View source for Gentamicin

{{Short description|Antibiotic medication}}
{{Use dmy dates|date=September 2024}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 443833957
| image = Gentamicin C2.svg
| image_class = skin-invert-image
| alt = 
| image2 = Gentamicin C1 ball-and-stick model from xtal 2016.png
| alt2 = 

<!--Clinical data-->
| pronounce = {{IPAc-en|ˌ|dʒ|ɛ|n|t|ə|ˈ|m|aɪ|s|ə|n}}
| tradename = Cidomycin, Genticyn, Garamycin, others
| Drugs.com = {{drugs.com|monograph|gentamicin-sulfate}}
| MedlinePlus = a682275
| DailyMedID = Gentamicin
| pregnancy_AU      = D
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Gentamicin Use During Pregnancy | website=Drugs.com | date=28 February 2019 | url=https://www.drugs.com/pregnancy/gentamicin.html | access-date=11 February 2020}}</ref>
| routes_of_administration = [[Intravenous therapy|Intravenous]], [[Ophthalmic drug administration|eye drop]], [[Intramuscular injection]], [[Topical administration]], [[ear drop]]
| class        = [[Aminoglycoside antibiotic]]
| ATC_prefix = D06
| ATC_suffix = AX07
| ATC_supplemental =  {{ATC|J01|GB03}} {{ATC|S01|AA11}} {{ATC|S02|AA14}} {{ATC|S03|AA06}} {{ATCvet|A07|AA91}} {{ATCvet|G01|AA91}} {{ATCvet|G51|AA04}} {{ATCvet|J51|GB03}}

<!-- Legal status -->
| legal_AU          = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU_comment  = 
| legal_BR          = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment  = 
| legal_CA          = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| 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          = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment  = 
| legal_US          = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_US_comment  = 
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web |title = Active substance: gentamicin (systemic use) | url = https://www.ema.europa.eu/documents/psusa/gentamicin-list-nationally-authorised-medicinal-products-psusa/00009159/202003_en.pdf | work = List of nationally authorised medicinal products | publisher = European Medicines Agency | date = 26 November 2020 }}</ref>
| legal_UN          = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment  = 
| legal_status = Rx only

<!-- Pharmacokinetic data -->
| bioavailability = limited bioavailability by mouth
| protein_bound = 0–10%
| elimination_half-life = 2 h
| excretion = Kidney

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 1403-66-3
| PubChem = 3467
| IUPHAR_ligand = 2427
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB00798
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 390067
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = T6Z9V48IKG
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08013
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 27412
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 195892

<!--Chemical data-->
| IUPAC_name = (3''R'',4''R'',5''R'')-2-<nowiki/>{[(1''S'',2''S'',3''R'',4''S'',6''R'')-4,6-<br />diamino-3-<nowiki/>{[(2''R'',3''R'',6''S'')-<br />3-amino-6-[(1''R'')-<br />1-(methylamino)ethyl]oxan-2-yl]oxy}-<br />2-hydroxycyclohexyl]oxy}-5-methyl-<br />4-(methylamino)oxane-3,5-diol
| C=21 | H=43 | N=5 | O=7
| smiles = O[C@]3(C)[C@H](NC)[C@@H](O)[C@@H](O[C@H]2[C@H](N)C[C@H](N)[C@@H](O[C@H]1O[C@H](C(NC)C)CC[C@H]1N)[C@@H]2O)OC3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C21H43N5O7/c1-9(25-3)13-6-5-10(22)19(31-13)32-16-11(23)7-12(24)17(14(16)27)33-20-15(28)18(26-4)21(2,29)8-30-20/h9-20,25-29H,5-8,22-24H2,1-4H3/t9?,10-,11+,12-,13+,14+,15-,16-,17+,18-,19-,20-,21+/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = CEAZRRDELHUEMR-URQXQFDESA-N
}}
{{Chembox
|container_only = yes
| Section3       = {{Chembox Hazards
| Hazards_ref = <ref>{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/Gentamicin#section=GHS-Classification|title=Gentamicin|website=PubChem|publisher=National Library of Medicine|access-date=November 20, 2024}}</ref>
| GHSPictograms = {{GHS08|Health Hazard}}{{GHS07|Irritant}}{{GHS09|Environmental Hazard}}
| HPhrases = {{H-phrases|317|334|360|360D|372|410}}
| PPhrases = {{P-phrases|203|233|260|264|270|271|272|273|280|284|302|352|304|340|318|319|321|333|317|342|316|362|364|391|403|405|501}}
  }}
}}
<!-- Definition and uses -->
'''Gentamicin''' is an [[aminoglycoside]] [[antibiotic]] used to treat several types of [[bacterial infection]]s.<ref name=AHFS2015>{{cite web|title = Gentamicin sulfate|url = https://www.drugs.com/monograph/gentamicin-sulfate.html|publisher = The American Society of Health-System Pharmacists|access-date = 15 August 2015|url-status = live|archive-url = https://web.archive.org/web/20150816010048/http://www.drugs.com/monograph/gentamicin-sulfate.html|archive-date = 16 August 2015}}</ref> This may include [[osteomyelitis|bone infections]], [[endocarditis]], [[pelvic inflammatory disease]], [[meningitis]], [[pneumonia]], [[urinary tract infections]], and [[sepsis]] among others.<ref name=AHFS2015/> It can be given [[Intravenous therapy|intravenously]], by [[intramuscular injection]], or [[topical]]ly.<ref name=AHFS2015/> Topical formulations may be used in burns or for infections of the outside of the eye.<ref>{{cite book| vauthors = Bartlett J |title=Clinical Ocular Pharmacology|date=2013|publisher=Elsevier|isbn=9781483193915|page=214|edition=s|url=https://books.google.com/books?id=kA8lBQAAQBAJ&pg=PA214|url-status=live|archive-url=https://web.archive.org/web/20151222132453/https://books.google.ca/books?id=kA8lBQAAQBAJ&pg=PA214|archive-date=22 December 2015}}</ref> It is often only used for two days until [[bacterial culture]]s determine what specific antibiotics the infection is sensitive to.<ref name="ap01">{{cite journal | vauthors = Moulds R, Jeyasingham M |journal=Australian Prescriber |title=Gentamicin: a great way to start |date=October 2010 |volume=33 |issue=5 |pages=134–135 |doi=10.18773/austprescr.2010.062 |doi-access=free }}</ref> The dose required should be monitored by blood testing.<ref name=AHFS2015/>

<!-- Side effects and mechanism -->
Gentamicin can cause [[ototoxic|inner ear problems]] and [[nephrotoxic|kidney problems]].<ref name=AHFS2015/> The inner ear problems can include problems with balance and [[hearing loss]].<ref name=AHFS2015/> These problems may be permanent.<ref name=AHFS2015/> If used during [[pregnancy]], it can cause harm to the developing fetus.<ref name=AHFS2015/> However, it appears to be safe for use during [[breastfeeding]].<ref name=GenB>{{cite web|title=Gentamicin use while breastfeeding|url=https://www.drugs.com/breastfeeding/gentamicin.html|access-date=15 August 2015|url-status=live|archive-url=https://web.archive.org/web/20150906222610/http://www.drugs.com/breastfeeding/gentamicin.html|archive-date=6 September 2015}}</ref> Gentamicin is a type of aminoglycoside <ref name=AHFS2015/> and works by disrupting the ability of the bacteria to make proteins, which typically [[bactericidal|kills the bacteria]].<ref name=AHFS2015/>

<!-- Society and culture -->
Gentamicin is naturally produced by the bacterium ''[[Micromonospora purpurea]]'',<ref name="pmid14184912">{{cite journal | vauthors = Weinstein MJ, Luedemann GM, Oden EM, Wagman GH, Rosselet JP, Marquez JA, Coniglio CT, Charney W, Herzog HL, Black J | title = Gentamicin, a new antibiotic complex from Micromonospora | journal = Journal of Medicinal Chemistry | volume = 6 | issue = 4 | pages = 463–464 | date = July 1963 | pmid = 14184912 | doi = 10.1021/jm00340a034 }}</ref><ref name=AHFS2015/> was patented in 1962, approved for medical use in 1964.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR  |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=507 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA507 }}</ref> The antibiotic is collected from the culture of the ''[[Micromonospora]]'' by perforating the cell wall of the bacterium. Current research is underway to understand the [[biosynthesis]] of this antibiotic in an attempt to increase expression and force secretion of gentamicin for higher [[titer]]. Gentamicin 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> The World Health Organization classifies gentamicin as critically important for human medicine.<ref>{{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 | id=License: CC BY-NC-SA 3.0 IGO | isbn=9789241515528 | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref>{{cite book| vauthors = Burchum J |title=Lehne's pharmacology for nursing care|date=2014|publisher=Elsevier Health Sciences|isbn=9780323340267|page=1051|url=https://books.google.com/books?id=C7_NBQAAQBAJ&pg=PA1052|url-status=live|archive-url=https://web.archive.org/web/20160311015121/https://books.google.ca/books?id=C7_NBQAAQBAJ&pg=PA1052|archive-date=11 March 2016}}</ref>

==Medical uses==
Gentamicin is active against a wide range of bacterial infections, mostly Gram-negative bacteria including ''[[Pseudomonas]]'', ''[[Proteus (bacterium)|Proteus]]'', ''[[Escherichia coli]]'', ''[[Klebsiella pneumoniae]]'', ''Enterobacter aerogenes'', ''[[Serratia]]'', and the Gram-positive ''[[Staphylococcus]]''.<ref name="Baxter Corporation">{{Cite web|url = http://www.baxter.ca/en/downloads/product_information/GENTAMICIN(E)_PM_AUG282012_EN.pdf|title = Gentamicin|access-date = 2 November 2015|publisher = Baxter Corporation|url-status = dead|archive-url = https://web.archive.org/web/20160304124731/http://www.baxter.ca/en/downloads/product_information/GENTAMICIN(E)_PM_AUG282012_EN.pdf|archive-date = 4 March 2016}}</ref> Gentamicin is used in the treatment of respiratory tract infections, urinary tract infections, blood, bone and soft tissue infections of these susceptible bacteria.<ref name="Product Monograph">{{Cite web|url = http://www.sandoz.ca/cs/groups/public/@sge_ca/documents/document/n_prod_1301121.pdf|title = Gentamicin Injection USP | work = Product Monograph|access-date = 2 November 2015|publisher = Sandoz Canada Inc|url-status = dead|archive-url = https://web.archive.org/web/20150412102019/http://www.sandoz.ca/cs/groups/public/%40sge_ca/documents/document/n_prod_1301121.pdf|archive-date = 12 April 2015}}</ref>

There is insufficient evidence to support gentamicin as the first line treatment of ''[[Neisseria gonorrhoeae]]'' infection.<ref>{{cite journal | vauthors = Hathorn E, Dhasmana D, Duley L, Ross JD | title = The effectiveness of gentamicin in the treatment of Neisseria gonorrhoeae: a systematic review | journal = Systematic Reviews | volume = 3 | article-number = 104 | date = September 2014 | pmid = 25239090 | pmc = 4188483 | doi = 10.1186/2046-4053-3-104 | doi-access = free }}</ref> Gentamicin is not used for ''[[Neisseria meningitidis]]'' or ''[[Legionella pneumophila]]'' bacterial infections (because of the risk of the person going into shock from lipid A [[endotoxin]] found in certain Gram-negative organisms). Gentamicin is also useful against ''[[Yersinia pestis]]'' (responsible for [[Plague (disease)|plague]]), its relatives, and ''[[Francisella tularensis]]'' (the organism responsible for [[tularemia]] often seen in hunters and trappers).<ref>{{cite book| vauthors = Goljan EF |title = Rapid Review Pathology|edition = 3rd|year = 2011|publisher = Elsevier|location = Philadelphia, Pennsylvania|isbn = 978-0-323-08438-3|pages = 241}}</ref>

Some ''[[Enterobacteriaceae]]'', ''[[Pseudomonas]] spp.'', ''[[Enterococcus]] spp.'', ''[[Staphylococcus aureus]]'' and other ''Staphylococcus spp.'' have varying degrees of [[antimicrobial resistance|resistance]] to gentamicin.<ref>{{cite web|title = Gentamicin spectrum of bacterial susceptibility and Resistance|url = http://www.toku-e.com/Upload/Products/PDS/20120604005203.pdf | publisher = TOKU-E |access-date = 15 May 2012|url-status = dead|archive-url = https://web.archive.org/web/20150220033338/http://www.toku-e.com/Upload/Products/PDS/20120604005203.pdf|archive-date = 20 February 2015}}</ref>
===Special populations===
====Pregnancy and breastfeeding====
Gentamicin is not recommended in pregnancy unless the benefits outweigh the risks for the mother. Gentamicin can cross the [[placenta]] and several reports of [[congenital hearing loss|irreversible bilateral congenital deafness]] in children have been seen. [[Intramuscular injection|Intramuscular]] injection of gentamicin in mothers can cause [[muscle weakness]] in the [[newborn]].<ref name="Product Monograph" />

The safety and efficacy for gentamicin in nursing mothers has not been established. Detectable gentamicin levels are found in human breast milk and in nursing babies.<ref name="Product Monograph" />

====Elderly====
In the elderly, [[renal function]] should be assessed before beginning therapy as well as during treatment due to a decline in glomerular filtration rate. Gentamicin levels in the body can remain higher for a longer period of time in this population. Gentamicin should be used cautiously in persons with [[Kidney|renal]], [[Auditory system|auditory]], [[Vestibular system|vestibular]], or [[Neuromuscular junction|neuromuscular]] dysfunction.<ref name="Baxter Corporation" />

====Children====
Gentamicin may not be appropriate to use in children, including babies. Studies have shown higher [[Serum (blood)|serum]] levels and a longer [[half-life]] in this population.<ref>{{cite journal | vauthors = Sato Y | title = Pharmacokinetics of antibiotics in neonates | journal = Acta Paediatrica Japonica | volume = 39 | issue = 1 | pages = 124–131 | date = February 1997 | pmid = 9124044 | doi = 10.1111/j.1442-200X.1997.tb03569.x | s2cid = 23564581 }}</ref> [[Kidney function]] should be checked periodically during therapy. Long-term effects of treatment can include hearing loss and balance problems. [[Hypocalcemia]], [[hypokalemia]], and [[muscle weakness]] have been reported when used by injection.<ref name="Baxter Corporation" />

==Contraindications==
Gentamicin should not be used if a person has a history of [[hypersensitivity]], such as [[anaphylaxis]], or other serious toxic reaction to gentamicin or any other [[aminoglycosides]].<ref name="Product Monograph" /> Greater care is required in people with [[myasthenia gravis]] and other neuromuscular disorders as there is a risk of worsening weakness.<ref name=AHFS2015/> Gentamicin should also be avoided when prescribing empirical antibiotics in the setting of possible infant botulism (Ampicillin with Gentamicin is commonly used as empiric therapy in infants) also due to worsening of neuromuscular function.<ref>{{cite journal | vauthors = Santos JI, Swensen P, Glasgow LA | title = Potentiation of Clostridium botulinum toxin aminoglycoside antibiotics: clinical and laboratory observations | journal = Pediatrics | volume = 68 | issue = 1 | pages = 50–54 | date = July 1981 | doi = 10.1542/peds.68.1.50 | pmid = 7243509 | s2cid = 36001577 }}</ref>

==Adverse effects==
Adverse effects of gentamicin can range from less severe reactions, such as nausea and vomiting, to more severe reactions including:<ref name="Baxter Corporation" />
* Low blood cell counts
* [[Hypersensitivity|Allergic reactions]] 
* [[Neuromuscular disease|Neuromuscular]] problems
* [[neuropathy|Nerve damage]] (neuropathy)
* [[Nephrotoxicity|Kidney damage]] (nephrotoxicity)
* [[Ototoxicity|Ear disorders]] (ototoxicity)
[[Nephrotoxicity]] and [[ototoxicity]] are thought to be dose related with higher doses causing greater chance of toxicity.<ref name="Baxter Corporation" /> These two toxicities may have delayed presentation, sometimes not appearing until after completing treatment.<ref name="Baxter Corporation" />

===Kidney damage===
[[Nephrotoxicity|Kidney damage]] is a problem in 10–25% of people who receive aminoglycosides, and gentamicin is one of the most nephrotoxic drugs of this class.<ref name="Lopez-Novoa_2011" /> Oftentimes, acute nephrotoxicity is reversible, but it may be fatal.<ref name="Baxter Corporation" /> The risk of nephrotoxicity can be affected by the dose, frequency, duration of therapy, and concurrent use of certain medications, such as [[Nonsteroidal anti-inflammatory drug|NSAIDs]], [[diuretics]], [[cisplatin]], [[ciclosporin]], [[cephalosporins]], [[amphotericin]], [[Iodinated contrast|iodide contrast media]], and [[vancomycin]].<ref name="Lopez-Novoa_2011" />

Factors that increase risk of nephrotoxicity include:<ref name="Lopez-Novoa_2011" />
* Increased age
* Reduced [[renal function]]
* Pregnancy
* [[Hypothyroidism]]
* Hepatic dysfunction
* Volume depletion
* [[Metabolic acidosis]]
* Sodium depletion
Kidney dysfunction is monitored by measuring [[creatinine]] in the blood, electrolyte levels, [[Oliguria|urine output]], [[Proteinuria|presence of protein in the urine]],  and concentrations of other chemicals, such as urea, in the blood.<ref name="Lopez-Novoa_2011">{{cite journal | vauthors = Lopez-Novoa JM, Quiros Y, Vicente L, Morales AI, Lopez-Hernandez FJ | title = New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view | journal = Kidney International | volume = 79 | issue = 1 | pages = 33–45 | date = January 2011 | pmid = 20861826 | doi = 10.1038/ki.2010.337 | doi-access = free }}</ref>

===Inner ear===
About 11% of the population who receives aminoglycosides experience damage to their [[inner ear]].<ref>{{cite journal | vauthors = East JE, Foweraker JE, Murgatroyd FD | title = Gentamicin induced ototoxicity during treatment of enterococcal endocarditis: resolution with substitution by netilmicin | journal = Heart | volume = 91 | issue = 5 | pages = e32 | date = May 2005 | pmid = 15831617 | pmc = 1768868 | doi = 10.1136/hrt.2003.028308 }}</ref> The common symptoms of inner ear damage include [[tinnitus]], hearing loss, [[vertigo]], [[ataxia|trouble with coordination]], and dizziness.<ref name="Selimoglu_2007" /> Chronic use of gentamicin can affect two areas of the ears. First, damage of the inner ear hair cells can result in irreversible hearing loss. Second, damage to the inner ear [[Vestibular system|vestibular]] apparatus can lead to balance problems.<ref name="Selimoglu_2007">{{cite journal | vauthors = Selimoglu E | title = Aminoglycoside-induced ototoxicity | journal = Current Pharmaceutical Design | volume = 13 | issue = 1 | pages = 119–126 | date = 1 January 2007 | pmid = 17266591 | doi = 10.2174/138161207779313731 }}</ref> To reduce the risk of ototoxicity during treatment, it is recommended to stay hydrated.<ref name="Baxter Corporation" />

Factors that increase the risk of inner ear damage include:<ref name="Baxter Corporation" /><ref name="Product Monograph" />
* Increased age
* [[Uremia|High blood uric acid levels]]
* Kidney dysfunction
* Liver dysfunction 
* Higher doses 
* Long courses of therapy
* Also taking strong diuretics (e.g., [[furosemide]])

==Pharmacology==
===Mechanism of action===
Gentamicin is a [[bactericidal]] antibiotic that works by binding the 30S subunit of the bacterial ribosome, negatively impacting [[translation (biology)|protein synthesis]]. The primary mechanism of action is generally accepted to work through ablating the ability of the ribosome to discriminate on proper [[transfer RNA]] and [[messenger RNA]] interactions.<ref>{{cite web|url =http://www.drugbank.ca/drugs/DB00798|work = DrugBank | title = Gentamicin|url-status =live|archive-url =https://web.archive.org/web/20131004221814/http://www.drugbank.ca/drugs/DB00798|archive-date =4 October 2013}}</ref> Typically, if an incorrect tRNA pairs with an mRNA [[Genetic code|codon]] at the [[A-site|aminoacyl site]] of the ribosome, [[adenosine]]s 1492 and 1493 are excluded from the interaction and retract, signaling the ribosome to reject the [[Aminoacyl-tRNA|aminoacylated tRNA]]::[[EF-Tu|Elongation Factor Thermo-Unstable]] complex.<ref>{{cite journal | vauthors = Dao EH, Poitevin F, Sierra RG, Gati C, Rao Y, Ciftci HI, Akşit F, McGurk A, Obrinski T, Mgbam P, Hayes B, De Lichtenberg C, Pardo-Avila F, Corsepius N, Zhang L, Seaberg MH, Hunter MS, Liang M, Koglin JE, Wakatsuki S, Demirci H | title = Structure of the 30S ribosomal decoding complex at ambient temperature | journal = RNA | volume = 24 | issue = 12 | pages = 1667–1676 | date = December 2018 | pmid = 30139800 | pmc = 6239188 | doi = 10.1261/rna.067660.118 }}</ref> However, when gentamicin binds at helix 44 of the [[16S ribosomal RNA|16S rRNA]], it forces the adenosines to maintain the position they take when there is a correct, or cognate, match between aa-tRNA and mRNA.<ref>{{cite journal | vauthors = Wilson DN | title = Ribosome-targeting antibiotics and mechanisms of bacterial resistance | journal = Nature Reviews. Microbiology | volume = 12 | issue = 1 | pages = 35–48 | date = January 2014 | pmid = 24336183 | doi = 10.1038/nrmicro3155 | s2cid = 9264620 }}</ref> This leads to the acceptance of incorrect aa-tRNAs, causing the ribosome to synthesize proteins with wrong [[amino acid]]s placed throughout (roughly every 1 in 500).<ref>{{cite book | vauthors = Garrett R, Douthwaite S, Liljas A, Matheson A, Moore P, Harry N  |title=The Ribosome |date=2000 |publisher=ASM Press |isbn=978-1-55581-184-6 |pages=419–429 }}</ref> The non-functional, mistranslated proteins misfold and aggregate, eventually leading to death of the bacterium. Moreover,  it has been observed that gentamicin can cause a substantial slowdown in the overall elongation rate of peptide chains in live bacterial cells, independent of the misincorporation of amino acids.<ref>{{cite journal | vauthors = Aguirre Rivera J, Larsson J, Volkov IL, Seefeldt AC, Sanyal S, Johansson M | title = Real-time measurements of aminoglycoside effects on protein synthesis in live cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 118 | issue = 9 | date = March 2021 | article-number = e2013315118 | pmid = 33619089 | pmc = 7936356 | doi = 10.1073/pnas.2013315118 | bibcode = 2021PNAS..11813315A | doi-access = free }}</ref> This finding indicates that gentamicin not only induces errors in protein synthesis but also broadly hampers the efficiency of the translation process itself.  An additional mechanism has been proposed based on crystal structures of gentamicin in a secondary binding site at helix 69 of the [[23S ribosomal RNA|23S rRNA]], which interacts with helix 44 and [[Ribosome Recycling Factor|proteins that recognize stop codons]]. At this secondary site, gentamicin is believed to preclude interactions of the ribosome with ribosome recycling factors, causing the two subunits of the ribosome to stay complexed even after translation completes, creating a pool of inactive ribosomes that can no longer [[bacterial translation#Initiation|re-initiate]] and translate new proteins.<ref>{{cite journal | vauthors = Borovinskaya MA, Pai RD, Zhang W, Schuwirth BS, Holton JM, Hirokawa G, Kaji H, Kaji A, Cate JH | title = Structural basis for aminoglycoside inhibition of bacterial ribosome recycling | journal = Nature Structural & Molecular Biology | volume = 14 | issue = 8 | pages = 727–732 | date = August 2007 | pmid = 17660832 | doi = 10.1038/nsmb1271 | s2cid = 31576287 }}</ref>

==Chemistry==
=== Structure ===
[[File:FixedC1primeStereospecific Gentamicin IUPAC Numbered copy.png|class=skin-invert-image|thumb]]
Since gentamicin is derived from the species ''[[Micromonospora]]'', the backbone for this [[antibiotic]] is the aminocyclitol [[2-deoxystreptamine]].<ref name="Yu">{{cite journal | vauthors = Yu Y, Zhang Q, Deng Z | title = Parallel pathways in the biosynthesis of aminoglycoside antibiotics | journal = F1000Research | volume = 6 | pages = 723 | date = 18 May 2017 | pmid = 28620453 | pmc = 5461906 | doi = 10.12688/f1000research.11104.1 | doi-access = free }}</ref><ref name="Dewick">{{cite book | vauthors = Dewick PM |title=Medicinal natural products : a biosynthetic approach |date=2009 |location=Chichester, West Sussex, United Kingdom | publisher = Wiley |isbn=978-0-470-74167-2 |pages=738–750 |edition=3rd}}</ref> This six carbon ring is substituted at the [[IUPAC nomenclature of organic chemistry|carbon positions]] 4 and 6 by the amino sugar molecules cyclic [[purpurosamine]] and [[garosamine]], respectively.<ref name="Kumar" /><ref name="Yu" /> The gentamicin complex, is differentiated into five major components (C<sub>1</sub>, C<sub>1a</sub>, C<sub>2</sub>, C<sub>2a</sub>, C<sub>2b</sub>) and multiple minor components by substitution at the 6' carbon of the purpurosamine unit indicated in the image to the right by R<sup>1</sup> and R<sup>2</sup>.<ref name="Kumar" /><ref name="Yu" /><ref name="Weinstein" /><ref name="Vydrin">{{cite journal | vauthors = Vydrin AF, Shikhaleev IV, Makhortov VL, Shcherenko NN, Kolchanova NV |title=Component Composition of Gentamicin Sulfate Preparations|journal=Pharmaceutical Chemistry Journal |date=2003 |volume=37 |issue=8 |pages=448–450 |doi=10.1023/a:1027372416983|s2cid=43731658 }}</ref> The R<sup>1</sup> and R<sup>2</sup> can have the follow substitutions for some of the species in the gentamicin complex.<ref name="Kumar" /><ref name="Daniels" /><ref name="Dewick" />
{| class="wikitable"
|+ Major component
|-
! C complex !! R<sup>1</sup> !! R<sup>2</sup>
|-
| C<sub>1</sub> || [[Methyl]] group || [[Methyl]] group
|-
| C<sub>1a</sub>|| [[Hydrogen]] || [[Hydrogen]]
|-
| C<sub>2</sub>|| [[Hydrogen]] || [[Methyl]] group
|-
| C<sub>2a</sub> || [[Hydrogen]] || [[Methyl]] group
|-
| C<sub>2b</sub> || [[Methyl]] group || [[Hydrogen]]
|}
Gentamicins consist of three [[hexosamines]]: gentosamine/garosamine, 2-deoxystreptamine, and purpurosamine (see illustrations, from left to right).<ref>{{cite journal | vauthors = Benveniste R, Davies J | title = Structure-activity relationships among the aminoglycoside antibiotics: role of hydroxyl and amino groups | journal = Antimicrobial Agents and Chemotherapy | volume = 4 | issue = 4 | pages = 402–409 | date = October 1973 | pmid = 4598613 | pmc = 444567 | doi = 10.1128/AAC.4.4.402 }}</ref><ref>{{cite journal | vauthors = Vastola AP, Altschaefl J, Harford S | title = 5-epi-Sisomicin and 5-epi-Gentamicin B: substrates for aminoglycoside-modifying enzymes that retain activity against aminoglycoside-resistant bacteria | journal = Antimicrobial Agents and Chemotherapy | volume = 17 | issue = 5 | pages = 798–802 | date = May 1980 | pmid = 6967296 | pmc = 283878 | doi = 10.1128/AAC.17.5.798 }}</ref>
{| class="wikitable centered"
! colspan="10" class="hintergrundfarbe6" |Gentamicine
|-
!Name
!Structure
![[CAS Registry Number|CAS number]]
![[PubChem]]
!Sum formula
!Molar mass
|-
|
* Gentamicin A
|[[File:Gentamicin_A.svg|class=skin-invert-image|200x200px]]
|13291-74-2
|{{PubChem|86474}}
|C<sub>18</sub>H<sub>36</sub>N<sub>4</sub>O<sub>10</sub>
|468.50 g·mol<sup>−1</sup>
|-
|
* Gentamicin A<sub>1</sub>
|[[File:Gentamicin_A1.svg|class=skin-invert-image|200x200px]]
|
|
|
|
|-
|
* Gentamicin A<sub>2</sub>
|[[File:Gentamicin_A2.svg|class=skin-invert-image|200x200px]]
|55715-66-7
|{{PubChem|86489}}
|C<sub>17</sub>H<sub>33</sub>N<sub>3</sub>O<sub>11</sub>
|455.46 g·mol<sup>−1</sup>
|-
|
* Gentamicin A<sub>3</sub>
|[[File:Gentamicin_A3.svg|class=skin-invert-image|200x200px]]
|55715-67-8
|{{PubChem|86490}}
|C<sub>18</sub>H<sub>36</sub>N<sub>4</sub>O<sub>10</sub>
|468.50 g·mol<sup>−1</sup>
|-
|
* Gentamicin A<sub>4</sub>
|[[File:Gentamicin_A4.svg|class=skin-invert-image|200x200px]]
|
|
|
|
|-
|
* Gentamicin B
* Betamicin
|[[File:Gentamicin_B.svg|class=skin-invert-image|200x200px]]
|36889-15-3
|{{PubChem|37569}}
|C<sub>19</sub>H<sub>38</sub>N<sub>4</sub>O<sub>10</sub>
|482.53 g·mol<sup>−1</sup>
|-
|
* Gentamicin B<sub>1</sub>
|[[File:Gentamicin_B1.svg|class=skin-invert-image|200x200px]]
|36889-16-4
|{{PubChem|3034288}}
|C<sub>20</sub>H<sub>40</sub>N<sub>4</sub>O<sub>10</sub>
|496.55 g·mol<sup>−1</sup>
|-
|
* Gentamicin C<sub>1</sub>
|[[File:Gentamicin_C1.svg|class=skin-invert-image|200x200px]]
|25876-10-2
|{{PubChem|441305}}
|C<sub>21</sub>H<sub>43</sub>N<sub>5</sub>O<sub>7</sub>
|477.59 g·mol<sup>−1</sup>
|-
|
* Gentamicin C<sub>1a</sub>
|[[File:Gentamicin_C1a.svg|class=skin-invert-image|200x200px]]
|26098-04-4
|{{PubChem|72396}}
|C<sub>19</sub>H<sub>39</sub>N<sub>5</sub>O<sub>7</sub>
|449.54 g·mol<sup>−1</sup>
|-
|
* Gentamicin C<sub>2</sub>
|[[File:Gentamicin_C2.svg|class=skin-invert-image|200x200px]]
|25876-11-3
|{{PubChem|72397}}
|C<sub>20</sub>H<sub>41</sub>N<sub>5</sub>O<sub>7</sub>
|463.57 g·mol<sup>−1</sup>
|-
|
* Gentamicin C<sub>2a</sub>
|[[File:Gentamicin_C2a.svg|class=skin-invert-image|200x200px]]
|59751-72-3
|
|C<sub>20</sub>H<sub>41</sub>N<sub>5</sub>O<sub>7</sub>
|463.57 g·mol<sup>−1</sup>
|-
|
* Gentamicin C<sub>2b</sub>
* Micronomicin
|[[File:Gentamicin_C2b.svg|class=skin-invert-image|200x200px]]
|52093-21-7
|{{PubChem|107677}}
|C<sub>20</sub>H<sub>41</sub>N<sub>5</sub>O<sub>7</sub>
|463.57 g·mol<sup>−1</sup>
|-
|}
[[Kinamycin|Kanamycins]] and [[tobramycin]] exhibit similar structures. [[Sisomicin]] is 4,5-dehydrogentamicin-C<sub>1a</sub>.

===Components===
Gentamicin is composed of a number of related gentamicin components and fractions which have varying degrees of antimicrobial potency.<ref>{{cite journal | vauthors = Weinstein MJ, Wagman GH, Oden EM, Marquez JA | title = Biological activity of the antibiotic components of the gentamicin complex | journal = Journal of Bacteriology | volume = 94 | issue = 3 | pages = 789–790 | date = September 1967 | pmid = 4962848 | pmc = 251956 | doi = 10.1128/JB.94.3.789-790.1967 }}</ref> The main components of gentamicin include members of the gentamicin C complex: gentamicin C<sub>1</sub>, gentamicin C<sub>1a</sub>, and gentamicin C<sub>2</sub> which compose approximately 80% of gentamicin and have been found to have the highest antibacterial activity. Gentamicin A, B, X, and a few others make up the remaining 20% of gentamicin and have lower antibiotic activity than the gentamicin C complex.<ref name="Vydrin" /> The exact composition of a given sample or lot of gentamicin is not well defined, and the level of gentamicin C components or other components in gentamicin may differ from lot-to-lot depending on the gentamicin manufacturer or manufacturing process. Because of this lot-to-lot variability, it can be difficult to study various properties of gentamicin including pharmacokinetics and microorganism susceptibility if there is an unknown combination of chemically related but different compounds.<ref>{{cite journal | vauthors = Isoherranen N, Lavy E, Soback S | title = Pharmacokinetics of gentamicin C(1), C(1a), and C(2) in beagles after a single intravenous dose | journal = Antimicrobial Agents and Chemotherapy | volume = 44 | issue = 6 | pages = 1443–1447 | date = June 2000 | pmid = 10817690 | pmc = 89894 | doi = 10.1128/aac.44.6.1443-1447.2000 }}</ref>

===Biosynthesis===
The complete [[biosynthesis]] of gentamicin is not entirely elucidated. The genes controlling the biosynthesis of gentamicin are of particular interest due to the difficulty in obtaining the antibiotic after production.<ref name="Vydrin" /><ref name="Weinstein">{{cite journal | vauthors = Weinstein MJ, Wagman GH, Oden EM, Marquez JA | title = Biological activity of the antibiotic components of the gentamicin complex | journal = Journal of Bacteriology | volume = 94 | issue = 3 | pages = 789–790 | date = September 1967 | pmid = 4962848 | pmc = 251956 | doi = 10.1128/jb.94.3.789-790.1967 }}</ref><ref name="Daniels" /><ref name="Wagman" /><ref name="Chu" >{{cite journal | vauthors = Chu J, Zhang S, Zhuang Y, Chen J, Li Y |title=Factors affecting the biosynthesis and secretion of gentamicin |journal=Process Biochemistry |date=December 2002 |volume=38 |issue=5 |pages=815–820 |doi=10.1016/S0032-9592(02)00230-3}}</ref> Since gentamicin is collected at the cell surface and the cell surface must be perforated somehow to obtain the antibiotic.<ref name="Vydrin" /><ref name="Weinstein" /><ref name="Daniels" /><ref name="Wagman" /><ref name="Chu"/> Many propose the amount of gentamicin collected after production could increase if the genes are identified and re-directed to secrete the antibiotic instead of collecting gentamicin at the cell surface.<ref name="Vydrin" /><ref name="Weinstein" /><ref name="Daniels" /><ref name="Wagman" /><ref name="Chu"/> Literature also agrees with the gentamicin biosynthesis pathway starting with D-[[Glucose-6-phosphate]] being [[dephosphorylation|dephopsphorylated]], [[transamination|transaminated]], [[dehydrogenation|dehydrogenated]] and finally [[glycosylation|glycosylated]] with D-[[glucosamine]] to generate [[paromamine]] inside ''[[Micromonospora]] echinospora''.<ref name="Kumar" /> The addition of D-[[xylose]] leads to the first intermediate of the gentamicin C complex pathway, gentamicin A2.<ref name="Kumar" /><ref name="TestaII" /> Gentamicin A2 is C-methylated and [[epimer]]ized into gentamicin X<sub>2</sub>, the first branch point of this biosynthesis pathway<ref name="TestaII">{{cite journal | vauthors = Testa RT, Tilley BC | title = Biotransformation, a new approach to aminoglycoside biosynthesis: II. Gentamicin | journal = The Journal of Antibiotics | volume = 29 | issue = 2 | pages = 140–146 | date = February 1976 | pmid = 931800 | doi = 10.7164/antibiotics.29.140 | doi-access = free }}</ref>

When X<sub>2</sub> is acted on by the [[cobalamin]]-dependent [[Radical (chemistry)|radical]] [[S-Adenosyl methionine|S-adenosyl-L-methionine]] enzyme GenK, the [[IUPAC nomenclature of organic chemistry|carbon position]] 6' is methylated to form the pharmacologically active intermediate G418<ref name="Kim">{{cite journal | vauthors = Kim HJ, McCarty RM, Ogasawara Y, Liu YN, Mansoorabadi SO, LeVieux J, Liu HW | title = GenK-catalyzed C-6' methylation in the biosynthesis of gentamicin: isolation and characterization of a cobalamin-dependent radical SAM enzyme | journal = Journal of the American Chemical Society | volume = 135 | issue = 22 | pages = 8093–8096 | date = June 2013 | pmid = 23679096 | pmc = 3796153 | doi = 10.1021/ja312641f }}</ref><ref name="TestaII" /><ref name="Kumar" /><ref name="Hong">{{cite journal | vauthors = Hong W, Yan L | title = Identification of gntK, a gene required for the methylation of purpurosamine C-6' in gentamicin biosynthesis | journal = The Journal of General and Applied Microbiology | volume = 58 | issue = 5 | pages = 349–356 | date = 2012 | pmid = 23149679 | doi = 10.2323/jgam.58.349 | doi-access = free }}</ref> G418 then undergoes [[dehydrogenation]] and [[amination]] at the C6' position  by the dehydrogenase gene, GenQ, to generate the pharmacologically active JI-20B, although another intermediate, 6'-dehydro-6'oxo-G418 (6'DOG) is proposed to be in-between this step and for which the gene GenB1 is proposed as the [[amination|aminating]] gene.<ref name="Kumar" /><ref name="Guo">{{cite journal | vauthors = Guo J, Huang F, Huang C, Duan X, Jian X, Leeper F, Deng Z, Leadlay PF, Sun Y | title = Specificity and promiscuity at the branch point in gentamicin biosynthesis | journal = Chemistry & Biology | volume = 21 | issue = 5 | pages = 608–618 | date = May 2014 | pmid = 24746560 | pmc = 4039129 | doi = 10.1016/j.chembiol.2014.03.005 }}</ref> JI-20B is [[dehydroxylation|dehydroxylated]] and [[epimer]]ized to first component of the gentamicin C complex, gentamicin C2a which then undergoes an epimerization by GenB2 and then a N-methylation by an unconfirmed gene to form the final product in this branch point, gentamicin C1.<ref name="TestaII" /><ref name="Guo" /><ref name="Kumar" /><ref name="Chen" />

When X<sub>2</sub> bypasses GenK and is directly [[dehydrogenase|dehydrogenated]] and [[amination|aminated]] by the GenQ enzyme, the other pharmacologically relevant intermediate JI-20A is formed.<ref name="Kumar" /><ref name="Guo"/> Although, there has been identification of an intermediate for this step, 6'-dehydro-6'-oxo-gentamicin X2 (6'-DOX), for which the enzyme GenB1 is purposed as the [[amination|aminating]] enzyme.<ref name="Guo" /> JI-20A is then [[dehydroxylation|dehydroxylated]] into the first component of the gentamicin C complex for this branch, gentamicin C1a via a catalytic reaction with GenB4.<ref name="Chen">{{cite journal | vauthors = Chen X, Zhang H, Zhou S, Bi M, Qi S, Gao H, Ni X, Xia H | title = The bifunctional enzyme, GenB4, catalyzes the last step of gentamicin 3',4'-di-deoxygenation via reduction and transamination activities | journal = Microbial Cell Factories | volume = 19 | issue = 1 | pages = 62 | date = March 2020 | pmid = 32156271 | pmc = 7063804 | doi = 10.1186/s12934-020-01317-0 | doi-access = free }}</ref> C1a then undergoes an N-methylation by an unconfirmed enzyme to form the final component, gentamicin C2b.<ref name="Guo" /><ref name="TestaII" /><ref name="Kumar" /><ref name="Chen" />

====Fermentation====
Gentamicin is only synthesized via submerged [[fermentation]] and inorganic sources of nutrients have been found to reduce production.<ref name="Kumar">{{cite journal | vauthors = Kumar CG, Himabindu M, Jetty A | title = Microbial biosynthesis and applications of gentamicin: a critical appraisal | journal = Critical Reviews in Biotechnology | volume = 28 | issue = 3 | pages = 173–212 | date = January 2008 | pmid = 18937107 | doi = 10.1080/07388550802262197 | s2cid = 83784820 }}</ref> Traditional fermentation used yeast beef broth,<ref name="Weinstein" /> but there has been research into optimizing the [[growth medium]] for producing gentamicin C complex due to the C complex currently being the only pharmaceutically relevant component.<ref name="Kumar" /> The main components of the growth medium are carbon sources, mainly sugars, but several studies found increased gentamicin production by adding vegetable and fish oils and decreased gentamicin production with the addition of [[glucose]], [[xylose]] and several [[carboxylic acid]]s.<ref name="Kumar" /> [[Tryptone]] and various forms of yeast and yeast derivatives are traditionally used as the nitrogen source in the growth medium, but several [[amino acids]], [[soybean meal]], [[corn steep liquor]], [[ammonium sulfate]], and [[ammonium chloride]] have proven to be beneficial additives.<ref name="Kumar" /><ref name ="Daniels">{{cite journal | vauthors = Daniels PJ, Luce C, Nagabhushan TL | title = The gentamicin antibiotics. 6. Gentamicin C2b, an aminoglycoside antibiotic produced by Micromonospora purpurea mutant JI-33 | journal = The Journal of Antibiotics | volume = 28 | issue = 1 | pages = 35–41 | date = January 1975 | pmid = 1092638 | doi = 10.7164/antibiotics.28.35 | doi-access = free }}</ref> [[Phosphate ion]]s, [[metal ions]] ([[cobalt]] and a few others at low concentration), various vitamins (mostly [[B vitamins]]), [[Nucleobase|purine and pyrimidine bases]] are also supplemented into the growth medium to increase gentamicin production, but the margin of increase is dependent on the species of ''Micromonospora'' and the other components in the growth medium.<ref name="Kumar" /><ref name ="Wagman">{{cite journal | vauthors = Wagman GH, Testa RT, Marquez JA | title = Antibiotic 6640. II. Fermentation, isolation, and properties | journal = The Journal of Antibiotics | volume = 23 | issue = 11 | pages = 555–558 | date = November 1970 | pmid = 5487130 | doi = 10.7164/antibiotics.23.555 | doi-access = free }}</ref> With all of these aforementioned additives, [[pH]] and [[aeration]] are key determining factors for the amount of gentamicin produced.<ref name="Kumar" /><ref name="Daniels" /> A range of pH from 6.8 to 7.5 is used for gentamicin biosynthesis and the aeration is determined by independent experimentation reliant on type of growth medium and species of ''Micromonospora''.<ref name="Kumar" /><ref name="Daniels" />

==History==
[[File:Gentamicin for injection.jpg|thumb|Gentamicin for injection]]

Gentamicin is produced by the fermentation of ''[[Micromonospora purpurea]]''. It was discovered in 1963 by Weinstein, Wagman et al. at Schering Corporation in Bloomfield, N.J. while working with source material (soil samples) provided by Rico Woyciesjes.<ref name="pmid14184912" /> When ''M.&nbsp;purpurea'' grows in culture it is a vivid purple colour similar to the colour of the dye [[Gentian Violet]] and hence this was why Gentamicin took then name it did. Subsequently, it was purified and the structures of its three components were determined by Cooper, et al., also at the Schering Corporation. It was initially used as a topical treatment for burns at burn units in Atlanta and San Antonio and was introduced into IV usage in 1971. It remains a mainstay for use in [[sepsis]].{{cn|date=March 2023}}

It is synthesized by ''[[Micromonospora]]'', a genus of [[Gram-positive bacteria]] widely present in the environment (water and soil). According to the [[American Medical Association]] Committee on Generic Names, antibiotics not produced by ''Streptomyces'' should not use ''y'' in the ending of the name, and to highlight their specific biological origins, gentamicin and other related antibiotics produced by this genus ([[verdamicin]], [[mutamicin]], [[sisomicin]], [[netilmicin]], and [[retymicin]]) have their spellings ending in ''~micin'' and not in ''~mycin''.<ref>{{cite journal | vauthors = Waisbren BA | title = Experiences with the new antibiotic gentamicin | journal = The Journal of Infectious Diseases | volume = 119 | issue = 4 | pages = 518–536 | date = 1 April 1969 | pmid = 4306977 | doi = 10.1093/infdis/119.4-5.528 }}</ref>

==Research==
Gentamicin is also used in [[molecular biology]] research as an antibacterial agent in tissue and cell culture, to prevent contamination of sterile cultures. Gentamicin is one of the few heat-stable antibiotics that remain active even after [[autoclave|autoclaving]], which makes it particularly useful in the preparation of some microbiological growth media.{{citation needed|date=September 2015}}

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite book | title=Medical Genetics Summaries | chapter=Gentamicin Therapy and MT-RNR1 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK285956/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | publisher=[[National Center for Biotechnology Information]] (NCBI) | year=2015 | pmid=28520359 | id=Bookshelf ID: NBK285956 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}
{{refend}}

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