Tobramycin

Description

Tobramycin sulfate is a water-soluble antibiotic belonging to the aminoglycoside group, derived from the actinomycete Streptomyces tenebrarius. Tobramycin for Injection, USP is presented as a white or off-white lyophilized porous cake intended for parenteral administration. Each vial contains tobramycin sulfate equivalent to 1200 mg of tobramycin; upon reconstitution, each mL contains 40 mg of tobramycin. The chemical structure of tobramycin sulfate is described as O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→6)-2-deoxy-L-streptamine, (2:5)(salt). Its chemical formula is (C18H37N5O9)2•5H2SO4, and it has a molecular weight of 1,425.39 g/mol.

Uses and Indications

Tobramycin is indicated for the treatment of serious bacterial infections caused by susceptible strains of designated microorganisms in various conditions. These include:

• Septicemia in neonates, children, and adults caused by Pseudomonas aeruginosa, Escherichia coli, and Klebsiella species.

• Lower respiratory tract infections due to P. aeruginosa, Klebsiella species, Enterobacter species, Serratia species, E. coli, and both penicillinase and non-penicillinase-producing strains of Staphylococcus aureus.

• Serious central nervous system infections, including meningitis, caused by susceptible organisms.

• Intra-abdominal infections, such as peritonitis, caused by E. coli, Klebsiella species, and Enterobacter species.

• Skin, bone, and skin structure infections due to P. aeruginosa, Proteus species, E. coli, Klebsiella species, Enterobacter species, and S. aureus.

• Complicated and recurrent urinary tract infections caused by P. aeruginosa, Proteus species (both indole-positive and indole-negative), E. coli, Klebsiella species, Enterobacter species, Serratia species, S. aureus, Providencia species, and Citrobacter species.

Tobramycin may also be considered for use in serious staphylococcal infections when penicillin or other potentially less toxic drugs are contraindicated.

No specific teratogenic or nonteratogenic effects have been mentioned.

Dosage and Administration

Tobramycin for Injection, USP may be administered either intramuscularly or intravenously, with recommended dosages being identical for both routes. Prior to treatment, the patient's pretreatment body weight should be obtained to ensure accurate dosage calculation. It is advisable to measure both peak and trough serum concentrations during therapy.

For patients with normal renal function, the following dosing regimens are recommended:

Adults with Serious Infections: Administer 3 mg/kg/day divided into three equal doses every 8 hours.

Adults with Life-Threatening Infections: Administer up to 5 mg/kg/day, divided into three or four equal doses. The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated.

Pediatric Patients (Greater than 1 Week of Age): Administer 6 to 7.5 mg/kg/day, divided into three or four equally divided doses (2 to 2.5 mg/kg every 8 hours or 1.5 to 1.89 mg/kg every 6 hours).

Premature or Full-Term Neonates (1 Week of Age or Less): Administer up to 4 mg/kg/day, divided into two equal doses every 12 hours.

Patients with Cystic Fibrosis: An initial dosage regimen of 10 mg/kg/day, divided into four equally divided doses, is recommended.

For patients with impaired renal function, a loading dose of 1 mg/kg should be administered, followed by dosage adjustments. Subsequent doses may be reduced and given at 8-hour intervals, or normal doses may be administered at extended intervals.

For intravenous administration, the usual volume of diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) is 50 to 100 mL for adult doses. The diluted solution should typically be infused over a period of 20 to 60 minutes. Tobramycin for Injection, USP should not be physically premixed with other drugs and must be administered separately according to the recommended dose and route.

Contraindications

Use of tobramycin is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Additionally, a history of hypersensitivity or serious toxic reactions to aminoglycosides may contraindicate the use of any other aminoglycoside due to the potential for cross-sensitivity among drugs in this class.

Tobramycin is not approved for intraocular or subconjunctival administration. The use of aminoglycosides via these routes has been associated with reports of macular necrosis.

Warnings and Precautions

This product contains sodium metabisulfite, which may induce allergic-type reactions, including anaphylactic symptoms and varying degrees of asthmatic episodes in susceptible individuals. Healthcare professionals should remain vigilant for signs of such reactions.

Serious allergic reactions, including anaphylaxis, as well as dermatologic reactions such as exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson Syndrome, have been reported infrequently in patients receiving tobramycin therapy. Although these events are rare, fatalities have been documented. In the event of an allergic reaction, the administration of the drug should be discontinued immediately, and appropriate medical intervention should be initiated.

Clostridium difficile-associated diarrhea (CDAD) has been observed with nearly all antibacterial agents, including tobramycin. The severity of CDAD can range from mild diarrhea to fatal colitis. It is essential to consider CDAD in any patient presenting with diarrhea following antibiotic use, as cases have been reported to occur up to two months post-administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic therapy not targeting C. difficile should be discontinued. Clinicians should ensure appropriate management, including fluid and electrolyte replacement, protein supplementation, antibiotic treatment for C. difficile, and surgical evaluation as clinically warranted.

Patients receiving Tobramycin for Injection, USP, and other aminoglycosides must be closely monitored due to the potential for ototoxicity and nephrotoxicity associated with these medications. Neurotoxicity may manifest as auditory and vestibular ototoxicity, with auditory changes being irreversible, typically bilateral, and potentially partial or total.

Renal and eighth-nerve function should be closely monitored in patients with known or suspected renal impairment, as well as in those with initially normal renal function who exhibit signs of renal dysfunction during therapy. Regular monitoring of peak and trough serum concentrations of aminoglycosides is recommended to ensure therapeutic efficacy while avoiding toxic levels.

Aminoglycosides should not be administered concurrently with potent diuretics, such as ethacrynic acid and furosemide, due to the increased risk of ototoxicity. Caution is advised when using tobramycin in premature and neonatal infants due to their renal immaturity, which can prolong the serum half-life of the drug.

During therapy, serum and urine specimens should be collected as indicated in the WARNINGS box. Monitoring of serum calcium, magnesium, and sodium levels is recommended. Peak and trough serum levels should be measured periodically, with prolonged concentrations above 12 mcg/mL being avoided. Rising trough levels above 2 mcg/mL may indicate tissue accumulation.

In cases of neuromuscular blockade, administration of calcium salts may facilitate reversal. It is important to note that aminoglycosides can cause fetal harm when administered to pregnant women.

Healthcare professionals should seek emergency medical assistance if patients exhibit signs of an allergic reaction, such as hives, difficulty breathing, or swelling of the face, lips, tongue, or throat. Additionally, patients should be advised to discontinue use and contact their healthcare provider if they experience severe diarrhea (watery or bloody) that may occur two months or more after the last dose of tobramycin.

Side Effects

Patients receiving Tobramycin for Injection, USP, and other aminoglycosides should be closely monitored due to the inherent potential for ototoxicity and nephrotoxicity associated with these medications.

Neurotoxicity is a significant concern, particularly in patients undergoing high-dose or prolonged therapy, those with prior exposure to ototoxic agents, and individuals experiencing dehydration. Symptoms of neurotoxicity may include dizziness, vertigo, tinnitus, roaring in the ears, and hearing loss, with the latter typically being irreversible and initially presenting as diminished high-tone acuity. The risk of auditory changes, which are usually bilateral and can be partial or total, increases with elevated peak or trough serum concentrations. Notably, patients may not exhibit symptoms during therapy that would indicate eighth-nerve toxicity, and irreversible bilateral deafness may continue to progress even after discontinuation of the drug. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching, and convulsions.

Nephrotoxicity has also been reported, characterized by changes in renal function indicated by rising blood urea nitrogen (BUN), non-protein nitrogen (NPN), and serum creatinine levels, as well as oliguria, cylindruria, and increased proteinuria. This adverse effect is particularly prevalent in patients with a history of renal impairment and those treated with higher doses or for extended periods. Clinical studies have shown that tobramycin may cause nephrotoxicity less frequently than gentamicin; however, some studies found no significant difference in nephrotoxic incidence between the two agents. It is important to note that nephrotoxicity may not become apparent until several days after therapy has ceased, although it is usually reversible.

Other adverse reactions potentially related to tobramycin sulfate include hematologic effects such as anemia, granulocytopenia, and thrombocytopenia, as well as systemic reactions like fever, rash, exfoliative dermatitis, itching, urticaria, nausea, vomiting, diarrhea, headache, lethargy, pain at the injection site, mental confusion, and disorientation. Laboratory abnormalities may also occur, including increased serum transaminases (SGOT, SGPT), elevated serum lactate dehydrogenase (LDH) and bilirubin levels, and decreased serum levels of calcium, magnesium, sodium, and potassium, along with leukopenia, leukocytosis, and eosinophilia.

Serious allergic reactions, including anaphylaxis and severe dermatologic reactions such as exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson syndrome, have been reported rarely, with some cases resulting in fatalities. Additionally, Clostridium difficile-associated diarrhea (CDAD) has been observed with the use of tobramycin, which can range from mild diarrhea to severe, potentially fatal colitis. CDAD may occur due to the alteration of normal colonic flora following antibiotic use, leading to overgrowth of C. difficile. Symptoms can manifest up to two months post-administration, necessitating careful medical history assessment in patients presenting with diarrhea after antibiotic therapy. If CDAD is suspected or confirmed, ongoing antibiotic treatment not targeting C. difficile may need to be discontinued, and appropriate management should be initiated as clinically indicated.

Given these potential adverse reactions, it is crucial for healthcare providers to remain vigilant and conduct thorough assessments throughout the course of treatment with Tobramycin.

Drug Interactions

Concurrent and sequential use of neurotoxic and/or nephrotoxic antibiotics, particularly other aminoglycosides, should be avoided to minimize the risk of ototoxicity and nephrotoxicity. Additionally, aminoglycosides should not be administered concurrently with potent diuretics, such as ethacrynic acid and furosemide, as these diuretics can enhance aminoglycoside toxicity by altering serum concentrations.

The inactivation of tobramycin by β-lactam-type antibiotics, including penicillins and cephalosporins, has been demonstrated both in vitro and in patients with severe renal impairment. Therefore, caution is advised when these agents are used in conjunction with tobramycin.

Monitoring of serum calcium, magnesium, and sodium levels is recommended during therapy with tobramycin, as these electrolytes can be affected by the drug. Prolonged concentrations of tobramycin above 12 mcg/mL should be avoided to prevent the risk of ototoxicity and nephrotoxicity. Rising trough levels of tobramycin, particularly those exceeding 2 mcg/mL, may indicate tissue accumulation and necessitate dosage adjustments.

Furthermore, neuromuscular blockade may occur in patients receiving tobramycin, especially in those also receiving neuromuscular blocking agents. It is important to note that tobramycin can cause fetal harm when administered to a pregnant woman, as it crosses the placenta.

Packaging & NDC

The table below lists all NDC Code configurations of Tobramycin, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Pediatric patients may require specific considerations regarding indications and dosage. Healthcare professionals should refer to the INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections for detailed information pertinent to pediatric use.

It is essential to evaluate the efficacy and safety of the treatment in children, as responses may differ from those observed in adults. Dosing adjustments may be necessary based on age, weight, or developmental stage. Careful monitoring is advised to ensure optimal therapeutic outcomes while minimizing potential risks.

Geriatric Use

Elderly patients may be at an increased risk of developing nephrotoxicity and ototoxicity while receiving tobramycin. Factors contributing to these risks include rising trough levels, excessive peak concentrations, dehydration, concomitant use of other neurotoxic or nephrotoxic medications, and cumulative dose. Therefore, it is essential to measure peak and trough serum levels periodically during therapy to ensure that drug levels remain within the therapeutic range and to avoid potentially toxic levels.

Tobramycin is primarily excreted by the kidneys, and the likelihood of experiencing toxic reactions to this medication may be heightened in patients with impaired renal function. Given that elderly patients often exhibit reduced renal function that may not be apparent through routine screening tests, such as blood urea nitrogen (BUN) or serum creatinine, a creatinine clearance determination is recommended for a more accurate assessment of renal function.

Due to the potential for impaired renal function, dose reduction of tobramycin is necessary for elderly patients. Close monitoring of renal function during treatment with aminoglycosides is particularly critical in this population to mitigate the risk of adverse effects.

Pregnancy

Aminoglycosides have the potential to cause fetal harm when administered to pregnant patients. These antibiotics are known to cross the placenta, and there have been multiple reports linking the use of streptomycin during pregnancy to cases of total irreversible bilateral congenital deafness in offspring. While serious side effects to the mother, fetus, or newborn have not been reported with the use of other aminoglycosides, caution is warranted.

If tobramycin is prescribed during pregnancy, or if a patient becomes pregnant while on tobramycin therapy, it is essential to inform her of the potential risks to the fetus. Healthcare professionals should weigh the benefits and risks of treatment in pregnant patients and consider alternative therapies when appropriate.

Lactation

Tobramycin should be used with caution in lactating mothers, particularly those with premature and neonatal infants, due to the renal immaturity of these infants and the potential for prolonged serum half-life of the drug. While there is no specific data on the excretion of tobramycin in human breast milk, caution is advised given the known risks associated with aminoglycosides.

Aminoglycosides, including tobramycin, have been associated with fetal harm when administered to pregnant women, and tobramycin crosses the placenta. There have been reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. However, serious side effects to the mother, fetus, or newborn have not been reported in the treatment of pregnant women with other aminoglycosides.

If tobramycin is used during pregnancy or if a lactating mother becomes pregnant while taking tobramycin, she should be informed of the potential hazards to the fetus. It is recommended that healthcare providers carefully consider the risks and benefits of tobramycin use in lactating mothers and their breastfed infants.

Renal Impairment

Patients with renal impairment should be closely monitored when treated with Tobramycin for Injection, USP, and other aminoglycosides due to the potential for nephrotoxicity. Nephrotoxicity is particularly concerning in patients with preexisting renal damage and in those with normal renal function who receive aminoglycosides for extended periods or at higher than recommended doses.

Renal and eighth-nerve function must be monitored closely in patients with known or suspected renal impairment, as well as in those whose renal function is initially normal but who exhibit signs of renal dysfunction during therapy. It is essential to periodically monitor peak and trough serum concentrations of aminoglycosides to ensure adequate therapeutic levels while avoiding potentially toxic concentrations. Prolonged serum concentrations above 12 mcg/mL should be avoided, and rising trough levels above 2 mcg/mL may indicate tissue accumulation.

Urine analysis should be conducted to assess for decreased specific gravity and increased excretion of protein, cells, and casts. Additionally, blood urea nitrogen, serum creatinine, and creatinine clearance should be measured periodically. Any evidence of renal function impairment necessitates discontinuation of the drug or dosage adjustment.

Tobramycin should be used with caution in premature and neonatal infants due to renal immaturity, which can prolong the serum half-life of the drug. The concurrent and sequential use of other neurotoxic and/or nephrotoxic antibiotics should be avoided. Advanced age and dehydration may further increase the risk of nephrotoxicity in patients. Furthermore, aminoglycosides should not be administered concurrently with potent diuretics, as these can enhance aminoglycoside toxicity by altering serum and tissue concentrations of the antibiotic.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to this medication. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the prescribing information.

Overdosage

The severity of signs and symptoms following a tobramycin overdose is influenced by several factors, including the administered dose, the patient's renal function, hydration status, age, and the presence of concurrent medications that may have similar toxicities.

Toxicity is particularly concerning in adults who receive doses exceeding 5 mg/kg/day and in children who are given more than 7.5 mg/kg/day. Nephrotoxicity is more likely to occur if trough blood concentrations do not decrease below 2 mcg/mL. Additionally, patients with underlying conditions such as myasthenia gravis or Parkinson’s disease may be at increased risk for neuromuscular blockade or respiratory paralysis following aminoglycoside administration.

In the event of suspected overdosage, it is imperative to contact the Regional Poison Control Center for the most current treatment recommendations. The initial management of a tobramycin overdose should focus on establishing a patent airway and ensuring adequate oxygenation and ventilation.

For patients with normal renal function who have experienced an overdose, it is essential to maintain adequate hydration to achieve a urine output of 3 to 5 mL/kg/hr. Continuous monitoring of fluid balance, creatinine clearance, and tobramycin plasma levels is necessary until the serum concentration falls below the critical threshold of 2 mcg/mL.

Patients exhibiting an elimination half-life greater than 2 hours or those with abnormal renal function may require hemodialysis to facilitate the removal of the drug from the system.

Nonclinical Toxicology

Aminoglycosides have been associated with teratogenic effects, particularly when administered to pregnant women. These antibiotics are capable of crossing the placenta, and there have been multiple reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. While serious side effects to the mother, fetus, or newborn have not been reported with other aminoglycosides, caution is advised. If tobramycin is used during pregnancy or if a patient becomes pregnant while on tobramycin, it is essential to inform her of the potential risks to the fetus.

Non-teratogenic effects of aminoglycosides include adverse impacts on both the vestibular and auditory branches of the eighth cranial nerve. These effects are particularly noted in patients receiving high doses or prolonged therapy, those with prior exposure to ototoxic agents, and individuals experiencing dehydration. Symptoms may encompass dizziness, vertigo, tinnitus, roaring in the ears, and hearing loss, with the latter typically being irreversible and initially presenting as a reduction in high-tone acuity. Additionally, changes in renal function have been observed, indicated by elevated blood urea nitrogen (BUN), non-protein nitrogen (NPN), and serum creatinine levels, as well as oliguria, cylindruria, and increased proteinuria. These renal effects are especially pronounced in patients with a history of renal impairment who are treated for extended periods or at higher doses than recommended, although adverse renal effects can also occur in patients with initially normal renal function.

Clinical studies and experimental animal studies have been conducted to evaluate the nephrotoxic potential of tobramycin in comparison to gentamicin. In certain clinical and animal studies, tobramycin was found to cause nephrotoxicity significantly less frequently than gentamicin. However, other clinical studies indicated no significant difference in the incidence of nephrotoxicity between the two antibiotics.

No specific details regarding animal pharmacology and toxicology are provided in the available data.

Postmarketing Experience

Serious allergic reactions, including anaphylaxis, and dermatologic reactions such as exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson Syndrome have been reported rarely in patients undergoing tobramycin therapy. Although these events are infrequent, fatalities have been documented.

Clostridium difficile-associated diarrhea (CDAD) has been observed with the use of nearly all antibacterial agents, including tobramycin. The severity of CDAD can range from mild diarrhea to fatal colitis, necessitating consideration in all patients presenting with diarrhea following antibiotic use. It is important to obtain a careful medical history, as CDAD has been reported to occur over two months after the administration of antibacterial agents.

Adverse effects on both the vestibular and auditory branches of the eighth cranial nerve have been noted, particularly in patients receiving high doses or prolonged therapy, those with prior exposure to ototoxic agents, and in cases of dehydration. Symptoms may include dizziness, vertigo, tinnitus, roaring in the ears, and hearing loss, with the latter typically being irreversible and initially manifesting as diminished high-tone acuity.

Changes in renal function, indicated by rising blood urea nitrogen (BUN), non-protein nitrogen (NPN), and serum creatinine levels, as well as oliguria, cylindruria, and increased proteinuria, have been reported. These changes are especially prevalent in patients with a history of renal impairment who are treated for extended periods or with higher than recommended doses. Adverse renal effects may also occur in patients with initially normal renal function.

Other adverse reactions potentially related to tobramycin sulfate include anemia, granulocytopenia, thrombocytopenia, fever, rash, exfoliative dermatitis, itching, urticaria, nausea, vomiting, diarrhea, headache, lethargy, pain at the injection site, mental confusion, and disorientation.

Laboratory abnormalities possibly associated with tobramycin include increased serum transaminases (SGOT, SGPT), elevated serum lactate dehydrogenase (LDH) and bilirubin levels, decreased serum calcium, magnesium, sodium, and potassium levels, as well as leukopenia, leukocytosis, and eosinophilia.

Patient Counseling

Patients should be counseled that antibacterial drugs, including tobramycin, are indicated solely for the treatment of bacterial infections and are ineffective against viral infections, such as the common cold. It is important for patients to understand that even if they begin to feel better early in the course of therapy, they must take the medication exactly as directed.

Healthcare providers should emphasize that skipping doses or failing to complete the full course of therapy can lead to decreased effectiveness of the treatment and may increase the risk of bacteria developing resistance, rendering tobramycin and other antibacterial drugs ineffective in the future.

Patients should also be informed that diarrhea is a common side effect associated with antibiotic use, typically resolving upon discontinuation of the medication. However, they should be made aware that in some cases, they may experience watery and bloody stools, with or without accompanying stomach cramps and fever, even up to two months after completing the antibiotic regimen. If such symptoms occur, patients should be advised to contact their physician promptly.

Storage and Handling

The product is supplied in accordance with the following specifications: it is available in various package configurations, with specific NDC numbers provided upon request.

For optimal storage conditions, the product should be maintained at a temperature range of 20° to 25°C (68° to 77°F), in compliance with USP Controlled Room Temperature guidelines. It is essential to ensure that the product is stored in a suitable container to protect its integrity and efficacy. Special handling requirements should be observed to maintain the quality of the product throughout its shelf life.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Tobramycin as submitted by Slate Run Pharmaceuticals, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)