Linezolid

drugbox
IUPAC_name = "N"- [3-(3-fluoro-4-morpholinophenyl)-
2-oxooxazolidin-5-yl] methyl] acetamide

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CAS_number = 165800-03-3
ATC_prefix = J01
ATC_suffix = XX08
PubChem = 441401
DrugBank = APRD01073
C=16 | H=20 | F=1 | N=3 | O=4
molecular_weight = 337.346 g/mol
bioavailability = ~100% (oral)
protein_bound = 31%
metabolism = Hepatic (50–70%)
elimination_half-life = 4.2–5.4 hours
excretion = Renal (80–85%)
pregnancy_category = C (Au), C (U.S.)
legal_status = S4 (Au), POM (UK), ℞-only (U.S.)
routes_of_administration = IV, oral

Linezolid (INN) (pronEng|lɪˈnɛzəlɪd) is a synthetic antibiotic of the oxazolidinone class used for the treatment of infections caused by multi-resistant bacteria including streptococcicite web |url=http://www.fda.gov/cder/foi/label/2008/021130s016,021131s013,021132s014lbl.pdf |title=ZYVOX^® (linezolid) Label Information |author=Pfizer |date=June 20, 2008 |accessdate=2008-08-24] and methicillin-resistant "Staphylococcus aureus" (MRSA).cite journal |author=Burkhardt O, Pletz MW, Mertgen CP, Welte T |title=Linezolid - the first oxazolidinone in the treatment of nosocomial MRSA pneumonia |journal=Recent Patents Anti-Infect Drug Disc |volume=2 |issue=2 |pages=123–30 |year=2007 |pmid=18221168 |doi=] It is marketed by Pfizer under the trade name Zyvox (in the United States) or Zyvoxid (in Europe).

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; nonetheless, it appears to be more cost-effective than vancomycin or teicoplanin. [cite journal |author=Grau S, Rubio-Terrés C |title=Pharmacoeconomics of linezolid |journal=Expert Opin Pharmacother |volume=9 |issue=6 |pages=987–1000 |year=2008 |month=April |pmid=18377341 |doi=10.1517/14656566.9.6.987 |url=]

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. [cite journal |author=Tsiodras S, Gold HS, Sakoulas G, "et al" |title=Linezolid resistance in a clinical isolate of Staphylococcus aureus |journal=Lancet |volume=358 |issue=9277 |pages=207–8 |year=2001 |month=July |pmid=11476839 |doi=10.1016/S0140-6736(01)05410-1 |url=]

Clinical use

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.

In combination with other drugs, linezolid has been used to treat tuberculosis.cite journal | journal=J Infect | volume=52 | issue=2 | year=2006 | pages=92–6 | doi=10.1016/j.jinf.2005.04.007 | title=Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB)—a report of ten cases | author=von der Lippea B, Sandvenb P, Brubakk O. ] The optimal dose for use in tuberculosis is not known. In adults, 600 mg dailycite journal | journal=J Antimicrob Chemother | year=2006 | volume=58 | issue=3 | pages=701–4 | title=Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis | author=Park IN, Hong SB, Oh YM, "et al." | pmid=16857689 | doi=10.1093/jac/dkl298] or 600 mg twice daily [cite journal | journal=J Antimicrob Chemother | year=2005 | volume=56 | issue=1 | pages=180–5 | title=Linezolid for the treatment of multidrug-resistant tuberculosis | author=Fortun J, Martin-Davila P, Navas E, "et al." | doi=10.1093/jac/dki148 | pmid=15911549] 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 fewer (the manufacturer's recommendation), but in patients who receive longer courses, or who have renal failure, the rate is much higher. [cite journal | author=Lin Y-H, Wu V-C, Tsai I-J, "et al." | title=High frequency of linezolid-associated thrombocytopenia among patients with renal insufficiency | journal=Int J Antimicrob Agents | vol=28 | issue=4 | pages=345–51 | doi=10.1016/j.ijantimicag.2006.04.017 | year=2006 | volume=28] The anemia and thrombocytopenia caused by linezolid are not prevented by concurrent administration of pyridoxine 125 mg daily. [cite journal | title=No effect of pyridoxine on the incidence of myelosuppression during prolonged linezolid treatment | author=Plachouras D, Giannitsioti E, Athanassia S, "et al." | journal=Clin Infect Dis | year=2006 | volume=43 | issue=9 | pages=e89–91 | url=http://www.journals.uchicago.edu/doi/full/10.1086/508280 | doi=10.1086/508280]

Linezolid is a weak monoamine oxidase inhibitor (MAOI), and should not be used concomitantly with other MAOIs, tyramine-containing foods, or pseudoephedrine; there have been postmarketing reports of serotonin syndrome when linezolid was given with serotonergic drugs. [cite web |url=http://www.medscape.com/viewarticle/580101 |title=FDA Safety Changes: Mirena, Zyvox, Orencia |author=Waknine, Yael |date=September 5, 2008 |publisher=Medscape |accessdate=2008-09-06 Freely available with registration.]

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. [cite journal | author=Soriano A, Miró O, Mensa J|title=Mitochondrial Toxicity Associated with Linezolid|journal=N Engl J Med | volume=353 | issue=21 | pages=2305–6|doi=10.1056/NEJM200511243532123|year=2005|pmid=16306535 ] Painful sensory neuropathy.cite journal |author=Chao CC, Sun HY, Chang YC, Hsieh ST |title=Painful neuropathy with skin denervation after prolonged use of linezolid |journal=J. Neurol. Neurosurg. Psychiatr. |volume=79 |issue=1 |pages=97–9 |year=2008 |pmid=17766431 |doi=10.1136/jnnp.2007.127910 |url=http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=17766431]

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.

References

External links

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