled eradication of bacterial persisters by aminoglycosides | journal = Nature | volume = 473 | issue = 7346 | pages = 216–20 | date = May 2011 | pmid = 21562562 | pmc = 3145328 | doi = 10.1038/nature10069 | bibcode = 2011Natur.473..216A }} [212] => [213] => Natural products may be screened for the ability to suppress bacterial [[virulence factor]]s too. Virulence factors are molecules, cellular structures and regulatory systems that enable bacteria to evade the body's immune defenses (e.g. [[urease]], [[staphyloxanthin]]), move towards, attach to, and/or invade human cells (e.g. [[type IV pili]], [[Bacterial adhesin|adhesin]]s, [[internalin]]s), coordinate the activation of virulence genes (e.g. [[quorum sensing]]), and cause disease (e.g. [[exotoxin]]s).{{cite journal | vauthors = Theuretzbacher U, Piddock LJ | title = Non-traditional Antibacterial Therapeutic Options and Challenges | journal = Cell Host & Microbe | volume = 26 | issue = 1 | pages = 61–72 | date = July 2019 | pmid = 31295426 | doi = 10.1016/j.chom.2019.06.004 | doi-access = free }}{{cite journal | vauthors = Cushnie TP, Lamb AJ | title = Recent advances in understanding the antibacterial properties of flavonoids | journal = International Journal of Antimicrobial Agents | volume = 38 | issue = 2 | pages = 99–107 | date = August 2011 | pmid = 21514796 | doi = 10.1016/j.ijantimicag.2011.02.014 | url = https://zenodo.org/record/1003263 | access-date = 19 July 2019 | archive-date = 26 July 2020 | archive-url = https://web.archive.org/web/20200726062743/https://zenodo.org/record/1003263 | url-status = live }}{{cite journal | vauthors = Mok N, Chan SY, Liu SY, Chua SL | title = Vanillin inhibits PqsR-mediated virulence in Pseudomonas aeruginosa | journal = Food & Function | volume = 11 | issue = 7 | pages = 6496–6508 | date = July 2020 | pmid = 32697213 | doi = 10.1039/D0FO00046A | hdl = 10397/88306 | s2cid = 220699939 | hdl-access = free }} Examples of natural products with antivirulence activity include the flavonoid [[epigallocatechin gallate]] (which inhibits [[listeriolysin O]]), the [[quinone]] tetrangomycin (which inhibits staphyloxanthin),{{cite journal | vauthors = Xue L, Chen YY, Yan Z, Lu W, Wan D, Zhu H | title = Staphyloxanthin: a potential target for antivirulence therapy | journal = Infection and Drug Resistance | volume = 12 | pages = 2151–2160 | date = July 2019 | pmid = 31410034 | pmc = 6647007 | doi = 10.2147/IDR.S193649 | doi-access = free }} and the [[sesquiterpene]] zerumbone (which inhibits ''[[Acinetobacter baumannii]]'' [[Bacteria#Movement|motility]]).{{cite journal | vauthors = Kim HR, Shin DS, Jang HI, Eom YB | title = Anti-biofilm and anti-virulence effects of zerumbone against ''Acinetobacter baumannii'' | journal = Microbiology | volume = 166 | issue = 8 | pages = 717–726 | date = August 2020 | pmid = 32463353 | doi = 10.1099/mic.0.000930 | doi-access = free }} [214] => [215] => ==== Immunoglobulin therapy ==== [216] => {{Main|Monoclonal antibody therapy}} [217] => Antibodies ([[anti-tetanus immunoglobulin]]) have been used in the treatment and prevention of [[tetanus]] since the 1910s,{{cite book| vauthors = Plotkin SA, Orenstein WA, Offit PA |author-link2=Walter Orenstein |author-link1=Stanley Plotkin |author-link3=Paul Offit|title=Vaccines|date=2012|publisher=Elsevier Health Sciences|isbn=978-1-4557-0090-5|pages=103, 757|url=https://books.google.com/books?id=hoigDQ6vdDQC&pg=PA103|language=en|url-status=live|archive-url=https://web.archive.org/web/20170109021821/https://books.google.ca/books?id=hoigDQ6vdDQC&pg=PA103|archive-date=2017-01-09}} and this approach continues to be a useful way of controlling bacterial diseases. The [[monoclonal antibody]] [[bezlotoxumab]], for example, has been approved by the [[Food and Drug Administration|US FDA]] and [[European Medicines Agency|EMA]] for recurrent [[Clostridium difficile infection|''Clostridium difficile'' infection]], and other monoclonal antibodies are in development (e.g. AR-301 for the adjunctive treatment of ''S. aureus'' [[ventilator-associated pneumonia]]). Antibody treatments act by binding to and neutralizing bacterial exotoxins and other virulence factors. [218] => [219] => ==== Phage therapy ==== [220] => {{Main|Phage therapy}} [221] => [[Image: Phage injecting its genome into bacteria.svg|thumb|upright=0.74|right| Phage injecting its genome into a bacterium. Viral replication and bacterial cell lysis will ensue.]] [222] => [[Phage therapy]] is under investigation as a method of treating antibiotic-resistant strains of bacteria. Phage therapy involves infecting bacterial pathogens with [[virus]]es. [[Bacteriophage]]s and their host ranges are extremely specific for certain bacteria, thus, unlike antibiotics, they do not disturb the host organism's [[intestinal microbiota]]. Bacteriophages, also known as phages, infect and kill bacteria primarily during lytic cycles.{{cite journal | vauthors = Sulakvelidze A, Alavidze Z, Morris JG | title = Bacteriophage therapy | journal = Antimicrobial Agents and Chemotherapy | volume = 45 | issue = 3 | pages = 649–59 | date = March 2001 | pmid = 11181338 | pmc = 90351 | doi = 10.1128/aac.45.3.649-659.2001 }} Phages insert their DNA into the bacterium, where it is transcribed and used to make new phages, after which the cell will lyse, releasing new phage that are able to infect and destroy further bacteria of the same strain. The high specificity of phage protects [[Mutualism (biology)|"good"]] bacteria from destruction.{{cite journal | vauthors = Dunne M, Rupf B, Tala M, Qabrati X, Ernst P, Shen Y, Sumrall E, Heeb L, Plückthun A, Loessner MJ, Kilcher S | title = Reprogramming Bacteriophage Host Range through Structure-Guided Design of Chimeric Receptor Binding Proteins | journal = Cell Reports | volume = 29 | issue = 5 | pages = 1336–1350.e4 | date = October 2019 | pmid = 31665644 | s2cid = 204967212 | doi = 10.1016/j.celrep.2019.09.062 | doi-access = free | hdl = 20.500.11850/374453 | hdl-access = free }} [223] => [224] => Some disadvantages to the use of bacteriophages also exist, however. Bacteriophages may harbour virulence factors or toxic genes in their genomes and, prior to use, it may be prudent to identify genes with similarity to known virulence factors or toxins by genomic sequencing. In addition, the oral and [[intravenous|IV]] administration of phages for the eradication of bacterial infections poses a much higher safety risk than topical application. Also, there is the additional concern of uncertain immune responses to these large antigenic cocktails.{{citation needed|date=January 2021}} [225] => [226] => There are considerable [[Regulation of therapeutic goods|regulatory]] hurdles that must be cleared for such therapies.{{cite journal | vauthors = Gill EE, Franco OL, Hancock RE | title = Antibiotic adjuvants: diverse strategies for controlling drug-resistant pathogens | journal = Chemical Biology & Drug Design | volume = 85 | issue = 1 | pages = 56–78 | date = January 2015 | pmid = 25393203 | pmc = 4279029 | doi = 10.1111/cbdd.12478 }} Despite numerous challenges, the use of bacteriophages as a replacement for antimicrobial agents against MDR pathogens that no longer respond to conventional antibiotics, remains an attractive option.{{cite journal | vauthors = Opal SM | title = Non-antibiotic treatments for bacterial diseases in an era of progressive antibiotic resistance | journal = Critical Care | volume = 20 | issue = 1 | pages = 397 | date = December 2016 | pmid = 27978847 | pmc = 5159963 | doi = 10.1186/s13054-016-1549-1 | doi-access = free }} [227] => [228] => ==== Fecal microbiota transplants ==== [229] => {{Main| Fecal microbiota transplant }} [230] => [[Image: E coli at 10000x, original.jpg|thumb|upright=0.74|right|Fecal microbiota transplants are an experimental treatment for ''C. difficile'' infection.]] [231] => Fecal microbiota transplants involve transferring the full [[intestinal microbiota]] from a healthy human donor (in the form of [[feces|stool]]) to patients with [[Clostridium difficile infection|''C. difficile'' infection]]. Although this procedure has not been officially approved by the [[Food and Drug Administration|US FDA]], its use is permitted under some conditions in patients with antibiotic-resistant ''C. difficile'' infection. Cure rates are around 90%, and work is underway to develop stool [[biobank|banks]], standardized products, and methods of [[Oral administration|oral delivery]]. Fecal microbiota transplantation has also been used more recently for inflammatory bowel diseases.{{cite journal | vauthors = D'Odorico I, Di Bella S, Monticelli J, Giacobbe DR, Boldock E, Luzzati R | title = Role of fecal microbiota transplantation in inflammatory bowel disease | journal = Journal of Digestive Diseases | volume = 19 | issue = 6 | pages = 322–334 | date = June 2018 | pmid = 29696802 | doi = 10.1111/1751-2980.12603 | s2cid = 24461869 }} [232] => [233] => ==== Antisense RNA-based treatments ==== [234] => {{see| Antisense RNA }} [235] => Antisense RNA-based treatment (also known as gene silencing therapy) involves (a) identifying bacterial [[gene]]s that encode essential [[protein]]s (e.g. the ''[[Pseudomonas aeruginosa]]'' genes ''acpP'', ''lpxC'', and ''rpsJ''), (b) synthesizing single stranded [[RNA]] that is complementary to the [[messenger RNA|mRNA]] encoding these essential proteins, and (c) delivering the single stranded RNA to the infection site using cell-penetrating peptides or [[liposome]]s. The antisense RNA then [[Nucleic acid hybridization|hybridizes]] with the bacterial mRNA and blocks its [[Translation (biology)|translation]] into the essential protein. Antisense RNA-based treatment has been shown to be effective in ''in vivo'' models of ''P. aeruginosa'' [[lung infection|pneumonia]]. [236] => [237] => In addition to silencing essential bacterial genes, antisense RNA can be used to silence bacterial genes responsible for antibiotic resistance. For example, antisense RNA has been developed that silences the ''S. aureus'' ''[[mecA]]'' gene (the gene that encodes modified [[penicillin-binding protein]] 2a and renders ''S. aureus'' strains [[Methicillin-resistant Staphylococcus aureus|methicillin-resistant]]). Antisense RNA targeting ''mecA'' mRNA has been shown to restore the susceptibility of methicillin-resistant staphylococci to [[oxacillin]] in both ''in vitro'' and ''in vivo'' studies. [238] => [239] => ==== CRISPR-Cas9-based treatments ==== [240] => In the early 2000s, a system was discovered that enables bacteria to defend themselves against invading viruses. The system, known as CRISPR-Cas9, consists of (a) an enzyme that destroys DNA (the [[nuclease]] [[Cas9]]) and (b) the DNA sequences of previously encountered viral invaders ([[CRISPR]]). These viral DNA sequences enable the nuclease to target foreign (viral) rather than self (bacterial) DNA.{{cite journal | vauthors = Ishino Y, Krupovic M, Forterre P | title = History of CRISPR-Cas from Encounter with a Mysterious Repeated Sequence to Genome Editing Technology | journal = Journal of Bacteriology | volume = 200 | issue = 7 | pages = e00580-17 | date = April 2018 | pmid = 29358495 | pmc = 5847661 | doi = 10.1128/JB.00580-17 }} [241] => [242] => Although the function of CRISPR-Cas9 in nature is to protect bacteria, the DNA sequences in the CRISPR component of the system can be modified so that the Cas9 nuclease targets bacterial [[antimicrobial resistance|resistance]] genes or bacterial [[virulence]] genes instead of viral genes. The modified CRISPR-Cas9 system can then be administered to bacterial pathogens using plasmids or bacteriophages. This approach has successfully been used to [[Gene silencing|silence]] antibiotic resistance and reduce the virulence of [[Shigatoxigenic and verotoxigenic Escherichia coli|enterohemorrhagic ''E. coli'']] in an ''in vivo'' model of infection. [243] => [244] => === Reducing the selection pressure for antibiotic resistance === [245] => [[Image:Share of population using safely managed sanitation facilities, OWID.svg|thumb|right|300px| Share of population using safely managed sanitation facilities in 2015.Ritchie, Roser, Mispy, Ortiz-Ospina (2018) [https://sdg-tracker.org/water-and-sanitation "Measuring progress towards the Sustainable Development Goals." (SDG 6)] {{Webarchive|url=https://web.archive.org/web/20201101050352/https://sdg-tracker.org/water-and-sanitation |date=1 November 2020 }} ''SDG-Tracker.org, website'']] [246] => In addition to developing new antibacterial treatments, it is important to reduce the [[selection pressure]] for the emergence and spread of [[antimicrobial resistance|antibiotic resistance]]. Strategies to accomplish this include well-established infection control measures such as infrastructure improvement (e.g. less crowded housing),{{cite web |url= https://www.ncbi.nlm.nih.gov/books/NBK535289/ |title= Household crowding |publisher= World Health Organization |access-date= 17 September 2020 |archive-date= 6 January 2021 |archive-url= https://web.archive.org/web/20210106220730/https://www.ncbi.nlm.nih.gov/books/NBK535289/ |url-status= live }}{{cite journal | vauthors = Ali SH, Foster T, Hall NL | title = The Relationship between Infectious Diseases and Housing Maintenance in Indigenous Australian Households | journal = International Journal of Environmental Research and Public Health | volume = 15 | issue = 12 | pages = Article 2827 | date = December 2018 | pmid = 30545014 | pmc = 6313733 | doi = 10.3390/ijerph15122827 | doi-access = free }} better sanitation (e.g. safe drinking water and food){{cite web|url= https://www.who.int/water_sanitation_health/publications/facts2004/en/|title= Water, sanitation and hygiene links to health|publisher= World Health Organization|access-date= 17 September 2020|archive-date= 7 September 2020|archive-url= https://web.archive.org/web/20200907205101/https://www.who.int/water_sanitation_health/publications/facts2004/en/|url-status= live}}{{cite journal | vauthors = Curtis V, Schmidt W, Luby S, Florez R, Touré O, Biran A | title = Hygiene: new hopes, new horizons | journal = The Lancet. Infectious Diseases | volume = 11 | issue = 4 | pages = 312–21 | date = April 2011 | pmid = 21453872 | pmc = 7106354 | doi = 10.1016/S1473-3099(10)70224-3 }} and vaccine development, other approaches such as [[antibiotic stewardship]],{{cite journal | vauthors = Gentry EM, Kester S, Fischer K, Davidson LE, Passaretti CL | title = Bugs and Drugs: Collaboration Between Infection Prevention and Antibiotic Stewardship | journal = Infectious Disease Clinics of North America | volume = 34 | issue = 1 | pages = 17–30 | date = March 2020 | pmid = 31836329 | doi = 10.1016/j.idc.2019.10.001 | s2cid = 209358146 }}{{cite journal | vauthors = Fierens J, Depuydt PO, De Waele JJ | title = A Practical Approach to Clinical Antibiotic Stewardship in the ICU Patient with Severe Infection | journal = Seminars in Respiratory and Critical Care Medicine | volume = 40 | issue = 4 | pages = 435–446 | date = August 2019 | pmid = 31585470 | doi = 10.1055/s-0039-1693995 | s2cid = 203720304 }} and experimental approaches such as the use of [[Prebiotic (nutrition)|prebiotics]] and [[probiotics]] to prevent infection.{{cite journal | vauthors = Newman AM, Arshad M | title = The Role of Probiotics, Prebiotics and Synbiotics in Combating Multidrug-Resistant Organisms | journal = Clinical Therapeutics | volume = 42 | issue = 9 | pages = 1637–1648 | date = September 2020 | pmid = 32800382 | pmc = 7904027 | doi = 10.1016/j.clinthera.2020.06.011 | doi-access = free }}{{cite journal | vauthors = Giordano M, Baldassarre ME, Palmieri V, Torres DD, Carbone V, Santangelo L, Gentile F, Panza R, Di Mauro F, Capozza M, Di Mauro A, Laforgia N | title = Management of STEC Gastroenteritis: Is There a Role for Probiotics? | journal = International Journal of Environmental Research and Public Health | volume = 16 | issue = 9 | pages = Article 1649 | date = May 2019 | pmid = 31083597 | pmc = 6539596 | doi = 10.3390/ijerph16091649 | doi-access = free }}{{cite journal | vauthors = Jha R, Das R, Oak S, Mishra P | title = Probiotics (Direct-Fed Microbials) in Poultry Nutrition and Their Effects on Nutrient Utilization, Growth and Laying Performance, and Gut Health: A Systematic Review | journal = Animals | volume = 10 | issue = 10 | pages = 1863 | date = October 2020 | pmid = 33066185 | pmc = 7602066 | doi = 10.3390/ani10101863 | doi-access = free }}{{cite journal | vauthors = Jha R, Mishra P | title = Dietary fiber in poultry nutrition and their effects on nutrient utilization, performance, gut health, and on the environment: a review | journal = Journal of Animal Science and Biotechnology | volume = 12 | issue = 1 | pages = 51 | date = April 2021 | pmid = 33866972 | pmc = 8054369 | doi = 10.1186/s40104-021-00576-0 | doi-access = free }} Antibiotic cycling, where antibiotics are alternated by clinicians to treat microbial diseases, is proposed, but recent studies revealed such strategies are ineffective against antibiotic resistance.{{cite journal | vauthors = Beckley AM, Wright ES | title = Identification of antibiotic pairs that evade concurrent resistance via a retrospective analysis of antimicrobial susceptibility test results | language = English | journal = The Lancet. Microbe | volume = 2 | issue = 10 | pages = e545–e554 | date = October 2021 | pmid = 34632433 | pmc = 8496867 | doi = 10.1016/S2666-5247(21)00118-X }}{{Cite journal| vauthors = Ma Y, Chua SL |date=2021-11-15|title=No collateral antibiotic sensitivity by alternating antibiotic pairs | journal=The Lancet Microbe|volume=3|issue=1 |pages=e7|language=English|doi=10.1016/S2666-5247(21)00270-6|pmid=35544116 |s2cid=244147577|issn=2666-5247|doi-access=free}} [247] => [248] => ==== Vaccines ==== [249] => [[Vaccine]]s rely on [[immune]] modulation or augmentation. Vaccination either excites or reinforces the immune competence of a host to ward off infection, leading to the activation of [[macrophages]], the production of [[antibody|antibodies]], [[inflammation]], and other classic immune reactions. Antibacterial vaccines have been responsible for a drastic reduction in global bacterial diseases.{{cite book |title= Emerging trends in antibacterial discovery: answering the call to arms |publisher= Horizon Scientific Press |year= 2011 | vauthors = Donald RG, Anderson AS | veditors = Miller PF |chapter= Current strategies for antibacterial vaccine development |page= 283}} Vaccines made from attenuated whole cells or lysates have been replaced largely by less reactogenic, cell-free vaccines consisting of purified components, including capsular polysaccharides and their conjugates, to protein carriers, as well as inactivated toxins (toxoids) and proteins.{{cite book |vauthors= Miller AA |veditors= Miller PF |year=2011 |title=Emerging trends in antibacterial discovery: answering the call to arms |publisher=[[Caister Academic Press]] |isbn= 978-1-904455-89-9}}{{page needed|date=December 2013}} [250] => [251] => == See also == [252] => {{Columns-list|colwidth=30em| [253] => * [[Anthelmintic]] [254] => * [[Antifungal]] [255] => * [[Antimalarial medication]] [256] => * [[Antiprotozoal]] [257] => * [[Antiviral drug]] [258] => * [[Magic bullet (medicine)]] [259] => * [[Prebiotic (nutrition)]] [260] => * [[Probiotic]] [261] => * [[List of antibiotics]]}} [262] => [263] => == References == [264] => {{Reflist|refs= [265] => [266] => [268] => [269] => {{cite journal | vauthors = Wiegand I, Hilpert K, Hancock RE | title = Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances | journal = Nature Protocols | volume = 3 | issue = 2 | pages = 163–75 | date = January 2008 | pmid = 18274517 | doi = 10.1038/nprot.2007.521 | s2cid = 3344950 }}{{cite journal | vauthors = Alekshun MN, Levy SB | title = Molecular mechanisms of antibacterial multidrug resistance | journal = Cell | volume = 128 | issue = 6 | pages = 1037–50 | date = March 2007 | pmid = 17382878 | doi = 10.1016/j.cell.2007.03.004 | s2cid = 18343252 | doi-access = free }} [271] => [272] => {{cite web|url=https://www.mcgill.ca/studenthealth/information/generalhealth/antibiotics/ |title=Antibiotics FAQ |access-date=17 February 2008 |publisher=McGill University, Canada |archive-url= https://web.archive.org/web/20080216195750/http://www.mcgill.ca/studenthealth/information/generalhealth/antibiotics/| archive-date= 16 February 2008}}{{cite news|url=https://www.theguardian.com/society/2010/aug/12/the-end-of-antibiotics-health-infections |location=London |work=The Guardian |title=Are you ready for a world without antibiotics? | vauthors = Boseley S |date=12 August 2010 |archive-url=https://web.archive.org/web/20101130054454/http://www.guardian.co.uk/society/2010/aug/12/the-end-of-antibiotics-health-infections |archive-date=30 November 2010 |url-status=live }}{{cite journal | vauthors = Mascio CT, Alder JD, Silverman JA | title = Bactericidal action of daptomycin against stationary-phase and nondividing Staphylococcus aureus cells | journal = Antimicrobial Agents and Chemotherapy | volume = 51 | issue = 12 | pages = 4255–60 | date = December 2007 | pmid = 17923487 | pmc = 2167999 | doi = 10.1128/AAC.00824-07 }} [274] => [275] => {{cite journal | vauthors = Baker-Austin C, Wright MS, Stepanauskas R, McArthur JV | title = Co-selection of antibiotic and metal resistance | journal = Trends in Microbiology | volume = 14 | issue = 4 | pages = 176–82 | date = April 2006 | pmid = 16537105 | doi = 10.1016/j.tim.2006.02.006 }}{{cite journal | vauthors = Levy SB | title = Balancing the drug-resistance equation | journal = Trends in Microbiology | volume = 2 | issue = 10 | pages = 341–2 | date = October 1994 | pmid = 7850197 | doi = 10.1016/0966-842X(94)90607-6 }}{{cite journal | vauthors = Bosch F, Rosich L | title = The contributions of Paul Ehrlich to pharmacology: a tribute on the occasion of the centenary of his Nobel Prize | journal = Pharmacology | volume = 82 | issue = 3 | pages = 171–9 | year = 2008 | pmid = 18679046 | pmc = 2790789 | doi = 10.1159/000149583 }}Calderon CB, Sabundayo BP (2007). 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Is contraceptive failure the result? | journal = Clinical Pharmacokinetics | volume = 36 | issue = 5 | pages = 309–13 | date = May 1999 | pmid = 10384856 | doi = 10.2165/00003088-199936050-00001 | s2cid = 25187892 }} [313] => [314] => {{cite journal | vauthors = Slama TG, Amin A, Brunton SA, File TM, Milkovich G, Rodvold KA, Sahm DF, Varon J, Weiland D | title = A clinician's guide to the appropriate and accurate use of antibiotics: the Council for Appropriate and Rational Antibiotic Therapy (CARAT) criteria | journal = The American Journal of Medicine | volume = 118 | issue = 7A | pages = 1S–6S | date = July 2005 | pmid = 15993671 | doi = 10.1016/j.amjmed.2005.05.007 | doi-access = free }} [316] => [317] => {{cite journal | vauthors = Ong S, Nakase J, Moran GJ, Karras DJ, Kuehnert MJ, Talan DA | title = Antibiotic use for emergency department patients with upper respiratory infections: prescribing practices, patient expectations, and patient satisfaction | journal = Annals of Emergency Medicine | volume = 50 | issue = 3 | pages = 213–20 | date = September 2007 | pmid = 17467120 | doi = 10.1016/j.annemergmed.2007.03.026 }}{{cite journal | vauthors = Metlay JP, Camargo CA, MacKenzie T, McCulloch C, Maselli J, Levin SK, Kersey A, Gonzales R | title = Cluster-randomized trial to improve antibiotic use for adults with acute respiratory infections treated in emergency departments | journal = Annals of Emergency Medicine | volume = 50 | issue = 3 | pages = 221–30 | date = September 2007 | pmid = 17509729 | doi = 10.1016/j.annemergmed.2007.03.022 }}{{cite journal | vauthors = Orme ML, Back DJ | title = Factors affecting the enterohepatic circulation of oral contraceptive steroids | journal = American Journal of Obstetrics and Gynecology | volume = 163 | issue = 6 Pt 2 | pages = 2146–52 | date = December 1990 | pmid = 2256523 | doi = 10.1016/0002-9378(90)90555-L | url = http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+57-63-6 | url-status = live | access-date = 11 March 2009 | df = dmy | archive-url = https://web.archive.org/web/20150713192148/http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+57-63-6 | archive-date = 13 July 2015 }}{{cite journal | vauthors = Hassan T | title = Pharmacologic considerations for patients taking oral contraceptives | journal = Connecticut Dental Student Journal | volume = 7 | pages = 7–8 | date = March 1987 | pmid = 3155374 }} [319] => [320] => {{cite news | vauthors = Pearson C |title=Antibiotic Resistance Fast-Growing Problem Worldwide |date=28 February 2007 |publisher=Voice of America |url= http://www.voanews.com/content/a-13-2007-02-28-voa33/405785.html |access-date=29 December 2008 |archive-url= https://web.archive.org/web/20081202191614/http://www.voanews.com/english/archive/2007-02/2007-02-28-voa33.cfm| archive-date= 2 December 2008 |url-status= live}} [322] => }} [323] => [324] => == Further reading == [325] => {{refbegin|30em}} [326] => * {{cite journal | vauthors = Gould K | title = Antibiotics: from prehistory to the present day | journal = The Journal of Antimicrobial Chemotherapy | volume = 71 | issue = 3 | pages = 572–5 | date = March 2016 | pmid = 26851273 | doi = 10.1093/jac/dkv484 | doi-access = free }} [327] => * {{cite journal | vauthors = Davies J, Davies D | title = Origins and evolution of antibiotic resistance | journal = Microbiology and Molecular Biology Reviews | volume = 74 | issue = 3 | pages = 417–33 | date = September 2010 | pmid = 20805405 | pmc = 2937522 | doi = 10.1128/MMBR.00016-10 }} [328] => * {{cite web|title=Antibiotics: MedlinePlus|url=https://medlineplus.gov/antibiotics.html?PHPSESSID=1550cb08d53a1c0c39064bf62aee6247|publisher=nih.gov|access-date=19 July 2016|archive-date=27 July 2016|archive-url=https://web.archive.org/web/20160727195825/https://medlineplus.gov/antibiotics.html|url-status=live}} [329] => * {{cite web|title=WHO's first global report on antibiotic resistance reveals serious, worldwide threat to public health|url=https://www.who.int/mediacentre/news/releases/2014/amr-report/en/|archive-url=https://web.archive.org/web/20140430150557/http://www.who.int/mediacentre/news/releases/2014/amr-report/en/|url-status=dead|archive-date=30 April 2014|website=WHO}} [330] => * {{cite journal | vauthors = Pugh R, Grant C, Cooke RP, Dempsey G | title = Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD007577 | date = August 2015 | volume = 2015 | pmid = 26301604 | pmc = 7025798 | doi = 10.1002/14651858.CD007577.pub3 }} [331] => * {{cite journal | vauthors = Giedraitienė A, Vitkauskienė A, Naginienė R, Pavilonis A | title = Antibiotic resistance mechanisms of clinically important bacteria | journal = Medicina | volume = 47 | issue = 3 | pages = 137–46 | date = 1 January 2011 | pmid = 21822035 | doi = 10.3390/medicina47030019 | doi-access = free }} [332] => {{refend}} [333] => [334] => == External links == [335] => {{Commons category|Antibiotics}} [336] => {{Library resources box |by=no |onlinebooks=no |others=yes lcheading=Antibiotics}} [337] => * {{Curlie|Health/Pharmacy/Drugs_and_Medications/Antibiotics/}} [338] => {{Scholia|topic}} [339] => {{Antibiotics social and layman issues}} [340] => {{Antibiotics}} [341] => {{Concepts in infectious disease}} [342] => {{Authority control}} [343] => [344] => [[Category:Antibiotics| ]] [345] => [[Category:Anti-infective agents]] [346] => [[Category:Bactericides|.]] [] => )

good wiki

Antibiotic

Antibiotics are a class of drugs that are used to treat and prevent bacterial infections in humans and animals. They work by either killing bacteria or stopping them from multiplying.

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They work by either killing bacteria or stopping them from multiplying. The use of antibiotics has greatly improved healthcare by allowing for the effective treatment of a wide range of bacterial infections. The discovery of antibiotics is often credited to Alexander Fleming, who first observed the antibacterial properties of penicillin in 1928. Since then, numerous types of antibiotics have been developed to target different types of bacteria. However, the overuse and misuse of antibiotics have led to the emergence of antibiotic-resistant bacteria, which pose a serious threat to global health. It is therefore important to use antibiotics judiciously to preserve their effectiveness for future generations.

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