Tobramycin

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Tobramycin
Tobramycin.svg
Tobramycin 1lc4.png
Names
Trade namesTobrex, Tobi, others
Other names47663, SPRC-AB01
  • (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]
Pregnancy
category
Routes of
use
IV, IM, inhalation, eye drop
External links
AHFS/Drugs.comSystemic: Monograph
Eyes: Monograph
US NLMTobramycin
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)
  • 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=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
  (verify)

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] 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.[7] 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.[8][9]

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.[10][11][12][13]

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.[14][5]

Spectrum of susceptibility

Tobramycin has a narrow spectrum of activity and is active against Gram-positive Staphylococcus aureus and various Gram-negative bacteria.[14] 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[15]

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:[16] 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[17] 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.[18] As a result, mRNA cannot be translated into protein, and cell death ensues.[19] Tobramycin also binds to RNA-aptamers,[20] 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.[21]

Society and culture

Cost

The cost of this medication in the U.S. is $28 (USD) for 30 ml injectable solution 40 mg/mL[22]

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 "Tobramycin (Systemic) Monograph for Professionals". Drugs.com. Retrieved 4 October 2021.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2021 – March 2021. p. 547. ISBN 978-0-85711-369-6.
  3. 3.0 3.1 "Tobramycin Use During Pregnancy". Drugs.com. 11 November 2019. Retrieved 28 April 2020.
  4. 4.0 4.1 "Tobramycin ophthalmic Use During Pregnancy". Drugs.com. 24 December 2019. Retrieved 28 April 2020.
  5. 5.0 5.1 "Tobramycin 40mg/ml Injection - Summary of Product Characteristics (SmPC)". (emc). 9 October 2018. Retrieved 28 April 2020.
  6. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 507. ISBN 9783527607495.
  7. "Tobramycin Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 5 October 2021.
  8. "Tobi- tobramycin solution". DailyMed. 5 October 2018. Retrieved 28 April 2020.
  9. "Tobi Podhaler". European Medicines Agency (EMA). 17 September 2018. Retrieved 28 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  10. "Tobrex- tobramycin ointment". DailyMed. 16 September 2019. Retrieved 28 April 2020.
  11. "Tobradex Eye Drops - Summary of Product Characteristics (SmPC)". (emc). 21 January 2020. Retrieved 28 April 2020.
  12. "Tobradex- tobramycin and dexamethasone ointment". DailyMed. 11 September 2019. Retrieved 28 April 2020.
  13. "Tobradex- tobramycin and dexamethasone suspension/ drops". DailyMed. 9 September 2019. Retrieved 28 April 2020.
  14. 14.0 14.1 "Tobramycin- tobramycin sulfate injection, powder, for solution". DailyMed. 11 October 2019. Retrieved 28 April 2020.
  15. "Tobramycin Susceptibility and Minimum Inhibitory Concentration (MIC) Data" (PDF). Toku-E.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. "Tobramycin Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 8 April 2021.

External links

External sites:
Identifiers: