Tobramycin

Identification

Name

Tobramycin

Accession Number

DB00684

Description

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.¹ 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.^1,2,13 However, tobramycin can also be administered intravenously and topically to treat a variety of infections caused by susceptible bacteria.^14,15 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.^1,12,13,15

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).^13,14,15

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 467.5145
Monoisotopic: 467.259127807
Chemical Formula: C₁₈H₃₇N₅O₉

Synonyms

3'-Deoxykanamycin B
Nebramycin 6
O-3-Amino-3-deoxy-alpha-D-glucopyranosyl-(1-4)-O-(2,6-diamino-2,3,6-trideoxy-alpha-D-ribohexopyranosyl-(1-4))-2-deoxy-D-streptamine
Tobramicina
Tobramycin
Tobramycine
Tobramycinum

External IDs

47663
Lilly 47663
SPRC-AB01

Pharmacology

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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) <25 or >80% predicted, or in those with Burkholderia cepacia.¹³

Tobramycin applied topically to the eyes is indicated for the treatment of external eye (and adjoining structure) infections by susceptible bacteria.¹⁴

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.).¹⁵ 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.¹⁵

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.^13,14,15

Associated Conditions

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Pharmacodynamics

Tobramycin is an aminoglycoside antibiotic derived from the actinomycete Streptomyces tenebrarius.¹⁵ It has a broad spectrum of activity against Gram-negative bacteria, including Enterobacteriaceae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Moraxella lacunata, Proteus spp., Haemophilus spp., Acinetobacter spp., Neisseria spp., and, importantly, Pseudomonas aeruginosa. Aminoglycosides also generally retain activity against the biothreat agents Yersinia pestis and Francisella tularensis. In addition, aminoglycosides are active against some Gram-positive bacteria such as Staphylococcus spp., including methicillin-resistant (MRSA) and vancomycin-resistant strains, Streptococcus spp., and Mycobacterium spp.^1,14

Like other aminoglycosides, tobramycin is taken up and retained by proximal tubule and cochlear cells in the kidney and ear, respectively, and hence carries a risk of nephrotoxicity and ototoxicity.^1,15 There is also a risk of neuromuscular block, which may be more pronounced in patients with preexisting neuromuscular disorders such as myasthenia gravis or Parkinson's disease.^1,13,15 Aminoglycosides can cross the placenta, resulting in total, irreversible, bilateral congenital deafness in babies born to mothers who were administered an aminoglycoside during pregnancy.^13,15 Due to the low systemic absorption of inhaled and topical tobramycin formulations, these effects are more pronounced with injected tobramycin than with other formulations.^13,14,15 However, all formulations carry a risk of hypersensitivity reactions, including potentially fatal cutaneous reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.^13,14,15

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.^13,14,15 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.^1,2

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.^1,3,4,5 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.^1,5 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").^1,5,6 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.^1,2

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.^7,8 Overall, aminoglycoside binding has several negative effects, including inhibiting translation initiation and elongation and ribosome recycling.^1,9,10 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.^8,10 Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation;¹¹ mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above.^1,6

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.^1,12 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.^1,12 Finally, due to the requirement for active transport of aminoglycosides across bacterial membranes, they are not active against obligately anaerobic bacteria.¹

Target	Actions	Organism
A16S ribosomal RNA	inhibitor	Enteric bacteria and other eubacteria
A23S ribosomal RNA	inhibitor	Enteric bacteria and other eubacteria
ABacterial outer membrane	incorporation into and destabilization	Bacteria
ACytoplasmic membrane	incorporation into and destabilization	Bacteria

Absorption

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 C_max was 1.02 ± 0.53 μg/mL, which was reached in one hour (T_max), while the sputum C_max was 1048 ± 1080 μg/g. Comparatively, for a 300 mg dose, the serum C_max was 1.04 ± 0.58 μg/mL, which was also reached within one hour, while the sputum C_max was 737 ± 1028 μg/g. The systemic exposure (AUC_0-12) 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 C_max measured one hour after dosing ranged from 1.48 ± 0.69 μg/mL to 1.99 ± 0.59 μg/mL.¹³

Volume of distribution

Inhalation tobramycin had an apparent volume of distribution in the central compartment of 85.1 L for a typical cystic fibrosis patient.¹³

Protein binding

Tobramycin binding to serum proteins is negligible.¹³

Metabolism

Tobramycin is not appreciably metabolized.¹³

Route of elimination

Tobramycin is primarily excreted unchanged in the urine.¹³

Half-life

Tobramycin has an apparent serum terminal half-life of ~3 hours following a single 112 mg inhaled dose in cystic fibrosis patients.¹³

Clearance

Inhaled tobramycin has an apparent serum clearance of 14.5 L/h in cystic fibrosis patients aged 6-58 years.¹³

Adverse Effects

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Toxicity

Toxicity information regarding tobramycin is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as nephrotoxicity, ototoxicity, neuromuscular blockade, and respiratory failure/paralysis. Symptomatic and supportive measures are recommended; hemodialysis may help clear excess tobramycin. Accidental ingestion of tobramycin is unlikely to result in an overdose, as aminoglycosides are poorly absorbed in the gastrointestinal tract.^13,15

Poor gastrointestinal absorption is reflected in animal studies. When administered by the intraperitoneal or subcutaneous route, the LD50 for mice and rats ranges from 367-1030 mg/kg while the oral LD50 values are more than 7500 mg/kg.¹⁶

Affected organisms

Enteric bacteria and other eubacteria

Pathways

Pathway	Category
Tobramycin Action Pathway	Drug action

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abacavir	Tobramycin may decrease the excretion rate of Abacavir which could result in a higher serum level.
Aceclofenac	Aceclofenac may decrease the excretion rate of Tobramycin which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Tobramycin which could result in a higher serum level.
Acenocoumarol	The risk or severity of bleeding can be increased when Tobramycin is combined with Acenocoumarol.
Acetaminophen	Tobramycin may decrease the excretion rate of Acetaminophen which could result in a higher serum level.
Acetazolamide	Acetazolamide may increase the excretion rate of Tobramycin which could result in a lower serum level and potentially a reduction in efficacy.
Acetylcholine	The therapeutic efficacy of Acetylcholine can be decreased when used in combination with Tobramycin.
Acetyldigitoxin	The risk or severity of adverse effects can be increased when Tobramycin is combined with Acetyldigitoxin.
Acetylsalicylic acid	Acetylsalicylic acid may decrease the excretion rate of Tobramycin which could result in a higher serum level.
Aclidinium	Tobramycin may decrease the excretion rate of Aclidinium which could result in a higher serum level.

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Food Interactions

No interactions found.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Tobramycin hydrochloride	01IX3OU168	95188-93-5	CVDADWBWFLWJNQ-TWDWGCDDSA-N
Tobramycin sulfate	HJT0RXD7JK	49842-07-1	ZEUUPKVZFKBXPW-TWDWGCDDSA-N

International/Other Brands

Aktob (Akorn) / Alveoterol (Tetrafarm) / Amgy (Kobec) / Bactob (Solitaire) / Belbarmicina (Quimica Luar) / Bideon Biotic (Fecofar) / Bioptic (Bausch & Lomb) / Bramitob (Torrex) / Gernebcin (Infectopharm) / Nebcin (Lilly) / Obracin (EuroCept) / Tobracin (Opso Saline) / Tobramaxin (Alcon)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Bethkis	Solution	300 mg/4mL	Respiratory (inhalation)	Chiesi USA, Inc.	2013-04-15	Not applicable
Kitabis Pak	Solution	300 mg/5mL	Respiratory (inhalation)	Catalent Pharma Solutions,Llc	2015-02-19	2018-03-22
Kitabis Pak	Solution	300 mg/5mL	Respiratory (inhalation)	Pari Respiratory Equipment, Inc.	2015-02-19	Not applicable
Nebcin Inj 1.2gm/30ml	Liquid		Intramuscular; Intravenous	Eli Lilly & Co. Ltd.	1986-12-31	2003-05-12
Nebcin Inj 10mg/ml	Liquid		Intramuscular; Intravenous	Eli Lilly & Co. Ltd.	1975-12-31	2003-05-12
Nebcin Inj 10mg/ml (vantage Vial)	Liquid		Intravenous	Eli Lilly & Co. Ltd.	1989-12-31	1997-05-20
Nebcin Inj 40mg/ml	Liquid		Intramuscular; Intravenous	Eli Lilly & Co. Ltd.	1975-12-31	2003-05-12
Nebcin Inj 60mg	Liquid		Intramuscular; Intravenous	Eli Lilly & Co. Ltd.	1978-12-31	1998-08-04
Nebcin Inj 80mg	Liquid		Intramuscular; Intravenous	Eli Lilly & Co. Ltd.	1978-12-31	1998-08-04
Tobi	Solution	300 mg	Respiratory (inhalation)	Bgp Pharma Ulc	1999-04-28	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Aj-tobramycin	Liquid		Intramuscular; Intravenous	Agila Jamp Canada Inc	Not applicable	Not applicable
Apo-tobramycin	Solution		Ophthalmic	Apotex Corporation	2002-09-18	Not applicable
Jamp-tobramycin	Solution		Intramuscular; Intravenous	Jamp Pharma Corporation	2014-03-11	Not applicable
PMS-tobramycin 0.3% Ophthalmic Solution	Liquid		Ophthalmic	Pharmascience Inc	1999-02-18	2017-09-30
Sandoz Tobramycin	Solution		Ophthalmic	Sandoz Canada Incorporated	2000-08-21	Not applicable
Teva-tobramycin	Solution		Respiratory (inhalation)	TEVA Canada Limited	2016-02-03	Not applicable
Tobramycin	Solution / drops	3 mg/1mL	Ophthalmic	Proficient Rx LP	2017-07-05	Not applicable
Tobramycin	Injection	40 mg/1mL	Intramuscular; Intravenous	Baxter Healthcare Corporation	2016-07-15	Not applicable
Tobramycin	Solution	3 mg/1mL	Ophthalmic	Directrx	2019-04-23	Not applicable
Tobramycin	Injection	1200 mg/30mL	Intravenous	Xellia Pharmaceuticals ApS	2014-04-10	Not applicable

Over the Counter Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
DW TOBRAMYCIN OPHTHALMIC SOLUTION	Liquid		Ophthalmic	บริษัท ฐิติรัตน์สานนท์ จำกัด	2006-06-06	Not applicable
TOBREX	Solution / drops		Ophthalmic	บริษัท โนวาร์ตีส (ประเทศไทย) จำกัด	2017-09-12	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
COMBİDEX %0.3 + %0.1 GÖZ DAMLASI, ÇÖZELTİ, 1 ADET	Tobramycin (0.3 %) + Dexamethasone (0.1 %)	Solution / drops	Ophthalmic	BİLİM İLAÇ SAN. VE TİC. A.Ş.	2020-08-14	Not applicable
COMBIDEX OFTALMIK SÜSPANSIYON, 5 ML	Tobramycin (3 mg/ml) + Dexamethasone (1 mg/ml)	Suspension	Ophthalmic	BİLİM İLAÇ SAN. VE TİC. A.Ş.	2020-08-14	2018-08-16
LOTEBRA % 0.5+ % 0.3 GÖZ DAMLASI, SÜSPANSİYON, 5 ML	Tobramycin (0.3 %) + Loteprednol etabonate (0.5 %)	Suspension / drops	Ophthalmic	ABDİ İBRAHİM İLAÇ SAN. VE TİC. A.Ş.	2020-08-14	Not applicable
OCUBRAX STERIL GOZ DAMLASI, 5 ML	Tobramycin (0.3 %) + Diclofenac (0.1 %)	Solution / drops	Ophthalmic	LİBA LABORATUARLARI A.Ş.	2020-08-14	2017-12-20
OFTAMYCIN-DX %0.3 + %0.1 STERİL GÖZ DAMLASI, ÇÖZELTİ, 5 ML 1 ADET	Tobramycin (0.3 %) + Dexamethasone (0.1 %)	Solution / drops	Ophthalmic	Deva Holding A.S.	2020-08-14	Not applicable
OPHTHABRACIND SOLUCIÓN OFTALMICA	Tobramycin sulfate (3 mg) + Dexamethasone sodium phosphate (1 mg)	Solution	Conjunctival; Ophthalmic		2007-03-29	2016-09-01
TobraDex	Tobramycin (3 mg/1mL) + Dexamethasone (1 mg/1mL)	Suspension / drops	Ophthalmic	A-S Medication Solutions	1988-09-15	2017-01-31
TobraDex	Tobramycin (3 mg/1mL) + Dexamethasone (1 mg/1mL)	Suspension / drops	Ophthalmic	ALCON LABORATORIES, INC.	1988-09-15	Not applicable
TobraDex	Tobramycin (3 mg/1g) + Dexamethasone (1 mg/1g)	Ointment	Ophthalmic	A S Medication Solutions	1988-10-15	Not applicable
Tobradex	Tobramycin (3 mg/1mL) + Dexamethasone (1 mg/1mL)	Suspension	Ophthalmic	Stat Rx USA	1988-09-15	Not applicable

Chemical Identifiers

UNII: VZ8RRZ51VK
CAS number: 32986-56-4
InChI Key: NLVFBUXFDBBNBW-PBSUHMDJSA-N
InChI: 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
IUPAC Name: (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
SMILES: NC[C@H]1O[C@H](O[C@@H]2[C@@H](N)C[C@@H](N)[C@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H]2O)[C@H](N)C[C@@H]1O

References

Synthesis Reference

Istvan Bakondi-Kovacs, "Metabolic controlled fermentation process for carbamoyl tobramycin production." U.S. Patent US20020197683, issued December 26, 2002.

US20020197683

General References

Serio AW, Keepers T, Andrews L, Krause KM: Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation. EcoSal Plus. 2018 Nov;8(1). doi: 10.1128/ecosalplus.ESP-0002-2018. [PubMed:30447062]
Bulitta JB, Ly NS, Landersdorfer CB, Wanigaratne NA, Velkov T, Yadav R, Oliver A, Martin L, Shin BS, Forrest A, Tsuji BT: Two mechanisms of killing of Pseudomonas aeruginosa by tobramycin assessed at multiple inocula via mechanism-based modeling. Antimicrob Agents Chemother. 2015 Apr;59(4):2315-27. doi: 10.1128/AAC.04099-14. Epub 2015 Feb 2. [PubMed:25645838]
Moore RA, Bates NC, Hancock RE: Interaction of polycationic antibiotics with Pseudomonas aeruginosa lipopolysaccharide and lipid A studied by using dansyl-polymyxin. Antimicrob Agents Chemother. 1986 Mar;29(3):496-500. doi: 10.1128/aac.29.3.496. [PubMed:3013085]
Hancock RE, Raffle VJ, Nicas TI: Involvement of the outer membrane in gentamicin and streptomycin uptake and killing in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1981 May;19(5):777-85. doi: 10.1128/aac.19.5.777. [PubMed:6794444]
Taber HW, Mueller JP, Miller PF, Arrow AS: Bacterial uptake of aminoglycoside antibiotics. Microbiol Rev. 1987 Dec;51(4):439-57. [PubMed:3325794]
Davis BD, Chen LL, Tai PC: Misread protein creates membrane channels: an essential step in the bactericidal action of aminoglycosides. Proc Natl Acad Sci U S A. 1986 Aug;83(16):6164-8. doi: 10.1073/pnas.83.16.6164. [PubMed:2426712]
O'Sullivan ME, Poitevin F, Sierra RG, Gati C, Dao EH, Rao Y, Aksit F, Ciftci H, Corsepius N, Greenhouse R, Hayes B, Hunter MS, Liang M, McGurk A, Mbgam P, Obrinsky T, Pardo-Avila F, Seaberg MH, Cheng AG, Ricci AJ, DeMirci H: Aminoglycoside ribosome interactions reveal novel conformational states at ambient temperature. Nucleic Acids Res. 2018 Oct 12;46(18):9793-9804. doi: 10.1093/nar/gky693. [PubMed:30113694]
Ying L, Zhu H, Shoji S, Fredrick K: Roles of specific aminoglycoside-ribosome interactions in the inhibition of translation. RNA. 2019 Feb;25(2):247-254. doi: 10.1261/rna.068460.118. Epub 2018 Nov 9. [PubMed:30413565]
Wallace BJ, Tai PC, Herzog EL, Davis BD: Partial inhibition of polysomal ribosomes of Escherichia coli by streptomycin. Proc Natl Acad Sci U S A. 1973 Apr;70(4):1234-7. doi: 10.1073/pnas.70.4.1234. [PubMed:4577795]
Borovinskaya MA, Pai RD, Zhang W, Schuwirth BS, Holton JM, Hirokawa G, Kaji H, Kaji A, Cate JH: Structural basis for aminoglycoside inhibition of bacterial ribosome recycling. Nat Struct Mol Biol. 2007 Aug;14(8):727-32. doi: 10.1038/nsmb1271. Epub 2007 Jul 29. [PubMed:17660832]
Tai PC, Wallace BJ, Davis BD: Streptomycin causes misreading of natural messenger by interacting with ribosomes after initiation. Proc Natl Acad Sci U S A. 1978 Jan;75(1):275-9. doi: 10.1073/pnas.75.1.275. [PubMed:343106]
Doi Y, Wachino JI, Arakawa Y: Aminoglycoside Resistance: The Emergence of Acquired 16S Ribosomal RNA Methyltransferases. Infect Dis Clin North Am. 2016 Jun;30(2):523-537. doi: 10.1016/j.idc.2016.02.011. [PubMed:27208771]
FDA Approved Drug Products: TOBI PODHALER (tobramycin) inhalation [Link]
FDA Approved Drug Products: TOBREX (tobramycin) ophthalmic [Link]
FDA Approved Drug Products: tobramycin for injection [Link]
Cayman Chemical: tobramycin MSDS [Link]

External Links

Human Metabolome Database: HMDB0014822
KEGG Drug: D00063
KEGG Compound: C00397
PubChem Compound: 36294
PubChem Substance: 46507662
ChemSpider: 33377
BindingDB: 50366778
RxNav: 10627
ChEBI: 28864
ChEMBL: CHEMBL1747
ZINC: ZINC000008214692
Therapeutic Targets Database: DAP000110
PharmGKB: PA451704
PDBe Ligand: TOY
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Tobramycin

AHFS Codes

08:12.02 — Aminoglycosides
52:04.04 — Antibacterials

PDB Entries

1lc4 / 1m4d / 3sg8 / 3vet / 4ebk / 4evy / 4jd6 / 4lfc / 4xje / 5cfs …

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FDA label

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MSDS

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Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Cystic Fibrosis (CF)	1
4	Completed	Treatment	Antibotics in Cementless Knees	1
4	Completed	Treatment	Blepharokeratoconjunctivitis	1
4	Completed	Treatment	Cataracts / Pseudoexfoliation Syndrome	1
4	Completed	Treatment	Chalazion / Hordeolum	1
4	Completed	Treatment	Conjunctivitis	1
4	Completed	Treatment	Cystic Fibrosis (CF)	4
4	Completed	Treatment	Fever / Malignancies / Neutropenia	1
4	Completed	Treatment	Inflammatory Reaction	1
4	Completed	Treatment	Knee Replacement Surgery	1

Pharmacoeconomics

Manufacturers

Alcon laboratories inc
Akorn inc
Alcon universal ltd
Altana inc
Bausch and lomb pharmaceuticals inc
Novex pharma
Falcon pharmaceuticals ltd
Novartis pharmaceuticals corp
Eli lilly and co
Akorn strides llc
Apothecon inc div bristol myers squibb
App pharmaceuticals llc
Astrazeneca lp
Baxter healthcare corp anesthesia and critical care
Hospira inc
Marsam pharmaceuticals llc
Teva parenteral medicines inc
X gen pharmaceuticals inc

Packagers

Advanced Pharmaceutical Services Inc.
Akorn Inc.
Alcon Laboratories
Apotex Inc.
APP Pharmaceuticals
A-S Medication Solutions LLC
Bausch & Lomb Inc.
Bristol-Myers Squibb Co.
Cardinal Health
Clipper Distributing Co. LLC
Darby Dental Supply Co. Inc.
Dispensing Solutions
Diversified Healthcare Services Inc.
E.R. Squibb and Sons LLC
Eye Care and Cure Corp.
Falcon Pharmaceuticals Ltd.
H.J. Harkins Co. Inc.
Hospira Inc.
Innoviant Pharmacy Inc.
Keltman Pharmaceuticals Inc.
Lake Erie Medical and Surgical Supply
Major Pharmaceuticals
Medical Ophthalmics
Medisca Inc.
MWI Veterinary Supply Co.
Novartis AG
Novex Pharma
Nucare Pharmaceuticals Inc.
Ocusoft
Palmetto Pharmaceuticals Inc.
PD-Rx Pharmaceuticals Inc.
Pharmedix
Physicians Total Care Inc.
Preferred Pharmaceuticals Inc.
Rebel Distributors Corp.
Redpharm Drug
Rx Veterinary Products
Stat Rx Usa
Strides Arcolab Limited
Taylor Pharmaceuticals
Teva Pharmaceutical Industries Ltd.
Vedco Inc.
Wilson Ophthalmic Corp.
X-Gen Pharmaceuticals

Dosage Forms

Form	Route	Strength
Powder	Respiratory (inhalation)
Solution	Respiratory (inhalation)	300 mg/4mL
Solution
Spray	Respiratory (inhalation)
Solution	Respiratory (inhalation)
Solution / drops	Auricular (otic)
Solution / drops	Intraocular
Solution	Conjunctival; Ophthalmic
Ointment	Conjunctival; Ophthalmic; Topical
Solution	Respiratory (inhalation)	300 mg/5mL
Liquid	Intramuscular; Intravenous
Liquid	Intravenous
Injection, solution	Intramuscular; Intravenous
Ointment	Conjunctival; Ophthalmic
Liquid	Ophthalmic
Solution	Ophthalmic
Suspension	Auricular (otic)
Suspension / drops	Auricular (otic)
Solution / drops	Conjunctival
Injection	Intramuscular; Intravenous
Solution	Oral	300 mg/5mL
Solution	Respiratory (inhalation)	300 mg
Capsule	Oral; Respiratory (inhalation)	28 mg/1
Capsule	Respiratory (inhalation)	28 mg
Powder, metered	Respiratory (inhalation)
Capsule, coated	Oral
Ointment	Ophthalmic
Suspension	Ophthalmic
Ointment	Conjunctival; Ophthalmic
Solution / drops	Ophthalmic
Solution / drops
Suspension / drops	Intraocular
Injection, solution	Parenteral
Ointment	Ophthalmic; Topical
Injection, solution
Injection	Intramuscular; Intravenous	10 mg/1mL
Injection	Intramuscular; Intravenous	40 mg/1mL
Injection	Intravenous	1200 mg/30mL
Injection	Intravenous	40 mg/1mL
Injection, powder, for solution	Intravenous	1200 mg/30mL
Injection, powder, lyophilized, for solution	Intravenous	1.2 g/30mL
Injection, solution	Intramuscular; Intravenous	10 mg/1mL
Injection, solution	Intramuscular; Intravenous	40 mg/1mL
Injection, solution	Intravenous	40 mg/1mL
Injection, solution, concentrate	Intravenous	10 mg/1mL
Solution	Ophthalmic	3 mg/1mL
Solution	Ophthalmic	3.0 mg/1mL
Solution	Oral	3 mg/1mL
Solution	Respiratory (inhalation)	60 mg/1mL
Solution / drops	Ophthalmic	3 mg/1mL
Solution / drops	Ophthalmic	3.0 mg/1mL
Suspension / drops	Ophthalmic
Solution	Parenteral
Powder, for solution	Intravenous
Injection, solution	Intravenous	0.8 mg/1mL
Injection, solution	Intravenous	1.2 mg/1mL
Inhalant	Respiratory (inhalation)	300 mg/5mL
Solution	Intramuscular; Intravenous
Solution	Ophthalmic; Topical
Injection, solution, concentrate	Intravenous
Suspension	Conjunctival; Ophthalmic
Solution	Conjunctival; Ophthalmic	3 mg
Ointment	Ophthalmic	0.3 %
Ointment	Ophthalmic	3 mg/1g
Solution	Ophthalmic	0.3 %
Solution / drops	Ophthalmic
Ointment	Ophthalmic
Solution	Conjunctival; Ophthalmic
Solution	Respiratory (inhalation)	170 mg
Liquid	Ophthalmic

Prices

Unit description	Cost	Unit
Tobi (1 Box = 56, 5ml Ampules = 280ml Total) 280ml Plastic Container	4461.42USD	plastic
Tobramycin 1.2 gm vial	338.25USD	vial
TobraDex 0.3-0.1% Suspension 10ml Bottle	200.43USD	bottle
TobraDex 0.3-0.1% Ointment 3.5 gm Tube	126.67USD	tube
TobraDex 0.3-0.1% Suspension 5ml Bottle	98.11USD	bottle
Tobrex 0.3% Ointment 3.5 gm Tube	80.02USD	tube
Tobrex 0.3% Solution 5ml Bottle	67.58USD	bottle
TobraDex 0.3-0.1% Suspension 2.5ml Bottle	54.99USD	bottle
Tobramycin sulfate powder	53.55USD	g
Tobradex eye drops	19.27USD	ml
Tobi 300 mg/5 ml solution	17.58USD	ml
Tobramycin Sulfate 0.3% Solution 5ml Bottle	15.99USD	bottle
Tobrex 0.3% eye drops	13.0USD	ml
Tobi 60 mg/ml Solution	11.4USD	ml
Tobramycin Sulfate 40 mg/ml Solution	3.6USD	ml
Tobramycin 40 mg/ml	3.14USD	ml
Tobramycin 0.3% eye drops	2.99USD	ml
Aktob 0.3% eye drops	2.85USD	ml
Tobrex 0.3 % Ointment	2.66USD	g
Tobramycin 10 mg/ml	2.26USD	ml
Tobrex 0.3 % Solution	1.88USD	ml
Pms-Tobramycin 0.3 % Solution	1.05USD	ml
Sandoz Tobramycin 0.3 % Solution	1.05USD	ml
Tobramycin 60 mg/50 ml ns	0.19USD	ml

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US5508269	No	1996-04-16	2014-10-19
US5149694	No	1992-09-22	2009-09-22
CA2414737	No	2009-01-06	2021-06-26
US7795316	No	2010-09-14	2028-08-03
US8101582	No	2012-01-24	2027-12-19
US8450287	No	2013-05-28	2027-12-19
US7368102	No	2008-05-06	2022-12-19
US8715623	No	2014-05-06	2022-12-19
US7559325	No	2009-07-14	2025-10-27
US7442388	No	2008-10-28	2020-05-10
US7097827	No	2006-08-29	2016-04-16
US8349294	No	2013-01-08	2020-05-10
US8069851	No	2011-12-06	2024-09-24
US7516741	No	2009-04-14	2024-01-11
US7939502	No	2011-05-10	2022-06-14
US6987094	No	2006-01-17	2022-09-22
US7696178	No	2010-04-13	2023-03-17
US10207066	No	2019-02-19	2030-11-04
US8664187	No	2014-03-04	2025-06-20
US8869794	No	2014-10-28	2028-09-12
US9421166	No	2016-08-23	2022-12-19
USRE47526	No	2004-04-09	2024-04-09

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	freely soluble	FDA Label
logP	-5.8	https://www.fishersci.com/store/msds?partNumber=AC455430010&productDescription=TOBRAMYCIN%2C+97%25+1GR&vendorId=VN00032119&countryCode=US&language=en

Predicted Properties

Property	Value	Source
Water Solubility	53.7 mg/mL	ALOGPS
logP	-3	ALOGPS
logP	-6.5	ChemAxon
logS	-0.94	ALOGPS
pKa (Strongest Acidic)	12.54	ChemAxon
pKa (Strongest Basic)	9.83	ChemAxon
Physiological Charge	5	ChemAxon
Hydrogen Acceptor Count	14	ChemAxon
Hydrogen Donor Count	10	ChemAxon
Polar Surface Area	268.17 Å²	ChemAxon
Rotatable Bond Count	6	ChemAxon
Refractivity	106.69 m³·mol^-1	ChemAxon
Polarizability	47.18 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	-	0.9313
Blood Brain Barrier	-	0.9794
Caco-2 permeable	-	0.759
P-glycoprotein substrate	Substrate	0.5933
P-glycoprotein inhibitor I	Non-inhibitor	0.7579
P-glycoprotein inhibitor II	Non-inhibitor	0.9086
Renal organic cation transporter	Non-inhibitor	0.8412
CYP450 2C9 substrate	Non-substrate	0.8361
CYP450 2D6 substrate	Non-substrate	0.8333
CYP450 3A4 substrate	Non-substrate	0.6662
CYP450 1A2 substrate	Non-inhibitor	0.9052
CYP450 2C9 inhibitor	Non-inhibitor	0.9359
CYP450 2D6 inhibitor	Non-inhibitor	0.923
CYP450 2C19 inhibitor	Non-inhibitor	0.9117
CYP450 3A4 inhibitor	Non-inhibitor	0.9728
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9398
Ames test	Non AMES toxic	0.7537
Carcinogenicity	Non-carcinogens	0.9469
Biodegradation	Not ready biodegradable	0.9052
Rat acute toxicity	1.7638 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9695
hERG inhibition (predictor II)	Non-inhibitor	0.7522

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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with our fully connected ADMET & drug target dataset.

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Details1. 16S ribosomal RNA

Kind

Nucleotide

Organism

Enteric bacteria and other eubacteria

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Aminoglycosides bind the 16S rRNA near the A site of the 30S ribosomal subunit, disrupting interactions between helix 44 (h44) and h45, causing impaired translation and the production of mistranslated proteins.

In prokaryotes, the 16S rRNA is essential for recognizing the 5' end of mRNA and hence positioning it correctly on the ribosome. The 16S rRNA has a characteristic secondary structure in which half of the nucleotides are base-paired. The 16S rRNA sequence has been highly conserved and is often used for evolutionary and species comparative analysis.

References

Doi Y, de Oliveira Garcia D, Adams J, Paterson DL: Coproduction of novel 16S rRNA methylase RmtD and metallo-beta-lactamase SPM-1 in a panresistant Pseudomonas aeruginosa isolate from Brazil. Antimicrob Agents Chemother. 2007 Mar;51(3):852-6. Epub 2006 Dec 11. [PubMed:17158944]
Bogaerts P, Galimand M, Bauraing C, Deplano A, Vanhoof R, De Mendonca R, Rodriguez-Villalobos H, Struelens M, Glupczynski Y: Emergence of ArmA and RmtB aminoglycoside resistance 16S rRNA methylases in Belgium. J Antimicrob Chemother. 2007 Mar;59(3):459-64. Epub 2007 Jan 15. [PubMed:17224412]
Chen SY, Lin TH: A molecular dynamics study on binding recognition between several 4,5 and 4,6-linked aminoglycosides with A-site RNA. J Mol Recognit. 2010 Sep-Oct;23(5):423-34. doi: 10.1002/jmr.1008. [PubMed:20029836]
O'Sullivan ME, Poitevin F, Sierra RG, Gati C, Dao EH, Rao Y, Aksit F, Ciftci H, Corsepius N, Greenhouse R, Hayes B, Hunter MS, Liang M, McGurk A, Mbgam P, Obrinsky T, Pardo-Avila F, Seaberg MH, Cheng AG, Ricci AJ, DeMirci H: Aminoglycoside ribosome interactions reveal novel conformational states at ambient temperature. Nucleic Acids Res. 2018 Oct 12;46(18):9793-9804. doi: 10.1093/nar/gky693. [PubMed:30113694]
Ying L, Zhu H, Shoji S, Fredrick K: Roles of specific aminoglycoside-ribosome interactions in the inhibition of translation. RNA. 2019 Feb;25(2):247-254. doi: 10.1261/rna.068460.118. Epub 2018 Nov 9. [PubMed:30413565]
Serio AW, Keepers T, Andrews L, Krause KM: Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation. EcoSal Plus. 2018 Nov;8(1). doi: 10.1128/ecosalplus.ESP-0002-2018. [PubMed:30447062]

Details2. 23S ribosomal RNA

Kind

Nucleotide

Organism

Enteric bacteria and other eubacteria

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

It is suggested that aminoglycoside binding to helix 69 (h69) of the 23S rRNA inhibits ribosome recycling.

In prokaryotes, the 23S rRNA is part of the large subunit (the 50S) that joins with the 30S small subunit to create the functional 70S ribosome. The ribosome is comprised of 3 RNAs: the 23S, the 16S and the 5S ribosomal RNAs. The 23S and the 5S associate with their respective proteins to make up the large subunit of the ribosome, while the 16S RNA associates with its proteins to make up the small subunit.

References

Ying L, Zhu H, Shoji S, Fredrick K: Roles of specific aminoglycoside-ribosome interactions in the inhibition of translation. RNA. 2019 Feb;25(2):247-254. doi: 10.1261/rna.068460.118. Epub 2018 Nov 9. [PubMed:30413565]
Borovinskaya MA, Pai RD, Zhang W, Schuwirth BS, Holton JM, Hirokawa G, Kaji H, Kaji A, Cate JH: Structural basis for aminoglycoside inhibition of bacterial ribosome recycling. Nat Struct Mol Biol. 2007 Aug;14(8):727-32. doi: 10.1038/nsmb1271. Epub 2007 Jul 29. [PubMed:17660832]

3. Bacterial outer membrane

Kind

Group

Organism

Bacteria

Pharmacological action

Yes

Actions

Incorporation into and destabilization

Curator comments

Aminoglycosides like tobramycin are known to bind to, and destabilize, the outer membrane of Gram-negative bacteria, primarily through interacting with teichoic acid and phospholipids.

References

Serio AW, Keepers T, Andrews L, Krause KM: Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation. EcoSal Plus. 2018 Nov;8(1). doi: 10.1128/ecosalplus.ESP-0002-2018. [PubMed:30447062]
Moore RA, Bates NC, Hancock RE: Interaction of polycationic antibiotics with Pseudomonas aeruginosa lipopolysaccharide and lipid A studied by using dansyl-polymyxin. Antimicrob Agents Chemother. 1986 Mar;29(3):496-500. doi: 10.1128/aac.29.3.496. [PubMed:3013085]
Hancock RE, Raffle VJ, Nicas TI: Involvement of the outer membrane in gentamicin and streptomycin uptake and killing in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1981 May;19(5):777-85. doi: 10.1128/aac.19.5.777. [PubMed:6794444]
Taber HW, Mueller JP, Miller PF, Arrow AS: Bacterial uptake of aminoglycoside antibiotics. Microbiol Rev. 1987 Dec;51(4):439-57. [PubMed:3325794]

4. Cytoplasmic membrane

Kind

Group

Organism

Bacteria

Pharmacological action

Yes

Actions

Incorporation into and destabilization

Curator comments

Aminoglycosides like tobramycin are known to bind to, and destabilize, the cytoplasmic membrane of both Gram-negative and Gram-positive bacteria, primarily through interacting with lipopolysaccharide and phospholipids. This also occurs indirectly as a result of the incorporation of misfolded proteins into the cell membrane.

References

Serio AW, Keepers T, Andrews L, Krause KM: Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation. EcoSal Plus. 2018 Nov;8(1). doi: 10.1128/ecosalplus.ESP-0002-2018. [PubMed:30447062]
Taber HW, Mueller JP, Miller PF, Arrow AS: Bacterial uptake of aminoglycoside antibiotics. Microbiol Rev. 1987 Dec;51(4):439-57. [PubMed:3325794]
Davis BD, Chen LL, Tai PC: Misread protein creates membrane channels: an essential step in the bactericidal action of aminoglycosides. Proc Natl Acad Sci U S A. 1986 Aug;83(16):6164-8. doi: 10.1073/pnas.83.16.6164. [PubMed:2426712]

Drug created on June 13, 2005 13:24 / Updated on April 16, 2021 12:23

Tobramycin

Identification

Structure for Tobramycin (DB00684)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

References

References

References

References