Amikacin

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Amikacin
Amikacin2.png
Amikacin ball-and-stick.png
Systematic (IUPAC) name
(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-hydroxy-butanamide
Clinical data
Trade names Generic (formerly Amikin)
AHFS/Drugs.com monograph
MedlinePlus a682661
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Legal status
Routes of
administration
Intramuscular, intravenous
Pharmacokinetic data
Protein binding 0-11%
Biological half-life 2-3 hours
Excretion Renal
Identifiers
CAS Registry Number 37517-28-5 YesY
ATC code D06AX12 J01GB06, S01AA21
PubChem CID: 37768
DrugBank DB00479 YesY
ChemSpider 34635 YesY
UNII 84319SGC3C YesY
KEGG D02543 YesY
ChEBI CHEBI:2637 YesY
ChEMBL CHEMBL177 YesY
Chemical data
Formula C22H43N5O13
Molecular mass 585.603 g/mol
 YesY (what is this?)  (verify)

Amikacin (formerly Apothecon's Amikin) is an aminoglycoside antibiotic used to treat different types of bacterial infections. Amikacin works by binding to the bacterial 30S ribosomal subunit, causing misreading of mRNA and leaving the bacterium unable to synthesize proteins vital to its growth.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[1]

Medical uses[edit]

Amikacin is most often used for treating severe, hospital-acquired infections with multidrug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter, and Enterobacter. Serratia marcescens and Providencia stuartii are also included in the spectrum. 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.

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

Liposomal amikacin for inhalation is currently in late stage clinical trials for the treatment of respiratory diseases, such as cystic fibrosis,[2] Pseudomonas aeruginosa,[3] non-tubercular mycobacterial infections[4] and bronchiectasis.[5][6]

Bacterial susceptibility data[edit]

Amikacin is usually used as a last-resort medication against multidrug-resistant bacteria. The following represents susceptibility data on a few medically significant microorganisms.

  • Pseudomonas aeruginosa - 0.5 μg/mL - 32 μg/mL
  • Pseudomonas aeruginosa (aminoglycoside-resistant) - 32 μg/mL - 64 μg/mL
  • Serratia marcescens - ≤0.25 μg/mL - 8 μg/mL
  • Serratia marcescens (multidrug-resistant) - 32 μg/mL

[7]

Adverse effects[edit]

Side-effects of amikacin are similar to those of other aminoglycosides. Kidney damage and hearing loss are the most important effects. Because of this potential, blood levels of the drug and markers of kidney function (creatinine) may be monitored. Moreover, doses are adjusted specifically based upon serum Creatinine clearance in clinical settings.[citation needed]

Administration[edit]

Amikacin may be administered once or twice a day but must be given by the intravenous or intramuscular route or via nebulization. There is no oral form available as amikacin is not absorbed orally. In people with kidney failure, dosage must be adjusted according to the creatinine clearance, usually by reducing the dosing frequency.

Resistance[edit]

Amikacin evades attacks by most of the antibiotic-inactivating enzymes that are responsible for antibiotic resistance in bacteria. This is accomplished by the L-hydroxyaminobuteroyl amide (L-HABA) moiety attached to N-1 (compare to kanamycin), which inhibits acetylation, phosphorylation, and adenylation in the distant amino sugar ring (C-2,C-3,C-4). To prevent the development of bacterial resistance to this antibiotic, its use is tightly regulated.

Synthesis[edit]

Amikacin, is a semisynthetic antibiotic that is synthesized from kanamycin. The primary amino group in this molecule is previously protected by acylating it with N-(carboxybenzyl)oxysuccinimide in DMF, after which the resulting product is treated with an ester synthesized from N-hydroxysuccinimide and (S)-N-Carbobenzyloxy-4-amino-2-hydroxybutyric acid, and as a result one of the unprotected remaining amino groups in the (desoxy)streptamine region of the molecule is selectively acylated. Further removal of the two Cbz protective groups via hydrogen reduction using a palladium on carbon catalyst, forms the desired amikacin.

References[edit]

  1. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  2. ^ "Randomized, open-label, active-controlled, multicenter study to assess the efficacy, safety and tolerability of Arikace™ in Cystic Fibrosis patients with chronic infection due to Pseudomonas aeruginosa" is a European Phase III clinical trial, being conducted across multiple sites in the EU, starting at the Royal Brompton Hospital, Department of Respiratory Medicine, in London. https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-000441-20/GB
  3. ^ http://www.clinicaltrials.gov/ct2/show/NCT01315678
  4. ^ "A Randomized, Double-Blind, Placebo-Controlled Study of Liposomal Amikacin for Inhalation (Arikace™) in Patients With Recalcitrant Nontuberculous Mycobacterial Lung Disease" is a Phase II clinical trial in collaboration with the US National Institute of Allergy and Infectious Diseases. http://www.clinicaltrials.gov/ct2/show/NCT01315236
  5. ^ "A Placebo Controlled, Randomized, Parallel Cohort, Safety And Tolerability Study Of 2 Dose Levels Of Liposomal Amikacin For Inhalation (Arikace™) In Patients With Bronchiectasis Complicated By Chronic Infection Due To Pseudomonas Aeruginosa" Phase II (completed). http://www.clinicaltrials.gov/ct2/show/NCT00775138
  6. ^ "A Study to Determine the Safety and Tolerability of Arikace™ Versus Placebo in Patients Who Have Bronchiectasis" is a Phase II clinical trial (as [4]) completed in the UK. http://www.ukctg.nihr.ac.uk/trialdetails/NCT00775138
  7. ^ http://www.toku-e.com/Assets/MIC/Amikacin%20hydrate.pdf
  8. ^ Kawaguchi, H.; Naito, T.; Nakagawa, S.; Fujisawa, K. I. I. (1972). "Bb-K8, A New Semisynthetic Aminoglycoside Antibiotic". The Journal of Antibiotics 25 (12): 695. doi:10.7164/antibiotics.25.695.  edit
  • Edson RS, Terrell CL. The aminoglycosides. Mayo Clin Proc. 1999 May;74(5):519-28. Review. PMID 10319086