Dosing

Dosing: Adult
Usual dosage: Oral, I.V.: 600 mg every 12 hours
Indication-specific dosing:
VRE infections including concurrent bacteremia: Oral, I.V.: 600 mg every 12 hours for 14-28 days
MRSA infections:
Brain abscess, subdural empyema, spinal epidural abscess (unlabeled use; Liu, 2011): Oral, I.V.: 600 mg every 12 hours for 4-6 weeks
Meningitis (unlabeled use; Liu, 2011): Oral, I.V.: 600 mg every 12 hours for 2 weeks
Osteomyelitis (unlabeled use; Liu, 2011): Oral, I.V.: 600 mg every 12 hours for a minimum of 8 weeks (some experts combine with rifampin)
Pneumonia (healthcare associated or community acquired) (Liu, 2011): Oral, I.V.: 600 mg every 12 hours for 7-21 days
Septic arthritis (unlabeled use; Liu, 2011): Oral, I.V.: 600 mg every 12 hours for 3-4 weeks
Septic thrombosis of cavernous or dural venous sinus (unlabeled use; Liu, 2011): Oral, I.V.: 600 mg every 12 hours for 4-6 weeks
Nosocomial pneumonia, complicated skin and skin structure infections, community-acquired pneumonia including concurrent bacteremia: Oral, I.V.: 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).

Dosing: Pediatric
Usual dosage: Oral, I.V.:
General Dosage for Neonates <7 Days of Age
Oral or IV
10 mg/kg every 12 hours initially; consider 10 mg/kg every 8 hours in neonates with inadequate response to the lower dosage.1 By 7 days of age, all neonates should receive 10 mg/kg every 8 hours.1
Children ≥12 years: Refer to adult dosing.

Indication-specific dosing:
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
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: Refer to adult dosing.
MRSA infections:
Brain abscess, subdural empyema, spinal epidural abscess (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: Refer to adult dosing.
Meningitis (unlabeled use; Liu, 2011): Oral, I.V.: Children ≥12 years: Refer to adult dosing.
Osteomyelitis (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: Refer to adult dosing.
Pneumonia (healthcare associated or community acquired) (Liu, 2011): Oral, I.V.:
Children ≤11 years: 10 mg/kg every 8 hours for 7-21 days (maximum: 600 mg/dose)
Children ≥12 years: Refer to adult dosing.
Septic arthritis (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: Refer to adult dosing.
Septic thrombosis of cavernous or dural venous sinus (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
Children ≥12 years: Refer to adult dosing.

Dosing: Geriatric
Refer to adult dosing.

Dosing: Renal Impairment
No adjustment is recommended.

Dosing: 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.

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

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 (limited to important or life-threatening): Anaphylaxis, anemia, angioedema, bullous skin disorders, creatinine increased, C. difficile-related complications, dyspepsia, hypertension, lactic acidosis, localized abdominal pain, optic neuropathy, pancytopenia, peripheral neuropathy, pruritus, seizures, serotonin syndrome (with concurrent use of other serotonergic agents), Stevens-Johnson syndrome, tooth discoloration, vision loss

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 Drug

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.

Interactions

Drugs Metabolized by Cytochrome P450
Linezolid is not an inducer of cytochrome P450 (CYP450) in rats. In addition, linezolid does not inhibit the activities of clinically significant human CYP isoforms (e.g., 1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by these major enzymes. Concurrent administration of linezolid does not substantially alter the pharmacokinetic characteristics of (S)-warfarin, which is extensively metabolized by CYP2C9. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without changes in dosage regimen.
Antibiotics
Aztreonam: The pharmacokinetics of linezolid or aztreonam are not altered when administered together.
Gentamicin: The pharmacokinetics of linezolid or gentamicin are not altered when administered together.
Rifampin: The effect of rifampin on the pharmacokinetics of linezolid was evaluated in a study of 16 healthy adult males. Volunteers were administered oral linezolid 600 mg twice daily for 5 doses with and without rifampin 600 mg once daily for 8 days. Co-administration of rifampin with linezolid resulted in a 21% decrease in linezolid Cmax [90% CI, 15% – 27%] and a 32% decrease in linezolid AUC0–12 [90% CI, 27% – 37%]. The mechanism of this interaction is not fully understood and may be related to the induction of hepatic enzymes
Monoamine Oxidase Inhibition
Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.
Adrenergic Agents: A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content

Pregnancy

C
Pregnancy Implications
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.

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

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