Cycloserine

💊 Key Principle: Antituberculous drugs must always be used in combination therapy — monotherapy rapidly selects for resistant Mycobacterium tuberculosis. Cycloserine is a second-line oral anti-TB drug reserved for use in multidrug-resistant tuberculosis (MDR-TB) and under specialist supervision. Always 🔗 check the BNF entry for dosing and safety guidance.

🧠 About

• Cycloserine is a broad-spectrum antibiotic that inhibits bacterial cell-wall synthesis.
• Structurally similar to the amino acid D-alanine and acts as a competitive inhibitor of enzymes in peptidoglycan assembly.
• Used primarily as part of MDR-TB regimens when first-line drugs (isoniazid, rifampicin) cannot be used.
• Highly lipophilic — crosses the blood–brain barrier and readily enters cerebrospinal fluid, accounting for both its utility and neurotoxicity.

⚙️ Mode of Action

• Inhibits peptidoglycan synthesis by blocking:
  • Alanine racemase (converts L-alanine → D-alanine).
  • D-alanine–D-alanine ligase (joins two D-alanines into a dipeptide used for cross-linking).
• This prevents bacterial cell-wall formation → cell lysis and death.
• Acts against Mycobacterium tuberculosis, Gram-positive and some Gram-negative organisms.
• Also inhibits GABA transaminase in the CNS → raised GABA levels → neurological and psychiatric toxicity.

💊 Indications & Dosing

• Active Pulmonary or Extrapulmonary Tuberculosis (as part of MDR-TB regimen):
  • Start with 250 mg twice daily for 2 weeks.
  • Titrate to 500 mg–1 g daily in two divided doses.
  • Do not exceed 1 g/day.
  • Adjust dose in the elderly or those with renal impairment (based on plasma concentration monitoring).
• Urinary Tract Infections (off-label, historical use): Active against *E. coli*, *Klebsiella*, and *Enterobacter*, but now rarely used due to CNS toxicity and resistance.

🧪 Pharmacology

• Class: Cyclic analogue of D-alanine; cell-wall synthesis inhibitor.
• Absorption: Good oral bioavailability.
• Distribution: Widely distributed; penetrates CSF and pleural fluid.
• Excretion: 70–90 % excreted unchanged in urine → accumulation in renal impairment.
• Half-life: 10 hours (prolonged if renal function reduced).

🤝 Interactions

• Alcohol increases neurotoxicity and seizure risk — avoid completely.
• Isoniazid co-administration increases CNS side-effects (both lower seizure threshold).
• Phenytoin levels may be raised due to metabolic inhibition.
• See BNF for further drug interaction details.

⚠️ Cautions

• Monitor renal function, serum drug levels (therapeutic range 20–35 mg/L), and mental state.
• Give pyridoxine (vitamin B₆) 100 mg/day to reduce CNS adverse effects.
• Avoid in those with history of depression, psychosis, or epilepsy.
• Discontinue if severe behavioural change or neurological symptoms develop.

⛔ Contraindications

• Epilepsy or history of seizures.
• Severe anxiety, depression, or psychosis.
• Severe renal insufficiency.
• Alcohol abuse — markedly increases CNS toxicity.
• Acute porphyria — may precipitate attacks.

💢 Side Effects

• CNS toxicity: headache, irritability, tremor, anxiety, depression, psychosis, seizures (dose-related).
• Peripheral neuropathy — prevent with pyridoxine.
• Gastrointestinal upset: nausea, vomiting, abdominal pain.
• Hepatotoxicity (rare), especially when combined with other TB drugs.

🧠 Clinical Pearls

• Cycloserine is invaluable in MDR-TB but should be reserved for specialist use with psychiatric screening and close biochemical monitoring.
• The CNS side-effects stem from its GABAergic interference — hence the nickname “psych-serine”.
• Therapeutic drug monitoring helps prevent toxicity, especially in those with renal dysfunction.
• Always combine with at least three other active anti-TB agents to prevent resistance.

📚 References

• BNF: Cycloserine
• WHO MDR-TB Guidelines (2023 update).
• British Thoracic Society MDR-TB Guidance (2022).
• UpToDate: “Treatment of multidrug-resistant tuberculosis in adults.”