When coupled with the Mycobacterium abscessus enzyme (PodA), tobramycin (0–50 ng/mL; 24 hours) dramatically lowers M. viability of aeruginosa cells [2].

In a mouse pneumonia model, tobramycin (50–400 mg/kg/day, intraperitoneal injection, every 4 hours) can kill germs at low doses [3].

Cell Viability Assay[2]
Cell Types: Pseudomonas aeruginosa
Tested Concentrations: 2,10,50 ng/mL
Incubation Duration: 24 hrs (hours)
Experimental Results: Cells compared to no protein or inactive Mycobacterium fortuitum enzyme (PodA) control Viability was greatly diminished, whereas PodA10 alone did not increase cell death.

Animal/Disease Models: Pseudomonas aeruginosa pneumonia mouse model female, Swiss-Webster mice [3]
Doses: 50, 100. , 150, 214, and 400 mg/kg/day Dosing: intraperitonealevery 4 hrs (hrs (hours))
Experimental Results: When tobramycin was used alone, at approximately 150 mg/kg/day, the response to wild-type bacteria was Close to maximum killing effect. When used in combination with meropenem, low doses of both drugs (60 and 50 mg/kg/day for meropenem and tobramycin, respectively) produced near-maximal effects (i.e., killing of bacterial cells).

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Animal/Disease Models: Mice, rats, cats, and dogs for toxicological evaluation [4]
Doses: 7.5, 15, 30, 120, 441,969 mg/kg
Route of Administration: subcutaneous injection, intravenous (iv) (iv)injection, intramuscularinjection
Experimental Results: sc LD50 values for mice and rats were 441 and 969 mg/kg respectively. Within 1 hour of treatment, rats and mice died preceded by central nervous system depression. intravenous (iv) (iv)doses of 100 mg/kg produced a moderate, transient decrease in blood pr

Absorption, Distribution and Excretion
Tobramycin administered by inhalation in cystic fibrosis patients showed greater variability in sputum as compared to serum. After a single 112 mg dose, the serum Cmax was 1.02 ± 0.53 μg/mL, which was reached in one hour (Tmax), while the sputum Cmax was 1048 ± 1080 μg/g. Comparatively, for a 300 mg dose, the serum Cmax was 1.04 ± 0.58 μg/mL, which was also reached within one hour, while the sputum Cmax was 737 ± 1028 μg/g. The systemic exposure (AUC0-12) was also similar between the two doses, at 4.6 ± 2.0 μg∙h/mL for the 112 mg dose and 4.8 ± 2.5 μg∙h/mL for the 300 mg dose. When tobramycin was administered over a four-week cycle at 112 mg twice daily, the Cmax measured one hour after dosing ranged from 1.48 ± 0.69 μg/mL to 1.99 ± 0.59 μg/mL.
Tobramycin is primarily excreted unchanged in the urine.
Inhalation tobramycin had an apparent volume of distribution in the central compartment of 85.1 L for a typical cystic fibrosis patient.
Inhaled tobramycin has an apparent serum clearance of 14.5 L/h in cystic fibrosis patients aged 6-58 years.
Tobramycin is poorly absorbed from the GI tract.
Tobramycin is rapidly absorbed following IM administration. 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 ug/mL and are attained within 30-90 minutes; at 6-8 hours after the dose, serum concentrations are 1 ug/mL or less. When the same dose is administered by IV infusion over 30-60 minutes, similar plasma concentrations of the drug are attained.
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 ug/mL after the first dose and 4.5-5.1 ug/mL after 10-16 doses. 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 ug/mL and trough serum concentrations ranged from 1.1-3.6 ug/mL in those weighing less than 2 kg. In those weighing 2 kg or more, peak serum concentrations ranged from 5-10.2 ug/mL and trough serum concentrations ranged from 0.7-2 ug/mL.
Bioavailability of tobramycin administered by oral inhalation via a nebulizer may be variable because of individual differences in nebulizer performance and airway pathology. Following oral inhalation via nebulization, tobramycin remains concentrated principally in the airways; the drug does not readily cross epithelial membranes. Tobramycin sputum concentrations are highly variable following oral inhalation, but the drug does not appear to accumulate in sputum following multiple doses. 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 ug/g (range: 35-7414 ug/g). 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 ug/g (range: 39-8085 ug/g) and sputum concentrations 2 hours after administration were approximately 14% of those obtained 10 minutes after administration. 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 ug/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 ug/mL at 1 hour after administration.
For more Absorption, Distribution and Excretion (Complete) data for Tobramycin (15 total), please visit the HSDB record page.

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Metabolism / Metabolites
Tobramycin is not appreciably metabolized.
Aminoglycosides are not metabolized and are excreted unchanged in the urine primarily by glomerular filtration. /Aminoglycosides/

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Biological Half-Life
Tobramycin has an apparent serum terminal half-life of ~3 hours following a single 112 mg inhaled dose in cystic fibrosis patients.
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.
When tobramycin is administered by oral inhalation using a nebulizer, any drug that is not absorbed systemically probably is eliminated principally in expectorated sputum.
... 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.
The plasma elimination half-life of tobramycin following parenteral administration usually is 2-3 hours in adults with normal renal function and has ranged from 50-70 hours in adults with impaired renal function. 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. 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.

Hepatotoxicity
Intravenous and intramuscular therapy with tobramycin is usually associated with no increase in rates of serum aminotransferase or bilirubin elevations. Only isolated case reports of acute liver injury with jaundice have been associated with aminoglycoside therapy including tobramycin, not all of which are very convincing. The hepatic injury is typically mixed but can evolve into a cholestatic hepatitis. The latency to onset is rapid, occurring within 1 to 3 weeks and is typically associated with skin rash, fever and sometimes eosinophilia. Recovery typically occurs within 1 to 2 months and chronic injury has not been described. Aminoglycosides are not mentioned in large case series of drug induced liver disease and acute liver failure; thus, hepatic injury due to tobramycin is rare if it occurs at all.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Tobramycin is poorly excreted into breastmilk. Newborn infants apparently absorb small amounts of other aminoglycosides, but serum levels with typical three times per day dosages are far below those attained when treating newborn infections and systemic effects of tobramycin are unlikely. Older infants would be expected to absorb even less tobramycin. Because there is little variability in the milk tobramycin levels during multiple daily dose regimens, timing breastfeeding with respect to the dose is of little or no benefit in reducing infant exposure. Data are not available with single daily dose regimens. Monitor the infant for possible effects on the gastrointestinal flora, such as diarrhea, candidiasis (e.g., thrush, diaper rash) or rarely, blood in the stool indicating possible antibiotic-associated colitis.
Maternal use of an ear drop or eye drop that contains tobramycin presents little or no risk for the nursing infant. A task force respiratory experts from Europe, Australia and New Zealand found that inhaled tobramycin is compatible with breastfeeding.
◉ Effects in Breastfed Infants
An infant was breastfed (extent not stated) until the 4th month postpartum. At 2 months of age, his mother was given a 2-week course of tobramycin 150 mg three times daily plus meropenem for a cystic fibrosis exacerbation. infant displayed no change in stool pattern during the maternal treatment and had normal renal function at 6 months of age.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Tobramycin binding to serum proteins is negligible.

[1]. Tobramycin.

[2]. VanDrisse CM, et.al. Computationally designed pyocyanin demethylase acts synergistically with tobramycin to kill recalcitrant Pseudomonas aeruginosa biofilms. Proc Natl Acad Sci U S A. 2021 Mar 23;118(12):e2022012118.

[3]. Louie A, et.al. Impact of meropenem in combination with tobramycin in a murine model of Pseudomonas aeruginosa pneumonia. Antimicrob Agents Chemother. 2013 Jun;57(6):2788-92.

[4]. Welles JS, et.al. Preclinical toxicology studies with tobramycin. Toxicol Appl Pharmacol. 1973 Jul;25(3):398-409.

Tobramycin Sulfate can cause developmental toxicity according to state or federal government labeling requirements.
Tobramycin is a amino cyclitol glycoside that is kanamycin B lacking the 3-hydroxy substituent from the 2,6-diaminoglucose ring. It has a role as an antibacterial agent, an antimicrobial agent and a toxin. It is functionally related to a kanamycin B. It is a conjugate base of a tobramycin(5+).
Aminoglycosides, many of which are derived directly from Streptomyces spp., are concentration-dependent bactericidal antibiotics with a broad spectrum of activity against Gram-positive and Gram-negative organisms. Inhaled tobramycin is notable for its use in treating chronic Pseudomonas aeruginosa infections in cystic fibrosis patients, as P. aeruginosa is notoriously inherently resistant to many antibiotics. However, tobramycin can also be administered intravenously and topically to treat a variety of infections caused by susceptible bacteria. Its use is limited in some cases by characteristic toxicities such as nephrotoxicity and ototoxicity, yet it remains a valuable option in the face of growing resistance to front-line antibiotics such as β-lactams and cephalosporins. Tobramycin was approved by the FDA in 1975 and is currently available in a variety of forms for administration by inhalation, injection, and external application to the eye (ophthalmic).
Tobramycin is an Aminoglycoside Antibacterial.
Tobramycin is a parenterally administered, broad spectrum aminoglycoside antibiotic that is widely used in the treatment of moderate to severe bacterial infections due to sensitive organisms. Despite its wide use, tobramycin has rarely been linked to instances of clinically apparent liver injury.
Tobramycin has been reported in Aspergillus fumigatus, Brassica napus, and other organisms with data available.
Tobramycin is an aminoglycoside antibiotic derived from Streptomyces tenebrarius with bacteriostatic activity. Following active transport into the cell, tobramycin binds irreversibly to a specific aminoglycoside receptor on the bacterial 30S ribosomal subunit and interferes with the initiation complex between messenger RNA and the 30S subunit, thereby inhibiting initiation of protein synthesis, consequently leading to bacterial cell death. In addition, tobramycin induces misreading of the mRNA template causing incorrect amino acids to be incorporated into the growing polypeptide chain, consequently interfering with protein elongation.
Tobramycin Sulfate is the sulfate salt of tobramycin, an aminoglycoside antibiotic derived from the bacterium Streptomyces tenebrarius with bactericidal activity. Following active transport into the cell, tobramycin binds irreversibly to a specific aminoglycoside receptor on the bacterial 30S ribosomal subunit and fixes the 30 S-50 S ribosomal complex at the start codon (AUG), interfering with the initiation of protein synthesis. In addition, this agent induces misreading of the mRNA template, which results in 1) detachment of the ribosomal complex and inhibition of protein elongation or 2) incorporation of the incorrect amino acids into the growing polypeptide chain and the production of abnormal or nonfunctional proteins. Altogether, cell permeability is altered and cell death ensues.
An aminoglycoside, broad-spectrum antibiotic produced by Streptomyces tenebrarius. It is effective against gram-negative bacteria, especially the PSEUDOMONAS species. It is a 10% component of the antibiotic complex, NEBRAMYCIN, produced by the same species.
See also: Tobramycin Sulfate (has salt form); Dexamethasone; tobramycin (component of); Loteprednol etabonate; tobramycin (component of) ... View More ...

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Drug Indication
Inhaled tobramycin is indicated for the management of cystic fibrosis patients with _Pseudomonas aeruginosa_, but is not recommended in patients under six years of age, those with forced expiratory volume in 1 second (FEV1) 80% predicted, or in those with _Burkholderia cepacia_. Tobramycin applied topically to the eyes is indicated for the treatment of external eye (and adjoining structure) infections by susceptible bacteria. Tobramycin injection is indicated in adult and pediatric patients for the treatment of serious bacterial infections, including septicemia (caused by _P. aeruginosa_, _Escherichia coli_, and _Klebsiella_ spp.), lower respiratory tract infections (caused by _P. aeruginosa_, _Klebsiella_ spp., _Enterobacter_ spp., _Serratia_ spp., _E. coli_, and _Staphylococcus aureus_, both penicillinase and non-penicillinase-producing strains), serious central-nervous-system infections (meningitis, caused by susceptible organisms), intra-abdominal infections including peritonitis (caused by _E. coli_, _Klebsiella_ spp., and _Enterobacter_ spp.), skin, bone, and skin structure infections (caused by _P. aeruginosa_, _Proteus_ spp., _E. coli_, _Klebsiella_ spp., _Enterobacter_ spp., _Serratia_ spp. and _S. aureus_), and complicated and recurrent urinary tract infections (caused by _P. aeruginosa_, _Proteus_ spp., _E. coli_, _Klebsiella_ spp., _Enterobacter_ spp., _Serratia_ spp., _S. aureus_, _Providencia_ spp., and _Citrobacter_ spp.). Aminoglycosides, including tobramycin, should generally not be used in uncomplicated urinary tract infections or staphylococcal infections unless less toxic antibiotics cannot be used and the bacteria in question are known to be sensitive to aminoglycosides. As with all antibiotics, tobramycin use should be limited to cases where bacterial infections are known or strongly suspected to be caused by sensitive organisms, and the possible emergence of resistance should be monitored closely.
FDA Label
Vantobra is indicated for the management of chronic pulmonary infection due to Pseudomonas aeruginosa in patients aged 6 years and older with cystic fibrosis (CF). Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Tobi Podhaler is indicated for the suppressive therapy of chronic pulmonary infection due to Pseudomonas aeruginosa in adults and children aged 6 years and older with cystic fibrosis. See sections 4. 4 and 5. 1 regarding data in different age groups. Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Vantobra is indicated for the management of chronic pulmonary infection due to Pseudomonas aeruginosa in patients aged 6 years and older with cystic fibrosis (CF). Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Treatment of Pseudomonas aeruginosa pulmonary colonisation in patients with bronchiectasis
Treatment of Pseudomonas aeruginosa pulmonary infection / colonisation in patients with cystic fibrosis
Treatment of Pseudomonas aeruginosa pulmonary infection / colonisation in patients with cystic fibrosis

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Mechanism of Action
Tobramycin is a 4,6-disubstituted 2-deoxystreptamine (DOS) ring-containing aminoglycoside antibiotic with activity against various Gram-negative and some Gram-positive bacteria. The mechanism of action of tobramycin has not been unambiguously elucidated, and some insights into its mechanism rely on results using similar aminoglycosides. In general, like other aminoglycosides, tobramycin is bactericidal and exhibits both immediate and delayed killing, which are attributed to different mechanisms, as outlined below. Aminoglycosides are polycationic at physiological pH, such that they readily bind to bacterial membranes ("ionic binding"); this includes binding to lipopolysaccharide and phospholipids within the outer membrane of Gram-negative bacteria and to teichoic acid and phospholipids within the cell membrane of Gram-positive bacteria. This binding displaces divalent cations and increases membrane permeability, which allows aminoglycoside entry. Additional aminoglycoside entry ("energy-dependent phase I") into the cytoplasm requires the proton-motive force, allowing access of the aminoglycoside to its primary intracellular target of the bacterial 30S ribosome. Mistranslated proteins produced as a result of aminoglycoside binding to the ribosome (see below) integrate into and disrupt the cell membrane, which allows more of the aminoglycoside into the cell ("energy-dependent phase II"). Hence, tobramycin and other aminoglycosides have both immediate bactericidal effects through membrane disruption and delayed bactericidal effects through impaired protein synthesis; observed experimental data and mathematical modelling support this two-mechanism model. Inhibition of protein synthesis was the first recognized effect of aminoglycoside antibiotics. Structural and cell biological studies suggest that aminoglycosides bind to the 16S rRNA in helix 44 (h44), near the A site of the 30S ribosomal subunit, altering interactions between h44 and h45. This binding also displaces two important residues, A1492 and A1493, from h44, mimicking normal conformational changes that occur with successful codon-anticodon pairing in the A site. Overall, aminoglycoside binding has several negative effects, including inhibiting translation initiation and elongation and ribosome recycling. Recent evidence suggests that the latter effect is due to a cryptic second binding site situated in h69 of the 23S rRNA of the 50S ribosomal subunit. Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation; mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above. Although direct mutation of the 16S rRNA is a rare resistance mechanism, due to the gene being present in numerous copies, posttranscriptional 16S rRNA modification by 16S rRNA methyltransferases (16S-RMTases) at the N7 position of G1405 or the N1 position of A1408 are common resistance mechanisms in aminoglycoside-resistant bacteria. These mutants also further support the proposed mechanism of action of aminoglycosides. Direct modification of the aminoglycoside itself through acetylation, adenylation, and phosphorylation by aminoglycoside-modifying enzymes (AMEs) are also commonly encountered resistance mutations. Finally, due to the requirement for active transport of aminoglycosides across bacterial membranes, they are not active against obligately anaerobic bacteria.
Aminoglycosides are usually bacterial in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits. /Aminoglycosides/
... Aminoglycosides are aminocyclitols that kill bacteria by inhibiting protein synthesis as they bind to the 16S rRNA and by disrupting the integrity of bacterial cell membrane. Aminoglycoside resistance mechanisms include: (a) the deactivation of aminoglycosides by N-acetylation, adenylylation or O-phosphorylation, (b) the reduction of the intracellular concentration of aminoglycosides by changes in outer membrane permeability, decreased inner membrane transport, active efflux, and drug trapping, (c) the alteration of the 30S ribosomal subunit target by mutation, and (d) methylation of the aminoglycoside binding site. ... /Aminoglycosides/

C18H37N5O9

467.51

467.259

32986-56-4

Tobramycin sulfate;49842-07-1

36294

White to off-white solid powder

1.5±0.1 g/cm3

775.4±60.0 °C at 760 mmHg

178ºC

422.8±32.9 °C

0.0±6.0 mmHg at 25°C

1.651

-3.41

10

14

6

32

609

14

C1[C@@H]([C@H]([C@@H]([C@H]([C@@H]1N)O[C@@H]2[C@@H]([C@H]([C@@H]([C@H](O2)CO)O)N)O)O)O[C@@H]3[C@@H](C[C@@H]([C@H](O3)CN)O)N)N

NLVFBUXFDBBNBW-PBSUHMDJSA-N

InChI=1S/C18H37N5O9/c19-3-9-8(25)2-7(22)17(29-9)31-15-5(20)1-6(21)16(14(15)28)32-18-13(27)11(23)12(26)10(4-24)30-18/h5-18,24-28H,1-4,19-23H2/t5-,6+,7+,8-,9+,10+,11-,12+,13+,14-,15+,16-,17+,18+/m0/s1

(2S,3R,4S,5S,6R)-4-amino-2-[(1S,2S,3R,4S,6R)-4,6-diamino-3-[(2R,3R,5S,6R)-3-amino-6-(aminomethyl)-5-hydroxyoxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-6-(hydroxymethyl)oxane-3,5-diol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ≥ 100 mg/mL (~213.90 mM)
DMSO : ~2 mg/mL (~4.28 mM)

Solubility in Formulation 1: 100 mg/mL (213.90 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)