Antibiotic (Systemic Drug)
- Parenteral aminoglycoside antibiotic with good activity against a variety of bacteria, predominantly gram-negative aerobic bacilli and staphylococci.
- Adverse effects: Nephrotoxicity, ototoxicity, neuromuscular blockade.
- Cats may be more sensitive to toxic effects.
- Risk factors for toxicity: greater in patients with preexisting renal disease, age (both neonatal and geriatric), fever, sepsis, and dehydration. 1
- In humans, amikacin solution is administered to adults over a 30 to 60 minute period with the total daily dose not exceeding 15 mg/kg/day.
- Typically prescribed to humans who suffer from cystic fibrosis as a treatment for bacterial infections.
- In mares, commonly prescribed for the treatment of uterine infections (endometritis, metritis and pyometra).
- Dose every 24 hours when used systemically.1
Amikacin is FDA-approved for intrauterine infusion in mares. It is used with intra-articular injection in foals to treat gram-negative septic arthritis. Intravenous regional limb perfusion (IVRLP) using amikacin in horses for the treatment of septic arthritis is actively being researched. It is also used topically to treat otitis externa in dogs, and may be impregnated in materials (eg, PMMA beads, gels) for local treatment of infections, particularly surgical implant-associated surgical site infections. 1
Amikacin is often used in settings in which gentamicin-resistant bacteria are a clinical problem. The inherent toxicity and parenteral administration 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 available. 1
Amikacin is FDA-approved for intrauterine infusion in mares. While parenteral use is only FDA-approved for use in dogs, amikacin is used clinically to treat serious gram-negative infections in most species.
The mechanism of action for amikacin, like the other aminoglycoside antibiotics, is upon susceptible bacteria, presumably by irreversibly binding to the 30S ribosomal subunit, thereby inhibiting protein synthesis. For bacterial infection, amikacin is considered a bactericidal concentration-dependent antibiotic.
Amikacin’s spectrum of activity includes coverage against many aerobic gram-negative and some aerobic gram-positive bacteria, including Escherichia coli, most species of Klebsiella spp, Proteus spp, Pseudomonas spp, Salmonella spp, Enterobacter spp, Serratia spp, Shigella spp, Mycoplasma spp, and Staphylococcus spp. Several strains of Pseudomonas aeruginosa, Proteus spp, and Serratia spp that are resistant to gentamicin will still be killed by amikacin.
In an in vitro study with canine E. coli isolates, amikacin demonstrated additive or synergistic antimicrobial activity in combination with ceftazidime and amoxicillin/clavulanate, but not in combination with enrofloxacin or marbofloxacin. 2 Antimicrobial activity of the aminoglycosides is enhanced in an alkaline environment. The aminoglycoside antibiotics are inactive against fungi, viruses, and most anaerobic bacteria. 1
Amikacin, like the other aminoglycosides is not appreciably absorbed after oral or intrauterine administration but is absorbed from local administration (not from skin or the urinary bladder) when used in irrigations during surgical procedures or in regional limb perfusion. Systemic absorption from impregnated materials is poorly described, but the potential for appreciable, and even high, serum drug levels (patients receive high doses during oral administration) must be considered. After IM administration in dogs and cats, peak levels occur from 0.5 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 SC) is greater than 90%. 1
After absorption, aminoglycosides are distributed primarily in the extracellular fluid. They are found in ascitic, pleural, pericardial, peritoneal, synovial, and abscess fluids; high levels are found in sputum, bronchial secretions, and bile. Aminoglycosides are minimally protein bound (<20%) to plasma proteins. 3
Aminoglycosides do not readily cross the blood-brain 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. Prostate levels have not been adequately assessed in animals, but amikacin has been shown to be effective in the treatment of chronic bacterial prostatitis in humans when fluoroquinolones cannot be used. 4 A maximum distal interphalangeal joint synovial fluid concentration of 600 micrograms/ml was reached 15 minutes after intravenous regional limb perfusion (IVRLP) in healthy adult horses, although significant interpatient variability was noted. Maximum serum amikacin concentration of 19 micrograms/mL was reached 25 minutes after IVRLP. 5 Aminoglycosides tend to accumulate in certain tissues such as the inner ear and kidneys, which 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 because of their higher extracellular fluid fractions. Aminoglycosides cross the placenta; fetal concentrations range from 15%-50% of those found in maternal serum. 1
Elimination of aminoglycosides after parenteral administration occurs almost entirely by glomerular filtration. The approximate elimination half-lives for amikacin have been reported to be 5 hours in foals, 1.14-2.3 hours in adult horses, 2.2-2.7 hours in calves, 1 hour in cows, 1.5 hours in sheep, and 0.5-2 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. 1
Contraindications / Precautions:
Aminoglycosides are contraindicated in patients that are hypersensitive to them. Because these drugs are often the only effective agents in severe gram-negative or multidrug-resistant staphylococcal 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 as needed. Patients with impaired renal function should not be given amikacin. While the serum half-life of amikacin is normally two hours, it is 50 hours in those with end-stage renal disease. The vast majority (95%) of amikacin from an IM or IV dose is secreted unchanged via glomerular filtration and into the urine within 24 hours. 1
Other risk factors for the development of toxicity include age (both neonatal and geriatric patients), fever, sepsis, and dehydration. Patients with normal renal function may be considered.
Because aminoglycosides can cause irreversible ototoxicity, they should be used with caution in working dogs (eg, “seeing-eye,” herding, dogs for the hearing impaired) and should be avoided in the treatment of otitis if an intact tympanic membrane is not known to be present. Amikacin is considered less ototoxic than gentamicin or streptomycin. 6
Aminoglycosides should be used with caution in patients with neuromuscular disorders (eg, myasthenia gravis) because of their neuromuscular blocking activity. Sighthounds may require reduced dosages of aminoglycosides, as they have significantly smaller volumes of distribution. 1
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 can be nephrotoxic and ototoxic. 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. Toxic effects on the eighth cranial nerve can result in hearing loss, loss of balance, or both. 1
Nephrotoxicity risks increase with prolonged therapy and are predominantly associated with accumulation of amikacin within tubular cells, something that is more likely to occur with repeated lower doses as compared with higher doses with prolonged (ie, q24h) dosing intervals.
Nephrotoxicity is usually manifested by nonoliguric renal failure, with increases in serum BUN and creatinine and decreases in urine specific gravity and creatinine clearance. Proteinuria and cells or casts may be seen in the urine. Nephrotoxicity is usually reversible once the drug is discontinued. Although amikacin is less nephrotoxic than other aminoglycosides, the incidence of nephrotoxicity is poorly described and caution and monitoring are required.
Ototoxicity (8th cranial nerve toxicity) of the aminoglycosides can manifest by either auditory and/or vestibular clinical signs and may be irreversible. Vestibular clinical signs are more frequent with streptomycin, gentamicin, or tobramycin. Auditory clinical signs are more frequent with amikacin or neomycin, but either form can occur with any of these drugs. Cats are apparently more sensitive to the vestibular effects of the aminoglycosides.
Aminoglycosides can also cause neuromuscular blockade, facial edema, pain/inflammation at injection site, peripheral neuropathy, and hypersensitivity reactions. Rarely, GI clinical signs and hematologic and hepatic effects have been reported. 1
The following drug interactions with amikacin have either been reported or are theoretical in humans or animals and may be of significance in veterinary patients.
- BETA-LACTAM ANTIBIOTICS (eg, penicillins, cephalosporins): May have synergistic effects against some bacteria; some potential for physical inactivation of aminoglycosides in vitro (do not mix together) and in vivo (patients in renal failure).
- CEPHALOSPORINS: The concurrent use of aminoglycosides with cephalosporins is somewhat controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with aminoglycosides, but this interaction has only been well documented with cephaloridine and cephalothin (both of which are no longer marketed). The potential synergistic effect may outweigh these unlikely risks; however, concurrent use of third- or fourth-generation cephalosporins with amikacin results in abundant and typically unnecessary duplication of the gram-negative spectrum.
- DIURETICS, LOOP (eg, furosemide, torsemide) or OSMOTIC (eg, mannitol): Concurrent use with loop or osmotic diuretics may increase the nephrotoxic or ototoxic potential of the aminoglycosides.
- NSAIDs: Because NSAIDs may cause nephrotoxic effects, some believe that concurrent use with aminoglycosides should be avoided.
- NEPHROTOXIC DRUGS, OTHER (eg, cisplatin, amphotericin B, polymyxin B, vancomycin): Potential for increased risk for nephrotoxicity.
- NEUROMUSCULAR BLOCKING AGENTS & ANESTHETICS, GENERAL: Concomitant use with general anesthetics or neuromuscular blocking agents could potentiate neuromuscular blockade. 1
Should an inadvertent overdose occur, 3 treatments have been recommended: 1) Hemodialysis is effective in reducing serum levels of the drug but is not a viable option for most veterinary patients. 2) Peritoneal dialysis also will reduce serum levels but is much less efficacious. 3) Complexation of drug with ticarcillin (12 – 20 g/day in humans) is reportedly nearly as effective as hemodialysis. Amikacin is less affected by this approach than either tobramycin or gentamicin, and it is assumed that reduction in serum levels will also be minimized.
In laboratory analysis, amikacin serum concentrations may be falsely decreased if the patient is also receiving beta-lactam antibiotics and the serum is stored before 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. 1
There is an FDA-approved course of treatment for systemic use in dogs, but most infectious disease clinicians now agree that aminoglycosides should be dosed once a day in most patients (mammals). This dosing regimen yields higher peak levels with resultant greater bacterial kill, and as aminoglycosides exhibit a postantibiotic effect, surviving susceptible bacteria generally do not replicate as rapidly even when antibiotic concentrations are below the MIC. Except where noted, all dosages are extra-label. 1
Horses - Uterine infusion (labeled dosage; FDA-approved): 2 g mixed with 200-mL sterile normal saline (0.9% sodium chloride for injection) and aseptically infused into uterus daily for 3 consecutive days.
Susceptible infections and empirical therapy (extra-label): Adults: 10 mg/kg IV or IM every 24 hours. Neonatal foals: 20 – 25 mg/kg IV or IM every 24 hours. It is strongly recommended to individualize dosage based on therapeutic drug monitoring.
Treatment of septic joints (extra-label): Intra-articular administration: 125 – 250 mg IA every 24 hours. 1
Intravenous Regional Limb Perfusion (IVRLP) administration in standing adult horses: 2 g (diluted to 30-60 mL with sterile saline) with 10-20 minute tourniquet time.8,17,18 Note: Despite the procedure’s name, amikacin is absorbed systemically and reaches potentially therapeutic concentrations. 5
Dogs - Labeled indications (Genitourinary tract infections [cystitis] caused by susceptible strains of Escherichia coli and Proteus spp. Skin and soft tissue infections caused by susceptible strains of Pseudomonas spp and Escherichia coli): 10 mg/kg SC or IM every 12 hours. Dogs with skin and soft tissue infections should be treated for a minimum of 7 days, and those with genitourinary infections should be treated for 7 to 21 days or until culture results are negative and there is no evidence of clinical signs. If no response is observed after 3 days of treatment, therapy should be discontinued and the case re-evaluated. Maximum duration of therapy should not exceed 30 days.
Susceptible infections and empirical therapy (extra-label): 15 – 30 mg/kg IV, IM, or SC every 24 hours. Note: In greyhounds (and potentially other sighthounds), a dose reduction to 10 mg/kg IV every 24 hours or 15 mg/kg SC/IM every 24 hours has been recommended.11 Septic patients may be started at 20 – 30 mg/kg IV every 24 hours. Note: Dosage should be adjusted based on kidney function and serum levels when possible.
Cats - Susceptible infections and empirical therapy (extra-label): 10 – 15 mg/kg IV, IM, or SC every 24 hours. Septic patients may be started at 20 mg/kg IV every 24 hours. Note: Dosage should be adjusted based on renal function and serum levels when possible. When renal function is significantly decreased (eg, IRIS stage II or III) and less nephrotoxic drugs cannot be used, dosage amount remains the same but dosing interval is increased.
Ferrets - Susceptible infections (extra-label):
a) 8 – 16 mg/kg IM or IV every 24 hours.7
b) 8 – 16 mg/kg/day SC, IM, or IV divided q8-24h.8
Rabbits/Rodents/Small Mammals (All extra-label) -
a) Rabbits: 8 – 16 mg/kg daily dose (may divide into q8-24h) SC, IM, or IV. Increased efficacy and decreased toxicity if given every 24 hours. If given IV, dilute into 4 mL/kg of saline and give over 20 minutes. 9
b) Rabbits: 5 – 10 mg/kg SC, IM, or IV divided q8-24h. Guinea pigs: 10 – 15 mg/kg SC, IM, or IV divided q8-24h. Chinchillas: 10 – 15 mg/kg SC, IM, or IV divided q8-24h. Hamsters, rats, mice: 10 mg/kg SC or IM every 12 hours. Prairie dogs: 5 mg/kg SC or IM every 12 hours. 8
c) Chinchillas: 2 – 5 mg/kg SC or IM q8-12h.10
New World Camelids - Susceptible infections and empirical therapy (extra-label) - 18 mg/kg IV or IM every 24 hours. 11
Birds - Susceptible infections (All extra-label):
a) Sunken eyes/sinusitis in macaws caused by susceptible bacteria: 40 mg/kg IM every 12 or 24 hours. Must also flush sinuses with saline mixed with appropriate antibiotic (10 – 30 mL per nostril). May require 2 weeks of treatment. 12
b) 15 mg/kg IM or SC every 12 hours.13
c) Gram-negative infections resistant to gentamicin: Dilute commercial solution and administer 15 – 20 mg/kg (0.015 mg/g) IM every 12 or 24 hours. 14
Reptiles - Susceptible infections (All extra-label):
a) Snakes: 5 mg/kg IM (forebody) loading dose, then 2.5 mg/kg q72h for 7-9 treatments. Commonly used in respiratory infections. Use a lower dose for Python curtus. 15
b) Study done in gopher snakes: 5 mg/kg IM loading dose, then 2.5 mg/kg q72h. House snakes at high end of their preferred optimum ambient temperature. 16
c) Bacterial shell diseases in turtles: 10 mg/kg (assume IM) every 24 hours in water turtles and every 48 hours in land turtles and tortoises for 7-10 days. Used commonly with a beta-lactam antibiotic. Recommended to begin therapy with 20 mL/kg fluid injection. Maintain hydration and monitor uric acid levels when possible. 17
d) Crocodilians: 2.25 mg/kg IM q72-96h.18
e) Gram-negative respiratory disease: 3.5 mg/kg IM, SC, or via lung catheter every 3-10 days for 30 days. 19
f) Gopher tortoises: 5 mg/kg IM every 48 hours at 30°C.20
Fish - Susceptible infections (extra-label) - 5 mg/kg IM loading dose, then 2.5 mg/kg every 72 hours for 5 treatments. 21
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