CYCLOSERINE
DESCRIPTION:
Cyclorine (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
C3H6N2O2.
ACTIONS/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 mcgm/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 (REF. 1) of determining the
susceptibility of strains of mycobacteria. Cycloserine MICs for susceptible
strains are 25 mcgm/mL or lower.
INDICATIONS AND USAGE:
Cyclorine 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, Cyclorine should be administered in conjunction with
other effective chemotherapy and not as the sole therapeutic agent.
Cyclorine may be effective in the treatment of acute urinary tract infections
caused by susceptible strains of gram-positive and gram- negative bacteria,
especially Enterobacter sp. 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
Cyclorine 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 Cyclorine 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 Cyclorine is closely related to excessive blood levels (above 30
mcgm/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 Cyclorine 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 Cyclorine daily should be closely observed for such symptoms. The
value of pyridoxine in preventing CNS toxicity from Cyclorine has not been
proved.
Administration of Cyclorine and other antituberculosis drugs has been associated
in a few instances with vitamin B12 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 mcgm/mL.
DRUG INTERACTIONS: Concurrent administration of ethionamide has been reported to
potentiate neurotoxic side effects.
Alcohol and Cyclorine 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 Cyclorine can cause fetal harm when administered to a pregnant woman or
can affect reproduction capacity. Cyclorine 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 Cyclorine, a decision should be made to 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.
DRUG INTERACTIONS:
Concurrent administration of ethionamide has been reported to potentiate
neurotoxic side effects.
Alcohol and Cyclorine 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.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
Most adverse reactions occurring during therapy with Cyclorine involve the
nervous system or are manifestations of drug hypersensitivity. The following
side effects have been observed in patients receiving Cyclorine:
NERVOUS SYSTEM SYMPTOMS (which appear to be related to higher dosages of the
drug, ie, 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 Cyclorine 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 5,290 mg/kg.
TREATMENT: To obtain up-to-date information about the treatment of overdose, a
good resource is your certified Regional Poison Control Center. Telephone
numbers of certified poison control centers are listed in the Physicians' Desk
Reference (PDR). 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:
Cyclorine 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. (REF. 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.
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.
************************************************************************