Terizidone

Terizidone is a condensation product of two cycloserine molecules with terephthalaldehyde. It is hydrolysed in the body to cycloserine and has the same activity and toxicity. It is used in some countries in place of cycloserine for rifampicin-resistant and multidrug-resistant tuberculosis, and programmes usually treat the two as interchangeable.

Class. Cycloserine prodrug; second-line antituberculosis drug.

Mechanism. Active through cycloserine: inhibition of alanine racemase and D-alanine ligase.

Pharmacokinetics. Hydrolysed to cycloserine after absorption. Cycloserine levels, tissue penetration and renal elimination follow cycloserine. Peak cycloserine level 20 to 35 mg/L is the aim.

Rifampicin-resistant and multidrug-resistant tuberculosis (adults).

• 15 to 20 mg/kg daily; usual 600 to 900 mg daily; maximum 900 mg daily.
• Titration: start 300 mg daily and increase every 3 to 7 days to the target.
• Frequency: single bedtime dose or two divided doses.
• Loading dose: none. Maintenance dose: 600 to 900 mg daily.
• Duration: set by the regimen, often 18 to 20 months in longer regimens.

Children. Weight-based, about 15 to 20 mg/kg daily, maximum 900 mg.

Pyridoxine cover. Pyridoxine 50 mg for every 300 mg of terizidone.

Main alternative. Cycloserine, where available.

Contraindications. Epilepsy, severe untreated depression, psychosis, severe anxiety, severe kidney impairment, alcohol dependence and hypersensitivity.

Serious adverse effects. Psychosis, suicidal ideation, depression, seizures, confusion and peripheral neuropathy.

Common adverse effects. Headache, dizziness, tremor, irritability, insomnia and drowsiness.

Interactions. Isoniazid and ethionamide add central nervous system toxicity; alcohol lowers the seizure threshold; phenytoin levels may rise.

Common prescribing errors. Full dose at start, omitting pyridoxine, dosing in kidney failure without reduction, and prescribing to patients with untreated psychiatric illness.

Special groups.

• Pregnancy: limited data; use only when no alternative.
• Breastfeeding: limited data; excretion in milk is expected because it is converted to cycloserine.
• Children: weight-based; monitor behaviour.
• Older adults: lower dose if clearance is poor.
• Kidney impairment: with CrCl under 30 mL/min, reduce to about 300 mg daily or 600 mg three times weekly with level monitoring.
• Liver impairment: no adjustment.

Formulations. Capsules 300 mg.

Administration. Take with or without food; larger dose at bedtime.

Baseline. Mental state, seizure history, creatinine and liver tests.

Monitoring. Mood and behaviour at every visit; creatinine monthly; cycloserine level where available.

Stopping thresholds. Stop for seizures, psychosis, suicidal ideation or intolerable neurotoxicity.

Referral and escalation. Psychiatry for mood or psychotic symptoms; manage within a drug-resistant tuberculosis programme.