Tobramycin

Tobramycin
Names
Trade namesTobrex, Tobi, others
Other names47663, SPRC-AB01
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
Clinical data
Drug classAminoglycoside[1]
Main usesSepsis, meningitis, urinary tract infections, bone infections, lung infections[2][1]
Side effectsHearing problems, balance problems, kidney problems[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
    Routes of
    use    		IV, IM, inhalation, eye drop
    External links
    AHFS/Drugs.comSystemic: Monograph
    Eyes: Monograph
    MedlinePlusa682660
    Legal
    License data
    Legal status
    • UK: POM (Prescription only) [5]
    • US: ℞-only
    • EU: Rx-only
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Protein binding< 30%
    Chemical and physical data
    FormulaC18H37N5O9
    Molar mass467.515 g·mol−1
    3D model (JSmol)
    SMILES
    • 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
    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 checkY
    • Key:NLVFBUXFDBBNBW-PBSUHMDJSA-N checkY

    Tobramycin is an antibiotic used to treat a variety of infections including sepsis, meningitis, urinary tract infections, bone infections, and lung infections.[2][1] This includes infections due to Pseudomonas.[1] It may be given by injection into a vein or muscle, or inhaled into the lungs.[2]

    Common side effects include hearing problems, balance problems, and kidney problems.[1] Other side effects may include paralysis and anaphylaxis.[1] The dose needs to be lowered in those with kidney problems.[1] Use in pregnancy may harm the baby.[1] It is an aminoglycoside.[1]

    Tobramycin was patented in 1965, and approved for medical use in 1974.[6] The eye drop is on the World Health Organization's List of Essential Medicines as an alternative to gentamicin.[7] It is available as a generic medication.[2] In the United Kingdom 80 mg for injection costs the NHS about £5 while a month of inhaled medication is about £780.[2] This amount of inhaled solution in the United States costs about 4,900 USD as of 2021.[8] It is made from Streptomyces tenebrarius.[1]

    Medical uses

    Like all aminoglycosides, tobramycin does not pass the gastro-intestinal tract, so for systemic use it can only be given intravenously or by injection into a muscle. Ophthalmic (tobramycin only, Tobrex, or combined with dexamethasone, sold as Tobradex) and nebulised formulations both have low systemic absorption. The formulation for injection is branded Nebcin. The nebulised formulation (brand name Tobi) is indicated in the treatment of exacerbations of chronic infection with Pseudomonas aeruginosa in people diagnosed with cystic fibrosis.[9][10]

    Tobrex is a 0.3% tobramycin sterile ophthalmic solution produced by Bausch & Lomb Pharmaceuticals. Benzalkonium chloride 0.01% is added as a preservative. It is available by prescription only in Bulgaria, Hungary, the United States, and Canada. In certain countries, it is available over the counter. Tobrex and Tobradex are indicated in the treatment of superficial infections of the eye, such as bacterial conjunctivitis.[11][12][13][14]

    Tobramycin (injection) is also indicated for various severe or life-threatening infections caused by susceptible strains: sepsis, meningitis, lower respiratory tract infections, intra-abdominal infections, skin infections, bone infections, and skin structure infections, complicated and recurrent urinary tract infections.[15][5]

    Spectrum of susceptibility

    Tobramycin has a narrow spectrum of activity and is active against Gram-positive Staphylococcus aureus and various Gram-negative bacteria.[15] Clinically, tobramycin is frequently used to eliminate Pseudomonas aeruginosa in cystic fibrosis patients. The following represents MIC susceptibility data for a few strains of Pseudomonas aeruginosa:

    • Pseudomonas aeruginosa - <0.25 µg/mL - 92 µg/mL [ref?]
    • Pseudomonas aeruginosa (non-mucoid) - 0.5 µg/mL - >512 µg/mL [ref?]
    • Pseudomonas aeruginosa (ATCC 27853) - 0.5 µg/mL - 2 µg/mL[16]

    The MIC for Klebsiella pneumoniae, KP-1, is 2.3±0.2 µg/mL at 25 °C [unpublished].

    Dosage

    For sepsis and meningitis it is often used at a dose of 1 mg/kg three times per day.[2] The maximum dose is generally 5 mg/kg in a day.[1]

    For lung infections due to Pseudomonas in people with cystic fibrosis it may be inhaled at a dose of 112 mg to 300 mg twice a day for 4 weeks.[2]

    Side effects

    Like other aminoglycosides, tobramycin is ototoxic:[17] it can cause hearing loss, or a loss of equilibrioception, or both in genetically susceptible individuals. These individuals carry a normally harmless genetic mutation that allows aminoglycosides such as tobramycin to affect cochlear cells. Aminoglycoside-induced ototoxicity is generally irreversible.

    As with all aminoglycosides, tobramycin is also nephrotoxic, it can damage or destroy the tissue of the kidneys. This effect can be particularly worrisome when multiple doses accumulate over the course of a treatment[18] or when the kidney concentrates urine by increasing tubular reabsorption during sleep. Adequate hydration may help prevent excess nephrotoxicity and subsequent loss of renal function. For these reasons parenteral tobramycin needs to be carefully dosed by body weight, and its serum concentration monitored. Tobramycin is thus said to be a drug with a narrow therapeutic index.

    Mechanism of action

    Tobramycin works by binding to a site on the bacterial 30S and 50S ribosome, preventing formation of the 70S complex.[19] As a result, mRNA cannot be translated into protein, and cell death ensues.[20] Tobramycin also binds to RNA-aptamers,[21] artificially created molecules to bind to certain targets. However, there seems to be no indication that Tobramycin binds to natural RNAs or other nucleic acids.

    The effect of tobramycin can be inhibited by metabolites of the Krebs (TCA) cycle, such as glyoxylate. These metabolites protect against tobramycin lethality by diverting carbon flux away from the TCA cycle, collapsing cellular respiration, and thereby inhibiting Tobramycin uptake and thus lethality.[22]

    Society and culture

    Cost

    The cost of this medication in the U.S. is $28 (USD) for 30 ml injectable solution 40 mg/mL[23]

    • Tobramycin costs (US)
      Tobramycin costs (US)
    • Tobramycin prescriptions (US)
      Tobramycin prescriptions (US)

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 "Tobramycin (Systemic) Monograph for Professionals". Drugs.com. Archived from the original on 21 January 2021. Retrieved 4 October 2021.
    2. 1 2 3 4 5 6 7 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 547. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    3. 1 2 "Tobramycin Use During Pregnancy". Drugs.com. 11 November 2019. Archived from the original on 9 August 2020. Retrieved 28 April 2020.
    4. 1 2 "Tobramycin ophthalmic Use During Pregnancy". Drugs.com. 24 December 2019. Archived from the original on 13 April 2020. Retrieved 28 April 2020.
    5. 1 2 "Tobramycin 40mg/ml Injection - Summary of Product Characteristics (SmPC)". (emc). 9 October 2018. Archived from the original on 9 August 2020. Retrieved 28 April 2020.
    6. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 507. ISBN 9783527607495. Archived from the original on 1 August 2020. Retrieved 20 September 2020.
    7. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
    8. ↑ "Tobramycin Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 16 January 2021. Retrieved 5 October 2021.
    9. ↑ "Tobi- tobramycin solution". DailyMed. 5 October 2018. Archived from the original on 17 August 2020. Retrieved 28 April 2020.
    10. ↑ "Tobi Podhaler". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 9 August 2020. Retrieved 28 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    11. ↑ "Tobrex- tobramycin ointment". DailyMed. 16 September 2019. Archived from the original on 17 August 2020. Retrieved 28 April 2020.
    12. ↑ "Tobradex Eye Drops - Summary of Product Characteristics (SmPC)". (emc). 21 January 2020. Archived from the original on 9 August 2020. Retrieved 28 April 2020.
    13. ↑ "Tobradex- tobramycin and dexamethasone ointment". DailyMed. 11 September 2019. Archived from the original on 17 August 2020. Retrieved 28 April 2020.
    14. ↑ "Tobradex- tobramycin and dexamethasone suspension/ drops". DailyMed. 9 September 2019. Archived from the original on 17 August 2020. Retrieved 28 April 2020.
    15. 1 2 "Tobramycin- tobramycin sulfate injection, powder, for solution". DailyMed. 11 October 2019. Archived from the original on 17 August 2020. Retrieved 28 April 2020.
    16. ↑ "Tobramycin Susceptibility and Minimum Inhibitory Concentration (MIC) Data" (PDF). Toku-E. Archived (PDF) from the original on 3 March 2016. Retrieved 25 September 2014.
    17. ↑ Lerner AM, Reyes MP, Cone LA, Blair DC, Jansen W, Wright GE, Lorber RR (May 1983). "Randomised, controlled trial of the comparative efficacy, auditory toxicity, and nephrotoxicity of tobramycin and netilmicin". Lancet. 1 (8334): 1123–6. doi:10.1016/S0140-6736(83)92864-7. PMID 6133153. S2CID 8303933.
    18. ↑ Pedersen SS, Jensen T, Osterhammel D, Osterhammel P (April 1987). "Cumulative and acute toxicity of repeated high-dose tobramycin treatment in cystic fibrosis". Antimicrobial Agents and Chemotherapy. 31 (4): 594–9. doi:10.1128/AAC.31.4.594. PMC 174783. PMID 3606063.
    19. ↑ Yang G, Trylska J, Tor Y, McCammon JA (September 2006). "Binding of aminoglycosidic antibiotics to the oligonucleotide A-site model and 30S ribosomal subunit: Poisson-Boltzmann model, thermal denaturation, and fluorescence studies". Journal of Medicinal Chemistry. 49 (18): 5478–90. doi:10.1021/jm060288o. PMID 16942021.
    20. ↑ Haddad J, Kotra LP, Llano-Sotelo B, Kim C, Azucena EF, Liu M, et al. (April 2002). "Design of novel antibiotics that bind to the ribosomal acyltransfer site". Journal of the American Chemical Society. 124 (13): 3229–37. doi:10.1021/ja011695m. PMID 11916405.
    21. ↑ Kotra LP, Haddad J, Mobashery S (December 2000). "Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance". Antimicrobial Agents and Chemotherapy. 44 (12): 3249–56. doi:10.1128/aac.44.12.3249-3256.2000. PMC 90188. PMID 11083623.
    22. ↑ Meylan S, Porter CB, Yang JH, Belenky P, Gutierrez A, Lobritz MA, et al. (February 2017). "Carbon Sources Tune Antibiotic Susceptibility in Pseudomonas aeruginosa via Tricarboxylic Acid Cycle Control". Cell Chemical Biology. 24 (2): 195–206. doi:10.1016/j.chembiol.2016.12.015. PMC 5426816. PMID 28111098.
    23. ↑ "Tobramycin Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 16 January 2021. Retrieved 8 April 2021.
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