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Linezolid


Pronunciation

 (li NE zoh lid)


U.S. Brand Names

 Zyvox™


Generic Available

 No


Canadian Brand Names

 Zyvoxam®


Use

 Treatment of vancomycin-resistant Enterococcus faecium (VRE) infections, nosocomial pneumonia caused by Staphylococcus aureus including MRSA or Streptococcus pneumoniae (including multidrug-resistant strains [MDRSP]), complicated and uncomplicated skin and skin structure infections (including diabetic foot infections without concomitant osteomyelitis), and community-acquired pneumonia caused by susceptible gram-positive organisms


Pregnancy Risk Factor

 C


Pregnancy Implications

 Teratogenic effects were not observed in animal studies. There are no adequate and well-controlled studies in pregnant women. Should be used in pregnancy only if the potential benefit justifies the risk to the fetus.


Lactation

 Excretion in breast milk unknown/use caution


Contraindications

 Hypersensitivity to linezolid or any other component of the formulation


Warnings/Precautions

 Myelosuppression has been reported and may be dependent on duration of therapy (generally >2 weeks of treatment); use with caution in patients with pre-existing myelosuppression, in patients receiving other drugs which may cause bone marrow suppression, or in chronic infection (previous or concurrent antibiotic therapy). Weekly CBC monitoring is recommended. Discontinue linezolid in patients developing myelosuppression (or in whom myelosuppression worsens during treatment).

Lactic acidosis has been reported with use. Patients who develop recurrent nausea and vomiting, unexplained acidosis, or low bicarbonate levels need immediate evaluation.

Linezolid has mild MAO inhibitor properties and has the potential to have the same interactions as other MAO inhibitors; use with caution in uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, or untreated hyperthyroidism; avoid use with serotonergic agents such as TCAs, venlafaxine, trazodone, sibutramine, meperidine, dextromethorphan, and SSRIs; consider alternatives before initiating outpatient treatment (unnecessary use may lead the development of resistance to linezolid)


Adverse Reactions

 Percentages as reported in adults; frequency similar in pediatric patients

1% to 10%:

Cardiovascular: Hypertension (1% to 3%)

Central nervous system: Headache (0.5% to 11%), insomnia (3%), dizziness (0.4% to 2%), fever (2%)

Dermatologic: Rash (2%)

Gastrointestinal: Nausea (3% to 10%), diarrhea (3% to 11%), vomiting (1% to 4%), constipation (2%), taste alteration (1% to 2%), tongue discoloration (0.2% to 1%), oral moniliasis (0.4% to 1%), pancreatitis

Genitourinary: Vaginal moniliasis (1% to 2%)

Hematologic: Thrombocytopenia (0.3% to 10%), anemia, leukopenia, neutropenia; Note: Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia; may be more common in patients receiving linezolid for >2 weeks)

Hepatic: Abnormal LFTs (0.4% to 1%)

Miscellaneous: Fungal infection (0.1% to 2%)

<1%: C. difficile -related complications, increase in creatinine, dyspepsia, localized abdominal pain, pruritus

Postmarketing and/or case reports: Lactic acidosis, peripheral neuropathy, optic neuropathy


Overdosage/Toxicology

 Treatment includes supportive care. Hemodialysis may improve elimination (30% of a dose is removed during a 3-hour hemodialysis session).


Drug Interactions

Adrenergic agents (eg, phenylpropanolamine, pseudoephedrine, sympathomimetic agents, vasopressor or dopaminergic agents) may cause hypertension.

Myelosuppressive medications: Concurrent use may increase risk of myelosuppression with linezolid.

Serotonergic agents (eg, TCAs, venlafaxine, trazodone, sibutramine, meperidine, dextromethorphan, and SSRIs) may cause a serotonin syndrome (eg, hyperpyrexia, cognitive dysfunction) when used concomitantly.

Tramadol: Concurrent use may increase risk of seizures.


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may contain tyramine, hypertensive crisis may result).

Food: Avoid foods (eg, cheese) and beverages containing tyramine in patients receiving linezolid (hypertensive crisis may result).


Stability

Infusion: Store at 25°C (77°F). Protect from light. Keep infusion bags in overwrap until ready for use. Protect infusion bags from freezing.

Oral suspension: Following reconstitution, store at room temperature; use reconstituted suspension within 21 days


Compatibility

Compatibility when admixed: Incompatible: Ceftriaxone

Y-site administration: Compatible: Amikacin, ampicillin, cytarabine, D5NS, D5W, heparin, LR, NS, ranitidine. Incompatible: Amphotericin B, chlorpromazine, diazepam, erythromycin, pentamidine, phenytoin, sulfamethoxazole/trimethoprim


Mechanism of Action

 Inhibits bacterial protein synthesis by binding to bacterial 23S ribosomal RNA of the 50S subunit. This prevents the formation of a functional 70S initiation complex that is essential for the bacterial translation process. Linezolid is bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci.


Pharmacodynamics/Kinetics

Absorption: Rapid and extensive

Distribution: Vdss: Adults: 40-50 L

Protein binding: Adults: 31%

Metabolism: Hepatic via oxidation of the morpholine ring, resulting in two inactive metabolites (aminoethoxyacetic acid, hydroxyethyl glycine); does not involve CYP

Bioavailability: 100%

Half-life elimination: Children 1 week (full-term) to 11 years: 1.5-3 hours; Adults: 4-5 hours

Time to peak: Adults: Oral: 1-2 hours

Excretion: Urine (30% as parent drug, 50% as metabolites); feces (9% as metabolites)

Nonrenal clearance: 65%; increased in children 1 week to 11 years


Dosage

VRE infections: Oral, I.V.:

Preterm neonates (<34 weeks gestational age): 10 mg/kg every 12 hours; neonates with a suboptimal clinical response can be advanced to 10 mg/kg every 8 hours. By day 7 of life, all neonates should receive 10 mg/kg every 8 hours.

Infants (excluding preterm neonates <1 week) and Children 11 years: 10 mg/kg every 8 hours for 14-28 days

Children 12 years and Adults: 600 mg every 12 hours for 14-28 days

Nosocomial pneumonia, complicated skin and skin structure infections, community acquired pneumonia including concurrent bacteremia: Oral, I.V.:

Infants (excluding preterm neonates <1 week) and Children 11 years: 10 mg/kg every 8 hours for 10-14 days

Children 12 years and Adults: 600 mg every 12 hours for 10-14 days

Uncomplicated skin and skin structure infections: Oral:

Infants (excluding preterm neonates <1 week) and Children <5 years: 10 mg/kg every 8 hours for 10-14 days

Children 5-11 years: 10 mg/kg every 12 hours for 10-14 days

Children 12-18 years: 600 mg every 12 hours for 10-14 days

Adults: 400 mg every 12 hours for 10-14 days

Elderly: No dosage adjustment required

Dosage adjustment in renal impairment: No adjustment is recommended. The two primary metabolites may accumulate in patients with renal impairment but the clinical significance is unknown. Weigh the risk of accumulation of metabolites versus the benefit of therapy. Both linezolid and the two metabolites are eliminated by dialysis. Linezolid should be given after hemodialysis.

Dosage adjustment in hepatic impairment: No dosage adjustment required for mild to moderate hepatic insufficiency (Child-Pugh Class A or B). Use in severe hepatic insufficiency has not been adequately evaluated.


Administration

I.V.: Administer intravenous infusion over 30-120 minutes. Do not mix or infuse with other medications. When the same intravenous line is used for sequential infusion of other medications, flush line with D5W, NS, or LR before and after infusing linezolid. The yellow color of the injection may intensify over time without affecting potency.

Oral suspension: Invert gently to mix prior to administration, do not shake.


Monitoring Parameters

 Weekly CBC and platelet counts, particularly in patients at increased risk of bleeding, with pre-existing myelosuppression, on concomitant medications that cause bone marrow suppression, in those who require >2 weeks of therapy, or in those with chronic infection who have received previous or concomitant antibiotic therapy.


Dietary Considerations

 Take with or without food. Suspension contains 20 mg phenylalanine per teaspoonful. Sodium content: 0.1 mEq/tablet; 0.4 mEq/5 mL; 1.7 mEq/100 mL infusion; 3.3 mEq/200 mL infusion; 5 mEq/300 mL infusion


Patient Education

 Oral: Take exactly as directed. Do not alter dosage without consulting prescriber. Complete full course of therapy even if condition appears controlled. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Avoid alcohol. Avoid tyramine-containing foods (eg, pickles, aged cheese, wine).

Oral/I.V.: You may experience GI discomfort, nausea, vomiting, taste alteration (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); mild headache (analgesic may help); or constipation (increase exercise, fluids, fruit, or fiber may help). Report immediately unresolved, liquid diarrhea; white plaques in mouth; skin rash or irritation; acute headache, dizziness, blurred vision; or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.


Anesthesia and Critical Care Concerns/Other Considerations

 Linezolid has mild MAO inhibitor properties and should be used with caution in patients with cardiovascular disease, particularly those with hypertension. Avoid use with sympathomimetic and dopaminergic agents.


Cardiovascular Considerations

 Linezolid has mild MAO inhibitor properties and should be used with caution in patients with cardiovascular disease, particularly those with hypertension. Avoid use with sympathomimetic and dopaminergic agents.


Dental Health: Effects on Dental Treatment

 Key adverse event(s) related to dental treatment: Oral moniliasis, taste alteration, and tongue discoloration.


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 Linezolid has mild monoamine oxidase inhibitor properties. The clinician is reminded that vasoconstrictors have the potential to interact with MAOIs to result in elevation of blood pressure. Caution is suggested.


Mental Health: Effects on Mental Status

 May cause insomnia and dizziness


Mental Health: Effects on Psychiatric Treatment

 Has mild MAO inhibitor properties and has the potential to have the same interactions as other MAO inhibitors; thrombocytopenia has been reported and may be dependent on duration of therapy (generally >2 weeks of treatment), caution with valproic acid; avoid use with serotonergic agents such as TCAs, venlafaxine, trazodone, sibutramine, meperidine, dextromethorphan, and SSRIs; may cause leukopenia, use caution with clozapine and carbamazepine


Dosage Forms

Infusion [premixed]: 200 mg (100 mL) [contains sodium 1.7 mEq]; 400 mg (200 mL) [contains sodium 3.3 mEq]; 600 mg (300 mL) [contains sodium 5 mEq]

Powder for oral suspension: 20 mg/mL (150 mL) [contains phenylalanine 20 mg/5 mL, sodium benzoate, and sodium 0.4 mEq/5 mL; orange flavor]

Tablet: 400 mg, 600 mg [each strength contains sodium 0.1 mEq/tablet]


References

Bain KT and Wittbrodt ET, "Linezolid for the Treatment of Resistant Gram-Positive Cocci," Ann Pharmacother , 2001, 35(5):566-75.

Perry CM and Jarvis B, "Linezolid: A Review of Its Use in the Management of Serious Gram-Positive Infections," Drugs , 2001, 61(4):525-51.


International Brand Names

 Linox® (IN); Zyvoxam® (CA); Zyvox® (BR, CR, GB, GT, HN, HU, IE, IL, PA, SG, SV, TH); Zyvoxid® (AT, BE, CH, CO, DE, DK, ES, FI, FR, HU, IT, NO, PL, PT, RO, SE, ZA)


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