Linezolid and Template:Infobox drug/testcases: Difference between pages

{{drugbox

| verifiedrevid = 408578405

| alt2 = Ball-and-stick model of linezolid

| InChI = 1/C16H20FN3O4/c1-11(21)18-9-13-10-20(16(22)24-13)12-2-3-15(14(17)8-12)19-4-6-23-7-5-19/h2-3,8,13H,4-7,9-10H2,1H3,(H,18,21)/t13-/m0/s1

| InChIKey = TYZROVQLWOKYKF-ZDUSSCGKBA

| smiles = O=C1O[C@@H](CNC(=O)C)CN1c3cc(F)c(N2CCOCC2)cc3

| CAS_number = 165800-03-3

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 390139

| ATC_prefix = J01

| ATC_suffix = XX08

| PubChem = 441401

| DrugBank = APRD01073

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D00947

| C=16 | H=20 | F=1 | N=3 | O=4

| molecular_weight = 337.346 g/mol

| bioavailability = ~100% (oral)

| protein_bound = Low (31%)

| metabolism = [[Liver|Hepatic]] (50–70%, [[cytochrome P450|CYP]] not involved)

| elimination_half-life = 4.2–5.4 hours (shorter in children)

| excretion = Nonrenal, [[kidney|renal]], and fecal

| licence_US = Linezolid

| pregnancy_category = C <small>([[Australia|Au]])</small>, C <small>([[United States|U.S.]])</small>

| legal_status = S4 <small>(Au)</small>, POM <small>([[United Kingdom|UK]])</small>, ℞-only <small>(U.S.)</small>

| routes_of_administration = [[Intravenous therapy|Intravenous infusion]], oral

}}

'''Linezolid''' ([[International Nonproprietary Name|INN]]) ({{pronEng|lɪˈnɛzəlɪd}}, {{Respell|li|NE|zə-lid}}) is a synthetic [[antibiotic]] used for the treatment of serious [[infection]]s caused by [[Gram-positive bacteria]] that are [[antibiotic resistance|resistant]] to several other antibiotics. A member of the [[2-Oxazolidone|oxazolidinone]] class of drugs, linezolid is active against most Gram-positive bacteria that cause disease, including [[Streptococcus|streptococci]], [[vancomycin-resistant enterococcus|vancomycin-resistant enterococci]] (VRE), and [[methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']] (MRSA).<ref name=PI>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021130s016,021131s013,021132s014lbl.pdf |title=ZYVOX (linezolid) Label Information |author=Pfizer |date=June 20, 2008 |accessdate=2008-08-24|format=PDF}}</ref> The main [[indication (medicine)|indications]] of linezolid are infections of the [[skin]] and [[soft tissue]]s and [[pneumonia]] (particularly [[hospital-acquired pneumonia]]), although [[off-label use]] for a variety of other infections is becoming popular. Linezolid is marketed by [[Pfizer]] under the trade names '''Zyvox''' (in the United States, United Kingdom, Australia, and several other countries), '''Zyvoxid''' (in Europe), and '''Zyvoxam''' (in Canada and Mexico). Generics are also available in India, such as '''Linospan''' ([[Cipla]]).

Discovered in the 1990s and first approved for use in 2000, linezolid was the first commercially available 1,3-oxazolidinone antibiotic. As of 2009, it is the only marketed oxazolidinone, although others are in development. As a [[protein synthesis inhibitor]], it stops the growth of bacteria by disrupting their [[protein biosynthesis|production of proteins]]. Although many antibiotics work this way, the exact [[mechanism of action]] of linezolid appears to be unique to the oxazolidinone class. Bacterial resistance to linezolid has remained very low since it was first detected in 1999, although it may be increasing.

When administered for short periods, linezolid is a relatively safe drug; it can be used in patients of all ages and in people with [[liver disease]] or [[renal failure|poor kidney function]]. Common [[adverse drug reaction|adverse effect]]s of short-term use include [[headache]], [[diarrhea]], and [[nausea]]. Long-term use, however, has been associated with serious adverse effects; linezolid can cause [[bone marrow suppression]] and [[thrombocytopenia|low platelet counts]], particularly when used for more than two weeks. If used for longer periods still, it may cause [[peripheral neuropathy]] (which can be irreversible), [[optic neuropathy|optic nerve damage]], and [[lactic acidosis]] (a buildup of [[lactic acid]] in the body), all most likely due to [[mitochondrial toxicity]].

Linezolid is quite expensive, as a course of treatment can cost up to several thousand U.S. dollars;<ref name=Lexi-Comp/> nonetheless, it appears to be more [[Cost-effectiveness analysis#CEA in pharmacoeconomics|cost-effective]] than comparable antibiotics,<ref name=Grau>{{cite journal |author=Grau S, Rubio-Terrés C |title=Pharmacoeconomics of linezolid |journal=Expert Opinion on Pharmacotherapy |volume=9 |issue=6 |pages=987–1000 |year=2008 |month=April |pmid=18377341 |doi=10.1517/14656566.9.6.987 |issn=1465-6566}}</ref> mostly because of the possibility of switching from [[intravenous therapy|intravenous]] to oral [[Route of administration|administration]] as soon as patients are stable enough, without the need for dose adjustments.

==History==

The [[2-Oxazolidone|oxazolidinone]]s have been known as [[monoamine oxidase inhibitor]]s since the late 1950s. Their antimicrobial properties were discovered by researchers at [[DuPont|E.I. duPont de Nemours]] in the 1970s.<ref name=Brickner>{{cite journal |author=Brickner SJ |title=Oxazolidinone antibacterial agents |journal=[[Current Pharmaceutical Design]] |year=1996 |volume=2 |issue=2 |pages=175–94 |url=http://books.google.com/?id=_HFitfA4OcUC&pg=PA175&lpg=PA175}} Detailed review of the discovery and development of the whole oxazolidinone class, including information on [[chemical synthesis|synthesis]] and [[structure-activity relationship]]s.</ref> In 1978, DuPont [[patent]]ed a series of oxazolidinone derivatives as being effective in the treatment of [[bacteria]]l and [[fungus|fungal]] [[plant pathology|plant disease]]s, and in 1984, another patent described their usefulness in treating bacterial infections in [[mammal]]s.<ref name=Brickner/><ref name=Moellering>{{cite journal |author=Moellering RC |title=Linezolid: the first oxazolidinone antimicrobial |journal=[[Annals of Internal Medicine]] |volume=138 |issue=2 |pages=135–42 |year=2003 |month=January |pmid=12529096 |url=http://www.annals.org/cgi/reprint/138/2/135.pdf |issn=0003-4819}}</ref> In 1987, DuPont scientists presented a detailed description of the oxazolidinones as a new class of antibiotics with a novel [[mechanism of action]].<ref name=Brickner/><ref name=Slee>{{cite journal |author=Slee AM, Wuonola MA, McRipley RJ, ''et al.'' |title=Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721 |journal=[[Antimicrobial Agents and Chemotherapy]] |volume=31 |issue=11 |pages=1791–7 |year=1987 |month=November |pmid=3435127 |pmc=175041 |url=http://aac.asm.org/cgi/reprint/31/11/1791.pdf |issn=0066-4804}}</ref> Early compounds were found to produce [[hepatotoxicity|liver toxicity]], however, and [[drug development|development]] was discontinued.<ref name=Livermore>{{cite journal |author=Livermore DM |title=Quinupristin/dalfopristin and linezolid: where, when, which and whether to use? |journal=Journal of Antimicrobial Chemotherapy |volume=46 |issue=3 |pages=347–50 |year=2000 |month=September |pmid=10980159 |url=http://jac.oxfordjournals.org/cgi/content/full/46/3/347 |doi=10.1093/jac/46.3.347 |issn=0305-7453}}</ref>

[[Pharmacia|Pharmacia &]] [[Upjohn]] (now part of Pfizer) started its own oxazolidinone research program in the 1990s. Studies of the compounds' [[structure-activity relationship|structure–activity relationship]]s led to the development of several subclasses of oxazolidinone derivatives, with varying safety profiles and antimicrobial activity. Two compounds were considered drug candidates: [[eperezolid]] (codenamed ''PNU-100592'') and linezolid (''PNU-100766'').<ref name=Barbachyn>{{cite journal |author=Barbachyn MR, Ford CW |title=Oxazolidinone structure-activity relationships leading to linezolid |journal=[[Angewandte Chemie|Angewandte Chemie (International Edition in English)]] |volume=42 |issue=18 |pages=2010–23 |year=2003 |month=May |pmid=12746812 |doi=10.1002/anie.200200528 |issn=1433-7851}}</ref><ref name=French/> In the preclinical stages of development, they were similar in safety and antibacterial activity, so they were taken to [[clinical trial#Phase I|Phase I]] [[clinical trial]]s to identify any difference in [[pharmacokinetics]].<ref name=Livermore/><ref name=Ford>{{cite journal |author=Ford CW, Zurenko GE, Barbachyn MR |title=The discovery of linezolid, the first oxazolidinone antibacterial agent |journal=Current Drug Targets&nbsp;– Infectious Disorders |volume=1 |issue=2 |pages=181–99 |year=2001 |month=August |pmid=12455414 |doi=10.2174/1568005014606099 |issn=1568-0053}}</ref> Linezolid was found to have a pharmacokinetic advantage—requiring only twice-daily dosage, while eperezolid needed to be given three times a day to achieve similar exposure—and therefore proceeded to further trials.<ref name=Barbachyn/> The U.S. [[Food and Drug Administration (United States)|Food and Drug Administration]] (FDA) approved linezolid on April 18, 2000.<ref>{{cite web |url=http://www.fda.gov/cder/foi/nda/2000/21130_Zyvox.htm |archiveurl=http://web.archive.org/web/20080110042651/http://www.fda.gov/cder/foi/nda/2000/21130_Zyvox.htm |archivedate=2008-01-10 |title=Drug Approval Package: Zyvox |date=November 20, 2001 |publisher=FDA [[Center for Drug Evaluation and Research]] |accessdate=2009-01-17}} Comprehensive review of the FDA approval process. Includes detailed reviews of the chemistry and pharmacology of linezolid, correspondence between the FDA and Pharmacia & Upjohn, and administrative documents.</ref> Approval followed in Brazil (June 2000),<ref>{{cite web |author=ANVISA |url=http://www.anvisa.gov.br/legis/resol/2000/474_00re.htm |title=Resolução nº 474, de 5 de junho de 2000 |language=Portuguese |date=June 5, 2000 |publisher=[[National Health Surveillance Agency]] |accessdate=2009-05-19}}</ref> the United Kingdom (January 2001),<ref name=French/><ref name=SPC/> Japan and Canada (April 2001),<ref>{{cite journal |author=Irinoda K, Nomura S, Hashimoto M |title=[Antimicrobial and clinical effect of linezolid (ZYVOX), new class of synthetic antibacterial drug] |language=Japanese |journal=Nippon Yakurigaku Zasshi |volume=120 |issue=4 |pages=245–52 |year=2002 |month=October |pmid=12425150 |issn=0015-5691 |doi=10.1254/fpj.120.245}}</ref><ref name=CanadaApproval>{{cite press release |url=http://www.docguide.com/news/content.nsf/news/917912FCF5C34DCA85256A46006E24B0 |title=Canada Approves Marketing Of Zyvoxam (Linezolid) For Gram Positive Infections |format= |date=May 8, 2001 |accessdate=2009-05-18}}</ref><ref>{{cite journal |author=Karlowsky JA, Kelly LJ, Critchley IA, Jones ME, Thornsberry C, Sahm DF |title=Determining Linezolid's baseline in vitro activity in Canada using gram-positive clinical isolates collected prior to its national release |journal=Antimicrobial Agents and Chemotherapy |volume=46 |issue=6 |pages=1989–92 |year=2002 |month=June |pmid=12019122 |pmc=127260 |doi=10.1128/AAC.46.6.1989-1992.2002 |issn=0066-4804 |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=12019122 |format=Free full text}}</ref> Europe (throughout 2001),<ref>{{cite press release |url=http://www.prnewswire.ca/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/07-25-2001/0001540814&EDATE= |title=Pharmacia Corporation Reports 17% Increase In Second-Quarter Earnings-Per-Share Driven By 61% Increase In Pharmaceutical Earnings |date=July 25, 2001 |accessdate=2009-05-19}}</ref> and other countries in Latin America and Asia.<ref name=CanadaApproval/>

As of 2009, linezolid is the only oxazolidinone antibiotic available.<ref name=Livermore2009>{{cite journal |author=Livermore DM, Mushtaq S, Warner M, Woodford N |title=Activity of oxazolidinone TR-700 against linezolid-susceptible and -resistant staphylococci and enterococci |journal=Journal of Antimicrobial Chemotherapy |volume=63 |issue=4 |pages=713–5 |year=2009 |month=April |pmid=19164418 |doi=10.1093/jac/dkp002 |issn=0305-7453}}</ref> Other members of this class have entered development, such as [[posizolid]] (AZD2563),<ref>{{cite journal |author=Howe RA, Wootton M, Noel AR, Bowker KE, Walsh TR, MacGowan AP |title=Activity of AZD2563, a novel oxazolidinone, against ''Staphylococcus aureus'' strains with reduced susceptibility to vancomycin or linezolid |journal=Antimicrobial Agents and Chemotherapy |volume=47 |issue=11 |pages=3651–2 |year=2003 |month=November |pmid=14576139 |pmc=253812 |doi=10.1128/AAC.47.11.3651-3652.2003 |issn=0066-4804 |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=14576139 |format=Free full text}}</ref> [[ranbezolid]] (RBx 7644),<ref>{{cite journal |author=Kalia V, Miglani R, Purnapatre KP, ''et al.'' |title=Mode of action of Ranbezolid against staphylococci and structural modeling studies of its interaction with ribosomes |journal=Antimicrobial Agents and Chemotherapy |volume=53 |issue=4 |pages=1427–33 |year=2009 |month=April |pmid=19075051 |doi=10.1128/AAC.00887-08 |issn=0066-4804 |pmc=2663096}}</ref> [[torezolid]] (TR-701),<ref name=Livermore2009/><ref>{{cite press release |url=http://www.medicalnewstoday.com/articles/136728.php |title=Trius Completes Enrollment In Phase 2 Clinical Trial Evaluating Torezolid (TR-701) In Patients With Complicated Skin And Skin Structure Infections |date=2009-01-27 |accessdate=2009-05-17}}</ref> and [[radezolid]] (RX-1741).<ref>{{cite web |url=http://www.rib-x.com/pipeline/rx_1741 |title= Rx 1741 |publisher=Rib-X Pharmaceuticals |year=2009 |accessdate=2009-05-17}}</ref>

==Spectrum of activity==

{{multiple image

| align = right

| direction = vertical

| footer = [[Scanning electron microscopy|Scanning electron micrograph]]s of [[vancomycin-resistant enterococcus|vancomycin-resistant ''Enterococcus'']] (top) and [[methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']] (bottom; false colors)

| width = 200

| image1 = Vancomycin-Resistant Enterococcus 01.jpg

| alt1 = Black and white micrograph: a band of sphere-shaped bacteria, clustered in pairs, extends across a gray field.

| image2 = CDC-10046-MRSA.jpg

| alt2 = Colorized micrograph: sphere-shaped bacteria clustered in grape-like bunches.

Linezolid is effective against all clinically important Gram-positive [[bacteria]]—those whose [[cell wall]] contains a thick layer of [[peptidoglycan]] and no [[bacterial outer membrane|outer membrane]]—notably ''[[Enterococcus faecium]]'' and ''[[Enterococcus faecalis]]'' (including [[vancomycin-resistant enterococcus|vancomycin-resistant enterococci]]), ''Staphylococcus aureus'' (including methicillin-resistant ''Staphylococcus aureus'', MRSA), ''[[Streptococcus agalactiae]]'', ''[[Streptococcus pneumoniae]]'', ''[[Streptococcus pyogenes]]'', the [[Streptococcus#Viridans and others|''viridans'' group streptococci]], ''[[Listeria monocytogenes]]'', and ''[[Corynebacterium]]'' species (the latter being among the most susceptible to linezolid, with [[minimum inhibitory concentration]]s routinely below 0.5&nbsp;mg/L).<ref name=PI/><ref name=Moellering/><ref name=Jones>{{cite journal |author=Jones RN, Stilwell MG, Hogan PA, Sheehan DJ |title=Activity of linezolid against 3,251 strains of uncommonly isolated gram-positive organisms: report from the SENTRY Antimicrobial Surveillance Program |journal=Antimicrobial Agents and Chemotherapy |volume=51 |issue=4 |pages=1491–3 |year=2007 |month=April |pmid=17210770 |pmc=1855453 |doi=10.1128/AAC.01496-06}}</ref> Linezolid is also highly active ''[[in vitro]]'' against several [[Mycobacterium|mycobacteria]].<ref name=Moellering/> It appears to be very effective against ''[[Nocardia]]'', but because of high cost and potentially serious adverse effects, authors have recommended that it be combined with other antibiotics or reserved for cases that have failed traditional treatment.<ref>{{cite journal |author=Jodlowski TZ, Melnychuk I, Conry J |title=Linezolid for the treatment of ''Nocardia'' spp. infections |journal=[[Annals of Pharmacotherapy]] |volume=41 |issue=10 |pages=1694–9 |year=2007 |month=October |pmid=17785610 |doi=10.1345/aph.1K196 |issn=1060-0280}}</ref>

Linezolid is considered [[bacteriostatic agent|bacteriostatic]] against most organisms—that is, it stops their growth and reproduction without actually killing them—but has some [[bactericide|bactericidal]] (killing) activity against streptococci.<ref name=PI/><ref name=DrugTherPerspect/> Some authors have noted that, despite its bacteriostatic effect ''in vitro'', linezolid "behaves" as a bactericidal antibiotic ''in vivo'' because it inhibits the production of [[exotoxin|toxin]]s by staphylococci and streptococci.<ref name=Barbachyn/> It also has a [[antimicrobial pharmacodynamics|post-antibiotic effect]] lasting one to four hours for most bacteria, meaning that bacterial growth is temporarily suppressed even after the drug is discontinued.<ref name=Herrmann>{{cite journal |author=Herrmann DJ, Peppard WJ, Ledeboer NA, Theesfeld ML, Weigelt JA, Buechel BJ |title=Linezolid for the treatment of drug-resistant infections |journal=Expert Review of Anti-infective Therapy |volume=6 |issue=6 |pages=825–48 |year=2008 |month=December |pmid=19053895 |doi=10.1586/14787210.6.6.825 |issn=1478-7210}}</ref>

===Gram-negative bacteria===

Linezolid has no clinically significant effect on most [[Gram-negative bacteria]]. ''[[Pseudomonas]]'' and the [[Enterobacteriaceae]], for instance, are not susceptible.<ref name=DrugTherPerspect/> ''In vitro'', it is active against ''[[Pasteurella multocida]]'',<ref name=PI/><ref>{{cite web |url=http://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1195733833519?p=1203409654995 |title=Animal Bites and ''Pasteurella multocida'': Information for Healthcare Staff |author=[No authors listed] |publisher=[[Health Protection Agency]] |date=August 5, 2008}} Retrieved on 2009-05-15.</ref> ''[[Fusobacterium]]'', ''[[Moraxella catarrhalis]]'', ''[[Legionella]]'', ''[[Bordetella]]'', and ''[[Elizabethkingia meningoseptica]]'', and moderately active (having a minimum inhibitory concentration for 90% of strains of 8&nbsp;mg/L) against ''[[Haemophilus influenzae]]''.<ref name=DrugTherPerspect/><ref name=InfectiousDiseases>{{cite book |author=Davaro RE, Glew RH, Daly JS |editor=Gorbach SL, Bartlett JG, Blacklow NR |chapter=Oxazolidinones, quinupristin-dalfopristin, and daptomycin |chapterurl=http://books.google.com/books?id=91altE1evAsC&pg=PP241 |title=Infectious diseases |publisher=Lippincott Williams & Wilkins |location=Hagerstown, MD |year=2004 |pages=241–3 |isbn=0-7817-3371-5 |accessdate=2009-06-20}}</ref> It has also been used to great effect as a second-line treatment for ''[[Capnocytophaga]]'' infections.<ref name=Sabbatani>{{cite journal |author=Sabbatani S, Manfredi R, Frank G, Chiodo F |title=Linezolid in the treatment of severe central nervous system infections resistant to recommended antimicrobial compounds |journal=Le Infezioni in Medicina |volume=13 |issue=2 |pages=112–9 |year=2005 |month=June |pmid=16220032 |url=http://www.infezmed.it/VisualizzaUnArticolo.aspx?Anno=2005&numero=2&ArticoloDaVisualizzare=Vol_13_2_2005_8 |issn=1124-9390}}</ref><ref>{{cite journal |unused_data=DUPLICATE DATA: doi=10.1038/sj.bmt.1703288 |author=Geisler WM, Malhotra U, Stamm WE |title=Pneumonia and sepsis due to fluoroquinolone-resistant ''Capnocytophaga gingivalis'' after autologous stem cell transplantation |journal=Bone Marrow Transplantation |volume=28 |issue=12 |pages=1171–3 |year=2001 |month=December |pmid=11803363 |doi=10.1038/sj.bmt.1703288 |issn=0268-3369 |format=Free full text}}</ref>

===Comparable antibiotics===

Linezolid's spectrum of activity against Gram-positive bacteria is similar to that of the [[glycopeptide antibiotic]] [[vancomycin]], which has long been the standard for treatment of MRSA infections, and the two drugs are often compared.<ref name=Herrmann/><ref name=Marino>{{cite book |author=Marino PL, Sutin KM |chapter=Antimicrobial therapy |title=The ICU book |publisher=Lippincott Williams & Wilkins |location=Hagerstown, MD |year=2007 |page=817 |isbn=0-7817-4802-X}}</ref> Other comparable antibiotics include [[teicoplanin]] (trade name Targocid, a glycopeptide like vancomycin), [[quinupristin/dalfopristin]] (Synercid, a combination of two [[streptogramin]]s, not active against ''E. faecalis''),<ref name=Livermore/> and [[daptomycin]] (Cubicin, a [[lipopeptide]]), and some agents still being developed, such as [[ceftobiprole]], [[dalbavancin]], and [[telavancin]]. Linezolid is the only one that can be taken by mouth.<ref name=Herrmann/> In the future, [[oritavancin]] and [[iclaprim]] may be useful oral alternatives to linezolid—both are in the early stages of clinical development.<ref name=Herrmann/>

==Therapeutic uses==

The main [[indication (medicine)|indication]] of linezolid is the treatment of severe infections caused by Gram-positive bacteria that are [[antibiotic resistance|resistant]] to other antibiotics; it should not be used against bacteria that are sensitive to drugs with a narrower spectrum of activity, such as [[penicillin]]s and [[cephalosporin]]s. In both the popular press and the scientific literature, linezolid has been called a "reserve antibiotic"—one that should be used sparingly so that it will remain effective as a [[drug of last resort]] against potentially intractable infections.<ref>{{cite news |first=David |last=Wroe |title=An antibiotic to fight immune bugs |work=[[The Age]] |date=2002-02-28 |accessdate=2009-05-16 |url=http://www.theage.com.au/articles/2002/02/27/1014704966995.html}}</ref><ref name=Wilson>{{cite journal |author=Wilson AP, Cepeda JA, Hayman S, Whitehouse T, Singer M, Bellingan G |title=In vitro susceptibility of Gram-positive pathogens to linezolid and teicoplanin and effect on outcome in critically ill patients |journal=Journal of Antimicrobial Chemotherapy |volume=58 |issue=2 |pages=470–3 |year=2006 |month=August |pmid=16735420 |doi=10.1093/jac/dkl233 |issn=0305-7453 |url=http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16735420 |format=Free full text}}</ref>

In the United States, the FDA-approved indications for linezolid use are: vancomycin-resistant ''Enterococcus'' infection, with or without [[bacteremia|bacterial invasion of the bloodstream]]; [[nosocomial pneumonia|hospital-]] and [[community-acquired pneumonia]] caused by ''S. aureus'' or ''S. pneumoniae''; [[complicated skin and skin structure infection]]s (cSSSI) caused by susceptible bacteria, including [[diabetic foot]] infection, unless complicated by [[osteomyelitis]] (infection of the bone and bone marrow); and ''uncomplicated'' skin and soft tissue infections caused by ''S. pyogenes'' or ''S. aureus''. The manufacturer advises against the use of linezolid for community-acquired pneumonia or ''uncomplicated'' skin and soft tissue infections caused by MRSA.<ref name=PI/> In the United Kingdom, pneumonia and cSSSIs are the only indications noted in the product labeling.<ref name=SPC>{{cite web |author=[No authors listed] |url=http://emc.medicines.org.uk/medicine/9857 |title=Zyvox 600 mg Film-Coated Tablets, 100 mg/5 ml Granules for Oral Suspension, 2 mg/ml Solution for Infusion&nbsp;– Summary of Product Characteristics (SPC) |publisher=electronic Medicines Compendium |date=2009-06-24 |accessdate=2009-07-03}}</ref>

Linezolid appears to be as safe and effective for use in children and newborns as it is in adults.<ref name=Herrmann/><!--Linezolid is available in three forms: as tablets, powder for the preparation of an oral suspension, and a ready-to-use solution for intravenous injection.<ref name=PI/><ref name=InfectiousDiseases/>-->

===Skin and soft tissue infections===

A large [[meta-analysis]] of randomized controlled trials found linezolid to be more effective than glycopeptide antibiotics (such as vancomycin and [[teicoplanin]]) and [[beta-lactam antibiotic]]s in the treatment of skin and soft tissue infections (SSTIs) caused by Gram-positive bacteria,<ref name=Falagas2008>{{cite journal |author=Falagas ME, Siempos II, Vardakas KZ |title=Linezolid versus glycopeptide or beta-lactam for treatment of Gram-positive bacterial infections: meta-analysis of randomised controlled trials |journal=Lancet Infectious Diseases |volume=8 |issue=1 |pages=53–66 |year=2008 |month=January |pmid=18156089 |doi=10.1016/S1473-3099(07)70312-2 |issn=1473-3099}} Structured abstract with quality assessment available at [http://www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?ID=12008005415 DARE].</ref> and smaller studies appear to confirm its superiority over teicoplanin in the treatment of all serious Gram-positive infections.<ref name=Tascini>{{cite journal |author=Tascini C, Gemignani G, Doria R, ''et al.'' |title=Linezolid treatment for gram-positive infections: a retrospective comparison with teicoplanin |journal=Journal of Chemotherapy (Florence, Italy) |volume=21 |issue=3 |pages=311–6 |year=2009 |month=June |pmid=19567352 |issn=1120-009X}}</ref>

In the treatment of diabetic foot infections, linezolid appears to be cheaper and more effective than vancomycin.<ref name=Chow>{{cite journal |author=Chow I, Lemos EV, Einarson TR |title=Management and prevention of diabetic foot ulcers and infections: a health economic review |journal=PharmacoEconomics |volume=26 |issue=12 |pages=1019–35 |year=2008 |pmid=19014203 |doi=10.2165/0019053-200826120-00005 |issn=1170-7690}}</ref> In a 2004 [[open-label study]], it was as effective as [[ampicillin/sulbactam]] and [[co-amoxiclav]], and far superior in patients with foot ulcers and no [[osteomyelitis]], but with significantly higher rates of adverse effects.<ref name=Lipsky>{{cite journal |author=Lipsky BA, Itani K, Norden C |title=Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate |journal=Clinical Infectious Diseases |volume=38 |issue=1 |pages=17–24 |year=2004 |month=January |pmid=14679443 |doi=10.1086/380449 |issn=1058-4838}}</ref><ref name=Pigrau>{{cite journal |author=Pigrau C, Almirante B |title=[Oxazolidinones, glycopeptides and cyclic lipopeptides&#93; |language=Spanish |journal=Enfermedades Infecciosas y Microbiología Clínica |volume=27 |issue=4 |pages=236–46 |year=2009 |month=April |pmid=19406516 |url=http://www.elsevier.es/revistas/ctl_servlet?_f=7064&articuloid=13136682 |doi=10.1016/j.eimc.2009.02.004}}</ref> A 2008 meta-analysis of 18 randomized controlled trials, however, found that linezolid treatment failed as often as other antibiotics, regardless of whether patients had osteomyelitis.<ref name=Vardakas>{{cite journal |author=Vardakas KZ, Horianopoulou M, Falagas ME |title=Factors associated with treatment failure in patients with diabetic foot infections: An analysis of data from randomized controlled trials |journal=Diabetes Research and Clinical Practice |volume=80 |issue=3 |pages=344–51 |year=2008 |month=June |pmid=18291550 |doi=10.1016/j.diabres.2008.01.009 |issn=0168-8227}}</ref>

Some authors have recommended that combinations of cheaper or more cost-effective drugs (such as [[co-trimoxazole]] with [[rifampicin]] or [[clindamycin]]) be tried before linezolid in the treatment of SSTIs when susceptibility of the causative organism allows it.<ref name=Pigrau/><ref>{{cite journal |author=Grammatikos A, Falagas ME |title=Linezolid for the treatment of skin and soft tissue infection |journal=Expert Review of Dermatology |volume=3 |issue=5 |pages=539–48 |year=2008 |doi=10.1586/17469872.3.5.539}}</ref>

===Pneumonia===

There appears to be no significant difference in treatment success rates between linezolid, glycopeptides, or appropriate beta-lactam antibiotics in the treatment of pneumonia.<ref name=Falagas2008/> [[Medical guideline|Clinical guideline]]s for the treatment of community-acquired pneumonia developed by the [[American Thoracic Society]] and the [[Infectious Diseases Society of America]] recommend that linezolid be reserved for cases in which MRSA has been confirmed as the causative organism, or when MRSA infection is suspected based on the clinical presentation.<ref name=USCAPGuidelines>{{cite journal |author=Mandell LA, Wunderink RG, Anzueto A, ''et al.'' |title=Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults |journal=Clinical Infectious Diseases |volume=44 |issue=Suppl 2 |pages=S27–72 |year=2007 |month=March |pmid=17278083 |doi=10.1086/511159 |issn=1058-4838}}</ref> The guidelines of the [[British Thoracic Society]] do not recommend it as first-line treatment, but rather as an alternative to vancomycin.<ref name=BTSCAPGuidelines>{{cite web |url=http://www.brit-thoracic.org.uk/Portals/0/Clinical%20Information/Pneumonia/Guidelines/MACAPrevisedApr04.pdf |title=BTS guidelines for the management of community acquired pneumonia in adults&nbsp;– 2004 update |author=BTS Pneumonia Guidelines Committee |publisher=[[British Thoracic Society]] |date=2004-04-30 |accessdate=2009-06-30}}</ref> Linezolid is also an acceptable second-line treatment for community-acquired pneumococcal pneumonia when penicillin resistance is present.<ref name=USCAPGuidelines/>

U.S. guidelines recommend either linezolid or vancomycin as the first-line treatment for hospital-acquired (nosocomial) MRSA pneumonia.<ref name=USHAPGuideline>{{cite journal |author=[[American Thoracic Society]], [[Infectious Diseases Society of America]] |title=Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia |journal=American Journal of Respiratory and Critical Care Medicine |volume=171 |issue=4 |pages=388–416 |year=2005 |month=February |pmid=15699079 |doi=10.1164/rccm.200405-644ST |issn=1073-449X |url=http://ajrccm.atsjournals.org/cgi/pmidlookup?view=long&pmid=15699079 |format=Free full text}}</ref> Some studies have suggested that linezolid is better than vancomycin against nosocomial pneumonia, particularly [[ventilator-associated pneumonia]] caused by MRSA, perhaps because the penetration of linezolid into bronchial fluids is much higher than that of vancomycin. Several issues in study design have been raised, however, calling into question results that suggest the superiority of linezolid.<ref name=Pigrau/> Regardless, linezolid's advantages include its high [[bioavailability]] (because it allows easy switching to oral therapy), and the fact that poor kidney function is not an obstacle to use (whereas achieving the correct dosage of vancomycin in patients with [[renal failure|renal insufficiency]] is very difficult).<ref name=USHAPGuideline/>

==Off-label use==

[[File:Endocarditis ultrasound.JPG|thumb|This [[echocardiography|echocardiogram]] shows vegetations on the [[tricuspid valve]] (white arrow) caused by infective endocarditis. The patient received conventional treatment, with [[ampicillin]], [[imipenem]], and [[glucocorticoid]]s, and recovered fully after heart surgery.<ref>{{cite journal |author=Koya D, Shibuya K, Kikkawa R, Haneda M |title=Successful recovery of infective endocarditis-induced rapidly progressive glomerulonephritis by steroid therapy combined with antibiotics: a case report |journal=BMC Nephrology |volume=5 |issue=1 |pages=18 |year=2004 |month=December |pmid=15610562 |pmc=544880 |doi=10.1186/1471-2369-5-18 |url=http://www.biomedcentral.com/1471-2369/5/18 |format=Free full text}}</ref>|alt=Side-by-side echocardiogram cross-sections of a human heart. In the second image a white arrow points at a mass on the tricuspid valve.]]

It is traditionally believed that so-called "deep" infections—such as osteomyelitis or [[infective endocarditis]]—should be treated with bactericidal antibiotics, not bacteriostatic ones. Nevertheless, preclinical studies were conducted to assess the efficacy of linezolid for these infections,<ref name=Barbachyn/> and the drug has been used successfully to treat them in clinical practice. Linezolid appears to be a reasonable therapeutic option for infective endocarditis caused by multi-resistant Gram-positive bacteria, despite a lack of high-quality evidence to support this use.<ref>{{cite journal |author=Pankey GA, Sabath LD |title=Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections |journal=[[Clinical Infectious Diseases]] |volume=38 |issue=6 |pages=864–70 |year=2004 |month=March |pmid=14999632 |doi=10.1086/381972 |issn=1058-4838}}</ref><ref name=Falagas>{{cite journal |author=Falagas ME, Manta KG, Ntziora F, Vardakas KZ |title=Linezolid for the treatment of patients with endocarditis: a systematic review of the published evidence |journal=Journal of Antimicrobial Chemotherapy |volume=58 |issue=2 |pages=273–80 |year=2006 |month=August |pmid=16735427 |doi=10.1093/jac/dkl219 |issn=0305-7453 |url=http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16735427 |format=Free full text}}</ref> Results in the treatment of enterococcal endocarditis have varied, with some cases treated successfully and others not responding to therapy.<ref>{{cite journal |author=Babcock HM, Ritchie DJ, Christiansen E, Starlin R, Little R, Stanley S |title=Successful treatment of vancomycin-resistant ''Enterococcus'' endocarditis with oral linezolid |journal=Clinical Infectious Diseases |volume=32 |issue=9 |pages=1373–5 |year=2001 |month=May |pmid=11303275 |doi=10.1086/319986 |issn=1058-4838}}</ref><ref>{{cite journal |author=Ang JY, Lua JL, Turner DR, Asmar BI |title=Vancomycin-resistant ''Enterococcus faecium'' endocarditis in a premature infant successfully treated with linezolid |journal=The Pediatric Infectious Disease Journal |volume=22 |issue=12 |pages=1101–3 |year=2003 |month=December |pmid=14688576 |doi=10.1097/01.inf.0000101784.83146.0c |issn=0891-3668}}</ref><ref>{{cite journal |author=Archuleta S, Murphy B, Keller MJ |title=Successful treatment of vancomycin-resistant ''Enterococcus faecium'' endocarditis with linezolid in a renal transplant recipient with human immunodeficiency virus infection |journal=Transplant Infectious Disease |volume=6 |issue=3 |pages=117–9 |year=2004 |month=September |pmid=15569227 |doi=10.1111/j.1399-3062.2004.00059.x |issn=1398-2273}}</ref><ref>{{cite journal |author=Zimmer SM, Caliendo AM, Thigpen MC, Somani J |title=Failure of linezolid treatment for enterococcal endocarditis |journal=Clinical Infectious Diseases |volume=37 |issue=3 |pages=e29–30 |year=2003 |month=August |pmid=12884185 |doi=10.1086/375877 |issn=1058-4838}}</ref><ref>{{cite journal |author=Tsigrelis C, Singh KV, Coutinho TD, Murray BE, Baddour LM |title=Vancomycin-resistant ''Enterococcus faecalis'' endocarditis: linezolid failure and strain characterization of virulence factors |journal=[[Journal of Clinical Microbiology]] |volume=45 |issue=2 |pages=631–5 |year=2007 |month=February |pmid=17182759 |pmc=1829077 |doi=10.1128/JCM.02188-06 |issn=0095-1137 |url=http://jcm.asm.org/cgi/pmidlookup?view=long&pmid=17182759 |format=Free full text}}</ref><ref>{{cite journal |author=Berdal JE, Eskesen A |title=Short-term success, but long-term treatment failure with linezolid for enterococcal endocarditis |journal=Scandinavian Journal of Infectious Diseases |volume=40 |issue=9 |pages=765–6 |year=2008 |pmid=18609208 |doi=10.1080/00365540802087209 |issn=0036-5548}}</ref> [[Evidence-based medicine#Qualification of evidence|Low- to medium-quality evidence]] is also mounting for its use in bone and joint infections, including chronic osteomyelitis, although adverse effects are a significant concern when long-term use is necessary.<ref>{{cite journal |author=Falagas ME, Siempos II, Papagelopoulos PJ, Vardakas KZ |title=Linezolid for the treatment of adults with bone and joint infections |journal=International Journal of Antimicrobial Agents |volume=29 |issue=3 |pages=233–9 |year=2007 |month=March |pmid=17204407 |doi=10.1016/j.ijantimicag.2006.08.030 |issn=0924-8579}} Review.</ref><ref>{{cite journal |author=Bassetti M, Vitale F, Melica G, ''et al.'' |title=Linezolid in the treatment of Gram-positive prosthetic joint infections |journal=Journal of Antimicrobial Chemotherapy |volume=55 |issue=3 |pages=387–90 |year=2005 |month=March |pmid=15705640 |doi=10.1093/jac/dki016 |issn=0305-7453 |url=http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15705640 |format=Free full text}}</ref><ref>{{cite journal |author=Aneziokoro CO, Cannon JP, Pachucki CT, Lentino JR |title=The effectiveness and safety of oral linezolid for the primary and secondary treatment of osteomyelitis |journal=Journal of Chemotherapy (Florence, Italy) |volume=17 |issue=6 |pages=643–50 |year=2005 |month=December |pmid=16433195 |issn=1120-009X}}</ref><ref>{{cite journal |author=Senneville E, Legout L, Valette M, ''et al.'' |title=Effectiveness and tolerability of prolonged linezolid treatment for chronic osteomyelitis: a retrospective study |journal=Clinical Therapeutics |volume=28 |issue=8 |pages=1155–63 |year=2006 |month=August |pmid=16982292 |doi=10.1016/j.clinthera.2006.08.001 |issn=0149-2918}}</ref><ref>{{cite journal |author=Rao N, Hamilton CW |title=Efficacy and safety of linezolid for Gram-positive orthopedic infections: a prospective case series |journal=Diagnostic Microbiology and Infectious Disease |volume=59 |issue=2 |pages=173–9 |year=2007 |month=October |pmid=17574788 |doi=10.1016/j.diagmicrobio.2007.04.006 |issn=0732-8893}}</ref><ref>{{cite journal |author=Papadopoulos A, Plachouras D, Giannitsioti E, Poulakou G, Giamarellou H, Kanellakopoulou K |title=Efficacy and tolerability of linezolid in chronic osteomyelitis and prosthetic joint infections: a case-control study |journal=Journal of Chemotherapy (Florence, Italy) |volume=21 |issue=2 |pages=165–9 |year=2009 |month=April |pmid=19423469 |issn=1120-009X}}</ref>

In combination with other drugs, linezolid has been used to [[Tuberculosis treatment|treat tuberculosis]].<ref name=Lippea2006>{{cite journal |author=von der Lippe B, Sandven P, Brubakk O |title=Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB)—a report of ten cases |journal=Journal of Infection |volume=52 |issue=2 |pages=92–6 |year=2006 |month=February |pmid=15907341 |doi=10.1016/j.jinf.2005.04.007 |issn=0163-4453}}</ref> The optimal dose for this purpose has not been established. In adults, daily and twice-daily dosing have been used to good effect. Many months of treatment are often required, and the rate of adverse effects is high regardless of dosage.<ref name="Park2006">{{cite journal |author=Park IN, Hong SB, Oh YM, ''et al.'' |title=Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis |journal=Journal of Antimicrobial Chemotherapy |volume=58 |issue=3 |pages=701–4 |year=2006 |month=September |pmid=16857689 |doi=10.1093/jac/dkl298 |issn=0305-7453 |url=http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16857689 |format=Free full text}}</ref><ref>{{cite journal |author=Fortún J, Martín-Dávila P, Navas E, ''et al.'' |title=Linezolid for the treatment of multidrug-resistant tuberculosis |journal=Journal of Antimicrobial Chemotherapy |volume=56 |issue=1 |pages=180–5 |year=2005 |month=July |pmid=15911549 |doi=10.1093/jac/dki148 |issn=0305-7453 |url=http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15911549 |format=Free full text}}</ref> There is not enough reliable evidence of efficacy and safety to support this indication as a routine use.<ref name=Herrmann/>

Linezolid has been studied as an alternative to vancomycin in the treatment of [[febrile neutropenia]] in cancer patients when Gram-positive infection is suspected.<ref>{{cite journal |author=Jaksic B, Martinelli G, Perez-Oteyza J, Hartman CS, Leonard LB, Tack KJ |title=Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer |journal=Clinical Infectious Diseases |volume=42 |issue=5 |pages=597–607 |year=2006 |month=March |pmid=16447103 |doi=10.1086/500139 |issn=1058-4838}} Criticism in {{doi|10.1086/504431}}; author reply in {{doi|10.1086/504437}}.</ref> It is also one of few antibiotics that diffuse into the [[vitreous humor]], and may therefore be effective in treating [[endophthalmitis]] (inflammation of the inner linings and cavities of the eye) caused by susceptible bacteria. Again, there is little evidence for its use in this setting, as infectious endophthalmitis is treated widely and effectively with vancomycin [[intravitreal administration|injected directly into the eye]].<ref name=Pigrau/>

===Infections of the central nervous system===

In animal studies of [[meningitis]] caused by ''Streptococcus pneumoniae'', linezolid was found to penetrate well into [[cerebrospinal fluid]], but its effectiveness was inferior to that of other antibiotics.<ref name=Moellering/><ref>{{cite journal |author=Cottagnoud P, Gerber CM, Acosta F, Cottagnoud M, Neftel K, Täuber MG |title=Linezolid against penicillin-sensitive and -resistant pneumococci in the rabbit meningitis model |journal=Journal of Antimicrobial Chemotherapy |volume=46 |issue=6 |pages=981–5 |year=2000 |month=December |pmid=11102418 |issn=0305-7453 |url=http://jac.oxfordjournals.org/cgi/content/full/46/6/981 |format=Free full text |doi=10.1093/jac/46.6.981}}</ref> There does not appear to be enough high-quality evidence to support the routine use of linezolid to treat bacterial meningitis. Nonetheless, it has been used successfully in many cases of [[central nervous system]] infection—including meningitis—caused by susceptible bacteria, and has also been suggested as a reasonable choice for this indication when treatment options are limited or when other antibiotics have failed.<ref name=Sabbatani/><ref>{{cite journal |author=Ntziora F, Falagas ME |title=Linezolid for the treatment of patients with central nervous system infection |journal=Annals of Pharmacotherapy |volume=41 |issue=2 |pages=296–308 |year=2007 |month=February |pmid=17284501 |doi=10.1345/aph.1H307 |issn=1060-0280}} Structured abstract with quality assessment available at [http://www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?ID=12007005296 DARE].</ref> The guidelines of the Infectious Diseases Society of America recommend linezolid as the first-line drug of choice for VRE meningitis, and as an alternative to vancomycin for MRSA meningitis.<ref>{{cite journal |author=Tunkel AR, Hartman BJ, Kaplan SL, ''et al.'' |title=Practice guidelines for the management of bacterial meningitis |journal=Clinical Infectious Diseases |volume=39 |issue=9 |pages=1267–84 |year=2004 |month=November |pmid=15494903 |doi=10.1086/425368 |issn=1058-4838}}</ref> Linezolid appears superior to vancomycin in treating community-acquired MRSA infections of the central nervous system, although very few cases of such infections have been published (as of 2009).<ref name=Naesens>{{cite journal |author=Naesens R, Ronsyn M, Druwé P, Denis O, Ieven M, Jeurissen A |title=Central nervous system invasion by community-acquired methicillin-resistant ''Staphylococcus aureus'': case report and review of the literature |journal=[[Journal of Medical Microbiology]] |volume= 58|issue= Pt 9|pages= 1247–51|year=2009 |month=June |pmid=19528145 |doi=10.1099/jmm.0.011130-0 |issn=0022-2615}}</ref>

===Catheter-related infections===

In March 2007, the FDA reported the results of a [[randomized controlled trial|randomized]], [[open-label trial|open-label]], phase III clinical trial comparing linezolid to vancomycin in the treatment of [[central venous catheter#Infection|catheter-related bloodstream infections]]. Patients treated with vancomycin could be switched to [[oxacillin]] or [[dicloxacillin]] if the bacteria that caused their infection was found to be susceptible, and patients in both groups (linezolid and vancomycin) could receive specific treatment against Gram-negative bacteria if necessary.<ref name=CRBSI>{{cite web |author=[No authors listed] |url=http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm085249.htm |title=Linezolid (marketed as Zyvox)&nbsp;– Healthcare Professional Sheet |date=March 16, 2007 |publisher=U.S. Food and Drug Administration |accessdate=2010-09-15}}</ref> The study itself was published in January 2009.<ref name=Wilcox>{{cite journal |author=Wilcox MH, Tack KJ, Bouza E, ''et al.'' |title=Complicated skin and skin-structure infections and catheter-related bloodstream infections: noninferiority of linezolid in a phase 3 study |journal=Clinical Infectious Diseases |volume=48 |issue=2 |pages=203–12 |year=2009 |month=January |pmid=19072714 |doi=10.1086/595686 |issn=1058-4838}}</ref>

Linezolid was associated with [[statistical significance|significant]]ly greater mortality than the comparator antibiotics. When data from all participants were pooled, the study found that 21.5% of those given linezolid died, compared to 16% of those not receiving it. The difference was found to be due to the inferiority of linezolid in the treatment of Gram-negative infections alone or mixed Gram-negative/Gram-positive infections. In participants whose infection was due to Gram-positive bacteria alone, linezolid was as safe and effective as vancomycin.<ref name=CRBSI/><ref name=Wilcox/> In light of these results, the FDA issued an alert reminding healthcare professionals that linezolid is not approved for the treatment of catheter-related infections or infections caused by Gram-negative organisms, and that more appropriate therapy should be instituted whenever a Gram-negative infection is confirmed or suspected.<ref name=CRBSI/>

==Adverse effects==

When used for short periods, linezolid is a relatively safe drug.<ref name=Marino/> Common [[Adverse drug reaction|side effects]] of linezolid use (those occurring in more than 1% of people taking linezolid) include diarrhea (reported by 3–11% of clinical trial participants), headache (1–11%), nausea (3–10%), vomiting (1–4%), rash (2%), constipation (2%), altered taste perception (1–2%), and discoloration of the tongue (0.2–1%).<ref name=Lexi-Comp/> Fungal infections such as [[Oral candidiasis|thrush]] and [[candidal vulvovaginitis|vaginal candidiasis]] may also occur as linezolid suppresses normal bacterial flora and opens a niche for fungi (so-called [[antibiotic candidiasis]]).<ref name=Lexi-Comp/> Less common (and potentially more serious) adverse effects include allergic reactions, [[pancreatitis]], and [[elevated transaminases]], which may be a sign of liver damage.<ref name=Lexi-Comp/><ref name=French>{{cite journal |author=French G |title=Safety and tolerability of linezolid |journal=Journal of Antimicrobial Chemotherapy |volume=51 |issue=Suppl 2 |pages=ii45–53 |year=2003 |month=May |pmid=12730142 |doi=10.1093/jac/dkg253 |issn=0305-7453 |url=http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12730142 |format=Free full text}} Review. Includes extensive discussion of the hematological adverse effects of linezolid.</ref> Unlike some antibiotics, such as [[erythromycin]] and the [[quinolone]]s, linezolid has no effect on the [[QT interval]], a measure of [[electrocardiography|cardiac electrical conduction]].<ref name=French/><ref name=Metaxas>{{cite journal |author=Metaxas EI, Falagas ME |title=Update on the safety of linezolid |journal=Expert Opinion on Drug Safety |volume=8 |issue=4 |pages=485–91 |year=2009 |month=July |pmid=19538105 |doi=10.1517/14740330903049706 |issn=1474-0338}}</ref> Adverse effects in children are similar to those that occur in adults.<ref name=Metaxas/>

Like nearly all antibiotics, linezolid has been associated with [[Clostridium difficile|''Clostridium difficile''-associated diarrhea]] (CDAD) and [[pseudomembranous colitis]], although the latter is uncommon, occurring in about one in two thousand patients in clinical trials.<ref name=Lexi-Comp/><ref name=French/><ref name=Metaxas/><ref>{{cite journal |author=Zabel LT, Worm S |title=Linezolid contributed to ''Clostridium difficile'' colitis with fatal outcome |journal=Infection |volume=33 |issue=3 |pages=155–7 |year=2005 |month=June |pmid=15940418 |doi=10.1007/s15010-005-4112-6 |issn=0300-8126}}</ref> ''C. difficile'' appears to be susceptible to linezolid ''in vitro'', and linezolid was even considered as a possible treatment for CDAD.<ref>{{cite journal |author=Peláez T, Alonso R, Pérez C, Alcalá L, Cuevas O, Bouza E |title=In vitro activity of linezolid against ''Clostridium difficile'' |journal=Antimicrobial Agents and Chemotherapy |volume=46 |issue=5 |pages=1617–8 |year=2002 |month=May |pmid=11959617 |pmc=127182 |doi=10.1128/AAC.46.5.1617-1618.2002 |issn=0066-4804 |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=11959617 |format=Free full text}}</ref>

As of 2009, linezolid is a "[[black triangle (pharmacology)|black triangle drug]]" in the United Kingdom, meaning that it is under intensive [[postmarketing surveillance]] by the [[Commission on Human Medicines]] of the [[Medicines and Healthcare products Regulatory Agency]].<ref name=SPC/>

===Long-term use===

[[Bone marrow suppression]], characterized particularly by [[thrombocytopenia]] (low platelet count), may occur during linezolid treatment; it appears to be the only adverse effect that occurs [[statistical significance|significantly]] more frequently with linezolid than with glycopeptides or beta-lactams.<ref name=Falagas2008/> It is uncommon in patients who receive the drug for 14 days or fewer, but occurs much more frequently in patients who receive longer courses or who have renal failure.<ref name=French/><ref>{{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=International Journal of Antimicrobial Agents | vol=28 | issue=4 | pages=345–51 | doi=10.1016/j.ijantimicag.2006.04.017 | year=2006 | volume=28 | pmid=16935472 | month=October | issn=0924-8579}}</ref> A 2004 [[case report]] suggested that [[pyridoxine]] (a form of [[vitamin B6|vitamin B₆]]) could reverse the anemia and thrombocytopenia caused by linezolid,<ref>{{cite journal |author=Spellberg B, Yoo T, Bayer AS |title=Reversal of linezolid-associated cytopenias, but not peripheral neuropathy, by administration of vitamin B6 |journal=Journal of Antimicrobial Chemotherapy |volume=54 |issue=4 |pages=832–5 |year=2004 |month=October |pmid=15317746 |doi=10.1093/jac/dkh405 |url=http://jac.oxfordjournals.org/cgi/content/full/54/4/832 |issn=0305-7453}}</ref> but a later, larger study found no protective effect.<ref>{{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=Clinical Infectious Diseases | year=2006 | volume=43 | issue=9 | pages=e89–91 | doi=10.1086/508280 | pmid=17029128 | month=November | issn=1058-4838}}</ref>

Long-term use of linezolid has also been associated with [[peripheral neuropathy]] and [[optic neuropathy]], which is most common after several months of treatment and may be irreversible.<ref name=Narita>{{cite journal |author=Narita M, Tsuji BT, Yu VL |title=Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome |journal=Pharmacotherapy |volume=27 |issue=8 |pages=1189–97 |year=2007 |month=August |pmid=17655517 |doi=10.1592/phco.27.8.1189 |issn=0277-0008}}</ref><ref name=Bressler>{{cite journal |author=Bressler AM, Zimmer SM, Gilmore JL, Somani J |title=Peripheral neuropathy associated with prolonged use of linezolid |journal=Lancet Infectious Diseases |volume=4 |issue=8 |pages=528–31 |year=2004 |month=August |pmid=15288827 |doi=10.1016/S1473-3099(04)01109-0 |issn=1473-3099}}</ref><ref name="pmid17766431">{{cite journal|author=Chao CC, Sun HY, Chang YC, Hsieh ST |title=Painful neuropathy with skin denervation after prolonged use of linezolid |journal=Journal of Neurology, Neurosurgery & Psychiatry |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|month= January|issn=0022-3050}}</ref><ref>{{cite journal |author=Saijo T, Hayashi K, Yamada H, Wakakura M |title=Linezolid-induced optic neuropathy |journal=American Journal of Ophthalmology |volume=139 |issue=6 |pages=1114–6 |year=2005 |month=June |pmid=15953450 |doi=10.1016/j.ajo.2004.11.047 |issn=0002-9394}}</ref> Although the mechanism of injury is still poorly understood, [[mitochondrial toxicity]] has been proposed as a cause;<ref name=Soriano/><ref name="Javaheri">{{cite journal |author=Javaheri M, Khurana RN, O'hearn TM, Lai MM, Sadun AA |title=Linezolid-induced optic neuropathy: a mitochondrial disorder? |journal=British Journal of Ophthalmology |volume=91 |issue=1 |pages=111–5 |year=2007 |month=January |pmid=17179125 |doi=10.1136/bjo.2006.102541 |issn=0007-1161 |pmc=1857552}}</ref> linezolid is toxic to [[mitochondria]], probably because of the similarity between mitochondrial and bacterial [[ribosome]]s.<ref name=McKee>{{cite journal |author=McKee EE, Ferguson M, Bentley AT, Marks TA |title=Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones |journal=Antimicrobial Agents and Chemotherapy |volume=50 |issue=6 |pages=2042–9 |year=2006 |month=June |pmid=16723564 |pmc=1479116 |doi=10.1128/AAC.01411-05 |issn=0066-4804 |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=16723564 |format=Free full text}}</ref> [[Lactic acidosis]], a potentially life-threatening buildup of [[lactic acid]] in the body, may also occur due to mitochondrial toxicity.<ref name=Soriano>{{cite journal | author=Soriano A, Miró O, Mensa J|title=Mitochondrial toxicity associated with linezolid |journal=[[New England Journal of Medicine]] |volume=353 |issue=21 | pages=2305–6 |doi=10.1056/NEJM200511243532123 |year=2005 |pmid=16306535 | month= November| issn=0028-4793}}</ref> Because of these long-term effects, the manufacturer recommends weekly [[complete blood count]]s during linezolid therapy to monitor for possible bone marrow suppression, and recommends that treatment last no more than 28 days.<ref name=PI/><ref name=French/> A more extensive monitoring protocol for early detection of toxicity in seriously ill patients receiving linezolid has been developed and proposed by a team of researchers in Melbourne, Australia. The protocol includes twice-weekly blood tests and [[liver function tests]]; measurement of serum [[lactic acid|lactate]] levels, for early detection of lactic acidosis; a review of all medications taken by the patient, interrupting the use of those that may [[drug interaction|interact]] with linezolid; and periodic eye and neurological exams in patients set to receive linezolid for longer than four weeks.<ref>{{cite journal |author=Bishop E, Melvani S, Howden BP, Charles PG, Grayson ML |title=Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients |journal=Antimicrobial Agents and Chemotherapy |volume=50 |issue=4 |pages=1599–602 |year=2006 |month=April |pmid=16569895 |pmc=1426936 |doi=10.1128/AAC.50.4.1599-1602.2006 |issn=0066-4804 |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=16569895 |format=Free full text}}</ref>

The adverse effects of long-term linezolid therapy were first identified during postmarketing surveillance. Bone marrow suppression was not identified during Phase III trials, in which treatment did not exceed 21 days. Although some participants of early trials did experience thrombocytopenia, it was found to be reversible and did not occur significantly more frequently than in controls (participants not taking linezolid).<ref name=Moellering/> There have also been postmarketing reports of [[seizure]]s, and, as of July 2009, a single case each of [[Bell's palsy]] (paralysis of the [[facial nerve]]) and [[nephrotoxicity|kidney toxicity]].<ref name=Metaxas/>

==Chemistry==

At [[pH#Living systems|physiological pH]], linezolid exists in an uncharged state. It is moderately water-soluble (approximately 3&nbsp;mg/mL), with a [[partition coefficient|log''P'']] of 0.55.<ref name=Herrmann/>

[[File:Linezolid showing oxazolidinone pharmacophore.svg|thumb|left|Numbered structure of linezolid, showing the [[pharmacophore]] required for good activity (in blue) and desirable structural features (in orange).|alt=Skeletal formula of N-{[(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide, highlighting the morpholino and fluoro groups in orange, with the rest in blue. The carbon atoms of the parent chain are numbered.]]

The oxazolidinone [[pharmacophore]]—the chemical "template" essential for antimicrobial [[biological activity|activity]]—consists of a [[2-Oxazolidone|1,3-oxazolidin-2-one]] [[functional group|moiety]] with an [[aryl]] group at position 3 and an ''S''-[[methyl group]], with another [[substituent]] attached to it, at position 5 (the ''R''-[[enantiomer]]s of all oxazolidinones are devoid of antibiotic properties).<ref name=Brickner/> In addition to this essential core, linezolid also contains several structural characteristics that improve its effectiveness and safety. An [[acetamide]] substituent on the 5-methyl group is the best choice in terms of antibacterial efficacy, and is used in all of the more active oxazolidinones developed thus far; in fact, straying too far from an acetamide group at this position makes the drug lose its antimicrobial power, although weak to moderate activity is maintained when some [[bioisostere|isosteric]] groups are used. A [[fluorine]] atom at the 3′ position practically doubles ''in vitro'' and ''in vivo'' activity, and the [[electron donor|electron-donating]] [[nitrogen]] atom in the [[morpholine]] ring helps maintain high antibiotic potency and an acceptable safety profile.<ref name=Brickner/><ref name=Barbachyn/>

The [[anticoagulant]] [[rivaroxaban]] (Xarelto) bears a striking structural similarity to linezolid; both drugs share the oxazolidinone pharmacophore, differing in only three areas (an extra ketone and chloro[[thiophene]], and missing the fluorine atom). However this similarity appears to carry no clinical significance.<ref>{{cite web |url=http://www.emea.europa.eu/humandocs/PDFs/EPAR/xarelto/H-944-en6.pdf |title=CHP Assessment Report for Xarelto (EMEA/543519/2008) |author=European Medicines Agency |year=2008 |accessdate=2009-06-11}}</ref>

{{-}}

===Synthesis===

Linezolid is a completely [[organic synthesis|synthetic]] drug: it does not occur in nature (unlike erythromycin and many other antibiotics) and was not developed by building upon a naturally occurring skeleton (unlike most [[beta-lactam antibiotic|beta-lactam]]s, which are [[semisynthesis|semisynthetic]]). Many approaches are available for oxazolidinone synthesis, and several routes for the synthesis of linezolid have been reported in the chemistry literature.<ref name=Brickner/><ref name=Xu>{{cite journal |author=Xu GY, Zhou Y, Xu MC |title=A convenient synthesis of antibacterial linezolid from (''S'')-glyceraldehyde acetonide |journal=Chinese Chemical Letters |volume=17 |issue=3 |pages=302–4 |year=2006 |url=http://www.imm.ac.cn/journal/ccl/1703/170306-302-b050449-p3.pdf}}</ref> Despite good [[yield (chemistry)|yields]], the original method (developed by Upjohn for [[pilot plant]]-scale production of linezolid and eperezolid) is lengthy, requires the use of expensive chemicals—such as [[palladium on carbon]] and the highly sensitive reagents [[methanesulfonyl chloride]] and [[n-Butyllithium|''n''-butyllithium]]—and needs low-temperature conditions.<ref name=Brickner/><ref name=Xu/><ref name=Kaiser>{{cite journal |author=Kaiser CR, Cunico W, Pinheiro AC, Oliveira AG, Peralta MA, Souza MV |title=[Oxazolidinones: a new class of compounds against tuberculosis] |language=Portuguese |journal=Revista Brasileira de Farmácia |volume=88 |issue=2 |pages=83–8 |year=2007 |url=http://www.abf.org.br/pdf/2007/RBF_V88_N2_2007/PAG83a88_OXAZOLIDINONAS.pdf}}</ref> Much of the high cost of linezolid has been attributed to the expense of its synthesis.<ref name=Kaiser/> A somewhat more concise and cost-effective route better suited to large-scale production was patented by Upjohn in 1998.<ref name=Barbachyn/><ref>{{US patent reference | number = 5837870 | y = 1997 | m = 03 | d = 28 | inventor = Pearlman BA, Perrault WR, Barbachyn MR, ''et al.'' | title = Process to prepare oxazolidinones}} Retrieved on 2009-06-13.</ref>

Later syntheses have included an "[[atom economy|atom-economical]]" method starting from [[D-Mannitol|<small>D</small>-mannitol]], developed by Indian pharmaceutical company [[Dr. Reddy's Laboratories|Dr. Reddy's]] and reported in 1999,<ref>{{cite journal |author=Lohray BB, Baskaran S, Rao BS, Reddy BY, Rao IN |title=A short synthesis of oxazolidinone derivatives linezolid and eperezolid: A new class of antibacterials |journal=[[Tetrahedron Letters]] |volume=40 |issue=26 |pages=4855–6 |year=1999 |month=June |doi=10.1016/S0040-4039(99)00893-X}}</ref> and a route starting from (''S'')-glyceraldehyde acetonide (prepared from [[vitamin C]]), developed by a team of researchers from [[Hunan Normal University]] in [[Changsha]], [[Hunan]], China.<ref name=Xu/> On June 25, 2008, during the 12th Annual Green Chemistry and Engineering Conference in New York, Pfizer reported the development of their "second-generation" synthesis of linezolid: a [[convergent synthesis|convergent]], [[green chemistry|green]] synthesis starting from (''S'')-[[epichlorohydrin]], with higher yield and a 56% reduction in total waste.<ref>Perrault WR, Keeler JB, Snyder WC, ''et al.'' (June 25, 2008). [http://acs.confex.com/acs/green08/techprogram/P52019.HTM "Convergent green synthesis of linezolid (Zyvox)"], in ''12th Annual Green Chemistry and Engineering Conference'', June 24–26, 2008, New York, NY. Retrieved on 2009-06-08.</ref>

==Pharmacokinetics==

[[File:Linezolid metabolism.svg|thumb|Major metabolites of linezolid|alt=Upper left: structural formula of the unaltered linezolid molecule, with the morpholino group highlighted in red. Lower left: main carboxylic acid metabolite, accounting for 10% of an excreted dose; the morpholine ring has been cleaved at the nitrogen atom. Lower right: structural formulae of two distinct molecules, a carboxylic acid and a lactone, with an equilibrium arrow between them; this metabolite accounts for 45% of a dose. Upper right: structure of a minor carboxylic acid metabolite, which accounts for aroune 3.3% of a dose.]]

One of the advantages of linezolid is its high [[bioavailability]] (close to 100%) when given by mouth: the entire dose reaches the bloodstream, as if it had been given [[intravenous therapy|intravenously]]. 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.<ref name="American Family Physician">{{cite journal |author=Ament PW, Jamshed N, Horne JP |title=Linezolid: its role in the treatment of gram-positive, drug-resistant bacterial infections |journal=[[American Family Physician]] |volume=65 |issue=4 |pages=663–70 |year=2002 |month=February |pmid=11871684 |url=http://www.aafp.org/afp/20020215/663.html |issn=0002-838X}}</ref>

Taking linezolid with food somewhat slows its absorption, but the [[area under the curve (pharmacokinetics)|area under the curve]] is not affected.<ref name=Herrmann/>

Linezolid has low [[plasma protein binding]] (approximately 31%, but highly variable) and an [[volume of distribution|apparent volume of distribution]] at [[steady state]] of around 40–50&nbsp;liters.<ref name=Lexi-Comp>{{cite web|url=http://www.merck.com/mmpe/lexicomp/linezolid.html |title=Linezolid |date=August 2008 |author=Lexi-Comp |work=[[Merck Manual of Diagnosis and Therapy|The Merck Manual Professional]]}} Retrieved on May 14, 2009.</ref> Peak serum concentrations (C_max) are reached one to two hours after administration of the drug.<!--and are around 13&nbsp;mg/L after a single dose and 16–19&nbsp;mg/L after repeated administration;<ref name=Lexi-Comp/><ref name=Herrmann/> trough concentrations (C_min) are 4–8&nbsp;mg/L.<ref name=Herrmann/> *see [[Wikipedia:Featured article candidates/Linezolid/archive1]] for an explanation of why this is commented out*--> Linezolid is readily distributed to all tissues in the body apart from [[bone]] matrix and [[white adipose tissue]].<ref name=Barbachyn/> Notably, the concentration of linezolid in the epithelial lining fluid of the [[lower respiratory tract]] is at least equal to, and often higher than, that achieved in serum (some authors have reported [[bronchus|bronchial]] fluid concentrations up to four times higher than serum concentrations), which may account for its [[efficacy]] in treating pneumonia. [[Cerebrospinal fluid]] (CSF) concentrations vary; peak CSF concentrations are lower than serum ones, due to slow diffusion across the [[blood-brain barrier]], and trough concentrations in the CSF are higher for the same reason.<ref name=Herrmann/> The average half-life is three hours in children, four hours in teenagers, and five hours in adults.<ref name=PI/>

Linezolid is [[drug metabolism|metabolized]] in the [[liver]], by [[redox|oxidation]] of the [[morpholine]] ring, without involvement of the [[cytochrome P450]] system. This metabolic pathway leads to two major inactive [[metabolite]]s (which each account for around 45% and 10% of an excreted dose at steady state), one minor metabolite, and several trace metabolites, none of which accounts for more than 1% of an excreted dose.<ref name=Slatter>{{cite journal |author=Slatter JG, Stalker DJ, Feenstra KL, ''et al.'' |title=Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [¹⁴C&#93;linezolid to healthy human subjects |journal=Drug Metabolism and Disposition |volume=29 |issue=8 |pages=1136–45 |date=August 1, 2001|pmid=11454733 |url=http://dmd.aspetjournals.org/cgi/content/full/29/8/1136 |last12=Peng |first12=GW |last13=Shobe |first13=EM |issn=0090-9556}}</ref> [[Clearance (medicine)|Clearance]] of linezolid varies with age and gender; it is fastest in children (which accounts for the shorter half-life), and appears to be 20% lower in women than in men.<ref name=PI/><ref name=Slatter/><ref name=Sisson>{{cite journal |author=Sisson TL, Jungbluth GL, Hopkins NK |title=Age and sex effects on the pharmacokinetics of linezolid |journal=European Journal of Clinical Pharmacology |volume=57 |issue=11 |pages=793–7 |year=2002 |month=January |pmid=11868801 |doi=10.1007/s00228-001-0380-y |issn=0031-6970}}</ref>

===Use in special populations===

In adults and children over the age of 12, linezolid is usually given every 12 hours, whether orally or intravenously.<ref name=Moellering/><ref name="American Family Physician"/> In younger children and infants, it is given every eight hours.<ref name=Buck>{{cite journal |author=Buck ML |title=Linezolid use for resistant Gram-positive infections in children |journal=Pediatric Pharmacotherapy |volume=9 |issue=6 |year=2003 |month=June |url=http://www.healthsystem.virginia.edu/alive/pediatrics/PharmNews/200306.pdf |accessdate=2009-06-08}}</ref> No dosage adjustments are required in the elderly, in people with mild-to-moderate liver failure, or in those with impaired kidney function.<ref name=Lexi-Comp/> In people requiring [[hemodialysis]], care should be taken to give linezolid after a session, because dialysis removes 30–40% of a dose from the body; no dosage adjustments are needed in people undergoing [[hemofiltration|continuous hemofiltration]],<ref name=Lexi-Comp/> although more frequent administration may be warranted in some cases.<ref name=Herrmann/> According to one study, linezolid may need to be given more frequently than normal in people with [[burn]]s affecting more than 20% of [[total body surface area|body area]], due to increased nonrenal clearance of the drug.<ref>{{cite journal |author=Lovering AM, Le Floch R, Hovsepian L, ''et al.'' |title=Pharmacokinetic evaluation of linezolid in patients with major thermal injuries |journal=Journal of Antimicrobial Chemotherapy |volume=63 |issue=3 |pages=553–9 |year=2009 |month=March |pmid=19153078 |doi=10.1093/jac/dkn541 |issn=0305-7453}}</ref>

Linezolid is in U.S. [[pregnancy category]] C, meaning there have been no adequate studies of its safety when used by pregnant women, and although animal studies have shown mild toxicity to the fetus, the benefits of using the drug may outweigh its risks.<ref name=PI/> It also passes into [[breast milk]], although the clinical significance of this (if any) is unknown.<ref name=InfectiousDiseases/>

==Mechanism of action==

{{further|[[Protein biosynthesis]] and [[Translation (genetics)#Basic mechanisms|Basic mechanisms of translation]]}}

[[File:Ribosome mRNA translation en.svg|thumb|Simplified schematic of mRNA translation. Linezolid occupies the A site (at center) and prevents tRNA from binding.|alt=Diagram: A colored ribbon, representing messenger RNA (mRNA), passes through a cartoon diagram of an assembled ribosome. Cartoon representations of transfer RNA (tRNA) enter and exit the ribosome and occupy its A and P sites. A string of colored spheres, representing a newly formed protein, comes out of the top of the ribosome.]]

The oxazolidinones are [[protein synthesis inhibitor]]s: they stop the growth and reproduction of bacteria by disrupting [[prokaryotic translation|translation]] of [[messenger RNA]] (mRNA) into [[protein]]s in the [[ribosome]]. Although its mechanism of action is not fully understood,<ref name=Skripkin>{{cite journal |author=Skripkin E, McConnell TS, DeVito J, ''et al.'' |title=Rχ-01, a new family of oxazolidinones that overcome ribosome-based linezolid resistance |journal=Antimicrobial Agents and Chemotherapy |volume=52 |issue=10 |pages=3550–7 |year=2008 |month=October |pmid=18663023 |pmc=2565890 |doi=10.1128/AAC.01193-07 |issn=0066-4804 |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=18663023 |format=Free full text}}</ref> linezolid appears to work on the first step of protein synthesis, ''[[Prokaryotic translation#Initiation|initiation]]'', unlike most other protein synthesis inhibitors, which inhibit ''[[Prokaryotic translation#Elongation|elongation]]''.<ref name="American Family Physician"/><ref name=Swaney>{{cite journal |author=Swaney SM, Aoki H, Ganoza MC, Shinabarger DL |title=The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria |journal=Antimicrobial Agents and Chemotherapy |volume=42 |issue=12 |pages=3251–5 |date=December 1, 1998|pmid=9835522 |pmc=106030 |url=http://aac.asm.org/cgi/content/full/42/12/3251 |issn=0066-4804}}</ref>

It does so by preventing the formation of the ''initiation complex'', composed of the [[30S]] and [[50S]] subunits of the ribosome, [[transfer RNA|tRNA]], and mRNA. Linezolid binds to the [[23S ribosomal RNA|23S]] portion of the 50S subunit (the center of [[peptidyl transferase]] activity),<ref name=Colca>{{cite journal |author=Colca JR, McDonald WG, Waldon DJ, ''et al.'' |title=Cross-linking in the living cell locates the site of action of oxazolidinone antibiotics |journal=[[Journal of Biological Chemistry]] |volume=278 |issue=24 |pages=21972–9 |year=2003 |month=June |pmid=12690106 |doi=10.1074/jbc.M302109200 |url=http://www.jbc.org/cgi/content/full/278/24/21972 |issn=0021-9258}}</ref> close to the [[binding site]]s of [[chloramphenicol]], [[lincomycin]], and other antibiotics. Due to this unique mechanism of action, [[cross-resistance]] between linezolid and other protein synthesis inhibitors is highly infrequent or nonexistent.<ref name=Moellering/><ref name=Herrmann/>

In 2008, the [[crystal structure]] of linezolid bound to the 50S subunit of a ribosome from the [[archaea]]n ''Haloarcula marismortui'' was elucidated by a team of scientists from [[Yale University]] and deposited in the [[Protein Data Bank]].<ref>{{cite journal |author=Ippolito JA, Kanyo ZF, Wang D, ''et al.'' |title=Crystal structure of the oxazolidinone antibiotic linezolid bound to the 50S ribosomal subunit |journal=[[Journal of Medicinal Chemistry]] |volume=51 |issue=12 |pages=3353–6 |year=2008 |month=June |pmid=18494460 |doi=10.1021/jm800379d |issn=0022-2623}}</ref> Another team in 2008 determined the structure of linezolid bound to a 50S subunit of ''[[Deinococcus radiodurans]]''. The authors proposed a refined model for the mechanism of action of oxazolidinones, finding that linezolid occupies the [[Prokaryotic translation#Initiation|A site]] of the 50S ribosomal subunit, inducing a [[conformational change]] that prevents tRNA from entering the site and ultimately forcing tRNA to separate from the ribosome.<ref>{{cite journal |author=Wilson DN, Schluenzen F, Harms JM, Starosta AL, Connell SR, Fucini P |title=The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning |journal=[[Proceedings of the National Academy of Sciences]] |volume=105 |issue=36 |pages=13339–44 |year=2008 |month=September |pmid=18757750 |pmc=2533191 |doi=10.1073/pnas.0804276105 |issn=0027-8424 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18757750 |format=Free full text}}</ref>

==Resistance==

Acquired resistance to linezolid was reported as early as 1999, in two patients with severe, multidrug-resistant ''[[Enterococcus faecium]]'' infection who received the drug through a [[expanded access|compassionate use]] program.<ref name=DrugTherPerspect>{{cite journal |title=Linezolid |journal=Drugs & Therapy Perspectives |volume=17 |issue=9 |pages=1–6 |year=2001 |url=http://www.medscape.com/viewarticle/406493 |author=[No authors listed]}}<!--not indexed in MEDLINE--> Free full text with registration at [[Medscape]].</ref> Linezolid-resistant ''[[Staphylococcus aureus]]'' was first isolated in 2001.<ref>{{cite journal |author=Tsiodras S, Gold HS, Sakoulas G, ''et al.'' |title=Linezolid resistance in a clinical isolate of ''Staphylococcus aureus'' |journal=[[Lancet (journal)|The Lancet]] |volume=358 |issue=9277 |pages=207–8 |year=2001 |month=July |pmid=11476839 |doi=10.1016/S0140-6736(01)05410-1 |issn=0140-6736}}</ref>

In the United States, resistance to linezolid has been monitored and tracked since 2004 through a program named LEADER, which (as of 2007) was conducted in 60 medical institutions throughout the country. Resistance has remained stable and extremely low—less than one-half of one percent of [[wikt:isolate|isolate]]s overall, and less than one-tenth of one percent of ''S. aureus'' samples.<ref name=Jones>{{cite journal |author=Jones RN, Ross JE, Castanheira M, Mendes RE |title=United States resistance surveillance results for linezolid (LEADER Program for 2007) |journal=Diagnostic Microbiology and Infectious Disease |volume=62 |issue=4 |pages=416–26 |year=2008 |month=December |pmid=19022153 |doi=10.1016/j.diagmicrobio.2008.10.010 |issn=0732-8893}}</ref> A similar, worldwide program—the "Zyvox Annual Appraisal of Potency and Spectrum Study", or ZAAPS—has been conducted since 2002. As of 2007, overall resistance to linezolid in 23 countries was less than 0.2%, and nonexistent among streptococci. Resistance was only found in Brazil, China, Ireland, and Italy, among [[Staphylococcus#Coagulase-negative|coagulase-negative staphylococci]] (0.28% of samples resistant), enterococci (0.11%), and ''S. aureus'' (0.03%).<ref name=ZAAPS2007>{{cite journal |author=Jones RN, Kohno S, Ono Y, Ross JE, Yanagihara K |title=ZAAPS International Surveillance Program (2007) for linezolid resistance: results from 5591 Gram-positive clinical isolates in 23 countries |journal=Diagnostic Microbiology and Infectious Disease |volume=64 |issue=2 |pages=191–201 |year=2009 |month=June |pmid=19500528 |doi=10.1016/j.diagmicrobio.2009.03.001 |issn=0732-8893}}</ref> In the United Kingdom and Ireland, no resistance was found in staphylococci collected from [[bacteremia]] cases between 2001 and 2006,<ref>{{cite journal |author=Hope R, Livermore DM, Brick G, Lillie M, Reynolds R |title=Non-susceptibility trends among staphylococci from bacteraemias in the UK and Ireland, 2001-06 |journal=Journal of Antimicrobial Chemotherapy |volume=62 |issue=Suppl 2 |pages=ii65–74 |year=2008 |month=November |pmid=18819981 |doi=10.1093/jac/dkn353 |url=http://jac.oxfordjournals.org/cgi/content/full/62/suppl_2/ii65 |issn=0305-7453}}</ref> although resistance in enterococci has been reported.<ref>{{cite journal |author=Auckland C, Teare L, Cooke F, ''et al.'' |title=Linezolid-resistant enterococci: report of the first isolates in the United Kingdom |journal=Journal of Antimicrobial Chemotherapy |volume=50 |issue=5 |pages=743–6 |year=2002 |month=November |pmid=12407134 |url=http://jac.oxfordjournals.org/cgi/content/full/50/5/743 |doi=10.1093/jac/dkf246 |issn=0305-7453}}</ref> Some authors have predicted that resistance in ''E. faecium'' will increase if linezolid use continues at current levels or increases.<ref name=Scheetz/>

===Mechanism===

The ''intrinsic'' resistance of most Gram-negative bacteria to linezolid is due to the activity of [[efflux (microbiology)|efflux pumps]], which [[active transport|actively]] "pump" linezolid out of the cell faster than it can accumulate.<ref name=Barbachyn/><ref>{{cite journal |author=Schumacher A, Trittler R, Bohnert JA, Kümmerer K, Pagès JM, Kern WV |title=Intracellular accumulation of linezolid in ''Escherichia coli'', ''Citrobacter freundii'' and ''Enterobacter aerogenes'': role of enhanced efflux pump activity and inactivation |journal=Journal of Antimicrobial Chemotherapy |volume=59 |issue=6 |pages=1261–4 |year=2007 |month=June |pmid=16971414 |doi=10.1093/jac/dkl380 |issn=0305-7453 |url=http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16971414 |format=Free full text}}</ref>

Gram-positive bacteria usually develop resistance to linezolid as the result of a [[point mutation]] known as ''G2576T'', in which a [[guanine]] base is replaced with [[thymine]] in [[base pair]] 2576 of the genes coding for 23S ribosomal RNA.<ref name=Saager>{{cite journal |author=Saager B, Rohde H, Timmerbeil BS, ''et al.'' |title=Molecular characterisation of linezolid resistance in two vancomycin-resistant (VanB) ''Enterococcus faecium'' isolates using Pyrosequencing |journal=European Journal of Clinical Microbiology & Infectious Diseases |volume=27 |issue=9 |pages=873–8 |year=2008 |month=September |pmid=18421487 |doi=10.1007/s10096-008-0514-6 |issn=0934-9723}}</ref><ref name=Besier>{{cite journal |author=Besier S, Ludwig A, Zander J, Brade V, Wichelhaus TA |title=Linezolid resistance in ''Staphylococcus aureus'': gene dosage effect, stability, fitness costs, and cross-resistances |journal=Antimicrobial Agents and Chemotherapy |volume=52 |issue=4 |pages=1570–2 |year=2008 |month=April |pmid=18212098 |pmc=2292563 |doi=10.1128/AAC.01098-07 |issn=0066-4804 |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=18212098 |format=Free full text}}</ref> This is the most common mechanism of resistance in staphylococci, and the only one known to date in isolates of ''E. faecium''.<ref name=Scheetz>{{cite journal |author=Scheetz MH, Knechtel SA, Malczynski M, Postelnick MJ, Qi C |title=Increasing incidence of linezolid-intermediate or -resistant, vancomycin-resistant ''Enterococcus faecium'' strains parallels increasing linezolid consumption |journal=Antimicrobial Agents and Chemotherapy |volume=52 |issue=6 |pages=2256–9 |year=2008 |month=June |pmid=18391028 |pmc=2415807 |doi=10.1128/AAC.00070-08 |issn=0066-4804 |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=18391028 |format=Free full text}}</ref> Other mechanisms have been identified in ''[[Streptococcus pneumoniae]]'' (including mutations in an RNA [[methyltransferase]] that methylates G2445 of the 23S rRNA and mutations causing increased [[gene expression|expression]] of [[ATP-binding cassette transporter|ABC transporter]] genes)<ref name=Feng2009>{{cite journal |author=Feng J, Lupien A, Gingras H, ''et al.'' |title=Genome sequencing of linezolid-resistant ''Streptococcus pneumoniae'' mutants reveals novel mechanisms of resistance |journal=Genome Research |volume=19 |issue=7 |pages=1214–23 |year=2009 |month=May |pmid=19351617 |doi=10.1101/gr.089342.108 |issn=1088-9051 |pmc=2704432}}</ref> and in ''[[Staphylococcus epidermidis]]''.<ref>{{cite journal |author=Lincopan N, de Almeida LM, Elmor de Araújo MR, Mamizuka EM |title=Linezolid resistance in ''Staphylococcus epidermidis'' associated with a G2603T mutation in the 23S rRNA gene |journal=International Journal of Antimicrobial Agents |volume= 34|issue= 3|pages= 281–2|year=2009 |month=April |pmid=19376688 |doi=10.1016/j.ijantimicag.2009.02.023 |issn=0924-8579}}</ref><ref>{{cite journal |author=Liakopoulos A, Neocleous C, Klapsa D, ''et al.'' |title=A T2504A mutation in the 23S rRNA gene responsible for high-level resistance to linezolid of ''Staphylococcus epidermidis'' |journal=Journal of Antimicrobial Chemotherapy |volume= 64|issue=1 |pages= 206–7|year=2009 |month=July |pmid=19429927 |doi=10.1093/jac/dkp167 |issn=0305-7453}}</ref>

==Interactions==

Linezolid is a weak [[monoamine oxidase inhibitor]] (MAOI), and should not be used concomitantly with other MAOIs, large amounts of [[tyramine]]-rich foods (such as pork, aged cheeses, alcoholic beverages, or smoked and pickled foods), or [[serotonergic]] drugs. There have been [[postmarketing surveillance|postmarketing reports]] of [[serotonin syndrome]] when linezolid was given with or soon after the discontinuation of serotonergic drugs, particularly [[selective serotonin reuptake inhibitor]]s such as [[paroxetine]] and [[sertraline]].<ref name=French/><ref>{{cite journal |author=Lawrence KR, Adra M, Gillman PK |title=Serotonin toxicity associated with the use of linezolid: a review of postmarketing data |journal=Clinical Infectious Diseases |volume=42 |issue=11 |pages=1578–83 |year=2006 |month=June |pmid=16652315 |doi=10.1086/503839 |issn=1058-4838}}</ref><ref name=Huang>{{cite journal |author=Huang V, Gortney JS |title=Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists |journal=Pharmacotherapy |volume=26 |issue=12 |pages=1784–93 |year=2006 |month=December |pmid=17125439 |doi=10.1592/phco.26.12.1784 |issn=0277-0008}}</ref><ref>{{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.</ref> It may also enhance the blood pressure-increasing effects of [[sympathomimetic drug]]s such as [[pseudoephedrine]] or [[phenylpropanolamine]].<ref name=Moellering/><ref name=Stalker>{{cite journal |author=Stalker DJ, Jungbluth GL |title=Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial |journal=Clinical Pharmacokinetics |volume=42 |issue=13 |pages=1129–40 |year=2003 |pmid=14531724 |doi=10.2165/00003088-200342130-00004 |issn=0312-5963}}</ref> It should also not be given in combination with [[pethidine]] ([[meperidine]]) under any circumstance due to the risk of [[serotonin syndrome]].

Linezolid does not [[enzyme inhibitor|inhibit]] or [[regulation of gene expression|induce]] the [[cytochrome P450]] (CYP) system, which is responsible for the metabolism of many commonly used drugs, and therefore does not have any CYP-related interactions.<ref name=PI/>

==Economic considerations==

{{further|[[Pharmacoeconomics]]|[[Disease burden]]}}

Linezolid is quite expensive; a course of treatment may cost several thousand U.S. dollars for the drug alone, not to mention other costs (such as those associated with hospital stay). However, because intravenous linezolid may be switched to an oral formulation (tablets or oral solution) without jeopardizing efficacy, patients may be discharged from hospital relatively early and continue treatment at home, whereas home treatment with injectable antibiotics may be impractical.<ref name=Grau/> Reducing the [[length of stay|length of hospital stay]] reduces the overall cost of treatment, even though linezolid may have a higher acquisition cost—that is, it may be more expensive—than comparable antibiotics.

Studies have been conducted in several countries with different [[health care system]] models to assess the [[cost-effectiveness analysis#CEA in pharmacoeconomics|cost-effectiveness]] of linezolid compared to glycopeptides such as vancomycin or teicoplanin. In most countries, linezolid was more cost-effective than comparable antibiotics for the treatment of hospital-acquired pneumonia and complicated skin and skin structure infections, either due to higher cure and survival rates or lower overall treatment costs.<ref name=Grau/>

In 2009, Pfizer paid $2.3&nbsp;billion and entered a corporate integrity agreement to settle charges that it had misbranded and illegally promoted four drugs, and caused false claims to be submitted to government healthcare programs for uses that were not medically accepted.<ref>{{cite news |url=http://news.bbc.co.uk/2/hi/business/8234533.stm |title=Pfizer agrees record fraud fine |publisher=[[BBC News]] |date=September 2, 2009 |accessdate=2009-09-12}}</ref> $1.3&nbsp;billion were to settle criminal charges of illegally marketing the anti-inflammatory [[valdecoxib]], while $1&nbsp;billion was paid in civil fines regarding illegal marketing of three other drugs, including Zyvox.<ref>{{cite news |url=http://www.nytimes.com/2009/09/03/business/03health.html |title=Pfizer pays $2.3 billion to settle marketing case |last=Harris |first=Gardiner |date=September 2, 2009 |work=[[The New York Times]] |accessdate=2009-09-12}}</ref>

==References==

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[[Category:Oxazolidinone antibiotics]]

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