Introduction to Cycloserine
Cycloserine is a broad-spectrum antibiotic primarily used as a second-line agent for treating active pulmonary and extrapulmonary tuberculosis (TB), especially multi-drug resistant strains (MDR-TB) [1.5.2, 1.5.4]. It is also occasionally used for urinary tract infections (UTIs) when other treatments have failed [1.5.1, 1.5.6]. Discovered in 1954 from a strain of Streptomyces, its mechanism of action is unique among antitubercular drugs [1.3.2, 1.5.4]. Cycloserine works by inhibiting bacterial cell wall synthesis. As a structural analog of the amino acid D-alanine, it competitively inhibits two essential enzymes, alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl), preventing the formation of peptidoglycan, a critical component of the bacterial cell wall [1.3.2, 1.3.5, 1.3.7]. This action is typically bacteriostatic but can be bactericidal depending on the drug concentration at the infection site [1.2.5]. Due to its potential for significant side effects, particularly affecting the central nervous system (CNS), its use is carefully managed [1.4.1].
Absolute Contraindications
Contraindications are specific situations in which a drug should not be used because it may be harmful to the patient. For cycloserine, these are primarily related to pre-existing neurological, psychiatric, and renal conditions.
The administration of cycloserine is strictly contraindicated in patients with the following conditions:
- Hypersensitivity: Patients with a known allergy or hypersensitivity to cycloserine or any of its components should not take the drug [1.2.2, 1.2.3].
- Epilepsy: Cycloserine can lower the seizure threshold and is therefore contraindicated in individuals with a history of epilepsy or seizure disorders [1.2.2, 1.2.4, 1.4.4].
- Severe Psychiatric Conditions: The drug should not be given to patients with a history of depression, severe anxiety, or psychosis. Cycloserine can cause or exacerbate these conditions, with potential for suicidal tendencies [1.2.2, 1.2.3, 1.2.4].
- Severe Renal Insufficiency: Cycloserine is primarily excreted by the kidneys. In patients with severe renal impairment, the drug can accumulate to toxic levels [1.2.2, 1.2.4]. Therefore, it is contraindicated in this population [1.2.3].
- Excessive Alcohol Use: Concurrent use of alcohol significantly increases the risk of seizures and is an absolute contraindication [1.2.2, 1.2.4, 1.4.2]. Patients with a history of chronic alcoholism are at a particularly high risk [1.4.2].
Precautions and High-Risk Populations
Beyond absolute contraindications, there are several situations where cycloserine must be used with extreme caution and close monitoring.
- Renal Impairment: For patients with mild to moderate renal dysfunction, dosage adjustments are necessary to prevent drug accumulation and toxicity. Regular monitoring of cycloserine blood levels is critical [1.2.4, 1.2.7]. Blood levels should be kept below 30 μg/mL to minimize toxicity [1.2.2, 1.2.4].
- Mental Health History: Even in the absence of severe psychosis or depression, patients with any history of mental illness should be monitored closely for CNS toxicity, which can manifest as confusion, disorientation, memory loss, hyperirritability, or changes in character [1.2.2, 1.5.2].
- Vitamin Deficiencies: Cycloserine therapy has been associated with vitamin B12 and folate deficiency, which can lead to megaloblastic or sideroblastic anemia. Caution is advised in patients with a predisposition to these deficiencies, such as the malnourished or elderly [1.2.2, 1.4.4, 1.5.2]. Co-administration of pyridoxine (vitamin B6) is often recommended to prevent or treat neurotoxic effects [1.2.5, 1.2.7].
- Drug Interactions: Concurrent administration with other drugs can increase the risk of adverse effects. Isoniazid and ethionamide can potentiate the neurotoxic side effects of cycloserine [1.2.4, 1.6.1]. The drug can also inhibit the metabolism of phenytoin, increasing its toxicity risk [1.2.5]. Patients should inform their healthcare provider of all medications they are taking [1.5.1].
Comparison of Cycloserine vs. Isoniazid Side Effects
| Feature | Cycloserine | Isoniazid |
|---|---|---|
| Primary Toxicity | Central Nervous System (CNS): confusion, psychosis, seizures, depression [1.2.2, 1.2.4] | Liver (Hepatotoxicity), Peripheral Neuropathy [1.6.1] |
| Contraindications | Epilepsy, severe anxiety/depression, psychosis, severe renal insufficiency, alcohol abuse [1.2.2, 1.2.4] | Acute liver disease, history of severe adverse reactions to isoniazid [1.6.1] |
| Common Side Effects | Drowsiness, headache, tremor, confusion, anxiety, dizziness [1.2.2, 1.4.2] | Numbness/tingling in extremities, elevated liver enzymes [1.2.5, 1.6.1] |
| Alcohol Interaction | Increases risk of seizures; contraindicated [1.2.4, 1.4.2] | Increases risk of hepatitis |
| Monitoring | Blood levels, renal function, mental status [1.2.4, 1.2.7] | Liver function tests (AST/ALT) [1.4.8] |
Conclusion
While cycloserine is a vital medication for treating drug-resistant tuberculosis, its use is limited by a narrow therapeutic window and a significant risk of toxicity, especially to the central nervous system. The primary contraindications include a history of hypersensitivity, epilepsy, severe psychiatric conditions like depression and psychosis, severe renal impairment, and excessive alcohol use [1.2.2, 1.2.4]. Careful patient selection, vigilant monitoring of blood levels and clinical symptoms, and proactive management of potential side effects are essential for safely administering this potent antibiotic. Discontinuation or dose reduction is necessary if patients develop allergic dermatitis or signs of CNS toxicity [1.2.4, 1.4.4].
For more information on the management of drug-resistant tuberculosis, consult the official guidelines from the World Health Organization (WHO).
