Linezolid for Drug Resistant Tuberculosis

Linezolid is an oxazolidinone antibacterial that is among the most active drugs against drug-resistant tuberculosis and is included in nearly all regimens for rifampicin-resistant disease. Its use is limited by myelosuppression and neuropathy, which depend on dose and duration. It is a reversible monoamine oxidase inhibitor and can cause serotonin toxicity.

Class. Oxazolidinone.

Mechanism. Binds the 23S rRNA of the 50S ribosomal subunit and blocks formation of the initiation complex. Resistance arises through rrl and rplC mutations.

Pharmacokinetics. Near-complete oral bioavailability, peak at 1 to 2 hours, half life about 5 hours. Oxidised to inactive metabolites, with about 30% excreted unchanged in urine. Metabolites accumulate in kidney failure.

Rifampicin-resistant tuberculosis and pre-extensively drug-resistant disease (adults). - 600 mg orally once daily. - Duration: 6 months in short regimens (with bedaquiline and pretomanid); longer, individualised courses in other regimens. - Loading dose: none. Maximum: 600 mg daily in current practice (older regimens used 1200 mg daily).

Dose reduction. - Reduce to 300 mg daily, or give 600 mg on alternate days, for anaemia, neutropenia, thrombocytopenia or early neuropathy. - Stop for severe toxicity.

Children (specialist). Weight-based; usually 10 mg/kg once daily from age 12 and 10 mg/kg twice daily under 12, maximum 600 mg a dose.

Main alternative. In patients who cannot take linezolid, regimens use other companion drugs; individualised specialist design.

Contraindications. Concurrent monoamine oxidase inhibitors, severe uncontrolled hypertension, phaeochromocytoma, carcinoid syndrome, and hypersensitivity.

Serious adverse effects. Anaemia, thrombocytopenia and neutropenia (usually after 2 weeks), peripheral and optic neuropathy (may be irreversible), lactic acidosis, serotonin syndrome, hypoglycaemia in diabetes, pancreatitis, and seizures.

Common adverse effects. Nausea, diarrhoea, headache, taste change and rash.

Interactions.

• Serotonergic drugs (SSRIs, SNRIs, tricyclics, tramadol, pethidine, buspirone, triptans, methylene blue, lithium).
• Adrenergic agents (pseudoephedrine, adrenaline, noradrenaline) raise blood pressure.
• Aged cheese, red wine and cured fish may cause hypertensive reactions.
• Additive neuropathy with ethambutol, isoniazid and ethionamide; rifampicin lowers linezolid levels.

Common prescribing errors. Continuing 1200 mg daily without need, not reducing with early cytopenia, and prescribing with antidepressants or opioids with serotonergic activity.

Special groups.

• Pregnancy: limited data; use only when needed.
• Breastfeeding: present in milk; monitor infant counts if unavoidable.
• Children: weight-based; monitor counts and vision.
• Older adults: higher myelosuppression risk.
• Kidney impairment: no dose change, but toxicity rises; check counts more often; give after dialysis.
• Liver impairment: no adjustment in mild to moderate; caution if severe.

Formulations. Tablets 600 mg and 300 mg, oral suspension and intravenous solution 2 mg/mL.

Administration. Once daily, with or without food. Intravenous dose is given over 30 to 120 minutes.

Baseline. Full blood count, liver tests, visual acuity and colour vision, neuropathy screen, glucose, drug review for serotonergic agents.

Monitoring. Full blood count weekly for the first month, then monthly; vision and neuropathy at each visit; lactate if unexplained nausea, vomiting or acidosis.

Stopping thresholds. Reduce or hold for clinically significant anaemia, neutrophils under 1.0 x 10^9/L or platelets under 50 x 10^9/L; stop for optic neuritis or progressive neuropathy.

Referral and escalation. Manage within a drug-resistant tuberculosis programme; ophthalmology for visual change.