My watch list
my.chemeurope.com  
Login  

Linezolid



Linezolid
Systematic (IUPAC) name
N-[[3-(3-fluoro-4-morpholinophenyl)-
2-oxooxazolidin-5-yl]methyl]acetamide
Identifiers
CAS number 165800-03-3
ATC code J01XX08
PubChem 441401
DrugBank APRD01073
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.

C (Au), C (U.S.)

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 and methicillin-resistant Staphylococcus aureus (MRSA). It is marketed under the trade name Zyvox (or Zyvoxid in Europe) (Pfizer).

It was the first commercially available oxazolidinone antibiotic and 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. Compared to the older antibiotics it is quite expensive.

The drug works by inhibiting the initiation of bacterial protein synthesis. 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.[1] 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]

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. First signs of resistance was reported in 2001.

Additional recommended knowledge

Contents

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.

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[3] or 600mg twice daily[4] 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.[3] The lower dose is not associated with a lower rate of adverse effects.[3]

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 less (the manufacturer's recommendation), but in patients who receive longer courses, or who have renal failure, the rate is much higher.[5] The anemia and thrombocytopenia caused by linezolid are not prevented by concurrent administration of pyridoxine 125mg daily.[6]

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.[7] Painful sensory neuropathy (PMID: 17766431).

A normal course of 28 doses can cost over $2000.

References

  1. ^ 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.
  2. ^ 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:10.1016/j.jinf.2005.04.007.
  3. ^ 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. PMID 16857689.
  4. ^ 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:10.1093/jac/dki148.
  5. ^ Lin Y-H, Wu V-C, Tsai I-J, et al.. "High frequency of linezolid-associated thrombocytopenia among patients with renal insufficiency". Int J Antimicrob Agents (4): 345–51. doi:10.1016/j.ijantimicag.2006.04.017.
  6. ^ 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.
  7. ^ Soriano A, Miró O, Mensa J. "Mitochondrial Toxicity Associated with Linezolid". N Engl J Med 353 (21): 2305–6.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Linezolid". A list of authors is available in Wikipedia.
Your browser is not current. Microsoft Internet Explorer 6.0 does not support some functions on Chemie.DE