Cycloserine

Description

Seromycin (Cycloserine Capsules, USP), 3-isoxazolidinone, 4-amino-, (R)- is a broad- spectrum antibiotic that is produced by a strain of Streptomyces orchidaceus and has also been synthesized. Cycloserine is a white to off-white powder that is soluble in water and stable in alkaline solution. It is rapidly destroyed at a neutral or acid pH.

Cycloserine has a pH between 5.5 and 6.5 in a solution containing 100 mg/mL. The molecular weight of cycloserine is 102.09, and it has an empirical formula of C 3 H 6 N 2 O 2 . The structural formula of cycloserine is as follows:

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Each capsule contains cycloserine, 250 mg (2.45 mmol); D & C Yellow No. 10, F D & C Blue No. 1, F D & C Red No. 3, F D & C Yellow No. 6, gelatin, iron oxide, talc, titanium dioxide, and other inactive ingredients.

Clinical Pharmacology

After oral administration, cycloserine is readily absorbed from the gastrointestinal tract, with peak blood levels occurring in 4 to 8 hours. Blood levels of 25 to 30 µg/mL can generally be maintained with the usual dosage of 250 mg twice a day, although the relationship of plasma levels to dosage is not always consistent. Concentrations in the cerebrospinal fluid, pleural fluid, fetal blood, and mother's milk approach those found in the serum. Detectable amounts are found in ascitic fluid, bile, sputum, amniotic fluid, and lung and lymph tissues. Approximately 65% of a single dose of cycloserine can be recovered in the urine within 72 hours after oral administration. The remaining 35% is apparently metabolized to unknown substances. The maximum excretion rate occurs 2 to 6 hours after administration, with 50% of the drug eliminated in 12 hours.

Microbiology

Cycloserine inhibits cell-wall synthesis in susceptible strains of gram-positive and gram-negative bacteria and in Mycobacterium tuberculosis .

Susceptibility Tests

Cycloserine clinical laboratory standard powder is available for both direct and indirect methods 1 of determining the susceptibility of strains of mycobacteria. Cycloserine MICs for susceptible strains are 25 µg/mL or lower.

Indications and Usage

Seromycin is indicated in the treatment of active pulmonary and extrapulmonary tuberculosis (including renal disease) when the causative organisms are susceptible to this drug and when treatment with the primary medications (streptomycin, isoniazid, rifampin, and ethambutol) has proved inadequate. Like all antituberculosis drugs, Seromycin should be administered in conjunction with other effective chemotherapy and not as the sole therapeutic agent.

Seromycin may be effective in the treatment of acute urinary tract infections caused by susceptible strains of gram-positive and gram-negative bacteria, especially Enterobacter spp. and Escherichia coli. It is generally no more and is usually less effective than other antimicrobial agents in the treatment of urinary tract infections caused by bacteria other than mycobacteria. Use of Seromycin in these infections should be considered only when more conventional therapy has failed and when the organism has been demonstrated to be susceptible to the drug.

Contraindications

Administration is contraindicated in patients with any of the following:

Hypersensitivity to cycloserine

Epilepsy

Depression, severe anxiety, or psychosis

Severe renal insufficiency

Excessive concurrent use of alcohol

Warnings

Administration of Seromycin should be discontinued or the dosage reduced if the patient develops allergic dermatitis or symptoms of CNS toxicity, such as convulsions, psychosis, somnolence, depression, confusion, hyperreflexia, headache, tremor, vertigo, paresis, or dysarthria.

The toxicity of Seromycin is closely related to excessive blood levels (above 30 µg/mL), as determined by high dosage or inadequate renal clearance. The ratio of toxic dose to effective dose in tuberculosis is small.

The risk of convulsions is increased in chronic alcoholics.

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

Precautions

General

Before treatment with Seromycin is initiated, cultures should be taken and the organism's susceptibility to the drug should be established. In tuberculous infections, the organism's susceptibility to the other antituberculosis agents in the regimen should also be demonstrated.

Anticonvulsant drugs or sedatives may be effective in controlling symptoms of CNS toxicity, such as convulsions, anxiety, and tremor. Patients receiving more than 500 mg of Seromycin daily should be closely observed for such symptoms. The value of pyridoxine in preventing CNS toxicity from Seromycin has not been proved.

Administration of Seromycin and other antituberculosis drugs has been associated in a few instances with vitamin B 12 and/or folic-acid deficiency, megaloblastic anemia, and sideroblastic anemia. If evidence of anemia develops during treatment, appropriate studies and therapy should be instituted.

Laboratory Tests

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

Drug Interactions

Concurrent administration of ethionamide has been reported to potentiate neurotoxic side effects.

Alcohol and Seromycin are incompatible, especially during a regimen calling for large doses of the latter. Alcohol increases the possibility and risk of epileptic episodes.

Concurrent administration of isoniazid may result in increased incidence of CNS effects, such as dizziness or drowsiness. Dosage adjustments may be necessary and patients should be monitored closely for signs of CNS toxicity.

Carcinogenesis, Mutagenicity, and Impairment of Fertility

Studies have not been performed to determine potential for carcinogenicity. The Ames test and unscheduled DNA repair test were negative. A study in 2 generations of rats showed no impairment of fertility relative to controls for the first mating but somewhat lower fertility in the second mating.

Pregnancy Category C

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 Seromycin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Seromycin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Because of the potential for serious adverse reactions in nursing infants from Seromycin, 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.

Usage in Pediatric Patients

Safety and effectiveness in pediatric patients have not been established.

Adverse Reactions

Most adverse reactions occurring during therapy with Seromycin involve the nervous system or are manifestations of drug hypersensitivity. The following side effects have been observed in patients receiving Seromycin:

Nervous system symptoms (which appear to be related to higher dosages of the drug, i.e., more than 500 mg daily)

Convulsions

Drowsiness and somnolence

Headache

Tremor

Dysarthria

Vertigo

Confusion and disorientation with loss of memory

Psychoses, possibly with suicidal tendencies

Character changes

Hyperirritability

Aggression

Paresis

Hyperreflexia

Paresthesia

Major and minor (localized) clonic seizures

Coma

Cardiovascular

Sudden development of congestive heart failure in patients receiving 1 to 1.5 g of Seromycin daily has been reported

Allergy (apparently not related to dosage)

Skin rash

Miscellaneous

Elevated serum transaminase, especially in patients with preexisting liver disease

Overdosage

Signs and Symptoms

Acute toxicity from cycloserine can occur if more than 1 g is ingested by an adult. Chronic toxicity from cycloserine is dose related and can occur if more than 500 mg is administered daily. Patients with renal impairment will accumulate cycloserine and may develop toxicity if the dosing regimen is not modified. Patients with severe renal impairment should not receive the drug. The central nervous system is the most common organ system involved with toxicity. Toxic effects may include headache, vertigo, confusion, drowsiness, hyperirritability, paresthesias, dysarthria, and psychosis. Following larger ingestions, paresis, convulsions, and coma often occur. Ethyl alcohol may increase the risk of seizures in patients receiving cycloserine.

The oral median lethal dose in mice is 5290 mg/kg.

Treatment

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Overdoses of cycloserine have been reported rarely. The following is provided to serve as a guide should such an overdose be encountered.

Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal.

In adults, many of the neurotoxic effects of cycloserine can be both treated and prevented with the administration of 200 to 300 mg of pyridoxine daily.

The use of hemodialysis has been shown to remove cycloserine from the bloodstream. This procedure should be reserved for patients with life-threatening toxicity that is unresponsive to less invasive therapy.

Dosage and Administration

Seromycin is effective orally and is currently administered only by this route. The usual dosage is 500 mg to 1 g daily in divided doses monitored by blood levels. 2 The initial adult dosage most frequently given is 250 mg twice daily at 12-hour intervals for the first 2 weeks. A daily dosage of 1 g should not be exceeded.

How Supplied

Seromycin is available as a 250 mg capsule with an opaque red cap and opaque gray body imprinted with "PU0012"and "F04" in edible black ink on both the cap and the body.

Bottles of 40 (No.12) NDC 0002-0604-40

Store at controlled room temperature, 20 ° to 25°C (68° to 77°F) [see USP].

References

  1. Kubica GP, Dye WE: Laboratory methods for clinical and public health -- mycobacteriology. US Department of Health, Education and Welfare, Public Health Service, 1967, pp 47-55, 66-70.
  2. Jones LR: Colorimetric determination of cycloserine, a new antibiotic. Anal Chem 1956;28:39.

Literature revised December 8, 2003

Eli Lilly and Company

Indianapolis, IN 46285, USA

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