Chemistry - An aminoglycoside derived from Streptomyces tenebrarius, tobramycin occurs as a white to off-white, hygroscopic powder that is freely soluble in water and very slightly soluble in alcohol. The sulfate salt is formed during the manufacturing process. The commercial injection is a clear, colorless solution and the pH is adjusted to 6-8 with sulfuric acid and/or sodium hydroxide.
Storage/Stability/Compatibility - Tobramycin sulfate for injection should be stored at room temperature (15-30°C); avoid freezing and temperatures above 40°C. Do not use the product if discolored.
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 with dextrose and alcohol solutions, Polysal, Polysal M, or Isolyte E, M or P) and compatible with the following drugs: aztreonam, bleomycin sulfate, calcium gluconate, cefoxitin sodium, ciprofloxacin lactate, clindamycin phosphate (not in syringes), floxacillin sodium, metronidazole (with or without sodium bicarbonate), ranitidine HCl, and verapamil HCl. Several other drugs have been demonstrated to be compatible at Y-sites (see Trissell for more info).
The following drugs or solutions are reportedly incompatible or only compatible in specific situations with tobramycin: cefamandole naftate, 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. See also the information in the Drug Interaction and Drug/Lab Interaction sections.
Pharmacology - Tobramycin, 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 a bactericidal antibiotic.
Tobramycin’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, 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 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.
Whether tobramycin is less nephrotoxic than either gentamicin or amikacin when used clinically is controversial. Laboratory studies indicate that in a controlled setting in laboratory animals, it may indeed be so.
Pharmacokinetics - Tobramycin, 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. 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 (other than streptomycin) are minimally protein bound (<20%) 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% 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. 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. 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.
Tobramycin can cross the placenta. It has been demonstrated to concentrate in fetal kidneys and while rare, may cause 8th cranial nerve toxicity or nephrotoxicity in fetuses. Total irreversible deafness has been reported in some human babies whose mothers received tobramycin during pregnancy. 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 inadvertent 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.
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 - Tobramycin 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 level.
Doses - Note: There is significant inter-patient 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 susceptible infections: 1 - 1.7 mg/kg q8h IV (slowly) or IM (Note: This is a human dose and should be used as a general guideline only) (Walker 1992)
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 -
Veterinary-Approved Products: None
Tobramycin Sulfate Injection 10 mg/ml in 6 & 7 ml vials and 40 mg/ml in 1.5 & 2 ml syringes and 2 & 30 ml vials ; Nebcin® (Lilly); Generic; (Rx)
Tobramycin Sulfate Powder for Injection: 30 mg/ml in 1.2 g vials Nebcin® (Lilly); Generic (Rx)
Also available in ophthalmic preparations.
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