Linezolid (Zyvox)

Linezolid in Brief
  • Generic name : Linezolid
  • Brand names: Zyvox® (Pharmacia & Upjohn), Zyvoxam, Zyvoxid
  • Therapeutic class: Antibiotic
  • Pharmacologic class: Oxazolidinone
  • FDA Approved: April 18, 2000
  • Pregnancy Category: C
  • Originally discovered: 1990s, USA, du Pont de Nemours USA

History

Linezolid (Zyvox) is the first member of a new class of synthetic antibacterials, 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 existing classes, which causes significant treatment problems around the world.

It is worth to emphasize that the oxazolidinones are the only new antibiotic class 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).

FDA approved uses
  • Vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia.
  • Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and MRSA) or Streptococcus pneumoniae.
  • Community-acquired pneumonia caused by Streptococcus pneumoniae, including concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only).
  • Complicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible and MRSA), Streptococcus pyogenes, or Streptococcus agalactiae.
  • Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes.

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

Off-label uses
  • Infections of the central nervous system8. Linezolid may be a choice when treatment options are limited or when other antibiotics have failed.
  • Intractable tuberculosis6, however, the long-term use of linezolid in treating tuberculosis is limited by its toxicity. Apart from the toxicity, linezolid is very expensive and is not an option for developing countries.
  • Infective endocarditis2
  • Bacteremia (the presence of bacteria in the blood) 9

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Linezolid "pros" and "cons"

Advantages:

  • Very effective. Linezolid is effective in treating serious or complicated infections caused by Gram-positive bacteria, including resistant species. 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. Linezolid is more effective than glycopeptides, macrolides and beta-lactams for skin and soft tissue infections.
  • 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 vancomycin or 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 is not required in people with impaired kidney or liver function.
  • Superior to glycopeptides or beta-lactams for the treatment of Gram-positive skin and soft-tissue infections and bacteraemia 3
  • 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. Because its mechanism of action is different, linezolid is not expected to show cross-resistance with existing antibiotics.
  • No effect on cytochrome P450 enzyme metabolizing system.

Disadvantages:

  • Quite expensive.
  • Linezolid is not active against 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 (abnormally small number of platelets in the circulating blood) 10. 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-lactams 3.
  • Potential for drug intreactions
    Linezolid is a weak monoamine oxidase inhibitor (MAOI) and can potentially interact with a variety of serotonergic agents. It should not 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. It 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 (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.

Mode of action

Linezolid has a unique structure and mechanism of action, which targets bacterial protein synthesis (i.e. production) at the earliest steps of the process. While most of the widely known antibiotics 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.

Time to clear out of the system

Linezolid half-life is 4-5.5 hours.

Further reading
References
  • 1. Slee AM, Wuonola MA, McRipley RJ, Zajac I, Zawada MJ, Bartholomew PT, Gregory WA, Forbes M. Oxazolidinones: in vitro and in vivo activities of DuP 105 and DuP 721. Antimicrob Agents Chemother. 1987 Nov;31(11):1791-7. PubMed
  • 2. Falagas ME, Manta KG, Ntziora F, Vardakas KZ. J Antimicrob Chemother. 2006 Aug;58(2):273-80
  • 3. Falagas ME, Siempos II, Vardakas KZ. 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. Antimicrob Agents Chemother. 2006 Jun;50(6):2042-9
  • 6. Koh WJ, Kwon OJ, Gwak H, Chung JW, Cho SN, Kim WS, Shim TS. Linezolid for the treatment of intractable multidrug-resistant and extensively drug-resistant tuberculosis. J Antimicrob Chemother. 2009 Aug;64(2):388-91.
  • 7. Garrabou G, Soriano A, Lopez S, Guallar JP, Giralt M, Villarroya F, Martinez JA, Casademont J, Cardellach F, Mensa J, Miro 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 central nervous system infection. Ann Pharmacother.. 2007 Feb;41(2):296-308. PubMed
  • 9. Jang HC, Kim SH, Kim KH, Kim CJ, Lee S, Song KH, Jeon JH, Park WB, Kim HB, Park SW, Kim NJ, Kim EC, Oh MD, Choe KW. Salvage treatment for persistent methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis. 2009 Aug 1;49(3):395-401 PubMed
  • 10. Hirano R, Sakamoto Y, Tachibana N, Ohnishi M. Retrospective analysis of the risk factors for linezolid-induced thrombocytopenia in adult Japanese patients. Int J Clin Pharm. 2014 Jun 10. PubMed

Published: November 16, 2009
Last updated: January 29, 2017

Interesting facts
Linezolid
  • Oxazolidinones represent a novel class of antibiotics unrelated to any other drug class.
  • There is an ongoing need to synthesize new antibiotics since bacteria develop various mechanisms of resistance. Detection of methicillin-resistant Staphylococcus aureus for the first time in 1996 happily coincided with the discovery of linezolid in the same year.
  • Linezolid is a completely synthetic agent: it does not occur in nature and was not developed by building upon a naturally occurring skeleton.
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