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Special Alerts
Zyvox®: Update on Serious CNS Reactions Reported with Specifically Implicated Serotonergic Psychiatric Medications Such as SSRIs and SNRIs
October 2011
The U.S. Food and Drug Administration (FDA) has acknowledged that drugs used for psychiatric treatment possess differing degrees of pro-serotonergic activity. Therefore, the FDA is not explicitly implicating psychiatric medications outside of the SSRIs and SNRIs at this time, as there appears to be insufficient evidence to define a comparable risk. Medications belonging to the tricyclic and MAOI classes, as well as other psychiatric medications, are listed in the updated bulletin as a precautionary measure, but without explicit wording to avoid concomitant use.
An updated list of medications to avoid or exercise caution with can be found at http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm.
Linezolid (Zyvox®): Serious CNS Reactions Reported with Concomitant Use of Serotonergic Psychiatric Medications
July 2011
The U.S. Food and Drug Administration (FDA) has issued a safety announcement regarding the potential for serotonin syndrome to develop in patients receiving linezolid (Zyvox®) and psychiatric medications with serotonergic effects including, SSRIs, SNRIs, tricyclic and MAOI antidepressants, and other medications with proserotonergic properties. Linezolid has been shown to inhibit monoamine oxidase A and may lead to increased levels of serotonin in the brain when combined with serotonergic psychiatric medications. For a complete list of medications not to be used with linezolid, please refer to the link below.
The FDA has received reports of serious CNS reactions with these combinations, thus prompting additional warnings to be added to the labels of linezolid and the respective psychiatric medications. Use of linezolid in life-threatening infections (eg, vancomycin-resistant Enterococcus faecium (VRE), nosocomial pneumonia and complicated skin infections caused by MRSA) should prompt immediate discontinuation of any serotonergic medication with close monitoring for CNS adverse effects for 2 weeks (5 weeks if discontinuing fluoxetine), or for 24 hours after the last linezolid dose. For nonemergent use of linezolid, discontinue serotonergic medication(s) at least 2 weeks (5 weeks with fluoxetine) prior to initiating linezolid therapy. Serotonergic psychiatric medications should not be initiated in any patient on linezolid, but can be started 24 hours after the last dose of the antibiotic.
Patients should notify their healthcare provider if they are taking any serotonergic psychiatric medications and reminded not to discontinue these medications without advice from their healthcare practitioner. Patients should be instructed to recognize the signs of CNS toxicity (eg, mental changes, muscle twitching, shivering, incoordination) and to report these symptoms immediately to their healthcare provider.
Pronunciation
(li NE zoh lid)
Generic Available (U.S.)
No
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
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 Considerations
Because adverse effects were observed in some animal studies, linezolid is classified pregnancy category C. There are no adequate and well-controlled studies in pregnant women.
Lactation
Excretion in breast milk unknown/use caution
Breast-Feeding Considerations
It is not known if linezolid is excreted in human milk. Linezolid has low protein binding and is 100% bioavailable orally which may increase the exposure to a nursing infant. The manufacturer advises caution if administering linezolid to a breast-feeding woman. Linezolid is used therapeutically in infants. Nondose-related effects could include modification of bowel flora.
Contraindications
Hypersensitivity to linezolid or any other component of the formulation; concurrent use or within 2 weeks of MAO inhibitors; patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or taking sympathomimetics (eg, pseudoephedrine), vasopressive agents (eg, epinephrine, norepinephrine), or dopaminergic agents (eg, dopamine, dobutamine) unless closely monitored for increased blood pressure; patients with carcinoid syndrome and/or taking SSRIs, tricyclic antidepressants, serotonin 5-HT1B,1D receptor agonists, meperidine, or buspirone unless closely monitored for sign/symptoms of serotonin syndrome
Warnings/Precautions
Concerns related to adverse effects:
• Lactic acidosis: Has been reported with use. Patients who develop recurrent nausea and vomiting, unexplained acidosis, or low bicarbonate levels need immediate evaluation.
• 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; consider discontinuation in patients developing myelosuppression (or in whom myelosuppression worsens during treatment).
• Peripheral and optic neuropathy (with vision loss): Has been reported and may occur primarily with extended courses of therapy >28 days; any symptoms of visual change or impairment warrant immediate ophthalmic evaluation and possible discontinuation of therapy.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.
Disease-related concerns:
• Carcinoid syndrome: Use with caution and closely monitor for serotonin syndrome in patients with carcinoid syndrome; linezolid has not been studied in patients with this condition. Use is contraindicated in the absence of close monitoring.
• Hypertension: Use with caution and closely monitor blood pressure in patients with uncontrolled hypertension; linezolid has not been studied in patients with this condition. Use is contraindicated in the absence of close monitoring.
• Hyperthyroidism: Use with caution and closely monitor blood pressure in patients with untreated hyperthyroidism; linezolid has not been studied in patients with this condition. Use is contraindicated in the absence of close monitoring.
• Pheochromocytoma: Use with caution and closely monitor blood pressure in patients with pheochromocytoma; linezolid has not been studied in patients with this condition. Use is contraindicated in the absence of close monitoring.
• Seizure disorder: Seizures have been reported; use with caution in patients with a history of seizures.
Concurrent drug therapy issues:
• Serotonin syndrome: Symptoms of agitation, confusion, hallucinations, hyper-reflexia, myoclonus, shivering, and tachycardia may occur with concomitant proserotonergic drugs (eg, SSRIs/SNRIs or triptans) or agents which reduce linezolid's metabolism; concurrent use with these medications is contraindicated unless patient is closely monitored for signs/symptoms of serotonin syndrome.
Special populations:
• Pediatrics: The manufacturer states that empiric use in pediatric patients with CNS infections is not recommended due to inconsistent concentrations in the CSF; however, there are multiple case reports describing successful treatment of documented VRE and Staphylococcus aureus CNS and shunt infections in the literature.
Dosage form specific issues:
• Phenylalanine: Oral suspension contains phenylalanine.
Other warnings/precautions:
• Appropriate use: Unnecessary use may lead to the development of resistance to linezolid; consider alternatives before initiating outpatient treatment.
• Catheter-related bloodstream infections (CRBSI): Linezolid should not be used in the empiric treatment of CRBSI, but may be appropriate for targeted therapy (Mermel, 2009).
• MAO inhibitor properties: Exhibits mild MAO inhibitor properties and has the potential to have the same interactions as other MAO inhibitors.
Adverse Reactions
Percentages as reported in adults; frequency similar in pediatric patients
>10%:
Central nervous system: Headache (<1% to 11%)
Gastrointestinal: Diarrhea (3% to 11%)
1% to 10%:
Central nervous system: Insomnia (3%), dizziness (≤2%), fever (2%)
Dermatologic: Rash (2%)
Gastrointestinal: Nausea (3% to 10%), lipase increased (3% to 4%), vomiting (1% to 4%), constipation (2%), taste alteration (1% to 2%), amylase increased (<1% to 2%), tongue discoloration (≤1%), oral moniliasis (≤1%), pancreatitis
Genitourinary: Vaginal moniliasis (1% to 2%)
Hematologic: Thrombocytopenia (<1% to 10%), hemoglobin decreased (1% to 7%), leukopenia (<1% to 2%), neutropenia (≤1%)
Hepatic: ALT increased (2% to 10%), AST increased (2% to 5%), alkaline phosphatase increased (<1% to 4%), bilirubin increased (≤1%)
Renal: BUN increased (≤2%)
Miscellaneous: Fungal infection (≤1% to 2%), lactate dehydrogenase increased (<1% to 2%)
<1% or frequency not defined: Blurred vision, C. difficile-related complications, creatinine increased, dyspepsia, hypertension, localized abdominal pain, pruritus
Postmarketing and/or case reports: Anaphylaxis, anemia, angioedema, bullous skin disorders, lactic acidosis, optic neuropathy, pancytopenia, peripheral neuropathy, seizures, serotonin syndrome (with concurrent use of other serotonergic agents), Stevens-Johnson syndrome, tooth discoloration, vision loss
Metabolism/Transport Effects
Inhibits Monoamine Oxidase
Drug Interactions
Alpha-/Beta-Agonists (Direct-Acting): MAO Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Primarily with oral administration of phenylephrine. Exceptions: Dipivefrin. Risk D: Consider therapy modification
Alpha-/Beta-Agonists (Indirect-Acting): MAO Inhibitors may enhance the hypertensive effect of Alpha-/Beta-Agonists (Indirect-Acting). Risk X: Avoid combination
Alpha1-Agonists: MAO Inhibitors may enhance the hypertensive effect of Alpha1-Agonists. Risk X: Avoid combination
Alpha2-Agonists (Ophthalmic): MAO Inhibitors may enhance the hypertensive effect of Alpha2-Agonists (Ophthalmic). Risk X: Avoid combination
Altretamine: May enhance the orthostatic hypotensive effect of MAO Inhibitors. Risk C: Monitor therapy
Amphetamines: MAO Inhibitors may enhance the hypertensive effect of Amphetamines. Risk X: Avoid combination
Anilidopiperidine Opioids: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Management: Avoid use of fentanyl (and other anilidopiperidine opioids when possible) in patients who have used a monoamine oxidase inhibitor within the past 14 days due to reports of unpredictable but severe adverse effects. Risk X: Avoid combination
Antidepressants (Serotonin Reuptake Inhibitor/Antagonist): MAO Inhibitors may enhance the adverse/toxic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). Risk X: Avoid combination
Antihypertensives: MAO Inhibitors may enhance the hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Antipsychotics: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk C: Monitor therapy
Atomoxetine: MAO Inhibitors may enhance the neurotoxic (central) effect of Atomoxetine. Risk X: Avoid combination
Beta2-Agonists: MAO Inhibitors may enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy
Bezafibrate: MAO Inhibitors may enhance the adverse/toxic effect of Bezafibrate. Risk X: Avoid combination
Buprenorphine: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
BuPROPion: MAO Inhibitors may enhance the neurotoxic (central) effect of BuPROPion. Risk X: Avoid combination
BusPIRone: May enhance the adverse/toxic effect of MAO Inhibitors. Specifically, blood pressure elevations been reported. Risk X: Avoid combination
CarBAMazepine: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
COMT Inhibitors: May enhance the adverse/toxic effect of MAO Inhibitors. Risk D: Consider therapy modification
Cyclobenzaprine: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination
Dexmethylphenidate: MAO Inhibitors may enhance the hypertensive effect of Dexmethylphenidate. Risk X: Avoid combination
Dextromethorphan: MAO Inhibitors may enhance the serotonergic effect of Dextromethorphan. This may cause serotonin syndrome. Risk X: Avoid combination
Diethylpropion: MAO Inhibitors may enhance the hypertensive effect of Diethylpropion. Risk X: Avoid combination
Doxapram: MAO Inhibitors may enhance the hypertensive effect of Doxapram. Risk C: Monitor therapy
HYDROmorphone: MAO Inhibitors may enhance the adverse/toxic effect of HYDROmorphone. Risk X: Avoid combination
Levodopa: May enhance the adverse/toxic effect of MAO Inhibitors. Of particular concern is the development of hypertensive reactions when levodopa is used with nonselective MAOI. Risk D: Consider therapy modification
Lithium: MAO Inhibitors may enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapy
MAO Inhibitors: May enhance the adverse/toxic effect of Linezolid. Risk X: Avoid combination
Maprotiline: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
Meperidine: MAO Inhibitors may enhance the serotonergic effect of Meperidine. This may cause serotonin syndrome. Risk X: Avoid combination
Methadone: MAO Inhibitors may enhance the adverse/toxic effect of Methadone. Management: Initial safety testing, where small incremental doses of methadone are given with the patient closely monitored (including vitals, etc.), is recommended if methadone is to be used with (or within 14 days of) an MAO inhibitor. Avoid transdermal selegiline. Risk D: Consider therapy modification
Methyldopa: MAO Inhibitors may enhance the adverse/toxic effect of Methyldopa. Risk X: Avoid combination
Methylene Blue: MAO Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Methylphenidate: MAO Inhibitors may enhance the hypertensive effect of Methylphenidate. Risk X: Avoid combination
Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Risk C: Monitor therapy
Mirtazapine: MAO Inhibitors may enhance the neurotoxic (central) effect of Mirtazapine. Risk X: Avoid combination
Mirtazapine: Linezolid may enhance the serotonergic effect of Mirtazapine. This could result in serotonin syndrome. Management: Consider alternatives. When this combination is indicated, closely monitor for signs/symptoms of serotonin toxicity/serotonin syndrome. If such symptoms occur, consider discontinuation of one or both agents. Risk D: Consider therapy modification
Nefazodone: Linezolid may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Management: Consider alternatives. When this combination is indicated, closely monitor for signs/symptoms of serotonin toxicity/serotonin syndrome. If such symptoms occur, consider discontinuation of one or both agents. Risk D: Consider therapy modification
Orthostatic Hypotension Producing Agents: MAO Inhibitors may enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Oxymorphone: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
Pizotifen: MAO Inhibitors may enhance the anticholinergic effect of Pizotifen. Risk X: Avoid combination
Reserpine: MAO Inhibitors may enhance the adverse/toxic effect of Reserpine. Existing MAOI therapy can result in paradoxical effects of added reserpine (e.g., excitation, hypertension). Management: Monoamine oxidase inhibitors (MAOIs) should be avoided or used with great caution in patients who are also receiving reserpine. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: MAO Inhibitors may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk X: Avoid combination
Selective Serotonin Reuptake Inhibitors: Linezolid may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Consider alternatives. When this combination is indicated, closely monitor for signs/symptoms of serotonin toxicity/serotonin syndrome. If such symptoms occur, consider discontinuation of one or both agents. Risk D: Consider therapy modification
Serotonin 5-HT1D Receptor Agonists: MAO Inhibitors may decrease the metabolism of Serotonin 5-HT1D Receptor Agonists. Management: If MAO inhibitor therapy is required, naratriptan, eletriptan or frovatriptan may be a suitable 5-HT1D agonist to employ. Exceptions: Eletriptan; Frovatriptan; Naratriptan. Risk X: Avoid combination
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Serotonin/Norepinephrine Reuptake Inhibitors: MAO Inhibitors may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This may cause serotonin syndrome. Risk X: Avoid combination
Serotonin/Norepinephrine Reuptake Inhibitors: Linezolid may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Consider alternatives. When this combination is indicated, closely monitor for signs/symptoms of serotonin toxicity/serotonin syndrome. If such symptoms occur, consider discontinuation of one or both agents. Risk D: Consider therapy modification
Sympathomimetics: Linezolid may enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Risk D: Consider therapy modification
Tapentadol: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
Tetrabenazine: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
Tetrahydrozoline: MAO Inhibitors may enhance the hypertensive effect of Tetrahydrozoline. Risk X: Avoid combination
Tetrahydrozoline (Nasal): MAO Inhibitors may enhance the hypertensive effect of Tetrahydrozoline (Nasal). Risk X: Avoid combination
TraMADol: May enhance the neuroexcitatory and/or seizure-potentiating effect of MAO Inhibitors. TraMADol may enhance the serotonergic effect of MAO Inhibitors. Management: Consider alternatives to combined treatment with tramadol and monoamine oxidase inhibitors due to an increased risk of serotonin syndrome and seizures. Avoid transdermal selegiline. Risk D: Consider therapy modification
TraZODone: Linezolid may enhance the serotonergic effect of TraZODone. This could result in serotonin syndrome. Management: Consider alternatives. When this combination is indicated, closely monitor for signs/symptoms of serotonin toxicity/serotonin syndrome. If such symptoms occur, consider discontinuation of one or both agents. Risk D: Consider therapy modification
Tricyclic Antidepressants: MAO Inhibitors may enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. Risk X: Avoid combination
Tricyclic Antidepressants: Linezolid may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Consider alternatives. When this combination is indicated, closely monitor for signs/symptoms of serotonin toxicity/serotonin syndrome. If such symptoms occur, consider discontinuation of one or both agents. Risk D: Consider therapy modification
Tryptophan: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: May cause additional CNS depressant effects and provide potential source of additional tyramine content. Management: Avoid ethanol.
Food: Concurrent ingestion of foods rich in tyramine may cause sudden and severe high blood pressure (hypertensive crisis). Food's freshness is also an important concern; improperly stored or spoiled food can create an environment where tyramine concentrations may increase. Management: Avoid tyramine-containing foods with MAOIs.
Herb/Nutraceutical: Ingestion of large quantities of supplements containing caffeine, tyrosine, tryptophan or phenylalanine.may increase the risk of severe side effects (eg, hypertensive reactions, serotonin syndrome). Management: Avoid supplements containing caffeine, tyrosine, tryptophan or phenylalanine.
Storage
Infusion: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Keep infusion bags in overwrap until ready for use. Protect infusion bags from freezing.
Oral suspension: Following reconstitution, store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Use reconstituted suspension within 21 days. Protect from light.
Tablet: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light; protect from moisture.
Reconstitution
Oral suspension: Reconstitute with 123 mL of distilled water (in 2 portions); shake vigorously. Concentration is 100 mg/5 mL. Prior to administration mix gently by inverting bottle; do not shake.
Compatibility
Stable in D51/2 NS, D5W, LR, NS
Y-site administration: Compatible: Acyclovir, alfentanil, amikacin, aminophylline, ampicillin, ampicillin/sulbactam, anidulafungin, aztreonam, buprenorphine, butorphanol, calcium gluconate, carboplatin, caspofungin, cefazolin, cefotetan, cefoxitin, ceftazidime, cefuroxime, cimetidine, ciprofloxacin, cisatracurium, cisplatin, clindamycin, cyclophosphamide, cyclosporine, cytarabine, dexamethasone sodium phosphate, dexmedetomidine, digoxin, diphenhydramine, dobutamine, dopamine, doripenem, doxorubicin, doxycycline, droperidol, enalaprilat, erythromycin lactobionate, esmolol, etoposide phosphate, famotidine, fenoldopam, fentanyl, fluconazole, fluorouracil, furosemide, ganciclovir, gemcitabine, gentamicin, granisetron, haloperidol, heparin, hydrocortisone sodium succinate, hydromorphone, hydroxyzine, ifosfamide, imipenem/cilastatin, labetalol, leucovorin calcium, levofloxacin, lidocaine, lorazepam, magnesium sulfate, mannitol, meperidine, meropenem, mesna, methotrexate, methylprednisolone sodium succinate, metoclopramide, metronidazole, midazolam, minocylcine, mitoxantrone, morphine, nalbuphine, naloxone, nicardipine, nitroglycerin, ondansetron, paclitaxel, pentobarbital, phenobarbital, piperacillin, piperacillin/tazobactam, potassium chloride, prochlorperazine, promethazine, propranolol, ranitidine, remifentanil, sodium bicarbonate, sufentanil, sulfamethoxazole/trimethoprim, theophylline, tigecycline, tobramycin, vancomycin, vasopressin, vecuronium, verapamil, vincristine, zidovudine. Incompatible: Amphotericin B, chlorpromazine, diazepam, pentamidine, phenytoin. Variable (consult detailed reference): Ceftriaxone.
Compatibility in syringe: Incompatible: Ceftriaxone.
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); minimally metabolized, may be mediated by cytochrome P450
Bioavailability: Oral: ~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% of total dose as parent drug, ~50% of total dose as metabolites); feces (~9% of total dose as metabolites)
Nonrenal clearance: Adults: ~65%
Dosage
Usual dosage: Oral, I.V.:
Children ≤11 years: 10 mg/kg (maximum: 600 mg/dose) every 8 hours
Children ≥12 years and Adults: 600 mg every 12 hours
Indication-specific dosing:
Pneumonia:
Community-acquired pneumonia (CAP):
Manufacturer's recommendation (includes concurrent bacteremia): Oral, I.V.:
Infants (excluding preterm neonates <1 week) and Children ≤11 years: 10 mg/kg/dose every 8 hours for 10-14 days
Children ≥12 years and Adults: 600 mg every 12 hours for 10-14 days. Note: May consider 7-day treatment course (versus manufacturer recommended 10-14 days) in patients with healthcare-, hospital-, and ventilator-associated pneumonia who have demonstrated good clinical response (ATS/IDSA, 2005).
Alternate recommendations:
Infants >3 months and Children ≤11 years (IDSA/PIDS, 2011):
S. pneumoniae (MICs to penicillin ≤2.0 mcg/mL), mild infection or step-down therapy (alternative to amoxicillin): Oral: 10 mg/kg/dose every 8 hours
S. pneumoniae (MICs to penicillin ≥4.0 mcg/mL):
Severe infection (alternative to ceftriaxone): I.V.: 10 mg/kg/dose every 8 hours
Mild infection, step-down therapy (preferred): Oral: 10 mg/kg/dose every 8 hours
S. aureus (methicillin-resistant/clindamycin-susceptible):
Severe infection (alternative to vancomycin or clindamycin): I.V.: 10 mg/kg/dose every 8 hours
Mild infection, step-down therapy (alternative to clindamycin): Oral: 10 mg/kg/dose every 8 hours
S. aureus (methicillin- and clindamycin-resistant):
Severe infection (alternative to vancomycin): I.V.: 10 mg/kg/dose every 8 hours
Mild infection, step-down therapy (preferred): Oral: 10 mg/kg/dose every 8 hours
Children ≤11 years (Liu, 2011): Oral, I.V.: S. aureus (methicillin-resistant): 10 mg/kg/dose every 8 hours for 7-21 days (maximum: 600 mg/dose)
Children ≥12 years (IDSA/PIDS, 2011):
S. pneumoniae (MICs to penicillin ≤2.0 mcg/mL), mild infection or step-down therapy (alternative to amoxicillin): Oral: 10 mg/kg/dose every 12 hours
S. pneumoniae (MICs to penicillin ≥4.0 mcg/mL)
Severe infection (alternative to ceftriaxone): I.V.: 10 mg/kg/dose every 12 hours
Mild infection, step-down therapy (preferred): Oral: 10 mg/kg/dose every 12 hours
S. aureus (methicillin-resistant/clindamycin-susceptible):
Severe infection (alternative to vancomycin/clindamycin): I.V.: 10 mg/kg/dose every 12 hours
Mild infection, step-down therapy (alternative to clindamycin): Oral: 10 mg/kg/dose every 12 hours
S. aureus (methicillin- and clindamycin-resistant):
Severe infection (alternative to vancomycin): I.V.: 10 mg/kg/dose every 12 hours
Mild infection, step-down therapy (preferred): Oral: 10 mg/kg/dose every 12 hours
Children ≥12 years and Adults: (Liu, 2011): Oral, I.V.: S. aureus (methicillin-resistant): 600 mg every 12 hours for 7-21 days
Healthcare-associated (HA) pneumonia: Oral, I.V.:
Manufacturer's recommendation:
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.
Note: May consider 7-day treatment course (versus manufacturer recommended 10-14 days) in patients with healthcare-, hospital-, and ventilator- associated pneumonia who have demonstrated good clinical response (ATS/IDSA, 2005).
Alternate recommendations (Liu, 2011): S. aureus (methicillin-resistant):
Children ≤11 years: 10 mg/kg/dose every 8 hours for 7-21 days (maximum: 600 mg/dose)
Children ≥12 years and Adults: 600 mg every 12 hours for 7-21 days
Skin and skin structure infections, complicated: 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.
Skin and skin structure infections, uncomplicated: 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; Note: 400 mg dose is recommended in the product labeling; however, 600 mg dose is commonly employed clinically; consider 5- to 10-day treatment course as opposed to the manufacturer recommended 10-14 days (Liu, 2011; Stevens, 2005)
VRE infections including concurrent bacteremia: Oral, I.V.:
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
Brain abscess, subdural empyema, spinal epidural abscess (S. aureus [methicillin-resistant]) (unlabeled use; Liu, 2011): Oral, I.V.:
Children ≤11 years: 10 mg/kg every 8 hours for 4-6 weeks (maximum: 600 mg/dose)
Children ≥12 years and Adults: 600 mg every 12 hours for 4-6 weeks
Meningitis (S. aureus [methicillin-resistant]) (unlabeled use; Liu, 2011): Oral, I.V.: Children ≥12 years and Adults: 600 mg every 12 hours for 2 weeks
Osteomyelitis (S. aureus [methicillin-resistant]) (unlabeled use; Liu, 2011): Oral, I.V.:
Infants (excluding preterm neonates <1 week) and Children ≤11 years: 10 mg/kg every 8 hours for a minimum of 4-6 weeks (maximum: 600 mg/dose)
Children ≥12 years and Adults: 600 mg every 12 hours for a minimum of 8 weeks (some experts combine with rifampin)
Septic arthritis (S. aureus [methicillin-resistant]) (unlabeled use; Liu, 2011): Oral, I.V.:
Infants (excluding preterm neonates <1 week) and Children ≤11 years: 10 mg/kg every 8 hours for 3-4 weeks (maximum: 600 mg/dose)
Children ≥12 years and Adults: 600 mg every 12 hours for 3-4 weeks
Septic thrombosis of cavernous or dural venous sinus (S. aureus [methicillin-resistant]) (unlabeled use; Liu, 2011): Oral, I.V.:
Children ≤11 years: 10 mg/kg every 8 hours for 4-6 weeks (maximum: 600 mg/dose)
Children ≥12 years and Adults: 600 mg every 12 hours for 4-6 weeks
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. Monitor for hematopoietic (eg, anemia, leukopenia, thrombocytopenia) and neuropathic (eg, peripheral neuropathy) adverse events when administering for extended periods.
Intermittent hemodialysis (administer after hemodialysis on dialysis days): Dialyzable (~30% removed during 3-hour dialysis session): If administration time is not immediately after dialysis session, may consider administration of a supplemental dose especially early in the treatment course to maintain levels above the MIC (Brier, 2003). Others have recommended no supplemental dose or dosage adjustment for patients on intermittent hemodialysis, peritoneal dialysis, or continuous renal replacement therapy (eg, CVVHD) (Heintz, 2009; Trotman, 2005)
Dosage adjustment in hepatic impairment:
Mild-to-moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment required
Severe hepatic impairment (Child-Pugh class C): Use has not been adequately evaluated
Administration: Oral
Oral suspension: Invert gently to mix prior to administration, do not shake. Administer without regard to meals.
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.
Monitoring Parameters
Weekly CBC, 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; visual function with extended therapy (≥3 months) or in patients with new onset visual symptoms, regardless of therapy length
Dietary Considerations
Take without regard to meals. Some products may contain sodium and/or phenylalanine. Avoid consuming large amounts of tyramine-containing foods/beverages. Some examples include aged or matured cheese, air-dried or cured meats (including sausages and salamis), fava or broad bean pods, tap/draft beers, Marmite concentrate, sauerkraut, soy sauce, and other soybean condiments.
Patient Education
Oral suspension: Store at room temperature and use within 21 days. Maintain adequate hydration unless instructed to restrict fluid intake. Avoid alcohol. Avoid tyramine-containing foods (eg, pickles, aged cheese, wine).
Oral/I.V.: You may experience mild headache, GI discomfort, nausea, vomiting, taste alteration, or constipation. Report immediately unresolved, white plaques in mouth; skin rash or irritation; acute headache, dizziness, blurred vision, or changes in visual acuity; tingling or numbness in extremities; or persistent diarrhea.
Geriatric Considerations
According to the manufacturer the pharmacokinetics of linezolid are not significantly altered in patients ≥65 years of age.
Anesthesia and Critical Care Concerns/Other Considerations
Linezolid has time-dependent kill characteristics; time for which the serum concentration remains above the MIC for a dosing period is the best predictor of efficacy. With prolonged exposure (>2 weeks), monitor closely for anemia, leukopenia, and thrombocytopenia.
Evidence-Based Information:
Trial Showing Increased Rate of Death in Catheter-Related Bloodstream Infections - March, 2007: The U.S. Food and Drug Administration (FDA) has issued an alert to healthcare professionals regarding an increased rate of death among patients treated with linezolid (Zyvox®) for catheter-related bacteremia and catheter-site infections. Healthcare professionals are reminded that linezolid is not approved for the treatment of catheter-related bloodstream, catheter-site, or gram-negative infections. Additional information is available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152993.htm
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 (serotonin reuptake inhibitors, tricyclic antidepressants, seronton 5-HT1 receptor agonists, meperidine, or buspirone). Linezolid can cause thrombocytopenia. Use cautiously in patients with thrombocytopenia, or in patients being started on medications that can cause thrombocytopenia (eg, heparin).
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 MAO-Is 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
Nursing: Physical Assessment/Monitoring
Assess for previous drug allergies before administering first dose. Serotonergic agents may increase resistance to linezolid and increase risk of serotonin syndrome, hypertension with adrenergic agents, or myelosuppression with other drugs that may cause bone marrow suppression. Assess weekly CBC and platelet count. Monitor for myelosuppression (anemia, leukopenia, pancytopenia, and thrombocytopenia; may be more common in patients receiving linezolid for >2 weeks), lactic acidosis, or peripheral or optic neuropathy. Instruct patient to follow a tyramine-free diet.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Infusion, premixed:
Zyvox®: 200 mg (100 mL); 600 mg (300 mL) [contains sodium 0.38 mg/mL]
Powder for suspension, oral:
Zyvox®: 100 mg/5 mL (150 mL) [contains phenylalanine 20 mg/5 mL, sodium 8.52 mg (0.4 mEq)/5 mL, sodium benzoate; orange flavor]
Tablet, oral:
Zyvox®: 600 mg [contains sodium 2.92 mg (0.1 mEq)/tablet]
Pricing: U.S. (www.drugstore.com)
Tablets (Zyvox)
600 mg (20): $1989.19
References
American Thoracic Society and Infectious Diseases Society of America, “Guidelines for the Management of Adults With Hospital-Acquired, Ventilator-Associated, and Healthcare-Associated Pneumonia,” Am J Respir Crit Care Med, 2005, 171(4):388-416.
Bain KT and Wittbrodt ET, “Linezolid for the Treatment of Resistant Gram-Positive Cocci,” Ann Pharmacother, 2001, 35(5):566-75.
Bradley JS, Byington CL, Shah SS, et al. “The Management of Community-Acquired Pneumonia in Infants and Children Older Than 3 Months of Age: Clinical Practice Guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America”, Clin Infect Dis, 2011, 53(7):e25-76.
Cook AM, Ramsey CN, Martin CA, et al, “Linezolid for the Treatment of a Heteroresistant Staphylococcus aureus Shunt Infection,” Pediatr Neurosurg, 2005, 41(2):102-4.
da Silva PS, Monteiro Neto H, and Sejas LM, “Successful Treatment of Vancomycin-Resistant Enterococcus Ventriculitis in a Child,” Braz J Infect Dis, 2007, 11(2):297-9.
Heintz BH, Matzke GR, Dager WE, “Antimicrobial Dosing Concepts and Recommendations for Critically Ill Adult Patients Receiving Continuous Renal Replacement Therapy or Intermittent Hemodialysis,” Pharmacotherapy, 2009, 29(5):562-77.
Lipsky BA, Berendt AR, Deery HG, et al, “Diagnosis and Treatment of Diabetic Foot Infections,” Clin Infect Dis, 2004, 39(7):885-910.
Liu C, Bayer A, Cosgrove SE, et al, “Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children: Executive Summary,” Clin Infect Dis, 2011, 52(3):285-92.
Mandell LA, Wunderink RG, Anzueto A, et al, “Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults,” Clin Infect Dis, 2007, 44(Suppl 2):27-72.
Mermel LA, Allon M, Bouza E, et al, “Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection: 2009 Update by the Infectious Diseases Society of America,” Clin Infect Dis, 2009, 49(1):1-45.
Milstone AM, Dick J, Carcon B, et al, “Cerebrospinal Fluid Penetration and Bacteriostatic Activity of Linezolid Against Enterococcus faecalis in a Child With a Ventriculoperitoneal Shunt Infection,” Pediatr Neurosurg, 2007, 43(5):406-9.
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.
Roberts JA and Lipman J, "Antibacterial Dosing in Intensive Care: Pharmacokinetics, Degree of Disease and Pharmacodynamics of Sepsis," Clin Pharmacokinet, 2006, 45(8):755-73.
Shaikh ZH, Peloquin CA, and Ericsson CD, “Successful Treatment of Vancomycin-Resistant Enterococcus faecium Meningitis With Linezolid: Case Report and Literature Review,” Scand J Infect Dis, 2001, 33(5):375-9.
Shulman KI and Walker SE, “A Reevaluation of Dietary Restrictions for Irreversible Monoamine Oxidase Inhibitors,” Psychiatr Ann, 2001, 31(6):378-84.
Shulman KI and Walker SE, “Refining the MAOI Diet: Tyramine Content of Pizzas and Soy Products,” J Clin Psychiatry, 1999, 60(3):191-3.
Stevens DL, Bisno AL, Chambers HF, et al, “Practice Guidelines for the Diagnosis and Management of Skin and Soft-Tissue Infections,” Clin Infect Dis, 2005, 41(10):1373-406.
Trotman RL, Williamson JC, Shoemaker DM, et al, "Antibiotic Dosing in Critically Ill Adult Patients Receiving Continuous Renal Replacement Therapy," Clin Infect Dis, 2005, 41(8):1159-66.
Walker SE, Shulman KI, Tailor SA, et al, “Tyramine Content of Previously Restricted Foods in Monoamine Oxidase Inhibitor Diets,” J Clin Psychopharmacol, 1996, 16(5):383-8.
Villani P, Regazzi MB, Marubbi F, et al, “Cerebrospinal Fluid Linezolid Concentrations in Postneurosurgical Central Nervous System Infections,” Antimicrob Agents Chemother, 2002, 46(3):936-7.
International Brand Names
Lexi-Comp.com
Last full review/revision February 2012
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