Linezolid

Linezolid

Clinical data
Pregnancy category	C (Au), C (U.S.)
Routes of administration	IV, oral
ATC code	J01XX08 (WHO)
Legal status
Legal status	S4 (Au), POM (UK), ℞-only (U.S.)
Pharmacokinetic data
Bioavailability	~100% (oral)
Protein binding	31%
Metabolism	Hepatic 50–70%
Elimination half-life	4.2–5.4 hours
Excretion	Renal 80–85%
Identifiers
IUPAC name N-[[3-(3-fluoro-4-morpholinophenyl)- 2-oxooxazolidin-5-yl]methyl]acetamide
CAS Number	165800-03-3
PubChem CID	441401
DrugBank	APRD01073
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C16H20FN3O4
Molar mass	337.346 g/mol

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Overview

Linezolid (INN) (IPA: Template:IPA) 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. 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 has been used to treat tuberculosis.

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.

Mechanism of Action

Linezolid works on the initiation of protein synthesis. It does this by stopping the 30S and 50S subunit 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). The optimal dose for use in tuberculosis is not known. In adults, 600mg daily or 600mg twice daily 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. The lower dose is not associated with a lower rate of adverse effects.

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. The anemia and thrombocytopenia caused by linezolid are not prevented by concurrent administration of pyridoxine 125mg daily.

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. Painful sensory neuropathy (PMID: 17766431).

External link

• http://www.zyvox.com/
• http://www.fda.gov/cder/drug/infopage/linezolid/default.htm