Zyvox is used for treating adults with certain serious bacterial infections that are often resistant to other antibiotics.

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Linezolid (INN) (conspicuous /lɪˈnɛzəlɪd/ ) is a synthetic antibiotic of the oxazolidinone class used for the treatment of serious infections caused by multi-ungovernable Gram-positive bacteria, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-opposed Staphylococcus aureus (MRSA). It is marketed by Pfizer under the trade name Zyvox (in the Synergetic States and several other countries), Zyvoxam (in Canada and Mexico), or Zyvoxid (in Europe).

Discovered in the fashionable 1980s and approved for use in 2000, linezolid was the first commercially available oxazolidinone antibiotic. Like numberless antibiotics, it is a protein synthesis inhibitor: it stops the growth of bacteria by disrupting their formation of proteins. Resistance to linezolid has remained very low since it was first detected in 1999, although it may be on the enlargement.

Common adverse effects of short-term linezolid use include headache, diarrhea, and nausea. Hanker-term use, however, has been associated with serious adverse affects; it may agent bone marrow suppression and low platelet counts, particularly when used for more than two weeks. If second-hand for longer periods still (several months at a time), linezolid may cause unessential neuropathy, optic nerve damage, and lactic acidosis, probably due to mitochondrial toxicity. Remedy using linezolid can be quite expensive, with prices for a course of treatment ranging up to some thousand U.S. dollars; nonetheless, it appears to be more cost-effective than vancomycin or teicoplanin, partly because of the admissibility opportunity to switch from intravenous therapy to oral treatment as soon as patients are well-balanced enough and without the need for dose adjustments.

History

The oxazolidinones have been known as monoamine oxidase inhibitors since the up to date 1950s. Their antimicrobial properties were discovered by researchers at E.I. duPont de Nemours in the 1970s; in 1978, duPont patented a series of oxazolidinone derivatives as being true belongings in the treatment of bacterial and fungal plant diseases. In 1984, another patent operation described their usefulness in treating bacterial infections in animals, and in 1987, duPont scientists published a itemized description of the oxazolidinones as making up a new class of antibiotics with a completely novel system of action. Early compounds were found to produce liver toxicity, still, and development was discontinued.

Pharmacia & Upjohn (now part of Pfizer) started their own oxazolidinone digging program in the 1990s, and two compounds were taken to Phase I clinical trials: linezolid (codenamed U-100766) and eperezolid, both of which were much less toxic and maintained first-class activity. Linezolid was found to have better pharmacokinetic properties, and it proceeded to more distant trials; Food and Drug Administration (FDA) approval was granted on April 18, 2000. Sanction followed in Brazil (June 2000), the United Kingdom (January 2001), Japan and Canada (April 2001), and Europe (during 2001), as well as other countries in Latin America and Asia.

Linezolid is the not oxazolidinone antibiotic available as of 2009. Other members of this class attired in b be committed to entered development, such as posizolid (AZD2563), ranbezolid (RBx 7644), torezolid (TR-701), and radezolid (RX-1741).

Susceptible bacteria

Linezolid is moving against all clinically important Gram-positive bacteria, notably Enterococcus faecium and Enterococcus faecalis (including vancomycin-intractable enterococci), Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus , MRSA), Streptococcus agalactiae , Streptococcus pneumoniae , Streptococcus pyogenes , the viridans society streptococci, and Listeria monocytogenes . It also appears to be highly effective against Nocardia , but because of its drugged cost and potentially serious adverse effects, authors have recommended that it be combined with other antibiotics or be taciturn for cases that have failed traditional treatment. Linezolid is considered bacteriostatic against most organisms, but has some bactericidal endeavour against streptococci.

It has almost no effect on Gram-negative bacteria; Pseudomonas and the Enterobacteriaceae, for example, are not susceptible at all. In vitro , however, linezolid is active against Pasteurella multocida , Moraxella catarrhalis , Legionella , and Bordetella , and somewhat active (minimum inhibitory concentration for 90% of strains, 8 mg/L) against Haemophilus influenzae .

Indications

Linezolid is most often reserved for the treatment of serious bacterial infections where older antibiotics pull someone's leg failed due to antibiotic resistance. In both the popular press and the scientific literature, it has been called a "avoidance antibiotic"—one that should be used sparingly so it will remain outstanding as a last line of defense against potentially intractable infections.

In the United States, the FDA-approved indications for linezolid use are: vancomycin-uncompliant Enterococcus infection, with or without bacteremia; nosocomial pneumonia and community-acquired pneumonia caused by S. aureus or S. pneumoniae ; tangled skin and skin structure infections (cSSSI) caused by susceptible bacteria, including diabetic foot infection, unless intricate by osteomyelitis; and uncomplicated skin and skin structure infections caused by S. pyogenes or S. aureus . The maker advises against the use of linezolid for community-acquired pneumonia or uncomplicated skin and coating structure infections caused by MRSA.

Linezolid is available in tablet form, verbal suspension powder, or in an inactive medium for intravenous injection.

Off-label use

It is traditionally believed that so-called "immersed" infections, such as osteomyelitis or infective endocarditis, should be treated with bactericidal, not bacteriostatic, antibiotics. Linezolid has, degree, been used successfully to treat such infections. It appears to be a reasonable beneficial option for infective endocarditis caused by multi-resistant Gram-positive bacteria, in defiance of a lack of high-quality evidence to support its use. Results in the treatment of enterococcal endocarditis force been variable, with some cases being treated successfully and others not responding to psychoanalysis. Low- to medium-quality evidence is also mounting for its use in bone and joint infections, including habitual osteomyelitis, although adverse effects are a significant concern when long-spell use is necessary.

In animal studies of meningitis caused by Staphylococcus pneumoniae , linezolid was originate to penetrate well into cerebrospinal fluid, but its effectiveness was inferior to that of other antibiotics. There does not become visible to be enough high-quality evidence to support the routine use of linezolid to treat bacterial meningitis. Nonetheless, it has been reach-me-down successfully in many cases of central nervous system infection—including meningitis—caused by susceptible bacteria, and has also been suggested as a plausible choice for this indication when treatment options are limited or when other antibiotics keep failed.

In vitro , linezolid is highly active against several mycobacteria, and, in bloc with other drugs, it has been used to treat tuberculosis. The optimal measure for use in tuberculosis is not known. In adults, daily and twice-daily dosing have both been toughened to good effect. Treatment often needs to be continued for many months, and the proportion rank of adverse effects is high. The lower dose is not associated with a lower upbraid of adverse effects.

Adverse effects

Common side effects—occurring in more than 1% of people prepossessing linezolid—include diarrhea, headache, nausea, vomiting, rashes, altered soup perception, constipation, and discoloration of the tongue. Thrush and vaginal candidiasis may also crop up (antibiotic candidiasis). Less common (and potentially more serious) adverse effects allow for allergic reactions, pancreatitis and elevated transaminases.

Like nearly all antibiotics, linezolid has been associated with Clostridium difficile -associated diarrhea (CDAD) and pseudomembranous colitis, although it is sheerest uncommon, occurring in about one out of every thousand patients in clinical trials. C. difficile appears to be susceptible to linezolid in vitro , and linezolid was settle considered as a possible treatment for CDAD.

Unlike some other antibiotics, such as erythromycin and the quinolones, linezolid has no virtually on the QT interval.

Long-term use

Bone marrow suppression, characterized particularly by thrombocytopenia, may suggest itself to during linezolid treatment. It is uncommon in patients who receive the drug for 14 days or fewer, but in patients who pocket longer courses, or who have renal failure, the rate is much higher. A 2004 occasion report suggested that pyridoxine (a form of vitamin B ₆ ) could reverse the anemia and thrombocytopenia caused by linezolid, but a later, larger on found no protective effect.

In addition to bone marrow suppression, long-title use of linezolid has also been associated with peripheral neuropathy and optic neuropathy, which may or may not be reversible. Although the physicalism of injury is still poorly understood, mitochondrial toxicity has been proposed as a induce. Linezolid is toxic to mitochondria, probably because of the similarity between mitochondrial and bacterial ribosomes. In ell to neuropathy, lactic acidosis is also a sign of mitochondrial toxicity. Because of these crave-term effects, the manufacturer recommends weekly complete blood counts during linezolid remedial programme to monitor possible bone marrow suppression, and recommends that treatment eventually no more than 28 days.

The adverse effects of long-term linezolid remedy were identified during postmarketing surveillance. Bone marrow suppression was not identified during Off III trials, in which treatment did not exceed 21 days. Although some participants of near the start trials did experience thrombocytopenia, it was found to be reversible and did not occur significantly more generally than in controls (participants not taking linezolid).

Chemistry

Synthesis

Linezolid is a totally synthetic antibiotic: it does not occur in nature (unlike, say, erythromycin) and was not developed by structure upon a naturally occurring skeleton (unlike most beta-lactam antibiotics in clinical use, which are semisynthetic). Uncountable approaches are available for oxazolidinone synthesis, and several routes for the synthesis of linezolid should prefer to been reported in the chemistry literature. Despite good yields, the original method (cast-off by Upjohn for pilot plant-scale production of linezolid and eperezolid) requires the use of n -butyllithium, a very sensitive reagent, and low-temperature conditions.

Later syntheses have included an "atom-cheap" method starting from -mannitol, developed by Indian pharmaceutical company Dr. Reddy's and reported in 1999, and a avenue starting from ( S )-glyceraldehyde acetonide (prepared from vitamin C), developed by a party of researchers from Hunan Normal University in Changsha, Hunan, China. In 2008, during the 12th Annual Unripened Chemistry and Engineering Conference, Pfizer reported the development of their "second-era" synthesis of linezolid, a convergent, green synthesis starting from ( S )-epichlorohydrin, with improved abandon and a 56% reduction in total waste.

Pharmacokinetics

One of the advantages of linezolid is its high bioavailability when accustomed by mouth, which is practically 100%. This means that people receiving intravenous linezolid may be switched to said linezolid as soon as their condition allows it, whereas comparable antibiotics, such as vancomycin, can just be given intravenously. Linezolid has low plasma protein binding (31%) and an apparent abundance of distribution at steady state of around 40–50 liters. The average half-subsistence is three hours in children, four hours in teenagers, and five hours in adults.

Linezolid is metabolized in the liver, by oxidation of the morpholine encompass, without involvement of the cytochrome P450 system. This metabolic pathway leads to two significant inactive metabolites (which each account for around 45% and 10% of an excreted measure at steady state), one minor metabolite, and several trace metabolites, none of which accounts for more than 1% of an excreted administer. Clearance of linezolid varies with age and gender; it is fastest in children (which accounts for the shorter half-spark of life), and appears to be 20% lower in women than in men.

In adults and children over the age of 12, linezolid is generally speaking given every 12 hours, whether orally or intravenously. In younger children and infants, it is preordained every eight hours. No dosage adjustments are required in the elderly, people with peaceful-to-moderate liver failure, or those with impaired kidney function. In people requiring hemodialysis, tribulation should be taken to give linezolid after a session, as dialysis removes linezolid from the heart; no adjustments are needed in people undergoing continuous hemofiltration (also known as endless renal replacement therapy). According to one study, linezolid may need to be given more over again than normal in people with major burns (affecting more than 20% of density area), due to increased nonrenal clearance of the drug.

Mechanism of action

Linezolid is a protein fusion inhibitor: it stops the growth and reproduction of bacteria by disrupting translation of go-between RNA (mRNA) into proteins in the ribosome. Unlike most other protein union inhibitors, which inhibit elongation , linezolid appears to work on the first journeying of protein synthesis, initiation .

It does this by preventing the formation of the initiation complex , composed of the 30S and 50S subunits of the ribosome, tRNA, and mRNA; the oxazolidinones are the solitary drugs that inhibit this particular step of the process. Linezolid binds to the 23S piece of the 50S subunit (the center of peptidyl transferase activity), close to the binding sites of chloramphenicol, lincomycin, and other antibiotics. Due to this one of a kind mechanism of action, there is no cross-resistance between linezolid and other protein composition inhibitors.

In 2008, the crystal structure of linezolid bound to the 50S subunit of a ribosome from the archaean Haloarcula marismortui was elucidated by a work together of scientists from Yale University and deposited in the Protein Data Bank. Also in 2008, the systematize of linezolid bound to a Deinococcus radiodurans 50S subunit was determined by another team. The authors proposed a new exemplar for the mechanism of action of oxazolidinones, finding that linezolid occupies the A site of the 50S ribosomal subunit, inducing a conformational novelty that prevents tRNA from entering the site and ultimately forcing it to detached from the ribosome.

Resistance

Acquired resistance to linezolid was reported as early as 1999, in two patients with punitive, multidrug-resistant Enterococcus faecium infection who received the drug through a compassionate use program. Linezolid-impenetrable to Staphylococcus aureus was first isolated in 2001.

In the United States, resistance to linezolid has been monitored and tracked since 2004 by virtue of a program named LEADER, which (as of 2007) was conducted in 60 medical institutions all the way through the country. Resistance has remained stable and extremely low (less than one-half of one percent of isolates). In the Concerted Kingdom and Ireland, no resistance was found in staphylococci collected from bacteremia cases between 2001 and 2006, although stubbornness in enterococci has been reported. Some authors have predicted that irregulars in E. faecium will increase if linezolid use continues at current levels or increases.

Contrivance

The intrinsic resistance of most Gram-negative bacteria to linezolid appears to be due to the project of efflux pumps, which actively "pump" linezolid out of the cell.

Gram-stubborn bacteria usually develop resistance to linezolid as the result of a point mutation known as G2576T , in which a guanine point of departure is replaced with thymine in base pair 2576 of the genes coding for 23S ribosomal RNA. This is the most public mechanism of resistance in staphylococci, and the only one known to date in isolates of Enterococcus faecium . Other mechanisms contain been identified in Streptococcus pneumoniae , including mutations in an RNA methyltransferase that methylates G2445 of the 23S rRNA and mutations causing increased show of ABC transporter genes, and in Staphylococcus epidermidis .

Interactions

Linezolid is a weak monoamine oxidase inhibitor (MAOI), and should not be in use accustomed to concomitantly with other MAOIs, tyramine-containing foods, or pseudoephedrine; there must been postmarketing reports of serotonin syndrome when linezolid was given with or tout de suite after discontinuing serotonergic drugs, particularly selective serotonin reuptake inhibitors such as paroxetine and sertraline. It may also lift the blood pressure-increasing effects of sympathomimetic drugs such as pseudoephedrine or phenylpropanolamine.

Linezolid does not hold back or induce the cytochrome P450 system, and therefore does not have any CYP450-associated interactions.

References

1. ^ ^{a b c d e f g h i j} Pfizer (June 20, 2008). "ZYVOX (linezolid) Label Information" (PDF) . http://www.accessdata.fda.gov/drugsatfda_docs/marker/2008/021130s016,021131s013,021132s014lbl.pdf . Retrieved on 2008-08-24 .  
2. ^ ^{a b c d e f g h} Lexi-Comp (August 2008). "Linezolid". The Merck Directions Professional . http://www.merck.com/mmpe/lexicomp/linezolid.html .   Retrieved on May 14, 2009.
3. ^ Grau S, Rubio-Terrés C (April 2008). "Pharmacoeconomics of linezolid". Superior Opinion on Pharmacotherapy 9 (6): 987–1000. doi: 10.1517/14656566.9.6.987 . PMID 18377341.  
4. ^ ^{a b c d} Brickner SJ (1996). "Oxazolidinone antibacterial agents". Prevailing Pharmaceutical Design 2 (2): 175–94 . http://books.google.com/books?id=_HFitfA4OcUC&pg=PA175&lpg=PA175 .   Elaborate review of the discovery and development of the whole oxazolidinone class, including information on combining and structure-activity relationships.
5. ^ ^{a b c d e f g} Moellering RC (January 2003). "Linezolid: the premier oxazolidinone antimicrobial". Annals of Internal Medicine 138 (2): 135–42. PMID 12529096 . http://www.annals.org/cgi/reprint/138/2/135.pdf .  
6. ^ Slee AM, Wuonola MA, McRipley RJ, et al. (November 1987). "Oxazolidinones, a new realm of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721". Antimicrobial Agents and Chemotherapy 31 (11): 1791–7. doi: 10.1128/AAC. . PMID 3435127. PMC: 175041 . http://aac.asm.org/cgi/pmidlookup?vision=long&pmid=3435127 .  
7. ^ ^{a b} Livermore DM (September 2000). "Quinupristin/dalfopristin and linezolid: where, when, which and whether to use?". Almanac of Antimicrobial Chemotherapy 46 (3): 347–50. doi: 10.1093/jac/46.3.347 . PMID 10980159 . http://jac.oxfordjournals.org/cgi/pmidlookup?view=dream of&pmid=10980159 .  
8. ^ ^{a b c d e f g h} French G (May 2003). "Safety and tolerability of linezolid". Journal of Antimicrobial Chemotherapy 51 Suppl 2 : ii45–53. doi: 10.1093/jac/dkg253 . PMID 12730142.   Survey. Includes extensive discussion of the hematological adverse effects of linezolid.
9. ^ Ford CW, Zurenko GE, Barbachyn MR (August 2001). "The finding of linezolid, the first oxazolidinone antibacterial agent". Current Drug Targets – Communicable Disorders 1 (2): 181–99. doi: 10.2174/1568005014606099 . PMID 12455414.  
10. ^ "Drug Approval Package: Zyvox". FDA Center for Drug Determination and Research. November 20, 2001 . http://www.fda.gov/cder/foi/nda/2000/21130_Zyvox.htm . Retrieved on 2009-01-17 .   Comprehensive criticize 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.
11. ^ ANVISA (June 5, 2000). "Resolução nº 474, de 5 de junho de 2000" (in Portuguese). Federal Health Surveillance Agency . http://www.anvisa.gov.br/legis/resol/2000/474_00re.htm . Retrieved on 2009-05-19 .  
12. ^ Irinoda K, Nomura S, Hashimoto M (October 2002). "" (in Japanese). Nippon Yakurigaku Zasshi 120 (4): 245–52. PMID 12425150.  
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