Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Vancomycin: Difference between pages

{{Short description|Antibiotic medication}}

{{Use dmy dates|date=December 2023}}

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| image2 = Vancomycin-from-xtal-1996-3D-balls.png

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| drug_name =

| pronounce = {{IPAc-en|v|æ|ŋ|k|ə|ˈ|m|aɪ|s|ᵻ|n}}{{refn|{{MerriamWebsterDictionary|vancomycin}}}}{{refn|{{cite web |url=https://www.oxforddictionaries.com/definition/english/vancomycin |archive-url=https://web.archive.org/web/20130920070219/http://oxforddictionaries.com/definition/english/vancomycin |url-status=dead |archive-date=20 September 2013 |title=vancomycin - definition of vancomycin in English from the Oxford dictionary |publisher=[[OxfordDictionaries.com]] |access-date=20 January 2016 }} }}

| tradename = Vancocin, others<ref name="Drugs.com-2019">{{cite web | title=Vancomycin | website=Drugs.com | date=2 December 2019 | url=https://www.drugs.com/international/vancomycin.html | access-date=24 December 2019 | archive-date=24 December 2019 | archive-url=https://web.archive.org/web/20191224190540/https://www.drugs.com/international/vancomycin.html | url-status=live }}</ref>

| Drugs.com = {{drugs.com|monograph|vancomycin-hydrochloride}}

| licence_CA = Vancomycin

| licence_EU = yes

| DailyMedID = Vancomycin

| licence_US = Vancomycin

| pregnancy_AU = B2

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Vancomycin Use During Pregnancy | website=Drugs.com | date=27 March 2019 | url=https://www.drugs.com/pregnancy/vancomycin.html | access-date=24 December 2019 | archive-date=6 June 2019 | archive-url=https://web.archive.org/web/20190606160102/https://www.drugs.com/pregnancy/vancomycin.html | url-status=live }}</ref>

| pregnancy_category =

| routes_of_administration = [[Intravenous]], [[Oral administration|oral]]

| class = [[Glycopeptide antibiotic]]

| ATC_prefix = A07

| ATC_suffix = AA09

| ATC_supplemental = {{ATC|J01|XA01}} {{ATC|S01|AA28}}

<!-- Legal status -->

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| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->

| legal_BR_comment =

| legal_CA = Rx-only

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled-->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment =

| legal_EU = Rx-only

| legal_EU_comment = <ref name="European Medicines Agency-2020">{{cite web |date=15 October 2020 |title=List of nationally authorised medicinal products |url=https://www.ema.europa.eu/en/documents/psusa/vancomycin-list-nationally-authorised-medicinal-products-psusa/00003097/202001_en.pdf |website=[[European Medicines Agency]] |access-date=27 April 2023 |archive-date=25 September 2023 |archive-url=https://web.archive.org/web/20230925070309/https://www.ema.europa.eu/en/documents/psusa/vancomycin-list-nationally-authorised-medicinal-products-psusa/00003097/202001_en.pdf |url-status=live }}</ref>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->

| legal_UN_comment =

| legal_status = <!--For countries not listed above-->

| elimination_half-life = 4 h to 11 h <small>(adults, normal renal function)</small><br />6 d to 10 d <small>(adults, impaired renal function)</small>

| excretion = urine (IV), feces (oral)

| index2_label = as HCl

| CAS_supplemental =

| PubChemSubstance = 46505261

| IUPHAR_ligand =

| UNII_Ref = {{fdacite|correct|FDA}}

| KEGG_Ref = {{keggcite|correct|kegg}}

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| KEGG2 = D00926

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| ChEMBL_Ref = {{ebicite|correct|EBI}}

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| synonyms =

| IUPAC_name = (1''S'',2''R'',18''R'',19''R'',22''S'',25''R'',28''R'',40''S'')- 48- {[(2''S'',3''R'',4''S'',5''S'',6''R'')- 3- {[(2''S'',4''S'',5''S'',6''S'')- 4- amino- 5- hydroxy- 4,6- dimethyloxan- 2- yl]oxy}- 4,5- dihydroxy- 6- (hydroxymethyl)oxan- 2- yl]oxy}- 22- (carbamoylmethyl)- 5,15- dichloro- 2,18,32,35,37- pentahydroxy- 19- [(2''R'')- 4- methyl- 2- (methylamino)pentanamido]- 20,23,26,42,44- pentaoxo- 7,13- dioxa- 21,24,27,41,43- pentaazaoctacyclo[26.14.2.2^3,6.2^14,17.1^8,12.1^29,33.0^10,25.0^34,39]pentaconta- 3,5,8(48),9,11,14,16,29(45),30,32,34,36,38,46,49- pentadecaene- 40- carboxylic acid

| SMILES = C[C@H]1[C@H]([C@@](C[C@@H](O1)O[C@@H]2[C@H]([C@@H]([C@H](O[C@H]2Oc3c4cc5cc3Oc6ccc(cc6Cl)[C@H]([C@H](C(=O)N[C@H](C(=O)N[C@H]5C(=O)N[C@@H]7c8ccc(c(c8)-c9c(cc(cc9O)O)[C@H](NC(=O)[C@H]([C@@H](c1ccc(c(c1)Cl)O4)O)NC7=O)C(=O)O)O)CC(=O)N)NC(=O)[C@@H](CC(C)C)NC)O)CO)O)O)(C)N)O

| StdInChI_comment =

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<!-- Definition and medical uses -->

'''Vancomycin''' is a [[glycopeptide antibiotic]] medication used to treat a number of [[bacterial infection]]s.<ref name=AHFS2015>{{cite web|title=Vancocin|url=https://www.drugs.com/monograph/vancocin.html|publisher=The American Society of Health-System Pharmacists|access-date=4 September 2015|url-status=live|archive-url=https://web.archive.org/web/20150906002445/http://www.drugs.com/monograph/vancocin.html|archive-date=6 September 2015}}</ref> It is used [[intravenously]] ([[Injection (medicine)|injection]] into a [[vein]]) as a treatment for complicated [[skin infection]]s, [[sepsis|bloodstream infection]]s, [[endocarditis]], bone and joint infections, and [[meningitis]] caused by [[methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']].<ref name="pmid21217178">{{cite journal | vauthors = Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray BE, J Rybak M, Talan DA, Chambers HF | title = Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant ''Staphylococcus aureus'' infections in adults and children: executive summary | journal = Clinical Infectious Diseases | volume = 52 | issue = 3 | pages = 285–92 | date = February 2011 | pmid = 21217178 | doi = 10.1093/cid/cir034 | doi-access = free }}</ref> Blood levels may be measured to determine the correct dose.<ref name=Ric2015/> Vancomycin is also taken [[Oral administration|orally]] (by mouth) as a treatment for severe [[Clostridium difficile colitis|''Clostridium difficile'' colitis]].<ref name=AHFS2015/> When taken orally it is poorly absorbed.<ref name=AHFS2015/>

<!-- Side effects and mechanism -->

Common side effects include pain in the area of injection and [[allergic reaction]]s.<ref name=AHFS2015/> Occasionally, [[hearing loss]], [[low blood pressure]], or [[bone marrow suppression]] occur.<ref name=AHFS2015/> Safety in pregnancy is not clear, but no evidence of harm has been found,<ref name=AHFS2015/><ref name="Australian Government-2015">{{cite web|title=Prescribing medicines in pregnancy database|url=http://www.tga.gov.au/hp/medicines-pregnancy.htm|work=Australian Government|date=September 2015|url-status=live|archive-url=https://web.archive.org/web/20140408040902/http://www.tga.gov.au/hp/medicines-pregnancy.htm#.U1Yw8Bc3tqw|archive-date=8 April 2014}}</ref> and it is likely safe for use when [[breastfeeding]].<ref name="Vancomycin use while Breastfeeding">{{cite web|title=Vancomycin use while Breastfeeding|url=https://www.drugs.com/breastfeeding/vancomycin.html|access-date=5 September 2015|url-status=live|archive-url=https://web.archive.org/web/20150907040510/http://www.drugs.com/breastfeeding/vancomycin.html|archive-date=7 September 2015}}</ref> It is a type of [[glycopeptide antibiotic]] and works by blocking the construction of a [[cell wall]].<ref name=AHFS2015/>

<!-- History, society and culture -->

Vancomycin was approved for medical use in the United States in 1958.<ref name="pmid16323120">{{cite journal |vauthors=Levine DP |title=Vancomycin: a history |journal=Clinical Infectious Diseases |volume=42 |issue= Suppl 1 |pages=S5–12 |date=January 2006 |pmid=16323120 |doi=10.1086/491709 |doi-access=free }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> The World Health Organization classifies vancomycin as critically important for human medicine.<ref name="World Health Organization-2019">{{cite book | vauthors=((World Health Organization)) | year=2019 | title=Critically important antimicrobials for human medicine | edition=6th revision | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | hdl=10665/312266 | isbn=978-92-4-151552-8 | hdl-access=free }}</ref> It is available as a generic medication.<ref name=Ric2015>{{cite book| vauthors = Hamilton R |title=Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition|date=2015|publisher=Jones & Bartlett Learning|isbn=978-1-284-05756-0|pages = 91}}</ref> Vancomycin is made by the soil bacterium ''[[Amycolatopsis orientalis]]''.<ref name=AHFS2015/>

==Medical uses==

Vancomycin is indicated for the treatment of serious, life-threatening infections by [[Gram-positive]] bacteria of both [[Aerobic bacteria|aerobic]] and [[Anaerobic bacteria|anaerobic]] types,<ref name="B978">{{cite book|doi=10.1016/B978-0-444-63749-9.00008-6 |title=From Natural Products to Drugs |series=Studies in Natural Products Chemistry |year=2016 | vauthors = Biondi S, Chugunova E, Panunzio M |volume=50 |pages=249–297 |isbn=978-0-444-63749-9 }}</ref> unresponsive to other antibiotics.<ref name="pmid31545906">{{cite journal |vauthors=Mühlberg E, Umstätter F, Kleist C, Domhan C, Mier W, Uhl P |title=Renaissance of vancomycin: approaches for breaking antibiotic resistance in multidrug-resistant bacteria |journal=Can J Microbiol |volume=66 |issue=1 |pages=11–16 |date=January 2020 |pmid=31545906 |doi=10.1139/cjm-2019-0309|hdl=1807/96894 |s2cid=202745549 |hdl-access=free }}</ref><ref name="pmid31899563">{{cite journal |vauthors=Stogios PJ, Savchenko A |title=Molecular mechanisms of vancomycin resistance |journal=Protein Sci |volume=29 |issue=3 |pages=654–669 |date=March 2020 |pmid=31899563 |pmc=7020976 |doi=10.1002/pro.3819 }}</ref><ref name="pmid25753888">{{cite journal |vauthors=Bruniera FR, Ferreira FM, Saviolli LR, Bacci MR, Feder D, da Luz Gonçalves Pedreira M, Sorgini Peterlini MA, Azzalis LA, Campos Junqueira VB, Fonseca FL |title=The use of vancomycin with its therapeutic and adverse effects: a review |journal=Eur Rev Med Pharmacol Sci |volume=19 |issue=4 |pages=694–700 |date=February 2015 |pmid=25753888 }}</ref>

The increasing emergence of vancomycin-resistant [[enterococcus|enterococci]] has resulted in the development of guidelines for use by the [[Centers for Disease Control]] Hospital Infection Control Practices Advisory Committee. These guidelines restrict use of vancomycin to these indications:<ref name="AMH2006">{{cite book | veditors = Rossi S | title = [[Australian Medicines Handbook]] | location = Adelaide | publisher = Australian Medicines Handbook | date = 2006 | isbn = 0-9757919-2-3 }}</ref><ref name=cdc>{{cite journal | title = Recommendations for preventing the spread of vancomycin resistance. Recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC) | journal = MMWR. Recommendations and Reports | volume = 44 | issue = RR-12 | pages = 1–13 | date = September 1995 | pmid = 7565541 | url = http://wonder.cdc.gov/wonder/prevguid/m0039349/m0039349.asp | url-status = live | archive-url = https://web.archive.org/web/20060923012326/http://wonder.cdc.gov/wonder/prevguid/m0039349/m0039349.asp | archive-date = 23 September 2006 }}</ref>

* treatment of serious infections caused by susceptible organisms [[Antimicrobial resistance|resistant]] to penicillins, such as [[MRSA|methicillin-resistant ''S.&nbsp;aureus'']] (MRSA) and multidrug-resistant ''[[Staphylococcus epidermidis|S. epidermidis]]'' (MRSE),

* treatment of infections in individuals with serious allergy to penicillins,

* treatment of [[pseudomembranous colitis]] caused by ''C.&nbsp;difficile''; in particular, in cases of relapse or where the infection is unresponsive to [[metronidazole]] treatment (for this indication, vancomycin is given orally, rather than by its typical intravenous route),

* treatment of infections caused by Gram-positive microorganisms in patients with serious allergies to beta-lactam antimicrobials,<ref name=cdc/>

* antibacterial prophylaxis for [[endocarditis]] following certain procedures in penicillin-[[hypersensitivity|hypersensitive]] individuals at high risk,<ref name=cdc/>

* surgical prophylaxis for major procedures involving implantation of [[prosthesis|prostheses]] in institutions with a high rate of MRSA or MRSE,<ref name=cdc/>

* early in treatment as an [[empiric therapy|empiric antibiotic]] for possible MRSA infection while waiting for culture identification of the infecting organism,

* halting the progression of [[primary sclerosing cholangitis]] and preventing symptoms; vancomycin does not cure the patient and success is limited,

* treatment of [[endophthalmitis]] by intravitreal injection for Gram-positive bacteria coverage; <ref name="pmid10691328">{{cite journal | vauthors = Lifshitz T, Lapid-Gortzak R, Finkelman Y, Klemperer I | title = Vancomycin and ceftazidime incompatibility upon intravitreal injection | journal = The British Journal of Ophthalmology | volume = 84 | issue = 1 | pages = 117–8 | date = January 2000 | pmid = 10691328 | pmc = 1723217 | doi = 10.1136/bjo.84.1.117a }}</ref> it has been used to prevent the condition, however, is not recommended due to the risk of side effects.<ref name="Office of the Commissioner">{{cite web|author=Office of the Commissioner|title=Safety Alerts for Human Medical Products - Intraocular Injections of a Compounded Triamcinolone, Moxifloxacin, and Vancomycin (TMV) Formulation: FDA Statement - Case of Hemorrhagic Occlusive Retinal Vasculitis|url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm578743.htm|website=www.fda.gov|access-date=6 October 2017|language=en|archive-date=3 October 2017|archive-url=https://web.archive.org/web/20171003211204/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm578743.htm|url-status=live}}</ref>

=== Spectrum of susceptibility ===

Vancomycin is a last resort medication for the treatment of [[sepsis]] and [[lower respiratory tract]], skin, and bone infections caused by Gram-positive bacteria. The [[minimum inhibitory concentration]] susceptibility data for a few medically significant bacteria are:<ref name="Vancomycin-TOKU-E">{{cite web |url=http://antibiotics.toku-e.com/antimicrobial_1182_1.html |title=Vancomycin (Vancocyn, Lyphocin) &#124; the Antimicrobial Index Knowledgebase - TOKU-E |access-date=26 February 2014 |url-status=live |archive-url=https://web.archive.org/web/20140227000847/http://antibiotics.toku-e.com/antimicrobial_1182_1.html |archive-date=27 February 2014 }}{{full citation needed|date=November 2014}}</ref>

* ''S. aureus'': 0.25&nbsp;μg/mL to 4.0&nbsp;μg/mL

* ''S. aureus'' (methicillin resistant or MRSA): 1&nbsp;μg/mL to 138&nbsp;μg/mL

* ''S. epidermidis'': ≤0.12&nbsp;μg/mL to 6.25&nbsp;μg/mL

==Side effects==

===Oral administration===

Common side effects associated with oral vancomycin administration (used to treat intestinal infections)<ref name="pmid29083794"/> include:

* gastrointestinal adverse effects (such as abdominal pain and nausea);<ref name="pmid29083794"/>

* dysgeusia (distorted sense of taste), in case of administration of vancomycin oral solution, but not in case of vancomycin capsules.<ref name="pmid29083794"/>

===Intravenous administration===

Serum vancomycin levels may be monitored in an effort to reduce side effects.<ref name="pmid38304144">{{cite journal |vauthors=Cafaro A, Barco S, Pigliasco F, Russo C, Mariani M, Mesini A, Saffioti C, Castagnola E, Cangemi G |title=Therapeutic drug monitoring of glycopeptide antimicrobials: An overview of liquid chromatography-tandem mass spectrometry methods |journal=J Mass Spectrom Adv Clin Lab |volume=31 |pages=33–39 |date=January 2024 |pmid=38304144 |doi=10.1016/j.jmsacl.2023.12.003 |pmc=10831154 |url=}}</ref> Still, the value of such monitoring has been questioned.<ref name="pmid8038306"/> Peak and trough levels are usually monitored, and for research purposes, the area under the concentration curve is also sometimes used.<ref name="pmid19586413"/> Toxicity is best monitored by looking at trough values.<ref name="pmid19586413">{{cite journal | vauthors = Lodise TP, Patel N, Lomaestro BM, Rodvold KA, Drusano GL | title = Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients | journal = Clinical Infectious Diseases | volume = 49 | issue = 4 | pages = 507–14 | date = August 2009 | pmid = 19586413 | doi = 10.1086/600884 | doi-access = free }}</ref>

Immunoassays are commonly used to measure levels of vancomycin.<ref name="pmid38304144"/>

Common [[adverse drug reaction]]s (≥1% of patients) associated with intravenous (IV) vancomycin include:

* pain, redness, or swelling at the injection site;<ref name="medline_a601167">{{cite web|url=https://medlineplus.gov/druginfo/meds/a601167.html|title=Vancomycin Injection: MedlinePlus Drug Information|website=medlineplus.gov|access-date=19 July 2023|archive-date=19 July 2023|archive-url=https://web.archive.org/web/20230719123049/https://medlineplus.gov/druginfo/meds/a601167.html|url-status=live}}</ref>

* vancomycin flushing syndrome (VFS), previously known as [[Vancomycin#Vancomycin Flushing Reaction (aka "Red man syndrome")|red man syndrome]] (or "redman syndrome");<ref name="pmid29083794">{{cite book | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK459263/ | pmid = 29083794 | year = 2023 | vauthors = Patel S, Preuss CV, Bernice F | chapter = Vancomycin | title = StatPearls [Internet] | location = Treasure Island (FL) | publisher = StatPearls Publishing | access-date = 19 July 2023 | archive-date = 11 April 2023 | archive-url = https://web.archive.org/web/20230411041350/https://www.ncbi.nlm.nih.gov/books/NBK459263/ | url-status = live }}</ref>

* thrombophlebitis, which is common when administered through peripheral catheters but not when central venous catheters are used, although central venous catheters are a predisposing factor for upper-extremity deep-vein thrombosis.<ref name="pmid22669879">{{cite journal |vauthors=Leroy S, Piquet P, Chidiac C, Ferry T |title=Extensive thrombophlebitis with gas associated with continuous infusion of vancomycin through a central venous catheter |journal=BMJ Case Rep |volume=2012 |pages= bcr2012006347|date=May 2012 |pmid=22669879 |pmc=4543351 |doi=10.1136/bcr-2012-006347}}</ref>

Damage to the kidneys ([[nephrotoxicity]]) and to the hearing ([[ototoxicity]]) were side effects of the early impure versions of vancomycin, and these were prominent in the clinical trials conducted in the mid-1950s.<ref name="pmid16323120" /><ref name="pmid16323117" /> Later trials using purer forms of vancomycin found [[nephrotoxicity]] is an infrequent adverse effect (0.1% to 1% of patients), but this is accentuated in the presence of [[aminoglycoside]]s.<ref name="pmid6219616">{{cite journal | vauthors = Farber BF, Moellering RC | title = Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981 | journal = Antimicrobial Agents and Chemotherapy | volume = 23 | issue = 1 | pages = 138–41 | date = January 1983 | pmid = 6219616 | pmc = 184631 | doi = 10.1128/AAC.23.1.138 }}</ref>

Rare adverse effects associated with intravenous (IV) vancomycin (<0.1% of patients) include: [[anaphylaxis]], [[toxic epidermal necrolysis]], [[erythema multiforme]], [[superinfection]], [[thrombocytopenia]], [[neutropenia]], [[leukopenia]], [[tinnitus]], [[dizziness]] and/or [[ototoxicity]], and [[Drug reaction with eosinophilia and systemic symptoms|DRESS syndrome]].<ref name="pmid22525393">{{cite journal | vauthors = Blumenthal KG, Patil SU, Long AA | title = The importance of vancomycin in drug rash with eosinophilia and systemic symptoms (DRESS) syndrome | journal = Allergy and Asthma Proceedings | volume = 33 | issue = 2 | pages = 165–71 | date = 1 April 2012 | pmid = 22525393 | doi = 10.2500/aap.2012.33.3498 }}</ref>

Vancomycin can induce platelet-reactive antibodies in the patient, leading to severe [[thrombocytopenia]] and bleeding with florid [[Petechia|petechial hemorrhages]], [[ecchymoses]], and wet [[purpura]].<ref name="pmid17329697">{{cite journal | vauthors = Von Drygalski A, Curtis BR, Bougie DW, McFarland JG, Ahl S, Limbu I, Baker KR, Aster RH | title = Vancomycin-induced immune thrombocytopenia | journal = The New England Journal of Medicine | volume = 356 | issue = 9 | pages = 904–10 | date = March 2007 | pmid = 17329697 | doi = 10.1056/NEJMoa065066 | doi-access = free }}</ref>

Historically, vancomycin has been considered a nephrotoxic and ototoxic drug, based on numerous case reports in the medical literature following initial approval by the FDA in 1958. However, as the use of vancomycin increased with the spread of MRSA beginning in the 1970s, toxicity risks were reassessed. With the removal of impurities present in earlier formulations of the drug,<ref name="pmid16323120"/> and with the introduction of [[therapeutic drug monitoring]], the risk for severe toxicity has been reduced.

====Nephrotoxicity====

The extent of nephrotoxicity for vancomycin remains controversial.<ref name="pmid6219616-2"/> In 1980s, vancomycin with a purity >&nbsp;90% was available, and kidney toxicity defined by an increase in serum creatinine of at least 0.5&nbsp;mg/dL, occurred in only about 5% of patients.<ref name="pmid6219616-2">{{cite journal | vauthors = Farber BF, Moellering RC Jr | title = Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981. | journal = Antimicrob Agents Chemother | volume = 1 | pages = 138–41 | date = 1983 | issue = 1 | doi = 10.1128/AAC.23.1.138 | pmid = 6219616 | pmc = 184631 }}</ref> However, dosing guidelines from the 1980s until 2008 recommended vancomycin trough concentrations between 5 and 15&nbsp;μg/mL.<ref name="Rybak 2009 p.">{{cite journal | vauthors = Rybak MJ, Lomaestro BM, Rotschafer JC, et al. | title = Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. | journal = Clin Infect Dis | volume = 49 | pages = 325–7 | date = 2009 | issue = 3 | doi = 10.1086/600877 | pmid = 19569969 | s2cid = 32585259 | doi-access = free }}</ref> Concern for treatment failures prompted recommendations for higher dosing (troughs 15 to 20 μg/mL) for serious infection, and acute kidney injury (AKI) rates attributable to the vancomycin increased.<ref name="Pais 2020 p.">{{cite journal | vauthors = Pais GM, Liu J, Zepcan S, Avedissian SN, Rhodes NJ, Downes KJ, Moorthy GS, Scheetz MH | title = Vancomycin-Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention | journal = Pharmacotherapy | volume = 40 | issue = 5 | pages = 438–454 | date = 2020 | doi = 10.1002/phar.2388 | pmid = 32239518 | pmc = 7331087 }}</ref>

Importantly, the risk of AKI increases with co-administration of other known nephrotoxins, in particular, aminoglycosides. Furthmore, the sort of infections treated with vancomycin may also cause AKI and sepsis is the most common cause of AKI in critically ill patients. Finally, studies in humans are mainly associations studies where the cause of AKI is usually multifacotorial.{{cn|date=March 2023}}

Animal studies have demonstrated that higher doses and longer duration of vancomycin exposure correlates with increased histopathologic damage and elevations in urinary biomarkers of AKI.37-38<ref name="Fuchs 2012 p.">{{cite journal | vauthors = Fuchs TC, Frick K, Emde B, Czasch S, von Landenberg F, Hewitt P | title = Evaluation of novel acute urinary rat kidney toxicity biomarker for subacute toxicity studies in preclinical trials. | journal = Toxicol Pathol | volume = 40 | pages = 1031–48 | date = 2012 | issue = 7 | doi = 10.1177/0192623312444618 | pmid = 22581810 | s2cid = 45358082 }}</ref> Damage is most prevalent at the proximal tubule, which is further supported by urinary biomarkers, such as kidney injury molecule-1 (KIM-1), clusterin, and osteopontin (OPN),<ref name="Pais 2019 p.">{{cite journal | vauthors = Pais GM, Avedissian SN, ODonnell JN et al. | title = Comparative performance of urinary biomarkers for vancomycin-induced kidney injury according to timeline of injury. | journal = Antimicrob Agents Chemother | year = 2019 | volume = 63 | issue = 7 | pages = e00079–19 | doi = 10.1128/AAC.00079-19 | pmid = 30988153 | pmc = 6591602 }}</ref>

and in humans, insulin-like growth factor binding protein 7 (IGFBP7) as part of the nephrocheck test.<ref name="Ostermann 2018 p.">{{cite journal | vauthors = Ostermann M, McCullough PA, Forni LG | title = Kinetics of Urinary Cell Cycle Arrest Markers for Acute Kidney Injury Following Exposure to Potential Renal Insults. | journal = Crit Care Med | volume = 46 | issue = 3 | pages = 375–383 | date = 2018 | doi = 10.1097/CCM.0000000000002847 | pmid = 29189343 | pmc = 5821475 }}</ref>

The mechanisms that underlie the pathogenesis of vancomycin nephrotoxicity are multifactorial but include interstitial nephritis, tubular injury due to oxidative stress, and cast formation.<ref name="Pais 2020 p."/>

[[Therapeutic drug monitoring]] can be used during vancomycin therapy to minimize the risk of nephrotoxicity associated with excessive drug exposure. Immunoassays are commonly utilized for measuring vancomycin levels.<ref name="pmid38304144"/>

In children, the concomitant administration of vancomycin and [[piperacillin/tazobactam]] has been associated with an elevated incidence of AKI, relative to other antibiotic regimens.<ref name="pmid38279799">{{cite journal |vauthors=Zhang M, Huang L, Zhu Y, Zeng L, Jia ZJ, Cheng G, Li H, Zhang L |title=Epidemiology of Vancomycin in Combination With Piperacillin/Tazobactam-Associated Acute Kidney Injury in Children: A Systematic Review and Meta-analysis |journal=Ann Pharmacother |volume= |pages=10600280231220379 |date=January 2024 |pmid=38279799 |doi=10.1177/10600280231220379 |s2cid=267300725 |url=}}</ref>

====Ototoxicity====<!-- This section is linked from Vancomycin (this page)-->

Attempts to establish rates of vancomycin-induced [[ototoxicity]] are even more difficult due to the scarcity of quality evidence. The current consensus is that clearly related cases of vancomycin ototoxicity are rare.<ref name="pmid31693679">{{cite journal |vauthors=Humphrey C, Veve MP, Walker B, Shorman MA |title=Long-term vancomycin use had low risk of ototoxicity |journal=PLOS ONE |volume=14 |issue=11 |pages=e0224561 |date=2019 |pmid=31693679 |pmc=6834250 |doi=10.1371/journal.pone.0224561 |bibcode=2019PLoSO..1424561H |doi-access=free }}</ref><ref name="pmid33767665">{{cite journal |vauthors=Rybak LP, Ramkumar V, Mukherjea D |title=Ototoxicity of Non-aminoglycoside Antibiotics |journal=Front Neurol |volume=12 |pages=652674 |date=2021 |pmid=33767665 |pmc=7985331 |doi=10.3389/fneur.2021.652674 |url= |doi-access=free }}</ref> The association between vancomycin serum levels and ototoxicity is also uncertain. While cases of ototoxicity have been reported in patients whose vancomycin serum level exceeded 80&nbsp;μg/mL,<ref name="pmid12225605">{{cite journal |vauthors=Launay-Vacher V, Izzedine H, Mercadal L, Deray G |title=Clinical review: use of vancomycin in haemodialysis patients |journal=Crit Care |volume=6 |issue=4 |pages=313–6 |date=August 2002 |pmid=12225605 |pmc=137311 |doi=10.1186/cc1516 |url= |doi-access=free }}</ref> cases have been reported in patients with therapeutic levels, as well. Thus, whether [[therapeutic drug monitoring]] of vancomycin for the purpose of maintaining "therapeutic" levels will prevent ototoxicity also remains unproven.<ref name="pmid12225605"/> Still, therapeutic drug monitoring can be used during vancomycin therapy to minimize the risk of ototoxicity associated with excessive drug exposure.<ref name="pmid38304144"/>

====Interactions with other nephrotoxins====

Another area of controversy and uncertainty concerns the question of whether, and if so, to what extent, vancomycin increases the toxicity of other nephrotoxins. Clinical studies have yielded variable results, but animal models indicate some increased nephrotoxic effect probably occurs when vancomycin is added to nephrotoxins such as aminoglycosides. However, a dose- or serum level-effect relationship has not been established.{{cn|date=March 2023}}

====Vancomycin Flushing Reaction (aka "Red man syndrome")====

{{see also|Erythroderma}}

Vancomycin is recommended to be administered in a dilute solution slowly, over at least 60 min (maximum rate of 10&nbsp;mg/min for doses >500&nbsp;mg)<ref name="AMH2006" /> due to the high incidence of pain and thrombophlebitis and to avoid an infusion reaction known as vancomycin flushing reaction. This phenomenon has been often clinically referred to as "red man syndrome". The reaction usually appears within 4 to 10&nbsp;min after the commencement or soon after the completion of an infusion and is characterized by flushing and/or an [[erythematous]] rash that affects the face, neck, and upper torso, attributed to the release of histamine from mast cells. This reaction is caused by the interaction of vancomycin with [[MRGPRX2]], a GPCR mediating IgE-independent mast cell degranulation.<ref name="pmid28367504">{{cite journal | vauthors = Azimi E, Reddy VB, Lerner EA | title = Brief communication: MRGPRX2, atopic dermatitis and red man syndrome | journal = Itch | volume = 2 | issue = 1 | pages = e5 | date = March 2017 | pmid = 28367504 | pmc = 5375112 | doi = 10.1097/itx.0000000000000005 }}</ref> Less frequently, [[hypotension]] and [[angioedema]] may also occur. Symptoms may be treated or prevented with [[antihistamine]]s, including [[diphenhydramine]], and are less likely to occur with slow infusion.<ref name="Sivagnanam2003">{{cite journal | vauthors = Sivagnanam S, Deleu D | title = Red man syndrome | journal = Critical Care | volume = 7 | issue = 2 | pages = 119–20 | date = April 2003 | pmid = 12720556 | pmc = 270616 | doi = 10.1186/cc1871 | doi-access = free }}</ref><ref name="Andrews">{{cite book | vauthors = James W, Berger T, Elston D | date = 2005 | title = Andrews' Diseases of the Skin: Clinical Dermatology | edition = 10th |pages=120–1| publisher = Saunders | isbn = 0-7216-2921-0 }}</ref>

==Dosing considerations==

The recommended intravenous dosage in adults is 500&nbsp;mg iv every 6 hours or 1000&nbsp;mg every 12 hours, with modification to achieve a therapeutic range as needed. The recommended oral dosage in the treatment of antibiotic-induced pseudomembranous enterocolitis is 125 to 500&nbsp;mg every 6 hours for 7 to 10 days.<ref name="pmid31644188">{{citation | publisher=National Institute of Diabetes and Digestive and Kidney Diseases | publication-place=Bethesda (MD) | year=2012 | pmid=31644188 | url=http://www.ncbi.nlm.nih.gov/books/NBK548881/ | access-date=25 February 2021 | page= | title=Vancomycin | archive-date=14 May 2021 | archive-url=https://web.archive.org/web/20210514164828/https://www.ncbi.nlm.nih.gov/books/NBK548881/ | url-status=live }}[[File:CC-BY icon.svg|50px]] Text was copied from this source, which is available under a [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License] {{Webarchive|url=https://web.archive.org/web/20171016050101/https://creativecommons.org/licenses/by/4.0/ |date=16 October 2017 }}.</ref>

Dose optimization and target attainment of vancomycin in children involves adjusting the dosage of the antibiotic to maximize its effectiveness while minimizing the risk of adverse effects, specifically acute kidney injury. Dose optimization is achieved through therapeutic drug monitoring (TDM), which allows to measure vancomycin levels in the blood and tailor the dosage accordingly. TDM using area under the curve (AUC)-guided dosing, preferably with Bayesian forecasting, is recommended to ensure that the AUC0-24h/minimal inhibitory concentration (MIC) ratio is maintained above a certain threshold (400-600) associated with optimal efficacy.<ref name="pmid38325652">{{cite journal | vauthors = Cafaro A, Stella M, Mesini A, Castagnola E, Cangemi G, Mattioli F, Baiardi G | title = Dose optimization and target attainment of vancomycin in children | journal = Clinical Biochemistry | volume = 125 | issue = | pages = 110728 | date = March 2024 | pmid = 38325652 | doi = 10.1016/j.clinbiochem.2024.110728 | s2cid = 267502279 }}</ref>

==Routes of administration==

In the [[United States]], vancomycin is approved by the [[Food and Drug Administration]] for either intravenous or oral administration.<ref name="pmid29083794"/>

===Intravenous===

Vancomycin must be given [[intravenous]]ly (IV) for systemic therapy, since it is poorly absorbed from the intestine. It is a large hydrophilic molecule that partitions poorly across the gastrointestinal [[mucosa]]. Due to short half-life, it is often injected twice daily.<ref name=VB2006>{{cite journal | vauthors = Van Bambeke F | title = Glycopeptides and glycodepsipeptides in clinical development: a comparative review of their antibacterial spectrum, pharmacokinetics and clinical efficacy | journal = Current Opinion in Investigational Drugs | volume = 7 | issue = 8 | pages = 740–9 | date = August 2006 | pmid = 16955686 }}</ref>

===Oral===

The only approved indication for oral vancomycin therapy is in the treatment of pseudomembranous colitis, where it must be given orally to reach the site of infection in the colon. Following oral administration, the fecal concentration of vancomycin is around 500&nbsp;μg/mL<ref name="pmid9314469">{{cite journal | vauthors = Edlund C, Barkholt L, Olsson-Liljequist B, Nord CE | title = Effect of vancomycin on intestinal flora of patients who previously received antimicrobial therapy | journal = Clinical Infectious Diseases | volume = 25 | issue = 3 | pages = 729–32 | date = September 1997 | pmid = 9314469 | doi = 10.1086/513755 | doi-access = free }}</ref> (sensitive strains of ''[[Clostridium difficile]]'' have a mean inhibitory concentration of ≤2&nbsp;μg/mL<ref name="pmid12019070">{{cite journal | vauthors = Peláez T, Alcalá L, Alonso R, Rodríguez-Créixems M, García-Lechuz JM, Bouza E | title = Reassessment of Clostridium difficile susceptibility to metronidazole and vancomycin | journal = Antimicrobial Agents and Chemotherapy | volume = 46 | issue = 6 | pages = 1647–50 | date = June 2002 | pmid = 12019070 | pmc = 127235 | doi = 10.1128/AAC.46.6.1647-1650.2002 }}</ref>)

===Inhaled (off-label)===

Inhaled vancomycin can also be used [[off-label]],<ref name="pmid31964790">{{cite journal |vauthors=Waterer G, Lord J, Hofmann T, Jouhikainen T |title=Phase I, Dose-Escalating Study of the Safety and Pharmacokinetics of Inhaled Dry-Powder Vancomycin (AeroVanc) in Volunteers and Patients with Cystic Fibrosis: a New Approach to Therapy for Methicillin-Resistant Staphylococcus aureus |journal=Antimicrob Agents Chemother |volume=64 |issue=3 |pages= |date=February 2020 |pmid=31964790 |pmc=7038285 |doi=10.1128/AAC.01776-19 |url=}}</ref> via [[nebulizer]], for the treatment of various infections of the upper and lower respiratory tract.<ref name="pmid25533880">{{cite journal |vauthors=Falagas ME, Trigkidis KK, Vardakas KZ |title=Inhaled antibiotics beyond aminoglycosides, polymyxins and aztreonam: A systematic review |journal=Int J Antimicrob Agents |volume=45 |issue=3 |pages=221–33 |date=March 2015 |pmid=25533880 |doi=10.1016/j.ijantimicag.2014.10.008 |url=}}</ref><ref name="Inhaled-Vancomycin-Monograph">{{cite web|url=https://pch.health.wa.gov.au/~/media/Files/Hospitals/PCH/General-documents/Health-professionals/ChAMP-Monographs/Vanomycin-Inhaled.pdf|title=Inhaled Vancomycin Monograph - Paediatric|publisher=Perth Children's Hospital (PCH)|access-date=19 July 2023|archive-date=14 March 2023|archive-url=https://web.archive.org/web/20230314160643/https://pch.health.wa.gov.au/~/media/Files/Hospitals/PCH/General-documents/Health-professionals/ChAMP-Monographs/Vanomycin-Inhaled.pdf|url-status=live}}</ref><ref name="Palmer-2017">{{cite book|doi=10.1183/1393003.congress-2017.OA4655 |chapter=Eradication of MRSA ventilator-associated infection with inhaled vancomycin |title=Respiratory Infections |year=2017 | vauthors = Palmer LB, Smaldone GC |pages=OA4655 }}</ref><ref name="MRSA-ventilator">{{cite web|url=https://dig.pharmacy.uic.edu/faqs/2020-2/march-2020-faqs/is-there-literature-describing-the-efficacy-or-safety-of-inhaled-vancomycin-to-treat-mrsa-ventilator-associated-tracheobronchitis/|title=Is there literature describing the efficacy or safety of inhaled vancomycin to treat MRSA ventilator-associated tracheobronchitis? &#124; Drug Information Group &#124; University of Illinois Chicago|access-date=19 July 2023|archive-date=19 July 2023|archive-url=https://web.archive.org/web/20230719102710/https://dig.pharmacy.uic.edu/faqs/2020-2/march-2020-faqs/is-there-literature-describing-the-efficacy-or-safety-of-inhaled-vancomycin-to-treat-mrsa-ventilator-associated-tracheobronchitis/|url-status=live}}</ref><ref name="pmid25143711">{{cite journal |vauthors=Zarogoulidis P, Kioumis I, Lampaki S, Organtzis J, Porpodis K, Spyratos D, Pitsiou G, Petridis D, Pataka A, Huang H, Li Q, Yarmus L, Hohenforst-Schmidt W, Pezirkianidis N, Zarogoulidis K |title=Optimization of nebulized delivery of linezolid, daptomycin, and vancomycin aerosol |journal=Drug Des Devel Ther |volume=8 |pages=1065–72 |date=2014 |pmid=25143711 |pmc=4136957 |doi=10.2147/DDDT.S66576 |url= |doi-access=free }}</ref>

===Rectal (off-label)===

Rectal administration is an [[off-label]] use of vancomycin for the treatment of ''[[Clostridium difficile]]'' infection.<ref name="pmid29083794"/>

==Therapeutic drug monitoring==

Plasma level monitoring of vancomycin is necessary due to the drug's biexponential distribution, intermediate hydrophilicity, and potential for ototoxicity and nephrotoxicity, especially in populations with poor renal function and/or increased propensity to bacterial infection. Vancomycin activity is considered to be time-dependent; that is, antimicrobial activity depends on the duration that the serum drug concentration exceeds the [[minimum inhibitory concentration]] <!-- (MIC) --> of the target organism. Thus, peak serum levels have not been shown to correlate with efficacy or toxicity; indeed, concentration monitoring is unnecessary in most cases. Circumstances in which [[therapeutic drug monitoring]] <!-- (TDM) --> is warranted include: patients receiving concomitant aminoglycoside therapy, patients with (potentially) altered [[pharmacokinetics|pharmacokinetic]] parameters, patients on [[hemodialysis|haemodialysis]], patients administered high-dose or prolonged treatment, and patients with impaired renal function. In such cases, trough concentrations are measured.<ref name="AMH2006" /><ref name="pmid8038306">{{cite journal | vauthors = Cantú TG, Yamanaka-Yuen NA, Lietman PS | title = Serum vancomycin concentrations: reappraisal of their clinical value | journal = Clinical Infectious Diseases | volume = 18 | issue = 4 | pages = 533–43 | date = April 1994 | pmid = 8038306 | doi = 10.1093/clinids/18.4.533 }}</ref><ref name="pmid8038307">{{cite journal | vauthors = Moellering RC | title = Monitoring serum vancomycin levels: climbing the mountain because it is there? | journal = Clinical Infectious Diseases | volume = 18 | issue = 4 | pages = 544–6 | date = April 1994 | pmid = 8038307 | doi = 10.1093/clinids/18.4.544 }}</ref><ref name="Karam1999">{{cite journal | vauthors = Karam CM, McKinnon PS, Neuhauser MM, Rybak MJ | s2cid = 24947921 | title = Outcome assessment of minimizing vancomycin monitoring and dosing adjustments | journal = Pharmacotherapy | volume = 19 | issue = 3 | pages = 257–66 | date = March 1999 | pmid = 10221365 | doi = 10.1592/phco.19.4.257.30933 }}</ref>

Therapeutic drug monitoring is also used for dose optimization of vancomycin in treating children.<ref name="pmid38325652"/>

Target ranges for serum vancomycin concentrations have changed over the years. Early authors suggested peak levels of 30 to 40&nbsp;mg/L and [[trough levels]] of 5 to 10&nbsp;mg/L,<ref name="pmid909314">{{cite journal | vauthors = Geraci JE | title = Vancomycin | journal = Mayo Clinic Proceedings | volume = 52 | issue = 10 | pages = 631–4 | date = October 1977 | pmid = 909314 }}</ref>

but current recommendations are that peak levels need not be measured and that [[trough levels]] of 10 to 15&nbsp;mg/L or 15 to 20&nbsp;mg/L, depending on the nature of the infection and the specific needs of the patient, may be appropriate.<ref name="pmid19106348">{{cite journal | vauthors = Rybak M, Lomaestro B, Rotschafer JC, Moellering R, Craig W, Billeter M, Dalovisio JR, Levine DP | title = Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists | journal = American Journal of Health-System Pharmacy | volume = 66 | issue = 1 | pages = 82–98 | date = January 2009 | pmid = 19106348 | doi = 10.2146/ajhp080434 | s2cid = 11692065 | citeseerx = 10.1.1.173.737 }}</ref><ref name="pmid19299472">{{cite journal | vauthors = Thomson AH, Staatz CE, Tobin CM, Gall M, Lovering AM | title = Development and evaluation of vancomycin dosage guidelines designed to achieve new target concentrations | journal = The Journal of Antimicrobial Chemotherapy | volume = 63 | issue = 5 | pages = 1050–7 | date = May 2009 | pmid = 19299472 | doi = 10.1093/jac/dkp085 | url = http://strathprints.strath.ac.uk/13001/ | doi-access = free | access-date = 15 September 2017 | archive-date = 15 September 2017 | archive-url = https://web.archive.org/web/20170915161446/http://strathprints.strath.ac.uk/13001/ | url-status = live }}</ref> Using measured vancomycin concentrations to calculate doses optimizes therapy in patients with [[augmented renal clearance]].<ref name="pmid31534058">{{cite journal | vauthors = Izumisawa T, Kaneko T, Soma M, Imai M, Wakui N, Hasegawa H, Horino T, Takahashi N | title = Augmented Renal Clearance of Vancomycin in Hematologic Malignancy Patients | journal = Biological & Pharmaceutical Bulletin | volume = 42 | issue = 12 | pages = 2089–2094 | date = December 2019 | pmid = 31534058 | doi = 10.1248/bpb.b19-00652 | doi-access = free }}</ref>

==Chemistry==

Vancomycin is a branched [[wikt:tricyclic|tricyclic]] [[Glycosylation|glycosylated]] [[nonribosomal peptide]] produced by the [[Actinomycetota]] species ''Amycolatopsis orientalis'' (formerly designated ''Nocardia orientalis'').

Vancomycin exhibits [[atropisomer]]ism—it has multiple chemically distinct [[rotamer]]s owing to the rotational restriction of some of the bonds. The form present in the drug is the thermodynamically more stable [[Conformational isomerism|conformer]].{{Citation needed|date=April 2011}}

==Biosynthesis==

Vancomycin is made by the soil bacterium ''[[Amycolatopsis orientalis]]''.<ref name=AHFS2015/>

[[Image:Vancomycin Modules.png|thumb|left|Figure 1: Modules and domains of vancomycin assembly]]

Vancomycin biosynthesis occurs primarily via three [[Nonribosomal peptide synthetase|nonribosomal protein syntheses]] (NRPSs) VpsA, VpsB, and VpsC.<ref name="pmid18414736">{{cite journal | vauthors = Samel SA, Marahiel MA, Essen LO | title = How to tailor non-ribosomal peptide products--new clues about the structures and mechanisms of modifying enzymes | journal = Molecular BioSystems | volume = 4 | issue = 5 | pages = 387–93 | date = May 2008 | pmid = 18414736 | doi = 10.1039/b717538h }}</ref> The [[enzymes]] determine the amino acid sequence during its assembly through its 7 modules. Before vancomycin is assembled through NRPS, the non-proteinogenic [[amino acids]] are first synthesized. <small>L</small>-tyrosine is modified to become the β-hydroxytyrosine (β-HT) and 4-hydroxyphenylglycine (4-Hpg) residues. 3,5 dihydroxyphenylglycine ring (3,5-DPG) is derived from acetate.<ref name="isbn0-471-49641-3">{{cite book | vauthors = Dewick PM |title=Medicinal natural products: a biosynthetic approach |publisher=Wiley |location=New York |year=2002 |isbn=978-0-471-49641-0}}{{page needed|date=November 2014}}</ref>

[[Image:Linear heptapeptide of Vancomycin.png|thumb|Figure 2: Linear heptapeptide, which consists of modified aromatic rings]]

Nonribosomal peptide synthesis occurs through distinct [[Protein domain|modules]] that can load and extend the [[protein]] by one amino acid per module through the [[amide]] bond formation at the contact sites of the activating domains.<ref name="pmid9545426">{{cite journal | vauthors = van Wageningen AM, Kirkpatrick PN, Williams DH, Harris BR, Kershaw JK, Lennard NJ, Jones M, Jones SJ, Solenberg PJ | title = Sequencing and analysis of genes involved in the biosynthesis of a vancomycin group antibiotic | journal = Chemistry & Biology | volume = 5 | issue = 3 | pages = 155–62 | date = March 1998 | pmid = 9545426 | doi = 10.1016/S1074-5521(98)90060-6 | doi-access = free }}</ref> Each module typically consists of an adenylation (A) domain, a [[peptidyl carrier protein]] (PCP) domain, and a condensation (C) domain. In the A domain, the specific amino acid is activated by converting into an aminoacyl adenylate enzyme complex attached to a 4'phosphopantetheine cofactor by thioesterification.<ref name="pmid1744112">{{cite journal | vauthors = Schlumbohm W, Stein T, Ullrich C, Vater J, Krause M, Marahiel MA, Kruft V, Wittmann-Liebold B | title = An active serine is involved in covalent substrate amino acid binding at each reaction center of gramicidin S synthetase | journal = The Journal of Biological Chemistry | volume = 266 | issue = 34 | pages = 23135–41 | date = December 1991 | doi = 10.1016/S0021-9258(18)54473-2 | pmid = 1744112 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1744112 | doi-access = free | access-date = 3 June 2008 | archive-date = 13 July 2024 | archive-url = https://web.archive.org/web/20240713122158/https://www.jbc.org/article/S0021-9258(18)54473-2/fulltext | url-status = live }}</ref><ref name="pmid8663196">{{cite journal | vauthors = Stein T, Vater J, Kruft V, Otto A, Wittmann-Liebold B, Franke P, Panico M, McDowell R, Morris HR | title = The multiple carrier model of nonribosomal peptide biosynthesis at modular multienzymatic templates | journal = The Journal of Biological Chemistry | volume = 271 | issue = 26 | pages = 15428–35 | date = June 1996 | pmid = 8663196 | doi = 10.1074/jbc.271.26.15428 | doi-access = free }}</ref> The complex is then transferred to the PCP domain with the expulsion of AMP. The PCP domain uses the attached 4'-phosphopantethein prosthetic group to load the growing peptide chain and their precursors.<ref name="pmid12167866">{{cite journal | vauthors = Kohli RM, Walsh CT, Burkart MD | s2cid = 4380296 | title = Biomimetic synthesis and optimization of cyclic peptide antibiotics | journal = Nature | volume = 418 | issue = 6898 | pages = 658–61 | date = August 2002 | pmid = 12167866 | doi = 10.1038/nature00907 | bibcode = 2002Natur.418..658K }}</ref> The organization of the modules necessary to biosynthesize Vancomycin is shown in Figure 1. In the biosynthesis of Vancomycin, additional modification domains are present, such as the [[epimerization]] (E) domain, which isomerizes the amino acid from one [[stereochemistry]] to another, and a thioesterase domain (TE) is used as a catalyst for cyclization and releases of the molecule via a [[thioesterase]] scission.{{cn|date=March 2023}}

[[Image:Biosynthesis of Vancomycin.png|thumb|left|Figure 3: Modifications necessary for vancomycin to become biologically active]]

A set of NRPS enzymes (peptide synthase VpsA, VpsB, and VpsC) are responsible for assembling the heptapeptide. (Figure 2).<ref name="pmid9545426"/> VpsA codes for modules 1, 2, and 3. VpsB codes for modules 4, 5, and 6, and VpsC codes for module 7. The vancomycin aglycone contains 4 D-amino acids, although the NRPSs only contain 3 epimerization domains. The origin of D-Leu at residue 1 is not known. The three peptide syntheses are located at the start of the region of the bacterial genome linked with antibiotic biosynthesis, and span 27 kb.<ref name="pmid9545426"/>

β-hydroxytyrosine (β-HT) is synthesized prior to incorporation into the heptapeptide backbone. L-tyrosine is activated and loaded on the NRPS VpsD, hydroxylated by OxyD, and released by the thioesterase Vhp.<ref name="pmid15342578">{{cite journal | vauthors = Puk O, Bischoff D, Kittel C, Pelzer S, Weist S, Stegmann E, Süssmuth RD, Wohlleben W | title = Biosynthesis of chloro-beta-hydroxytyrosine, a nonproteinogenic amino acid of the peptidic backbone of glycopeptide antibiotics | journal = Journal of Bacteriology | volume = 186 | issue = 18 | pages = 6093–100 | date = September 2004 | pmid = 15342578 | pmc = 515157 | doi = 10.1128/JB.186.18.6093-6100.2004 }}</ref> The timing of the chlorination by halogenase VhaA during biosynthesis is currently undetermined, but is proposed to occur before the complete assembly of the heptapeptide.<ref name="pmid24756572">{{cite journal | vauthors = Schmartz PC, Zerbe K, Abou-Hadeed K, Robinson JA | title = Bis-chlorination of a hexapeptide-PCP conjugate by the halogenase involved in vancomycin biosynthesis | journal = Organic & Biomolecular Chemistry | volume = 12 | issue = 30 | pages = 5574–7 | date = August 2014 | pmid = 24756572 | doi = 10.1039/C4OB00474D | url = http://www.zora.uzh.ch/id/eprint/103226/1/manuscript.pdf | doi-access = free | access-date = 2 February 2024 | archive-date = 2 February 2024 | archive-url = https://web.archive.org/web/20240202143359/https://www.zora.uzh.ch/id/eprint/103226/1/manuscript.pdf | url-status = live }}</ref>

After the linear heptapeptide molecule is synthesized, vancomycin has to undergo further modifications, such as oxidative cross-linking and [[glycosylation]], in trans{{Clarify|date=August 2011}} by distinct enzymes, referred to as tailoring enzymes, to become biologically active (Figure 3). To convert the linear heptapeptide to cross-linked, glycosylated vancomycin, six enzymes, are required. The enzymes OxyA, OxyB, OxyC, and OxyD are cytochrome P450 enzymes. OxyB catalyzes oxidative cross-linking between residues 4 and 6, OxyA between residues 2 and 4, and OxyC between residues 5 and 7. This cross-linking occurs while the heptapeptide is covalently bound to the PCP domain of the 7th NRPS module. These P450s are recruited by the X domain present in the 7th NRPS module, which is unique to glycopeptide antibiotic biosynthesis.<ref name="pmid25686610">{{cite journal | vauthors = Haslinger K, Peschke M, Brieke C, Maximowitsch E, Cryle MJ | s2cid = 4466657 | title = X-domain of peptide synthetases recruits oxygenases crucial for glycopeptide biosynthesis | journal = Nature | volume = 521 | issue = 7550 | pages = 105–9 | date = May 2015 | pmid = 25686610 | doi = 10.1038/nature14141 | bibcode = 2015Natur.521..105H | url = http://www.nature.com/articles/nature14141 | url-access = subscription | access-date = 23 June 2020 | archive-date = 24 February 2021 | archive-url = https://web.archive.org/web/20210224172657/https://www.nature.com/articles/nature14141 | url-status = live }}</ref> The cross-linked heptapeptide is then released by the action of the TE domain, and methyltransferase Vmt then ''N''-methylates the terminal leucine residue. GtfE then joins D-glucose to the phenolic oxygen of residue 4, followed by the addition of [[vancosamine]] catalyzed by GtfD.{{cn|date=March 2023}}

Some of the glycosyltransferases capable of glycosylating vancomycin and related nonribosomal peptides display notable permissivity and have been employed for generating libraries of differentially glycosylated analogs through a process known as [[glycorandomization]].<ref name="pmid14608364">{{cite journal | vauthors = Fu X, Albermann C, Jiang J, Liao J, Zhang C, Thorson JS | s2cid = 2469387 | title = Antibiotic optimization via in vitro glycorandomization | journal = Nature Biotechnology | volume = 21 | issue = 12 | pages = 1467–9 | date = December 2003 | pmid = 14608364 | doi = 10.1038/nbt909 }}</ref><ref name="pmid15816740">{{cite journal | vauthors = Fu X, Albermann C, Zhang C, Thorson JS | title = Diversifying vancomycin via chemoenzymatic strategies | journal = Organic Letters | volume = 7 | issue = 8 | pages = 1513–5 | date = April 2005 | pmid = 15816740 | doi = 10.1021/ol0501626 }}</ref><ref name="pmid22984807">{{cite journal | vauthors = Peltier-Pain P, Marchillo K, Zhou M, Andes DR, Thorson JS | title = Natural product disaccharide engineering through tandem glycosyltransferase catalysis reversibility and neoglycosylation | journal = Organic Letters | volume = 14 | issue = 19 | pages = 5086–9 | date = October 2012 | pmid = 22984807 | pmc = 3489467 | doi = 10.1021/ol3023374 }}</ref>

{{clear}}

==Total synthesis==

Both the vancomycin [[aglycone]]<ref name="pmid29711601">{{cite journal | vauthors = Evans DA, Wood MR, Trotter BW, Richardson TI, Barrow JC, Katz JL | title = Total Syntheses of Vancomycin and Eremomycin Aglycons | journal = Angewandte Chemie | volume = 37 | issue = 19 | pages = 2700–2704 | date = October 1998 | pmid = 29711601 | doi = 10.1002/(SICI)1521-3773(19981016)37:19<2700::AID-ANIE2700>3.0.CO;2-P | doi-access = free | title-link = doi }}</ref><ref name="Herzner-2008">{{cite book |title= Organic Synthesis Highlights |volume= IV |pages= 281–288 | veditors = Schmalz HG |year= 2008 |publisher= John Wiley & Sons |chapter= 38. Crossing the Finishing Line: Total Syntheses of the Vancomycin Aglycon | vauthors = Herzner H, Rück-Braun K |doi= 10.1002/9783527619979.ch38 |isbn= 978-3-527-61997-9 }}</ref> and the complete vancomycin molecule<ref name="Nicolaou-1999">{{cite journal | vauthors = Nicolaou KC, Mitchell HJ, Jain NF, Winssinger N, Hughes R, Bando T | year = 1999 | title = Total Synthesis of Vancomycin | journal = Angew. Chem. Int. Ed. | volume = 38 | issue = 1–2| pages = 240–244 | doi = 10.1002/(SICI)1521-3773(19990115)38:1/2<240::AID-ANIE240>3.0.CO;2-5 }}</ref> have been targets successfully reached by [[total synthesis]]. The target was first achieved by David Evans in October 1998, KC Nicolaou in December 1998, Dale Boger in 1999, and more selectively synthesized again by Dale Boger in 2020.<ref name="pmid29711601" /><ref name="pmid29375134">{{cite journal | vauthors = Winssinger N | title = Biography of Professor Nicolaou: a journey to the extremes of molecular complexity | journal = The Journal of Antibiotics | volume = 71 | issue = 2 | pages = 149–150 | date = February 2018 | pmid = 29375134 | doi = 10.1038/ja.2017.144 | doi-access = free | title-link = doi | department = Editorial }}</ref><ref name="pmid32885969">{{Cite journal |url=https://doi.org/10.1021/jacs.0c07433.s001 |title=Next-Generation Total Synthesis of Vancomycin | vauthors = Moore MJ, Qu S, Tan C, Cai Y, Mogi Y, Keith DJ, Boger DL | journal = J. Am. Chem. Soc. | year = 202 | volume = 142 | issue = 37 | pages = 16039–16050 | doi = 10.1021/jacs.0c07433 |pmid=32885969 |access-date=13 July 2024 |archive-date=13 July 2024 |archive-url=https://web.archive.org/web/20240713122125/https://doi.org/10.1021/jacs.0c07433.s001 |url-status=live | format = PDF | pmc = 7501256 }}</ref>

== Mechanism of action ==

[[Image:Vancomysin AntimicrobAgentsChemother 1990 1342 commons.jpg|thumbnail|Crystal structure of a short peptide <small>L</small>-Lys-<small>D</small>-Ala-<small>D</small>-Ala (bacterial cell wall precursor, in green) bound to vancomycin (blue) through [[hydrogen bond]]s<ref name="pmid2386365">{{cite journal | vauthors = Knox JR, Pratt RF | title = Different modes of vancomycin and D-alanyl-D-alanine peptidase binding to cell wall peptide and a possible role for the vancomycin resistance protein | journal = Antimicrobial Agents and Chemotherapy | volume = 34 | issue = 7 | pages = 1342–7 | date = July 1990 | pmid = 2386365 | pmc = 175978 | doi = 10.1128/AAC.34.7.1342 }}</ref>]]

Vancomycin targets bacterial cell wall synthesis by binding to the basic building block of the bacterial cell wall of Gram-positive bacteria, whether it is of [[Aerobic bacteria|aerobic]] or [[Anaerobic bacteria|anaerobic]] type.<ref name="B978"/> Specifically, vancomycin forms hydrogen bonds with the <small>D</small>-alanyl-<small>D</small>-alanine (<small>D</small>-Ala-<small>D</small>-Ala) peptide motif of the peptidoglycan precursor, a crucial component of the bacterial cell wall.<ref name="pmid31545906"/>

Peptidoglycan is a polymer that provides structural support to the bacterial cell wall. The peptidoglycan precursor is synthesized in the cytoplasm and then transported across the cytoplasmic membrane to the periplasmic space, where it is assembled into the cell wall. The assembly process involves two enzymatic activities: transglycosylation and transpeptidation. Transglycosylation involves the polymerization of the peptidoglycan precursor into long chains, while transpeptidation involves the cross-linking of these chains to form a three-dimensional mesh-like structure.<ref name="pmid31545906"/>

Vancomycin inhibits bacterial cell wall synthesis by binding to the <small>D</small>-Ala-<small>D</small>-Ala peptide motif of the peptidoglycan precursor, thereby preventing its processing by the transglycosylase; as such vancomycin disrupts the transglycosylation activity of the cell wall synthesis process. The disruption leads to an incomplete and corrupted cell wall, which makes the replicating bacteria vulnerable to external forces such as osmotic pressure, so that the bacteria cannot survive and are eliminated by the immune system.<ref name="pmid31545906"/>

Gram-negative bacteria are insensitive to vancomycin due to their different cell wall morphology. The outer membrane of Gram-negative bacteria contains lipopolysaccharide, which acts as a barrier to vancomycin penetration. That is why vancomycin is mainly used to treat infections caused by Gram-positive bacteria<ref name="pmid31545906"/> (except some nongonococcal species of ''[[Neisseria]]'').<ref name="pmid30408494">{{cite journal |vauthors=Crew PE, McNamara L, Waldron PE, McCulley L, Jones SC, Bersoff-Matcha SJ |title=Unusual Neisseria species as a cause of infection in patients taking eculizumab |journal=J Infect |volume=78 |issue=2 |pages=113–118 |date=February 2019 |pmid=30408494 |pmc=7224403 |doi=10.1016/j.jinf.2018.10.015 }}</ref><ref name="pmid6790572">{{cite journal |vauthors=Mirrett S, Reller LB, Knapp JS |title=Neisseria gonorrhoeae strains inhibited by vancomycin in selective media and correlation with auxotype |journal=J Clin Microbiol |volume=14 |issue=1 |pages=94–9 |date=July 1981 |pmid=6790572 |pmc=271907 |doi=10.1128/jcm.14.1.94-99.1981}}</ref>

The large [[hydrophilic]] molecule of vancomycin is able to form [[hydrogen bond]] interactions with the terminal <small>D</small>-alanyl-<small>D</small>-alanine moieties of the NAM/NAG-peptides. Under normal circumstances, this is a five-point interaction.{{jargon|date=March 2024}} This binding of vancomycin to the <small>D</small>-Ala-<small>D</small>-Ala prevents cell wall synthesis of the long polymers of ''N''-acetylmuramic acid (NAM) and ''N''-acetylglucosamine (NAG) that form the backbone strands of the bacterial cell wall, and prevents the backbone polymers from cross-linking with each other.<ref name="Clinical-Pharmacology-2021">{{cite web |url=http://www.clinicalpharmacology-ip.com/Forms/Monograph/monograph.aspx?cpnum=638&sec=monmech |title=Clinical Pharmacology<!-- Bot generated title --> |access-date=10 September 2011 |archive-date=27 August 2021 |archive-url=https://web.archive.org/web/20210827175717/http://www.clinicalpharmacology-ip.com/Forms/login.aspx?ReturnUrl=%2fForms%2fMonograph%2fmonograph.aspx%3fcpnum%3d638%26sec%3dmonmech&cpnum=638&sec=monmech |url-status=dead }}</ref>

{{wide image|Vancomycin resistance.svg|800px|

Mechanism of vancomycin action and resistance: This diagram shows only one of two ways vancomycin acts against bacteria (inhibition of cell wall cross-linking) and only one of many ways that bacteria can become resistant to it.

# Vancomycin is added to the bacterial environment while it is trying to synthesize new cell wall. Here, the cell wall strands have been synthesized, but not yet cross-linked.

# Vancomycin recognizes and binds to the two <small>D</small>-ala residues on the end of the peptide chains. However, in resistant bacteria, the last <small>D</small>-ala residue has been replaced by a <small>D</small>-lactate, so vancomycin cannot bind.

# In the resistant bacteria, cross-links are successfully formed; still, in the nonresistant (sensitive) bacteria, the vancomycin bound to the peptide chains prevents them from interacting properly with the cell wall cross-linking enzyme.

# In the resistant bacteria, stable cross-links are formed. In the sensitive bacteria, cross-links cannot be formed and the cell wall falls apart.

}}

==Plant tissue culture==

Vancomycin is one of the few antibiotics used in plant tissue culture to eliminate Gram-positive bacterial infection. It has relatively low toxicity to plants.<ref name="Vancomcyin for plant tissue culture">{{cite web|url=http://www.toku-e.com/Upload/Products/index/Vancomycin%20HCl.pdf|archiveurl=https://web.archive.org/web/20120504095939/http://www.toku-e.com/Upload/Products/index/Vancomycin%20HCl.pdf|url-status=dead|title=vancomcin for plant cell culture|archivedate=4 May 2012}}</ref><ref name="pazuki">{{cite journal | vauthors = Pazuki A, Asghari J, Sohani MM, Pessarakli M, Aflaki F |s2cid=84495391 |year=2014 |title= Effects of Some Organic Nitrogen Sources and Antibiotics on Callus Growth of Indica Rice Cultivars |journal= Journal of Plant Nutrition |volume=38 |issue=8 |pages=1231–1240 |doi=10.1080/01904167.2014.983118 }}</ref>

==Antibiotic resistance==

===Intrinsic resistance===

A few Gram-positive bacteria are intrinsically resistant to vancomycin: ''[[Leuconostoc]]'' and ''[[Pediococcus]]'' species, but these organisms rarely cause diseases in humans.<ref name="Swenson1990">{{cite journal | vauthors = Swenson JM, Facklam RR, Thornsberry C | title = Antimicrobial susceptibility of vancomycin-resistant Leuconostoc, Pediococcus, and Lactobacillus species | journal = Antimicrobial Agents and Chemotherapy | volume = 34 | issue = 4 | pages = 543–9 | date = April 1990 | pmid = 2344161 | pmc = 171641 | doi = 10.1128/AAC.34.4.543 }}</ref> Most ''[[Lactobacillus]]'' species are also intrinsically resistant to vancomycin,<ref name="Swenson1990"/> with the exception of ''[[Lactobacillus acidophilus|L. acidophilus]]'' and ''[[Lactobacillus delbrueckii|L. delbrueckii]]'', which are sensitive.<ref name="pmid9569701">{{cite journal | vauthors = Hamilton-Miller JM, Shah S | title = Vancomycin susceptibility as an aid to the identification of lactobacilli | journal = Letters in Applied Microbiology | volume = 26 | issue = 2 | pages = 153–4 | date = February 1998 | pmid = 9569701 | doi = 10.1046/j.1472-765X.1998.00297.x | s2cid = 221924592 | doi-access = free }}</ref> Other Gram-positive bacteria with intrinsic resistance to vancomycin include ''[[Erysipelothrix rhusiopathiae]]'', ''[[Weissella|Weissella confusa]]'', and ''[[Clostridium innocuum]]''.<ref name="pmid18159347">{{cite journal | vauthors = Romney M, Cheung S, Montessori V | title = Erysipelothrix rhusiopathiae endocarditis and presumed osteomyelitis | journal = The Canadian Journal of Infectious Diseases | volume = 12 | issue = 4 | pages = 254–6 | date = July 2001 | pmid = 18159347 | pmc = 2094827 | doi = 10.1155/2001/912086 | doi-access = free }}</ref><ref name="pmid15150227">{{cite journal | vauthors = David V, Bozdogan B, Mainardi JL, Legrand R, Gutmann L, Leclercq R | title = Mechanism of intrinsic resistance to vancomycin in Clostridium innocuum NCIB 10674 | journal = Journal of Bacteriology | volume = 186 | issue = 11 | pages = 3415–22 | date = June 2004 | pmid = 15150227 | pmc = 415764 | doi = 10.1128/JB.186.11.3415-3422.2004 }}</ref><ref name="pmid21596906">{{cite journal | vauthors = Kumar A, Augustine D, Sudhindran S, Kurian AM, Dinesh KR, Karim S, Philip R | title = Weissella confusa: a rare cause of vancomycin-resistant Gram-positive bacteraemia | journal = Journal of Medical Microbiology | volume = 60 | issue = Pt 10 | pages = 1539–1541 | date = October 2011 | pmid = 21596906 | doi = 10.1099/jmm.0.027169-0 | doi-access = free }}</ref>

Most Gram-negative bacteria are intrinsically resistant to vancomycin because their outer membranes are impermeable to large glycopeptide molecules<ref name="Quintiliani Jr-1995">{{cite book | vauthors = Quintiliani Jr R, Courvalin P | chapter=Mechanisms of Resistance to Antimicrobial Agents | title=Manual of Clinical Microbiology | veditors=Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH | publisher=ASM Press | location=Washington DC | year=1995 | edition=6th | pages=[https://archive.org/details/manualofclinical0000murr/page/1319 1319] | isbn=978-1-55581-086-3 | chapter-url-access=registration | chapter-url=https://archive.org/details/manualofclinical0000murr | url=https://archive.org/details/manualofclinical0000murr/page/1319 }}</ref> (with the exception of some non-[[Neisseria gonorrhoeae|gonococcal]] ''[[Neisseria]]'' species).<ref name="pmid7342289">{{cite journal | vauthors = Geraci JE, Wilson WR | title = Vancomycin therapy for infective endocarditis | journal = Reviews of Infectious Diseases | volume = 3 | issue = suppl | pages = S250-8 | year = 1981 | pmid = 7342289 | doi = 10.1093/clinids/3.Supplement_2.S250 }}</ref>

===Acquired resistance===

Evolution of [[Antimicrobial resistance|microbial resistance]] to vancomycin is a growing problem, in particular, within healthcare facilities such as hospitals. While newer alternatives to vancomycin exist, such as [[linezolid]] (2000) and [[daptomycin]] (2003), the widespread use of vancomycin makes resistance to the drug a significant worry, especially for individual patients if resistant infections are not quickly identified and the patient continues the ineffective treatment. [[Vancomycin-resistant Enterococcus|Vancomycin-resistant ''Enterococcus'']] <!-- (VRE) --> emerged in 1986.<ref name="pmid10706902">{{cite journal |vauthors=Murray BE |title=Vancomycin-resistant enterococcal infections |journal=The New England Journal of Medicine |volume=342 |issue=10 |pages=710–21 |date=March 2000 |pmid=10706902 |doi=10.1056/NEJM200003093421007 |url=https://www.nejm.org/doi/10.1056/NEJM200003093421007 |quote="The first reports of vancomycin-resistant enterococci (later classified as VanA type of resistance) involved strains of E. faecium that were resistant to vancomycin and teicoplanin (another glycopeptide) and that were isolated from patients in France and England in 1986. Vancomycin-resistant E. faecalis, subsequently classified as VanB type, was recovered from patients in Missouri in 1987." |url-access=subscription |access-date=11 September 2022 |archive-date=11 September 2022 |archive-url=https://web.archive.org/web/20220911090912/https://www.nejm.org/doi/10.1056/NEJM200003093421007 |url-status=live }}</ref> Vancomycin resistance evolved in more common pathogenic organisms during the 1990s and 2000s, including [[vancomycin-resistant Staphylococcus aureus|vancomycin-intermediate ''S. aureus'']] (VISA) and [[vancomycin-resistant Staphylococcus aureus|vancomycin-resistant ''S. aureus'']] (VRSA).<ref name="Smith1999">{{cite journal | vauthors = Smith TL, Pearson ML, Wilcox KR, Cruz C, Lancaster MV, Robinson-Dunn B, Tenover FC, Zervos MJ, Band JD, White E, Jarvis WR | title = Emergence of vancomycin resistance in Staphylococcus aureus. Glycopeptide-Intermediate Staphylococcus aureus Working Group | journal = The New England Journal of Medicine | volume = 340 | issue = 7 | pages = 493–501 | date = February 1999 | pmid = 10021469 | doi = 10.1056/NEJM199902183400701 | doi-access = free }}</ref><ref name="McDonald2005">{{cite journal | vauthors = McDonald LC, Killgore GE, Thompson A, Owens RC, Kazakova SV, Sambol SP, Johnson S, Gerding DN | s2cid = 43628397 | title = An epidemic, toxin gene-variant strain of Clostridium difficile | journal = The New England Journal of Medicine | volume = 353 | issue = 23 | pages = 2433–41 | date = December 2005 | pmid = 16322603 | doi = 10.1056/NEJMoa051590 | doi-access = free }}</ref> Agricultural use of [[avoparcin]], another similar glycopeptide antibiotic, may have contributed to the evolution of vancomycin-resistant organisms.<ref name="pmid11168181">{{cite journal | vauthors = Acar J, Casewell M, Freeman J, Friis C, Goossens H | title = Avoparcin and virginiamycin as animal growth promoters: a plea for science in decision-making | journal = Clinical Microbiology and Infection | volume = 6 | issue = 9 | pages = 477–82 | date = September 2000 | pmid = 11168181 | doi = 10.1046/j.1469-0691.2000.00128.x | doi-access = free }}</ref><ref name="pmid9234429">{{cite journal | vauthors = Bager F, Madsen M, Christensen J, Aarestrup FM | title = Avoparcin used as a growth promoter is associated with the occurrence of vancomycin-resistant Enterococcus faecium on Danish poultry and pig farms | journal = Preventive Veterinary Medicine | volume = 31 | issue = 1–2 | pages = 95–112 | date = July 1997 | pmid = 9234429 | doi = 10.1016/S0167-5877(96)01119-1 | s2cid = 4958557 }}</ref><ref name="pmid10474607">{{cite journal | vauthors = Collignon PJ | title = Vancomycin-resistant enterococci and use of avoparcin in animal feed: is there a link? | journal = The Medical Journal of Australia | volume = 171 | issue = 3 | pages = 144–6 | date = August 1999 | pmid = 10474607 | doi = 10.5694/j.1326-5377.1999.tb123568.x | s2cid = 24378463 | author-link = Peter Collignon }}</ref><ref name="pmid17298380">{{cite journal | vauthors = Lauderdale TL, Shiau YR, Wang HY, Lai JF, Huang IW, Chen PC, Chen HY, Lai SS, Liu YF, Ho M | title = Effect of banning vancomycin analogue avoparcin on vancomycin-resistant enterococci in chicken farms in Taiwan | journal = Environmental Microbiology | volume = 9 | issue = 3 | pages = 819–23 | date = March 2007 | pmid = 17298380 | doi = 10.1111/j.1462-2920.2006.01189.x | bibcode = 2007EnvMi...9..819L | url = http://ir.nhri.org.tw/bitstream/3990099045/1956/1/000244078500024.pdf | access-date = 20 April 2018 | archive-date = 10 May 2019 | archive-url = https://web.archive.org/web/20190510090150/http://ir.nhri.org.tw/bitstream/3990099045/1956/1/000244078500024.pdf | url-status = live }}</ref>

One mechanism of resistance to vancomycin involves the alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits, under normal conditions, <small>D</small>-alanyl-<small>D</small>-alanine, to which vancomycin binds. The <small>D</small>-alanyl-<small>D</small>-lactate variation results in the loss of one hydrogen-bonding interaction (4, as opposed to 5 for <small>D</small>-alanyl-<small>D</small>-alanine) possible between vancomycin and the peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity. The <small>D</small>-alanyl-<small>D</small>-serine variation causes a six-fold loss of affinity between vancomycin and the peptide, likely due to steric hindrance.<ref name="pmid11807177">{{cite journal | vauthors = Pootoolal J, Neu J, Wright GD | title = Glycopeptide antibiotic resistance | journal = Annual Review of Pharmacology and Toxicology | volume = 42 | pages = 381–408 | year = 2002 | pmid = 11807177 | doi = 10.1146/annurev.pharmtox.42.091601.142813 }}</ref>

In enterococci, this modification appears to be due to the expression of an enzyme that alters the terminal residue. Three main resistance variants have been characterised to date among resistant ''Enterococcus faecium'' and ''E. faecalis'' populations:

* VanA - enterococcal resistance to vancomycin and [[teicoplanin]]; inducible on exposure to these agents

* VanB - lower-level enterococcal resistance; inducible by vancomycin, but strains may remain susceptible to teicoplanin

* VanC - least clinically important; enterococci resistant only to vancomycin; constitutive resistance

Variant of vancomycin has been tested that binds to the resistant D-lactic acid variation in vancomycin-resistant bacterial cell walls, and also binds well to the original target (vancomycin-susceptible bacteria).<ref name="pmid21823662">{{cite journal | vauthors = Xie J, Pierce JG, James RC, Okano A, Boger DL | title = A redesigned vancomycin engineered for dual D-Ala-D-ala And D-Ala-D-Lac binding exhibits potent antimicrobial activity against vancomycin-resistant bacteria | journal = Journal of the American Chemical Society | volume = 133 | issue = 35 | pages = 13946–9 | date = September 2011 | pmid = 21823662 | pmc = 3164945 | doi = 10.1021/ja207142h | author-link5 = Dale L. Boger }}</ref><ref name="pmid28559345">{{cite journal | vauthors = Okano A, Isley NA, Boger DL | title = Peripheral modifications of [Ψ[CH₂NH]Tpg⁴]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 26 | pages = E5052–E5061 | date = June 2017 | pmid = 28559345 | pmc = 5495262 | doi = 10.1073/pnas.1704125114 | author-link3 = Dale L. Boger | doi-access = free | bibcode = 2017PNAS..114E5052O }}</ref>

=== "Re-gained" vancomycin ===

In 2020 a team at the [[University Hospital Heidelberg]] (Germany) re-gained the antibacterial power of vancomycin by modifying the molecule with a cationic [[oligopeptide]]. The oligopeptide consists of six [[arginin]] units in Position V_N. In comparison to the unmodified vancomycin the activity against vancomycin-resistant bacteria could be enhanced by a factor of 1,000.<ref name="pmid32190958">{{cite journal | vauthors = Umstätter F, Domhan C, Hertlein T, Ohlsen K, Mühlberg E, Kleist C, Zimmermann S, Beijer B, Klika KD, Haberkorn U, Mier W, Uhl P | title = Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides | journal = Angewandte Chemie | volume = 59 | issue = 23 | pages = 8823–8827 | date = June 2020 | pmid = 32190958 | pmc = 7323874 | doi = 10.1002/anie.202002727 }}</ref><ref name="mw-EP">{{cite patent | inventor = Mier W, Umstätter F, Uhl P, Domhan C | url = https://patents.google.com/patent/EP3846854A2/en | title = Improved polypeptide coupled antibiotics. | country = EP | number = 3846854A2 | pridate = 4 September 2019 }} {{Webarchive|url=https://web.archive.org/web/20211008071101/https://patents.google.com/patent/EP3846854A2/en |date=8 October 2021 }}</ref> This pharmacon is still in [[preclinical development]].

== History ==

Vancomycin was first isolated in 1953, by [[Edmund Kornfeld]] (working at [[Eli Lilly and Company|Eli Lilly]]) from a bacteria in a soil sample collected from the interior jungles of [[Borneo]] by a missionary, William M. Bouw (1918–2006).<ref name="Shnayerson">{{cite book | vauthors = Shnayerson M, Plotkin M | date = 2003 | title = The Killers Within: The Deadly Rise of Drug-Resistant Bacteria | publisher = Back Bay Books | isbn = 978-0-316-73566-7 }}</ref> The organism that produced it was eventually named ''[[Amycolatopsis orientalis]]''.<ref name="pmid16323120"/> The original indication for vancomycin was for the treatment of penicillin-resistant ''Staphylococcus aureus''.<ref name="pmid16323120"/><ref name="pmid16323117">{{cite journal | vauthors = Moellering RC | title = Vancomycin: a 50-year reassessment | journal = Clinical Infectious Diseases | volume = 42 | issue = Suppl 1 | pages = S3-4 | date = January 2006 | pmid = 16323117 | doi = 10.1086/491708 | doi-access = free }}</ref>

The compound was initially called compound 05865, but was eventually given the generic name vancomycin, derived from the term "vanquish".<ref name="pmid16323120"/> One advantage that was quickly apparent was that staphylococci did not develop significant resistance, despite serial passage in culture media containing vancomycin. The rapid development of penicillin resistance by staphylococci led to its being fast-tracked for approval by the [[Food and Drug Administration]].<!-- (FDA) --> In 1958, Eli Lilly first marketed vancomycin hydrochloride under the trade name Vancocin.<ref name="pmid16323117"/>

Vancomycin never became the first-line treatment for ''S. aureus'' for several reasons:

# It possesses poor oral bioavailability, so must be given intravenously for most infections.

# β-Lactamase-resistant semisynthetic penicillins such as [[methicillin]] (and its successors, [[nafcillin]] and [[cloxacillin]]) were subsequently developed, which have better activity against non-MRSA staphylococci.

# Early trials used early, impure forms of the drug ("Mississippi mud"), which were found to be toxic to the [[inner ear]] and to the kidneys;<ref name="pmid7043707">{{cite journal | vauthors = Griffith RS | title = Introduction to vancomycin | journal = Reviews of Infectious Diseases | volume = 3 | issue = suppl | pages = S200-4 | year = 1981 | pmid = 7043707 | doi = 10.1093/clinids/3.Supplement_2.S200 }}</ref> these findings led to vancomycin's being relegated to the position of a drug of last resort.<ref name="pmid16323117"/>

In 2004, Eli Lilly licensed Vancocin to [[ViroPharma]] in the U.S., Flynn Pharma in the UK, and [[Aspen Pharmacare]] in Australia. The [[patent]] had expired in the early 1980s, and the FDA authorized the sale of several generic versions in the US, including from manufacturers Bioniche Pharma, [[Baxter Healthcare]], [[Sandoz]], [[Akorn]]-[[Strides Shasun|Strides]], and [[Hospira]].<ref name="Orange-Book-2016">{{cite web|url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm|archiveurl=https://web.archive.org/web/20160817081251/http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm|url-status=dead|title=Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations<!-- Bot generated title -->|archivedate=17 August 2016}}</ref>

==Research==

The combination of vancomycin powder and povidone-iodine lavage may reduce the risk of periprosthetic joint infection in hip and knee arthroplasties. <ref name="pmid36470703">{{cite journal |vauthors=Martin VT, Zhang Y, Wang Z, Liu QL, Yu B |title=A systematic review and meta-analysis comparing intrawound vancomycin powder and povidone iodine lavage in the prevention of periprosthetic joint infection of hip and knee arthroplasties |journal=J Orthop Sci |volume=29 |issue=1 |pages=165–176 |date=January 2024 |pmid=36470703 |doi=10.1016/j.jos.2022.11.013 |s2cid=254215681}}</ref>

== References ==

{{Reflist}}

{{Antidiarrheals, intestinal anti-inflammatory/anti-infective agents}}

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[[Category:Drugs developed by Eli Lilly and Company]]

[[Category:Glycopeptide antibiotics]]

[[Category:Halogen-containing natural products]]

[[Category:Nephrotoxins]]

[[Category:Total synthesis]]

[[Category:World Health Organization essential medicines]]

[[Category:Wikipedia medicine articles ready to translate]]