Editing Vancomycin (section)

===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> but 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 vancomycin levels.<ref name="pmid38304144"/>

Common [[adverse drug reaction]]s (≥1% of patients) associated with intravenous 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 were prominent in 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 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. 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,<ref name="pmid16323120"/> and with the introduction of [[therapeutic drug monitoring]], the risk of 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> But 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. 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.<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref>

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> 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 underlying 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, 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= 58|pages=1034–1044 |date=January 2024 |issue=10 |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 lack of good data. The 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. 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> 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.<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 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}}

====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]] 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>