AHFS Class:

• Aminoglycosides 8:12.02

Generic Name(s):

• Tobramycin Sulfate

Associated Monographs

• Aminoglycosides General Statement

Tobramycin is an aminoglycoside antibiotic.5,6

Bone and Joint Infections

Tobramycin is used parenterally for the treatment of serious bone and joint infections caused by susceptible Enterobacter , Escherichia coli , Klebsiella , Proteus , Pseudomonas aeruginosa , or Staphylococcus aureus .1,2,3,250,251,252,253,254 Tobramycin usually is used as an adjunct to other appropriate anti-infectives.5,6,17,38

Intra-abdominal Infections

Tobramycin is used parenterally for the treatment of serious intra-abdominal infections (including peritonitis) caused by susceptible Enterobacter , E. coli , or Klebsiella .1,2,3,250,251,252,253,254 Tobramycin usually is used as an adjunct to other appropriate anti-infectives (e.g., clindamycin, metronidazole, piperacillin and tazobactam, ampicillin and sulbactam)5,6,17,38

The Infectious Diseases Society of America (IDSA) states that patients with community-acquired intra-abdominal infections of mild to moderate severity may receive initial treatment with an empiric regimen of the fixed combination of ampicillin and sulbactam, cefazolin or cefuroxime in conjunction with metronidazole, the fixed combination of ticarcillin and clavulanate, ertapenem monotherapy, or a fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin) in conjunction with metronidazole.38 Patients who are immunosuppressed or have more severe community-acquired intra-abdominal infections should receive a regimen that has a broader spectrum of activity such as meropenem monotherapy; imipenem and cilastatin monotherapy; a third or fourth generation cephalosporin (cefotaxime, ceftriaxone, ceftazidime, cefepime) in conjunction with metronidazole; ciprofloxacin in conjunction with metronidazole; the fixed combination of piperacillin and tazobactam; or aztreonam in conjunction with metronidazole.38

The IDSA states that aminoglycosides are not recommended for routine use in community-acquired intra-abdominal infections; however, an aminoglycoside may be included in empiric regimens for the treatment of nosocomial intra-abdominal infections, depending on local patterns of in vitro susceptibility of nosocomial isolates.38 IDSA states that aminoglycosides generally should be reserved for when β-lactams and fluoroquinolones cannot be used.38 Other clinicians suggest that severely ill patients and those with prolonged hospitalization should receive an initial regimen that includes an antipseudomonal agent such as an antipseudomonal penicillin (ticarcillin and clavulanate, piperacillin and tazobactam), a carbapenem (imipenem or meropenem), ceftazidime, or cefepime used in conjunction with metronidazole.17 These clinicians state that an aminoglycoside also could be included in the empiric regimen.17

Meningitis and Other CNS Infections

Tobramycin is used parenterally for the treatment of CNS infections (meningitis) caused by susceptible bacteria.1,2,3,36,37,250,251,252,253,254 Like other aminoglycosides, tobramycin should not be used alone for the treatment of meningitis.36,37 To provide higher tobramycin CSF concentrations for the treatment of meningitis, tobramycin has been given intrathecally† or intraventricularly† concomitantly with IM or IV administration.6,9,19 Although concomitant parenteral and intrathecal or intraventricular therapy may result in higher anti-infective CSF concentrations, such therapy also may be associated with increased mortality in neonates.46

Respiratory Tract Infections

Tobramycin is used parenterally for the treatment of serious respiratory tract infections caused by susceptible S. aureus , Enterobacter , E. coli , Klebsiella , Serratia , or Ps. aeruginosa .1,2,3,5,6,39,42,43,250,251,252,253,254

Parenteral tobramycin is used in conjunction with other appropriate anti-infectives for the treatment of community-acquired pneumonia (CAP) or nosocomial pneumonia and may be included in initial empiric combination regimens in severely ill patients and/or when multidrug-resistant gram-negative bacteria may be involved.39,42,43 For empiric treatment of nosocomial pneumonia, tobramycin is used as an adjunct to an appropriate β-lactam (e.g., ceftriaxone, cefotaxime, cefepime, piperacillin and tazobactam, ticarcillin and clavulanate) or carbapenem (e.g., imipenem, meropenem);5,6,17,39,42 if oxacillin-resistant (methicillin-resistant) staphylococci may be involved, the initial empiric regimen also should include linezolid or vancomycin.39

Cystic Fibrosis Patients

Tobramycin is used parenterally for management of acute exacerbations of pulmonary Ps. aeruginosa infections in adults and children with cystic fibrosis.6,25,27,28,29,30,31,32,248 Parenteral tobramycin usually is used in conjunction with an antipseudomonal β-lactam (e.g., ceftazidime) or carbapenem (e.g., imipenem, meropenem) in these patients.27,28,29,30,248 There is evidence from clinical studies that a once-daily tobramycin regimen is at least as effective as a 3-times daily tobramycin regimen for management of exacerbations of pulmonary Ps. aeruginosa infections in cystic fibrosis patients.27,28,29,47

Oral Inhalation

Commercially available tobramycin solution for oral inhalation is administered via nebulization for the management of bronchopulmonary Ps. aeruginosa infections in cystic fibrosis patients 6 years of age or older.241,243,244,245,248 There is evidence that a regimen of tobramycin oral inhalation is more effective than placebo for early treatment of Ps. aeruginosa infections in cystic fibrosis patients and may improve lung function and reduce the frequency of exacerbations.33,34 Use of tobramycin oral inhalation solution can be considered for suppressive therapy in cystic fibrosis patients colonized with Ps. aeruginosa if they are 6 years of age or older and have a forced expiratory volume in 1 second (FEV₁) that is 25-75% of the predicted value.241,245 Safety and efficacy of the solution for oral inhalation have not been established in pediatric patients younger than 6 years of age, in patients with FEV₁ less than 25% or exceeding 75% of the predicted value, or in patients colonized with Burkholderia cepacia (formerly Ps. cepacia ).241

Results of randomized, double-blind, placebo-controlled studies in cystic fibrosis patients 6 years of age or older with Ps. aeruginosa indicate that tobramycin solution for oral inhalation given in conjunction with standard therapy for cystic fibrosis can improve lung function, decrease the density of P. aeruginosa in expectorated sputum, and reduce the need for hospitalization and parenteral therapy with antipseudomonal anti-infectives.241,243,244 At baseline, the FEV₁ in all study patients was 25-75% of the predicted value.241,243 Patients were randomized to receive 3 cycles of tobramycin solution for oral inhalation (300 mg twice daily given using a hand-held reusable nebulizer [PARI LC PLUS^®] connected to a Pulmo-Aide^® compressor) or placebo (sodium chloride solution flavored with 1.25 mg of quinine sulfate to mimic the taste of the active treatment); each cycle consisted of 28 days of administration of drug or placebo followed by 28 days without administration of drug or placebo.241,242,243 Besides tobramycin solution for oral inhalation or placebo, patients received standard therapy recommended for patients with cystic fibrosis, such as oral and parenteral anti-infectives active against Pseudomonas , β₂-adrenergic agonists, cromolyn sodium, orally inhaled corticosteroids, and techniques for clearance of the airway;241,242 about 77% of patients also received concurrent therapy with dornase alfa.241

Tobramycin solution for inhalation was superior to placebo based on the primary end point of lung function at 20 weeks (at the end of the third cycle), measured as FEV₁ and expressed as the percentage of the predicted value.243 At 20 weeks, the change in lung function in patients who received the drug was an average 10% increase in FEV₁ over baseline compared with an average 2% decrease in FEV₁ in those who received placebo.243

Tobramycin solution for oral inhalation also was superior to placebo based on the primary end point of the density of P. aeruginosa in sputum at 20 weeks, calculated as the log₁₀ value for the sum of colony forming units (CFUs) per g of sputum.243 At 20 weeks, there was an average decrease of 0.8 log₁₀ CFU per g of sputum from baseline in patients who received the drug compared with an average increase of 0.3 log₁₀ CFU per g of sputum in those who received placebo.243 The greatest reductions in the density of P. aeruginosa in sputum in patients who received the drug were observed during the first 2 cycles of administration.243 At 4 weeks (after the initial 28-day treatment regimen), there was an average reduction of 1.9 log₁₀ CFU per g of sputum in patients treated with the drug;243 at 12 weeks (after the second 28-day treatment regimen), there was an average reduction of 1.8 log₁₀ CFU per g of sputum in those treated with the drug.243 During the periods when patients were alternated off of administration of tobramycin solution for oral inhalation, the density of P. aeruginosa in sputum in patients treated with the drug approached values calculated at the start of the first cycle of administration of the drug.243

The average duration of hospitalization was 5.1 days in patients who received tobramycin solution for oral inhalation and 8.1 days in those who received placebo.241,242,243 Parenteral anti-infectives active against Pseudomonas were administered for an average of 9.6 days in patients who received tobramycin solution for oral inhalation and 14.1 days in patients who received placebo.241,242,243 One or more courses of parenteral anti-infectives active against Pseudomonas were administered to 39% of patients who received tobramycin solution for oral inhalation and 52% of patients who received placebo.243

In vitro susceptibility testing of Ps. aeruginosa isolates obtained from patients in these clinical studies indicates that susceptibility of most isolates was not adversely affected by 3 treatment cycles of tobramycin oral inhalation therapy.241,244 However, Ps. aeruginosa isolates with increased tobramycin MICs were reported in some patients who received the drug.241,244 The relationship between clinical outcome and in vitro susceptibility of Ps. aeruginosa to tobramycin is unclear.241 There was no evidence of improvement in FEV₁ or reduction in the bacterial density in sputum in a limited number of patients who had clinical isolates of P. aeruginosa that were resistant to tobramycin (MICs of 128 mcg/mL or greater) at study entry.241

Septicemia

Tobramycin is used parenterally for the treatment of septicemia caused by susceptible E. coli , Klebsiella , or Ps. aeruginosa .1,2,3,250,251,252,253,254

Tobramycin is used as an adjunct to an appropriate β-lactam (e.g., ceftriaxone, cefotaxime, cefepime, piperacillin and tazobactam, ticarcillin and clavulanate) or carbapenem (e.g., imipenem, meropenem) for empiric treatment of life-threatening septicemia.17

Skin and Skin Structure Infections

Tobramycin is used parenterally for the treatment of serious skin and skin structure infections caused by susceptible S. aureus , Enterobacter , E. coli , Klebsiella , Proteus , or Ps. aeruginosa .1,2,3,250,251,252,253,254 Tobramycin is used as an adjunct to other appropriate anti-infectives.17

Urinary Tract Infections

Tobramycin is used parenterally for the treatment of serious complicated and recurrent UTIs caused by susceptible S. aureus , Citrobacter , Enterobacter , E. coli , Klebsiella , Proteus , Providencia , Serratia , or Ps. aeruginosa .1,2,3,250,251,252,253,254 Tobramycin is used as an adjunct to other appropriate anti-infectives.17

Tobramycin is not indicated for uncomplicated initial episodes of urinary tract infections unless the causative organism is resistant to other less-toxic alternatives.1,2,3,250,251,252,253,254

Empiric Therapy in Febrile Neutropenic Patients

Tobramycin is used parenterally for empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients†.6,18 Tobramycin is used in conjunction with an appropriate antipseudomonal cephalosporin (e.g., ceftazidime, ceftriaxone, cefepime), extended-spectrum penicillin (e.g., piperacillin and tazobactam, ticarcillin and clavulanate), or carbapenem (e.g., imipenem, meropenem).18

Published protocols for the treatment of infections in febrile neutropenic patients should be consulted for specific recommendations regarding selection of the initial empiric regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients.18 Consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients also is advised.18

Reconstitution and Administration

Tobramycin sulfate is administered by IM injection or IV infusion.1,2,3,250,251,252,253,254

Commercially available tobramycin solution for oral inhalation is administered via nebulization.241,245 The oral inhalation solution should not be administered IV, IM, subcutaneously, or intrathecally.241

Tobramycin sulfate has been administered intrathecally† or intraventricularly† in conjunction with IM or IV administration of the drug.6,9,19

Patients should be well hydrated prior to and during tobramycin therapy since dehydration increases the risk of toxicity.1,2,3,250,251,252,253,254

Renal function should be assessed prior to and periodically during amikacin therapy.1,2,3,250,251,252,253,254 Patients should be under close clinical observation because of the risk of ototoxicity and nephrotoxicity.1,2,3,250,251,252,253,254 (See Cautions in the Aminoglycosides General Statement 8:12.02.)

Parenteral Administration

The commercially available pharmacy bulk packages of tobramycin sulfate powder254 or solution2,253 should be used for preparing solutions for IV infusion and should not be used to prepare solutions for IM injection. Commercially available premixed tobramycin sulfate solutions in 0.9% sodium chloride injection are for IV infusion only.252

Tobramycin sulfate solutions should be inspected visually for particulate matter and discoloration before use.1,2,3,250,251,252,253,254

IM Injection

For IM injection, the appropriate dose of tobramycin sulfate should be withdrawn from multiple-dose vials containing 10 or 40 mg of tobramycin per mL.1,3,251

Solutions prepared from or commercially available in pharmacy bulk packages253,254 or ADD-Vantage^® vials250 and the commercially available premixed solutions of tobramycin sulfate in 0.9% sodium chloride injection252 should not be administered IM.

IV Infusion

IV infusions of tobramycin sulfate should be given over 20-60 minutes.1,2,3,6,251,253 Infusion periods of less than 20 minutes should not be used because this infusion rate may result in peak serum tobramycin concentrations exceeding 12 mcg/mL.1,2,3,251,253

For adults, IV infusions of tobramycin sulfate can be prepared from multiple-dose vials of tobramycin sulfate solution containing 10 or 40 mg of tobramycin per mL by diluting the calculated tobramycin dose in 50-100 mL of 0.9% sodium chloride injection or 5% dextrose injection.1,3,251 For pediatric patients, the volume of diluent should be proportionately less than for adults.1,3,251

Alternatively, IV infusions can be prepared using the single-dose ADD-Vantage^® vials of tobramycin sulfate.250 The contents of these vials should be diluted according to the manufacturer's directions using only 50 or 100 mL ADD-Vantage flexible diluent containers and should be used within 24 hours after dilution.250 The ADD-Vantage vials are not intended for multiple-dose or IM use and should be used only when 80-mg doses of the drug are required.250

IV infusions also can be prepared using the commercially available pharmacy bulk package of tobramycin sulfate powder254 or the commercially available pharmacy bulk package of tobramycin sulfate solution.253 The sterile powder is reconstituted by adding 30 mL of sterile water for injection to a vial labeled as containing 1.2 g of tobramycin (pharmacy bulk package) to provide a solution containing 40 mg of tobramycin per mL.254 This solution should be refrigerated and used within 96 hours; if stored at room temperature, the solution must be used within 24 hours.254 If the pharmacy bulk package of tobramycin sulfate solution containing 40 mg of tobramycin per mL is used, IV infusion solutions should be prepared according to the manufacturer's directions.253

Alternatively, commercially available premixed tobramycin sulfate in 0.9% sodium chloride injection containing 0.8 or 1.2 mg of tobramycin per mL can be used.252 These premixed solutions should not be diluted or buffered prior to administration and should be given only by IV infusion.252 These solutions are provided in single-dose flexible containers; additives should not be introduced into the injection container and the containers should not be used in series.252 However, if the dose needed is greater or less than that in the container, the manufacturer states that the appropriate amount of tobramycin sulfate solution can be introduced into or removed from the container.252 The manufacturer's instructions should be consulted for proper use of commercially available premixed tobramycin sulfate in 0.9% sodium chloride injection.252

Tobramycin sulfate should not be admixed with other drugs or infused simultaneously through the same tubing with other drugs.1,2,3,7,250,251,252,253,254 If a β-lactam anti-infective (e.g., cephalosporin, penicillin) is administered concomitantly with tobramycin, the drugs should not be admixed and should be administered separately.1,2,3,7,250,251,252,253,254

Oral Inhalation

Commercially available tobramycin solution for oral inhalation is administered via nebulization.241,245

Tobramycin solution for oral inhalation should be administered using a PARI LC PLUS^® nebulizer (a hand-held, reusable nebulizer) connected to a DeVilbiss Pulmo-Aide^® compressor.241,245

Prior to administration of tobramycin solution for oral inhalation, the manufacturers' information should be reviewed to ensure thorough familiarity with the use and maintenance of the nebulizer and compressor.241 Tobramycin solution for oral inhalation should be administered while the patient is sitting or standing upright and breathing normally through the mouthpiece of the nebulizer.241 Patients may find that breathing through the mouth may be aided by using nose clips.241 A nebulizer treatment period of about 15 minutes usually is required to completely administer the usual dose of tobramycin solution for oral inhalation.241

Tobramycin solution for oral inhalation should not be diluted prior to administration and should not be admixed with other drugs (e.g., dornase alfa) in the nebulizer. 241,245 Patients usually receive tobramycin solution for oral inhalation in conjunction with various other standard therapies recommended for patients with cystic fibrosis.241,245 The manufacturer and some clinicians recommend that patients should receive other therapies prior to doses of tobramycin solution for oral inhalation.241,245 Based on protocols used in clinical studies evaluating tobramycin solution for oral inhalation, it has been recommended that patients receive doses of inhaled bronchodilators first, then dornase alfa administered by oral inhalation, then chest physiotherapy, then tobramycin solution administered by oral inhalation.245 If orally inhaled corticosteroids, cromolyn sodium, or nedocromil sodium also are indicted in the patient, these drugs should be administered following the dose of tobramycin solution for oral inhalation.245

Dosage

Parenteral Dosage

Dosage of tobramycin sulfate and tobramycin are expressed in terms of tobramycin.1,2,3,250,251,252,253,254 IM and IV dosage is identical.1,2,3,250,251,252,253,254

Like other aminoglycosides, dosage of tobramycin should be individualized taking into consideration the patient's pretreatment body weight, renal status, severity of the infection, and susceptibility of the causative organism.1,2,3,5,6,8,200,201,202,203,204,250,251,252,253,254 The manufacturers state that dosage in obese patients may be calculated using the patient's estimated lean body weight plus 40% of the excess weight.1,2,3,250,251,252,253,254 Many clinicians recommend that tobramycin dosage be determined using appropriate pharmacokinetic methods for calculating dosage requirements and patient-specific pharmacokinetic parameters (e.g., elimination rate constant, volume of distribution) derived from serum concentration-time data.8,200,201,202,203,204

Whenever possible, especially in patients with life-threatening infections, suspected toxicity or nonresponse to treatment, decreased or varying renal function, and/or when increased aminoglycoside clearance (e.g., patients with cystic fibrosis, burns) or prolonged therapy is likely, peak and trough serum concentrations of tobramycin should be determined periodically and dosage should be adjusted to maintain desired serum concentrations.8,221,222,223,224,225,226,227,228,229 (See Dosage and Administration: Dosage, in the Aminoglycosides General Statement 8:12.02.) A causal relationship between maintenance of certain peak or trough serum concentrations or other pharmacodynamic endpoints and clinical response or toxicity has not been established to date for tobramycin dosing regimens.205,206,218,219,220 However, for tobramycin administered in conventional dosage regimens (i.e., multiple daily doses), peak serum concentrations of 4-10 mcg/mL and trough concentrations that do not exceed 1-2 mcg/mL have been suggested.5,6,8 Tobramycin serum concentrations greater than 10-12 mcg/mL may be associated with toxicity.8

Parenteral aminoglycosides historically have been administered in dosage regimens that include multiple daily doses,5,6,216 and current prescribing information for IM or IV tobramycin only includes dosage regimens that involve multiple daily doses (usually 3 or 4 doses daily).1,2,3,250,251,252,253,254 However, there is evidence that once-daily† (single-daily) aminoglycoside dosage regimens are at least as effective as, may provide superior pharmacokinetics, and may be less toxic than conventional dosage regimens employing multiple daily doses of the drugs.25,27,28,29,35,47,48,204,205,206,207,208,209,210,211,212,213,214,215,216,217,229,230,231,232,233,234,235,236,237,238,239,240 Once-daily parenteral aminoglycoside regimens should not be used in all patients.5,52 Additional controlled trials in children, patients with renal dysfunction, cystic fibrosis patients, and other appropriate patient groups are needed to fully define optimal use of once-daily aminoglycoside dosing regimens.26,204,205,207,208,209,210,216,230,233,236,239,240,49,50,51,52,53 In addition, the most appropriate methods for optimizing dosage selection for once-daily regimens and monitoring serum aminoglycoside concentrations in patients receiving such regimens have not been clearly established.35,49,51,52,53,54,55,56,57,58,237,239 (See Dosage and Administration: Dosage, in the Aminoglycosides General Statement 8:12.02.)

The usual duration of parenteral tobramycin therapy is 7-10 days.1,2,3,250,251,252,253,254 Although a longer course of treatment may be necessary in difficult and complicated infections, renal, auditory, and vestibular function should be closely monitored because neurotoxicity is more likely to occur when treatment is extended longer than 10 days.250,251,252,253,254

General Adult Dosage

The usual IM or IV dosage of tobramycin recommended by the manufacturers for adults with normal renal function is 3 mg/kg daily given in 3 equally divided doses at 8-hour intervals.1,2,3,250,251,252,253,254 The manufacturers state that adults with life-threatening infections may receive up to 5 mg/kg daily given IM or IV in 3 or 4 equally divided doses, but dosage should be reduced to 3 mg/kg daily as soon as clinically indicated.1,2,3,250,251,252,253,254

The manufacturers state that, to prevent increased toxicity and excessive tobramycin concentrations, dosage should not exceed 5 mg/kg daily unless serum concentrations of the drug are monitored.1,2,3,250,251,252,253,254

Adults have received parenteral tobramycin in a once-daily† regimen of 4-5 mg/kg once daily.6 A parenteral dosage of 7 mg/kg once daily also has been used.35

Meningitis

If parenteral tobramycin is used for the treatment of meningitis, some clinicians recommend that adults receive 5 mg/kg daily given in 3 divided doses.37

Tobramycin doses of 5-20 mg have been administered intrathecally† or intraventricularly† once daily in adults.6,19,37

Cystic Fibrosis Patients

When parenteral tobramycin sulfate is used in patients with cystic fibrosis, altered pharmacokinetics may result in increased clearance and reduced serum aminoglycoside concentrations.1,2,3,6,250,251,252,253,254 Therefore, monitoring tobramycin serum concentrations during treatment is especially important as a basis for determining appropriate dosage.1,2,3,6,250,251,252,253,254

If parenteral tobramycin is used in patients with cystic fibrosis, an initial regimen of 10-15 mg/kg daily given in 3 or 4 equally divided doses usually is used and subsequent dosage adjusted based on serum tobramycin concentrations.1,2,3,27,28,29,31,32,250,251,252,253,254 Alternatively, a once-daily† parenteral tobramycin regimen of 7-15 mg/kg given once daily by IV infusion has been used in adults with cystic fibrosis.25,27,28,29,45 In some patients, this dosage was used initially and subsequent dosage adjusted based on serum tobramycin concentrations.45 Tobramycin usually is continued for 14 days in these patients.27,28,30

For oral inhalation dosage in patients with cystic fibrosis, see Dosage: Oral Inhalation Dosage.

General Pediatric Dosage

The manufacturers recommend that pediatric patients older than 1 week of age receive IM or IV tobramycin in a dosage of 6-7.5 mg/kg daily given in 3 or 4 equally divided doses (2-2.5 mg/kg every 8 hours or 1.5-1.89 mg/kg every 6 hours).1,2,3,250,251,252,253,254 The manufacturers state that dosage in neonates 1 week of age or younger should not exceed 4 mg/kg daily given in equally divided doses at 12-hour intervals.1,2,3,250,251,252,253,254

The American Academy of Pediatrics (AAP) recommends that neonates younger than 1 week of age receive IM or IV tobramycin in a dosage of 2.5 mg/kg every 18-24 hours if they weigh less than 1.2 kg or 2.5 mg/kg every 12 hours if they weigh 1.2 kg or more.249 For neonates 1-4 weeks of age, the AAP recommends a dosage of 2.5 mg/kg every 18-24 hours for those weighing less than 1.2 kg, 2.5 mg/kg every 8 or 12 hours for those weighing 1.2-2 kg, or 2.5 mg/kg every 8 hours for those weighing more than 2 kg.249

The AAP recommends that pediatric patients beyond the newborn period receive IM or IV tobramycin in a dosage of 3-7.5 mg/kg daily given in 3 equally divided doses for the treatment of severe infections.249 The AAP states that tobramycin is inappropriate for the treatment of mild to moderate infections.249

The AAP states that a once-daily† IM or IV regimen (5-6 mg/kg once every 24 hours) is investigational in children.249 A once-daily regimen of 7-15 mg/kg given by IV infusion once daily has been used in children with cystic fibrosis.25,28,45,47,48 In some patients, this dosage was used initially and subsequent dosage adjusted based on serum tobramycin concentrations.45

If parenteral tobramycin is used for the treatment of meningitis, some clinicians recommend that neonates 7 days of age or younger receive 4 or 5 mg/kg daily given in 2 divided doses and that older neonates and children receive 6 or 7.5 mg/kg daily given in 3 divided doses.36,37 Smaller doses and longer intervals between doses may be indicated in neonates weighing less than 2 kg.36,37

Oral Inhalation Dosage

Cystic Fibrosis Patients

Dosage of commercially available tobramycin solution for oral inhalation is the same for all patients regardless of age or body weight.241,245 The drug is given in an intermittent dosage regimen that involves alternating 28-day periods when the drug is given with 28-day periods when the drug is not given.241,245

The dosage of tobramycin solution for oral inhalation recommended for the management of acute exacerbations of pulmonary Ps. aeruginosa infections in adults and children 6 years of age or older with cystic fibrosis is 300 mg twice daily for 28 days.241,245 Doses should be administered using the recommended nebulizer system every 12 hours (or at intervals as close to every 12 hours as possible); doses should not be administered at intervals less than 6 hours.241 Each 28-day regimen of tobramycin solution for oral inhalation should be followed by a 28-day period when the drug is not administered.241,245

Dosage in Renal Impairment

In patients with impaired renal function, doses and/or frequency of administration of tobramycin must be modified in response to serum concentrations of the drug and the degree of renal impairment.1,2,3,6,8,250,251,252,253,254 There are various methods to determine dosage and a wide variation in dosage recommendations for these patients.1,2,3,6,8,250,251,252,253,254 However, even when one of these methods is used, peak and trough serum concentrations of the drug should be monitored, especially in patients with changing renal function.1,2,3,6,8,250,251,252,253,254

The manufacturers recommend an initial loading dose of 1 mg/kg with subsequent dosage adjusted either by using reduced doses at 8-hour intervals or using usual doses at prolonged intervals.1,2,3,250,251,252,253,254 If serum concentrations of tobramycin are unavailable, dosage adjustments in patients with renal impairment may be guided by creatinine clearance or serum creatinine concentrations because these values correlate with the half-life of tobramycin.1,2,3,250,251,252,253,254 The manufacturers' information should be consulted for a nomogram based on creatinine clearance or serum creatinine concentrations that can be used to determine the amount of reduced dose that can be given at the usual dosing intervals.1,2,3,250,251,252,253,254 Alternatively, if creatinine clearance is not available and the patient's condition is stable, the manufacturers state that the usual dosage of the drug can be given at a reduced dosage frequency that is calculated by multiplying the patient's steady-state serum creatinine (in mg/dL) by 6.1,2,3,250,251,252,253,254 Many clinicians recommend the dosing method of Sarubbi and Hull, which is based on corrected creatinine clearance. (See Dosage and Administration: Dosage in Renal Impairment, in the Aminoglycosides General Statement 8:12.02.)

In adults with renal failure undergoing hemodialysis, some clinicians recommend supplemental doses of 50-75% of the initial loading dose at the end of each dialysis period.8 Serum tobramycin concentrations should be monitored in dialysis patients and dosage adjusted as needed to maintain desired serum concentrations.8,24

Pharmacokinetics

The pharmacokinetics of tobramycin are similar to those of the other aminoglycosides.5,6 In all studies described in the Pharmacokinetics section, tobramycin was administered parenterally as the sulfate salt; dosages and concentrations of the drug are expressed in terms of tobramycin.

Absorption

Tobramycin is poorly absorbed from the GI tract.5

Tobramycin is rapidly absorbed following IM administration.5 Following IM administration of a single dose of tobramycin of 1 mg/kg in adults with normal renal function, peak serum tobramycin concentrations average 4-6 mcg/mL and are attained within 30-90 minutes; at 6-8 hours after the dose, serum concentrations are 1 mcg/mL or less.13,15,22 When the same dose is administered by IV infusion over 30-60 minutes, similar plasma concentrations of the drug are attained.15

In one study in neonates receiving IM tobramycin in a dosage of 2 mg/kg every 12 hours, peak serum concentrations of the drug were attained 0.5-1 hour after a dose and ranged from 4.9-5.2 mcg/mL after the first dose and 4.5-5.1 mcg/mL after 10-16 doses.12 In neonates 2-7 days of age receiving tobramycin in a dosage of 2.5 mg/kg by IV infusion every 12 hours, steady-state peak serum concentrations ranged from 3.5-9.9 mcg/mL and trough serum concentrations ranged from 1.1-3.6 mcg/mL in those weighing less than 2 kg.20 In those weighing 2 kg or more, peak serum concentrations ranged from 5-10.2 mcg/mL and trough serum concentrations ranged from 0.7-2 mcg/mL.20

Bioavailability of tobramycin administered by oral inhalation via a nebulizer may be variable because of individual differences in nebulizer performance and airway pathology.241 Following oral inhalation via nebulization, tobramycin remains concentrated principally in the airways; the drug does not readily cross epithelial membranes.241 Tobramycin sputum concentrations are highly variable following oral inhalation, but the drug does not appear to accumulate in sputum following multiple doses.241 Following an initial 300-mg dose of commercially available tobramycin solution for oral inhalation given via a nebulizer, sputum concentrations of the drug at 10 minutes averaged 1237 mcg/g (range: 35-7414 mcg/g).241 After 20 weeks of intermittent therapy (300-mg twice daily for 28 days followed by 28 days without the drug), sputum concentrations 10 minutes after administration averaged 1154 mcg/g (range: 39-8085 mcg/g) and sputum concentrations 2 hours after administration were approximately 14% of those obtained 10 minutes after administration.241 Following a single 300-mg dose of the commercially available tobramycin solution for oral inhalation given via nebulization in patients with cystic fibrosis, serum tobramycin concentrations averaged 0.95 mcg/mL at 1 hour after administration; after 20 weeks of intermittent therapy (300 mg twice daily for 28 days followed by 28 days without the drug), serum tobramycin concentrations averaged 1.05 mcg/mL at 1 hour after administration.241

Distribution

The volume of distribution of tobramycin in neonates 2-7 days of age has ranged from 0.5-1.24 L/kg.20

Tobramycin is rapidly distributed into most body tissues and fluids following IM or IV administration, including bronchial secretions,6 sputum,6 and peritoneal,6 synovial,6 and abscess fluids.1 Low concentrations occur in bile.1

Only very low concentrations of tobramycin are distributed into CSF following IM or IV administration, even in patients with meningitis.6,15,23 In one adult with meningitis, intrathecal administration of 3-8 mg of tobramycin every 48 hours in conjunction with IM administration of 3 mg/kg daily resulted in CSF concentrations of the drug averaging 15-46 mcg/mL during the first 24 hours and 3-9 mcg/mL at 48 hours.9

Tobramycin crosses the placenta and is distributed into amniotic fluid.1,6,15

Tobramycin is distributed into milk.41 Following IM or IV administration, tobramycin concentrations in milk are very low or undetectable.40,41

Elimination

The plasma elimination half-life of tobramycin following parenteral administration usually is 2-3 hours in adults with normal renal function6,8,10,14,15,16 and has ranged from 50-70 hours in adults with impaired renal function.5,6,8,15,21,22,24

The serum elimination half-life of tobramycin is reported to average 4.6 hours in full-term infants weighing more than 2.5 kg and 8.7 hours in infants weighing less than 1.5 kg.12 In one study in neonates 2-7 days of age, elimination half-life ranged from 5.68-13.6 hours in those weighing less than 2 kg and 3.54-6.73 hours in those weighing 2 kg or more.20

In adults with normal renal function, up to 84% of a single 1-mg/kg IM dose of tobramycin is excreted unchanged by glomerular filtration within 8 hours and up to 93% is excreted unchanged within 24 hours.12,13 Peak urine concentrations of tobramycin may range from 75-100 mcg/mL following a single IM dose of 1 mg/kg in adults with normal renal function.11 Complete recovery of the dose in urine requires approximately 10-20 days in patients with normal renal function, and terminal elimination half-lives of greater than 100 hours have been reported in adults with normal renal function following repeated IM or IV administration of the drug.16

When tobramycin is administered by oral inhalation using a nebulizer, any drug that is not absorbed systemically probably is eliminated principally in expectorated sputum.241

Total body clearance of tobramycin is approximately 20% higher in patients with cystic fibrosis than in patients without the disease; however, renal clearance is similar.44

Tobramycin is removed by hemodialysis and peritoneal dialysis.6,15,21,22,24

Chemistry and Stability

Chemistry

Tobramycin is an aminoglycoside antibiotic obtained from cultures of Streptomyces tenebrarius .1,2,3,5,6,250,251,252,253,254 Tobramycin occurs as a white to off-white, hygroscopic powder and is freely soluble in water and very slightly soluble in alcohol.4 The drug is commercially available as the sulfate salt for parenteral administration1,2,3,250,251,252,253,254 and as the base for administration by oral inhalation via a nebulizer.241

Parenteral

Commercially available tobramycin sulfate solutions containing 10 or 40 mg of tobramycin per mL are clear, colorless, aqueous solutions; sulfuric acid and/or sodium hydroxide is added during manufacture to adjust the pH to 3-6.5.1,2,3,250,251,252,253 The solutions in multiple-dose vials or single-dose ADD-Vantage^® vials contain sodium metabisulfite;1,3,250,251 some multiple-dose vials contain phenol as a preservative.1,3 Solutions in pharmacy bulk packages contain sodium metabisulfite, but do not contain other preservatives.2,253

The commercially available powder for injection for IV infusion (pharmacy bulk package) is formulated without sodium bisulfite or preservatives; sulfuric acid and/or sodium hydroxide may be added during manufacture to adjust the pH.254

The commercially available premixed solutions containing 0.8 or 1.2 mg of tobramycin per mL in 0.9% sodium chloride injection are clear, colorless solutions that do not contain a preservative; these solutions have an osmolarity of approximately 313 or 316 mOsm/L, respectively.252 Sulfuric acid and/or sodium hydroxide is added during manufacture to adjust the pH to 3-6.5.252

Oral Inhalation

Commercially available tobramycin solution for oral inhalation occurs as a clear, slightly yellow, aqueous solution.241 Each 5-mL single-use ampul containing 300 mg of tobramycin contains 11.25 mg of sodium chloride in sterile water for injection; sulfuric acid and sodium hydroxide are added during the manufacture of the solution to adjust the pH to 6.241 The solution for oral inhalation does not contain preservatives.241

Stability

Parenteral

Tobramycin sulfate solution in multiple-dose vials should be stored at 20-25°C1,251 or 15-30°C,3 depending on the manufacturer. Tobramycin sulfate is stable for 24 hours at room temperature in many IV infusion solutions; however, the drug is incompatible with IV solutions containing alcohol.7

Tobramycin sulfate solution in single-dose ADD-Vantage^® vials should be stored at 20-25°C.250 After the vials have been connected to an appropriate ADD-Vantage^® diluent container and activated for dilution, resultant solutions should be used within 24 hours.250

Tobramycin sulfate powder for injection for IV infusion (pharmacy bulk package) should be stored at 15-30°C.254 Following reconstitution, solutions containing 40 mg of tobramycin per mL prepared from the pharmacy bulk package should be refrigerated and used within 96 hours; if stored at room temperature, the reconstituted solution must be used within 24 hours.254

Tobramycin sulfate solution containing 40 mg of tobramycin per mL (pharmacy bulk package) should be stored at 20-25°C.2,253 After the container has been entered to prepare IV solutions, any unused portion remaining in the vial should be discarded within 4 hours.2,253

Commercially available premixed tobramycin sulfate in 0.9% sodium chloride injection provided in single-dose flexible plastic containers should be stored at 25°C; freezing should be avoided.252 Although brief exposure to temperatures up to 40°C does not adversely affect these solutions, exposure to excessive heat should be avoided.252

Tobramycin sulfate solutions should not be admixed with other drugs.1,2,3,250,251,252,253,254

Oral Inhalation

Commercially available tobramycin solution for oral inhalation should be stored at 2-8°C.241 If refrigeration is not available, intact or opened foil pouches containing ampuls of the solution for oral inhalation may be stored at room temperature up to 25°C for up to 28 days.241 The ampuls should not be exposed to intense light.241 Tobramycin solution for oral inhalation may darken if stored at room temperature, but this does not indicate a change in the quality of the preparation.241 Any tobramycin solution for oral inhalation that is cloudy or has visible particles should be discarded.241 In addition, any tobramycin solution for oral inhalation that has been stored at 2-8°C beyond the expiration date stamped on the ampul or stored for longer than 28 days at room temperature should be discarded.241

Additional Information

For further information on chemistry and stability, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, and dosage and administration of tobramycin, see the Aminoglycosides General Statement 8:12.02.

Only references cited for selected revisions after 1984 are available electronically.

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