Cycloserine

Usage

Cycloserine is an antibiotic primarily used in combination with other antituberculosis agents for the treatment of drug-resistant tuberculosis (TB) caused by Mycobacterium tuberculosis. It is a second-line agent, meaning it is used when first-line drugs are ineffective or cannot be tolerated. It may also be used for treating urinary tract infections (UTIs) caused by susceptible strains of Gram-positive and Gram-negative bacteria, especially when other antibiotics have failed.

• Pharmacological Classification: Antibiotic (second-line antituberculosis agent).

• Mechanism of Action: Cycloserine inhibits bacterial cell wall synthesis by interfering with the formation of peptidoglycans. It acts by inhibiting two enzymes, D-alanine racemase and D-alanyl-D-alanine synthetase, both of which are crucial for peptidoglycan synthesis. This weakens the bacterial cell wall, leading to cell lysis and bacterial death.

Alternate Names

• International Nonproprietary Name (INN): Cycloserine
• Brand name: Seromycin

How It Works

• Pharmacodynamics: Cycloserine exerts its antibacterial effect by disrupting bacterial cell wall synthesis, which is crucial for bacterial survival.

• Pharmacokinetics:

  • Absorption: Cycloserine is well-absorbed orally, reaching peak plasma concentrations within 3 to 4 hours. Food can reduce its absorption.
  • Distribution: It is widely distributed throughout the body, including the cerebrospinal fluid, which is important for treating tuberculosis meningitis.
  • Metabolism: Minimal hepatic metabolism.
  • Elimination: Primarily excreted unchanged in the urine. The elimination half-life is about 10 hours. Renal impairment significantly prolongs the half-life.

• Mode of Action: Cycloserine inhibits bacterial cell wall synthesis by competitively inhibiting D-alanine racemase and D-alanyl-D-alanine synthetase. These enzymes are involved in the early stages of peptidoglycan synthesis.

• Elimination Pathways: Predominantly renal excretion (70-80% as unchanged drug). Minimal hepatic metabolism.

Dosage

Standard Dosage

Adults:

• Tuberculosis: Initial dose is 250 mg orally every 12 hours for 14 days, followed by 500-1000 mg/day in divided doses (every 12 hours or once daily if tolerated) for 18-24 months, not to exceed 1000 mg/day. Therapeutic drug monitoring is recommended to maintain serum concentrations within the therapeutic range (15-40 mcg/mL). Pyridoxine (vitamin B6) supplementation is often given concurrently to prevent neurotoxic side effects.
• Urinary Tract Infection: Initial dose is 250 mg orally every 12 hours for 14 days, then 500-1000 mg/day in divided doses. Maximum daily dose is 1000 mg.

Children:

• Tuberculosis: 10-20 mg/kg/day orally in divided doses, up to a maximum of 1000 mg/day for 18-24 months. Dose adjustments based on therapeutic drug monitoring are recommended.
• Urinary Tract Infection: Similar to tuberculosis dosing, adjusted for weight.

Special Cases:

• Elderly Patients: Dosage should be reduced in elderly patients with renal impairment. Start with a low dose and monitor closely.
• Patients with Renal Impairment: Dose adjustment is crucial. Dosage frequency should be reduced based on creatinine clearance.
• Patients with Hepatic Dysfunction: No specific dosage adjustments are typically needed as cycloserine undergoes minimal hepatic metabolism.
• Patients with Comorbid Conditions: Use with extreme caution in patients with epilepsy, depression, anxiety, psychosis, or history of alcohol abuse due to the increased risk of central nervous system (CNS) toxicity.

Clinical Use Cases

Cycloserine is not typically used in settings like intubation, surgical procedures, mechanical ventilation, or the intensive care unit (ICU). Its primary role is in the long-term treatment of drug-resistant tuberculosis and, less commonly, UTIs. It’s not indicated for emergency situations like status epilepticus or cardiac arrest.

Dosage Adjustments

Dose adjustments may be needed in patients with renal dysfunction, based on their creatinine clearance.

Side Effects

Common Side Effects

• Headache
• Dizziness
• Drowsiness
• Tremor
• Mood changes (irritability, anxiety, depression)

Rare but Serious Side Effects

• Seizures
• Psychosis
• Suicidal ideation
• Peripheral neuropathy
• Heart failure
• Hypersensitivity reactions (rash, hepatitis)

Long-Term Effects

• Vitamin B6 deficiency
• Peripheral neuropathy

Adverse Drug Reactions (ADR)

• Psychosis
• Seizures
• Severe depression and suicidal thoughts
• Hypersensitivity reactions

Contraindications

• Hypersensitivity to cycloserine
• Epilepsy
• Severe depression, anxiety, or psychosis
• Severe renal insufficiency
• Alcohol abuse
• History of seizure disorder

Drug Interactions

• Alcohol: Increases the risk of seizures. Concurrent use is contraindicated.
• Isoniazid and Ethionamide: Increased risk of neurotoxicity.
• Other CNS Depressants (e.g., benzodiazepines, opioids): Additive CNS depression.
• Warfarin: Cycloserine may enhance the anticoagulant effect of warfarin. Monitor INR closely.
• Ethionamide: Increased risk of neurologic side effects.
• Hormonal Contraceptives: May decrease effectiveness of hormonal contraceptives.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C. Use only if potential benefit justifies the risk to the fetus.
• Breastfeeding: Cycloserine passes into breast milk. Monitor breastfed infants for potential adverse effects. Vitamin B6 supplementation may be necessary for both the mother and the infant.

Drug Profile Summary

• Mechanism of Action: Inhibits bacterial cell wall synthesis.
• Side Effects: CNS toxicity (headache, dizziness, drowsiness, tremor, mood changes, seizures, psychosis), hypersensitivity reactions.
• Contraindications: Epilepsy, severe renal insufficiency, alcohol abuse, severe psychiatric disorders.
• Drug Interactions: Alcohol, isoniazid, ethionamide, CNS depressants, warfarin.
• Pregnancy & Breastfeeding: Category C; use with caution. Monitor breastfed infants.
• Dosage: 250-1000 mg/day, adjusted based on condition, renal function, and patient response.
• Monitoring Parameters: Serum cycloserine levels, renal function, mental status, liver function tests.

Popular Combinations

Cycloserine is typically used in combination with other antituberculosis agents for the treatment of drug-resistant tuberculosis. Specific combinations and dosages are determined based on the patient’s resistance profile and according to established treatment guidelines. Always consult current guidelines.

Precautions

• General Precautions: Monitor renal function, mental status, and liver function tests. Assess for history of seizures, depression, anxiety, and psychosis.
• Pregnant Women: Avoid unless potential benefits outweigh the risks.
• Breastfeeding Mothers: Monitor infants for side effects. Supplement with vitamin B6.
• Children & Elderly: Adjust dosage based on weight and renal function, respectively.
• Lifestyle Considerations: Avoid alcohol.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Cycloserine?

A: The standard adult dosage for tuberculosis is 250 mg orally every 12 hours for 14 days, then 500-1000 mg/day in divided doses. Children: 10-20 mg/kg/day in divided doses, up to a maximum of 1000 mg/day. Renal impairment requires dose adjustments.

Q2: What are the major side effects of Cycloserine?

A: Common side effects include headache, dizziness, drowsiness, tremor, and mood changes. Serious side effects include seizures, psychosis, and suicidal ideation.

Q3: Is Cycloserine safe during pregnancy?

A: Cycloserine is a Pregnancy Category C drug, meaning its safety during pregnancy has not been established. Use only if the potential benefit justifies the risk to the fetus.

Q4: Can Cycloserine be used with other TB drugs?

A: Yes, cycloserine is typically used in combination with other antituberculosis drugs, especially in cases of drug-resistant TB. Always follow current guidelines.

Q5: What monitoring is required during Cycloserine treatment?

A: Monitor serum cycloserine levels, renal function, mental status, and liver function tests.

Q6: How does Cycloserine interact with alcohol?

A: Alcohol can increase the risk of seizures and other neurotoxic side effects. Alcohol consumption should be avoided during cycloserine treatment.

Q7: What are the contraindications for using Cycloserine?

A: Contraindications include epilepsy, severe depression, anxiety or psychosis, severe renal insufficiency, alcohol abuse, and hypersensitivity to cycloserine.

Q8: How is Cycloserine eliminated from the body?

A: It is primarily eliminated unchanged through renal excretion (70-80%).

Q9: Can Cycloserine be used to treat UTIs?

A: Yes, in some cases, cycloserine can be used to treat UTIs caused by susceptible bacteria, especially when other antibiotics have failed.

Q10: What should I do if a patient develops CNS toxicity while taking Cycloserine?

A: Discontinue or reduce the dosage of cycloserine and provide supportive care. Pyridoxine supplementation may be helpful. Consult a neurologist if necessary.