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Linezolid (Zyvox) is the first member of a new class of synthetic antibacterial drugs, the oxazolidinone class, approved for use in the United States and the world.

Oxazolidinones were first discovered in the late 1970s at E. I. du Pont de Nemours & Co. and were of great interest because of their activity against methicillin-resistant organisms1.

However, further development of these early compounds was discontinued as they were found to produce liver toxicity. In the 1990s the class was re-investigated and linezolid was discovered in 1996 as a result of intensive research at Pharmacia & Upjohn (now part of Pfizer).

In recent years, the discovery and development of structurally novel antibiotics with distinct mechanisms of action have become particularly important because of the emerging resistance of bacteria to all classes of existing drugs, which causes significant treatment problems around the world.

It is worth to emphasize that the oxazolidinones are the only new class of antibiotic that have been discovered and successfully implemented in practice over the past 40 years.

Linezolid is marketed by Pfizer under the trade name Zyvox (in the United States and several other countries), Zyvoxam (in Canada and Mexico), or Zyvoxid (in Europe).

• Vancomycin-resistant Enterococcus faecium infections
• Nosocomial pneumonia
• Complicated and uncomplicated skin and skin structure infections
• Community-acquired pneumonia caused by susceptible strains of specific organisms

Linezolid is not indicated for the treatment of Gram-negative infections.

Off-label and investigational uses of Linezolid include:

• Infections of the central nervous system8. Linezolid may be a reasonable choice when treatment options are limited or when other antibiotics have failed.
• Drug resistant tuberculosis6, however, the long-term use of linezolid in treating tuberculosis is limited by its toxicity. Apart from the toxicity, this drug is very expensive and is not an option for developing countries.
• Infective endocarditis9

Advantages:

• Very effective. Linezolid (Zyvox) is effective in treating serious or complicated infections caused by Gram-positive bacteria, including some that are resistant to other antibiotics. It has excellent activity against virtually all important gram-positive pathogens, including difficult-to-treat methicillin-resistant staphylococci, penicillin-resistant pneumococci, macrolide-resistant streptococci, and vancomycin-resistant enterococci.
• Excellent (100%) bioavailability, that is the entire dose reaches the bloodstream when given by mouth. This means that people receiving intravenous linezolid may be switched to oral linezolid as soon as their condition allows it, whereas comparable antibiotics (such as vancomycin and quinupristin/dalfopristin) can only be given intravenously. This property allows to shorten the hospital stay.
• Convenient dosage regimen. Its elimination half-life allows dosing twice per day, and alteration of drug dosage is not required in people with impaired kidney or liver function.
• Superior to glycopeptides or beta-lactam antibiotics for the treatment of Gram-positive infections3
• Well-tolerated. When used for short periods, linezolid is a relatively safe. The most frequently reported side effects are diarrhea, headache, nausea and vomiting.
• Resistance is unlikely. Resistance to linezolid has been reported in a small number of patients infected with E. faecium.
• Low potential for cross-resistance with other antimicrobials. Because its mechanism of action differs from that of other antibacterials, linezolid is not expected to show cross-resistance with existing antibiotics.
• No effect on cytochrome P450 enzyme metabolizing system.

Disadvantages:

• Cost. Compared to the older antibiotics it is quite expensive.
• No clinical useful Gram-negative activity. Linezolid is not active against infections caused by Gram negative pathogens.
• Hematologic side effects
  Myelosuppression (decrease in the production of blood cells). Long-term treatment with linezolid may result in fully reversible myelosuppression4, a rare but serious side effect. Myelosuppression has occurred in patients receiving high doses for more than 2 weeks.
  Thrombocytopenia (condition in which there is an abnormally small number of platelets in the circulating blood). The current FDA approved product insert warns about the risk of developing reversible thrombocytopenia, particularly when used for more than two weeks. Thrombocytopenia occurs more frequently with linezolid than with glycopeptides or beta-lactam antibiotics3.
• Potential for drug intreactions
  Linezolid is a weak monoamine oxidase inhibitor (MAOI) and can potentially interact with a variety of serotonergic agents. It cannot be used with tyramine containing foods or pseudoephedrine.
• Mitochondrial toxicity
  Linezolid is toxic to mitochondria, probably because of the similarity between mitochondrial and bacterial ribosomes5. Linezolid inhibits mitochondrial protein synthesis, leading to decreased mitochondrial enzymatic activity, which causes linezolid-related lactic acidosis (a potentially life-threatening buildup of lactic acid in the body)7.
• Neurotoxicity (nerve damage)
  The long-term use of linezolid (more than 28 days) may cause peripheral neuropathy (which can be irreversible) and optic nerve damage. Linezolid-related nerve damage is possibly connected to the capacity of linezolid to interfere with mitochondrial function.

Linezolid has a unique structure and mechanism of action, which targets bacterial protein synthesis (i.e. production) at an exceedingly early stage in the process that is different from any other antibiotic. Most of the widely known antibiotics (tetracyclines, macrolides) inhibit bacterial protein synthesis at the elongation stage, linezolid works by inhibiting the bacterial protein synthesis at the initiation step. Without protein production, bacteria cannot multiply and die.

Linezolid may also inhibit virulence factor expression and decrease toxin production in gram-positive pathogens.

Linezolid is bacteriostatic against enterococci and staphylococci, and bactericidal for the majority of streptococci.

Initially there were hopes that bacteria would be unable to develop resistance to linezolid. However, in 2003 Staphylococcus aureus was first identified as being resistant to this medication.

Linezolid half-life is 4-5 hours.

• Linezolid (Zyvox) versus Other Medications

• 1. Slee AM, Wuonola MA, McRipley RJ, Zajac I, Zawada MJ, Bartholomew PT, Gregory WA, Forbes M. Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721. Antimicrobial Agents and Chemotherapy 1987 Nov;31(11):1791-7.
• 2.
• 3. Falagas ME, Siempos II, Vardakas KZ. Linezolid versus glycopeptide or beta-lactam for treatment of Gram-positive bacterial infections: meta-analysis of randomised controlled trials. Lancet Infect Dis. 2008 Jan;8(1):53-66
• 4. Green SL, Maddox JC, Huttenbach ED. Linezolid and reversible myelosuppression. JAMA. 2001 Mar 14;285(10):1291
• 5. McKee EE, Ferguson M, Bentley AT, Marks TA. Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones. Antimicrobial Agents and Chemotherapy. 2006 Jun;50(6):2042-9
• 6. Koh WJ, Kwon OJ, Gwak H, Chung JW, Cho SN, Kim WS, Shim TS. Daily 300 mg dose of linezolid for the treatment of intractable multidrug-resistant and extensively drug-resistant tuberculosis. Journal of Antimicrobial Chemotherapy 2009 Aug;64(2):388-91.
• 7. Garrabou G, Soriano A, López S, Guallar JP, Giralt M, Villarroya F, Martínez JA, Casademont J, Cardellach F, Mensa J, Miró O. Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia. Antimicrob Agents Chemother. 2007 Mar;51(3):962-7
• 8. Ntziora F, Falagas ME. Linezolid for the treatment of patients with central nervous system infection. The Annals of Pharmacotherapy. 2007 Feb;41(2):296-308.
• 9. Falagas ME, Manta KG, Ntziora F, Vardakas KZ. Linezolid for the treatment of patients with endocarditis: a systematic review of the published evidence. J Antimicrob Chemother. 2006 Aug;58(2):273-80

Published: November 16, 2009
Last updated: January 07, 2010