Tobramycin

Tobramycin does not pass the gastro-intestinal tract, so for systemic use it can only be given intravenously or by injection into a muscle. Eye drops and ointments (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.{{cite web | title=Tobi- tobramycin solution | website=DailyMed | date=5 October 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=94f9e516-6bf6-4e30-8dde-8833c25c2560 | access-date=28 April 2020}}{{cite web | title=Tobi Podhaler | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/tobi-podhaler | access-date=28 April 2020}} {{PD-notice}}

Tobramycin eye drops (with or without dexamethasone) are indicated in the treatment of superficial infections of the eye, such as bacterial conjunctivitis.{{cite web | title=Tobrex- tobramycin ointment | website=DailyMed | date=16 September 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cdd423c5-a231-47d4-bf51-00b5c29e6a60 | access-date=28 April 2020}}{{cite web | title=Tobradex Eye Drops – Summary of Product Characteristics (SmPC) | website=(emc) | date=21 January 2020 | url=https://www.medicines.org.uk/emc/product/1324/smpc | access-date=28 April 2020}}{{cite web | title=Tobradex- tobramycin and dexamethasone ointment | website=DailyMed | date=11 September 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5538d748-215c-4e3e-b940-ac9baf07d8a1 | access-date=28 April 2020}}{{cite web | title=Tobradex- tobramycin and dexamethasone suspension/ drops | website=DailyMed | date=9 September 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=22b59456-d26a-4f23-b052-3d73e00181eb | access-date=28 April 2020}}

Tobramycin, in its injectable form, 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.{{cite web | title=Tobramycin- tobramycin sulfate injection, powder, for solution | website=DailyMed | date=11 October 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d62ff359-912b-4be1-9fc2-2dde8777eefb | access-date=28 April 2020}}

Tobramycin has a narrow spectrum of activity and is active against Gram-positive Staphylococcus aureus and various Gram-negative bacteria. Clinically, tobramycin is frequently used to eliminate Pseudomonas aeruginosa in cystic fibrosis patients. {{cn|date=March 2023}}The following represents the minimum inhibitory concentration (MIC) susceptibility data for a few strains of Pseudomonas aeruginosa:

• Pseudomonas aeruginosa - <0.25 μg/mL – 92 μg/mL{{medical citation needed|date=February 2024}}
• Pseudomonas aeruginosa (non-mucoid) – 0.5 μg/mL - >512 μg/mL{{medical citation needed|date=February 2024}}
• Pseudomonas aeruginosa (ATCC 27853) – 0.5 μg/mL – 2 μg/mL{{cite web | title = Tobramycin Susceptibility and Minimum Inhibitory Concentration (MIC) Data | url = http://www.toku-e.com/Assets/MIC/Tobramycin.pdf | work = Toku-E }}

The MIC for Klebsiella pneumoniae, KP-1, is 2.3±0.2 μg/mL at 25 °C [unpublished]{{clarify|date=February 2024}}.{{medical citation needed|date=February 2024}}

Tobramycin is contraindicated in people with hypersensitivity against aminoglycoside antibiotics.{{cite book|title=Austria-Codex|veditors = Haberfeld H|at=Tobrex Augentropfen|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2021|language=German}} The Infusion is also contraindicated in people with myasthenia gravis.

Like other aminoglycosides, a major side effect for tobramycin is ototoxicity or a loss of equilibrioception, or both in genetically susceptible individuals.{{cite journal | vauthors = Lerner AM, Reyes MP, Cone LA, Blair DC, Jansen W, Wright GE, Lorber RR | title = Randomised, controlled trial of the comparative efficacy, auditory toxicity, and nephrotoxicity of tobramycin and netilmicin | journal = Lancet | volume = 1 | issue = 8334 | pages = 1123–6 | date = May 1983 | pmid = 6133153 | doi = 10.1016/S0140-6736(83)92864-7 | s2cid = 8303933 }} Other side effects include nephrotoxicity, neuromuscular toxicity, and hypersensitivity reactions.{{cite journal | vauthors = Neu HC | title = Tobramycin: an overview | journal = The Journal of Infectious Diseases | volume = 134 | issue = Suppl | pages = S3–19 | date = August 1976 | pmid = 787451 | doi = 10.1093/infdis/134.supplement_1.s3 | jstor = 30106949 }} Nephrotoxicity can be particularly worrisome when multiple doses accumulate over the course of a treatment{{cite journal | vauthors = Pedersen SS, Jensen T, Osterhammel D, Osterhammel P | title = Cumulative and acute toxicity of repeated high-dose tobramycin treatment in cystic fibrosis | journal = Antimicrobial Agents and Chemotherapy | volume = 31 | issue = 4 | pages = 594–9 | date = April 1987 | pmid = 3606063 | pmc = 174783 | doi = 10.1128/AAC.31.4.594 }} 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.{{Cite book | vauthors = Reyhanoglu G, Reddivari AK | chapter = Tobramycin| chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK551695/| title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing | date = January 2022 | pmid = 31869159 }} 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.{{cn|date=March 2023}}

Muscle relaxants and diethylether can add to the neuromuscular blocking effects of tobramycin.

Methoxyflurane, when used as an inhalational anesthetic, can aggravate the nephrotoxic effects of injected tobramycin. Likewise, combining injected tobramycin with other nephrotoxic or ototoxic drugs can lead to more adverse effects; examples include amphotericin B, ciclosporin, cisplatin, vancomycin, and the diuretic furosemide. Other diuretics can also increase the risk for side effects because they raise tobramycin concentrations in the body fluids.

Combining tobramycin with beta-lactam antibiotics can be desirable because of their synergistic effects. However, when they are given through the same drip, as well as in people with reduced kidney function, they can react with each other to form antibiotically inactive amides.

Tobramycin works by binding to a site on the bacterial 30S and 50S ribosome, preventing formation of the 70S complex.{{cite journal | vauthors = Yang G, Trylska J, Tor Y, McCammon JA | title = Binding of aminoglycosidic antibiotics to the oligonucleotide A-site model and 30S ribosomal subunit: Poisson-Boltzmann model, thermal denaturation, and fluorescence studies | journal = Journal of Medicinal Chemistry | volume = 49 | issue = 18 | pages = 5478–90 | date = September 2006 | pmid = 16942021 | doi = 10.1021/jm060288o }} As a result, mRNA cannot be translated into protein, and cell death ensues.{{cite journal | vauthors = Haddad J, Kotra LP, Llano-Sotelo B, Kim C, Azucena EF, Liu M, Vakulenko SB, Chow CS, Mobashery S | display-authors = 6 | title = Design of novel antibiotics that bind to the ribosomal acyltransfer site | journal = Journal of the American Chemical Society | volume = 124 | issue = 13 | pages = 3229–37 | date = April 2002 | pmid = 11916405 | doi = 10.1021/ja011695m | bibcode = 2002JAChS.124.3229H }} Tobramycin also binds to RNA-aptamers,{{cite journal | vauthors = Kotra LP, Haddad J, Mobashery S | title = Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance | journal = Antimicrobial Agents and Chemotherapy | volume = 44 | issue = 12 | pages = 3249–56 | date = December 2000 | pmid = 11083623 | pmc = 90188 | doi = 10.1128/aac.44.12.3249-3256.2000 }} 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.{{cn|date=March 2023}}

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.{{cite journal | vauthors = Meylan S, Porter CB, Yang JH, Belenky P, Gutierrez A, Lobritz MA, Park J, Kim SH, Moskowitz SM, Collins JJ | display-authors = 6 | title = Carbon Sources Tune Antibiotic Susceptibility in Pseudomonas aeruginosa via Tricarboxylic Acid Cycle Control | journal = Cell Chemical Biology | volume = 24 | issue = 2 | pages = 195–206 | date = February 2017 | pmid = 28111098 | pmc = 5426816 | doi = 10.1016/j.chembiol.2016.12.015 }}

Tobramycin is not absorbed in the gut. When given as infusion, it is distributed in the extracellular fluid. It can accumulate in the kidney's tubular cells and in the lymph of the inner ear. Only low concentrations reach the central nervous system and breast milk. Tobramycin passes the placenta: in the fetus, 20% of the mother's concentrations have been measured.

The substance is neither bound to plasma proteins, nor is it metabolized. It is excreted in unchanged form via the kidneys with a biological half-life of about 2 to 3 hours. Elimination from deep compartments such as the renal cortex follows after 8 to 12 hours. In newborns the half-life is 4.6 hours on average; in those with a low birth weight it is as long as 8.7 hours on average. People with reduced kidney function also have a longer half-life for tobramycin, while in those with severe burns it can be shorter.

Tobramycin was patented in 1965, and approved for medical use in 1974. Tobramycin is on the World Health Organization's List of Essential Medicines. In 2022, tobramycin was the 281st most commonly prescribed medication in the United States, with more than 600,000 prescriptions.

Tobrex eye drops are a 0.3% tobramycin sterile ophthalmic solution produced by Alcon Pharmaceuticals. Benzalkonium chloride 0.01% is added to Tobrex as a preservative.{{cn|date=February 2024}}

In Egypt, tobramycin (in the form of eye drops) is sold under the brand Tobrin, produced by EIPICo.{{cn|date=February 2024}}

{{Reflist}}

• {{cite journal | vauthors = Davis BD | title = Mechanism of bactericidal action of aminoglycosides | journal = Microbiological Reviews | volume = 51 | issue = 3 | pages = 341–50 | date = September 1987 | pmid = 3312985 | pmc = 373115 | doi = 10.1128/MMBR.51.3.341-350.1987 }}

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Category:Aminoglycoside antibiotics

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