Linezolid

Linezolid is an oxazolidinone with oral and IV forms of equal strength, active against MRSA, vancomycin-resistant enterococci, penicillin-resistant pneumococci and Mycobacterium tuberculosis. It is a core drug in drug-resistant tuberculosis regimens. Myelosuppression and neuropathy appear with courses over 2 weeks.

Classification. Oxazolidinone.

Mechanism. Binds the 23S rRNA of the 50S ribosomal subunit and blocks formation of the initiation complex; bacteriostatic against staphylococci and enterococci, bactericidal against some streptococci. It is also a weak, reversible, non-selective monoamine oxidase inhibitor.

Spectrum. MRSA, MSSA, coagulase-negative staphylococci, vancomycin-resistant enterococci, streptococci including penicillin-resistant pneumococci, Nocardia, Mycobacterium tuberculosis (including multidrug-resistant strains) and nontuberculous mycobacteria. Not active against Enterobacterales or Pseudomonas.

Pharmacokinetics. Oral bioavailability about 100%. Half-life 5 to 7 hours. Protein binding about 31%. Excellent tissue and lung penetration; CSF levels about 70% of serum. Two thirds oxidised to inactive metabolites that accumulate in renal failure.

Maximum 1200 mg daily (600 mg every 12 hours); most courses 14 days or less.

Adults, oral or IV.

• Hospital-acquired and community-acquired pneumonia, complicated skin and soft tissue infection, MRSA infection: 600 mg every 12 hours for 10 to 14 days.
• Vancomycin-resistant enterococcal infection: 600 mg every 12 hours for 14 to 28 days.
• Bone and joint infection (specialist): 600 mg every 12 hours; prolonged courses carry high toxicity risk, and 300 to 600 mg once daily after 2 weeks is sometimes used with monitoring.
• Drug-resistant tuberculosis: 600 mg once daily (reduced to 300 mg once daily after the first 1 to 2 months, depending on tolerance) as part of a multidrug regimen under specialist direction.
• Nocardia infection (alternative): 600 mg every 12 hours as part of a multidrug regimen.

Children. Under 12 years: 10 mg/kg every 8 hours (maximum 600 mg a dose), and 10 mg/kg every 12 hours for infants under 7 days and preterm infants under 34 weeks, moving to every 8 hours after 7 days. 12 years and over: adult dose. Drug-resistant tuberculosis: 10 mg/kg once daily under 12 years (maximum 600 mg), 600 mg once daily at 12 years and over, with the same dose reduction.

Alternatives. Vancomycin, daptomycin, tedizolid, trimethoprim sulfamethoxazole, clindamycin, doxycycline.

Contraindications. Concurrent monoamine oxidase inhibitors (stop 2 weeks before); hypersensitivity; uncontrolled hypertension, phaeochromocytoma, thyrotoxicosis, carcinoid, or concurrent serotonergic drugs unless closely monitored.

Adverse effects. Diarrhoea, nausea, headache, taste change, candidiasis. Serious: myelosuppression (thrombocytopenia, anaemia, neutropenia: dose and duration related, usually after 10 to 14 days), peripheral and optic neuropathy (prolonged use), lactic acidosis, serotonin syndrome, hypoglycaemia in diabetes, hypertension with tyramine-rich food, seizures, Clostridioides difficile infection.

Interactions. - Serotonergic drugs (selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, tricyclics, tramadol, pethidine, triptans, buspirone): risk of serotonin syndrome. - Adrenergic agents (pseudoephedrine, dopamine, adrenaline, salbutamol at high dose): pressor effect. - Rifampicin (lowers linezolid levels by about a third), insulin and oral antidiabetic drugs (hypoglycaemia). - Tyramine-rich food over 100 mg a meal (mature cheese, fermented soya, tap beer).

Common prescribing errors. Prolonged use without blood counts, combining with a serotonergic antidepressant, giving it in unstable renal failure without monitoring, and missing visual symptoms.

Special groups.

• Pregnancy: avoid unless no alternative (limited data); used in drug-resistant tuberculosis when needed.
• Breastfeeding: avoid; monitor the infant if used.
• Older adults: higher risk of cytopenia; monitor weekly.
• Kidney impairment: no dose adjustment, but metabolites accumulate and thrombocytopenia is more frequent; monitor counts closely.
• Haemodialysis: give after the session.
• Liver impairment: no adjustment.
• Region: affordable generics are widely used in drug-resistant tuberculosis programmes in East Africa; blood count monitoring is the practical limit.

Preparation. Oral with or without food. IV: 600 mg (300 mL of ready solution) infused over 30 to 120 minutes; do not mix with other drugs and avoid prolonged light exposure.

Baseline and monitoring. - Baseline: full blood count, medication review for serotonergic drugs and monoamine oxidase inhibitors, vision check, glucose in diabetes, blood pressure. - During treatment: full blood count weekly for the first 2 weeks then every 2 to 4 weeks; lactate if unexplained nausea, vomiting or acidosis; visual acuity and colour vision monthly in prolonged courses; neuropathy review.

Stop rules. Stop for platelets under 50 000 cells/microlitre (or a fall of 30% or more), severe anaemia or neutropenia, optic neuritis or visual loss, lactic acidosis, serotonin syndrome or severe neuropathy.

Referral and escalation. Specialist tuberculosis or infectious diseases input for all prolonged courses; ophthalmology for visual symptoms; haematology for persistent cytopenia.