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Linezolid

Pronunciation

Pronunciation

(li NE zoh lid)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Zyvox: 2 mg/mL (100 mL, 300 mL)

Generic: 2 mg/mL (300 mL)

Suspension Reconstituted, Oral:

Zyvox: 100 mg/5 mL (150 mL) [orange flavor]

Generic: 100 mg/5 mL (150 mL)

Tablet, Oral:

Zyvox: 600 mg

Generic: 600 mg

Brand Names: U.S.

  • Zyvox

Pharmacologic Category

  • Antibiotic, Oxazolidinone

Pharmacology

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.

Absorption

Rapid and extensive

Distribution

Vdss: Adults: 40 to 50 L

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

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%

Time to Peak

Adults: Oral: 1 to 2 hours

Half-Life Elimination

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

Protein Binding

Adults: 31%

Special Populations: Renal Function Impairment

Pharmacokinetics of linezolid are not altered in patients with renal insufficiency. Metabolites A and B may accumulate in patients with renal insufficiency; the significance of this accumulation is not known. Approximately 30% of a dose is eliminated in a 3-hour dialysis session.

Special Populations: Children

Cmax and Vd are similar regardless of age in children. Weight-based clearance (Cl) varies as a function of age. Weight-based Cl is most rapid in children >1 week to 11 years of age, resulting in lower AUC and shorter half-life compared with adults. By adolescence, mean Cl values approach those observed in the adult population. Preterm (<34 weeks gestational age) neonates <7 days of age may have lower clearance than full-term neonates <7 days of age and may require less frequent dosing.

Use: Labeled Indications

Enterococcal infections, vancomycin-resistant: Treatment of vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia.

Pneumonia:

Community-acquired: Treatment of community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only).

Hospital-acquired or healthcare-associated: Treatment of hospital-acquired or healthcare-associated pneumonia caused by S. aureus (methicillin-susceptible and -resistant isolates), or S. pneumoniae.

Skin and skin structure infections:

Complicated: Treatment of complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by S. aureus (methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae.

Uncomplicated: Treatment of uncomplicated skin and skin structure infections caused by S. aureus (methicillin-susceptible isolates) or S. pyogenes.

Limitations of use: Linezolid has not been studied in the treatment of decubitus ulcers. Linezolid is not indicated for treatment of gram-negative infections; if a concomitant gram-negative pathogen is documented or suspected, initiate specific therapy immediately.

Use: Unlabeled

Treatment of brain abscess, subdural empyema, spinal epidural abscess (S. aureus [methicillin-resistant]), meningitis (S. aureus [methicillin-resistant]), osteomyelitis (S. aureus [methicillin-resistant]), prosthetic joint infection, septic arthritis (S. aureus [methicillin-resistant]), septic thrombosis of cavernous or dural venous sinus (S. aureus [methicillin-resistant])

Contraindications

Hypersensitivity to linezolid or any component of the formulation; concurrent use or within 2 weeks of MAO inhibitors

Dosage

Usual dosage: Oral, IV:

Infants and Children ≤11 years: 10 mg/kg every 8 hours (maximum: 600 mg/dose)

Children ≥12 years, Adolescents, and Adults: 600 mg every 12 hours

Indication-specific dosing:

Enterococcal infections, vancomycin-resistant, including concurrent bacteremia: Oral, IV:

Infants and Children ≤11 years: 10 mg/kg every 8 hours for 14 to 28 days

Children ≥12 years, Adolescents, and Adults: 600 mg every 12 hours for 14 to 28 days

Pneumonia:

Community-acquired (CAP):

Manufacturer's labeling (includes concurrent bacteremia): Oral, IV:

Infants and Children ≤11 years: 10 mg/kg/dose every 8 hours for 10 to 14 days

Children ≥12 years, Adolescents, and Adults: 600 mg every 12 hours for 10 to 14 days

Alternate dosing:

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): IV: 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): IV: 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): IV: 10 mg/kg/dose every 8 hours

Mild infection, step-down therapy (preferred): Oral: 10 mg/kg/dose every 8 hours

Infants and Children ≤11 years (Liu 2011): Oral, IV: S. aureus (methicillin-resistant): 10 mg/kg/dose every 8 hours for 7 to 21 days (maximum: 600 mg/dose)

Children ≥12 years and Adolescents (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): IV: 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): IV: 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): IV: 10 mg/kg/dose every 12 hours

Mild infection, step-down therapy (preferred): Oral: 10 mg/kg/dose every 12 hours

Children ≥12 years, Adolescents, and Adults: (Liu 2011): Oral, IV: S. aureus (methicillin-resistant): 600 mg every 12 hours for 7 to 21 days

Hospital-acquired or healthcare-associated: Oral, IV:

Manufacturer's labeling:

Infants and Children ≤11 years: 10 mg/kg every 8 hours for 10 to 14 days

Children ≥12 years, Adolescents, and Adults: 600 mg every 12 hours for 10 to 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 dosing (Liu 2011): S. aureus (methicillin-resistant):

Children ≤11 years: 10 mg/kg/dose every 8 hours for 7 to 21 days (maximum: 600 mg/dose)

Children ≥12 years, Adolescents, and Adults: 600 mg every 12 hours for 7 to 21 days

Skin and skin structure infections, complicated: Oral, IV:

Infants and Children ≤11 years: 10 mg/kg every 8 hours for 10 to 14 days

Children ≥12 years, Adolescents, and Adults: 600 mg every 12 hours for 10 to 14 days. Note: For diabetic foot infections, initial treatment duration is up to 4 weeks depending on severity of infection and response to therapy (Lipsky 2012).

Skin and skin structure infections, uncomplicated: Oral:

Infants and Children <5 years: 10 mg/kg every 8 hours for 10 to 14 days

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

Children ≥12 years and Adolescents: 600 mg every 12 hours for 10 to 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 to 14 days (Liu 2011; Stevens 2014). For diabetic foot infections, may extend treatment duration up to 4 weeks if slow to resolve (Lipsky 2012).

Brain abscess, subdural empyema, spinal epidural abscess (S. aureus [methicillin-resistant]) (off-label use) (Liu 2011): Oral, IV: Note: The manufacturer does not recommend the use of linezolid for empiric treatment of pediatric CNS infections since therapeutic linezolid concentrations are not consistently achieved or maintained in the CSF of patients with ventriculoperitoneal shunts.

Infants and Children ≤11 years: 10 mg/kg every 8 hours for 4 to 6 weeks (maximum: 600 mg/dose)

Children ≥12 years, Adolescents, and Adults: 600 mg every 12 hours for 4 to 6 weeks

Meningitis (S. aureus [methicillin-resistant]) (off-label use) (Liu 2011): Oral, IV:

Infants and Children ≤11 years: 10 mg/kg every 8 hours for 2 weeks (maximum: 600 mg/dose)

Children ≥12 years, Adolescents, and Adults: 600 mg every 12 hours for 2 weeks

Osteomyelitis (S. aureus [methicillin-resistant]) (off-label use) (Liu 2011): Oral, IV:

Infants and Children ≤11 years: 10 mg/kg every 8 hours for a minimum of 4 to 6 weeks (maximum: 600 mg/dose)

Children ≥12 years, Adolescents, and Adults: 600 mg every 12 hours for a minimum of 8 weeks (some experts combine with rifampin)

Prosthetic joint infection (off-label use): Adults: Oral, IV:

Enterococcus spp (penicillin-susceptible or -resistant) (alternative treatment): 600 mg every 12 hours for 4-6 weeks (consider adding an aminoglycoside) followed by an oral antibiotic suppressive regimen (Osmon 2013)

Staphylococci (oxacillin-sensitive or -resistant) (alternative treatment): 600 mg every 12 hours for 2 to 6 weeks used in combination with rifampin followed by oral antibiotic treatment and suppressive regimens (Osmon 2013)

Septic arthritis (S. aureus [methicillin-resistant]) (off-label use) (Liu 2011): Oral, IV:

Infants and Children ≤11 years: 10 mg/kg every 8 hours for 3 to 4 weeks (maximum: 600 mg/dose)

Children ≥12 years, Adolescents, and Adults: 600 mg every 12 hours for 3 to 4 weeks

Septic thrombosis of cavernous or dural venous sinus (S. aureus [methicillin-resistant]) (off-label use; Liu 2011): Oral, IV:

Children ≤11 years: 10 mg/kg every 8 hours for 4 to 6 weeks (maximum: 600 mg/dose)

Children ≥12 years, Adolescents, and Adults: 600 mg every 12 hours for 4 to 6 weeks

Elderly: Refer to adult dosing

Dosage adjustment in renal impairment:

Mild to severe impairment: No dosage adjustment necessary. The two primary metabolites may accumulate in patients with renal impairment but the clinical significance is unknown; use with caution.

End-stage renal disease (ESRD) on intermittent hemodialysis (IHD):

Manufacturer's labeling: Dialyzable (~30% removed during 3-hour dialysis session): Administer after hemodialysis on dialysis days.

Alternate dosing: 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). However, others have recommended no supplemental dose or dosage adjustment for patients on IHD (Heintz 2009; Trotman 2005).

Peritoneal dialysis: No supplemental dose or dosage adjustment needed (Heintz 2009; Trotman 2005).

Continuous renal replacement therapy (eg, CVVHD): No supplemental dose or dosage adjustment needed (Heintz 2009; Trotman 2005).

Dosage adjustment in hepatic impairment:

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied)

Reconstitution

Oral suspension: Refer to manufacturer’s product labeling for reconstitution instructions. Prior to administration mix gently by inverting bottle; do not shake.

Administration

IV: Administer intravenous infusion over 30 to 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: Administer without regard to meals.

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

Dietary Considerations

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.

Compatibility

Stable in D51/2 NS, D5W, LR, NS

Y-site administration: Incompatible with amphotericin B, chlorpromazine, diazepam, pentamidine, phenytoin

Storage

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

Oral suspension: Store at 25°C (77°F); following reconstitution store at room temperature and use suspension within 21 days. Protect from light.

Tablet: Store at 25°C (77°F). Protect from light and moisture.

Drug Interactions

Alcohol (Ethyl): May enhance the adverse/toxic effect of MAO Inhibitors. 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. Avoid combination

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Apraclonidine: MAO Inhibitors may enhance the adverse/toxic effect of Apraclonidine. MAO Inhibitors may increase the serum concentration of Apraclonidine. Avoid combination

AtoMOXetine: MAO Inhibitors may enhance the neurotoxic (central) effect of AtoMOXetine. Avoid combination

Atropine (Ophthalmic): MAO Inhibitors may enhance the hypertensive effect of Atropine (Ophthalmic). Avoid combination

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Betahistine: MAO Inhibitors may increase the serum concentration of Betahistine. Monitor therapy

Bezafibrate: MAO Inhibitors may enhance the adverse/toxic effect of Bezafibrate. Avoid combination

Blood Glucose Lowering Agents: MAO Inhibitors may enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Brimonidine (Ophthalmic): MAO Inhibitors may enhance the adverse/toxic effect of Brimonidine (Ophthalmic). MAO Inhibitors may increase the serum concentration of Brimonidine (Ophthalmic). Monitor therapy

Brimonidine (Topical): MAO Inhibitors may enhance the adverse/toxic effect of Brimonidine (Topical). MAO Inhibitors may increase the serum concentration of Brimonidine (Topical). Monitor therapy

Buprenorphine: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

BuPROPion: MAO Inhibitors may enhance the hypertensive effect of BuPROPion. Avoid combination

BusPIRone: May enhance the adverse/toxic effect of MAO Inhibitors. Specifically, blood pressure elevations been reported. Avoid combination

CarBAMazepine: May enhance the adverse/toxic effect of MAO Inhibitors. Management: Avoid concurrent use of carbamazepine during, or within 14 days of discontinuing, treatment with a monoamine oxidase inhibitor. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

COMT Inhibitors: May enhance the adverse/toxic effect of MAO Inhibitors. Consider therapy modification

Cyclobenzaprine: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

Cyproheptadine: MAO Inhibitors may enhance the anticholinergic effect of Cyproheptadine. Cyproheptadine may diminish the serotonergic effect of MAO Inhibitors. Avoid combination

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dexmethylphenidate: MAO Inhibitors may enhance the hypertensive effect of Dexmethylphenidate. Avoid combination

Dextromethorphan: MAO Inhibitors may enhance the serotonergic effect of Dextromethorphan. This may cause serotonin syndrome. Avoid combination

Diethylpropion: MAO Inhibitors may enhance the hypertensive effect of Diethylpropion. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Domperidone: MAO Inhibitors may enhance the adverse/toxic effect of Domperidone. MAO Inhibitors may diminish the therapeutic effect of Domperidone. Domperidone may diminish the therapeutic effect of MAO Inhibitors. Monitor therapy

EPINEPHrine (Oral Inhalation): MAO Inhibitors may enhance the hypertensive effect of EPINEPHrine (Oral Inhalation). Avoid combination

Epinephrine (Racemic): MAO Inhibitors may enhance the hypertensive effect of Epinephrine (Racemic). Monitor therapy

Hydrocodone: MAO Inhibitors may enhance the adverse/toxic effect of Hydrocodone. Management: Consider alternatives to this combination when possible. Consider therapy modification

HYDROmorphone: MAO Inhibitors may enhance the adverse/toxic effect of HYDROmorphone. Avoid combination

Isometheptene: MAO Inhibitors may enhance the adverse/toxic effect of Isometheptene. 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. Management: The concomitant use of nonselective monoamine oxidase inhibitors (MAOIs) and levodopa is contraindicated. Discontinue the nonselective MAOI at least two weeks prior to initiating levodopa. Monitor patients taking a selective MAOIs and levodopa. Consider therapy modification

Levonordefrin: MAO Inhibitors may enhance the hypertensive effect of Levonordefrin. Avoid combination

Lithium: MAO Inhibitors may enhance the adverse/toxic effect of Lithium. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

MAO Inhibitors: May enhance the adverse/toxic effect of Linezolid. Avoid combination

Maprotiline: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Meperidine: MAO Inhibitors may enhance the serotonergic effect of Meperidine. This may cause serotonin syndrome. Avoid combination

Mequitazine: MAO Inhibitors may enhance the anticholinergic effect of Mequitazine. Avoid combination

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

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. Consider therapy modification

Methyldopa: MAO Inhibitors may enhance the adverse/toxic effect of Methyldopa. Avoid combination

Methylene Blue: MAO Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Methylphenidate: MAO Inhibitors may enhance the hypertensive effect of Methylphenidate. 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. Monitor therapy

Mianserin: MAO Inhibitors may enhance the neurotoxic effect of Mianserin. Avoid combination

Mirtazapine: Linezolid may enhance the serotonergic effect of Mirtazapine. This could result in serotonin syndrome. Avoid combination

Moclobemide: MAO Inhibitors may enhance the adverse/toxic effect of Moclobemide. Avoid combination

Morphine (Liposomal): MAO Inhibitors may enhance the adverse/toxic effect of Morphine (Liposomal). Avoid combination

Morphine (Systemic): MAO Inhibitors may enhance the adverse/toxic effect of Morphine (Systemic). Avoid combination

Nefazodone: Linezolid may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Avoid combination

OxyCODONE: MAO Inhibitors may enhance the adverse/toxic effect of OxyCODONE. Management: Per Canadian labeling, use of oxycodone is contraindicated in patients who either are receiving MAO inhibitors or have used them within 14 days. Though not contraindicated in U.S. prescribing information, consider alternatives when possible. Consider therapy modification

Oxymorphone: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Pholcodine: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

Pizotifen: MAO Inhibitors may enhance the anticholinergic effect of Pizotifen. 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. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: Linezolid may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Avoid combination

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. Avoid combination

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Tedizolid. Consider therapy modification

Serotonin/Norepinephrine Reuptake Inhibitors: Linezolid may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Avoid combination

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. 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. Consider therapy modification

Tapentadol: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Tetrabenazine: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Tetrahydrozoline (Nasal): MAO Inhibitors may enhance the hypertensive effect of Tetrahydrozoline (Nasal). Avoid combination

Tianeptine: May enhance the adverse/toxic effect of MAO Inhibitors. 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. Consider therapy modification

TraZODone: Linezolid may enhance the serotonergic effect of TraZODone. This could result in serotonin syndrome. Avoid combination

Tricyclic Antidepressants: Linezolid may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Avoid combination

Tryptophan: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Adverse Reactions

Percentages as reported in adults; frequency similar in pediatric patients unless otherwise noted.

>10%:

Central nervous system: Headache (<1% to 11%)

Gastrointestinal: Diarrhea (3% to 11%)

Hematologic & oncologic: Decreased hemoglobin (1% to 16%), thrombocytopenia (<1% to 13%), leukopenia (children 1% to 12%; adults <1% to 2%)

1% to 10%:

Central nervous system: Insomnia (3%), dizziness (≤3%), vertigo (children 1%)

Dermatologic: Skin rash (1% to 2%), pruritus (children 1%)

Endocrine & metabolic: Increased amylase (<1% to 2%), increased lactate dehydrogenase (<1% to 2%)

Gastrointestinal: Nausea (1% to 10%), vomiting (1% to 9%), increased serum lipase (3% to 4%), constipation (2%), dysgeusia (1% to 2%), loose stools (children 1% to 2%), oral candidiasis (1% to 2%), abdominal pain (≤2%), tongue discoloration (≤1%), pancreatitis

Genitourinary: Vulvovaginal candidiasis (1% to 2%)

Hematologic & oncologic: Neutropenia (children 1% to 6%; adults ≤1%), anemia (children ≤6%; adults ≤2%), eosinophilia (children ≤2%)

Hepatic: Increased serum ALT (≤10%), increased serum bilirubin (children ≤6%; adults ≤1%), increased serum AST (adults 2% to 5%), increased serum alkaline phosphatase (<1% to 4%), abnormal hepatic function tests (≤2%)

Infection: Fungal infection (≤1% to 2%)

Renal: Increased blood urea nitrogen (≤2%), increased serum creatinine (<1% to 2%)

Miscellaneous: Fever (2%)

<1% (Limited to important or life-threatening): Anaphylaxis, angioedema, bullous skin disease, Clostridium difficile-associated diarrhea, convulsions, hypertension, hypoglycemia, lactic acidosis, optic neuropathy, pancytopenia, peripheral neuropathy, rhabdomyolysis, seizures, serotonin syndrome (with concurrent use of other serotonergic agents), Stevens-Johnson syndrome, vision loss

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 preexisting 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 in adults and children 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.

• Serotonin syndrome: Symptoms of agitation, confusion, hallucinations, hyper-reflexia, myoclonus, shivering, and tachycardia may occur with concomitant proserotonergic drugs, agents which reduce linezolid's metabolism, or in patients with carcinoid syndrome. Avoid use in such patients unless clinically appropriate and under close monitoring for signs/symptoms of serotonin syndrome or neuroleptic malignant syndrome-like reactions.

• 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. Do not use in the absence of close monitoring.

• Diabetes mellitus: Hypoglycemic episodes have been reported; use with caution and closely monitor glucose in diabetic patients. Dose reductions/discontinuation of concurrent hypoglycemic agents or discontinuation of linezolid may be required.

• Hypertension: Use with caution and closely monitor blood pressure in patients with uncontrolled hypertension; linezolid has not been studied in patients with this condition. Do not use 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. Do not use 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. Do not use 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:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: The manufacturer does not recommend the use of linezolid for empiric treatment of pediatric CNS infections since therapeutic linezolid concentrations are not consistently achieved or maintained in the CSF of patients with ventriculoperitoneal shunts. However, limited data in the form of case reports in pediatric and adult patients suggest that linezolid may be useful in treating gram-positive CNS infections that have failed to respond to other treatment options describing successful treatment of documented VRE and Staphylococcus aureus CNS and shunt infections in the literature (Cook 2005; da Silva 2007; Milstone 2007; Shaikh 2001; Villani 2002).

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

• Phenylalanine: Some products may contain 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).

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; in patients with renal impairment, monitor for hematopoietic (eg, anemia, leukopenia, thrombocytopenia) and neuropathic (eg, peripheral neuropathy) adverse events when administering for extended periods.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse effects were observed in some animal reproduction studies at doses that were also maternally toxic. Information related to linezolid use during pregnancy is limited.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dyspepsia. Have patient report immediately to prescriber signs of lactic acidosis, ecchymosis, hemorrhaging, vision changes, paresthesia, vaginal yeast infection, chills, pharyngitis, signs of pseudomembranous colitis (rare), or signs serotonin syndrome (ie, dizziness, severe headache, agitation, hallucinations, tachycardia, arrhythmia, flushing, tremors, hyperhidrosis, change in balance, severe nausea, significant diarrhea) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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