TOBRAMYCIN SULFATE
Chemistry - An aminoglycoside derived from Streptomyces tenebrarius, tobramycin occurs as awhite to off-white, hygroscopic powder that is freely soluble in water and very slightly soluble inalcohol. The sulfate salt is formed during the manufacturing process. The commercial injection is aclear, colorless solution and the pH is adjusted to 6-8 with sulfuric acid and/or sodium hydroxide.
While the manufacturers state that tobramycin should not be mixed with other drugs, it is reportedly compatible and stable in most commonly used intravenous solutions (not compatible withdextrose and alcohol solutions, Polysal, Polysal M, or Isolyte E, M or P) and compatible with thefollowing drugs: aztreonam, bleomycin sulfate, calcium gluconate, cefoxitin sodium, ciprofloxacinlactate, clindamycin phosphate (not in syringes), floxacillin sodium, metronidazole (with or withoutsodium bicarbonate), ranitidine HCl, and verapamil HCl. Several other drugs have beendemonstrated to be compatible at Y-sites (see Trissell for more info).
The following drugs or solutions are reportedly incompatible or only compatible in specificsituations with tobramycin: cefamandole naftate, furosemide and heparin sodium. Compatibility isdependent upon factors such as pH, concentration, temperature and diluents used. It is suggested toconsult specialized references for more specific information (e.g., Handbook on Injectable Drugsby Trissel; see bibliography).
In vitro inactivation of aminoglycoside antibiotics by beta-lactam antibiotics is well documented.
See also the information in the Drug Interaction and Drug/Lab Interaction sections.
Tobramycin'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, Shigella, Mycoplasma, and Staphylococcus.
Antimicrobial activity of the aminoglycosides are enhanced in an alkaline environment.
The aminoglycoside antibiotics are inactive against fungi, viruses and most anaerobic bacteria.
Whether tobramycin is less nephrotoxic than either gentamicin or amikacin when used clinically iscontroversial. Laboratory studies indicate that in a controlled setting in laboratory animals, it mayindeed be so.
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 (other than streptomycin) areminimally protein bound (<20%) to plasma proteins. Aminoglycosides do not readily cross theblood-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 lungtissues after parenteral dosing. Aminoglycosides tend to accumulate in certain tissues such as theinner ear and kidneys, that may help explain their toxicity. Aminoglycosides cross the placenta andfetal concentrations range from 15-50% of those found in maternal serum.
Elimination of aminoglycosides after parenteral administration occurs almost entirely byglomerular filtration. Patients with decreased renal function can have significantly prolonged half-lives. In humans with normal renal function, elimination rates can be highly variable with theaminoglycoside 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.
Tobramycin can cross the placenta. It has been demonstrated to concentrate in fetal kidneys andwhile rare, may cause 8th cranial nerve toxicity or nephrotoxicity in fetuses. Total irreversibledeafness has been reported in some human babies whose mothers received tobramycin duringpregnancy. Because the drug should only be used in serious infections, the benefits of therapy mayexceed 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 - Tobramycin 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 level.
Storage, Stability, Compatibility
Tobramycin sulfate for injection should be stored at roomtemperature (15-30°C); avoid freezing and temperatures above 40°C. Do not use the product ifdiscolored.While the manufacturers state that tobramycin should not be mixed with other drugs, it is reportedly compatible and stable in most commonly used intravenous solutions (not compatible withdextrose and alcohol solutions, Polysal, Polysal M, or Isolyte E, M or P) and compatible with thefollowing drugs: aztreonam, bleomycin sulfate, calcium gluconate, cefoxitin sodium, ciprofloxacinlactate, clindamycin phosphate (not in syringes), floxacillin sodium, metronidazole (with or withoutsodium bicarbonate), ranitidine HCl, and verapamil HCl. Several other drugs have beendemonstrated to be compatible at Y-sites (see Trissell for more info).
The following drugs or solutions are reportedly incompatible or only compatible in specificsituations with tobramycin: cefamandole naftate, furosemide and heparin sodium. Compatibility isdependent upon factors such as pH, concentration, temperature and diluents used. It is suggested toconsult specialized references for more specific information (e.g., Handbook on Injectable Drugsby Trissel; see bibliography).
In vitro inactivation of aminoglycoside antibiotics by beta-lactam antibiotics is well documented.
See also the information in the Drug Interaction and Drug/Lab Interaction sections.
Pharmacology - TOBRAMYCIN SULFATE
Tobramycin, like the other aminoglycoside antibiotics, act on susceptible bacteriapresumably by irreversibly binding to the 30S ribosomal subunit thereby inhibiting proteinsynthesis. It is considered to be a bactericidal antibiotic.Tobramycin'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, Shigella, Mycoplasma, and Staphylococcus.
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 there are no approved veterinary tobramycin products in the U.S., tobramycin may be useful clinically to treat serious gram negative infections in most species. It isoften used in settings where gentamicin-resistant bacteria are a clinical problem. The inherenttoxicity of the aminoglycosides limit their systemic use to serious infections when there is either adocumented lack of susceptibility to other less toxic antibiotics or when the clinical situationdictates immediate treatment of a presumed gram negative infection before culture and susceptibilityresults are reported.Whether tobramycin is less nephrotoxic than either gentamicin or amikacin when used clinically iscontroversial. Laboratory studies indicate that in a controlled setting in laboratory animals, it mayindeed be so.
Pharmacokinetics - TOBRAMYCIN SULFATE
Tobramycin, 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 oralaminoglycosides with hemorrhagic or necrotic enteritises may absorb appreciable quantities of thedrug. Subcutaneous injection results in slightly delayed peak levels and with more variability thanafter 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 (other than streptomycin) areminimally protein bound (<20%) to plasma proteins. Aminoglycosides do not readily cross theblood-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 lungtissues after parenteral dosing. Aminoglycosides tend to accumulate in certain tissues such as theinner ear and kidneys, that may help explain their toxicity. Aminoglycosides cross the placenta andfetal concentrations range from 15-50% of those found in maternal serum.
Elimination of aminoglycosides after parenteral administration occurs almost entirely byglomerular filtration. Patients with decreased renal function can have significantly prolonged half-lives. In humans with normal renal function, elimination rates can be highly variable with theaminoglycoside 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.
Tobramycin can cross the placenta. It has been demonstrated to concentrate in fetal kidneys andwhile rare, may cause 8th cranial nerve toxicity or nephrotoxicity in fetuses. Total irreversibledeafness has been reported in some human babies whose mothers received tobramycin duringpregnancy. Because the drug should only be used in serious infections, the benefits of therapy mayexceed 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 inadvertent 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 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 - Tobramycin 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 level.