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Pharmacology Base

Amikacin

Pharmacodynamics

EMA Antibiotic Classification: C Caution

Amikacin is a semi-synthetic aminoglycoside antimicrobial agent that acts as a bactericidal, concentration-dependent antibiotic and nephrotoxin. Amikacin inhibits bacterial protein synthesis in susceptible bacteria through irreversible binding to the 30S ribosomal subunit (WHO, 2024).

Mechanism of Action

Amikacin inhibits bacterial protein synthesis in susceptible bacteria through irreversible binding to the 30S ribosomal subunit, causing misreading of t-RNA. This prevents bacteria from synthesising critical proteins (PubChem, 2024).

Clinical Applications

  • Gram-Negative Bacteria: Aminoglycosides are useful mainly in treating infections involving aerobic, Gram-negative bacteria (eg Pseudomonas, Acinetobacter, and Enterobacter). 

  • Gram-Positive Bacteria: Infections caused by Gram-positive bacteria can also be treated with aminoglycosides; however, other antibiotics may be more potent and less nephrotoxic to patients (PubChem, 2024).

  • Mycobacteria: Some mycobacteria, including the bacteria that cause tuberculosis, are susceptible to aminoglycosides. 

Pharmacokinetics

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Distribution

  • Amikacin diffuses readily through extracellular fluids and is excreted in the urine unchanged, primarily by glomerular filtration. Following parenteral administration, Amikacin has been found in pleural fluid, amniotic fluid, and the peritoneal cavity (PubChem, 2024).

Metabolism

  • Minimal; Aminoglycosides are not metabolised and are excreted unchanged in the urine primarily by glomerular filtration.

Elimination

  • Primarily renal; In humans, 94-98% of a single IM or IV dose of amikacin is excreted unchanged by glomerular filtration within 24 hours.

Precautions

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Significant Adverse Effects

  • Nephrotoxicity: These are usually reversible when the drug is discontinued. Reports of toxic nephropathy and acute renal failure have been received during postmarketing surveillance.

  • Ototoxicity: Toxic effects on the eighth cranial nerve can result in hearing loss, loss of balance, or both.

Significant Contraindications

  • Dehydration: Do not use in hypovolaemic animals or those with impaired glomerular filtration.

  • Pre-existing Renal Disease: Avoid use in Chronic Kidney Disease (CKD) and Acute Kidney Injury (AKI)

  • Allergy, hypersensitivity: Amikacin sulphate injection is contraindicated in patients with known allergy to amikacin or any formulation component.

  • Myasthenia gravis: Aminoglycosides may impair neuromuscular transmission and should not be given to patients with myasthenia gravis.

Significant Interactions

  • Anaesthetics: Potential for neuromuscular blockade.

  • Cephalosporins: Potential for additive nephrotoxicity and potential for synergistic effect with first or second-generation agents

  • Loop Diuretics (Furosemide, Torsemide): increased potential for nephrotoxic or ototoxic effects

  • Osmotic Diuretics  (eg, mannitol): increased potential for nephrotoxic or ototoxic effects

  • NSAIDs: Increased risk of nephrotoxicity

  • Penicillins: Potential for a synergistic effect.

Reproductive Safety

  • Pregnancy: Avoid use; potential for harm. In zebrafish, amikacin induced embryonic toxicity and reduced survival rate

  • Lactation: Amikacin is poorly excreted into milk.

  • Fertility: Amikacin administered subcutaneously to rats did not impair male or female fertility.

  • Carcinogenicity and mutagenicity: Long-term animal studies have not been performed to evaluate carcinogenic potential and mutagenicity.

Overdose Information

  • Effects: There is a general risk for nephrotoxic, ototoxic and neurotoxic (neuromuscular blockage) reactions.

  • Clinical Response: Active fluid therapy to decontaminate through accelerated excretion. Consider dialysis.

Availability

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  • UK Animal Preparations: None located (VMD, 2024).

  • UK Human Preparations: Amikacin 250 mg/ml Injection; 590 mg amikacin in a liposomal formulation (EMC, 2024).

Identifiers

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  • IUPAC Name: (2S)-4-amino-N-[(1R,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,5S,6R)-6-(aminomethyl)-3,4,5-trihydroxyoxan-2-yl]oxy-3-hydroxycyclohexyl]-2-hydroxybutanamide (WHO, 2024).

  • Molecular Formula: C22H43N5O13 (WHO, 2024)

  • Pharmacotherapeutic Group: Antiinfectives for systemic use

  • EMA Antibiotic Classification: C Caution (EMA, 2024)

  • UK Authorised Species: None located (VMD, 2024).

  • ATC Code: J01GB06 (WHO, 2024)

  • ATC vet code(s): QD06AX12 amikacin; QJ01GB06 amikacin; QJ01RA06 cefepime and amikacin; QS01AA21 amikacin; J01 - Antibacterials for systemic use; J01G - Aminoglycoside antibacterials; J01GB - Other aminoglycosides; J01GB06 - Amikacin (WHO, 2024)

Resources

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  1. EMA, 2024. Categorisation of antibiotics for use in animals [WWW Document]. URL https://www.ema.europa.eu/en/documents/report/infographic-categorisation-antibiotics-use-animals-prudent-and-responsible-use_en.pdf

  2. EMC, 2024. EMC Search Results - (EMC) [WWW Document]. URL https://www.medicines.org.uk/emc/search?q=amikacin (accessed 6.21.24).

  3. KuKanich, B., Coetzee, J.F., 2008. Comparative pharmacokinetics of amikacin in Greyhound and Beagle dogs. J Vet Pharmacol Ther 31, 102–107. https://doi.org/10.1111/j.1365-2885.2008.00938.x

  4. Meyer, R.D., 1977. Patterns and mechanisms of emergence of resistance to amikacin. J Infect Dis 136, 449–452. https://doi.org/10.1093/infdis/136.3.449

  5. NCBI, 2012. Clinical and Research Information on Drug-Induced Liver Injury | Amikacin. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (MD).

  6. Plumb, 2024. Amikacin [WWW Document]. URL https://app.plumbs.com/drug/i4lS9zaIxkPROD?source=search&searchQuery=Amikacin (accessed 6.21.24).

  7. PubChem, 2024. Amikacin | PubMed | Compound Summary [WWW Document]. PubChem. URL https://pubchem.ncbi.nlm.nih.gov/compound/37768 (accessed 6.21.24).

  8. Sizar, O., Rahman, S., Sundareshan, V., 2024. Amikacin, in: StatPearls. StatPearls Publishing, Treasure Island (FL).

  9. VMD, 2024. Product Information Database - Search [WWW Document]. URL https://www.vmd.defra.gov.uk/productinformationdatabase/search (accessed 6.21.24).

  10. WHO, 2024. ATCDDD - ATCvet Index [WWW Document]. URL https://atcddd.fhi.no/atcvet/atcvet_index/ (accessed 6.21.24).

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