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

{{Short description|Antibiotic medication}}

{{Use dmy dates|date=March 2024}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 464364466

| width =

| alt =

| image2 = Amikacin 3D ball-and-stick 4P20.png

| width2 =

| alt2 =

| caption =

<!-- Clinical data -->

| pronounce =

| tradename = Amikin, Amiglyde-V, Arikayce, others

| DailyMedID = Amikacin

| pregnancy_AU = D

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Amikacin Use During Pregnancy | website=Drugs.com | date=2 December 2019 | url=https://www.drugs.com/pregnancy/amikacin.html | access-date=13 March 2020}}</ref>

| pregnancy_category=

| routes_of_administration = [[Intramuscular injection|Intramuscular]], [[Intravenous therapy|intravenous]], [[Inhalation administration|inhalation]]

| class = [[Aminoglycoside]]

| ATCvet =

| ATC_prefix = D06

| ATC_suffix = AX12

| ATC_supplemental = {{ATC|J01|GB06}}, {{ATC|S01|AA21}}, {{ATC|J01|RA06}}, {{ATCvet|D06|AX12}}, {{ATCvet|J01|GB06}}, {{ATCvet|S01|AA21}}, {{ATCvet|J01|RA06}}

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024}}</ref>

| 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_comment = <ref>{{cite web | title=Amikacin 250 mg/ml Injection - Summary of Product Characteristics (SmPC) | website=(emc) | date=16 September 2015 | url=https://www.medicines.org.uk/emc/medicine/619 | access-date=13 March 2020}}</ref>

| legal_US_comment = <ref name="Arikayce FDA label" />

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Arikayce liposomal EPAR">{{cite web | title=Arikayce liposomal EPAR | website=European Medicines Agency | date=21 July 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/arikayce-liposomal | access-date=4 March 2023}}</ref><ref>{{cite web | title=Arikayce liposomal Product information | website=Union Register of medicinal products | url=https://ec.europa.eu/health/documents/community-register/html/h1469.htm | access-date=3 March 2023}}</ref>

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

| legal_UN_comment =

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

<!-- Pharmacokinetic data -->

| bioavailability = >90%<ref name="plumb"/>

| protein_bound = 0–11%

| metabolism = Mostly unmetabolized

| metabolites =

| >

| elimination_half-life = 2–3 hours

| duration_of_action =

| excretion = [[Kidney]]

<!-- Identifiers -->

| index2_label = as salt

| CAS_supplemental =

| IUPHAR_ligand =

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| KEGG2_Ref = {{keggcite|correct|kegg}}

| KEGG2 = D00865

| NIAID_ChemDB =

| PDB_ligand =

| synonyms =

<!-- Chemical and physical data -->

| IUPAC_name = (2''S'')-4-Amino-''N''-[(2''S'',3''S'',4''R'',5''S'')-5-amino-2-[(2''S'',3''R'',4''S'',5''S'',6''R'')-4-amino-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4-[(2''R'',3''R'',4''S'',5''R'',6''R'')-6-(aminomethyl)-3,4,5-trihydroxy-oxan-2-yl]oxy-3-hydroxy-cyclohexyl]-2-hydroxybutanamide

| C=22 | H=43 | N=5 | O=13

| SMILES = O=C(N[C@H]3[C@H](O[C@H]1O[C@@H]([C@@H](O)[C@H](N)[C@H]1O)CO)[C@@H](O)[C@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](N)C3)[C@@H](O)CCN

| StdInChI_comment =

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Amikacin''' is an [[antibiotic]] medication used for a number of [[bacterial infections]].<ref name=AHFS2016>{{cite web|url=https://www.drugs.com/monograph/amikacin-sulfate.html|title=Amikacin Sulfate|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220231044/https://www.drugs.com/monograph/amikacin-sulfate.html|archive-date=20 December 2016}}</ref> This includes [[joint infections]], [[intra-abdominal infection]]s, [[meningitis]], [[pneumonia]], [[sepsis]], and [[urinary tract infection]]s.<ref name=AHFS2016/> It is also used for the treatment of [[multidrug-resistant tuberculosis]].<ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free |page=137}}</ref> It is used by injection [[intravenous|into a vein using an IV]] or [[intramuscular|into a muscle]].<ref name=AHFS2016/>

<!-- Side effects and mechanism -->

Amikacin, like other [[aminoglycoside|aminoglycoside antibiotics]], can cause [[hearing loss]], balance problems, and [[kidney problems]].<ref name=AHFS2016/> Other side effects include [[paralysis]], resulting in the inability to breathe.<ref name=AHFS2016/> If used during [[pregnancy]] it may cause permanent deafness in the baby.<ref name=AHFS2016/><ref name="Drugs.com pregnancy" /> Amikacin works by blocking the function of the bacteria's [[30S ribosomal subunit]], making it unable to produce [[protein]]s.<ref name=AHFS2016/>

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

Amikacin was patented in 1971, and came into commercial use in 1976.<ref>{{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|url-status=live|archive-url=https://web.archive.org/web/20161220092307/https://books.google.ca/books?id=FjKfqkaKkAAC&pg=PA507|archive-date=20 December 2016}}</ref><ref>{{cite book|title=Oxford Handbook of Infectious Diseases and Microbiology|date=2009|publisher=OUP Oxford|isbn=9780191039621|page=56|url=https://books.google.com/books?id=5W-WBQAAQBAJ&pg=PT56|url-status=live|archive-url=https://web.archive.org/web/20151124232554/https://books.google.ca/books?id=5W-WBQAAQBAJ&pg=PT56|archive-date=24 November 2015}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is derived from [[kanamycin]].<ref name=AHFS2016/>

{{TOC limit}}

==Medical uses==

Amikacin is most often used for treating severe infections with [[multidrug resistance|multidrug-resistant]], aerobic [[Gram-negative]] bacteria, especially ''[[Pseudomonas]]'', ''[[Acinetobacter]]'', ''[[Enterobacter]]'', ''[[E. coli]]'', ''[[Proteus (bacterium)|Proteus]]'', ''[[Klebsiella]]'', and ''[[Serratia]]''.<ref name="Amikacin sulfate FDA label">{{cite web | title=Amikacin sulfate injection, solution | website=DailyMed | date=10 April 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c0f57839-1c9b-49e5-8c7a-708e2d16495d | access-date=13 March 2020}}</ref> The only [[Gram-positive]] bacteria that amikacin strongly affects are ''[[Staphylococcus]]''<ref name="Amikacin sulfate FDA label" /> and ''[[Nocardia]]''.<ref>{{cite book | vauthors = Scholar EM, Pratt WB | title=The Antimicrobial Drugs | date=22 May 2000 | pages=15–19 | url=https://books.google.com/books?id=gACeB8XCnpgC&pg=PA15 | edition=2nd | publisher=Oxford University Press, USA | isbn=978-0-19-975971-2 | url-status=live | archive-url=https://web.archive.org/web/20170910172330/https://books.google.com/books?id=gACeB8XCnpgC&pg=PA15 | archive-date=10 September 2017 }}</ref> Amikacin can also be used to treat non-tubercular [[Mycobacterium|mycobacterial]] infections and tuberculosis (if caused by sensitive strains) when first-line drugs fail to control the infection.<ref name=AHFS2016 /> It is rarely used alone.<ref name=cunha>{{cite journal | vauthors = Cunha BA | title = New uses for older antibiotics: nitrofurantoin, amikacin, colistin, polymyxin B, doxycycline, and minocycline revisited | journal = The Medical Clinics of North America | volume = 90 | issue = 6 | pages = 1089–1107 | date = November 2006 | pmid = 17116438 | doi = 10.1016/j.mcna.2006.07.006 | series = Antimicrobial Therapy | s2cid = 30373734 }}</ref>

It is often used in the following situations:<ref name=AHFS2016 />

* [[Bronchiectasis]]<ref name=medscape>{{cite web | work=Medscape | title=amikacin (Rx) | publisher=WebMD | access-date=9 August 2017 | url=http://reference.medscape.com/drug/amikin-amikacin-342516#0 | url-status=live | archive-url=https://web.archive.org/web/20170809083119/http://reference.medscape.com/drug/amikin-amikacin-342516 | archive-date=9 August 2017 }}</ref>

* Bone and joint infections

* [[Granulocytopenia]], when combined with [[ticarcillin]], in people with cancer<ref name="aronson">{{cite book |editor=Aronson J. K.| title=Meyler's Side Effects of Drugs | chapter=Amikacin | location=Oxford | date=2016 | edition=16th | publisher=Elsevier | isbn=978-0-444-53716-4 | pages=207–209}}</ref>

* Intra-abdominal infections (such as [[peritonitis]]) as an adjunct to other medicines, like [[clindamycin]], [[metronidazole]], [[piperacillin]]/[[tazobactam]], or [[ampicillin]]/[[sulbactam]]

* [[Meningitis]]:

** for meningitis by ''E. coli'', as an adjunct to [[imipenem]]

** for meningitis caused by ''Pseudomonas'', as an adjunct to [[meropenem]]

** for meningitis caused by ''Acinetobacter'', as an adjunct to imipenem or [[colistin]]

** for [[neonatal meningitis]] caused by ''[[Streptococcus agalactiae]]'' or ''[[Listeria monocytogenes]]'', as an adjunct to ampicillin

** for neonatal meningitis caused by Gram negative bacteria such as ''E. coli'', as adjunct to a [[Cephalosporin#Classification|3rd-generation cephalosporin]]

* Mycobacterial infections, including as a second-line agent for active [[tuberculosis]].<ref>{{cite book | vauthors = Vardanyan R, Hruby V | title=Synthesis of Best-Seller Drugs | chapter=Chapter 32: Antimicobacterial Drugs | location=Boston| date=2016| publisher=Academic Press | isbn=978-0-12-411492-0 | pages=669–675}}</ref> It is also used for infections by ''[[Mycobacterium avium]]'', ''[[Mycobacterium abscessus|M. abcessus]]'', ''[[Mycobacterium chelonae|M. chelonae]]'', and ''[[Mycobacterium fortuitum|M. fortuitum]]''.

* ''[[Rhodococcus equi]]'', which causes an infection resembling tuberculosis

* Respiratory tract infections, including as an adjunct to [[beta-lactam]]s or [[carbapenem]] for [[hospital-acquired pneumonia]]

* [[Sepsis]], including that in neonates,<ref name="Amikacin sulfate FDA label" /> as an adjunct to beta-lactams or carbapenem

* Skin and suture-site infections<ref name="Amikacin sulfate FDA label" />

* [[Urinary tract infection]]s that are caused by bacteria resistant to less toxic drugs (often by ''[[Enterobacteriaceae]]'' or ''P. aeruginosa)''

Amikacin may be combined with a beta-lactam antibiotic for [[empiric therapy]] for people with [[neutropenia]] and [[fever]].<ref name=AHFS2016 />

===Available forms===

A liposome inhalation suspension is also available and approved to treat [[Mycobacterium avium complex]] (MAC) in the United States,<ref name="FDA PR">{{cite press release |title=FDA approves a new antibacterial drug to treat a serious lung disease using a novel pathway to spur innovation |url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibacterial-drug-treat-serious-lung-disease-using-novel-pathway-spur-innovation |website=U.S. [[Food and Drug Administration]] (FDA) |access-date=12 November 2018 }} {{PD-notice}}</ref><ref name="Arikayce FDA label">{{cite web | title=Arikayce- amikacin suspension | website=DailyMed | date=30 September 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=499ab990-2b21-474f-aaba-d86388965f40 | access-date=13 March 2020}}</ref> and in the European Union.<ref name="Arikayce liposomal EPAR" />

Amikacin liposome inhalation suspension is the first drug approved under the US [[limited population pathway for antibacterial and antifungal drugs]] (LPAD pathway).<ref name="FDA PR" /> It also was approved under the [[Accelerated approval (FDA)|accelerated approval]] pathway.<ref name="FDA PR" /> The US [[Food and Drug Administration]] (FDA) granted the application for amikacin liposome inhalation suspension [[Fast track (FDA)|fast track]], [[breakthrough therapy]], [[priority review]], and [[Food and Drug Administration Safety and Innovation Act#GAIN|qualified infectious disease product]] (QIDP) designations.<ref name="FDA PR" /> The FDA granted approval of Arikayce to Insmed, Inc.<ref name="FDA PR" />

The safety and efficacy of amikacin liposome inhalation suspension, an inhaled treatment taken through a nebulizer, was demonstrated in a randomized, controlled clinical trial where patients were assigned to one of two treatment groups.<ref name="FDA PR" /> One group of patients received amikacin liposome inhalation suspension plus a background multi-drug antibacterial regimen, while the other treatment group received a background multi-drug antibacterial regimen alone.<ref name="FDA PR" /> By the sixth month of treatment, 29 percent of patients treated with amikacin liposome inhalation suspension had no growth of mycobacteria in their sputum cultures for three consecutive months compared to 9 percent of patients who were not treated with amikacin liposome inhalation suspension.<ref name="FDA PR" />

===Special populations===

Amikacin should be used in smaller doses in the elderly, who often have age-related decreases in kidney function, and children, whose kidneys are not fully developed yet. It is considered [[pregnancy category]] D in both the United States and Australia, meaning they have a probability of harming the fetus.<ref name=AHFS2016/> Around 16% of amikacin crosses the placenta; while the half-life of amikacin in the mother is 2 hours, it is 3.7 hours in the fetus.<ref name="Amikacin sulfate FDA label" /> A pregnant woman taking amikacin with another aminoglycoside has a possibility of causing [[congenital deafness]] in her child. While it is known to cross the placenta, amikacin is only partially secreted in breast milk.<ref name=AHFS2016/>

In general, amikacin should be avoided in infants.<ref name=ettinger>{{cite book | vauthors = Ettinger SJ, Feldman EC | title=Textbook of Veterinary Internal Medicine | date=24 December 2009 | pages=1976, 523 | url=https://books.google.com/books?id=4Qzau1jagOYC&pg=PA1976 | publisher=Elsevier Health Sciences | isbn=978-1-4377-0282-8 | url-status=live | archive-url=https://web.archive.org/web/20170910172330/https://books.google.com/books?id=4Qzau1jagOYC&pg=PA1976 | archive-date=10 September 2017 }}</ref> Infants also tend to have a larger volume of distribution due to their higher concentration of [[extracellular fluid]], where aminoglycosides reside.<ref name=plumb />

The elderly tend to have amikacin stay longer in their system; while the average clearance of amikacin in a 20-year-old is 6 L/hr, it is 3 L/hr in an 80-year-old.<ref name=maire>{{cite book | vauthors = Maire P, Bourguignon L, Goutelle S, Ducher M, Jelliffe R | chapter=Chapter 20 – Individualizing Drug Therapy in the Elderly | veditors = Jelliffe RW, Neely M | title=Individualized Drug Therapy for Patients | location=Boston | date=2017 | publisher=Academic Press | isbn=978-0-12-803348-7 | pages=373–382}}</ref>

Clearance is even higher in people with cystic fibrosis.<ref name="eghianruwa">{{cite book | vauthors = Eghianruwa K | title=Essential Drug Data for Rational Therapy in Veterinary Practice | date=2014 | page=16 | url=https://books.google.com/books?id=h4zCAgAAQBAJ&pg=PA16 | publisher=Author House | isbn=978-1-4918-0000-3 | url-status=live | archive-url=https://web.archive.org/web/20170910172330/https://books.google.com/books?id=h4zCAgAAQBAJ&pg=PA16 | archive-date=10 September 2017 }}</ref>

In people with muscular disorders such as [[myasthenia gravis]] or [[Parkinson's disease]], amikacin's paralytic effect on neuromuscular junctions can worsen muscle weakness.<ref name=AHFS2016/>

==Adverse effects==

Side-effects of amikacin are similar to those of other aminoglycosides. [[Nephrotoxicity|Kidney damage]] and [[ototoxicity]] (which can lead to hearing loss) are the most important effects, occurring in 1–10% of users.<ref name=medscape /> The nephro- and ototoxicity are thought to be due to aminoglycosides' tendency to accumulate in the kidneys and inner ear.<ref name=plumb />

[[File:Right osseous labyrinth svg hariadhi.svg|thumb|Diagram of the inner ear. Amikacin causes damage to the cochlea and vestibules.|300x300px]]

Amikacin can cause neurotoxicity if used at a higher dose or for longer than recommended. The resulting effects of neurotoxicity include [[vertigo]], [[numbness]], [[Paresthesia|tingling]] of the skin ([[paresthesia]]), muscle [[Convulsion|twitching]], and [[seizures]].<ref name=AHFS2016 /> Its toxic effect on the 8th [[cranial nerve]] causes ototoxicity, resulting in loss of balance and, more commonly, hearing loss.<ref name="plumb" >{{cite book | vauthors = Plumb DC | title=Plumb's Veterinary Drug Handbook | chapter=Amikacin Sulfate | location=Stockholm, Wisconsin; Ames, Iowa | date=2011 | edition=7th | publisher=Wiley | isbn=978-0-470-95964-0 | pages=39–43}}</ref> Damage to the [[cochlea]], caused by the forced [[apoptosis]] of the [[hair cell]]s, leads to the loss of high-frequency hearing and happens before any clinical hearing loss can be detected.<ref name="Amikacin sulfate FDA label" /><ref name="morris">{{cite book | vauthors = Morris DO, Kennis RA | title=Clinical Dermatology, An Issue of Veterinary Clinics: Small Animal Practice, E-Book | date=11 October 2012 | page=29 | url=https://books.google.com/books?id=TsKQVAWxHg4C&pg=PA29 | publisher=Elsevier Health Sciences | isbn=978-1-4557-7377-0 | url-status=live | archive-url=https://web.archive.org/web/20170910172330/https://books.google.com/books?id=TsKQVAWxHg4C&pg=PA29 | archive-date=10 September 2017 }}</ref> Damage to the [[Vestibule of the ear|ear vestibules]], most likely by creating excessive oxidative [[free radicals]]. It does so in a time-dependent rather than dose-dependent manner, meaning that risk can be minimized by reducing the duration of use.<ref name="corti">{{cite journal | vauthors = Corti N, Taegtmeyer A, Imhof A | title=Miscellaneous antibacterial drugs | journal=Side Effects of Drugs Annual | series=A worldwide yearly survey of new data in adverse drug reactions | date=1 January 2011 | doi=10.1016/B978-0-444-53741-6.00026-X | issn=0378-6080 | volume=33 | pages=509–540| isbn=9780444537416 }}</ref>

Amikacin causes nephrotoxicity (damage to the kidneys), by acting on the [[proximal renal tubule]]s. It easily ionizes to a [[cation]] and binds to the [[anionic]] sites of the epithelial cells of the proximal tubule as part of receptor-mediated [[pinocytosis]]. The concentration of amikacin in the [[renal cortex]] becomes ten times that of amikacin in the plasma;<ref name="ettinger" /> it then most likely interferes with the metabolism of [[phospholipids]] in the [[lysosomes]], which causes lytic enzymes to leak into the cytoplasm.<ref name="plumb" /> Nephrotoxicity results in increased serum [[creatinine]], [[blood urea nitrogen]], [[red blood cells]], and [[white blood cells]], as well as [[albuminuria]] (increased output of [[albumin]] in the urine), [[glycosuria]] (excretion of glucose into the urine), decreased urine [[specific gravity]], and [[oliguria]] (decrease in overall urine output).<ref name="Amikacin sulfate FDA label" /><ref name="morris" /> It can also cause [[urinary casts]] to appear.<ref name="plumb" /> The changes in [[renal tubular]] function also change the electrolyte levels and acid-base balance in the body, which can lead to [[hypokalemia]] and [[acidosis]] or [[alkalosis]].<ref name="corti" /> Nephrotoxicity is more common in those with pre-existing hypokalemia, [[hypocalcemia]], [[hypomagnesemia]], acidosis, low [[Renal function#Glomerular filtration rate|glomerular filtration rate]], [[diabetes]] mellitus, dehydration, fever, and [[sepsis]], as well as those taking [[Prostaglandins|antiprostaglandins]].<ref name=AHFS2016 /><ref name="ettinger" /><ref name="plumb" /><ref name="corti" /> The toxicity usually reverts once the antibiotic course has been completed,<ref name="plumb" /> and can be avoided altogether by less frequent dosing (such as once every 24 hours rather than once every 8 hours).<ref name="ettinger" />

Amikacin can cause neuromuscular blockade (including acute muscular paralysis) and respiratory paralysis (including [[apnea]]).<ref name=AHFS2016 />

Rare side effects (occurring in fewer than 1% of users) include allergic reactions, [[skin rash]], [[drug fever|fever]], [[headache]]s, [[tremor]], [[nausea]] and [[vomiting]], [[eosinophilia]], [[arthralgia]], [[anemia]], [[hypotension]], and hypomagnesemia. In intravitreous injections (where amikacin is injected into the eye), macular [[infarction]] can cause permanent vision loss.<ref name="Amikacin sulfate FDA label" /><ref name=medscape />

The amikacin liposome inhalation suspension prescribing information includes a boxed warning regarding the increased risk of respiratory conditions including hypersensitivity pneumonitis (inflamed lungs), bronchospasm (tightening of the airway), exacerbation of underlying lung disease and hemoptysis (spitting up blood) that have led to hospitalizations in some cases.<ref name="FDA PR" /><ref name="Arikayce FDA label" /> Other common side effects in patients taking amikacin liposome inhalation suspension are dysphonia (difficulty speaking), cough, ototoxicity (damaged hearing), upper airway irritation, musculoskeletal pain, fatigue, diarrhea and nausea.<ref name="FDA PR" /><ref name="Arikayce FDA label" />

==Contraindications==

Amikacin should be avoided in those who are sensitive to ''any'' aminoglycoside, as they are cross-allergenic (that is, an allergy to one aminoglycoside also confers hypersensitivity to other aminoglycosides). It should also be avoided in those sensitive to [[sulfite]] (seen more among people with asthma),<ref name="Amikacin sulfate FDA label" /> since most amikacin usually comes with [[sodium metabisulfite]], which can cause an allergic reaction.<ref name=AHFS2016 />

In general, amikacin should not be used with or just before/after another drug that can cause neurotoxicity, ototoxicity, or nephrotoxicity. Such drugs include other aminoglycosides; the antiviral [[acyclovir]]; the antifungal [[amphotericin B]]; the antibiotics [[bacitracin]], [[capreomycin]], colistin, [[polymyxin B]], and [[vancomycin]]; and [[cisplatin]], which is used in [[chemotherapy]].<ref name=AHFS2016 />

Amikacin should not be used with [[neuromuscular blocking agents]], as they can increase muscle weakness and paralysis.<ref name=AHFS2016 />

== Interactions ==

Amikacin can be inactivated by other beta-lactams, though not to the extent as other aminoglycosides, and is still often used with [[penicillins]] (a type of beta-lactam) to create an additive effect against certain bacteria, and carbapenems, which can have a synergistic effect against some Gram-positive bacteria. Another group of beta-lactams, the cephalosporins, can increase the nephrotoxicity of aminoglycoside as well as randomly elevating [[creatinine]] levels. The antibiotics [[chloramphenicol]], clindamycin, and [[tetracycline]] have been known to inactivate aminoglycosides in general by pharmacological antagonism.<ref name=AHFS2016 />

The effect of amikacin is increased when used with drugs derived from the [[botulinum toxin]],<ref name=medscape /> [[anesthetic]]s, neuromuscular blocking agents, or large doses of blood that contains [[citrate]] as an [[anticoagulant]].<ref name=AHFS2016 />

Potent diuretics not only cause ototoxicity themselves, but they can also increase the concentration of amikacin in the serum and tissue, making the ototoxicity even more likely.<ref name=AHFS2016 /> [[Quinidine]] also increases levels of amikacin in the body.<ref name=medscape /> The [[NSAID]] [[indomethacin]] can increase serum aminoglycoside levels in premature infants.<ref name=AHFS2016 /> Contrast mediums such as [[ioversol]] increases the nephrotoxicity and otoxicity caused by amikacin.<ref name=medscape />

Amikacin can decrease the effect certain vaccines, such as the live [[BCG vaccine]] (used for tuberculosis), the [[cholera vaccine]], and the live [[typhoid vaccine]] by acting as a pharmacological antagonist.<ref name=medscape />

==Pharmacology==

===Mechanism of action===

[[File:010 small subunit-1FKA.gif|thumb|The 30S subunit of the prokaryotic ribosome. The orange represents the 16S rRNA, and the blue represents the various proteins attached.]]

Amikacin irreversibly binds to [[16S ribosomal RNA|16S rRNA]] and the RNA-binding [[Prokaryotic small ribosomal subunit#Structure|S12 protein]] of the [[30S]] subunit of prokaryotic [[ribosome]] and inhibits protein synthesis by changing the ribosome's shape so that it cannot read the [[mRNA]] [[codon]]s correctly.<ref name="Amikacin sulfate FDA label" /><ref name="bauman">{{cite book | vauthors = Bauman RW | title=Microbiology: with diseases by body system | location=Boston | date=2015 | edition=4th | publisher=Pearson | isbn=978-0-321-91855-0}}</ref> It also interferes with the region that interacts with the [[wobble base]] of the [[tRNA]] anticodon.<ref name="drugbank">{{cite web|url=https://www.drugbank.ca/drugs/DB00479|title=Amikacin|date=2 August 2017|work=DrugBank|access-date=10 August 2017|url-status=live|archive-url=https://web.archive.org/web/20170816150102/https://www.drugbank.ca/drugs/DB00479|archive-date=16 August 2017}}</ref> It works in a concentration-dependent manner, and has better action in an alkaline environment.<ref name="plumb" />

At normal doses, amikacin-sensitive bacteria respond within 24–48 hours.<ref name="Amikacin sulfate FDA label" />

====Resistance====

Amikacin evades attacks by all antibiotic-inactivating enzymes that are responsible for [[antibiotic resistance]] in bacteria, except for aminoacetyltransferase and [[nucleotidyltransferase]].<ref name=mudd>{{cite web | vauthors = Mudd E | title=O Aminoglycosides | work=Pharmacological Sciences | access-date=14 August 2017 | date=7 August 2017 | url=https://www.pharmacologicalsciences.us/pharmaceutical-chemistry/o-aminoglycosides.html | url-status=live | archive-url=https://web.archive.org/web/20170816105922/https://www.pharmacologicalsciences.us/pharmaceutical-chemistry/o-aminoglycosides.html | archive-date=16 August 2017 }}</ref> This is accomplished by the <small>L</small>-hydroxyaminobuteroyl amide (L-HABA) moiety attached to N-1 (compare to [[kanamycin]], which simply has a hydrogen), which blocks the access and decreases the affinity of aminoglycoside-inactivating enzymes.<ref name=mudd /><ref name=kondo>{{cite journal | vauthors = Kondo S, Hotta K | title = Semisynthetic aminoglycoside antibiotics: Development and enzymatic modifications | journal = Journal of Infection and Chemotherapy | volume = 5 | issue = 1 | pages = 1–9 | date = March 1999 | pmid = 11810483 | doi = 10.1007/s101560050001 | s2cid = 38981498 }}</ref><ref name=park>{{cite journal | vauthors = Park JW, Ban YH, Nam SJ, Cha SS, Yoon YJ | title = Biosynthetic pathways of aminoglycosides and their engineering | journal = Current Opinion in Biotechnology | volume = 48 | pages = 33–41 | date = December 2017 | pmid = 28365471 | doi = 10.1016/j.copbio.2017.03.019 | series = Chemical biotechnology: Pharmaceutical biotechnology }}</ref> Amikacin ends up with only one site where these enzymes can attack, while gentamicin and tobramycin have six.<ref name=cunha />

Bacteria that are resistant to [[streptomycin]] and capreomycin are still susceptible to amikacin; bacteria that are resistant to kanamycin have varying susceptibility to amikacin. Resistance to amikacin also confers resistance to kanamycin and capreomycin.<ref name=caminero>{{cite journal | vauthors = Caminero JA, Sotgiu G, Zumla A, Migliori GB | title = Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis | journal = The Lancet. Infectious Diseases | volume = 10 | issue = 9 | pages = 621–629 | date = September 2010 | pmid = 20797644 | doi = 10.1016/S1473-3099(10)70139-0 }}</ref>

Resistance to amikacin and kanamycin in ''Mycobacterium'', the causative agent of tuberculosis, is due to a mutation in the ''rrs'' gene, which codes for the 16S rRNA. Mutations such as these reduce the binding affinity of amikacin to the bacteria's ribosome.<ref name="ahmad">{{cite journal | vauthors = Ahmad S, Mokaddas E | title = Current status and future trends in the diagnosis and treatment of drug-susceptible and multidrug-resistant tuberculosis | journal = Journal of Infection and Public Health | volume = 7 | issue = 2 | pages = 75–91 | date = 1 March 2014 | pmid = 24216518 | doi = 10.1016/j.jiph.2013.09.001 | doi-access = }}</ref> Variations of aminoglycoside [[acetyltransferase]] (AAC) and aminoglycoside [[adenylyltransferase]] (AAD) also confer resistance: resistance in ''Pseudomonas aeruginosa'' is caused by AAC(6')-IV, which also confers resistance to kanamycin, gentamicin, and tobramycin, and resistance in ''[[Staphylococcus aureus]]'' and ''[[S. epidermidis]]'' is caused by AAD(4',4''), ''which also confers resistance to kanamycin, tobramycin, and apramycin.<ref name="kondo" /> Some strains of ''S. aureus'' can also inactivate amikacin by phosphorylating it.<ref name="aronson" />

===Pharmacokinetics===

Amikacin is not absorbed orally and thus must be administered parenterally. It reaches peak serum concentrations in 0.5–2 hours when administered intramuscularly. Less than 11% of the amikacin actually binds to plasma proteins. It is distributed into the [[heart]], [[gallbladder]], [[lungs]], and [[bone]]s, as well as in [[bile]], [[sputum]], [[interstitial fluid]], [[pleural fluid]], and [[synovial fluids]]. It is usually found at low concentrations in the [[cerebrospinal fluid]], except when administered intraventricularly.<ref name=AHFS2016 /> In infants, amikacin is normally found at 10–20% of plasma levels in the spinal fluid, but the amount reaches 50% in cases of meningitis.<ref name="Amikacin sulfate FDA label" /> It does not easily cross the [[blood–brain barrier]] or enter ocular tissue.<ref name=plumb />

While the half-life of amikacin is normally two hours, it is 50 hours in those with end-stage renal disease.<ref name=cunha />

The majority (95%) of amikacin from an intramuscular or intravenous dose is secreted unchanged via [[glomerular filtration]] and into the urine within 24 hours.<ref name=AHFS2016 /><ref name=cunha /> Factors that cause amikacin to be excreted via urine include its relatively low molecular weight, high water solubility, and unmetabolized state.<ref name=ettinger />

==Chemistry==

Amikacin is derived from [[kanamycin A]]:<ref name=kawaguchi>{{cite journal | vauthors = Kawaguchi H, Naito T, Nakagawa S, Fujisawa KI | title = BB-K 8, a new semisynthetic aminoglycoside antibiotic | journal = The Journal of Antibiotics | volume = 25 | issue = 12 | pages = 695–708 | date = December 1972 | pmid = 4568692 | doi = 10.7164/antibiotics.25.695 | url = https://www.jstage.jst.go.jp/article/antibiotics1968/25/12/25_12_695/_pdf | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20170816105728/https://www.jstage.jst.go.jp/article/antibiotics1968/25/12/25_12_695/_pdf | archive-date = 16 August 2017 }}</ref><ref name=monteleone>{{cite book | vauthors = Monteleone PM, Muhammad N, Brown RD, McGrory JP, Hanna SA | title=Amikacin Sulfate | date=1 January 1983| doi=10.1016/S0099-5428(08)60163-X | issn=0099-5428 | volume=12 | pages=37–71| series=Analytical Profiles of Drug Substances | publisher=Academic Press | isbn=9780122608124 }}</ref>

[[File:Amikacin synthesis 2.svg|center|The synthesis of amikacin|800x800px]]

==Veterinary uses==

While amikacin is only FDA-approved for use in dogs and for intrauterine infection in horses, it is one of the most common aminoglycosides used in veterinary medicine,<ref name=forney>{{cite web | vauthors = Forney B | title=Amikacin for Veterinary Use | work=Wedgewood Pharmacy | access-date=9 August 2017 | url=http://www.wedgewoodpetrx.com/learning-center/professional-monographs/amikacin-for-veterinary-use.html | url-status=live | archive-url=https://web.archive.org/web/20170816110344/http://www.wedgewoodpetrx.com/learning-center/professional-monographs/amikacin-for-veterinary-use.html | archive-date=16 August 2017 }}</ref> and has been used in dogs, cats, [[guinea pig]]s, [[chinchilla]]s, [[hamster]]s, [[rat]]s, [[mice]], [[prairie dog]]s, [[cattle]], [[bird]]s, [[snake]]s, [[turtle]]s and [[tortoise]]s, [[crocodilia]]ns, [[Frog|bullfrogs]], and [[fish]]<!--no, really-->.<ref name=plumb /><ref>{{cite book | vauthors = Riviere JE, Papich MG | title=Veterinary Pharmacology and Therapeutics | date=13 May 2013 | page=931 | url=https://books.google.com/books?id=xAPa4WDzAnQC&pg=PA931 | publisher=John Wiley & Sons | isbn=978-1-118-68590-7 | url-status=live | archive-url=https://web.archive.org/web/20170910172330/https://books.google.com/books?id=xAPa4WDzAnQC&pg=PA931 | archive-date=10 September 2017 }}</ref><ref>{{cite book | vauthors = Mader DR, Divers SJ | title=Current Therapy in Reptile Medicine and Surgery – E-Book | date=12 December 2013 | page=382 | url=https://books.google.com/books?id=2phWAgAAQBAJ&pg=PA382 | publisher=Elsevier Health Sciences | isbn=978-0-323-24293-6 | url-status=live | archive-url=https://web.archive.org/web/20170910172330/https://books.google.com/books?id=2phWAgAAQBAJ&pg=PA382 | archive-date=10 September 2017 }}</ref> It is often used for respiratory infections in snakes, bacterial shell disease in turtles, and [[sinusitis]] in [[macaw]]s. It is generally contraindicated in [[rabbit]]s and [[hare]]s (though it has still been used) because it harms the balance of [[Gut flora|intestinal microflora]].<ref name=plumb />

In dogs and cats, amikacin is commonly used as a topical antibiotic for [[ear infections]] and for [[Corneal ulcers in animals|corneal ulcers]], especially those that are caused by ''Pseudomonas aeruginosa''. The ears are often cleaned before administering the medication, since [[pus]] and cellular debris lessen the activity of amikacin.<ref name=forney /> Amikacin is administered to the eye when prepared as an ophthalmic ointment or solution, or when injected [[conjunctiva|subconjunctivally]].<ref>{{cite book | vauthors = Maggs D, Miller P, Ofri R | title=Slatter's Fundamentals of Veterinary Ophthalmology – E-Book | date=7 August 2013 | page=37 | url=https://books.google.com/books?id=8QCduRN3zR0C&pg=PA37 | publisher=Elsevier Health Sciences | isbn=978-0-323-24196-0 | url-status=live | archive-url=https://web.archive.org/web/20170910172330/https://books.google.com/books?id=8QCduRN3zR0C&pg=PA37 | archive-date=10 September 2017 }}</ref> Amikacin in the eye can be accompanied by [[cephazolin]]. Despite its use there amikacin (and all aminoglycosides) are toxic to intraocular structures.<ref>{{cite book | vauthors = Hsu WH | title=Handbook of Veterinary Pharmacology | date=25 April 2013 | publisher=John Wiley & Sons | isbn=978-1-118-71416-4 | url=https://books.google.com/books?id=MGhScg9GZGAC&pg=PT486 | page=486}}</ref>

In horses, amikacin is FDA-approved for uterine infections (such as [[endometriosis]] and [[pyometra]]) when caused by susceptible bacteria.<ref name="Amiglyde-V FDA label">{{cite web | publisher = U.S. National Library of Medicine | title=Amiglyde-V- amikacin sulfate injection | work=DailyMed | access-date=8 August 2017 | date=9 March 2017 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e2abecaf-9532-45a0-a284-5697b2aa38f1 | url-status=live | archive-url=https://web.archive.org/web/20170816110928/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e2abecaf-9532-45a0-a284-5697b2aa38f1 | archive-date=16 August 2017 }}</ref> It is also used in topical medication for the eyes and [[arthroscopic lavage]]; when combined with a cephalosporin, is used to treat [[Subcutaneous tissue|subcutaneous]] infections that are caused by ''Staphylococcus''. For infections in the limbs or joints, it is often administered with a cephalosporin via [[limb perfusion]] directly into the limb or [[joint injection|injected into the joint]].<ref name=forney /><ref name=orsini>{{cite journal | vauthors = Orsini JA | title=Update on Managing Serious Wound Infections in Horses: Wounds Involving Joints and Other Synovial Structures | journal=Journal of Equine Veterinary Science | date=1 August 2017| doi=10.1016/j.jevs.2017.01.016 | issn=0737-0806 | volume=55 | pages=115–122}}</ref> Amikacin is also injected into the joints with the anti-arthritic medication [[Adequan]] in order to prevent infection.<ref>{{cite book | vauthors = Wanamaker BP, Massey K | title=Applied Pharmacology for Veterinary Technicians – E-Book | date=25 March 2014 | page=392 | publisher=Elsevier Health Sciences | isbn=978-0-323-29170-5}}</ref>

Side effects in animals include nephrotoxicity, ototoxicity, and [[injection site reaction|allergic reactions at IM injection sites]]. Cats tend to be more sensitive to the vestibular damage caused by ototoxicity. Less frequent side effects include neuromuscular blockade, facial [[edema]], and [[peripheral neuropathy]].<ref name="plumb" /><ref name=forney />

The half-life in most animals is one to two hours.<ref name=papich>{{cite book | vauthors = Papich MG | title=Saunders Handbook of Veterinary Drugs: Small and Large Animal | chapter=Amikacin | date=October 2015 | chapter-url=https://books.google.com/books?id=ip8_CwAAQBAJ&pg=PA25 | edition=4th | publisher=Elsevier Health Sciences | isbn=978-0-323-24485-5 | pages=25–27 | url-status=live | archive-url=https://web.archive.org/web/20170910172330/https://books.google.com/books?id=ip8_CwAAQBAJ&pg=PA25 | archive-date=10 September 2017 }}</ref>

Treating overdoses of amikacin requires [[Hemodialysis|kidney dialysis]] or [[peritoneal dialysis]], which reduce serum concentrations of amikacin, and/or penicillins, some of which can form complexes with amikacin that deactivate it.<ref name=plumb />

== References ==

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{{Antibiotics and chemotherapeutics for dermatological use}}

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[[Category:Aminoglycoside antibiotics]]

[[Category:Anti-tuberculosis drugs]]

[[Category:Butyramides]]

[[Category:World Health Organization essential medicines]]

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

[[Category:Orphan drugs]]