GENTAMICIN SULFATE
Chemistry - An aminoglycoside obtained from cultures of Micromonaspora purpurea, gentamicin sulfate occurs as a white to buff powder that is soluble in water and insoluble in alcohol. The commercial product is actually a combination of gentamicin sulfate C1, C2 and C3, but all these compounds apparently have similar antimicrobial activities. Commercially available injections have a pH from 3 - 5.5.
The soluble powder should be stored from 2-30°C. Do not store or offer medicated drinking water in rusty containers or the drug may be destroyed.
While the manufacturer does not recommend that gentamicin be mixed with other drugs, it is reportedly compatible and stable in all commonly used intravenous solutions and with the following drugs: bleomycin sulfate, cefoxitin sodium, cimetidine HCl, clindamycin phosphate, methicillin sodium, metronidazole (with and without sodium bicarbonate), penicillin G sodium and verapamil HCl.
The following drugs or solutions are reportedly incompatible or only compatible in specific situations with gentamicin: amphotericin B, ampicillin sodium, carbenicillin disodium, cefamandole naftate, cephalothin sodium, cephapirin sodium, dopamine HCl, furosemide, and heparin 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.
Gentamicin is very susceptible to this effect and it is usually recommended to avoid mixing these compounds together. Refer to the Drug Interaction section in the amikacin sulfate monograph for more information.
Various gentamicin products are approved for parenteral use in dogs, cats, chickens, turkeys andswine. Although routinely used parenterally in horses, gentamicin is only approved for intrauterineinfusion in that species. Oral products are approved for gastrointestinal infections in swine andturkeys. For more information refer to the Dosage section below.
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 arefound in ascitic, pleural, pericardial, peritoneal, synovial and abscess fluids and high levels are foundin sputum, bronchial secretions and bile. Aminoglycosides are minimally protein bound (<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the blood-brainbarrier or penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% of thosefound in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissues afterparenteral dosing. Aminoglycosides tend to accumulate in certain tissues, such as the inner ear andkidneys, which 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. 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 gentamicin have been reported to be 1.82- 3.25hours in horses, 2.2-2.7 hours in calves, 2.4 hours in sheep, 1.8 hours in cows, 1.9 hours in swine, 1 hour in rabbits, and 0.5-1.5 hours in dogs and cats. Patients with decreased renal function canhave significantly prolonged half-lives. In humans with normal renal function, elimination rates canbe 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 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 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 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 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 - Gentamicin 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.
Storage, Stability, Compatibility
Gentamicin sulfate for injection and the oral solution shouldbe stored at room temperature (15-30°C); freezing or temperatures above 40°C should be avoided.The soluble powder should be stored from 2-30°C. Do not store or offer medicated drinking water in rusty containers or the drug may be destroyed.
While the manufacturer does not recommend that gentamicin be mixed with other drugs, it is reportedly compatible and stable in all commonly used intravenous solutions and with the following drugs: bleomycin sulfate, cefoxitin sodium, cimetidine HCl, clindamycin phosphate, methicillin sodium, metronidazole (with and without sodium bicarbonate), penicillin G sodium and verapamil HCl.
The following drugs or solutions are reportedly incompatible or only compatible in specific situations with gentamicin: amphotericin B, ampicillin sodium, carbenicillin disodium, cefamandole naftate, cephalothin sodium, cephapirin sodium, dopamine HCl, furosemide, and heparin 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.
Gentamicin is very susceptible to this effect and it is usually recommended to avoid mixing these compounds together. Refer to the Drug Interaction section in the amikacin sulfate monograph for more information.
Pharmacology - GENTAMICIN SULFATE
Gentamicin has a mechanism of action and spectrum of activity (primarily gramnegative aerobes) similar to the other aminoglycosides. This information is outlined in more detailin the amikacin monograph. Gentamicin resistance by certain bacteria, principally Klebsiella, E. coliand Pseudomonas aeruginosa is a continuing concern for many areas. However, most strains ofgentamicin-resistant bacteria of these species remain susceptible to amikacin.Uses, Indications
The inherent toxicity of the aminoglycosides limit their systemic (parenteral)use to the treatment of serious gram negative infections when there is either a documented lack ofsusceptibility to other less toxic antibiotics or when the clinical situation dictates immediatetreatment of a presumed gram negative infection before culture and susceptibility results are reported.Various gentamicin products are approved for parenteral use in dogs, cats, chickens, turkeys andswine. Although routinely used parenterally in horses, gentamicin is only approved for intrauterineinfusion in that species. Oral products are approved for gastrointestinal infections in swine andturkeys. For more information refer to the Dosage section below.
Pharmacokinetics - GENTAMICIN SULFATE
Gentamicin, like the other aminoglycosides is not appreciably absorbed afteroral or intrauterine administration, but is absorbed from topical administration (not skin or urinarybladder) when used in irrigations during surgical procedures. Patients receiving oralaminoglycosides with hemorrhagic or necrotic enteritises may absorb appreciable quantities of thedrug. 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 arefound in ascitic, pleural, pericardial, peritoneal, synovial and abscess fluids and high levels are foundin sputum, bronchial secretions and bile. Aminoglycosides are minimally protein bound (<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the blood-brainbarrier or penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% of thosefound in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissues afterparenteral dosing. Aminoglycosides tend to accumulate in certain tissues, such as the inner ear andkidneys, which 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. 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 gentamicin have been reported to be 1.82- 3.25hours in horses, 2.2-2.7 hours in calves, 2.4 hours in sheep, 1.8 hours in cows, 1.9 hours in swine, 1 hour in rabbits, and 0.5-1.5 hours in dogs and cats. Patients with decreased renal function canhave significantly prolonged half-lives. In humans with normal renal function, elimination rates canbe 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 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 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 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 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.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 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 - Gentamicin 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.