Chemicals / Complex Chemical Agents/ Chemical:

Amikacin (with special reference to Hedgehogs, Elephants and Cranes)

INFORMATION AVAILABLE

GENERAL CHEMICAL INFORMATION THERAPEUTIC INFORMATION [DOSE, FREQUENCY & ROUTE] NUTRITIONAL INFORMATION
TOXICITY INFORMATION ENVIRONMENTAL INFORMATION
Information in this page has been entered to support the current volumes of Wildpro and further information will be added as new volumes are completed. This page is not intended to substitute for the manufacturer's data sheet and the information is not yet complete for all species, or for all contra-indications etc.

CAUTION: Before any pharmaceutical product is used, the manufacturer's data sheet, containing information on uses, dosage and administration, contra-indications, warnings etc., should always be consulted. It is important to remember that licensing of pharmaceutical products for use in a particular species/condition, as well as mandatory meat and milk withdrawal times for food-producing animals, varies between countries and changes with time. Withdrawal times also may vary between different pharmaceutical formulations and depending on route of administration. In the EU, the prescription cascade must be followed (see LCofC1.2H and W564.Apr05.w1); note that specific restrictions apply for food-producing animals. In the USA, FARAD may be consulted regarding residues and meat and milk withdrawal times.

General Chemical Information

Summary 
Bactericidal aminoglycoside antibiotic. (B263)

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Names and Formulae
Type Semi-synthetic aminoglycoside antibiotic derived from kanamycin. (B263)
Alternative Names Antibiotic BB-K8. (W324)
Chemical Formula C22H43N5O13 (W324)
Chemical Structure --
Molecular Weight 585.6074. (W324)
Related Chemicals --

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Physical Properties / Chemistry
Appearance
  • Amikacin sulphate: white crystalline powder. (B263)

  • Commercially prepared injection: clear to straw coloured fluid. (B263)

Melting point --
Boiling point --
Density --
Water solubility
  • Amikacin sulphate: sparingly soluble in water. (B263)
Other solubility  
Acid/Base
  • pH of the commercially prepared injection is adjusted to 3.5-5.5 with sulphuric acid. (B263)

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Pharmacology & General Information
Pharmacology
  • Aminoglycoside antibiotics bind irreversibly to the 50S ribosomal subunit and inhibit protein synthesis in at least three ways. (B135.45.w45, B263)
  • Bactericidal, with a concentration-dependent mechanism. (B201, B263)
  • Initial penetration through the cell membrane is partially an oxygen-dependent active process (therefore aminoglycosides are relatively ineffective against strict anaerobes), and partially passive diffusion (which may be enhanced greatly by the presence of drugs such as penicillins which affect the cell wall). (B135.45.w45)
  • Aminoglycosides may impair neuromuscular transmission and at very high doses, aminoglycosides cause neuromuscular blockade resulting in respiratory paralysis. (B201.1.w1, B135.45.w45)
Storage / Stability
  • Store at room temperature (15-30C), avoiding freezing and temperatures above 40C. (B263)
  • Stable for at least two years at room temperature. (B263)
  • No loss of potency following autoclaving of commercially available solution for 60 minutes at 120C and 15 pounds of pressure. (B263)
Legal Category (In UK)
  • POM (Human). (B201.1.w1)

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References

Associated Techniques

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ORGANISATIONS

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ELECTRONIC LIBRARY
(Further Reading)
Click image for full contents list of ELECTRONIC LIBRARY

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Authors Debra Bourne (V.w5); Gracia Vila-Garcia (V.w67)
Referees Suzanne I. Boardman (V.w6); Becki Lawson (V.w26); Susan Mikota (V.w72)

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Therapeutic Information

Uses/Indications
Activity
Appropriate Use
  • Used most commonly against serious Virbac bacterial infections. (B263)
  • Particularly used where gentamicin-resistant bacteria are a clinical problem. (B263)
  • In mares: for intrauterine infusion. (B263)
  • In foals: for intra-articular injection to treat Gram-negative septic arthritis. (B263)
Limitations
  • Aminoglycosides are inactive against most anaerobic bacteria, since active transport of the aminoglycosides into the bacterial cell is an oxygen-dependent process. (B135.45.w45, B263)
  • Inactive against fungi and viruses.(B263)
  • Due to inherent toxicity, systemic use of aminoglycoside antibiotics is limited to situations in which the organisms causing infection are known not to be susceptible to other, less toxic, antibiotics, or when the clinical situation is such that immediate treatment of a presumed Gram-negative infection is required in advance of culture and sensitivity results. (B263)
Notes
  • Enhanced activity in alkaline conditions. (B263)
  • Therapeutic levels in serum 2-25 g/ml (dependent on microbe sensitivity). (B263)

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Pharmacokinetics and Drug Interactions
Absorption /Bioavailability
  • Minimal absorption following oral administration if the gut is intact. (B135.45.w45, B263)
  • Minimal absorption following intrauterine administration. (B263)
  • Appreciable absorption may occur from the gut in individuals with haemorrhagic enteritis, necrotic enteritis or gut ulceration. (B135.45.w45, B263)
  • Absorbed following topical irrigation of surgical sites (not including skin, urinary bladder) including peritoneal cavity. (B201, B263)
  • Intramuscular injection gives more than 90% bioavailability with peak levels at 30-60 minutes after injection (dogs and cats)
  • Subcutaneous injection gives more than 90% bioavailability with peak levels slightly later than following intramuscular injection and with greater variability. (B263)
  • Intrathecal or intraventricular injection is required if high CSF levels are needed. (B135.45.w45)
Distribution
  • Aminoglycosides are distributed mainly in the extracellular fluid.(B263)
  • Highly polar and do not readily enter cells. (B135.45.w45)
  • Therapeutic levels are reached in bone, heart, gall bladder and lung (following parenteral administration). (B263)
  • Present in ascitic fluid, pleural, pericardial and peritoneal fluids, synovial fluid and abscesses. (B263)
    • In pleural fluid and synovial fluid aminoglycosides may, with prolonged therapy, reach 50-90% of plasma concentrations. (B135.45.w45)
  • High levels in sputum, bronchial secretions, bile. (B263)
    • In bile may reach 30% of blood level. (B135.45.w45)
  • CSF levels unpredictable: 0 to 50% of serum levels. (B263); aminoglycosides may reach 20% of serum levels in the CSF if there is active inflammation and higher in neonatal meningitis. (B135.45.w45)
  • Accumulate in the inner ear and in the kidneys. (B263)
  • Aminoglycosides do not readily penetrate the eye. (B135.45.w45)
  • Cross the placenta: fetal concentrations 15 to50% of maternal serum concentrations.(B263)

Volume of distribution:

  • Adult cats and dogs: 0.15-0.3 L/kg. (B263)
  • In horses: 0.26-0.58 L/kg. (B263)
  • May be higher volume of distribution in neonates and juveniles due to higher extracellular fluid fractions.(B263)
Plasma Protein binding / Storage
  • Plasma protein binding minimal (less than 20%).(B263)
Elimination Route
  • Elimination of aminoglycosides is mainly by glomerular filtration. (B263)
    • Excretion of aminoglycosides is greatly reduced if renal function is impaired. (B135.45.w45)
  • Minimal metabolic breakdown of aminoglycosides by the host. (B135.45.w45)
Elimination half-life / Clearance Rate Elimination half-life: 
  • Horses: 1.14-2.23 hours. (B263)
  • Calves: 2.2-2.7 hours. (B263)
  • Dogs and cats: 0.5-2.0 hours. (B263)
  • Human: half-life of aminoglycosides in serum 2-3 hours. (B135.45.w45)
  • May be significantly prolonged in individuals with decreased renal function. (B263)
Drug Interactions
  • Use with caution in conjunction with other drugs which may be nephrotoxic, ototoxic or neurotoxic, including amphotericin B, other aminoglycosides, acyclovir, bacitracin, cisplatin, methoxyflurane, polymixin B, vancomycin. (B263)
  • Controversy regarding concurrent use with cephalosporins due to potentially additive nephrotoxicity; this has been well documented only with cephalothrin and with the no-longer-marketed cephaloridine. (B263)
  • May get increased nephrotoxicity or ototoxicity if used concurrently with loop diuretics (furosemide, ethacrynic acid) or osmotic diuretics (mannitol, urea). (B263)
  • Neuromuscular blockade could be potentiated if used with general anaesthetics or neuromuscular blocking agents. (B263)
  • Synergism is seen when aminoglycosides are used in conjunction with beta-lactam antibiotics. (B201)
    • Synergism may occur if used concurrently with beta-lactam antibiotics against Pseudomonas aeruginosa and enterococci; the effect is unpredictable and its usefulness in clinical situations has been questioned. (B263)
  • Physical incompatibility reported (or compatibility only in certain situations): aminophylline, amphotericin B, ampicillin sodium, carbenicillin disodium, cefazolin sodium, cephalothin sodium, cephapirin sodium, chlorothiazide sodium, dexamethasone sodium phosphate, erythomycin gluceptate, heparin sodium, methicillin sodium, nitrofurantoin sodium, oxacillin sodium, oxytetracycline HCl, penicillin G potassium, phenytoin sodium, potassium chloride (in dextran 6% in sodium chloride 0.9%; stable with potassium chloride in "standard solution, tetracycline HCl, thiopental sodium, vitamin B-complex with C, warfarin sodium.. (B263)
  • Physical compatibility reported with: all commonly used intravenous solutions, amobarbital sodium, ascorbic acid injection, bleomycin sulphate, calcium chloride/gluconate, cefoxitin sodium, chloramphenicol sodium succinate, chlorampheniramine maleate, cimetidine HCl, clindamycin phosphate, colistimethate sodium, dimenhydrinate, diphenhydramine HCl, epinephrine HCl, ergonovine maleate, hyaluronidase, hydrocortisone sodium phosphate/succinate, lincomycin HCl, metaraminol bitartrate, metronidazole (with and without sodium bicarbonate), norepinephrine bitartrate, pentobarbital sodium, phenobarbital sodium, phytonadione, polymixin B sulphate, prochlorperazine edisylate, promethazine HCl, secobarbital sodium, sodium bicarbonate, succinylcholine chloride, vancomycin HCl, verapamil HCl. (B263)
  • Compatibility is affected by factors including pH, concentration, temperature and diluents used. (B263)
  • In vitro it is well documented that beta-lactam antibiotics inactivate aminoglycosides by forming complexes with them (B201, B135.45.w45); amikacin is less susceptible to this than other members of this group, nevertheless it is usually recommended that mixing in the same syringe or intravenous bag should be avoided unless administration is prompt after such mixing. (B263)

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Administration
Formulations available --
Doses / Administration Routes / Frequencies

Use of Drugs (Medication):

  • Before administration of any pharmaceutical product the manufacturer's datasheet must be consulted regarding operator safety, relevant withdrawal times etc.
  • Many drugs are not registered for use in particular species and additional care should be taken in their use, with proper regard for possible toxic effects. 
  • Consideration should be given to relevant legislation regarding the use of drugs.
  • In the UK, guidelines regarding the use of drugs are set out in the Royal College of Veterinary Surgeons' Guide to Professional Conduct 2000: (See: LCofC1 - RCVS Guide to Professional Conduct 2000 - Choice of Medicinal Products).
In mammals: 
  • Generally once daily dosing is recommended to give high peak levels with resultant greater bactericidal effect. The post-antibiotic effect of aminoglycosides continues to decrease the replication rate of susceptible bacteria once drug levels have fallen below minimal inhibitory concentration (MIC), and may decrease the development of adaptive resistance. (B263)
  • In individuals which are neutropaenic or otherwise immunosuppressed, dosing at intervals of eight hours may be beneficial. (B263)
  • An increased dosing interval (longer than one day) may be required in individuals with significantly diminished renal function. (B263)

Elephants:

Loxodonta africana - African Elephant

  • An elephant with enteritis was given 3.77 mg/kg intravenously every 12 hours initially, increasing to 5-6 mg/kg every 12 hours to reach the therapeutic range. (P30.1.w5)
  • Two grams of amikacin diluted to 20 ml with 1:1 local anaesthetic and heparinised saline were administered by Regional Digital Intravenous Perfusion in Elephants to treat osteomyelitis of the second phalange (a complication of a sole abscess) in an adult elephant. (P30.1.w9)

The following information is taken with permission directly from the Elephant Care International website (W580.Aug2005.w3):

Elephants:

a) 6-8 mg/kg IM q 24 h (Lodwick et.al., 1994)

Elephant References:

a) Lodwick,L.J., Dubach,J.M., Phillips,L.G., Brown,C.S., and Jandreski,M.A. 1994. Pharmacokinetics of amikacin in African elephants (Loxodonta africana). Zoo Wildl.Med. 25:(3):367-375 Abstract: Two adult females were given single i.v. injections of 8 mg/kg. Trials using 3 mg/kg and 6 mg/kg i.m. were conducted with three adult females. Serum concentrations of amikacin were measured serially over a 24-49 h period. After i.v. administration of 8 mg/kg, the elimination half-lives (t0.5) were 4.0 and 3.7 h, the volumes of distribution at steady state were 0.21 and 0.18 litres/kg, and total body clearances were 41.8 and 40.8 ml/h/kg. At i.m. doses of 3 and 6 mg/kg, the peak concentrations observed ranged from 4.8 to 8.4 g/ml and 14.2 to 21.8 g/ml, respectively. The time at observed peak concentration was between 1 and 3 h, and t0.5 ranged from 3.8 to 5.9 h for the lower dose and from 3.7 to 6.3 h for the higher dose. Following the single dose trials, one elephant was treated with amikacin at a dose of 7 mg/kg i.m. at 24 h intervals for 21 days, and serum amikacin concentrations were determined 2 to 4 times on each of 11 days. Mean (SD) peak serum concentration for this elephant was 19.02.8 g/ml, and mean serum concentration at 24 h (through) was 1.70.4 g/ml. There was indication in this one elephant of a mild, reversible renal tubular insult based on a slight transient elevation in serum creatinine and the presence of casts in the urine. These changes resolved soon after the end of treatment. These preliminary results suggest that amikacin administered at 6-8 mg/kg i.m. once every 24 h would be appropriate for elephants with bacterial infections suspected to be susceptible to amikacin.

Cranes

  • 10 mg/kg intramuscularly every 12 hours. (B115.8.w4, B336.20.w20) or subcutaneously. (B12.56.w14)
    • Broad-spectrum. Less nephrotoxic than Gentamicin, but ensure adequate hydration. Often used in conjunction with Piperacillin sodium to increase the spectrum of action. (B12.56.w14, B115.8.w4)
Monitoring parameters
  • Efficacy, as indicated by bacterial culture, clinical signs, white blood cell counts, other signs associated with infection. (B263)
  • Monitoring of serum drug levels are recommended when amikacin is used systemically, measuring peak level (about 30 minutes after administration) and trough level (just prior to the next dose). (B135.45.w45, B263)
  • Monitoring for adverse effects is essential, including: gross monitoring of vestibular toxicity (vertigo, ataxia, loss of balance) or auditory toxicity (hearing loss, with high-frequency tones lost first), renal function tests prior to therapy and urinalyses during therapy (first sign of impending nephrotoxicity is often urinary casts). (B135.45.w45, B263)
  • In individuals with pre-existing renal disease, monitoring and dosage adjustments are required. (B263)

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Withdrawal period / Withholding time
Notes Before the use of any pharmaceutical product in food-producing animals the label instructions for the product should be consulted regarding withdrawal requirements.

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Toxic Information

Toxic effects of Pharmaceutical Products
Contraindications / Precautions
  • Contraindicated in individuals with known hypersensitivity to aminoglycosides.(B263)
  • Use only with extreme caution in patients with pre-existing renal disease. (B263)
  • Use with caution and with serum monitoring and dosage adjustment in neonatal individuals and in geriatric individuals
  • Use with caution in individuals , fever, sepsis, dehydration. (B263)
  • Use with caution in "working" dogs. such as sheep dogs, "seeing-eye" dogs, hearing dogs for the deaf, due to the risk of irreversible ototoxicity and deafness. (B263)
  • Use with caution in individuals with neuromuscular disorders (such as myasthenia gravis). (B263)
  • Contraindicated in lagomorphs (Lagomorpha - Lagomorphs (Order)) (rabbits/hares) due to adverse effect on the balance of gastrointestinal flora. (B263)
  • Avoid administration simultaneous with other drugs which are potentially ototoxic. (B135.45.w45)
Adverse Effects / Side Effects / Warnings
  • Nephrotoxic: tubular necrosis, probably related to interference in the phospholipid metabolism in proximal tubular cells lysosomes with resultant leakage of proteolytic enzymes into the cytoplasm. (B263)
    • Manifests as increase in blood urea nitrogen (BUN), creatinine and non-protein nitrogen in the serum. In the urine, decreased specific gravity and creatinine clearance, sometimes with proteinuria and presence of cells or casts. (B263)
    • Usually reversible once the drug is withdrawn. (B263)
  • Ototoxic (toxicity to the 8th cranial nerve).
    • May show auditory or vestibular signs. (B263)
    • May be irreversible. (B263)
    • Amikacin is more likely to cause auditory than vestibular signs. (B263)
    • Cats are very sensitive to vestibular effects from aminoglycosides. (B263)

Other side effects:

  • Neuromuscular blockade. (B263)
  • Facial oedema. (B263)
  • Injection site pain/inflammation. (B263)
  • Peripheral neuropathy. (B263)
  • Hypersensitivity reactions.(B263)
  • Gastrointestinal signs (rare) (B263)
  • Haematological effects (rare). (B263)
  • Hepatic effects (rare). (B263)
  • Rarely may cause 8th cranial nerve toxicity or nephrotoxicity in fetuses. (B263)
Operator Warnings Before the use of any pharmaceutical product the label instructions for the product should be consulted regarding operator safety/warnings.
Overdose / Acute Toxicity
  • May be treated by:
    • Dialysis (not a viable option in veterinary patients). (B263)
    • Peritoneal dialysis (less efficacious).(B263)
    • Administration of carbenicillin or ticarcillin (in humans 12-20 g/day) to complex with the aminoglycoside. This may be less effective with amikacin than with other aminoglycosides. (B263)

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Detailed Toxicological Information
Classification --
Acute Toxicity --
Chronic Toxicity --
Reproductive effects --
Teratogenic effects --
Mutagenic effects --
Carcinogenic effects --
Organ toxicity --
Bird Toxicity --
Aquatic organism activity --
Other organism toxicity --

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Nutrient Information

Nutritional Data
Sources --
Biological Use --
Recommended Daily Allowance / Recommended level in food --
Stability in food (Storage time) --
Interactions --

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External / Environmental Information

External / Environmental Uses
Use --
Formulation --
Application method --
Application Concentration --
Persistence of Effect / Frequency of Application --

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Effects on the Environment
Effects in the aquatic environment --
Effects on land --

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Persistence in the Environment
Breakdown in soil and groundwater --
Breakdown in water --
Breakdown in vegetation --

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