Linezolid

ADMINISTRATION ROUTES:

PO, IV

ALTERNATIVE NAMES:

Zyvox, Linezolid Kabi

ICU INDICATIONS:

Treatment of infections cause by susceptible organisms Treatment of drug-resistant tuberculosis

Linezolid is only active against Gram-positive bacteria. It has particular use in enterococcal infections (including VRE) and complex infections caused by S.aureus (both MSSA & MRSA).

PRESENTATION AND ADMINISTRATION:

IV:

600 mg linezolid in 300 ml single-use infusion bag or bottle (2mg/ml).

Clear, colourless to yellow isotonic solution. Keep bags in foil wrap until ready to use.

Give 600 mg undiluted over 30 - 120 minutes. Do not add any other drugs or additives to the bag/bottle and do not administer in series connections with other drugs.

If using same IV line for sequential drug administration, flush infusion line prior to and following linezolid administration with a compatible solution. Linezolid is compatible with: 5% dextrose, 0.9% sodium chloride, Hartmann’s.

PO:

Tablets:

600 mg tablets (white, capsule-shaped). Give with or without food.

Oral suspension:

Zyvox 20 mg/ml dry white granules/powder for reconstitution.

• Add total 123 mL of distilled water in two portions
• Add first half of water then shake vigorously to wet all powder
• Add remaining water and shake to obtain uniform suspension
• Following reconstitution, gently mix by inverting bottle 3 - 5 times; do not shake again
• Store reconstituted suspension at room temperature & use within 21 days

Final volume will be 150 ml with a linezolid concentration of 20 mg/ml. A 600 mg dose is provided by 30 ml of reconstituted suspension.

DOSAGE:

IV:

Adults:

600 mg IV or PO BD

DOSAGE IN RENAL FAILURE AND RENAL REPLACEMENT THERAPY:

Although no dose adjustment in renal impairment is suggested by the manufacturer, there is an increased risk of toxicity (thrombocytopenia) in patients with renal impairment.

Dose in renal impairment

Dose in renal replacement therapy

DOSAGE IN PAEDIATRICS:

Neonates to < 12 years old:

10 mg/kg IV or PO TDS

Children ≥ 12 years old:

600 mg IV or PO BD

CLINICAL PHARMACOLOGY:

Linezolid is an oxazolidinone antibiotic which disrupts bacterial protein synthesis by binding to the 50S ribosomal subunit. It only has activity against Gram-positive bacteria with no clinical activity against Gram-negative organisms. It is bacteriostatic against enterococci and staphylococci, and bactericidal against most strains of streptococci.

Aerobes, Gram-Positive:

• Enterococcus faecalis (including vancomycin-resistant isolates)
• Enterococcus faecium
• Staphylococcus aureus (MRSA and MSSA)
• Staphylococcus epidermidis
• Staphylococcus haemolyticus
• Streptococcus agalactiae (group B streptococci)
• Streptococcus pneumonia
• Streptococcus pyogenes (group A beta-haemolytic streptococci)
• Viridans group streptococci (S mutans, S salivarius, S anginosus, S mitis, S sanguinis, S bovis)
• Corynebacterium
• Bacillus anthtracis (agent of anthrax)

Anaerobes, Gram-Positive:

• Listeria species

Other Microorganisms:

• Nocardia species
• Mycobacterium tuberculosis

CONTRAINDICATIONS:

1. Hypersensitivity to linezolid
2. Use of a monoamine oxidase inhibitor (MAOI) concurrently or within the previous two weeks

WARNINGS:

Monoamine Oxidase Inhibition

Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI). Due to inhibition of catecholamine breakdown, there is a risk of causing severe hypertension when MAOIs are administered in conjunction with vasopressors including ephedrine, metaraminol, adrenaline, noradrenaline and dopamine. Patients receiving linezolid in conjunction with these medications require close monitoring of their blood pressure. Linezolid is not recommended in patients with uncontrolled hypertension, phaeochromocytoma or uncontrolled thyrotoxicosis.

Potential Serotonergic Interactions

MAOIs also inhibit the breakdown of serotonin. For this reason linezolid is not recommended in patients with carcinoid syndrome or those taking any of the following medication:

• Selective Serotonin Reuptake Inhibitors (SSRIs) e.g. citalopram, fluoxetine, paroxetine, sertraline
• Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs) e.g. venlafaxine, tramadol
• Tricyclic antidepressants e.g. amitriptyline, imipramine,
• Triptans
• Pethidine
• Buspirone

PRECAUTIONS:

General:

Myelosuppression

Thrombocytopenia, anaemia, leucopenia and pancytopenia have been reported in patients receiving linezolid. The patient's full blood count should be monitored, particularly in those with pre-existing myelosuppression, renal or hepatic impairment, or who are receiving more than 10 days treatment with linezolid, or concurrent treatment with other myelosuppressive drugs.

Peripheral and optic neuropathy

Cases have been reported in patients treated with linezolid, primarily in those receiving treatment for longer than the maximum recommended duration of 28 days. Refer any patient with symptoms of new visual impairment on linezolid for ophthalmic evaluation.

Lactic acidosis

Lactic acidosis has been reported with use of linezolid and does not appear to be linked to duration of therapy. Serum lactate should be measured at least twice weekly in patients at increased risk for toxicity (renal or hepatic impairment and/or low body weight).

Laboratory Tests: Therapeutic drug monitoring of linezolid levels is not routine but may be considered in patients on prolonged therapy, with renal or liver impairment, body weight extremes or other reasons for pharmacokinetic variability. If required, a trough level should be taken 48 hours after initiation or dose change and immediately before the next dose.

Therapeutic linezolid level is 2 - 7 mg/L or 4 x MIC of organism. There is an increased risk of thrombocytopenia with trough level > 7 mg/L. Exposure thresholds for adverse effects other than thrombocytopenia are poorly defined.

Drug/Laboratory Test Interactions:

None

IMPORTANT DRUG INTERACTIONS IN ICU:

See WARNINGS above. Co-administration with rifampicin reduces available serum linezolid.

ADVERSE REACTIONS:

General: Lactic acidosis, SIADH

Cardiovascular: Hypertension (see MAO inhibition above)

Neurological: Seizures, serotonin syndrome (agitated delirium, hyperpyrexia, tremor, hyperreflexia), peripheral and optic neuropathy (limb weakness/numbness, visual disturbance), headache, dizziness

Haematological: Pancytopenia, thrombocytopenia, anaemia, leucopenia

Gastrointestinal: Antibiotic-associated pseudomembranous colitis, abdominal pain, diarrhoea, nausea and vomiting, LFT derangement, taste disturbance

Skin/dental: Rash, tooth discolouration