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Linezolid is effective against all clinically important [[Gram-positive bacteria]], notably ''[[Enterococcus faecium]]'' and ''[[Enterococcus faecalis]]'' (including [[vancomycin-resistant enterococcus|vancomycin-resistant enterococci]]), ''Staphylococcus aureus'' (including [[methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']], MRSA), ''[[Streptococcus agalactiae]]'', ''[[Streptococcus pneumoniae]]'', ''[[Streptococcus pyogenes]]'', the [[Streptococcus#Viridans and others|''viridans'' group streptococci]], and ''[[Listeria monocytogenes]]'',<ref name=PI/><ref name=Moellering/> and, ''in vitro'', is highly active against several [[Mycobacterium|mycobacteria]].<ref name=Moellering/> It also appears to be highly 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}}</ref> Linezolid is considered [[bacteriostatic]] against most organisms, but has some [[bactericidal]] 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/>
Linezolid is effective against all clinically important [[Gram-positive bacteria]], notably ''[[Enterococcus faecium]]'' and ''[[Enterococcus faecalis]]'' (including [[vancomycin-resistant enterococcus|vancomycin-resistant enterococci]]), ''Staphylococcus aureus'' (including [[methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']], MRSA), ''[[Streptococcus agalactiae]]'', ''[[Streptococcus pneumoniae]]'', ''[[Streptococcus pyogenes]]'', the [[Streptococcus#Viridans and others|''viridans'' group streptococci]], and ''[[Listeria monocytogenes]]'',<ref name=PI/><ref name=Moellering/> and, ''in vitro'', is highly active against several [[Mycobacterium|mycobacteria]].<ref name=Moellering/> It also appears to be highly 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}}</ref> Linezolid is considered [[bacteriostatic]] against most organisms, but has some [[bactericidal]] 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/>


Linezolid has been compared to [[quinupristin/dalfopristin]] (Synercid), another protein synthesis inhibitor active against multi-resistant Gram-positive bacteria. Quinupristin/dalfopristin has lower [[minimum inhibitory concentration|MIC]]s for staphylococci, streptococci, and ''E. faecium'', but is not active against ''E. faecalis'', can only be given through a [[central venous catheter]], and has been associated with severe joint and muscle pain.<ref name=Livermore/>
Linezolid's spectrum of activity against Gram-positive bacteria is similar to that of vancomycin (with the exception of VRE, which is by definition not susceptible to the latter), and the two drugs are often compared.<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 |pages=817 |isbn=0-7817-4802-X}}</ref> <!--Other comparable antibiotics include [[teicoplanin]], [[quinupristin/dalfopristin]] (Synercid, a [[combination antibiotic|combination]] of two [[streptogramin]]s), and [[daptomycin]] (Cubicin, a [[lipopeptide]]).--> Linezolid has been compared to [[quinupristin/dalfopristin]] (Synercid), another protein synthesis inhibitor active against multi-resistant Gram-positive bacteria. Quinupristin/dalfopristin has lower [[minimum inhibitory concentration|MIC]]s for staphylococci, streptococci, and ''E. faecium'', but is not active against ''E. faecalis'', can only be given through a [[central venous catheter]], and has been associated with severe joint and muscle pain.<ref name=Livermore/>


===Gram-negative bacteria===
===Gram-negative bacteria===
Line 81: Line 81:


==Adverse effects==
==Adverse effects==
Common [[Adverse drug reaction|side effects]] of linezolid use<ref>Defined as occurring in more than 1% of people taking linezolid.</ref> include diarrhea (reported by 3–11% of clinical trial participants), headache (1–11%), nausea (3–10%), vomiting (1–4%), rashes (2%), constipation (2%), altered taste perception (1–2%), and discoloration of the tongue (0.2–1%).<ref name=Lexi-Comp/> [[Oral candidiasis|Thrush]] and [[candidal vulvovaginitis|vaginal candidiasis]] may also occur ([[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 Suppl 2 |issue= |pages=ii45–53 |year=2003 |month=May |pmid=12730142 |doi=10.1093/jac/dkg253}} 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]].<ref name=French/>
When used for short periods of time, linezolid is a relatively safe drug.<ref name=Marino/> Common [[Adverse drug reaction|side effects]] of linezolid use<ref>Defined as occurring in more than 1% of people taking linezolid.</ref> include diarrhea (reported by 3–11% of clinical trial participants), headache (1–11%), nausea (3–10%), vomiting (1–4%), rashes (2%), constipation (2%), altered taste perception (1–2%), and discoloration of the tongue (0.2–1%).<ref name=Lexi-Comp/> [[Oral candidiasis|Thrush]] and [[candidal vulvovaginitis|vaginal candidiasis]] may also occur ([[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 Suppl 2 |issue= |pages=ii45–53 |year=2003 |month=May |pmid=12730142 |doi=10.1093/jac/dkg253}} 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]].<ref name=French/>


Like nearly all antibiotics, linezolid has been associated with [[Clostridium difficile|''Clostridium difficile''-associated diarrhea]] (CDAD) and [[pseudomembranous colitis]], although it is very uncommon, occurring in about one out of every thousand patients in clinical trials.<ref name=Lexi-Comp/><ref name=French/><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}}</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}}</ref>
Like nearly all antibiotics, linezolid has been associated with [[Clostridium difficile|''Clostridium difficile''-associated diarrhea]] (CDAD) and [[pseudomembranous colitis]], although it is very uncommon, occurring in about one out of every thousand patients in clinical trials.<ref name=Lexi-Comp/><ref name=French/><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}}</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}}</ref>

Revision as of 17:41, 6 July 2009

{{drugbox | IUPAC_name = N-{[(5S)- 3-[3-fluoro-4-(morpholin-4-yl)phenyl]- 2-oxo- 1,3-oxazolidin- 5-yl] methyl} acetamide | image = Linezolid.svg | image2 = Linezolid-from-xtal-2008-3D-balls.png | CAS_number = 165800-03-3 | ChemSpiderID = 390139 | ATC_prefix = J01 | ATC_suffix = XX08 | PubChem = 441401 | DrugBank = APRD01073 | C=16 | H=20 | F=1 | N=3 | O=4 | molecular_weight = 337.346 g/mol | bioavailability = ~100% (oral) | protein_bound = Low (31%) | metabolism = Hepatic (50–70%, CYP not involved) | elimination_half-life = 4.2–5.4 hours | excretion = Nonrenal, renal, and fecal | licence_US = Linezolid | pregnancy_category = C (Au), C (U.S.) | legal_status = S4 (Au), POM (UK), ℞-only (U.S.) | routes_of_administration = Intravenous infusion, oral }} Linezolid (INN) (Template:PronEng, li-NE-zə-lid) is a synthetic antibiotic of the oxazolidinone class used for the treatment of serious infections caused by multi-resistant Gram-positive bacteria, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA).[1] It is marketed by Pfizer under the trade name Zyvox (in the United States, United Kingdom, Australia, and several other countries), Zyvoxam (in Canada and Mexico), or Zyvoxid (in Europe).

Discovered in the late 1980s and approved for use in 2000, linezolid was the first commercially available oxazolidinone antibiotic, and is the only one as of 2009. Like many antibiotics, it is a protein synthesis inhibitor: it stops the growth of bacteria by disrupting their production of proteins. Resistance to linezolid has remained very low since it was first detected in 1999, although it may be on the increase.

Common adverse effects of short-term linezolid use include headache, diarrhea, and nausea. Long-term use has been associated with serious adverse affects; linezolid may cause bone marrow suppression and low platelet counts, particularly when used for more than two weeks. If used for longer periods still (several months at a time), it may cause peripheral neuropathy, optic nerve damage, and lactic acidosis, probably due to mitochondrial toxicity. Linezolid is quite expensive, with prices for a course of treatment ranging up to several thousand U.S. dollars;[2] nonetheless, it appears to be more cost-effective than vancomycin or teicoplanin,[3] partly because of the possibility to switch from intravenous therapy to oral treatment as soon as patients are stable enough and without the need for dose adjustments.

History

The oxazolidinones have been known as monoamine oxidase inhibitors since the late 1950s, and their antimicrobial properties were discovered by researchers at E.I. duPont de Nemours in the 1970s.[4] In 1978, duPont patented a series of oxazolidinone derivatives as being effective in the treatment of bacterial and fungal plant diseases.[4][5] In 1984, another patent described their usefulness in treating bacterial infections in mammals, and in 1987, duPont scientists presented a detailed description of the oxazolidinones as making up a new class of antibiotics with a completely novel mechanism of action.[4][6] Early compounds were found to produce liver toxicity, however, and development was discontinued.[7]

Pharmacia & Upjohn (now part of Pfizer) started their own oxazolidinone research program in the 1990s. Extensive structure-activity relationship studies led to the development of several subclasses of oxazolidinone derivatives, with varying safety profiles and antimicrobial activity. Two compounds were found to be potential drug candidates: eperezolid (codenamed PNU-100592) and linezolid (PNU-100766).[8][9] In the preclinical stages of development, both were essentially identical in safety and antibacterial activity, so both were taken to Phase I clinical trials to identify any potential difference in pharmacokinetics.[7][10] 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.[8] U.S. Food and Drug Administration (FDA) approval was granted on April 18, 2000.[11] Approval followed in Brazil (June 2000),[12] the United Kingdom (January 2001),[9][13] Japan and Canada (April 2001),[14][15][16] Europe (throughout 2001),[17] and other countries in Latin America and Asia.[15]

Linezolid is the only oxazolidinone antibiotic available as of 2009.[18] Other members of this class have entered development, such as posizolid (AZD2563),[19] ranbezolid (RBx 7644),[20] torezolid (TR-701),[18][21] and radezolid (RX-1741).[22]

Spectrum of activity

Linezolid is effective against all clinically important Gram-positive bacteria, notably Enterococcus faecium and Enterococcus faecalis (including vancomycin-resistant enterococci), Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus, MRSA), Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, the viridans group streptococci, and Listeria monocytogenes,[1][5] and, in vitro, is highly active against several mycobacteria.[5] It also appears to be highly 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.[23] Linezolid is considered bacteriostatic against most organisms, but has some bactericidal activity against streptococci.[1][24] 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 toxins by staphylococci and streptococci.[8]

Linezolid's spectrum of activity against Gram-positive bacteria is similar to that of vancomycin (with the exception of VRE, which is by definition not susceptible to the latter), and the two drugs are often compared.[25] Linezolid has been compared to quinupristin/dalfopristin (Synercid), another protein synthesis inhibitor active against multi-resistant Gram-positive bacteria. Quinupristin/dalfopristin has lower MICs for staphylococci, streptococci, and E. faecium, but is not active against E. faecalis, can only be given through a central venous catheter, and has been associated with severe joint and muscle pain.[7]

Gram-negative bacteria

Linezolid has no clinically significant effect on most Gram-negative bacteria. Pseudomonas and the Enterobacteriaceae, for instance, are not susceptible at all.[24] In vitro, it is active against Pasteurella multocida,[1][26] Fusobacterium, Moraxella catarrhalis, Legionella, Bordetella, and Elizabethkingia meningoseptica, and moderately active (minimum inhibitory concentration for 90% of strains, 8 mg/L) against Haemophilus influenzae.[24][27] It has also been used to great effect as a second-line treatment for Capnocytophaga infections.[28][29]

Indications

The main indication of linezolid is treatment of severe infections caused by Gram-positive bacteria that are resistant to other antibiotics. In both the popular press and the scientific literature, it has been called a "reserve antibiotic"—one that should be used sparingly so it will remain effective as a last line of defense against potentially intractable infections.[30][31]

In the United States, the FDA-approved indications for linezolid use are: vancomycin-resistant Enterococcus infection, with or without bacteremia; hospital- and community-acquired pneumonia caused by S. aureus or S. pneumoniae; complicated skin and skin structure infections (cSSSI) caused by susceptible bacteria, including diabetic foot infection, unless complicated by osteomyelitis; 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.[1] In the United Kingdom, pneumonia and cSSSIs are the only indications noted in the product labeling.[13]

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.[1][27]

Skin and soft tissue infections

A large, well-designed meta-analysis of randomized controlled trials found linezolid to be more effective than glycopeptide antibiotics (such as vancomycin and teicoplanin) and beta-lactam antibiotics in the treatment of skin and soft tissue infections (SSTIs) caused by Gram-positive bacteria,[32] and smaller studies appear to confirm its superiority over teicoplanin in the treatment of all serious Gram-positive infections.[33]

In the treatment of diabetic foot infections, linezolid appears to be cheaper and more effective than vancomycin.[34] 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.[35][36] A 2008 meta-analysis of 18 randomized controlled trials, however, found that linezolid treatment failed as often as that with other antibiotics, regardless of whether patients had osteomyelitis.[37]

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.[36]

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.[32] Clinical guidelines 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.[38] British Thoracic Society guidelines do not recommend it as first-line treatment, but rather as an alternative to vancomycin.[39] Linezolid is also an acceptable second-line treatment for community-acquired pneumococcal pneumonia when penicillin resistance is present.[38]

U.S. guidelines recommend either linezolid or vancomycin as the first-line treatment for hospital-acquired (nosocomial) MRSA pneumonia.[40] 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 results that suggest the superiority of linezolid into question.[36] Nevertheless, the high bioavailability of linezolid is an advantage (because it allows easy switching to oral therapy), as is the fact that kidney function is not an obstacle to the use of linezolid, whereas achieving correct dosage of vancomycin in patients with renal insufficiency is very difficult.[40]

Off-label use

This echocardiogram shows vegetations on the tricuspid valve, caused by infective endocarditis.
The patient was not treated with linezolid (he received more conventional treatment, with ampicillin, imipenem, and glucocorticoids) and recovered fully after heart surgery.[41]

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,[8] and it has been used successfully to treat them in clinical practice. It 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.[42][43] Results in the treatment of enterococcal endocarditis have been variable, with some cases being treated successfully and others not responding to therapy.[44][45][46][47][48][49] 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.[50][51][52][53][54][55]

In combination with other drugs, linezolid has been used to treat tuberculosis.[56] The optimal dose for this purpose is not known. In adults, daily and twice-daily dosing have both been used to good effect.[57][58] Treatment often needs to be continued for many months, and the rate of adverse effects is high regardless of dosage.[57]

Linezolid has been studied as an alternative to vancomycin in the treatment of febrile neutropenia in cancer patients when Gram-positive infection is suspected.[59] It is also one of few antibiotics that diffuse into the vitreous humor, and may therefore be effective in treating endophthalmitis caused by susceptible bacteria. There is little evidence for its use in this setting, however, as infectious endophthalmitis is widely and effectively treated with intravitreal vancomycin.[36]

Central nervous system infections

In animal studies of meningitis caused by Staphylococcus pneumoniae, linezolid was found to penetrate well into cerebrospinal fluid (concentrations were 29% of those reached in serum), but its effectiveness was inferior to that of other antibiotics. 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.[60][28] It 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 in the literature thus far.[61]

Catheter-related infections

In March 2007, the FDA reported the results of a randomized, open-label, phase III clinical trial comparing linezolid to vancomycin in the treatment of catheter-related bloodstream infections. Vancomycin-treated patients could be switched to oxacillin or dicloxacillin if the bacteria causing 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.[62] The study itself was published in January 2009.[63]

All around, linezolid was associated with significantly greater mortality than the comparator antibiotics: when data from all study participants was pooled, 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 patients with Gram-negative infections alone and those with mixed Gram-negative/Gram-positive disease. In participants whose infection was due to Gram-positive bacteria alone, linezolid was as safe and effective as vancomycin.[62][63] 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.[62]

Adverse effects

When used for short periods of time, linezolid is a relatively safe drug.[25] Common side effects of linezolid use[64] include diarrhea (reported by 3–11% of clinical trial participants), headache (1–11%), nausea (3–10%), vomiting (1–4%), rashes (2%), constipation (2%), altered taste perception (1–2%), and discoloration of the tongue (0.2–1%).[2] Thrush and vaginal candidiasis may also occur (antibiotic candidiasis).[2] Less common (and potentially more serious) adverse effects include allergic reactions, pancreatitis, and elevated transaminases, which may be a sign of liver damage.[2][9] Unlike some antibiotics, such as erythromycin and the quinolones, linezolid has no effect on the QT interval.[9]

Like nearly all antibiotics, linezolid has been associated with Clostridium difficile-associated diarrhea (CDAD) and pseudomembranous colitis, although it is very uncommon, occurring in about one out of every thousand patients in clinical trials.[2][9][65] C. difficile appears to be susceptible to linezolid in vitro, and linezolid was even considered as a possible treatment for CDAD.[66]

As of June 2009, linezolid is a "black triangle drug" in the United Kingdom, meaning it is under intensive postmarketing surveillance by the Commission on Human Medicines of the Medicines and Healthcare products Regulatory Agency.[13]

Long-term use

Bone marrow suppression, characterized particularly by thrombocytopenia, may occur during linezolid treatment; it appears to be the only adverse effect that occurs significantly more frequently with linezolid than with glycopeptides or beta-lactams.[32] 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.[9][67] A 2004 case report suggested that pyridoxine (a form of vitamin B6) could reverse the anemia and thrombocytopenia caused by linezolid,[68] but a later, larger study found no protective effect.[69]

In addition to bone marrow suppression, 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.[70][71][72][73] Although the mechanism of injury is still poorly understood, mitochondrial toxicity has been proposed as a cause;[74][75] linezolid is toxic to mitochondria, probably because of the similarity between mitochondrial and bacterial ribosomes.[76] Lactic acidosis may also occur due to mitochondrial toxicity.[74] Because of these long-term effects, the manufacturer recommends weekly complete blood counts during linezolid therapy to monitor possible bone marrow suppression, and recommends that treatment last no more than 28 days.[1][9] 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 a review of all medications taken by the patient, interrupting the use of those that may interact with linezolid; twice-weekly blood tests and liver function tests; measurement of serum lactate levels; and periodic eye and neurological exams in patients set to receive linezolid for longer than four weeks.[77]

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).[5]

Chemistry

Numbered structure of linezolid, showing the pharmacophore required for good activity (in blue) and desirable structural features (in orange).

The oxazolidinone pharmacophore—the chemical “template” essential for antimicrobial efficacy—consists of a 1,3-oxazolidin-2-one moiety with an aryl group at position 3 and an S-methyl group, with another substituent attached to it, at position 5 (the R-enantiomers of all oxazolidinones are devoid of antibiotic properties).[4] 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, which is the best choice in terms of antibacterial efficacy and is used in all of the more active oxazolidinones developed thus far; a fluorine atom at the 3′ position, which practically doubles in vitro and in vivo activity; and the electron-donating nitrogen atom in the morpholine ring, which helps maintain high antibiotic potency and an acceptable safety profile.[4][8]

The anticoagulant rivaroxaban (Xarelto) bears a striking structural similarity to linezolid; both drugs share the structural features mentioned above. This similarity appears to carry no clinical significance.[78]

Synthesis

Linezolid is a completely synthetic antibiotic: it does not occur in nature (unlike erythromycin and many others) and was not developed by building upon a naturally occurring skeleton (unlike most beta-lactam antibiotics, which are semisynthetic). Many approaches are available for oxazolidinone synthesis, and several routes for the synthesis of linezolid have been reported in the chemistry literature.[4][79] Despite good 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—and needs low-temperature conditions.[4][79][80] Much of the high cost of linezolid has been attributed to the expense of its synthesis.[80] A somewhat more concise and cost-effective route better suited to large-scale production was patented by Upjohn in 1998.[8][81]

Later syntheses have included an "atom-economical" method starting from D-mannitol, developed by Indian pharmaceutical company Dr. Reddy's and reported in 1999,[82] 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.[79] 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, green synthesis starting from (S)-epichlorohydrin, with higher yield and a 56% reduction in total waste.[83]

Pharmacokinetics

Major metabolites of linezolid

One of the advantages of linezolid is its high bioavailability when given by mouth, which is practically 100%. 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.[84] Linezolid has low plasma protein binding (31%) and an apparent volume of distribution at steady state of around 40–50 liters.[2] It is readily distributed to all tissues in the body apart from bone matrix and white adipose tissue.[8] The average half-life is three hours in children, four hours in teenagers, and five hours in adults.[1]

Linezolid is metabolized in the liver, by oxidation of the morpholine ring, without involvement of the cytochrome P450 system. This metabolic pathway leads to two major inactive metabolites (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.[85] 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.[1][85][86]

Use in special populations

In adults and children over the age of 12, linezolid is usually given every 12 hours, whether orally or intravenously.[5][84] In younger children and infants, it is given every eight hours.[87] No dosage adjustments are required in the elderly, people with mild-to-moderate liver failure, or those with impaired kidney function.[2] In people requiring hemodialysis, care should be taken to give linezolid after a session, because dialysis removes it from the body; no adjustments are needed in people undergoing continuous hemofiltration (also known as continuous renal replacement therapy).[2] According to one study, linezolid may need to be given more frequently than normal in people with burns affecting more than 20% of body area, due to increased nonrenal clearance of the drug.[88]

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.[1] It also passes into breast milk, although the clinical significance of this (if any) is unknown.[27]

Mechanism of action

Simplified schematic of mRNA translation. Linezolid occupies the A site (at right) and prevents tRNA from binding.

The oxazolidinones are protein synthesis inhibitors: they stop the growth and reproduction of bacteria by disrupting translation of messenger RNA (mRNA) into proteins in the ribosome. Although its mechanism of action is not fully understood,[89] linezolid appears to work on the first step of protein synthesis, initiation, unlike most other protein synthesis inhibitors, which inhibit elongation.[84][90]

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 only drugs that inhibit this particular step of the process. Linezolid binds to the 23S portion of the 50S subunit (the center of peptidyl transferase activity),[91] close to the binding sites of chloramphenicol, lincomycin, and other antibiotics. Due to its unique mechanism of action, there is no cross-resistance between linezolid and other protein synthesis inhibitors.[5]

In 2008, the crystal structure of linezolid bound to the 50S subunit of a ribosome from the archaean Haloarcula marismortui was elucidated by a team of scientists from Yale University and deposited in the Protein Data Bank.[92] Also in 2008, the structure of linezolid bound to a Deinococcus radiodurans 50S subunit was determined by another team. The authors proposed a refined model for the mechanism of action of oxazolidinones, finding that linezolid occupies the 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.[93]

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 compassionate use program.[24] Linezolid-resistant Staphylococcus aureus was first isolated in 2001.[94]

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 isolates).[95] In the United Kingdom and Ireland, no resistance was found in staphylococci collected from bacteremia cases between 2001 and 2006,[96] although resistance in enterococci has been reported.[97] Some authors have predicted that resistance in E. faecium will increase if linezolid use continues at current levels or increases.[98]

Mechanism

The intrinsic resistance of most Gram-negative bacteria to linezolid is due to the activity of efflux pumps, which actively "pump" linezolid out of the cell faster than it can accumulate.[8][99]

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.[100][101] This is the most common mechanism of resistance in staphylococci, and the only one known to date in isolates of Enterococcus faecium.[98] 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 expression of ABC transporter genes)[102] and in Staphylococcus epidermidis.[103][104]

Interactions

Linezolid is a weak monoamine oxidase inhibitor (MAOI), and should not be used concomitantly with other MAOIs, tyramine-rich foods (such as pork, aged cheeses, alcoholic beverages, or smoked and pickled foods), or serotonergic drugs. There have been postmarketing reports of serotonin syndrome when linezolid was given with or soon after discontinuing serotonergic drugs, particularly selective serotonin reuptake inhibitors such as paroxetine and sertraline.[9][105][106][107] It may also enhance the blood pressure-increasing effects of sympathomimetic drugs such as pseudoephedrine or phenylpropanolamine.[5][108]

Linezolid does not inhibit or induce the cytochrome P450 system, and therefore does not have any CYP450-related interactions.[1]

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