Tobramycin sulfate is available as a 10-mg/mL (pediatric) solution for injection in 2-mL multiple-dose vials and a 40-mg/mL solution for injection in 2- or 30-mL multiple-dose vials and a 50-mL pharmacy bulk package.3947; 3948; 3949 Each mL contains the equivalent of tobramycin 10 or 40 mg as the sulfate with sodium metabisulfite 3 or 3.2 mg and edetate disodium 0.1 mg in water for injection.3947; 3948 The solution also contains sulfuric acid and may contain sodium hydroxide for pH adjustment.3947; 3948 Some formulations also may contain phenol as a preservative.3948
Tobramycin sulfate is also available as a lyophilized powder in pharmacy bulk vials containing the equivalent of tobramycin 1.2 g with sulfuric acid and/or sodium hydroxide for pH adjustment.3950 The vial should be reconstituted with 30 mL of sterile water for injection to yield a solution containing tobramycin 40 mg/mL.3950 Solutions prepared from pharmacy bulk packages are intended only for intravenous infusion after dilution in a compatible solution.3950
Tobramycin sulfate also is available as a premixed, ready-to-use solution in sodium chloride 0.9% for infusion in single-dose flexible plastic containers containing the equivalent of tobramycin 60 mg in 50 mL (1.2 mg/mL) or 80 mg in 100 mL (0.8 mg/mL).3951 The solution contains sulfuric acid and may contain sodium hydroxide for pH adjustment.3951
pH
The pH of the injection and premixed, ready-to-use solution is adjusted to 3 to 6.5.3947; 3951
Osmolality
The osmolality of tobramycin sulfate at a tobramycin concentration of 10 mg/mL was 133 mOsm/kg by freezing-point depression and 213 mOsm/kg by vapor pressure.1071
The osmolality of tobramycin sulfate prepared at a tobramycin concentration 1 mg/mL was 254 mOsm/kg in dextrose 5% and 288 mOsm/kg in sodium chloride 0.9%. At 2.5 mg/mL, the osmolality was 261 mOsm/kg in dextrose 5% and 283 mOsm/kg in sodium chloride 0.9%.1375
The osmolality of tobramycin (as the sulfate) 80 mg was calculated for the following dilutions:1054
| Osmolality (mOsm/kg) | ||
|---|---|---|
| Diluent | 50 mL | 100 mL |
| Dextrose 5% | 289 | 285 |
| Sodium chloride 0.9% | 319 | 315 |
Osmolarity
The premixed, ready-to-use solutions have calculated osmolarities of 316 and 313 mOsm/L for the 60-mg in 50 mL and 80-mg in 100 mL products, respectively.3951
Tobramycin sulfate is administered by intramuscular injection or intermittent intravenous infusion.3947; 3948 Intramuscular doses are administered undiluted.3947; 3948 For intravenous infusion in adults, dilution of the dose in 50 to 100 mL of infusion solution (e.g., sodium chloride 0.9% or dextrose 5%) is recommended; smaller volumes should be used in pediatric patients.3947 The infusion is administered over 20 to 60 minutes.3947 Infusion periods should not be less than 20 minutes; such shorter periods could result in excessive peak serum concentrations.3947
Solutions prepared from pharmacy bulk packages are intended only for intravenous infusion after dilution in a compatible solution.3949; 3950
Tobramycin sulfate injection is a clear, colorless solution.3947; 3948 Intact vials of the injection solution or lyophilized powder should be stored at controlled room temperature.3947; 3948; 3950 Reconstituted solutions in the pharmacy bulk package should be used within 24 hours and any unused portion discarded.3950
The premixed, ready-to-use solution in intact containers should be stored at controlled room temperature and protected from freezing.3951
Tobramycin sulfate is stable for several weeks at pH 1 to 11 at temperatures from 5 to 27°C. It can be autoclaved without loss.145
Freezing Solutions
Tobramycin sulfate reconstituted to a tobramycin concentration of 40 mg/mL and immediately frozen in the original container is stable for up to 12 weeks when stored at -10 to -20°C.4
Tobramycin sulfate (Lilly) prepared at a tobramycin concentration of 160 mg/50 mL in dextrose 5% in polyvinyl chloride (PVC) bags frozen at -20°C for 30 days and then thawed by exposure to ambient temperature or microwave radiation was evaluated. The solutions showed no evidence of precipitation or color change and showed 6% or less loss. Subsequent storage of the admixture at room temperature for 24 hours also yielded a physically compatible solution which exhibited little or no additional loss.555
Tobramycin sulfate (Dista) prepared at a tobramycin concentration of 120 mg/50 mL in dextrose 5% and sodium chloride 0.9% in PVC bags lost 9% activity in 28 days when frozen at -20°C.981
Minibags of tobramycin sulfate in dextrose 5% or sodium chloride 0.9%, frozen at -20°C for up to 35 days, were thawed at room temperature and in a microwave oven, with care taken that the thawed solution temperature never exceeded 25°C. No significant differences in tobramycin sulfate concentrations occurred between the 2 thawing methods.1192
Syringes
Samples of a 40-mg/mL tobramycin solution prepared from tobramycin sulfate (Lilly) from a reconstituted 1.2-g vial were stored in Monoject plastic syringes at both 25 and 4°C. After 2 months, no significant change in concentration was detected in samples at either storage temperature. The authors did note that the manufacturer does not recommend storage in plastic syringes because of possible incompatibility with the plunger heads.736
Tobramycin (as the sulfate) (Dista) 120 mg diluted with 1 mL of sodium chloride 0.9% to a final volume of 4 mL was stable (less than a 10% loss) when stored in polypropylene syringes (Becton Dickinson) for 48 hours at 25°C under fluorescent light.1159
Elastomeric Reservoir Pumps
Tobramycin sulfate (Lilly) prepared at a tobramycin concentration of 0.8 mg/mL in both dextrose 5% and sodium chloride 0.9% was evaluated for binding potential to natural rubber elastomeric reservoirs (Baxter). No binding was found after storage for 2 weeks at 35°C with gentle agitation.2014
Sorption
Tobramycin sulfate was shown not to exhibit sorption to PVC bags and tubing, polyethylene tubing, Silastic tubing, and polypropylene syringes.536; 606
Tobramycin sulfate (Qualimed) prepared at a tobramycin concentration of 1.5 mg/mL in both dextrose 5% and in sodium chloride 0.9% was packaged in PVC bags (Macropharma) and in multilayer bags composed of polyethylene, polyamide, and polypropylene (Bieffe Medital). The solutions were delivered through PVC administration sets (Abbott) over 1 hour and evaluated for drug loss. No loss due to sorption to any of the plastic materials was found.2269
Filtration
Tobramycin sulfate (Lilly) prepared at a tobramycin concentration of 0.3 mg/mL in dextrose 5% and sodium chloride 0.9% was filtered through a 0.22-µm cellulose ester membrane filter (Ivex-HP, Millipore) over 6 hours. No significant drug loss due to binding to the filter was noted.1034
Tobramycin sulfate prepared at a tobramycin concentration of 5 and 10 mg/55 mL in dextrose 5% and sodium chloride 0.9% filtered over 20 minutes through a 0.22-µm cellulose ester filter set (Ivex-2, Millipore) was evaluated. Little or no binding of the drug to the filter occurred.1003
No significant loss due to sorption to a 0.22-µm cellulose ester filter (Continu-Flo 2C0252s, Travenol) occurred from a solution containing tobramycin sulfate (Dista) prepared at a tobramycin concentration of 80 mg/100 mL in dextrose 5% administered over 30 minutes. No difference in drug recovery was found between filtered and unfiltered solutions. However, 10% or more of the solution may remain in the tubing unless the sets are flushed.1132
Central Venous Catheter
Tobramycin sulfate (Lilly) prepared at a tobramycin concentration of 1 mg/mL in dextrose 5% was found to be compatible with the ARROWg+ard Blue Plus (Arrow International) chlorhexidine-bearing triple-lumen central catheter. Essentially complete delivery of the drug was found with little or no drug loss occurring. Furthermore, chlorhexidine delivered from the catheter remained at trace amounts with no substantial increase due to the delivery of the drug through the catheter.2335
Drugs in Syringe Compatibility
Y-Site Injection Compatibility (1:1 Mixture)
Additional Compatibility Information
Peritoneal Dialysis Solutions
Tobramycin base (Lilly) 3 and 10 mg/L in peritoneal dialysis concentrate with dextrose 50% (McGaw) retained about 50 to 60% of initial activity in 7 hours and about 15 to 30% in 24 hours at room temperature.1044
The stability of tobramycin sulfate (Lilly) prepared at a tobramycin concentration of 10 mg/L in peritoneal dialysis solutions (Dianeal 137 and PD-2) with heparin sodium 500 units/L was evaluated. Approximately 102 ± 20% activity remained after 24 hours at 25°C.1228
In another study, the stability of tobramycin sulfate (Lilly) was evaluated in peritoneal dialysis concentrates containing dextrose 30 and 50% (Dianeal) as well as in a diluted solution containing dextrose 2.5%. The tobramycin concentrations were 100 and 160 mg/L in the peritoneal dialysate concentrates and 5 and 8 mg/L in the diluted solution. Tobramycin sulfate was found to be stable in the diluted peritoneal dialysis solution for at least 24 hours at 23°C. However, greater decomposition occurred in the concentrates, with a 10% loss in as little as 9 to 15 hours.1229
The retention of antimicrobial activity of tobramycin sulfate (Lilly) prepared at a tobramycin concentration of 120 mg/L alone and with vancomycin hydrochloride (Lilly) prepared at a tobramycin concentration of 1 g/L was evaluated in Dianeal PD-2 (Travenol) with dextrose 1.5%. Little or no loss of either antibiotic occurred in 8 hours at 37°C. Tobramycin sulfate alone retained activity for at least 48 hours at 4 and 25°C. With vancomycin hydrochloride, the activity of both antibiotics was retained for up to 48 hours; however, the authors recommended refrigeration at 4°C for storage longer than 24 hours.1414
Ceftazidime (Fortaz) 125 mg/L and tobramycin sulfate (Lilly) prepared at a tobramycin concentration of 8 mg/L in Dianeal PD-2 with dextrose 2.5% (Baxter) were visually compatible and chemically stable. After 16 hours of storage at 25°C under fluorescent light, the loss of both drugs was less than 3%. Additional storage for 8 hours at 37°C, to simulate the maximum peritoneal dwell time, showed tobramycin sulfate concentrations of 96% and ceftazidime concentrations of 92 to 96%.1652
Tobramycin sulfate (Lilly) prepared at a tobramycin concentration of 25 mcg/mL combined separately with the cephalosporins cefazolin sodium (Lilly) and cefoxitin sodium (MSD) at base drug concentrations of 125 mcg/mL in peritoneal dialysis solution (Dianeal 1.5%) exhibited enhanced rates of lethality to Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa compared to any of the drugs alone.1623
ß-Lactam Antibiotics
In common with other aminoglycoside antibiotics, tobramycin sulfate activity may be impaired by the ß-lactam antibiotics. The inactivation is dependent on concentration, temperature, and time of exposure.68; 497; 498; 574; 575; 654; 740; 814; 816; 817; 832; 824; 973; 1005; 1052; 1420
The clinical significance of these interactions appears to be primarily confined to patients with renal failure.218; 334; 361; 364; 616; 737; 816; 847; 952 Literature reports of greatly reduced aminoglycoside levels in such patients have appeared frequently.363; 365; 366; 367; 614; 666; 962 In addition, the interaction may be clinically important if assays for aminoglycoside levels in serum are sufficiently delayed.576; 618; 735; 824; 832; 847; 1052
Most authors believe that in vitro mixing of penicillins with aminoglycoside antibiotics should be avoided but that clinical use of the drugs in combination can be of great value. It is generally recommended that the drugs be given separately in such combined therapy.157; 218; 222; 224; 361; 364; 368; 369; 370
For a list of references cited in the text of this monograph, search the monograph titled References.