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It is structurally related to the cytostatic fluorouracil and to floxuridine. It is available in oral and in some countries also in injectable form. A common brand name is Ancobon®. The drug is dispensed in capsules of 250 mg and 500 mg strength. The injectable form is diluted in 250ml saline solution to contain 2.5 grams totally (10mg per ml). The solution is physically incompatible with other drugs including amphotericin B.
Additional recommended knowledge
Mechanisms of action
Two major mechanisms of action have been elucidated, one is that the drug is intrafungally converted into the cytostatic flourouracil that undergoes further steps of activation and finally interacts as 5-fluorouridinetriphosphate with RNA biosynthesis and disturbs therefore the building of certain essential proteins. The other mechanism is the conversion into 5-flourodeoxyuridinemonophosphate which inhibits fungal DNA synthesis.
Spectrum of susceptible fungi and resistance
Flucytosine is active in vitro as well as in vivo against some strains of Candida and Cryptococcus. Limited studies demonstrate that flucytosine may be of value against infections with Sporothrix, Aspergillus, Cladosporium, Exophila, and Phialophora. Resistance is quite commonly seen as well in treatment naive patients and under current treatment with flucytosine. In different strains of Candida resistance has been noted to occur in 1 to 50% of all specimens obtained from patients.
Flucytosine is well absorbed (75 to 90%) from the gastrointestinal tract. Intake with meals slows the resorption, but does not decrease the amount resorbed. Following an oral dose of 2 grams peak serum levels are reached after approximately 6 hours. The time to peak level decreases with continued therapy. After 4 days peak levels are measured after 2 hours. The drug is eliminated renally. In normal patients flucytosine has reportedly a half-life of 2.5 to 6 hours. In patients with impaired renal function higher serum levels are seen and the drug tends to cumulate in these patients. The drug is mainly excreted unchanged in the urine (90% of an oral dose) and only traces are metabolized and excreted in the feces. Therapeutic serum levels range from 25 to 100mcg/ml. Serum levels in excess of 100mcg are associated with a higher incidence of side-effects. Periodic measurements of serum levels are recommended for all patients and are a must in patients with renal damage.
Symptoms and their severities are unknown, because flucytosine is used under close medical supervision, but expected to be an excess of the usually encountered side effects on the bone marrow, gastrointestinal tract, liver and kidney function. Vigorous hydration and hemodialysis may be helpful to remove the drug from the body. Hemodialysis is particular useful in patients with impaired renal function.
It is not known if flucytosine is a human carcinogen. The issue has been raised because traces of 5-fluorouracil, which is a known carcinogen, are found in the colon resulting from the metabolization of flucytosine.
Oral flucytosine is indicated for the treatment of serious infections caused by susceptible strains of Candida or Cryptococcus neoformans. It can also be used for the treatment of chronomycosis (chromoblastomycosis), if susceptible strains cause the infection. Flucytosine must not be used as a sole agent in life-threatening fungal infections due to relatively weak antifungal effects and fast development of resistance, but rather in combination with amphotericin B and/or azole antifungals such as fluconazole or itraconazole. Minor infections such as candidal cystitis may be treated with flucytosine alone. In some countries, treatment with slow intravenous infusions for no more than a week is also a therapeutic option, particular if the disease is life-threatening.
Contraindications and cautions
Special Patient Groups
Pregnancy and lactation
In animal models (rats), flucytosine has been found to be teratogenic. Sufficient human data does not exist. Pregnant women should be given flucytosine only if the potential benefits exceed the potential harm to the fetus.
It is not known if flucytosine is distributed in human breast milk. Given the potential risk to the child, the patient should not breastfeed during treatment with flucytosine.
The efficacy and safety in patients under 18 years of age has not been determined.
For details see Contraindications and Cautions. Flucytosine may increase the toxicity of amphotericin B and vice versa, although the combination may be life-saving and should be used whenever indicated (e.g., cryptococcal meningitis). The cytostatic cytarabine inhibits the antimycotic activity of flucytosine.
The recommended daily dose is 50 to 150mg per kilogram of bodyweight orally, divided in 4 equal doses every 6 hours. If problems exist to swallow a complete single dose, the dose may be given in several partial amounts over 15 minutes. The dose for intravenous infusions is 50mg per kg infused over 20 to 40 minutes every 6 hours. The duration of treatment depends on the clinical situation, but generally does not exceed 7 days.
Use in immunocompromised patients
Serious fungal infections often occur in immunocompromised (e.g. HIV-infected) patients. These patients benefit from combination therapy including flucytosine, but the incidence of side-effects of a combination therapy, particular with amphotericin B, may be higher than in immunocompetent patients.
In some countries, such as Switzerland, flucytosine has been licensed to treat cats, dogs and birds (in most cases together with amphotericin B) for the same indications as in humans.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Flucytosine". A list of authors is available in Wikipedia.|