The main use of linezolid is the treatment of severe infections caused by aerobicGram-positive bacteria that are resistant to other antibiotics; it should not be used against bacteria that are sensitive to drugs with a narrower spectrum of activity, such as penicillins and cephalosporins. 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.[20][21][22]
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 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,[24] and smaller studies appear to confirm its superiority over teicoplanin in the treatment of all serious Gram-positive infections.[25]
In the treatment of diabetic foot infections, linezolid appears to be cheaper and more effective than vancomycin.[26] In a 2004 open-label study, it was as effective as ampicillin/sulbactam and amoxicillin/clavulanic acid, and far superior in patients with foot ulcers and no osteomyelitis, but with significantly higher rates of adverse effects.[27][28] 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.[29]
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.[28][30]
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.[33] 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.[28] Regardless, linezolid's advantages include its high oral bioavailability—which allows easy switching to oral therapy—and the fact that poor kidney function is not an obstacle to use.[33] In contrast, achieving the correct dosage of vancomycin in patients with kidney failure is very difficult.[33]
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 treat tuberculosis.[50] 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.[51][52] There is not enough reliable evidence of efficacy and safety to support this indication as a routine use.[23]
Linezolid has been studied as an alternative to vancomycin in the treatment of febrile neutropenia in cancer patients when Gram-positive infection is suspected.[53] 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 injected directly into the eye.[28]
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]
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. 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]
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]
Linezolid's spectrum of activity against Gram-positive bacteria is similar to that of the glycopeptide antibioticvancomycin, 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.[12] Common 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%).[64] It has also been known to cause thrombocytopenia. Fungal infections such as thrush and vaginal candidiasis may also occur as linezolid suppresses normal bacterial flora and opens a niche for fungi (so-called antibiotic candidiasis).[64] Less common (and potentially more serious) adverse effects include allergic reactions, pancreatitis, and elevated transaminases, which may be a sign of liver damage.[64][73] Unlike some antibiotics, such as erythromycin and the quinolones, linezolid has no effect on the QT interval, a measure of cardiac electrical conduction.[73][74] Adverse effects in children are similar to those that occur in adults.[74]
Like nearly all antibiotics, linezolid has been associated with Clostridium difficile-associated diarrhea (CDAD) and pseudomembranous colitis, although the latter is uncommon, occurring in about one in two thousand patients in clinical trials.[64][73][74][75]C. difficile appears to be susceptible to linezolid in vitro, and linezolid was even considered as a possible treatment for CDAD.[76]
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 chemotherapy-induced peripheral neuropathy, a progressive and enduring often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs.[80] Chemotherapy drugs associated with CIPN include thalidomide, the epothilones such as ixabepilone, the vinca alkaloidsvincristine and vinblastine,[81][82][83] the taxanespaclitaxel and docetaxel, the proteasome inhibitors such as bortezomib, and the platinum-based drugs cisplatin, oxaliplatin and carboplatin.[80][84][85] and optic neuropathy, which is most common after several months of treatment and may also be irreversible.[86][87][88][89][90] Although the mechanism of injury is still poorly understood, mitochondrial toxicity has been proposed as a cause;[91][92] linezolid is toxic to mitochondria, probably because of the similarity between mitochondrial and bacterial ribosomes.[93]Lactic acidosis, a potentially life-threatening buildup of lactic acid in the body, may also occur due to mitochondrial toxicity.[91] Because of these long-term effects, the manufacturer recommends weekly complete blood counts during linezolid therapy to monitor for possible bone marrow suppression, and recommends that treatment last no more than 28 days.[8][73] 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 lactate levels, for early detection of lactic acidosis; a review of all medications taken by the patient, interrupting the use of those that may interact with linezolid; and periodic eye and neurological exams in patients set to receive linezolid for longer than four weeks.[94]
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]
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]
In 2008, the crystal structure of linezolid bound to the 50S subunit of a ribosome from the archaeanHaloarcula marismortui was elucidated by a team of scientists from Yale University and deposited in the Protein Data Bank.[102] 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 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.[103]
Pharmacokinetics
One of the advantages of linezolid is that it has an absolute oral bioavailability of 100% due to its rapid and complete absorption after oral administration;[9] in other words, the entire dose reaches the bloodstream, as if it had been given intravenously.[9] 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.[9][62]
Taking linezolid with food somewhat slows its absorption, but the area under the curve is not affected.[23]
Linezolid's plasma protein binding is approximately 31% (range 4–32%) and its volume of distribution at steady state averages 36.1–47.3 liters in healthy adult volunteers.[9]Peak plasma concentrations (Cmax) are reached one to two hours after administration of the drug. Linezolid is readily distributed to all tissues in the body apart from bone matrix and white adipose tissue.[35] Notably, the concentration of linezolid in the epithelial lining fluid (ELF) of the lower respiratory tract is at least equal to, and often higher than, that achieved in serum (some authors have reported bronchial fluid concentrations up to four times higher than serum concentrations), which may account for its efficacy in treating pneumonia. However, a meta-analysis of clinical trials found that linezolid was not superior to vancomycin, which achieves lower concentrations in the ELF.[104]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.[23] The average half-life is three hours in children, four hours in teenagers, and five hours in adults.[8]
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.[105]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.[8][105][106] There is a strong correlation between linezolid clearance and creatinine clearance.[107]
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 pharmacophore—the chemical "template" essential for antimicrobial activity—consists of a 1,3-oxazolidin-2-onemoiety 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).[108] 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 isosteric groups are used. A fluorine atom at the 3′ position practically doubles in vitro and in vivo activity, and the electron-donatingnitrogen atom in the morpholine ring helps maintain high antibiotic potency and an acceptable safety profile.[35][108]
The anticoagulantrivaroxaban (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 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-lactams, 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.[108][110] 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.[108][110][111] Much of the high cost of linezolid has been attributed to the expense of its synthesis.[111] A somewhat more concise and cost-effective route better suited to large-scale production was patented by Upjohn in 1998.[35][112]
Later syntheses have included an "atom-economical" method starting from D-mannitol, developed by Indian pharmaceutical company Dr. Reddy's and reported in 1999,[113] and a route starting from (S)-glyceraldehyde acetonide (prepared from ascorbic acid), developed by a team of researchers from Hunan Normal University in Changsha, Hunan, China.[110] On 25 June 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.[114]
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 isolates overall, and less than one-tenth of one percent of S. aureus samples.[116] A similar, worldwide program—the "Zyvox Annual Appraisal of Potency and Spectrum Study", or ZAAPS—has been conducted since 2002. As of 2007[update], 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 coagulase-negative staphylococci (0.28% of samples resistant), enterococci (0.11%), and S. aureus (0.03%).[117] In the United Kingdom and Ireland, no resistance was found in staphylococci collected from bacteremia cases between 2001 and 2006,[118] although resistance in enterococci has been reported.[119] Some authors have predicted that resistance in E. faecium will increase if linezolid use continues at current levels or increases.[120] Nevertheless, linezolid continues to be an important antimicrobial agent with near-complete activity (0.05% resistance).[107]
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.[35][121]
Pharmacia &Upjohn (now part of Pfizer) started its own oxazolidinone research program in the 1990s. Studies of the compounds' structure–activity relationships 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).[35][73] In the preclinical stages of development, they were similar in safety and antibacterial activity, so they were taken to Phase Iclinical trials to identify any difference in pharmacokinetics.[72][128] 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.[35] The U.S. Food and Drug Administration (FDA) approved linezolid on 18 April 2000.[129] Approval followed in Brazil (June 2000),[130] the United Kingdom (January 2001),[7][73] Japan and Canada (April 2001),[131][132][133] Europe (throughout 2001),[134] and other countries in Latin America and Asia.[132]
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]
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 health care system models to assess the 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.[141]
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]
^ abcdefghij"Linezolid". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
^ abWorld Health Organization (2015). The selection and use of essential medicines. Twentieth report of the WHO Expert Committee 2015 (including 19th WHO Model List of Essential Medicines and 5th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization. pp. 26–33. hdl:10665/189763. ISBN9789241209946. ISSN0512-3054. WHO technical report series;994.
^ abcMarino PL, Sutin KM (2007). "Antimicrobial therapy". The ICU book. Hagerstown, MD: Lippincott Williams & Wilkins. p. 817. ISBN978-0-7817-4802-5.
^Mendes RE, Deshpande LM, Jones RN (April 2014). "Linezolid update: stable in vitro activity following more than a decade of clinical use and summary of associated resistance mechanisms". Drug Resistance Updates. 17 (1–2): 1–12. doi:10.1016/j.drup.2014.04.002. PMID24880801. Emergence of resistance has been limited ... It is still uncertain whether the occurrences of such isolates are becoming more prevalent.
^World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
^Bozdogan B, Appelbaum PC (February 2004). "Oxazolidinones: activity, mode of action, and mechanism of resistance". International Journal of Antimicrobial Agents. 23 (2): 113–9. doi:10.1016/j.ijantimicag.2003.11.003. PMID15013035.
^ abcFalagas ME, Siempos II, Vardakas KZ (January 2008). "Linezolid versus glycopeptide or beta-lactam for treatment of Gram-positive bacterial infections: meta-analysis of randomised controlled trials". Lancet Infectious Diseases. 8 (1): 53–66. doi:10.1016/S1473-3099(07)70312-2. ISSN1473-3099. PMID18156089. Structured abstract with quality assessment available at DAREArchived 4 October 2011 at the Wayback Machine.
^Vardakas KZ, Horianopoulou M, Falagas ME (June 2008). "Factors associated with treatment failure in patients with diabetic foot infections: An analysis of data from randomized controlled trials". Diabetes Research and Clinical Practice. 80 (3): 344–51. doi:10.1016/j.diabres.2008.01.009. PMID18291550.
^Falagas ME, Siempos II, Papagelopoulos PJ, Vardakas KZ (March 2007). "Linezolid for the treatment of adults with bone and joint infections". International Journal of Antimicrobial Agents. 29 (3): 233–9. doi:10.1016/j.ijantimicag.2006.08.030. ISSN0924-8579. PMID17204407. Review.
^Aneziokoro CO, Cannon JP, Pachucki CT, Lentino JR (December 2005). "The effectiveness and safety of oral linezolid for the primary and secondary treatment of osteomyelitis". Journal of Chemotherapy. 17 (6): 643–50. doi:10.1179/joc.2005.17.6.643. ISSN1120-009X. PMID16433195. S2CID46391229.
^Senneville E, Legout L, Valette M, et al. (August 2006). "Effectiveness and tolerability of prolonged linezolid treatment for chronic osteomyelitis: a retrospective study". Clinical Therapeutics. 28 (8): 1155–63. doi:10.1016/j.clinthera.2006.08.001. ISSN0149-2918. PMID16982292.
^Rao N, Hamilton CW (October 2007). "Efficacy and safety of linezolid for Gram-positive orthopedic infections: a prospective case series". Diagnostic Microbiology and Infectious Disease. 59 (2): 173–9. doi:10.1016/j.diagmicrobio.2007.04.006. ISSN0732-8893. PMID17574788.
^Papadopoulos A, Plachouras D, Giannitsioti E, Poulakou G, Giamarellou H, Kanellakopoulou K (April 2009). "Efficacy and tolerability of linezolid in chronic osteomyelitis and prosthetic joint infections: a case-control study". Journal of Chemotherapy. 21 (2): 165–9. doi:10.1179/joc.2009.21.2.165. ISSN1120-009X. PMID19423469. S2CID12400080.
^von der Lippe B, Sandven P, Brubakk O (February 2006). "Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB)--a report of ten cases". The Journal of Infection. 52 (2): 92–6. doi:10.1016/j.jinf.2005.04.007. PMID15907341.
^Geisler WM, Malhotra U, Stamm WE (December 2001). "Pneumonia and sepsis due to fluoroquinolone-resistant Capnocytophaga gingivalis after autologous stem cell transplantation". Bone Marrow Transplantation. 28 (12): 1171–3. doi:10.1038/sj.bmt.1703288. ISSN0268-3369. PMID11803363. S2CID34825943.
^Lin YH, Wu VC, Tsai IJ, Ho YL, Hwang JJ, Tsau YK, et al. (October 2006). "High frequency of linezolid-associated thrombocytopenia among patients with renal insufficiency". International Journal of Antimicrobial Agents. 28 (4): 345–351. doi:10.1016/j.ijantimicag.2006.04.017. PMID16935472.
^Grisold W, Oberndorfer S, Windebank AJ (2012). "Chemotherapy and polyneuropathies"(PDF). European Association of Neurooncology Magazine. 12 (1). Archived(PDF) from the original on 6 October 2014.
^Renslo AR (May 2010). "Antibacterial oxazolidinones: emerging structure-toxicity relationships". Expert Review of Anti-infective Therapy. 8 (5): 565–74. doi:10.1586/eri.10.26. PMID20455685. S2CID23670767.
^ abZhanel GG, Love R, Adam H, Golden A, Zelenitsky S, Schweizer F, et al. (February 2015). "Tedizolid: a novel oxazolidinone with potent activity against multidrug-resistant gram-positive pathogens". Drugs. 75 (3): 253–70. doi:10.1007/s40265-015-0352-7. PMID25673021. S2CID3334681.
^Ippolito JA, Kanyo ZF, Wang D, Franceschi FJ, Moore PB, Steitz TA, et al. (June 2008). "Crystal structure of the oxazolidinone antibiotic linezolid bound to the 50S ribosomal subunit". Journal of Medicinal Chemistry. 51 (12): 3353–6. doi:10.1021/jm800379d. PMID18494460.
^Kalil AC, Murthy MH, Hermsen ED, Neto FK, Sun J, Rupp ME (September 2010). "Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: a systematic review and meta-analysis". Critical Care Medicine. 38 (9): 1802–8. doi:10.1097/CCM.0b013e3181eb3b96. PMID20639754. S2CID6289226.
^Sisson TL, Jungbluth GL, Hopkins NK (January 2002). "Age and sex effects on the pharmacokinetics of linezolid". European Journal of Clinical Pharmacology. 57 (11): 793–7. doi:10.1007/s00228-001-0380-y. PMID11868801. S2CID38863420.
^US patent 5837870, Pearlman BA, Perrault WR, Barbachyn MR, et al., "Process to prepare oxazolidinones", issued 1997-03-28 Retrieved on 13 June 2009.
^Lohray BB, Baskaran S, Rao BS, Reddy BY, Rao IN (June 1999). "A short synthesis of oxazolidinone derivatives linezolid and eperezolid: A new class of antibacterials". Tetrahedron Letters. 40 (26): 4855–6. doi:10.1016/S0040-4039(99)00893-X.
^Jones RN, Ross JE, Castanheira M, Mendes RE (December 2008). "United States resistance surveillance results for linezolid (LEADER Program for 2007)". Diagnostic Microbiology and Infectious Disease. 62 (4): 416–26. doi:10.1016/j.diagmicrobio.2008.10.010. PMID19022153.
^Jones RN, Kohno S, Ono Y, Ross JE, Yanagihara K (June 2009). "ZAAPS International Surveillance Program (2007) for linezolid resistance: results from 5591 Gram-positive clinical isolates in 23 countries". Diagnostic Microbiology and Infectious Disease. 64 (2): 191–201. doi:10.1016/j.diagmicrobio.2009.03.001. PMID19500528.
^Liakopoulos A, Neocleous C, Klapsa D, et al. (July 2009). "A T2504A mutation in the 23S rRNA gene responsible for high-level resistance to linezolid of Staphylococcus epidermidis". Journal of Antimicrobial Chemotherapy. 64 (1): 206–7. doi:10.1093/jac/dkp167. PMID19429927.
^Ford CW, Zurenko GE, Barbachyn MR (August 2001). "The discovery of linezolid, the first oxazolidinone antibacterial agent". Current Drug Targets. Infectious Disorders. 1 (2): 181–99. doi:10.2174/1568005014606099. PMID12455414.
^"Drug Approval Package: Zyvox". FDA Center for Drug Evaluation and Research. 20 November 2001. Archived from the original on 10 January 2008. Retrieved 17 January 2009. 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.
Patient-based medical care provided across age, gender and specialty boundaries General practice is the name given in various nations, such as the United Kingdom, India, Australia, New Zealand and South Africa to the services provided by general practitioners. In some nations, such as the US, similar services may be described as family medicine or primary care. The term Primary Care in the UK may also include services provided by community pharmacy, optometrist, dental surgery and community hear…
Moussa Marega Marega bersama Porto pada 2018Informasi pribadiNama lengkap Moussa Marega[1]Tanggal lahir 14 April 1991 (umur 33)Tempat lahir Les Ulis, PrancisTinggi 1,84 m (6 ft 1⁄2 in)[2]Posisi bermain PenyerangInformasi klubKlub saat ini SharjahNomor 91Karier junior2006–2010 ÉvryKarier senior*Tahun Tim Tampil (Gol)2010–2011 Évry 4 (0)2011–2012 FC Issy 0 (0)2012–2013 Le Poiré-sur-Vie 31 (5)2013–2014 Amiens 33 (9)2014 Espérance de Tunis 0 (0…
Russian activities in Ukraine You can help expand this article with text translated from the corresponding article in Ukrainian. (June 2022) Click [show] for important translation instructions. View a machine-translated version of the Ukrainian article. Machine translation, like DeepL or Google Translate, is a useful starting point for translations, but translators must revise errors as necessary and confirm that the translation is accurate, rather than simply copy-pasting machine-translate…
Digital Magazine This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (March 2022) The LocalTypeNews WebsiteFormatOnline NewspaperFounded2019 (2019)HeadquartersToronto, Ontario, CanadaISSN2817-4720Websitethelocal.to The Local is a Toronto-based general interest online magazine covering urban health and social issues. It was founded in 2019 as a not-for-profit organization, with Tai Huyn…
Airport in Morocco OUD redirects here. For other uses, see Oud (disambiguation). Oujda Angad Airportمطار وجدة أنجاد (Arabic)Aéroport d'Oujda-Angad (French)IATA: OUDICAO: GMFOSummaryAirport typePublicOperatorONDAServesOujda, MoroccoElevation AMSL1,535 ft / 468 mCoordinates34°47′14″N 001°55′26″W / 34.78722°N 1.92389°W / 34.78722; -1.92389MapOUDLocation of airport in MoroccoRunways Direction Length Surface m ft 06/24 3,000 9…
Questa voce o sezione sugli argomenti case editrici e aziende statunitensi non cita le fonti necessarie o quelle presenti sono insufficienti. Puoi migliorare questa voce aggiungendo citazioni da fonti attendibili secondo le linee guida sull'uso delle fonti. Segui i suggerimenti del progetto di riferimento. Ziff Davis Inc.Logo Stato Stati Uniti Forma societariaControllata Fondazione1927 a Chicago Fondata da William Bernard Ziff Sr. Bernard G. Davis Sede principaleNew York GruppoJ2 G…
ХристианствоБиблия Ветхий Завет Новый Завет Евангелие Десять заповедей Нагорная проповедь Апокрифы Бог, Троица Бог Отец Иисус Христос Святой Дух История христианства Апостолы Хронология христианства Раннее христианство Гностическое христианство Вселенские соборы Ни…
This article includes a list of references, related reading, or external links, but its sources remain unclear because it lacks inline citations. Please help improve this article by introducing more precise citations. (November 2020) (Learn how and when to remove this message) Administrative law of the United States General Rulemaking Notice of proposed rulemaking Adjudication Administrative law judge Code of Federal Regulations Federal Register Statutory framework Administrative Procedure Act F…
1999 Japanese-French film After the RainJapanese film posterDirected byTakashi KoizumiScreenplay byAkira Kurosawa[1]Story byShugoro YamamotoProduced byMasato Hara[1]Starring Akira Terao Yoshiko Miyazaki Shiro Mifune Mieko Harada Tatsuya Nakadai CinematographyShoji Ueda[1][Link is incorrect, goes to photographer with same name. Use <https://letterboxd.com/cinematography/shoji-ueda/> for cinematographer~a Kurosawa stalwart.Edited byHideto Aga[1]Music byMasaru …
2013 single by RüfüsTake MeSingle by Rüfüsfrom the album Atlas Released8 March 2013 (2013-03-08)Length4:03LabelSweat It OutSongwriter(s) Jon George Tyrone Lindqvist James Hunt Producer(s) Jon George Tyrone Lindqvist James Hunt Rüfüs singles chronology This Summer / Selena(2012) Take Me (2013) Desert Night (2013) Take Me is a song by Australian alternative dance group Rüfüs. The song was released on 8 March 2013 as the lead single from the group's debut studio album, Atlas …
The results of the 1885 UK general election in Scotland, showing the western Highlands and Caithness having elected MPs from the Crofters Party The Crofters' Party was the parliamentary arm of the Highland Land League. It gained five MPs in the 1885 general election and a sixth the following year. The Highland Land League had started on the Isle of Skye, and in 1884 protest action was much more widespread: many thousands of crofters became members of the Highland Land League. A number of candida…
SMP Negeri 17 SurabayaInformasiDidirikan19 Mei 1982Jumlah kelasVII,VIII,IXJurusan atau peminatanUmumRentang kelasVII, VIII, IXKurikulumKurikulum 2013Jumlah siswa1.082 siswaAlamatLokasiJl. Raya Tenggilis Mejoyo No.1, Surabaya, Jawa TimurMoto SMP Negeri (SMPN) 17 Surabaya, merupakan salah satu Sekolah Menengah Pertama Negeri yang ada di Provinsi Jawa Timur, Indonesia. Sama dengan SMP pada umumnya di Indonesia masa pendidikan sekolah di SMPN 17 Surabaya ditempuh dalam waktu tiga tahun pel…
Music genre Progressive soulOther names Prog-soul black prog black rock progressive R&B Stylistic origins Soul funk progressive rock psychedelic soul jazz fusion Cultural originsLate 1960s – early 1970s, United StatesDerivative forms Neo soul alternative R&B[nb 1] Other topics Afrofuturism album era avant-funk Black Arts Movement concept album funk rock progressive rap psychedelic funk recording studio as an instrument Progressive soul (often shortened to prog-soul; also called…
American television series Celebrity Rehab with Dr. DrewStarringDr. Drew PinskyCountry of originUnited StatesOriginal languageEnglishNo. of seasons6No. of episodes50 (list of episodes)ProductionExecutive producersDrew PinskyJohn IrwinHoward LapidesDamian SullivanBrad KuhlmanProducersJack Siefert (season 1)[1]Duncan White (season 2)Lisa DigiovineDanita JonesCinematographyJeff Rhoads (season 1)[1]David Ortkiese (season 1)[1]Stefanos Kafatos (season 2)Running time60 minutes9…
هذه المقالة بحاجة لصندوق معلومات. فضلًا ساعد في تحسين هذه المقالة بإضافة صندوق معلومات مخصص إليها. لوحة الموناليزا للفنان الإيطالي ليوناردو دا فينشي, إحدى روائع عصر النهضة المصطلح ذاته ظهر في عام 1767 وأصله الفرنسي beaux arts الذي أصبح fine arts وتمت ترجمته حرفيا للغات العالم.[1][…
Overview of the status of women in Fiji This page's infobox may require expansion, verification, or otherwise need cleanup. Please make sure that the infobox meets Wikipedia's guidelines for infoboxes. There might be relevant comments on the talk page. You may also want to view the infobox template page to view the full parameter list and read guidance on usage of that infobox. Women in FijiNative Fijian women, 1935.Gender Inequality Index[1]Value0.318 (2021)Rank77th out of 191 Global Ge…
Bishop of Rome (189–199) Pope SaintVictor IBishop of RomeStained glass image of Pope-Saint Victor, with anachronistic papal tiara (Semmering, Austria)ChurchCatholic ChurchPapacy began189Papacy ended199PredecessorEleutheriusSuccessorZephyrinusPersonal detailsBorn140–160 ADAfrica Proconsulare, Roman EmpireDied199 ADRome, Roman EmpireSainthoodFeast day28 July or 11 JanuaryOther popes named Victor Pope Victor I (died 199) was a Roman African prelate of the Catholic Church who served as Bishop of…
Material ability to absorb energy and plastically deform without fracturing This article is about toughness of physical objects. For the mathematical concept in graph theory, see Graph toughness. This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed.Find sources: Toughness – news · newspapers · books · scholar · JSTOR (January 201…