Chemistry - A semi-synthetic aminoglycoside derived from kanamycin, amikacin occurs as a white, crystalline powder that is sparingly soluble in water. The sulfate salt is formed during the manufacturing process. 1.3 grams of amikacin sulfate is equivalent to 1 gram of amikacin. Amikacin may also be expressed in terms of units. 50,600 Units are equal to 50.9 mg of base. The commercial injection is a clear to straw-colored solution and the pH is adjusted to 3.5 - 5.5 with sulfuric acid.
Storage/Stability/Compatibility - Amikacin sulfate for injection should be stored at room temperature (15-30°C); freezing or temperatures above 40°C should be avoided. Solutions may become very pale yellow with time, but this does not indicate a loss of potency.
Amikacin is stable for at least 2 years at room temperature. Autoclaving commercially available solutions at 15 pounds of pressure at 120°C for 60 minutes did not result in any loss of potency.
Amikacin sulfate is reportedly compatible and stable in all commonly used intravenous solutions and with the following drugs: amobarbital sodium, ascorbic acid injection, bleomycin sulfate, calcium chloride/gluconate, cefoxitin sodium, chloramphenicol sodium succinate, chlorpheniramine 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 or without sodium bicarbonate), norepinephrine bitartrate, pentobarbital sodium, phenobarbital sodium, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine HCl, secobarbital sodium, sodium bicarbonate, succinylcholine chloride, vancomycin HCl and verapamil HCl.
The following drugs or solutions are reportedly incompatible or only compatible in specific situations with amikacin: aminophylline, amphotericin B, ampicillin sodium, carbenicillin disodium, cefazolin sodium, cephalothin sodium, cephapirin sodium, chlorothiazide sodium, dexamethasone sodium phosphate, erythromycin 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” solutions), tetracycline HCl, thiopental sodium, vitamin B-complex with C and warfarin sodium. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).
In vitro inactivation of aminoglycoside antibiotics by beta-lactam antibiotics is well documented. While amikacin is less susceptible to this effect, it is usually recommended to avoid mixing these compounds together in the same syringe or IV bag, unless administration occurs promptly. See also the information in the Drug Interaction and Drug/Lab Interaction sections.
Pharmacology - Amikacin, like the other aminoglycoside antibiotics, act on susceptible bacteria presumably by irreversibly binding to the 30S ribosomal subunit thereby inhibiting protein synthesis. It is considered to be an bactericidal antibiotic.
Amikacin’s spectrum of activity include coverage against many aerobic gram negative and some aerobic gram positive bacteria, including most species of E. coli, Klebsiella, Proteus, Pseudomonas, Salmonella, Enterobacter, Serratia, and Shigella, Mycoplasma, and Staphylococcus. Several strains of Pseudomonas aeruginosa, Proteus, and Serratia that are resistant to gentamicin will still be killed by amikacin.
Antimicrobial activity of the aminoglycosides are enhanced in an alkaline environment.
The aminoglycoside antibiotics are inactive against fungi, viruses and most anaerobic bacteria.
Uses/Indications - While parenteral use is only approved in dogs, amikacin is used clinically to treat serious gram negative infections in most species. It is often used in settings where gentamicin-resistant bacteria are a clinical problem. The inherent toxicity of the aminoglycosides limit their systemic use to serious infections when there is either a documented lack of susceptibility to other less toxic antibiotics or when the clinical situation dictates immediate treatment of a presumed gram negative infection before culture and susceptibility results are reported. Amikacin is also approved for intrauterine infusion in mares.
Pharmacokinetics - Amikacin, like the other aminoglycosides is not appreciably absorbed after oral or intrauterine administration, but it is absorbed from topical administration (not skin or urinary bladder) when used in irrigations during surgical procedures. Patients receiving oral aminoglycosides with hemorrhagic or necrotic enteritises may absorb appreciable quantities of the drug. After IM administration to dogs and cats, peak levels occur from 1/2 to 1 hour later. Subcutaneous injection results in slightly delayed peak levels and with more variability than after IM injection. Bioavailability from extravascular injection (IM or SQ) is greater than 90%.
After absorption, aminoglycosides are distributed primarily in the extracellular fluid. They are found in ascitic, pleural, pericardial, peritoneal, synovial and abscess fluids, and high levels are found in sputum, bronchial secretions and bile. Aminoglycosides are minimally protein bound (<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the bloodbrain barrier nor penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% of those found in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissues after parenteral dosing. Aminoglycosides tend to accumulate in certain tissues such as the inner ear and kidneys, that may help explain their toxicity. Volumes of distribution have been reported to be 0.15-0.3 L/kg in adult cats and dogs, and 0.26-0.58 L/kg in horses. Volumes of distribution may be significantly larger in neonates and juvenile animals due to their higher extracellular fluid fractions. Aminoglycosides cross the placenta and fetal concentrations range from 15-50% of those found in maternal serum.
Elimination of aminoglycosides after parenteral administration occurs almost entirely by glomerular filtration. The elimination half-lives for amikacin have been reported to be 1.14-2.3 hours in horses, 2.2-2.7 hours in calves, and 0.5-1.5 hours in dogs and cats. Patients with decreased renal function can have significantly prolonged half-lives. In humans with normal renal function, elimination rates can be highly variable with the aminoglycoside antibiotics.
Contraindications/Precautions/Reproductive Safety - Aminoglycosides are contraindicated in patients who are hypersensitive to them. Because these drugs are often the only effective agents in severe gram-negative infections there are no other absolute contraindications to their use. However, they should be used with extreme caution in patients with preexisting renal disease with concomitant monitoring and dosage interval adjustments made. Other risk factors for the development of toxicity include age (both neonatal and geriatric patients), fever, sepsis and dehydration.
Because aminoglycosides can cause irreversible ototoxicity, they should be used with caution in “working” dogs (e.g., “seeing-eye”, herding, dogs for the hearing impaired, etc.).
Aminoglycosides should be used with caution in patients with neuromuscular disorders (e.g., myasthenia gravis) due to their neuromuscular blocking activity.
Because aminoglycosides are eliminated primarily through renal mechanisms, they should be used cautiously, preferably with serum monitoring and dosage adjustment in neonatal or geriatric animals.
Aminoglycosides are generally considered contraindicated in rabbits/hares as they adversely affect the GI flora balance in these animals.
Aminoglycosides can cross the placenta and while rare, may cause 8th cranial nerve toxicity or nephrotoxicity in fetuses. Because the drug should only be used in serious infections, the benefits of therapy may exceed the potential risks.
Adverse Effects/Warnings - The aminoglycosides are infamous for their nephrotoxic and ototoxic effects. The nephrotoxic (tubular necrosis) mechanisms of these drugs are not completely understood, but are probably related to interference with phospholipid metabolism in the lysosomes of proximal renal tubular cells, resulting in leakage of proteolytic enzymes into the cytoplasm. Nephrotoxicity is usually manifested by increases in BUN, creatinine, nonprotein nitrogen in the serum and decreases in urine specific gravity and creatinine clearance. Proteinuria and cells or casts may also be seen in the urine. Nephrotoxicity is usually reversible once the drug is discontinued. While gentamicin may be more nephrotoxic than the other aminoglycosides, the incidences of nephrotoxicity with all of these agents require equal caution and monitoring.
Ototoxicity (8th cranial nerve toxicity) of the aminoglycosides can be manifested by either auditory and/or vestibular symptoms and may be irreversible. Vestibular symptoms are more frequent with streptomycin, gentamicin, or tobramycin. Auditory symptoms are more frequent with amikacin, neomycin, or kanamycin, but either forms can occur with any of the drugs. Cats are apparently very sensitive to the vestibular effects of the aminoglycosides.
The aminoglycosides can also cause neuromuscular blockade, facial edema, pain/inflammation at injection site, peripheral neuropathy and hypersensitivity reactions. Rarely, GI symptoms, hematologic and hepatic effects have been reported.
Overdosage/Acute Toxicity - Should an inadvertant overdosage be administered, three treatments have been recommended. Hemodialysis is very effective in reducing serum levels of the drug, but is not a viable option for most veterinary patients. Peritoneal dialysis also will reduce serum levels, but is much less efficacious. Complexation of drug with either carbenicillin or ticarcillin (12-20 g/day in humans) is reportedly nearly as effective as hemodialysis. Since amikacin is less affected by this effect than either tobramycin or gentamicin, it is assumed that reduction in serum levels will also be minimized using this procedure.
Drug Interactions - Aminoglycosides should be used with caution with other nephrotoxic, ototoxic, and neurotoxic drugs. These include amphotericin B, other aminoglycosides, acyclovir, bacitracin (parenteral use), cisplatin, methoxyflurane, polymyxin B, or vancomycin. The concurrent use of aminoglycosides with cephalosporins is controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with aminoglycosides, but this interaction has only been well documented with cephaloridine (no longer marketed) and cephalothin. Concurrent use with loop (furosemide, ethacrynic acid) or osmotic diuretics (mannitol, urea) may increase the nephrotoxic or ototoxic potential of the aminoglycosides. Concomitant use with general anesthetics or neuromuscular blocking agents could potentiate neuromuscular blockade. Synergism against Pseudomonas aeruginosa and enterococci may occur with beta-lactam antibiotics and the aminoglycosides. This effect is apparently not predictable and its clinical usefulness is in question.
Drug/Laboratory Interactions - Amikacin serum concentrations may be falsely decreased if the patient is also receiving beta-lactam antibiotics and the serum is stored prior analysis. It is recommended that if assay is delayed, samples be frozen and if possible, drawn at times when the beta-lactam antibiotic is at a trough.
Doses - Note: There is significant interpatient variability with regards to aminoglycoside pharmacokinetic parameters. To insure therapeutic levels and to minimize the risks for toxicity development, it is recommended to consider monitoring serum levels for this drug.
For small animals, one pair of authors (Aronson and Aucoin 1989) make the following recommendations with regard to minimizing risks of toxicity yet maximizing efficacy:
1) Dose according to animal size. The larger the animal, the smaller the dose (on a mg/kg basis).
2) The more risk factors (age, fever, sepsis, renal disease, dehydration) the smaller the dose.
3) In old patients or those suspected of renal disease, increase dosing interval from q8h to q16-24h.
4) Determine serum creatinine prior to therapy and adjust by changes in level even if it remains in “normal range”.
5) Monitor urine for changes in sediment (e.g., casts) or concentrating ability. Not very useful in patients with UTI.
6) Therapeutic drug monitoring is recommended when possible.
For susceptible infections:
a) 6.6 mg/kg IM or IV tid (Robinson 1987)
b) For gram negative respiratory infections: 6.6 mg/kg IM or IV q4-6 h; IV use is recommended for bronchopneumonia. (Beech 1987a)
c) In foals: 7.5 mg/kg IV q12h; monitor serum levels if possible. (Caprile and Short 1987)
d) 4.4 - 6.6 mg/kg IV or IM bid - tid, tid if severe infection (serious life-threatening). (Orsini et al. 1985)
e) 4 - 8 mg/kg q8-12h IM (Baggot and Prescott 1987)
For uterine infusion:
a) 2 grams mixed with 200 ml sterile normal saline (0.9% sodium chloride for injection) and aseptically infused into uterus daily for 3 consecutive days. (Package insert; Amiglyde-V®—Fort Dodge)
a) 6-8 mg/kg IM q 24 h (Lodwick et.al., 1994)
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 µg/ml and 14.2 to 21.8 µg/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 19.0±2.8 µg/ml, and mean serum concentration at 24 h (through) was 1.7±0.4 µg/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.
Monitoring Parameters -
1) Efficacy (cultures, clinical signs and symptoms associated with infection)
2) Renal toxicity; baseline urinalysis, serum creatinine/BUN. Casts in the urine are often the initial sign of impending nephrotoxicity. Frequency of monitoring during therapy is controversial. It can be said that monitoring daily urinalyses early in the course of treatment or daily creatinines once casts are seen or increases are noted in serum creatinine levels are not too frequent .
3) Gross monitoring of vestibular or auditory toxicity is recommended
4) Serum levels if possible; see the reference by Aronson and Aucoin in Ettinger (Aronson and Aucoin 1989) for more information.
Client Information - With appropriate training, owners may give subcutaneous injections at home, but routine monitoring of therapy for efficacy and toxicity must still be done. Clients should also understand that the potential exists for severe toxicity (nephrotoxicity, ototoxicity) developing from this medication.
Dosage Forms/Preparations/FDA Approval Status -
Amikacin Sulfate; Injection 50 mg (of amikacin base) per ml in 50 ml vials; Amiglyde-V® (Fort Dodge); Generic; (Rx) Approved for use in dogs.
Amikacin Sulfate Intrauterine Solution 250 mg (of amikacin base) per ml in 48 ml vials; Amiglyde-V® (Fort Dodge); (Rx) Approved for use in horses.
Amikacin Injection 50 mg (of amikacin base) and 250 mg (of amikacin base) per ml; Amikin® (Apothecon); Generic (Rx)
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