Linezolid
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Linezolid
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| Systematic (IUPAC) name | |
| N-[[3-(3-fluoro-4-morpholinophenyl)- 2-oxooxazolidin-5-yl]methyl]acetamide |
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| Identifiers | |
| CAS number | |
| ATC code | J01 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C16H20FN3O4 |
| Mol. mass | 337.346 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ~100% (oral) |
| Protein binding | 31% |
| Metabolism | Hepatic 50–70% |
| Half life | 4.2–5.4 hours |
| Excretion | Renal 80–85% |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status |
S4 (Au), POM (UK), ℞-only (U.S.) |
| Routes | IV, oral |
Linezolid (INN) (pronounced /lɪˈnɛzəlɪd/) is a synthetic antibiotic, the first of the oxazolidinone class, used for the treatment of infections caused by multi-resistant bacteria including streptococcus[citation needed] and methicillin-resistant Staphylococcus aureus (MRSA).[1] It is marketed under the trade name Zyvox (or Zyvoxid in Europe) (Pfizer).
Linezolid was the first commercially available oxazolidinone antibiotic. Therapy using linezolid can be quite expensive, with prices for a course of treatment ranging up to several thousands of dollars.
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[edit] Usage
It is usually reserved for the treatment of serious bacterial infections where older antibiotics have failed due to antibiotic resistance. Conditions such as skin infections or nosocomial pneumonia where methicillin or penicillin resistance is found are indicators for linezolid use.
Linezolid is effective against gram-positive pathogens, notably Enterococcus faecium, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. It has almost no effect on gram-negative bacteria and is only bacteriostatic against most Enterococcus species. Linezolid also provides some anaerobic coverage.
Linezolid has been used to treat tuberculosis.[2]
[edit] History
The oxazolidinone class was discovered by researchers at E.I. duPont de Nemours and reported in 1987. Upjohn developed linezolid (Upjohn is now part of Pfizer) and Food and Drug Administration (FDA) approval was granted in April of 2000. It is sold in the U.S. under the tradename Zyvox in either tablet form, oral suspension powder, or in an inactive medium for intravenous injection.
Initially there was hope that bacteria would be unable to develop resistance to it. However, in 2001 Staphylococcus aureus was first identified as being resistant to linezolid.[3]
[edit] Mechanism of Action
Linezolid works on the initiation of protein synthesis. It does this by stopping the 30S and 50S subunits of the ribosome from binding together. Linezolid binds on the 23S portion of the 50S subunit close to the peptidyl transferase and chloramphenicol binding sites. This then stops the interaction with the 30S subunit.
[edit] Dosing
The adult dose of linezolid is 600mg twice daily orally or intravenously for a maximum of 14 days. The dose in children is 10mg/kg orally or intravenously three times a day for a maximum of 14 days.
Linezolid has been used in the treatment of tuberculosis (in combination with other drugs).[2] The optimal dose for use in tuberculosis is not known. In adults, 600mg daily[4] or 600mg twice daily[5] have both been used to good effect. The treatment often needs to be continued for many months and the rate of adverse effects is high.[4] The lower dose is not associated with a lower rate of adverse effects.[4]
[edit] Adverse effects
Side effects include rashes, loss of appetite, diarrhea, nausea, constipation and fever. A small number of patients will incur a severe allergic reaction, or tinnitus, or pseudomembranous colitis. Thrombocytopenia is uncommon in patients who receive linezolid for 14 days or fewer (the manufacturer's recommendation), but in patients who receive longer courses, or who have renal failure, the rate is much higher.[6] The anemia and thrombocytopenia caused by linezolid are not prevented by concurrent administration of pyridoxine 125mg daily.[7]
Linezolid is a weak monoamine oxidase inhibitor (MAOI) and cannot be used with tyramine containing foods or pseudoephedrine.
Linezolid is toxic to mitochondria (probably because of the similarity between mitochondrial and bacterial ribosomes). Signs of mitochondrial toxicity include lactic acidosis and peripheral neuropathy.[8] Painful sensory neuropathy.[9]
[edit] External links
[edit] References
- ^ Burkhardt O, Pletz MW, Mertgen CP, Welte T (2007). "Linezolid - the first oxazolidinone in the treatment of nosocomial MRSA pneumonia". Recent Patents Anti-Infect Drug Disc 2 (2): 123–30. PMID 18221168.
- ^ a b von der Lippea B, Sandvenb P, Brubakk O. (2006). "Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB)—a report of ten cases". J Infect 52 (2): 92–6. doi:.
- ^ Tsiodras S, Gold HS, Sakoulas G, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet. 2001 Jul 21;358(9277):207-8.
- ^ a b c Park IN, Hong SB, Oh YM, et al. (2006). "Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis". J Antimicrob Chemother 58 (3): 701–4. doi:. PMID 16857689.
- ^ Fortun J, Martin-Davila P, Navas E, et al. (2005). "Linezolid for the treatment of multidrug-resistant tuberculosis". J Antimicrob Chemother 56 (1): 180–5. doi:.
- ^ Lin Y-H, Wu V-C, Tsai I-J, et al. (2006). "High frequency of linezolid-associated thrombocytopenia among patients with renal insufficiency". Int J Antimicrob Agents 28 (4): 345–51. doi:.
- ^ Plachouras D, Giannitsioti E, Athanassia S, et al. (2006). "No effect of pyridoxine on the incidence of myelosuppression during prolonged linezolid treatment". Clin Infect Dis 43 (9): e89–91. doi:.
- ^ Soriano A, Miró O, Mensa J. "Mitochondrial Toxicity Associated with Linezolid". N Engl J Med 353 (21): 2305–6.
- ^ Chao CC, Sun HY, Chang YC, Hsieh ST (2008). "Painful neuropathy with skin denervation after prolonged use of linezolid". J. Neurol. Neurosurg. Psychiatr. 79 (1): 97–9. doi:. PMID 17766431.
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