Cycloserine

Cycloserine is an Antitubercular agent belonging to Broad-spectrum antibiotic/ Drug Resistant TB.

Cycloserine is used in the treatment as 2^nd line drug in Tuberculosis and Urinary tract infection.

It is readily and almost completely absorbed from the GI tract and get widely distributed into body tissues and fluids, including the CSF, placenta, and breast milk and undergoes Hepatic Metabolism.

It get excreted Via urine by glomerular filtration (as unchanged drug).

The Tmax of Cycloserine was within 3-4 hr.

Cycloserine shows common side effects like swelling, rapid weight gain, little or no urinating; · severe dizziness, spinning sensation, ringing or roaring

Cycloserine is available in the form of capsules.

Cycloserine is available in India, Germany, Canada, Italy.

Cycloserine is a cyclic polypeptide antimicrobial. It is administered as a mixture of Cycloserine IA and Cycloserine IB. The mechanism of action of Cycloserine is not well understood. Mycobacterial species that have become resistant to other agents are usually still sensitive to the action of Cycloserine. However, significant cross-resistance with viomycin, kanamycin, and neomycin occurs.

Cycloserine is used in the treatment of Tuberculosis and Urinary tract infection.

Cycloserine is approved for use in the following clinical indications

● Tuberculosis: Treatment of active pulmonary or extrapulmonary tuberculosis, in combination with other agents, when treatment with primary tuberculosis therapy has proved inadequate

● Urinary tract infection: May be effective in treatment of acute urinary tract infection caused by susceptible strains of gram-positive and gram-negative bacteria, especially Enterobacter spp. And Escherichia coli.

Cycloserine is available in various strengths as 250 mg.

Cycloserine is available in the form of injection.

• Dosage Adjustment in Kidney Patient

CrCl 50-80 mL/min: Administer at every 12-16hr

CrCl 10-49 mL/min: Administer at every 24-36hr

CrCl <10 mL/min: Administer at every 36-48hr

• Dosage Adjustment in Hepatic impairment Patient

No Dosage Adjustment is required

● Dosage Adjustment for Pediatric Patients

Active tuberculosis infection (excluding meningitis); treatment (second-line therapy):

• Note: Recommendations often change due to epidemiology (resistance) and emerging information; consult CDC and WHO for current recommendations for detailed information. Always use as part of a multidrug regimen . Concomitant pyridoxine is recommended to prevent cycloserine-induced neuropathy.
• Infants, Children, and Adolescents <15 years; weighing ≤40 kg: Oral: 15 to 20 mg/kg/day divided every 12 to 24 hours (if tolerability issues, may divide into 2 doses); maximum daily dose: 1,000 mg/day . Note: Some patients may be unable to tolerate recommended doses; experts suggest beginning with a low once daily dose and gradually increasing as tolerated; serum concentrations targeted at 25 to 30 mcg/mL have been suggested to minimize toxicity.
• Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: Oral: 10 to 15 mg/kg/day divided every 12 to 24 hours; usual dose 250 to 500 mg; maximum daily dose: 1,000 mg/day Note: Patients are often unable to tolerate the maximum dose divided twice daily (eg, in adults, 500 mg twice daily); therefore, experts suggest beginning with a low once daily dose and gradually increasing as tolerated; may consider therapeutic drug monitoring; serum concentrations targeted at 25 to 30 mcg/mL have been suggested to minimize toxicity
• Hypersensitivity. Patient w/ epilepsy, depression, severe anxiety, psychosis, or in those who misuse alcohol. Severe renal impairment.

● Administration of Cycloserine should be discontinued or the dosage reduced if the patient develops allergic dermatitis or symptoms of central nervous system toxicity such as convulsions, psychosis, somnolence, depression, confusion, hyper-reflexia, headache, tremor, vertigo, paresis or dysarthria.

● Toxicity is usually associated with blood levels of greater than 30mg/l, which may be the result of high dosage or inadequate renal clearance. The therapeutic index for this drug is low. The risk of convulsions is increased in chronic alcoholics.

● Patients should be monitored by haematological, renal excretion, blood level and liver function studies.

● Before treatment with cycloserine is begun, cultures should be taken and the susceptibility of the organism to the drug should be established. In tuberculous infections, sensitivity to the other anti-tuberculous agents in the regimen should also be demonstrated.

● Blood levels should be determined at least weekly for patients having reduced renal function, for individuals receiving a daily dosage of more than 500mg, and for those showing signs and symptoms suggestive of toxicity. The dosage should be adjusted to keep the blood level below 30mg/l.

● Anticonvulsant drugs or sedatives may be effective in controlling symptoms of central nervous system toxicity, such as convulsions, anxiety or tremor.

● Patients receiving more than 500mg of cycloserine daily should be closely observed for such symptoms. The value of pyridoxine in preventing CNS toxicity from cycloserine has not been proven.

● Administration of cycloserine and other anti-tuberculous drugs has been associated in a few instances with vitamin B₁₂ and/or folic acid deficiency, megaloblastic anaemia and sideroblastic anaemia. If evidence of anaemia develops during treatment, appropriate investigations and treatment should be carried out.

● Cycloserine has been associated with clinical exacerbations of porphyria and is not recommended in porphyric patients.

Cycloserine may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

It is not known if Cycloserine is present in breast milk.

Cycloserine is not significantly absorbed when administered orally, limiting any potential exposure via breast milk. The manufacturer recommends that caution be exercised when administering Cycloserine to breastfeeding women. Patients with multidrug-resistant tuberculosis and a sputum smear-positive test should avoid breastfeeding when possible.

Concentrations in the mother’s milk approach those found in the serum. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Concentrations in fetal blood approach those found in the serum. A study in 2 generations of rats given doses up to 100 mg/kg/day demonstrated no teratogenic effect in offspring. It is not known whether cycloserine can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. Cycloserine should be given to a pregnant woman only if clearly needed.

May be taken with or without food. May be taken after meals if GI discomfort occurs.

• Common Adverse effects

Drowsiness, somnolence, dizziness, headache, lethargy, depression, tremor, dysarthria, hyperreflexia, paraesthesia, nervousness, anxiety, vertigo, confusion, disorientation, loss of memory, paresis, major and minor clonic seizures

• Less Common Adverse effects:

Psychosis (possibly w/ suicidal tendencies), personality changes, hyperirritability, aggression; elevated serum aminotransferase levels, esp in patients w/ pre-existing liver disease.

• Rare Adverse effects

Hypersensitivity reactions including rash and photosensitivity; cardiac arrhythmias and sudden CHF.

Concomitant use w/ other anti-TB drugs may lead to vit B12 and/or folic acid deficiency, megaloblastic and sideroblastic anaemia. Increased incidence of CNS effects w/ ethionamide and isoniazid. May inhibit hepatic metabolism of phenytoin.

The common side effects of Cycloserine include the following swelling, rapid weight gain, little or no urinating; · severe dizziness, spinning sensation, ringing or roaring

Symptoms:

Headache, vertigo, confusion, drowsiness, hyper-irritability, paraesthesias, dysarthria and psychosis; paresis, convulsions and coma often occur in larger doses.

Management:

Symptomatic and supportive treatment. Activated charcoal may be more effective than emesis or lavage in reducing absorption. May give 200-300 mg of pyridoxine HCl daily to treat and prevent neurotoxic events. Haemodialysis may remove the drug from the bloodstream but should only be used for life-threatening toxicity.

Pharmacodynamic

Cycloserine, a broad-spectrum antibiotic, may be bactericidal or bacteriostatic, depending on its concentration at the site of infection and the susceptibility of the organism. Cycloserine works by blocking the formation of these peptidoglycans. By doing this the walls of the bacteria become weak and it results in the death of the bacteria

Pharmacokinetics

• Absorption: Readily and almost completely absorbed from the GI tract. Time to peak plasma concentration: 3-4 hr.
• Distribution: Widely distributed into body tissues and fluids, including the CSF, placenta, and breast milk.
• Metabolism: Hepatic.
• Excretion: Via urine by glomerular filtration (as unchanged drug). Plasma half-life: Approx 10 hr.

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Cycloserine -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Cycloserine
• https://europepmc.org/article/med/6988203