Linezolid

(BAN, USAN, rINN)
Linezolid Chemical formula
Synonyms: Linetsolidi; Linézolide; Linezolidum; PNU-100766; U-100766. N{[(S)-3-(3-Fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl]methyl}acetamide.
Cyrillic synonym: Линезолид.

💊 Chemical information

Chemical formula: C16H20FN3O4 = 337.3.
CAS — 165800-03-3.
ATC — J01XX08.
ATC Vet — QJ01XX08.

Incompatibility and stability.

References. 1. Zhang Y, et al. Compatibility and stability of linezolid injection admixed with three quinolone antibiotics. Ann Pharmacother 2000; 34: 996–1001.

💊 Adverse Effects and Precautions

The adverse effects most frequently reported in patients given linezolid include diarrhoea, nausea and vomiting, metallic taste, headache, insomnia, constipation, rashes, dizziness, fever, oral and vaginal candidiasis, and abnormal liver function tests. Lactic acidosis has been reported. Convulsions have also been reported in patients treated with linezolid. In some of these cases, a history of seizures or risk factors for seizures was reported. There have been rare reports of bullous skin eruptions including Stevens-Johnson syndrome. Peripheral and optic neuropathy, sometimes progressing to loss of vision, have occurred rarely, mainly in patients given linezolid for more than 28 days. Visual blurring has been reported in some patients given less than 28 days of treatment. Reversible myelosuppression including anaemia, leucopenia, pancytopenia and, in particular, thrombocytopenia has been reported and blood counts should be monitored weekly in patients receiving linezolid. Patients particularly at risk are those who have received linezolid for more than 10 to 14 days, who are receiving other bone marrow suppressant drugs, or who have pre-existing myelosuppression or severe renal impairment. Patients with mixed (Gram-negative and Gram-positive) infections are at a higher risk of mortality when linezolid is given as monotherapy (see Increased Mortality, below); linezolid must therefore be used with appropriate antibacterial cover for Gram-negative organisms in such patients.
1. Rubinstein E, et al. Worldwide assessment of linezolid’s clinical safety and tolerability: comparator-controlled phase III studies. Antimicrob Agents Chemother 2003; 47: 1824–31
2. Bishop E, et al. Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients. Antimicrob Agents Chemother 2006; 50: 1599–1602.

Effects on the blood.

Reversible myelosuppression with red cell hypoplasia occurred in 3 patients treated with linezolid.1Features of the myelosuppression were considered by some1,2 to be similar to those associated with chloramphenicol, although this was disputed by the manufacturers.3 There have been reports of thrombocytopenia occurring at a higher incidence than that reported by the manufacturers; in one study,4 6 of 19 patients who had been treated with linezolid developed thrombocytopenia, while another5 found that it occurred in 23 of 48 patients given the drug for more than 5 days. During the initial 8 months of licensed use in the UK 12 reports of haematopoietic disorders (including thrombocytopenia, anaemia, leucopenia, and pancytopenia) were received by the UK CSM.6 Studies have shown that the risk of thrombocytopenia and anaemia is increased in patients on prolonged linezolid therapy with pre-existing myelosuppression7,8 or severe renal impairment.9
1. Green SL, et al. Linezolid and reversible myelosuppression. JAMA 2001; 285: 1291
2. Lawyer MC, Lawyer EZ. Linezolid and reversible myelosuppression. JAMA 2001; 286: 1974
3. Arellano FM. Linezolid and reversible myelosuppression. JAMA 2001; 286: 1973–4
4. Attassi K, et al. Thrombocytopenia associated with linezolid therapy. Clin Infect Dis 2002; 34: 695–8
5. Orrick JJ, et al. Thrombocytopenia secondary to linezolid administration: what is the risk? Clin Infect Dis 2002; 35: 348–9
6. Committee on Safety of Medicines/Medicines Control Agency. Reminder: linezolid (Zyvox) and myelosuppression. Current Problems 2001; 27: 14. Also available at: http:// www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON007456&RevisionSelectionMethod= LatestReleased (accessed 11/01/08
7. Senneville E, et al. Risk factors for anaemia in patients on prolonged linezolid therapy for chronic osteomyelitis: a case-control study. J Antimicrob Chemother 2004; 54: 798–802
8. Grau S, et al. Linezolid: low pre-treatment platelet values could increase the risk of thrombocytopenia. J Antimicrob Chemother 2005; 56: 440–1
9. Wu V-C, et al. High frequency of linezolid-associated thrombocytopenia and anemia among patients with end-stage renal disease. Clin Infect Dis 2006; 42: 66–72.

Effects on the eyes.

See under Effects on the Nervous System, below.

Effects on mitochondria.

Linezolid appears to inhibit mitochondrial protein synthesis when given for prolonged courses. This decreases cellular energy production in tissues that are highly dependent on oxidative phosphorylation, such as the optic nerve, skeletal muscles, liver, and kidneys, leading to adverse effects such as lactic acidosis1 or hyperlactataemia,1,2 and optic3and/or peripheral neuropathy1 (see also below). Encephalopathy, lactic acidosis, optic neuropathy, skeletal myopathy, and renal failure were reported1 in a 63-year-old woman after a 4-month course of linezolid. The symptoms resolved when linezolid was stopped; however, the patient remained blind and disorientated. In contrast, bilateral mitochondrial optic neuropathy seen3 in a 6year-old boy after a 1-year course of oral linezolid resolved 3 months after linezolid treatment was stopped. In another study2reversible hyperlactataemia was reported in 5 patients given linezolid for 1 to 3 months. Mitochondrial activity and lactic acid levels returned to normal when linezolid therapy was stopped.
1. De Vriese AS, et al. Linezolid-induced inhibition of mitochondrial protein synthesis. Clin Infect Dis 2006; 42: 1111–1117
2. Garrabou G, et al. Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia. Antimicrob Agents Chemother 2007; 51: 962–7
3. Javaheri M, et al. Linezolid-induced optic neuropathy: a mitochondrial disorder? Br J Ophthalmol 2007; 91: 111–15. Correction. ibid.; 403.

Effects on the nervous system.

The Australian Adverse Drug Reactions Advisory Committee1 stated in February 2003 that it had received 4 reports of peripheral neuropathy in patients who had taken linezolid for 6 to 9 months; none of these cases had resolved at the time of the report. They suggested that the risk of peripheral neuropathy should be considered when treatment was extended beyond 28 days. There have been several published reports of peripheral and optic neuropathy associated with linezolid,2-9 with some attributing these effects to the inhibition of mitochondrial protein synthesis by linezolid. For further discussion see Effects on Mitochondria, above. The regulatory authority in the UK has warned that patients should be advised to report any symptoms of visual impairment immediately, including changes in visual acuity or colour vision, blurred vision, or visual field defects.10 Any linezolid-treated patient with new visual symptoms should be evaluated promptly and referred to an ophthalmologist if necessary; regular monitoring is advised in all patients who may require treatment for more than 28 days.
1. Adverse Drug Reactions Advisory Committee (ADRAC). Linezolid and peripheral neuropathy. Aust Adverse Drug React Bull 2003; 22: 3. Also available at: http://www.tga.gov.au/ adr/aadrb/aadr0302.htm (accessed 11/01/08
2. Corallo CE, Paull AE. Linezolid-induced neuropathy. Med J Aust 2002; 177: 332
3. Rho JP, et al. Linezolid-associated peripheral neuropathy. Mayo Clin Proc 2004; 79: 927–30
4. Lee E, et al. Linezolid-associated toxic optic neuropathy: a report of 2 cases. Clin Infect Dis 2003; 37: 1389–91
5. Bressler AM, et al. Peripheral neuropathy associated with prolonged use of linezolid. Lancet Infect Dis 2004; 4: 528–31
6. Willcox D. Linezolid (Zyvoxam) and neuropathy Can Adverse React News 2005; 15: 2
7. Zivkovic SA, Lacomis D. Severe sensory neuropathy associated with long-term linezolid use. Neurology 2005; 64: 926–7
8. Legout L, et al. Linezolid-induced neuropathy. Clin Infect Dis 2004; 38: 767–8
9. Rucker JC, et al. Linezolid-associated toxic optic neuropathy. Neurology 2006; 66: 595–8
10. Commission on Human Medicines/Medicines and Healthcare products Regulatory Agency. Linezolid (Zyvox): severe optic neuropathy. Current Problems 2006; 31: 2–3. Also available at: http:// www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2023860&RevisionSelectionMethod= LatestReleased (accessed 11/01/08)

Increased mortality.

In March 2007, the FDA1 issued an alert advising that an open-label, randomised study comparing linezolid to vancomycin, oxacillin, or dicloxacillin in the treatment of seriously ill patients with intravascular catheter-related bloodstream infections, including catheter-site infections, had found that death rates were significantly higher in patients treated with linezolid (78 of 363) than in the comparator arm (58 of 363), particularly in those with Gram-negative or mixed infections. Mortality did not differ for patients with purely Gram-positive infections. The FDA1 and the UK manufacturer2 therefore advised that linezolid should not be used in infections caused by Gram-negative bacteria and should only be used in mixed Gram-positive and Gram-negative infections when appropriate cover for Gram-negative organisms is given at the same time. Licensed product information now reflects these warnings.
1. FDA. Information for healthcare professionals: linezolid (marketed as Zyvox) (issued 16th March 2007). Available at: http:// www.fda.gov/cder/drug/InfoSheets/HCP/linezolidHCP.pdf (accessed 11/01/08
2. Pfizer, UK. Important safety information (issued 28th February, 2007). Available at: http://www.mhra.gov.uk/home/idcplg? IdcService=GET_FILE&dDocName=con2030646& RevisionSelectionMethod=Latest (accessed 11/01/08)

💊 Interactions

Linezolid is a reversible, nonselective MAOI and therefore has the potential to interact with adrenergic and serotonergic drugs. Enhanced pressor activity has been reported in patients receiving linezolid with phenylpropanolamine or pseudoephedrine and initial doses of dopamine or adrenaline should be reduced. There have also been cases of serotonin syndrome when linezolid was taken with serotonin reuptake inhibitors, and similar symptoms when it was taken with dextromethorphan. The interactions of conventional MAOIs, both with other drugs and with foods, are described under Phenelzine.

Antidepressants.

Serotonin syndrome has been reported in patients taking linezolid with serotonergic antidepressants such as venlafaxine and SSRIs.

Opioid analgesics.

For a report of an interaction between linezolid and pethidine, attributed to linezolid’s inhibitory actions on monoamine oxidase.

💊 Antimicrobial Action

Linezolid is an oxazolidinone antibacterial with activity against a range of aerobic Gram-positive bacteria including vancomycin-resistant enterococci and meticillin-resistant Staphylococcus aureus. It is less active against Gram-negative bacteria, but has some in-vitro activity against Haemophilus influenzae, Legionella spp., Moraxella catarrhalis (Branhamella catarrhalis), Neisseria gonorrhoeae, and Pasteurella spp. It is not active against Acinetobacter spp., Enterobacteriaceae, or Pseudomonas spp. Oxazolidinone antibacterials are bacteriostatic and act by inhibition of ribosomal protein synthesis. Cross-resistance between oxazolidinones and other classes of antibacterial is considered unlikely. Resistant strains of enterococci and meticillin-resistant
Staph. aureus have been reported.
1. Noskin GA, et al. In vitro activities of linezolid against important Gram-positive bacterial pathogens including vancomycinresistant enterococci. Antimicrob Agents Chemother 1999; 43: 2059–62
2. Cercenado E, et al. In vitro activity of linezolid against multiply resistant Gram-positive clinical isolates. J Antimicrob Chemother 2001; 47: 77–81
3. Gemmell CG. Susceptibility of a variety of clinical isolates to linezolid: a European inter-country comparison. J Antimicrob Chemother 2001; 48: 47–52
4. Livermore DM. Linezolid in vitro: mechanism and antibacterial spectrum. J Antimicrob Chemother 2003; 51 (suppl S2): ii9–ii16
5. Jones RN, et al. Activity of linezolid against 3,251 strains of uncommonly isolated Gram-positive organisms: report from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother 2007; 51: 1491–3.

Resistance.

There have been reports of linezolid resistance in enterococci, involving both Enterococcus faecium1-4 and E. faecalis.2 There is also concern over the emergence of linezolid resistance in staphylococci, such as meticillin-resistant Staphylococcus aureus,5,6 Staph. auricularis,7 and Staph. epidermidis.7,8A survey9 of reported resistance to linezolid in the USA found that it was still rare but was no longer limited to enterococci having also occurred in Staph. epidermidis and Streptococcus oralis.
1. Gonzales RD, et al. Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid. Lancet 2001; 357: 1179
2. Auckland C, et al. Linezolid-resistant enterococci: report of the first isolates in the United Kingdom. J Antimicrob Chemother 2002; 50: 743–6
3. Herrero IA, et al. Nosocomial spread of linezolid-resistant, vancomycin-resistant Enterococcus faecium. N Engl J Med 2002; 346: 867–9
4. Seedat J, et al. Rapid emergence of resistance to linezolid during linezolid therapy of an Enterococcus faecium infection. Antimicrob Agents Chemother 2006; 50: 4217–19
5. Tsiodras S, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 2001; 358: 207–8
6. Wilson P, et al. Linezolid resistance in clinical isolates of Staphylococcus aureus. J Antimicrob Chemother 2003; 51: 186–8
7. Cieloszyk K, et al. Linezolid resistance in three isolates of coagulase-negative staphylococci. Ann Pharmacother 2007; 41: 526–7
8. Kelly S, et al. Linezolid resistance in coagulase-negative staphylococci. J Antimicrob Chemother 2006; 58: 898–9
9. Mutnick AH, et al. Linezolid resistance since 2001: SENTRY Antimicrobial Surveillance Program. Ann Pharmacother 2003; 37: 769–74.

💊 Pharmacokinetics

Linezolid is rapidly and extensively absorbed after oral doses and maximum plasma concentrations are achieved after 1 to 2 hours. It is about 31% bound to plasma proteins. Linezolid is reported to be distributed into bone, fat, lungs, muscle, skin blister fluids, and into the CSF. It is metabolised mainly by oxidation to 2 main inactive metabolites, the hydroxyethyl glycine metabolite (PNU-142586) and the aminoethoxyacetic acid metabolite (PNU-142300); other minor inactive metabolites have also been identified. About 40% of a dose is excreted in the urine as PNU-142586, 30% as linezolid, and 10% as PNU-142300. Small amounts of metabolites are excreted in the faeces. The elimination half-life of linezolid is about 5 to 7 hours. Children exhibit more rapid clearance of linezolid than adults; half-life is reported to range from about 2 to 4 hours, increasing with age.
1. MacGowan AP. Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections. J Antimicrob Chemother 2003; 51 (suppl S2): ii17–ii25
2. Stalker DJ, Jungbluth GL. Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial. Clin Pharmacokinet 2003; 42: 1129–40
3. Whitehouse T, et al. Pharmacokinetic studies of linezolid and teicoplanin in the critically ill. J Antimicrob Chemother 2005; 55: 333–40.

💊 Uses and Administration

Linezolid is an oxazolidinone antibacterial used for the treatment of Gram-positive infections of the skin and respiratory tract, including those due to vancomycinresistant enterococci and meticillin-resistant Staphylococcus aureus. It is given, orally or by intravenous infusion (over 30 to 120 minutes), in a usual adult dose of 600 mg every 12 hours for 10 to 14 days; treatment for up to 28 days may be necessary if there is vancomycin resistance. In uncomplicated skin and skin structure infections an oral dose of 400 mg every 12 hours for 10 to 14 days is usually sufficient. For doses in neonates and children, see below.
1. Plouffe JF. Emerging therapies for serious gram-positive bacterial infections: a focus on linezolid. Clin Infect Dis 2000; 31(suppl 4): S144–S149
2. Perry CM, Jarvis B. Linezolid: a review of its use in the management of serious gram-positive infections. Drugs 2001; 61: 525–51
3. Bain KT, Wittbrodt ET. Linezolid for the treatment of resistant gram-positive cocci. Ann Pharmacother 2001; 35: 566–75
4. Paladino JA. Linezolid: an oxazolidinone antimicrobial agent. Am J Health-Syst Pharm 2002; 59: 2413–25
5. Birmingham MC, et al. Linezolid for the treatment of multidrug-resistant, Gram-positive infections: experience from a compassionate-use program. Clin Infect Dis 2003; 36: 159–68
6. Wilcox MH. Efficacy of linezolid versus comparator therapies in Gram-positive infections. J Antimicrob Chemother 2003; 51 (suppl S2): ii27–ii35
7. Falagas ME, et al. Linezolid for the treatment of patients with endocarditis: a systematic review of the published evidence. J Antimicrob Chemother 2006; 58: 273–80
8. Ntziora F, Falagas ME. Linezolid for the treatment of patients with central nervous system infection. Ann Pharmacother 2007; 41: 296–308
9. Falagas ME, et al. Linezolid for the treatment of adults with bone and joint infections. Int J Antimicrob Agents 2007; 29: 233–9
10. Manfredi R. Le prospettive terapeutiche di linezolid nelle infezioni da patogeni Gram-positivi multiresistenti. Recenti Prog Med 2007; 98: 143–54
11. Falagas ME, et al. Linezolid versus glycopeptide or beta-lactam for treatment of Gram-positive bacterial infections: meta-analysis of randomised controlled trials. Lancet Infect Dis 2008; 8: 53–66.

Administration in children.

UK licensed product information does not recommend the use of linezolid in children and adolescents below 18 years of age. However, the BNFC suggests the following doses of linezolid in the treatment of pneumonia or complicated skin and soft-tissue infections, given orally or by intravenous infusion over 30 to 120 minutes:
neonates up to 7 days old: 10 mg/kg every 12 hours, increasing to every 8 hours if response is poor
7 days to 12 years of age: 10 mg/kg (to a maximum of 600 mg) every 8 hours
12 to 18 years: usual adult doses (see above). Similar doses are licensed in the USA. US licensed product information also suggests that in the treatment of uncomplicated skin and skin structure infections, oral doses given every 12 hours are sufficient in those aged 5 to 11 years. Further references.
1. Cuzzolin L, Fanos V. Linezolid: a new antibiotic for newborns and children? J Chemother 2006; 18: 573–81
2. Velissariou IM. Use of linezolid in children: an overview of recent advances. Expert Rev Anti Infect Ther 2006; 4: 947–52.

Administration in renal impairment.

Linezolid should be used with caution in patients with renal impairment (creatinine clearance less than 30 mL/minute). Although no dosage adjustment is required, licensed product information states that peak plasma concentrations of linezolid’s two major metabolites were about tenfold higher in such patients after several days of treatment. As about 30% of a dose is removed during 3 hours of haemodialysis it is recommended that linezolid should be given after dialysis.

Mycobacterial infections.

A systematic review1 noted that linezolid has been used with some success as an adjunct in the treatment of multidrug-resistant tuberculosis; it has also been tried in nontuberculous mycobacterial infections. However, serious adverse effects such as peripheral or optic neuropathy (in 11 of 24 patients), and anaemia (10 of 24) were observed. The review concluded that although there was limited evidence suggesting linezolid may be effective as second-line adjunct therapy for patients with mycobacterial infections, its usefulness is limited by the frequent potentially severe complications of prolonged linezolid use.
1. Ntziora F, Falagas ME. Linezolid for the treatment of patients with mycobacterial infections: a systematic review. Int J Tuberc Lung Dis 2007; 11: 606–11. Correction. ibid.; 936. (title change)

💊 Preparations

Proprietary Preparations

Arg.: Zyvox; Austral.: Zyvox; Austria: Zyvoxid; Belg.: Zyvoxid; Braz.: Zyvox; Canad.: Zyvoxam; Chile: Zyvox; Cz.: Zyvoxid; Denm.: Zyvoxid; Fin.: Zyvoxid; Fr.: Zyvoxid; Ger.: Zyvoxid; Gr.: Zyvoxid; Hong Kong: Zyvox; Hung.: Zyvox†; Zyvoxid†; India: Linospan; Linox; Lizolid; Indon.: Zyvox; Irl.: Zyvox; Israel: Zyvoxid; Ital.: Zyvoxid; Malaysia: Zyvox; Mex.: Zyvoxam; Neth.: Zyvoxid; Norw.: Zyvoxid; NZ: Zyvox; Philipp.: Zyvox; Pol.: Zyvoxid; Port.: Zyvoxid; Rus.: Zyvox (Зивокс); S.Afr.: Zyvoxid; Singapore: Zyvox; Spain: Zyvoxid; Swed.: Zyvoxid; Switz.: Zyvoxid; Thai.: Zyvox; UK: Zyvox; USA: Zyvox; Venez.: Zyvox.
Published April 14, 2019.