Cycloserine

Cycloserine is a D-alanine analogue antibiotic and a companion drug in regimens for rifampicin-resistant and multidrug-resistant tuberculosis. It is active against mycobacteria but has a narrow therapeutic index, and central nervous system toxicity limits its use. Pyridoxine is given routinely with it.

Class. Cycloserine; cell wall synthesis inhibitor (second-line antituberculosis).

Mechanism. Inhibits alanine racemase and D-alanine ligase, blocking peptidoglycan precursor synthesis.

Pharmacokinetics. Absorption over 70% orally, peak at 3 to 4 hours, half life about 10 hours, good penetration into cerebrospinal fluid and tissue. About 60 to 70% excreted unchanged in urine, so it accumulates in kidney failure. Therapeutic peak level 20 to 35 mg/L; toxicity is common over 35 mg/L.

Rifampicin-resistant and multidrug-resistant tuberculosis (adults). - Target 10 to 15 mg/kg daily; usual 500 to 750 mg daily, maximum 1000 mg daily. - Titration: start 250 mg once daily and increase by 250 mg every 3 to 7 days to 500 mg, then to 750 mg if tolerated. - Frequency: single bedtime dose or 250 to 500 mg twice daily. - Loading dose: none. Maintenance dose: 500 to 750 mg daily. - Duration: set by the regimen, often 18 to 20 months in longer regimens.

Children. 15 to 20 mg/kg daily, maximum 1000 mg daily.

Pyridoxine cover. Pyridoxine 50 mg for every 250 mg of cycloserine, to reduce neurological toxicity.

Main alternative. Terizidone, which is converted to cycloserine in the body.

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; cycloserine can raise phenytoin levels.

Common prescribing errors. Starting at full dose, omitting pyridoxine, prescribing to patients with untreated psychiatric illness or epilepsy, and not reducing the dose in kidney failure.

Special groups. - Pregnancy: limited data; use only when no alternative. - Breastfeeding: excreted in milk; infant monitoring needed. - Children: 15 to 20 mg/kg with monitoring for behavioural change. - Older adults: reduce dose if kidney clearance is poor. - Kidney impairment: with CrCl under 30 mL/min, give 250 mg daily or 500 mg three times weekly, with level monitoring. - Liver impairment: no adjustment.

Formulations. Capsules 250 mg.

Administration. Take with or without food; food reduces nausea. Give the larger dose at bedtime.

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

Monitoring. Mental state and mood at every visit; creatinine monthly; peak level 2 to 4 hours after the dose when available.

Stopping thresholds. Stop for seizures, psychosis, suicidal ideation, or peak level over 35 mg/L with symptoms.

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