vancomycin

Vancomycin is indicated for the treatment of serious, life-threatening infections by Gram-positive bacteria of both aerobic and anaerobic types{{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 }} that are unresponsive to other antibiotics.{{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 }}{{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 }}{{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 }}

The increasing emergence of vancomycin-resistant enterococci (VRE) 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:{{cite book | veditors = Rossi S | title = Australian Medicines Handbook | location = Adelaide | publisher = Australian Medicines Handbook | date = 2006 | isbn = 0-9757919-2-3 }}{{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 }}

• treatment of serious infections caused by susceptible organisms resistant to penicillins, such as methicillin-resistant S. aureus (MRSA) and multidrug-resistant S. epidermidis (MRSE),
• treatment of infections in individuals with serious allergy to penicillins,
• treatment of pseudomembranous colitis caused by C. 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 intravenously),
• treatment of infections caused by Gram-positive microorganisms in patients with serious allergies to beta-lactam antimicrobials,
• antibacterial prophylaxis for endocarditis after certain procedures in penicillin-hypersensitive people at high risk,
• surgical prophylaxis for major procedures involving implantation of prostheses in institutions with a high rate of MRSA or MRSE,
• early in treatment as an 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;{{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 }} it has been used to prevent the condition but is not recommended due to the risk of side effects.{{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=dead}}

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:{{cite web |url=http://antibiotics.toku-e.com/antimicrobial_1182_1.html |title=Vancomycin (Vancocyn, Lyphocin) | 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}}

• S. aureus: 0.25 μg/mL to 4.0 μg/mL
• S. aureus (methicillin resistant or MRSA): 1 μg/mL to 138 μg/mL
• S. epidermidis: ≤0.12 μg/mL to 6.25 μg/mL

Common side effects associated with oral vancomycin administration (used to treat intestinal infections) include:

• gastrointestinal adverse effects (such as abdominal pain and nausea);
• dysgeusia (distorted sense of taste), in case of administration of vancomycin oral solution, but not in case of vancomycin capsules.

Serum vancomycin levels may be monitored in an effort to reduce side effects,{{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=}} but the value of such monitoring has been questioned. Peak and trough levels are usually monitored, and for research purposes the area under the concentration curve is also sometimes used. Toxicity is best monitored by looking at trough values.{{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 }} Immunoassays are commonly used to measure vancomycin levels.

Common adverse drug reactions (≥1% of patients) associated with intravenous vancomycin include:

• pain, redness, or swelling at the injection site;{{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}}
• vancomycin flushing syndrome (VFS), previously known as red man syndrome (or "redman syndrome");{{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 }}
• 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.{{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}}

Damage to the kidneys (nephrotoxicity) and to the hearing (ototoxicity) were side effects of the early, impure versions of vancomycin, and were prominent in clinical trials conducted in the mid-1950s. 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 aminoglycosides.{{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 }}

Rare adverse effects associated with intravenous vancomycin (<0.1% of patients) include anaphylaxis, toxic epidermal necrolysis, erythema multiforme, superinfection, thrombocytopenia, neutropenia, leukopenia, tinnitus, dizziness and/or ototoxicity, and DRESS syndrome.{{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 }}

Vancomycin can induce platelet-reactive antibodies in the patient, leading to severe thrombocytopenia and bleeding with florid petechial hemorrhages, ecchymoses, and wet purpura.{{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 }}

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. But as its use 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, and with the introduction of therapeutic drug monitoring, the risk of severe toxicity has been reduced.

The extent of nephrotoxicity for vancomycin remains controversial. In 1980s, vancomycin with a purity > 90% was available, and kidney toxicity defined by an increase in serum creatinine of at least 0.5 mg/dL occurred in only about 5% of patients.{{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 }} But dosing guidelines from the 1980s until 2008 recommended vancomycin trough concentrations between 5 and 15 μg/mL.{{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 }} 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.{{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 }}

Importantly, the risk of AKI increases with co-administration of other known nephrotoxins, in particular aminoglycosides. Furthermore, 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.{{cite journal | url=https://link.springer.com/article/10.1007/s00134-017-4799-8 | doi=10.1007/s00134-017-4799-8 | title=Diagnostic work-up and specific causes of acute kidney injury | date=2017 | journal=Intensive Care Medicine | volume=43 | issue=6 | pages=829–840 | pmid=28444409 | vauthors = Darmon M, Ostermann M, Cerda J, Dimopoulos MA, Forni L, Hoste E, Legrand M, Lerolle N, Rondeau E, Schneider A, Souweine B, Schetz M | url-access=subscription }}{{cite journal | doi=10.3389/fmed.2021.678434 | doi-access=free | title=Clinical Characteristics and Risk Factors Associated with Acute Kidney Injury Inpatient with Exertional Heatstroke: An over 10-Year Intensive Care Survey | date=2021 | journal=Frontiers in Medicine | volume=8 | pmid=34095181 | pmc=8170299 | vauthors = Wu M, Wang C, Liu Z, Zhong L, Yu B, Cheng B, Liu Z }}{{cite journal | doi=10.1007/s00134-021-06454-7 | title=Acute kidney injury in the critically ill: An updated review on pathophysiology and management | date=2021 | journal=Intensive Care Medicine | volume=47 | issue=8 | pages=835–850 | pmid=34213593 | vauthors = Pickkers P, Darmon M, Hoste E, Joannidis M, Legrand M, Ostermann M, Prowle JR, Schneider A, Schetz M | pmc=8249842 }}{{cite journal | doi=10.1186/s13613-024-01360-9 | doi-access=free | title=Biomarkers in acute kidney injury | date=2024 | journal=Annals of Intensive Care | volume=14 | issue=1 | page=145 | pmid=39279017 | pmc=11402890 | vauthors = Ostermann M, Legrand M, Meersch M, Srisawat N, Zarbock A, Kellum JA }}

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{{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 }} 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).{{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 }} In humans, insulin-like growth factor binding protein 7 (IGFBP7) as part of the nephrocheck test.{{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 }}

The mechanisms underlying the pathogenesis of vancomycin nephrotoxicity are multifactorial but include interstitial nephritis, tubular injury due to oxidative stress, and cast formation.

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.

In children, concomitant administration of vancomycin and piperacillin/tazobactam has been associated with an elevated incidence of AKI relative to other antibiotic regimens.{{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= 58|pages=1034–1044 |date=January 2024 |issue=10 |pmid=38279799 |doi=10.1177/10600280231220379 |s2cid=267300725 |url=}}

====Ototoxicity====

Attempts to establish rates of vancomycin-induced ototoxicity are even more difficult due to lack of good data. The consensus is that clearly related cases of vancomycin ototoxicity are rare.{{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 }}{{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 }} The association between vancomycin serum levels and ototoxicity is also uncertain. Cases of ototoxicity have been reported in patients whose vancomycin serum level exceeded 80 μg/mL,{{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 }} but cases have also been reported in patients with therapeutic levels. Thus it remains unknown whether therapeutic drug monitoring of vancomycin for the purpose of maintaining "therapeutic" levels prevents ototoxicity. Still, therapeutic drug monitoring can be used during vancomycin therapy to minimize the risk of ototoxicity associated with excessive drug exposure.

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

{{see also|Erythroderma}}

Vancomycin is recommended to be administered in a dilute solution slowly, over at least 60 min (maximum rate of 10 mg/min for doses >500 mg) 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 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.{{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 }} Less frequently, hypotension and angioedema occur. Symptoms may be treated or prevented with antihistamines, including diphenhydramine, and are less likely to occur with slow infusion.{{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 }}{{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 }}

The recommended intravenous dosage in adults is 500 mg every 6 hours or 1000 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 mg every 6 hours for 7 to 10 days.{{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 }}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 }}.

Dose optimization and target attainment of vancomycin in children involves adjusting the dosage to maximize effectiveness while minimizing the risk of adverse effects, specifically acute kidney injury. Dose optimization is achieved by therapeutic drug monitoring (TDM), which allows measurement of vancomycin levels in the blood. 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.{{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 }}

In the United States, vancomycin is approved by the Food and Drug Administration for intravenous and oral administration.

Vancomycin must be given intravenously 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 its short half-life, it is often injected twice daily.{{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 }}

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. After oral administration, the fecal concentration of vancomycin is around 500 μg/mL{{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 }} (sensitive strains of Clostridioides difficile have a mean inhibitory concentration of ≤2 μg/mL{{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 }})

Inhaled vancomycin can also be used off-label,{{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=}} via nebulizer, to treat various infections of the upper and lower respiratory tract.{{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=}}{{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}}{{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 }}{{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? | Drug Information Group | 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}}{{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 }}

Rectal administration is an off-label use of vancomycin for the treatment of Clostridioides difficile infection.

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 time-dependent; that is, antimicrobial activity depends on how long the serum drug concentration exceeds the minimum inhibitory concentration 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 is warranted include patients receiving concomitant aminoglycoside therapy, patients with (potentially) altered pharmacokinetic parameters, patients on haemodialysis, patients administered high-dose or prolonged treatment, and patients with impaired renal function. In such cases, trough concentrations are measured.{{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 }}{{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 }}{{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 }}

Therapeutic drug monitoring is also used for dose optimization of vancomycin in treating children.

Target ranges for serum vancomycin concentrations have changed over the years. Early authors suggested peak levels of 30 to 40 mg/L and trough levels of 5 to 10 mg/L,{{cite journal | vauthors = Geraci JE | title = Vancomycin | journal = Mayo Clinic Proceedings | volume = 52 | issue = 10 | pages = 631–4 | date = October 1977 | pmid = 909314 }} but current recommendations are that peak levels need not be measured and that trough levels of 10 to 15 mg/L or 15 to 20 mg/L, depending on the nature of the infection and the specific patient's needs, may be appropriate.{{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 }}{{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 }} Measuring vancomycin concentrations to calculate doses optimizes therapy in patients with augmented renal clearance.{{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 }}

Vancomycin is a branched tricyclic glycosylated nonribosomal peptide produced by the Actinomycetota species Amycolatopsis orientalis (formerly designated Nocardia orientalis).

Vancomycin exhibits atropisomerism—it has multiple chemically distinct rotamers owing to the rotational restriction of some of the bonds. The form present in the drug is the thermodynamically more stable conformer.{{Citation needed|date=April 2011}}

Vancomycin is made by the soil bacterium Amycolatopsis orientalis.

Image:Vancomycin Modules.png

Vancomycin biosynthesis occurs primarily via three nonribosomal protein synthases (NRPSs) VpsA, VpsB, and VpsC.{{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 }} 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. L-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.{{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}}

Image:Linear heptapeptide of Vancomycin.png

Nonribosomal peptide synthesis occurs through distinct 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.{{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 }} 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.{{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 | doi-access = free }}{{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 }} 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.{{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 }} 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

A set of NRPS enzymes (peptide synthase VpsA, VpsB, and VpsC) are responsible for assembling the heptapeptide. (Figure 2). 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 unknown. The three peptide syntheses are at the start of the region of the bacterial genome linked with antibiotic biosynthesis, and span 27 kb.

β-hydroxytyrosine (β-HT) is synthesized before incorporation into the heptapeptide backbone. L-tyrosine is activated and loaded on the NRPS VpsD, hydroxylated by OxyD, and released by the thioesterase Vhp.{{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 }} The timing of the chlorination by halogenase VhaA during biosynthesis is undetermined, but is proposed to occur before the complete assembly of the heptapeptide.{{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 }}

After the linear heptapeptide molecule is synthesized, vancomycin must 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 in the 7th NRPS module, which is unique to glycopeptide antibiotic biosynthesis.{{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 }} 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 used to generate libraries of differentially glycosylated analogs through glycorandomization.{{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 }}{{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 }}{{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 }}

{{clear}}

Both the vancomycin aglycone{{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 }}{{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 }} and the complete vancomycin molecule{{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 }} 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 Boger in 2020.{{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 }}{{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 }}

Image:Vancomysin AntimicrobAgentsChemother 1990 1342 commons.jpgs{{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 }}]]

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 or anaerobic type. Specifically, vancomycin forms hydrogen bonds with the D-alanyl-D-alanine (D-Ala-D-Ala) peptide motif of the peptidoglycan precursor, a component of the bacterial cell wall.

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.

Vancomycin inhibits bacterial cell wall synthesis by binding to the D-Ala-D-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.

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 (except some nongonococcal species of Neisseria).{{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 }}{{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}}

The large hydrophilic molecule of vancomycin is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Under normal circumstances, this is a five-point interaction. This binding of vancomycin to the D-Ala-D-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.{{cite web |url=http://www.clinicalpharmacology-ip.com/Forms/Monograph/monograph.aspx?cpnum=638&sec=monmech |title=Clinical Pharmacology |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 }}

{{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.

1. 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.
2. Vancomycin recognizes and binds to the two D-ala residues on the end of the peptide chains. However, in resistant bacteria, the last D-ala residue has been replaced by a D-lactate, so vancomycin cannot bind.
3. 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.
4. In the resistant bacteria, stable cross-links are formed. In the sensitive bacteria, cross-links cannot be formed and the cell wall falls apart.

}}

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.{{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}}{{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 }}

A few Gram-positive bacteria, such as Leuconostoc and Pediococcus, are intrinsically resistant to vancomycin, but they rarely cause disease in humans.{{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 }} Most Lactobacillus species are also intrinsically resistant to vancomycin, except for L. acidophilus and L. delbrueckii, which are sensitive.{{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 }} Other Gram-positive bacteria with intrinsic resistance to vancomycin include Erysipelothrix rhusiopathiae, Weissella confusa, and Clostridium innocuum.{{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 }}{{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 }}{{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 }}

Most Gram-negative bacteria are intrinsically resistant to vancomycin because their outer membranes are impermeable to large glycopeptide molecules{{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 }} (with the exception of some non-gonococcal Neisseria species).{{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 }}

Evolution of microbial resistance to vancomycin is a growing problem, especially in 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 it a significant worry, especially for individual patients if resistant infections are not quickly identified and the patient continues an ineffective treatment. Vancomycin-resistant Enterococcus emerged in 1986.{{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 }} Vancomycin resistance evolved in more common pathogenic organisms during the 1990s and 2000s, including vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA).{{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 }}{{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 }} Agricultural use of avoparcin, another similar glycopeptide antibiotic, may have contributed to the evolution of vancomycin-resistant organisms.{{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 }}{{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 }}{{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 }}{{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 }}

One mechanism of resistance to vancomycin involves the alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits, under normal conditions, D-alanyl-D-alanine, to which vancomycin binds. The D-alanyl-D-lactate variation results in the loss of one hydrogen-bonding interaction (4, as opposed to 5 for D-alanyl-D-alanine) possible between vancomycin and the peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity. The D-alanyl-D-serine variation causes a six-fold loss of affinity between vancomycin and the peptide, likely due to steric hindrance.{{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 }}

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

A 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).{{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 | bibcode = 2011JAChS.13313946X | author-link5 = Dale L. Boger }}{{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 }}

In 2020 a team at the University Hospital Heidelberg (Germany) regained vancomycin's antibacterial power 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.{{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 }}{{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 }} This pharmacon is still in preclinical development.

Vancomycin was first isolated in 1953 by Edmund Kornfeld (working at Eli Lilly) from a bacteria in a soil sample collected from the interior jungles of Borneo by a missionary, William M. Bouw.{{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 }} The organism that produced it was eventually named Amycolatopsis orientalis. The original indication for vancomycin was to treat penicillin-resistant Staphylococcus aureus.{{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 }}

The compound was initially called compound 05865, but was later given the generic name vancomycin, derived from the term "vanquish". One quickly apparent advantage 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. In 1958, Eli Lilly first marketed vancomycin hydrochloride under the trade name Vancocin.

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

1. It possesses poor oral bioavailability, so must be given intravenously for most infections.
2. 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.
3. 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;{{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 }} these findings led to the relegation of vancomycin to a drug of last resort.

In 2004, Eli Lilly licensed Vancocin to ViroPharma in the U.S., Flynn Pharma in the UK, and Aspen Pharmacare in Australia. The patent expired in the early 1980s, and the FDA authorized the sale of several generic versions in the U.S., including from manufacturers Bioniche Pharma, Baxter Healthcare, Sandoz, Akorn-Strides, and Hospira.{{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|archivedate=17 August 2016}}

The combination of vancomycin powder and povidone-iodine lavage may reduce the risk of periprosthetic joint infection in hip and knee arthroplasties. {{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}}

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