Oxazolidinones

Oxazolidinones (linezolid, tedizolid, and contezolid in some regions; sutezolid and delpazolid are investigational for tuberculosis) are synthetic protein synthesis inhibitors with activity against resistant Gram-positive cocci including MRSA, vancomycin-resistant enterococci and penicillin-resistant pneumococci, and against Mycobacterium tuberculosis and Nocardia. Linezolid has near-complete oral bioavailability, which allows early oral switch.

Mechanism. Binding to the 23S rRNA of the 50S ribosomal subunit blocks formation of the initiation complex, a unique early site that explains the absence of cross-resistance with other classes. Activity is bacteriostatic against staphylococci and enterococci and bactericidal against most streptococci.

Pharmacokinetics. Linezolid: 100 percent oral bioavailability, half-life 5 hours, 30 percent protein-bound, wide tissue and CSF penetration, non-enzymatic oxidation to inactive metabolites with some accumulation in renal failure. Tedizolid: once daily, half-life 12 hours.

Resistance. 23S rRNA mutations, the cfr methyltransferase gene, optrA and poxtA; resistance is uncommon but increasing in enterococci and coagulase-negative staphylococci.

• Linezolid: the principal agent; marrow and neuropathy toxicity limit courses.
• Tedizolid: more potent and less myelosuppression or serotonergic effect; licensed for skin infection; limited availability.
• Contezolid: oral agent approved in China; fewer marrow effects reported.
• Tuberculosis candidates: sutezolid and delpazolid.

Adult regimens (normal renal function).

• Linezolid 600 mg orally or IV every 12 hours. Usual durations: skin infection 10 to 14 days; pneumonia 10 to 14 days; bone and joint infection longer, with close monitoring.
• MDR and rifampicin-resistant tuberculosis (all-oral regimens): linezolid 600 mg daily, with dose reduction to 300 mg daily if marrow or neuropathy toxicity occurs.
• Nocardiosis: 600 mg every 12 hours as part of combination therapy, then dose-reduce.
• Tedizolid 200 mg orally or IV once daily for 6 days (skin infection).
• Children: linezolid 10 mg/kg every 8 hours (maximum 600 mg each dose) under 12 years; 600 mg every 12 hours from 12 years.

Selection. MRSA pneumonia (alternative to vancomycin, with higher lung penetration), VRE infection, MRSA skin and bone infection when oral step-down is wanted, MDR tuberculosis, and when vancomycin is unsuitable because of renal risk. Not first line for MRSA bacteraemia or endocarditis, since it is bacteriostatic. Keep to 28 days or less where possible.

Contraindications. Concurrent monoamine oxidase inhibitors or use within 2 weeks; uncontrolled hypertension, phaeochromocytoma, carcinoid or thyrotoxicosis (unless monitored); concurrent serotonergic drugs without monitoring.

Serious effects.

• Myelosuppression, especially thrombocytopenia from days 10 to 14, more frequent in renal impairment, low baseline platelets and long courses.
• Peripheral and optic neuropathy (courses over 28 days; may be irreversible).
• Lactic acidosis; hypoglycaemia in diabetic patients on insulin or sulphonylureas.
• Serotonin syndrome with SSRIs, SNRIs, tricyclic antidepressants, pethidine, tramadol, triptans, buspirone, methylene blue.
• Tyramine-related hypertension with very high tyramine intake (large amounts of aged cheese, cured meats, soy sauces).

Monitoring.

• Full blood count at baseline and weekly (twice weekly with renal impairment or baseline anaemia or thrombocytopenia).
• Visual acuity and colour vision monthly for courses over 28 days, with prompt review for visual symptoms.
• Lactate if unexplained nausea, vomiting or acidosis.
• Where available, linezolid trough of 2 to 7 mg/L in prolonged therapy or renal impairment.

Special groups. Pregnancy: avoided unless benefits outweigh risk (including MDR tuberculosis). Breastfeeding: avoided or temporarily interrupted. Renal impairment: no dose change, but toxicity is more likely and level monitoring is helpful. Hepatic impairment: no adjustment. Region: oral linezolid is used within tuberculosis programmes in East Africa, and monitoring blood counts is a key practical limit.