Linezolid
Clinical data | |
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Pronunciation | /lɪˈnɛzəlɪd, -ˈneɪz-/ |
Trade names | Zyvox, Zyvoxam, others |
AHFS/Drugs.com | Monograph |
MedlinePlus | a602004 |
License data | |
Pregnancy category |
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Oxazolidinone antibiotic | |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | ~100% (oral) |
Protein binding | Low (31%) |
Metabolism | Liver (50–70%, CYP not involved) |
Elimination half-life | 3–7 hours;[9] longer half-life in CSF than plasma[9] |
Excretion | non-kidney, kidney, and fecal[10] |
Identifiers | |
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Linezolid is an
When given for short periods, linezolid is a relatively safe antibiotic.
As a
Linezolid was discovered in the mid-1990s, and was approved for commercial use in 2000.
Medical uses
The main use of linezolid is the treatment of severe infections caused by
In the United States, the indications for linezolid use approved by the U.S.
Linezolid appears to be as safe and effective for use in children and newborns as it is in adults.[23]
Skin and soft tissue infections
A large
In the treatment of diabetic foot infections, linezolid appears to be cheaper and more effective than vancomycin.
Some authors have recommended that combinations of cheaper or more cost-effective drugs (such as
Pneumonia
No significant difference appears in treatment success rates between linezolid, glycopeptides, or appropriate beta-lactam antibiotics in the treatment of pneumonia.[24] 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.[31] The guidelines of the British Thoracic Society do not recommend it as first-line treatment, but rather as an alternative to vancomycin.[32] Linezolid is also an acceptable second-line treatment for community-acquired pneumococcal pneumonia when penicillin resistance is present.[31]
U.S. guidelines recommend either linezolid or vancomycin as the first-line treatment for hospital-acquired (nosocomial) MRSA pneumonia.
Other
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,[35] 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.[36][37] Results in the treatment of enterococcal endocarditis have varied, with some cases treated successfully and others not responding to therapy.[38][39][40][41][42][43] 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.[44][45][46][47][48][49]
In combination with other drugs, linezolid has been used to
Linezolid has been studied as an alternative to vancomycin in the treatment of
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.[54][55] 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.[56][57] 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.[58] 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[update]).[59]
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. 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.[60] The study itself was published in January 2009.[61]
Linezolid was associated with significantly 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.[60][61] 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.[60]
Specific populations
In adults and children over the age of 12, linezolid is usually given every 12 hours, whether orally or intravenously.[54][62] In younger children and infants, it is given every eight hours.[63] No dosage adjustments are required in the elderly, in people with mild-to-moderate liver failure, or in those with impaired kidney function.[64] 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 continuous hemofiltration,[64] although more frequent administration may be warranted in some cases.[23] 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.[65]
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.[8] It also passes into breast milk, although the clinical significance of this (if any) is unknown.[66]
Spectrum of activity
Linezolid is effective against all clinically important Gram-positive
Linezolid is considered bacteriostatic against most organisms—that is, it stops their growth and reproduction without actually killing them—but has some bactericidal (killing) activity against streptococci.[8][69] 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.[35] It also has a post-antibiotic effect lasting one to four hours for most bacteria, meaning that bacterial growth is temporarily suppressed even after the drug is discontinued.[23]
Gram-negative bacteria
Linezolid has no clinically significant effect on most Gram-negative bacteria. Pseudomonas and the Enterobacteriaceae, for instance, are not susceptible.[69] In vitro, it is active against Pasteurella multocida,[8][70] Fusobacterium, Moraxella catarrhalis, Legionella, Bordetella, and Elizabethkingia meningoseptica, and moderately active (having a minimum inhibitory concentration for 90% of strains of 8 mg/L) against Haemophilus influenzae.[66][69] It has also been used to great effect as a second-line treatment for Capnocytophaga infections.[56][71]
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.[12][23] Other comparable antibiotics include glycopeptide antibiotics such as teicoplanin (trade name Targocid), dalbavancin (Dalvance), oritavancin (Orbactiv), and telavancin (Vibativ); quinupristin/dalfopristin (Synercid, a combination of two streptogramins, not active against E. faecalis);[72] daptomycin (Cubicin, a lipopeptide); and ceftobiprole (Zevtera, a 5th-generation cephalosporin). Linezolid is the only one that can be taken by mouth for the treatment of systemic infections.[23]
Adverse effects
When used for short periods, linezolid is a relatively safe drug.
Like nearly all antibiotics, linezolid has been associated with
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 significantly more frequently with linezolid than with glycopeptides or beta-lactams.[24] 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.[73][77] A 2004 case report suggested that pyridoxine (a form of vitamin B6) could reverse the anemia and thrombocytopenia caused by linezolid,[78] but a later, larger study found no protective effect.[79]
Long-term use of linezolid has also been associated with
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).[54] There have also been postmarketing reports of seizures, and, as of 2009[update], a single case each of Bell's palsy (paralysis of the facial nerve) and kidney toxicity.[74] Evidence of protein synthesis inhibition in mammalian cells by linezolid has been published.[95]
Interactions
Linezolid is a weak, non-selective, reversible
Linezolid does not inhibit or 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.[8]
Pharmacology
Pharmacodynamics
Linezolid, like other
In 2008, the
Pharmacokinetics
One of the advantages of linezolid is that it has an
Linezolid's
Linezolid is
Chemistry
At physiological pH (7.4), linezolid exists in an uncharged state. It is moderately water-soluble (approximately 3 mg/mL), with a logP of 0.55.[23]
The oxazolidinone
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 chlorothiophene, and missing the fluorine atom). However this similarity appears to carry no clinical significance.[109]
Synthesis
Linezolid is a completely
Later syntheses have included an "
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.[69] Linezolid-resistant Staphylococcus aureus was first isolated in 2001.[115]
In the United States, resistance to linezolid has been monitored and tracked since 2004 through a program named LEADER, which (as of 2007[update]) was conducted in 60 medical institutions throughout the country. Resistance has remained stable and extremely low—less than one-half of one percent of
Mechanism
The intrinsic resistance of most Gram-negative bacteria to linezolid is due to the activity of
Gram-positive bacteria usually develop resistance to linezolid as the result of a
History
The oxazolidinones have been known as monoamine oxidase inhibitors since the late 1950s. Their antimicrobial properties were discovered by researchers at E.I. duPont de Nemours in the 1970s.[108] In 1978, DuPont patented a series of oxazolidinone derivatives as being effective in the treatment of bacterial and fungal plant diseases, and in 1984, another patent described their usefulness in treating bacterial infections in mammals.[54][108] In 1987, DuPont scientists presented a detailed description of the oxazolidinones as a new class of antibiotics with a novel mechanism of action.[108][127] Early compounds were found to produce liver toxicity, however, and development was discontinued.[72]
As of 2009[update], linezolid was the only oxazolidinone antibiotic available.[135] Other members of this class have entered development, such as posizolid (AZD2563),[136] ranbezolid (RBx 7644),[137] and radezolid (RX-1741).[138] In 2014, the FDA approved tedizolid phosphate, a second-generation oxazolidinone derivative, for acute bacterial skin and skin structure infection.[139][140]
Society and culture
Economics
Linezolid was quite expensive in 2009; a course of treatment may cost one or two thousand U.S. dollars for the drug alone,[64] not to mention other costs (such as those associated with hospital stay). With the medication becoming generic the price has decreased. In India as of 2015 a month of linezolid, as would be used to treat tuberculosis cost about US$60.[11]
However, because intravenous linezolid may be switched to an oral formulation (tablets or oral solution) without jeopardizing efficacy, people may be discharged from hospital relatively early and continue treatment at home, whereas home treatment with injectable antibiotics may be impractical.[141] Reducing the 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
In 2009, Pfizer paid $2.3 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 had not been approved by the United States Food and Drug Administration.[142] $1.3 billion was paid to settle criminal charges of illegally marketing the anti-inflammatory valdecoxib, while $1 billion was paid in civil fines regarding illegal marketing of three other drugs, including Zyvox.[143]
Brand names
A | Amizole 500 (Kenya), Anozilad (Poland), Antizolid (Greece), Arlid (India), Arlin (Bangladesh), Averozolid & Debacozoline (Egypt) |
B | |
C | |
D | Dilizolen (Poland, Slovakia, Netherlands, Bulgaria) |
E | Entavar (India) |
F | |
G | Grampolid (Netherlands), Grampolyve (Netherlands), Gramposimide (Poland, Netherlands), Grampoxid (Netherlands) |
H | |
I | |
J | |
K | |
L | Linzolid (Bangladesh), Lidobact (Netherlands), Linez (Bangladesh, Egypt), Linezolid Accord (Netherlands), Linezolid Amneal (Netherlands), Linezolid Betapharm (Netherlands), Linezolid Farmaprojects (Netherlands), Linezolid Fresenius Kabi (Netherlands), Linezolid GNP (Egypt), Linezolid Hetero (Netherlands), Linezolid Kabi (Croatia, Poland), Linezolid Mylan (Netherlands), Linezolid Pfizer (Netherlands), Linezolid Pliva (Croatia), Linezolid Polpharma (Netherlands, Poland), Linezolid Richet (Argentina), Linezolid Sandoz (Belgium, Switzerland, Netherlands, Slovakia, Estonia, Croatia, Poland), Linezolid Teva (Netherlands, Romania), Linezolid Zentiva (Poland), Linezolida Teva (Portugal), Linezone (Turkey), Linid (India), Linosept (India), Linozid (Bangladesh), Linxyd (Netherlands), Linzowin (India), Litrecan (Argentina), Livegramide (Netherlands), Lizbid (India), Lizemox (India), Lizolid (India, Vietnam), Lizoliden (Netherlands), Lizomac (India), Lizomed (India), Lizorex (India), Lizox (Netherlands), Lorezogram (Netherlands), Lynvox (Netherlands), Lynz (Croatia) |
M | |
N | Natlinez (Netherlands) |
O | |
P | Pneumolid (Croatia, Netherlands, Poland, Romania, Bulgaria) |
Q | |
R | Ralinz (India), Respenzo (Egypt) |
S | Synzolid (Netherlands) |
T | |
U | |
V | Voxazoldin (Egypt) |
W | |
X | |
Y | |
Z | Zenix (Bosnia and Herzegovina, Serbia), Zizolid (Turkey), Zodlin (India), Zolinid (Bulgaria), Zyvox (Georgia, Chile, Argentina, Australia, China, Ecuador, Egypt, United Kingdom, Hong Kong, Indonesia, Ireland, South Korea, Malta, Malaysia, New Zealand, Philippines, Singapore, Thailand, Taiwan, Japan, United States), Zyvoxam (Canada), Zyvoxid (Israel, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Denmark, Estonia, Spain, Finland, France, Greece, Germany, Croatia, Iceland, Lithuania, Latvia, Netherlands, Norway, Portugal, Romania, Sweden, Slovakia, Tunisia, Turkey, South Africa, Poland, Italy, Bosnia and Herzegovina) |
Generic Combination | Brand Name |
---|---|
linezolid and cefixime | Zifi-Turbo (India) |
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