AMIKACIN SULFATE
Chemistry - A semi-synthetic aminoglycoside derived from kanamycin, amikacin occurs as awhite, crystalline powder that is sparingly soluble in water. The sulfate salt is formed during themanufacturing 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. Thecommercial injection is a clear to straw-colored solution and the pH is adjusted to 3.5 - 5.5 withsulfuric acid.
Amikacin is stable for at least 2 years at room temperature. Autoclaving commercially availablesolutions 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 solutionsand with the following drugs: amobarbital sodium, ascorbic acid injection, bleomycin sulfate, calcium chloride/gluconate, cefoxitin sodium, chloramphenicol sodium succinate, chlorpheniraminemaleate, cimetidine HCl, clindamycin phosphate, colistimethate sodium, dimenhydrinate, diphenhydramine HCl, epinephrine HCl, ergonovine maleate, hyaluronidase, hydrocortisone sodiumphosphate/succinate, lincomycin HCl, metaraminol bitartrate, metronidazole (with or without sodiumbicarbonate), norepinephrine bitartrate, pentobarbital sodium, phenobarbital sodium, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine HCl, secobarbital sodium, sodiumbicarbonate, succinylcholine chloride, vancomycin HCl and verapamil HCl.
The following drugs or solutions are reportedly incompatible or only compatible in specificsituations with amikacin: aminophylline, amphotericin B, ampicillin sodium, carbenicillin disodium, cefazolin sodium, cephalothin sodium, cephapirin sodium, chlorothiazide sodium, dexamethasonesodium phosphate, erythromycin gluceptate, heparin sodium, methicillin sodium, nitrofurantoinsodium, 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 warfarinsodium. Compatibility is dependent upon factors such as pH, concentration, temperature anddiluents 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 thesecompounds together in the same syringe or IV bag, unless administration occurs promptly. See alsothe information in the Drug Interaction and Drug/Lab Interaction sections.
Amikacin's spectrum of activity include coverage against many aerobic gram negative and someaerobic gram positive bacteria, including most species of E. coli, Klebsiella, Proteus, Pseudomonas,
Salmonella, Enterobacter, Serratia, and Shigella, Mycoplasma, and Staphylococcus. Several strainsof Pseudomonas aeruginosa, Proteus, and Serratia that are resistant to gentamicin will still bekilled 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.
Amikacin is also approved for intrauterine infusion in mares.
After IM administration to dogs and cats, peak levels occur from 1/2 to 1 hour later. Subcutaneousinjection 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 arefound in ascitic, pleural, pericardial, peritoneal, synovial and abscess fluids, and high levels arefound in sputum, bronchial secretions and bile. Aminoglycosides are minimally protein bound(<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the blood - brain barrier nor penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% ofthose found in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissuesafter parenteral dosing. Aminoglycosides tend to accumulate in certain tissues such as the inner earand kidneys, that may help explain their toxicity. Volumes of distribution have been reported to be0.15-0.3 L/kg in adult cats and dogs, and 0.26-0.58 L/kg in horses. Volumes of distribution may besignificantly 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 inmaternal serum.
Elimination of aminoglycosides after parenteral administration occurs almost entirely byglomerular filtration. The elimination half-lives for amikacin have been reported to be 1.14-2.3hours in horses, 2.2-2.7 hours in calves, and 0.5-1.5 hours in dogs and cats. Patients with decreasedrenal function can have significantly prolonged half-lives. In humans with normal renal function, elimination rates can be highly variable with the aminoglycoside antibiotics.
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 usedcautiously, preferably with serum monitoring and dosage adjustment in neonatal or geriatricanimals.
Aminoglycosides are generally considered contraindicated in rabbits/hares as they adversely affectthe GI flora balance in these animals.
Aminoglycosides can cross the placenta and while rare, may cause 8th cranial nerve toxicity ornephrotoxicity in fetuses. Because the drug should only be used in serious infections, the benefitsof therapy may exceed the potential risks.
Nephrotoxicity is usually manifested by increases in BUN, creatinine, nonprotein nitrogen in theserum and decreases in urine specific gravity and creatinine clearance. Proteinuria and cells or castsmay 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 ofnephrotoxicity 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 frequentwith 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 verysensitive to the vestibular effects of the aminoglycosides.
The aminoglycosides can also cause neuromuscular blockade, facial edema, pain/inflammation atinjection site, peripheral neuropathy and hypersensitivity reactions. Rarely, GI symptoms, hematologic and hepatic effects have been reported.
The concurrent use of aminoglycosides with cephalosporins is controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with aminoglycosides, but thisinteraction has only been well documented with cephaloridine (no longer marketed) andcephalothin.
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 potentiateneuromuscular 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 ifthe patient is also receiving beta-lactam antibiotics and the serum is stored prior analysis. It isrecommended that if assay is delayed, samples be frozen and if possible, drawn at times when thebeta-lactam antibiotic is at a trough.
Amikacin may also be expressed in terms of units. 50, 600 Units are equal to 50.9 mg of base. Thecommercial injection is a clear to straw-colored solution and the pH is adjusted to 3.5 - 5.5 withsulfuric 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 becomevery 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 availablesolutions 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 solutionsand with the following drugs: amobarbital sodium, ascorbic acid injection, bleomycin sulfate, calcium chloride/gluconate, cefoxitin sodium, chloramphenicol sodium succinate, chlorpheniraminemaleate, cimetidine HCl, clindamycin phosphate, colistimethate sodium, dimenhydrinate, diphenhydramine HCl, epinephrine HCl, ergonovine maleate, hyaluronidase, hydrocortisone sodiumphosphate/succinate, lincomycin HCl, metaraminol bitartrate, metronidazole (with or without sodiumbicarbonate), norepinephrine bitartrate, pentobarbital sodium, phenobarbital sodium, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine HCl, secobarbital sodium, sodiumbicarbonate, succinylcholine chloride, vancomycin HCl and verapamil HCl.
The following drugs or solutions are reportedly incompatible or only compatible in specificsituations with amikacin: aminophylline, amphotericin B, ampicillin sodium, carbenicillin disodium, cefazolin sodium, cephalothin sodium, cephapirin sodium, chlorothiazide sodium, dexamethasonesodium phosphate, erythromycin gluceptate, heparin sodium, methicillin sodium, nitrofurantoinsodium, 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 warfarinsodium. Compatibility is dependent upon factors such as pH, concentration, temperature anddiluents 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 thesecompounds together in the same syringe or IV bag, unless administration occurs promptly. See alsothe information in the Drug Interaction and Drug/Lab Interaction sections.
Pharmacology - AMIKACIN SULFATE
Amikacin, like the other aminoglycoside antibiotics, act on susceptible bacteriapresumably 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 someaerobic gram positive bacteria, including most species of E. coli, Klebsiella, Proteus, Pseudomonas,
Salmonella, Enterobacter, Serratia, and Shigella, Mycoplasma, and Staphylococcus. Several strainsof Pseudomonas aeruginosa, Proteus, and Serratia that are resistant to gentamicin will still bekilled 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 totreat 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 theirsystemic use to serious infections when there is either a documented lack of susceptibility to otherless toxic antibiotics or when the clinical situation dictates immediate treatment of a presumed gramnegative infection before culture and susceptibility results are reported.Amikacin is also approved for intrauterine infusion in mares.
Pharmacokinetics - AMIKACIN SULFATE
Amikacin, like the other aminoglycosides is not appreciably absorbed afteroral or intrauterine administration, but it is absorbed from topical administration (not skin or urinarybladder) 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. Subcutaneousinjection 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 arefound in ascitic, pleural, pericardial, peritoneal, synovial and abscess fluids, and high levels arefound in sputum, bronchial secretions and bile. Aminoglycosides are minimally protein bound(<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the blood - brain barrier nor penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% ofthose found in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissuesafter parenteral dosing. Aminoglycosides tend to accumulate in certain tissues such as the inner earand kidneys, that may help explain their toxicity. Volumes of distribution have been reported to be0.15-0.3 L/kg in adult cats and dogs, and 0.26-0.58 L/kg in horses. Volumes of distribution may besignificantly 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 inmaternal serum.
Elimination of aminoglycosides after parenteral administration occurs almost entirely byglomerular filtration. The elimination half-lives for amikacin have been reported to be 1.14-2.3hours in horses, 2.2-2.7 hours in calves, and 0.5-1.5 hours in dogs and cats. Patients with decreasedrenal 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 inpatients who are hypersensitive to them. Because these drugs are often the only effective agents insevere 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 withconcomitant monitoring and dosage interval adjustments made. Other risk factors for thedevelopment 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 usedcautiously, preferably with serum monitoring and dosage adjustment in neonatal or geriatricanimals.
Aminoglycosides are generally considered contraindicated in rabbits/hares as they adversely affectthe GI flora balance in these animals.
Aminoglycosides can cross the placenta and while rare, may cause 8th cranial nerve toxicity ornephrotoxicity in fetuses. Because the drug should only be used in serious infections, the benefitsof 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 completelyunderstood, but are probably related to interference with phospholipid metabolism in the lysosomesof 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 theserum and decreases in urine specific gravity and creatinine clearance. Proteinuria and cells or castsmay 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 ofnephrotoxicity 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 frequentwith 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 verysensitive to the vestibular effects of the aminoglycosides.
The aminoglycosides can also cause neuromuscular blockade, facial edema, pain/inflammation atinjection 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 treatmentshave been recommended. Hemodialysis is very effective in reducing serum levels of the drug, but isnot a viable option for most veterinary patients. Peritoneal dialysis also will reduce serum levels, butis much less efficacious. Complexation of drug with either carbenicillin or ticarcillin (12-20 g/dayin humans) is reportedly nearly as effective as hemodialysis. Since amikacin is less affected by thiseffect than either tobramycin or gentamicin, it is assumed that reduction in serum levels will also beminimized 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 thisinteraction has only been well documented with cephaloridine (no longer marketed) andcephalothin.
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 potentiateneuromuscular 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 ifthe patient is also receiving beta-lactam antibiotics and the serum is stored prior analysis. It isrecommended that if assay is delayed, samples be frozen and if possible, drawn at times when thebeta-lactam antibiotic is at a trough.