Amikacin

Inhalation/Respiratory
Mycobacterium avium complex infections

Intramuscular, Intravenous
Uncomplicated urinary tract infections

Intramuscular, Intravenous
Severe Gram-negative infections, Susceptible Gram-negative infections, Susceptible staphylococcal infections

Pharmacogenomics:

Amikacin is an aminoglycoside antibiotic that inhibits bacterial protein synthesis by binding to the 16S ribosomal RNA (rRNA) subunit of the bacterial 30S ribosome, which is responsible for messenger RNA (mRNA) translation within the prokaryotic cell.

The MT-RNR1 gene encodes the human 12S rRNA subunit, which is the mitochondrial homologue of the prokaryotic 16S rRNA subunit. Some variants in the MT-RNR1 gene appear to cause the human 12S rRNA subunit to resemble the bacterial 16S rRNA subunit more closely, therefore allowing the aminoglycosides to bind more readily. The presence of these gene variants may increase the risk of aminoglycoside-induced ototoxicity, including hearing loss, even when serum levels are within the normal range.

Although MT-RNR1 gene variants are rare and penetrance is uncertain, genetic testing may be considered but the testing should not delay urgently needed aminoglycoside treatment.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of May 2021:

Phenotype and Genotype	Implications	Recommendations
MT-RNR1 increased risk of aminoglycoside-induced hearing loss Patients with MT-RNR1 variant associated with increased risk of aminoglycoside-induced hearing loss e.g. m.1095T>C, m.1494C>T, m.1555A>G	Very high risk of developing hearing loss if amikacin is administered.	Avoid the use of amikacin unless the increased risk of permanent hearing loss is outweighed by the severity of the infection and the lack of alternative therapies. If no effective alternative is available, frequently evaluate patients for hearing loss during treatment and ensure all appropriate precautions are employed (e.g. shortest possible duration, lowest possible dose, renal function monitoring, therapeutic drug monitoring, hydration).
MT-RNR1 normal risk of aminoglycoside-induced hearing loss Patients with no detectable MT-RNR1 increased risk variant or variant associated with normal risk of aminoglycoside-induced hearing loss e.g. m.827A>G	Normal risk of developing hearing loss if amikacin is administered.	Use amikacin at standard doses for the shortest possible time course with therapeutic drug monitoring. Regularly evaluate for hearing loss in accordance with the local guidelines.
MT-RNR1 uncertain risk of aminoglycoside-induced hearing loss Patients with MT-RNR1 variant associated with uncertain risk of aminoglycoside-induced hearing loss e.g. m.663A>G, m.669T>C, m.747A>G, m.786G>A, m.807A>G, m.807A>C, m.839A>G, m.896A>G, m.930A>G, m.951G>A, m.960C>del, m.961T>G, m.961T>del, m.961T>del+Cn, m.988G>A, m.1189T>C, m.1243T>C, m.1520T>C, m.1537C>T, m.1556C>T	Weak or no evidence of increased risk of MT-RNR1-associated hearing loss if amikacin is administered.	Use amikacin at standard doses for the shortest possible time course with therapeutic drug monitoring. Regularly evaluate for hearing loss in accordance with the local guidelines.

Intravenous/Intramuscular:
Dosage adjustment may be needed.

IV infusion: Dilute with an appropriate volume of compatible IV infusion fluid (e.g. NaCl 0.9%, dextrose 5%). Refer to specific product or local guidelines for further instructions on reconstitution. Inhalation: Shake the vial well for at least 10-15 seconds until a uniform mixture is achieved, then pour directly into the medication reservoir of the nebuliser handset.

Incompatible with amphotericin B, chlorothiazide Na, erythromycin gluceptate, heparin, nitrofurantoin Na, phenytoin Na, thiopentone Na, warfarin Na, some penicillins and cephalosporins.

Hypersensitivity to amikacin and other aminoglycoside antibiotics. Myasthenia gravis. Concomitant or sequential administration of oral or topical drugs that are neurotoxic, ototoxic or nephrotoxic; concomitant use with potent diuretics.

Patient with pre-existing vertigo, tinnitus, hearing loss, vestibular damage; family history of aminoglycoside-induced deafness; neuromuscular disorders (e.g. Parkinson's disease), hypocalcaemia. Dehydrated patients. Used as a 2nd-line treatment for staphylococcal infections. Patients with certain MT-RNR1 gene variants (e.g. m.1555A>G). Renal impairment. Neonates, children, and elderly. Pregnancy and lactation.

Significant: Hypersensitivity, neurotoxicity, ototoxicity, nephrotoxicity, neuromuscular blockade, respiratory paralysis, fungal or bacterial superinfection, Clostridium difficile-associated diarrhoea (CDAD), pseudomembranous colitis (prolonged use). Inhalation: Bronchospasm, haemoptysis, hypersensitivity pneumonitis and alveolitis; COPD, infective exacerbation of COPD or bronchiectasis.
Blood and lymphatic system disorders: Anaemia, eosinophilia.
Ear and labyrinth disorders: Tinnitus, hypoacusis, vertigo.
Gastrointestinal disorders: Nausea, vomiting; diarrhoea, dry mouth, laryngitis, oral candidiasis, dysgeusia (inhalation).
General disorders and administration site conditions: Pyrexia, injection site pain (IM); fatigue (inhalation).
Investigations: Decreased weight (inhalation).
Metabolism and nutrition disorders: Hypomagnesaemia.
Musculoskeletal and connective tissue disorders: Arthralgia, muscle twitching; musculoskeletal pain (inhalation).
Nervous system disorders: Balance disorder, headache, paraesthesia, tremor.
Renal and urinary disorders: Oliguria, albuminuria, azotaemia, RBC urine, WBC urine.
Respiratory, thoracic and mediastinal disorders: Cough, dyspnoea, dysphonia, wheezing, increased sputum, vocal cord inflammation, throat irritation, oropharyngeal pain (inhalation).
Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria.
Vascular disorders: Hypotension.

IM/IV/Parenteral: D

Perform culture and susceptibility tests; consult local institutional recommendations before treatment initiation due to antibiotic resistance risks. Monitor renal function, urine (e.g. specific gravity, excretion of proteins, presence of cells or casts), BUN, creatinine, appropriately timed peak and trough concentrations, eighth cranial nerve function (especially in patients with known or suspected renal impairment). Perform hearing tests (audiograms) at baseline and periodically. Assess for signs and symptoms of ototoxicity, neurotoxicity and nephrotoxicity; vital signs, temperature, weight, input and output.

Symptoms: Nephrotoxicity, ototoxicity and neuromuscular blockade with respiratory arrest. Management: Administer ionic Ca (e.g. as gluconate or lactobionate in 10-20% solution) to treat neuromuscular blockade with respiratory arrest. Perform either peritoneal dialysis, haemodialysis, or continuous arteriovenous haemofiltration to reduce serum amikacin levels.

Additive neurotoxic, ototoxic or nephrotoxic effects with amphotericin B, bacitracin, cisplatin, ciclosporin, cefaloridine, paromomycin, polymyxin B, colistin, tacrolimus, vancomycin, viomycin, IV mannitol, or other aminoglycosides. Increased risk of ototoxicity with potent diuretics (e.g. etacrynic acid or furosemide); may increase risk of toxicity with IV diuretics. May increase risk of respiratory paralysis with anaesthetics or neuromuscular blocking agents (e.g. tubocurarine, succinylcholine, decamethonium, atracurium, rocuronium, vecuronium, opioid analgesic, massive transfusions with citrated anticoagulated blood). Increased risk of nephrotoxicity and may increase serum creatinine levels with cephalosporins. May reduce antibacterial activity with penicillins. Increased risk of hypocalcaemia with bisphosphonates. Increased risk of nephrotoxicity and ototoxicity with platinum drugs. May increase serum concentration with indometacin in neonates.

Description:
Mechanism of Action: Amikacin, an antibiotic with bactericidal activity, inhibits bacterial protein synthesis by irreversibly binding to 30S ribosomal subunits.
Pharmacokinetics:
Absorption: Rapidly absorbed (IM); variable (inhalation). Time to peak plasma concentration: 1 hour (IM); within 30 minutes (IV).
Distribution: Readily diffuses into extracellular fluids (highly hydrophilic) but poorly penetrates the blood-brain barrier (even with inflamed meninges). Crosses the placenta and enters breast milk. Volume of distribution: 0.25 L/kg (systemic); 5.0 L/kg (inhalation). Plasma protein binding: 0-11% (systemic); ≤10% (inhalation).
Excretion: Via urine (94-98% as unchanged drug [systemic]; 7.42% as unchanged drug [inhalation]). Elimination half-life: 2-3 hours (systemic); approx 5.9-19.5% (inhalation).

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 37768, Amikacin. https://pubchem.ncbi.nlm.nih.gov/compound/Amikacin. Accessed Aug. 15, 2023.

Parenteral: Store below 25°C. Diluted solution may be stored below 25°C for up to 24 hours. Inhalation: Store between 2-8°C. Do not freeze. Can be stored below 25°C for up to 4 weeks.

Aminoglycosides

D06AX12 - amikacin ; Belongs to the class of other topical antibiotics used in the treatment of dermatological diseases.
S01AA21 - amikacin ; Belongs to the class of antibiotics. Used in the treatment of eye infections.
J01GB06 - amikacin ; Belongs to the class of other aminoglycosides. Used in the systemic treatment of infections.

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McDermott JH, Wolf J, Hoshitsuki K et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype. Clinical Pharmacology & Therapeutics. 2022 Feb;111(2):366-372. doi: 10.1002/cpt.2309. Accessed 19/04/2023

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