colistin

Colistin has been effective in treating infections caused by Pseudomonas, Escherichia, and Klebsiella species. The following represents minimum inhibitory concentration (MIC) susceptibility data for a few medically significant microorganisms:{{cite web|url=http://antibiotics.toku-e.com/antimicrobial_958_2.html|title=Polymyxin E (Colistin) – The Antimicrobial Index Knowledgebase – TOKU-E|access-date=28 May 2016|url-status=live|archive-url=http://archive.wikiwix.com/cache/20160528051253/http://antibiotics.toku-e.com/antimicrobial_958_2.html|archive-date=28 May 2016}}{{cite web |url=http://www.toku-e.com/Assets/MIC/Colistin%20sulfate%20USP.pdf |title= Colistin sulfate, USP Susceptibility and Minimum Inhibitory Concentration (MIC) Data | date = 3 March 2016 |access-date=2014-02-10 |url-status=live |archive-url=https://web.archive.org/web/20160304002442/http://www.toku-e.com/Assets/MIC/Colistin%20sulfate%20USP.pdf |archive-date=2016-03-04 }}

• Escherichia coli: 0.12–128 μg/mL
• Klebsiella pneumoniae: 0.25–128 μg/mL
• Pseudomonas aeruginosa: ≤0.06–16 μg/mL

For example, colistin in combination with other drugs is used to attack P. aeruginosa biofilm infection in lungs of patients with cystic fibrosis.{{cite journal | vauthors = Herrmann G, Yang L, Wu H, Song Z, Wang H, Høiby N, Ulrich M, Molin S, Riethmüller J, Döring G | display-authors = 6 | title = Colistin-tobramycin combinations are superior to monotherapy concerning the killing of biofilm Pseudomonas aeruginosa | journal = The Journal of Infectious Diseases | volume = 202 | issue = 10 | pages = 1585–1592 | date = November 2010 | pmid = 20942647 | doi = 10.1086/656788 | doi-access = free }} Biofilms have a low-oxygen environment below the surface where bacteria are metabolically inactive, and colistin is highly effective in this environment. However, P. aeruginosa reside in the top layers of the biofilm, where they remain metabolically active.{{cite journal | vauthors = Pamp SJ, Gjermansen M, Johansen HK, Tolker-Nielsen T | title = Tolerance to the antimicrobial peptide colistin in Pseudomonas aeruginosa biofilms is linked to metabolically active cells, and depends on the pmr and mexAB-oprM genes | journal = Molecular Microbiology | volume = 68 | issue = 1 | pages = 223–240 | date = April 2008 | pmid = 18312276 | doi = 10.1111/j.1365-2958.2008.06152.x | s2cid = 44556845 | doi-access = free }} This is because surviving tolerant cells migrate to the top of the biofilm via pili and form new aggregates via quorum sensing.{{cite journal | vauthors = Chua SL, Yam JK, Hao P, Adav SS, Salido MM, Liu Y, Givskov M, Sze SK, Tolker-Nielsen T, Yang L | display-authors = 6 | title = Selective labelling and eradication of antibiotic-tolerant bacterial populations in Pseudomonas aeruginosa biofilms | journal = Nature Communications | volume = 7 | pages = 10750 | date = February 2016 | pmid = 26892159 | pmc = 4762895 | doi = 10.1038/ncomms10750 | bibcode = 2016NatCo...710750C }}

Two forms of colistin are available commercially: colistin sulfate and colistimethate sodium (colistin methanesulfonate sodium, colistin sulfomethate sodium). Colistin sulfate is cationic; colistimethate sodium is anionic. Colistin sulfate is stable, whereas colistimethate sodium is readily hydrolysed to a variety of methanesulfonated derivatives. Colistin sulfate and colistimethate sodium are eliminated from the body by different routes. With respect to Pseudomonas aeruginosa, colistimethate is the inactive prodrug of colistin. The two drugs are not interchangeable.

• Colistimethate sodium may be used to treat Pseudomonas aeruginosa infections in patients with cystic fibrosis, and it has come into recent use for treating multidrug-resistant Acinetobacter infection, although resistant forms have been reported.{{cite journal | vauthors = Reis AO, Luz DA, Tognim MC, Sader HS, Gales AC | title = Polymyxin-resistant Acinetobacter spp. isolates: what is next? | journal = Emerging Infectious Diseases | volume = 9 | issue = 8 | pages = 1025–1027 | date = August 2003 | pmid = 12971377 | pmc = 3020604 | doi = 10.3201/eid0908.030052 }}{{cite book|chapter-url=http://www.horizonpress.com/hsp/abs/absacineto.html| vauthors = Towner KJ |year= 2008 |chapter=Molecular Basis of Antibiotic Resistance in Acinetobacter spp.|title=Acinetobacter Molecular Biology|publisher=Caister Academic Press|isbn=978-0-306-43902-5|archive-url=https://web.archive.org/web/20120207002814/http://www.horizonpress.com/hsp/abs/absacineto.html|archive-date=2012-02-07}} Colistimethate sodium has also been given intrathecally and intraventricularly in Acinetobacter baumannii and Pseudomonas aeruginosa meningitis and ventriculitis{{cite journal | vauthors = Benifla M, Zucker G, Cohen A, Alkan M | title = Successful treatment of Acinetobacter meningitis with intrathecal polymyxin E | journal = The Journal of Antimicrobial Chemotherapy | volume = 54 | issue = 1 | pages = 290–292 | date = July 2004 | pmid = 15190037 | doi = 10.1093/jac/dkh289 | doi-access = free }}{{cite journal | vauthors = Yagmur R, Esen F | title = Intrathecal colistin for treatment of Pseudomonas aeruginosa ventriculitis: report of a case with successful outcome | journal = Critical Care | volume = 10 | issue = 6 | pages = 428 | year = 2006 | pmid = 17214907 | pmc = 1794456 | doi = 10.1186/cc5088 | doi-access = free }}{{cite journal | vauthors = Motaouakkil S, Charra B, Hachimi A, Nejmi H, Benslama A, Elmdaghri N, Belabbes H, Benbachir M | display-authors = 6 | title = Colistin and rifampicin in the treatment of nosocomial infections from multiresistant Acinetobacter baumannii | journal = The Journal of Infection | volume = 53 | issue = 4 | pages = 274–278 | date = October 2006 | pmid = 16442632 | doi = 10.1016/j.jinf.2005.11.019 }}{{cite journal | vauthors = Karakitsos D, Paramythiotou E, Samonis G, Karabinis A | title = Is intraventricular colistin an effective and safe treatment for post-surgical ventriculitis in the intensive care unit? | journal = Acta Anaesthesiologica Scandinavica | volume = 50 | issue = 10 | pages = 1309–1310 | date = November 2006 | pmid = 17067336 | doi = 10.1111/j.1399-6576.2006.01126.x | s2cid = 25679033 }} Some studies have indicated that colistin may be useful for treating infections caused by carbapenem-resistant isolates of Acinetobacter baumannii.
• Colistin sulfate may be used to treat intestinal infections, or to suppress colonic flora. Colistin sulfate is also used in topical creams, powders, and otic solutions.
• Colistin A (polymyxin E1) and colistin B (polymyxin E2) can be purified individually to research and study their effects and potencies as separate compounds.

Colistin sulfate and colistimethate sodium may both be given intravenously, but the dosing is complicated. The different labeling of the parenteral products of colistin methanesulfonate in different parts of the world was noted by Li et al.{{cite journal | vauthors = Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, Paterson DL | title = Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections | journal = The Lancet. Infectious Diseases | volume = 6 | issue = 9 | pages = 589–601 | date = September 2006 | pmid = 16931410 | doi = 10.1016/s1473-3099(06)70580-1 }} Colistimethate sodium manufactured by Xellia (Colomycin injection) is prescribed in international units, whereas colistimethate sodium manufactured by Parkdale Pharmaceuticals (Coly-Mycin M Parenteral) is prescribed in milligrams of colistin base:

• Colomycin 1,000,000 units is 80 mg colistimethate;
• Coly-mycin M 150 mg colistin base is 360 mg colistimethate or 4,500,000 units.{{cite web|url=http://www.emea.europa.eu/pdfs/vet/mrls/081502en.pdf |date=January 2002 |archive-url=https://web.archive.org/web/20060718185047/http://www.emea.europa.eu/pdfs/vet/mrls/081502en.pdf |archive-date=18 July 2006 |title=COMMITTEE FOR VETERINARY MEDICINAL PRODUCTS: COLISTIN: SUMMARY REPORT (2) |publisher=European Medicines Agency}} NB. Colistin base has an assigned potency of 30 000 IU/mg

Because colistin was introduced into clinical practice over 50 years ago, it was never subject to the regulations that modern drugs are subject to, and therefore there is no standardised dosing of colistin and no detailed trials on pharmacology or pharmacokinetics. The optimal dosing of colistin for most infections is therefore unknown. Colomycin has a recommended intravenous dose of 1 to 2 million units three times daily for patients weighing 60 kg or more with normal renal function. Coly-Mycin has a recommended dose of 2.5 to 5 mg/kg colistin base a day, which is equivalent to 6 to 12 mg/kg colistimethate sodium per day. For a 60 kg man, therefore, the recommended dose for Colomycin is 240 to 480 mg of colistimethate sodium, yet the recommended dose for Coly-Mycin is 360 to 720 mg of colistimethate sodium. Likewise, the recommended "maximum" dose for each preparation is different (480 mg for Colomycin and 720 mg for Coly-Mycin). Each country has different generic preparations of colistin, and the recommended dose depends on the manufacturer. This complete absence of any regulation or standardisation of dose makes intravenous colistin dosing difficult for the physician. {{Citation needed|date=August 2010}}

Colistin has been used in combination with rifampicin; evidence of in vitro synergy exists,{{cite journal | vauthors = Ahmed N, Wahlgren NG | title = Effects of blood pressure lowering in the acute phase of total anterior circulation infarcts and other stroke subtypes | journal = Cerebrovascular Diseases | volume = 15 | issue = 4 | pages = 235–243 | year = 2003 | pmid = 12686786 | doi = 10.1159/000069498 | s2cid = 12205902 }}{{cite journal | vauthors = Hogg GM, Barr JG, Webb CH | title = In-vitro activity of the combination of colistin and rifampicin against multidrug-resistant strains of Acinetobacter baumannii | journal = The Journal of Antimicrobial Chemotherapy | volume = 41 | issue = 4 | pages = 494–495 | date = April 1998 | pmid = 9598783 | doi = 10.1093/jac/41.4.494 | doi-access = free }} and the combination has been used successfully in patients.{{cite journal | vauthors = Petrosillo N, Chinello P, Proietti MF, Cecchini L, Masala M, Franchi C, Venditti M, Esposito S, Nicastri E | display-authors = 6 | title = Combined colistin and rifampicin therapy for carbapenem-resistant Acinetobacter baumannii infections: clinical outcome and adverse events | journal = Clinical Microbiology and Infection | volume = 11 | issue = 8 | pages = 682–683 | date = August 2005 | pmid = 16008625 | doi = 10.1111/j.1469-0691.2005.01198.x | doi-access = free }} There is also in vitro evidence of synergy for colistimethate sodium used in combination with other antipseudomonal antibiotics.{{cite journal | vauthors = Rynn C, Wootton M, Bowker KE, Alan Holt H, Reeves DS | title = In vitro assessment of colistin's antipseudomonal antimicrobial interactions with other antibiotics | journal = Clinical Microbiology and Infection | volume = 5 | issue = 1 | pages = 32–36 | date = January 1999 | pmid = 11856210 | doi = 10.1111/j.1469-0691.1999.tb00095.x | doi-access = free }}

Colistimethate sodium aerosol (Promixin; Colomycin Injection) is used to treat pulmonary infections, especially in cystic fibrosis. In the UK, the recommended adult dose is 1–2 million units (80–160 mg) nebulised colistimethate twice daily.{{cite web |title=Promixin 1 million International Units (IU) Powder for Nebuliser Solution |date=12 January 2016 |work=Patient Information Leafle |publisher=electronic Medicines Compendium (eMC) |url=http://www.medicines.org.uk/emc/medicine/13532 |url-status=live |archive-url=https://web.archive.org/web/20170716220848/https://www.medicines.org.uk/emc/medicine/13532 |archive-date=16 July 2017 }}{{cite web |title=Colomycin Injection |date=18 May 2016 |work=Summary of Product Characteristics |publisher=electronic Medicines Compendium (eMC) |url=http://www.medicines.org.uk/emc/medicine/1590 |url-status=dead |archive-url=https://web.archive.org/web/20170716220739/https://www.medicines.org.uk/emc/medicine/1590 |archive-date=16 July 2017 |access-date=3 June 2017 }} Nebulized colistin has also been used to decrease severe exacerbations in patients with chronic obstructive pulmonary disease and infection with Pseudomonas aeruginosa.{{cite journal | vauthors = Bruguera-Avila N, Marin A, Garcia-Olive I, Radua J, Prat C, Gil M, Ruiz-Manzano J | title = Effectiveness of treatment with nebulized colistin in patients with COPD | journal = International Journal of Chronic Obstructive Pulmonary Disease | volume = 12 | pages = 2909–2915 | year = 2017 | pmid = 29042767 | pmc = 5634377 | doi = 10.2147/COPD.S138428 | doi-access = free }}

Resistance to colistin is rare, but has been described. {{As of |2017}}, no agreement exists about how to define colistin resistance. The {{ill|Société Française de Microbiologie|fr}} uses a MIC cut-off of 2 mg/L, whereas the British Society for Antimicrobial Chemotherapy sets a MIC cutoff of 4 mg/L or less as sensitive, and 8 mg/L or more as resistant. No standards for describing colistin sensitivity are given in the United States.

The first known colistin-resistance gene in a plasmid which can be transferred between bacterial strains is mcr-1. It was found in 2011 in China on a pig farm where colistin is routinely used and became publicly known in November 2015.{{cite journal | vauthors = Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J | display-authors = 6 | title = Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study | journal = The Lancet. Infectious Diseases | volume = 16 | issue = 2 | pages = 161–168 | date = February 2016 | pmid = 26603172 | doi = 10.1016/S1473-3099(15)00424-7 }}{{Cite news|url=https://www.theatlantic.com/health/archive/2017/01/colistin-resistance-spread/512705/|title=Resistance to the Antibiotic of Last Resort Is Silently Spreading| vauthors = Zhang S |newspaper=The Atlantic|access-date=2017-01-12|url-status=live|archive-url=https://web.archive.org/web/20170113075911/https://www.theatlantic.com/health/archive/2017/01/colistin-resistance-spread/512705/|archive-date=2017-01-13|name-list-style=vanc}} The presence of this plasmid-borne gene was confirmed starting December 2015 in South-East Asia, several European countries,{{cite web|url=http://phenomena.nationalgeographic.com/2015/12/03/colistin-r-2/|title=Apocalypse Pig Redux: Last-Resort Resistance in Europe| vauthors = McKenna M |work=Phenomena|access-date=28 May 2016|url-status=dead|archive-url=https://web.archive.org/web/20160528163333/http://phenomena.nationalgeographic.com/2015/12/03/colistin-r-2/|archive-date=28 May 2016|date=2015-12-03}} and the United States.{{Cite web|url=https://www.sciencedaily.com/releases/2016/05/160526152033.htm|title=First discovery in United States of colistin resistance in a human E. coli infection|website=www.sciencedaily.com|access-date=2016-05-27|url-status=live|archive-url=https://web.archive.org/web/20160527122712/https://www.sciencedaily.com/releases/2016/05/160526152033.htm|archive-date=2016-05-27}} It is found in certain strains of the bacteria Paenibacillus polymyxa.{{cn|date=September 2021}}

India reported the first detailed colistin-resistance study, which mapped 13 colistin-resistant infections recorded over 18 months. It concluded that pan-drug-resistant infections, particularly those in the bloodstream, have a higher mortality. Multiple other cases were reported from other Indian hospitals.{{Cite web|url = http://www.journalindex.net/visit.php?j=4730|title = Emergence of Pan drug resistance amongst gram negative bacteria! The First case series from India|date = December 2014}}{{Cite web|url =http://timesofindia.indiatimes.com/city/pune/New-worry-Resistance-to-last-antibiotic-surfaces-in-India/articleshow/45664238.cms|title =New worry: Resistance to 'last antibiotic' surfaces in India|website =The Times of India|date =28 December 2014|url-status =live|archive-url =https://web.archive.org/web/20141231060313/http://timesofindia.indiatimes.com/city/pune/New-worry-Resistance-to-last-antibiotic-surfaces-in-India/articleshow/45664238.cms|archive-date =31 December 2014}} Although resistance to polymyxins is generally less than 10%, it is more frequent in the Mediterranean and South-East Asia (Korea and Singapore), where colistin resistance rates are increasing.{{cite journal | vauthors = Bialvaei AZ, Samadi Kafil H | title = Colistin, mechanisms and prevalence of resistance | journal = Current Medical Research and Opinion | volume = 31 | issue = 4 | pages = 707–721 | date = April 2015 | pmid = 25697677 | doi = 10.1185/03007995.2015.1018989 | s2cid = 33476061 | doi-access = free }} Colistin-resistant E. coli was identified in the United States in May 2016.{{cite web |title=Discovery of first mcr-1 gene in E. coli bacteria found in a human in United States |work=cdc.gov |publisher=U.S. Department of Health and Human Services |date=31 May 2016 |url=https://www.cdc.gov/media/releases/2016/s0531-mcr-1.html |access-date=6 July 2016 |archive-url=https://web.archive.org/web/20160711041705/http://www.cdc.gov/media/releases/2016/s0531-mcr-1.html |archive-date=2016-07-11 |url-status=live }}

A recent review from 2016 to 2021 fount that E. coli is the dominant species harbouring mcr genes. Plasmid - mediated colistin resistance is also conferred upon other species that carry different genes resistant to antibiotics. The emergence of the mcr-9 gene is quite remarkable.{{cite journal | vauthors = Chatzidimitriou M, Kavvada A, Kavvadas D, Kyriazidi MA, Meletis G, Chatzopoulou F, Chatzidimitriou D | title = mcr Genes Conferring Colistin Resistance in Enterobacterales; a Five Year Overview | journal = Acta Medica Academica | volume = 50 | issue = 3 | pages = 365–371 | date = December 2021 | pmid = 35164512 | doi = 10.5644/ama2006-124.355 | s2cid = 246826086 | doi-access = free }}

Use of colistin to treat Acinetobacter baumannii infections has led to the development of resistant bacterial strains. They have also developed resistance to the antimicrobial compounds LL-37 and lysozyme, produced by the human immune system. This cross-resistance is caused by gain-of-function mutations to the pmrB gene, which controls the expression of lipid A phosphoethanolamine transferases (similar to mcr-1) located on the bacterial chromosome.{{cite journal | vauthors = Napier BA, Burd EM, Satola SW, Cagle SM, Ray SM, McGann P, Pohl J, Lesho EP, Weiss DS | display-authors = 6 | title = Clinical use of colistin induces cross-resistance to host antimicrobials in Acinetobacter baumannii | journal = mBio | volume = 4 | issue = 3 | pages = e00021–e00013 | date = May 2013 | pmid = 23695834 | pmc = 3663567 | doi = 10.1128/mBio.00021-13 }} Similar results have been obtained with mcr-1 positive E. coli, which became better at surviving a mixture of animal antimicrobial peptides in vitro and more effective at killing infected caterpillars.{{cite journal | vauthors = Jangir PK, Ogunlana L, Szili P, Czikkely M, Shaw LP, Stevens EJ, Yu Y, Yang Q, Wang Y, Pál C, Walsh TR, MacLean CR | display-authors = 6 | title = The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence | journal = eLife | volume = 12 | pages = e84395 | date = April 2023 | pmid = 37094804 | pmc = 10129329 | doi = 10.7554/eLife.84395 | doi-access = free }}

Not all resistance to colistin and some other antibiotics is due to the presence of resistance genes.{{cite web | vauthors = McKay B |title=Common 'Superbug' Found to Disguise Resistance to Potent Antibiotic |work=wsj.com |publisher=Wall Street Journal |date=6 March 2018 |url=https://www.wsj.com/articles/common-superbug-found-to-disguise-resistance-to-potent-antibiotic-1520334001 |access-date=1 Nov 2018 |archive-url=https://web.archive.org/web/20180403014411/https://www.wsj.com/articles/common-superbug-found-to-disguise-resistance-to-potent-antibiotic-1520334001 |archive-date=2018-04-03 |url-status=live }} Heteroresistance, the phenomenon wherein apparently genetically identical microbes exhibit a range of resistance to an antibiotic,{{cite journal | vauthors = El-Halfawy OM, Valvano MA | title = Antimicrobial heteroresistance: an emerging field in need of clarity | journal = Clinical Microbiology Reviews | volume = 28 | issue = 1 | pages = 191–207 | date = January 2015 | pmid = 25567227 | pmc = 4284305 | doi = 10.1128/CMR.00058-14 }} has been observed in some species of Enterobacter since at least 2016 and was observed in some strains of Klebsiella pneumoniae in 2017–2018.{{cite journal | vauthors = Band VI, Satola SW, Burd EM, Farley MM, Jacob JT, Weiss DS | title = Carbapenem-Resistant Klebsiella pneumoniae Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection | journal = mBio | volume = 9 | issue = 2 | pages = e02448–17 | date = March 2018 | pmid = 29511071 | pmc = 5844991 | doi = 10.1128/mBio.02448-17 }} In some cases this phenomenon has significant clinical consequences.

{{Div col}}

• Brucella
• Burkholderia cepacia
• Chryseobacterium indologenes
• Edwardsiella
• Elizabethkingia meningoseptica
• Francisella tularensis spp.
• Gram-negative cocci
• Helicobacter pylori
• Moraxella catarrhalis
• Morganella spp.
• Neisseria gonorrhoeae and Neisseria meningitidis
• Proteus
• Providencia
• Serratia
• Some strains of Stenotrophomonas maltophilia{{cite journal | vauthors = Markou N, Apostolakos H, Koumoudiou C, Athanasiou M, Koutsoukou A, Alamanos I, Gregorakos L | title = Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative bacilli in critically ill patients | journal = Critical Care | volume = 7 | issue = 5 | pages = R78–R83 | date = October 2003 | pmid = 12974973 | pmc = 270720 | doi = 10.1186/cc2358 | doi-access = free }}

{{div col end}}

• Aeromonas
• Vibrio
• Prevotella
• Fusobacterium
• Escherichia coli

The main toxicities described with intravenous treatment are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves),{{cite journal | vauthors = Wolinsky E, Hines JD | title = Neurotoxic and nephrotoxic effects of colistin in patients with renal disease | journal = The New England Journal of Medicine | volume = 266 | issue = 15 | pages = 759–762 | date = April 1962 | pmid = 14008070 | doi = 10.1056/NEJM196204122661505 }}{{cite journal | vauthors = Koch-Weser J, Sidel VW, Federman EB, Kanarek P, Finer DC, Eaton AE | title = Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy | journal = Annals of Internal Medicine | volume = 72 | issue = 6 | pages = 857–868 | date = June 1970 | pmid = 5448745 | doi = 10.7326/0003-4819-72-6-857 }}{{cite journal | vauthors = Ledson MJ, Gallagher MJ, Cowperthwaite C, Convery RP, Walshaw MJ | title = Four years' experience of intravenous colomycin in an adult cystic fibrosis unit | journal = The European Respiratory Journal | volume = 12 | issue = 3 | pages = 592–594 | date = September 1998 | pmid = 9762785 | doi = 10.1183/09031936.98.12030592 | doi-access = free }}{{cite journal | vauthors = Li J, Nation RL, Milne RW, Turnidge JD, Coulthard K | title = Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria | journal = International Journal of Antimicrobial Agents | volume = 25 | issue = 1 | pages = 11–25 | date = January 2005 | pmid = 15620821 | doi = 10.1016/j.ijantimicag.2004.10.001 }} but this may reflect the very high doses given, which are much higher than the doses currently recommended by any manufacturer and for which no adjustment was made for pre-existing renal disease. Neuro- and nephrotoxic effects appear to be transient and subside on discontinuation of therapy or reduction in dose.{{cite journal | vauthors = Beringer P | title = The clinical use of colistin in patients with cystic fibrosis | journal = Current Opinion in Pulmonary Medicine | volume = 7 | issue = 6 | pages = 434–440 | date = November 2001 | pmid = 11706322 | doi = 10.1097/00063198-200111000-00013 | s2cid = 38084953 }}

At a dose of 160 mg colistimethate IV every eight hours, very little nephrotoxicity is seen.{{cite journal | vauthors = Conway SP, Etherington C, Munday J, Goldman MH, Strong JJ, Wootton M | title = Safety and tolerability of bolus intravenous colistin in acute respiratory exacerbations in adults with cystic fibrosis | journal = The Annals of Pharmacotherapy | volume = 34 | issue = 11 | pages = 1238–1242 | date = November 2000 | pmid = 11098334 | doi = 10.1345/aph.19370 | s2cid = 42625124 }}{{cite journal | vauthors = Littlewood JM, Koch C, Lambert PA, Høiby N, Elborn JS, Conway SP, Dinwiddie R, Duncan-Skingle F | display-authors = 6 | title = A ten year review of colomycin | journal = Respiratory Medicine | volume = 94 | issue = 7 | pages = 632–640 | date = July 2000 | pmid = 10926333 | doi = 10.1053/rmed.2000.0834 | doi-access = free }} Indeed, colistin appears to have less toxicity than the aminoglycosides that subsequently replaced it, and it has been used for extended periods up to six months with no ill effects.{{cite journal | vauthors = Stein A, Raoult D | title = Colistin: an antimicrobial for the 21st century? | journal = Clinical Infectious Diseases | volume = 35 | issue = 7 | pages = 901–902 | date = October 2002 | pmid = 12228836 | doi = 10.1086/342570 | doi-access = free }} Colistin-induced nephrotoxicity is particularly likely in patients with hypoalbuminemia.{{cite journal | vauthors = Giacobbe DR, di Masi A, Leboffe L, Del Bono V, Rossi M, Cappiello D, Coppo E, Marchese A, Casulli A, Signori A, Novelli A, Perrone K, Principe L, Bandera A, Vender LE, Misin A, Occhilupo P, Melone M, Ascenzi P, Gori A, Luzzati R, Viscoli C, Di Bella S | display-authors = 6 | title = Hypoalbuminemia as a predictor of acute kidney injury during colistin treatment | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 11968 | date = August 2018 | pmid = 30097635 | pmc = 6086859 | doi = 10.1038/s41598-018-30361-5 | name-list-style = vanc | bibcode = 2018NatSR...811968G }}

The main toxicity described with aerosolised treatment is bronchospasm,{{cite journal | vauthors = Maddison J, Dodd M, Webb AK | title = Nebulized colistin causes chest tightness in adults with cystic fibrosis | journal = Respiratory Medicine | volume = 88 | issue = 2 | pages = 145–147 | date = February 1994 | pmid = 8146414 | doi = 10.1016/0954-6111(94)90028-0 | doi-access = free }} which can be treated or prevented with the use of β2-adrenergic receptor agonists such as salbutamol{{cite journal | vauthors = Kamin W, Schwabe A, Krämer I | title = Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers | journal = Journal of Cystic Fibrosis | volume = 5 | issue = 4 | pages = 205–213 | date = December 2006 | pmid = 16678502 | doi = 10.1016/j.jcf.2006.03.007 | doi-access = free }} or following a desensitisation protocol.{{cite journal | vauthors = Domínguez-Ortega J, Manteiga E, Abad-Schilling C, Juretzcke MA, Sánchez-Rubio J, Kindelan C | title = Induced tolerance to nebulized colistin after severe reaction to the drug | journal = Journal of Investigational Allergology & Clinical Immunology | volume = 17 | issue = 1 | pages = 59–61 | year = 2007 | pmid = 17323867 }}

Colistin is a polycationic peptide and has both hydrophilic and lipophilic moieties.{{cite journal | vauthors = Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, Paterson DL | title = Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections | journal = The Lancet. Infectious Diseases | volume = 6 | issue = 9 | pages = 589–601 | date = September 2006 | pmid = 16931410 | doi = 10.1016/S1473-3099(06)70580-1 }} These cationic regions interact with the bacterial outer membrane by displacing magnesium and calcium bacterial counter ions in the lipopolysaccharide.{{citation needed|date=March 2017}} The hydrophobic and hydrophilic regions interact with the cytoplasmic membrane just like a detergent, solubilizing the membrane in an aqueous environment.{{citation needed|date=March 2017}} This effect is bactericidal even in an isosmolar environment.{{citation needed|date=March 2017}}

Colistin binds to lipopolysaccharides and phospholipids in the outer cell membrane of Gram-negative bacteria. It competitively displaces divalent cations (Ca²⁺ and Mg²⁺) from the phosphate groups of membrane lipids, which leads to disruption of the outer cell membrane, leakage of intracellular contents and bacterial death.

No clinically useful absorption of colistin occurs in the gastrointestinal tract. For systemic infection, colistin must therefore be given by injection.

Colistimethate is eliminated by the kidneys, but colistin is eliminated by non-renal mechanism(s) that are as of yet not characterised.{{cite journal | vauthors = Li J, Milne RW, Nation RL, Turnidge JD, Smeaton TC, Coulthard K | title = Pharmacokinetics of colistin methanesulphonate and colistin in rats following an intravenous dose of colistin methanesulphonate | journal = The Journal of Antimicrobial Chemotherapy | volume = 53 | issue = 5 | pages = 837–840 | date = May 2004 | pmid = 15044428 | doi = 10.1093/jac/dkh167 | doi-access = free }}{{cite journal | vauthors = Li J, Milne RW, Nation RL, Turnidge JD, Smeaton TC, Coulthard K | title = Use of high-performance liquid chromatography to study the pharmacokinetics of colistin sulfate in rats following intravenous administration | journal = Antimicrobial Agents and Chemotherapy | volume = 47 | issue = 5 | pages = 1766–1770 | date = May 2003 | pmid = 12709357 | pmc = 153303 | doi = 10.1128/AAC.47.5.1766-1770.2003 }}

Colistin was first isolated in Japan in 1949 by Y. Koyama, from a flask of fermenting Bacillus polymyxa var. colistinus,{{cite journal | vauthors = Koyama Y, Kurosasa A, Tsuchiya A, Takakuta K | title = A new antibiotic 'colistin' produced by spore-forming soil bacteria | journal = J Antibiot (Tokyo) | volume = 3 | year = 1950 }} and became available for clinical use in 1959.{{Cite web | vauthors = MacLaren G, Spelman D | date = 22 November 2022 | veditors = Hopper DC, Hall KK |url=http://www.uptodate.com/contents/colistin-an-overview|title=Colistin: An overview| work = UpToDate | publisher = Wolters Kluwer |access-date=2016-06-06|url-status=live|archive-url=https://web.archive.org/web/20160531122851/http://www.uptodate.com/contents/colistin-an-overview|archive-date=2016-05-31}}

Colistimethate sodium, a less toxic prodrug, became available for injection in 1959. In the 1980s, polymyxin use was widely discontinued because of nephro- and neurotoxicity. As multi-drug resistant bacteria became more prevalent in the 1990s, colistin started to get a second look as an emergency solution, in spite of toxicity.{{cite journal | vauthors = Falagas ME, Kasiakou SK | title = Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections | journal = Clinical Infectious Diseases | volume = 40 | issue = 9 | pages = 1333–1341 | date = May 2005 | pmid = 15825037 | doi = 10.1086/429323 | s2cid = 21679015 | doi-access = free }}

Colistin has also been used in agriculture, particularly in China from the 1980s onwards. Chinese production for agriculture exceeded 2700 tons in 2015. China banned colistin use for livestock growth promotion in 2016.{{cite news | vauthors = Schoenmakers K |title=How China is getting its farmers to kick their antibiotics habit |url=https://www.nature.com/articles/d41586-020-02889-y |access-date=2 August 2021 |publisher=Nature |date=21 October 2020}}

The biosynthesis of colistin requires the use of three amino acids: threonine, leucine, and 2,4-diaminobutryic acid. The linear form of colistin is synthesized before cyclization. Non-ribosomal peptide biosynthesis begins with a loading module and then the addition of each subsequent amino acid. The subsequent amino acids are added with the help of an adenylation domain (A), a peptidyl carrier protein domain (PCP), an epimerization domain (E), and a condensation domain (C). Cyclization is accomplished by a thioesterase.{{cite book | vauthors = Dewick PM | title = Medicinal Natural Products | edition = Third | publisher = John Wiley & Sons | date = 2009 }} The first step is to have a loading domain, 6-methylheptanoic acid, associate with the A and PCP domains. Now with a C, A, and PCP domain that is associated with 2,4-diaminobutryic acid. This continues with each amino acid until the linear peptide chain is completed. The last module will have a thioesterase to complete the cyclization and form the product colistin. File:Wiki biosynthesis colistin.png

{{Reflist}}

• {{Cite journal|url = http://www.nature.com/news/spread-of-antibiotic-resistance-gene-does-not-spell-bacterial-apocalypse-yet-1.19037|title = Spread of antibiotic-resistance gene does not spell bacterial apocalypse — yet| vauthors = Reardon S |date = December 2015|journal = Nature|doi =10.1038/nature.2015.19037 | doi-access=free |name-list-style=vanc }}

• {{cite web |title=Colistin topics page (bibliography) |publisher=Science.gov |url=http://www.science.gov/topicpages/c/colistin.html}}

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