Amikacin

Source: Wikipedia, the free encyclopedia.

Amikacin
Clinical data
Trade namesAmikin, Amiglyde-V, Arikayce, others
AHFS/Drugs.comMonograph
MedlinePlusa682661
License data
Pregnancy
category
inhalation
Drug classAminoglycoside
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability>90%[8]
Protein binding0–11%
MetabolismMostly unmetabolized
Elimination half-life2–3 hours
ExcretionKidney
Identifiers
  • (2S)-4-Amino-N-[(2S,3S,4R,5S)-5-amino-2-[(2S,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4-[(2R,3R,4S,5R,6R)-6-(aminomethyl)-3,4,5-trihydroxy-oxan-2-yl]oxy-3-hydroxy-cyclohexyl]-2-hydroxybutanamide
JSmol)
  • 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
  • InChI=1S/C22H43N5O13/c23-2-1-8(29)20(36)27-7-3-6(25)18(39-22-16(34)15(33)13(31)9(4-24)37-22)17(35)19(7)40-21-14(32)11(26)12(30)10(5-28)38-21/h6-19,21-22,28-35H,1-5,23-26H2,(H,27,36)/t6-,7+,8-,9+,10+,11-,12+,13+,14+,15-,16+,17-,18+,19-,21+,22+/m0/s1 checkY
  • Key:LKCWBDHBTVXHDL-RMDFUYIESA-N checkY
  (verify)

Amikacin is an

into a muscle.[9]

Amikacin, like other

30S ribosomal subunit, making it unable to produce proteins.[9]

Amikacin was patented in 1971, and came into commercial use in 1976.

kanamycin.[9]

Medical uses

Amikacin is most often used for treating severe infections with

Gram-positive bacteria that amikacin strongly affects are Staphylococcus[14] and Nocardia.[15] Amikacin can also be used to treat non-tubercular mycobacterial infections and tuberculosis (if caused by sensitive strains) when first-line drugs fail to control the infection.[9] It is rarely used alone.[16]

It is often used in the following situations:[9]

Amikacin may be combined with a beta-lactam antibiotic for empiric therapy for people with neutropenia and fever.[9]

Available forms

A liposome inhalation suspension is also available and approved to treat Mycobacterium avium complex (MAC) in the United States,[20][5] and in the European Union.[6]

Amikacin liposome inhalation suspension is the first drug approved under the US limited population pathway for antibacterial and antifungal drugs (LPAD pathway).[20] It also was approved under the accelerated approval pathway.[20] The US Food and Drug Administration (FDA) granted the application for amikacin liposome inhalation suspension fast track, breakthrough therapy, priority review, and qualified infectious disease product (QIDP) designations.[20] The FDA granted approval of Arikayce to Insmed, Inc.[20]

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.[20] 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.[20] 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.[20]

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

congenital deafness in her child. While it is known to cross the placenta, amikacin is only partially secreted in breast milk.[9]

In general, amikacin should be avoided in infants.[21] Infants also tend to have a larger volume of distribution due to their higher concentration of extracellular fluid, where aminoglycosides reside.[8]

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.[22]

Clearance is even higher in people with cystic fibrosis.[23]

In people with muscular disorders such as myasthenia gravis or Parkinson's disease, amikacin's paralytic effect on neuromuscular junctions can worsen muscle weakness.[9]

Adverse effects

Side-effects of amikacin are similar to those of other aminoglycosides. Kidney damage and ototoxicity (which can lead to hearing loss) are the most important effects, occurring in 1–10% of users.[17] The nephro- and ototoxicity are thought to be due to aminoglycosides' tendency to accumulate in the kidneys and inner ear.[8]

Diagram of the inner ear. Amikacin causes damage to the cochlea and vestibules.

Amikacin can cause neurotoxicity if used at a higher dose or for longer than recommended. The resulting effects of neurotoxicity include

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.[25]

Amikacin causes nephrotoxicity (damage to the kidneys), by acting on the

antiprostaglandins.[9][21][8][25] The toxicity usually reverts once the antibiotic course has been completed,[8] and can be avoided altogether by less frequent dosing (such as once every 24 hours rather than once every 8 hours).[21]

Amikacin can cause neuromuscular blockade (including acute muscular paralysis) and respiratory paralysis (including apnea).[9]

Rare side effects (occurring in fewer than 1% of users) include allergic reactions,

fever, headaches, 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.[14][17]

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.[20][5] 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.[20][5]

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),[14] since most amikacin usually comes with sodium metabisulfite, which can cause an allergic reaction.[9]

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.[9]

Amikacin should not be used with

neuromuscular blocking agents, as they can increase muscle weakness and paralysis.[9]

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.[9]

The effect of amikacin is increased when used with drugs derived from the

citrate as an anticoagulant.[9]

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.

indomethacin can increase serum aminoglycoside levels in premature infants.[9] Contrast mediums such as ioversol increases the nephrotoxicity and otoxicity caused by amikacin.[17]

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.[17]

Pharmacology

Mechanism of action

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

tRNA anticodon.[27] It works in a concentration-dependent manner, and has better action in an alkaline environment.[8]

At normal doses, amikacin-sensitive bacteria respond within 24–48 hours.[14]

Resistance

Amikacin evades attacks by all antibiotic-inactivating enzymes that are responsible for

kanamycin, which simply has a hydrogen), which blocks the access and decreases the affinity of aminoglycoside-inactivating enzymes.[28][29][30] Amikacin ends up with only one site where these enzymes can attack, while gentamicin and tobramycin have six.[16]

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.[31]

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.

S. epidermidis is caused by AAD(4',4), which also confers resistance to kanamycin, tobramycin, and apramycin.[29] Some strains of S. aureus can also inactivate amikacin by phosphorylating it.[18]

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

synovial fluids. It is usually found at low concentrations in the cerebrospinal fluid, except when administered intraventricularly.[9] 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.[14] It does not easily cross the blood–brain barrier or enter ocular tissue.[8]

While the half-life of amikacin is normally two hours, it is 50 hours in those with end-stage renal disease.[16]

The majority (95%) of amikacin from an intramuscular or intravenous dose is secreted unchanged via

glomerular filtration and into the urine within 24 hours.[9][16] Factors that cause amikacin to be excreted via urine include its relatively low molecular weight, high water solubility, and unmetabolized state.[21]

Chemistry

Amikacin is derived from kanamycin A:[33][34]

The synthesis of amikacin
The synthesis of amikacin

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,

intestinal microflora.[8]

In dogs and cats, amikacin is commonly used as a topical antibiotic for

cephazolin. Despite its use there amikacin (and all aminoglycosides) are toxic to intraocular structures.[39]

In horses, amikacin is FDA-approved for uterine infections (such as

Adequan in order to prevent infection.[42]

Side effects in animals include nephrotoxicity, ototoxicity, and 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.[8][35]

The half-life in most animals is one to two hours.[43]

Treating overdoses of amikacin requires 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.[8]

References

  1. ^ a b "Amikacin Use During Pregnancy". Drugs.com. 2 December 2019. Retrieved 13 March 2020.
  2. FDA
    . Retrieved 22 October 2023.
  3. ^ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  4. ^ "Amikacin 250 mg/ml Injection - Summary of Product Characteristics (SmPC)". (emc). 16 September 2015. Retrieved 13 March 2020.
  5. ^ a b c d "Arikayce- amikacin suspension". DailyMed. 30 September 2018. Retrieved 13 March 2020.
  6. ^ a b "Arikayce liposomal EPAR". European Medicines Agency. 21 July 2020. Retrieved 4 March 2023.
  7. ^ "Arikayce liposomal Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  8. ^
    ISBN 978-0-470-95964-0
    .
  9. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z "Amikacin Sulfate". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  10. ISBN 9789241547659
    .
  11. ISBN 9783527607495. Archived
    from the original on 20 December 2016.
  12. ISBN 9780191039621. Archived
    from the original on 24 November 2015.
  13. hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  14. ^ a b c d e f g h i j k l "Amikacin sulfate injection, solution". DailyMed. 10 April 2019. Retrieved 13 March 2020.
  15. ISBN 978-0-19-975971-2. Archived
    from the original on 10 September 2017.
  16. ^
    S2CID 30373734
    .
  17. ^ a b c d e f g "amikacin (Rx)". Medscape. WebMD. Archived from the original on 9 August 2017. Retrieved 9 August 2017.
  18. ^
    ISBN 978-0-444-53716-4
    .
  19. ISBN 978-0-12-411492-0
    .
  20. ^ a b c d e f g h i j "FDA approves a new antibacterial drug to treat a serious lung disease using a novel pathway to spur innovation". U.S. Food and Drug Administration (FDA) (Press release). Retrieved 12 November 2018. Public Domain This article incorporates text from this source, which is in the public domain.
  21. ^
    ISBN 978-1-4377-0282-8. Archived
    from the original on 10 September 2017.
  22. ISBN 978-0-12-803348-7
    .
  23. ISBN 978-1-4918-0000-3. Archived
    from the original on 10 September 2017.
  24. ^
    ISBN 978-1-4557-7377-0. Archived
    from the original on 10 September 2017.
  25. ^
    ISSN 0378-6080
    .
  26. ISBN 978-0-321-91855-0
    .
  27. ^ "Amikacin". DrugBank. 2 August 2017. Archived from the original on 16 August 2017. Retrieved 10 August 2017.
  28. ^ a b Mudd E (7 August 2017). "O Aminoglycosides". Pharmacological Sciences. Archived from the original on 16 August 2017. Retrieved 14 August 2017.
  29. ^
    S2CID 38981498
    .
  30. PMID 28365471
    .
  31. PMID 20797644
    .
  32. PMID 24216518
    .
  33. PMID 4568692. Archived
    from the original on 16 August 2017.
  34. ISSN 0099-5428
    .
  35. ^ a b c d Forney B. "Amikacin for Veterinary Use". Wedgewood Pharmacy. Archived from the original on 16 August 2017. Retrieved 9 August 2017.
  36. ISBN 978-1-118-68590-7. Archived
    from the original on 10 September 2017.
  37. ISBN 978-0-323-24293-6. Archived
    from the original on 10 September 2017.
  38. ISBN 978-0-323-24196-0. Archived
    from the original on 10 September 2017.
  39. ISBN 978-1-118-71416-4
    .
  40. ^ "Amiglyde-V- amikacin sulfate injection". DailyMed. U.S. National Library of Medicine. 9 March 2017. Archived from the original on 16 August 2017. Retrieved 8 August 2017.
  41. ISSN 0737-0806
    .
  42. ISBN 978-0-323-29170-5
    .
  43. ISBN 978-0-323-24485-5. Archived
    from the original on 10 September 2017.
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