Flucytosine

Overview

Flucytosine (Ancobon®) is an antifungal agent used only in combination with other antifungal drugs for serious systemic fungal infections. Its use is confined almost entirely to cats, because dogs develop toxic skin reactions. It has excellent penetration into the central nervous system and achieves high concentrations in the urine, making it particularly useful in infections involving these sites.

Flucytosine must never be used as a single agent, because resistance develops rapidly – particularly in Cryptococcus infections. Flucytosine may be combined with amphotericin B. Combination with an azole antifungal is also described; however, recommendations regarding concurrent azole use are conflicting, with some guidance advising against this combination.

Mechanism of Action (MOA): Flucytosine enters fungal cells, where cytosine deaminase converts it to fluorouracil; this competes with uracil and interferes with pyrimidine metabolism, RNA and protein synthesis. Fungi lacking cytosine deaminase are not susceptible. Human cells have little or no enzyme activity, but the activity in dog and cat cells is unclear. It also disrupts DNA synthesis by inhibiting thymidylate formation, leading to impaired fungal cell replication.

Indications

Flucytosine is used for serious systemic fungal infections and must be given as part of combination antifungal therapy to improve efficacy and limit resistance; in practice its use is largely confined to cats, because dogs develop severe skin reactions.

• Cryptococcosis: Commonly used in combination with amphotericin B or azole antifungals, especially in cases involving the central nervous system due to excellent CNS penetration.
• Candidiasis: Used as part of combination therapy for systemic and urinary yeast infections such as candidiasis; high urinary concentrations are attainable, which makes it useful when the urinary tract is involved. Candidiasis has its own rows in the cat dose table.
• Aspergillosis: Flucytosine has been used adjunctively with other antifungal agents for aspergillosis with central nervous system involvement; in-vitro synergy with amphotericin B has been demonstrated against Aspergillus.
• Histoplasmosis (central nervous system involvement): Flucytosine has also been used with amphotericin B, as part of rifampin-containing treatment, for histoplasmosis with central nervous system involvement.
• Chromomycosis (chromoblastomycosis): Some systemic or subcutaneous infections may respond when used in combination therapy.

Dosage (Reference)

Dog

In dogs, flucytosine is generally not recommended due to the risk of severe cutaneous and mucocutaneous drug reactions. If used, it must be administered with extreme caution and always in combination with another antifungal agent.

Cat

In cats, flucytosine is used as part of combination antifungal therapy for systemic fungal infections, and several alternative regimens are described for cryptococcosis.

Warnings & Precautions

Flucytosine therapy requires careful patient selection and close monitoring, given its potential for serious toxicity involving the bone marrow, skin, kidneys and liver.

• Contraindication: Avoid use in patients with known hypersensitivity to flucytosine.
• Use in dogs: Extreme caution is required, as severe cutaneous or mucocutaneous drug reactions may develop within 10–20 days (and up to 6 weeks). Lesions may affect the nasal planum, lips, eyelids and scrotum, with the scrotum and nasal planum reported as primary sites.
• Renal impairment: Use with extreme caution; reduced clearance can lead to drug accumulation and toxicity. Adjust the dose or the dosing interval to keep the peak serum concentration below 100 micrograms/mL; one published approach is to divide the dose by the serum creatinine value once azotaemia develops, and haematological, renal and hepatic parameters should be monitored throughout.
• Myelosuppression risk: Use cautiously in patients with preexisting hematologic disease or those receiving other bone marrow–suppressive drugs.
• Hepatic disease: Use cautiously with appropriate monitoring due to potential for increased liver enzymes.
• Combination therapy required: Should not be used as a single agent due to rapid development of resistance; always combine with another antifungal.
• Drug confusion risk: Do not confuse flucytosine with fluorouracil. Fluorouracil causes a severe, potentially fatal neurotoxicity in cats and must not be given to them in any form – and the cat is the species in which flucytosine is mainly used.
• Pregnancy: Flucytosine crosses the placenta and has caused teratogenic effects in rats, though not in rabbits or mice; it may be teratogenic. Use it in pregnant animals only when the benefit of treatment outweighs the risk to the offspring.
• Nursing: It is not known whether flucytosine is excreted in milk. Because of the potential for serious adverse reactions in nursing offspring, consider using a milk replacer.
• Handling: Pregnant women should take precautions when handling this medication; it has caused birth defects in laboratory animals.

Drug Interactions

Interactions with flucytosine relate to altered absorption, additive toxicity such as bone marrow suppression, and changes in renal function that alter clearance. Those listed below have been reported or are theoretical in humans or animals; none has been specifically reported in animals.

• Antacids (aluminum- or magnesium-containing): May delay absorption of flucytosine.
• Amphotericin B: Flucytosine and amphotericin B have synergistic antifungal activity. Although this combination may permit lower doses, nephrotoxicity remains a concern. Amphotericin B–induced renal dysfunction can reduce flucytosine elimination and lead to accumulation; monitor renal function and adjust the flucytosine dose if necessary.
• Cytarabine: May reduce antifungal efficacy due to competition at the site of action.
• Myelosuppressive drugs (e.g., azathioprine, chloramphenicol, antineoplastics): Antineoplastics, azathioprine, chloramphenicol and methimazole may cause additive myelosuppression.
• Zidovudine: Increased risk of neutropenia.

Side Effects & Overdose

Side Effects

The most commonly reported adverse effects include gastrointestinal disturbances and hematologic abnormalities, particularly anemia and thrombocytopenia. Toxicity may occur when serum concentrations exceed 100 micrograms/mL.

• Gastrointestinal effects: Inappetence, vomiting, and diarrhea are the most frequently observed adverse effects.
• Myelosuppression (dose-dependent): May result in anemia, leukopenia, or thrombocytopenia.
• Oral ulceration: Can develop during treatment.
• Increased hepatic enzymes: Increased liver enzymes and hepatic toxicity may occur.
• Cutaneous reactions (dogs): Severe mucocutaneous eruptions with ulceration, crusting, exudation and depigmentation may occur, primarily seen on the scrotum and nasal planum. Lesions should resolve within 2 to 3 weeks of stopping treatment, and were less severe where the drug was discontinued immediately.
• CNS effects (cats): Aberrant behaviour and seizures have been reported in a cat with no concurrent central nervous system infection.
• Severe skin reactions in cats: Toxic epidermal necrolysis has been reported anecdotally in cats treated with flucytosine, so drug eruptions are not confined to dogs.
• Kidney effects: Renal toxicity may occur. Because flucytosine accumulates in patients with renal insufficiency, side effects may be more likely to develop in cats concurrently treated with amphotericin B.

Overdose

Limited information on the acute toxicity of flucytosine is available.

• Enhanced toxicity: Prolonged serum concentrations above 100 micrograms/mL may be associated with an increased incidence of toxicity.
• Management: A substantial overdose should be handled with gut emptying, activated charcoal and a cathartic, unless one of these is contraindicated.
• Supportive care: Monitor renal function, CBC, and hepatic parameters closely.
• Dialysis: Flucytosine can be removed by dialysis.
• Poison control: Where an overdose has occurred or is suspected, consult a 24-hour poison control centre that provides veterinary-specific advice.

Key Notes

Practical clinical insights for the safe and effective use of flucytosine, which in small animals is used almost entirely in cats:

• Excellent tissue penetration: Cerebrospinal fluid concentrations may reach 60% to 100% of serum concentrations, and high urinary concentrations are attainable – which is what makes flucytosine useful in central nervous system and urinary fungal infections.
• Rapid oral absorption: Flucytosine is well absorbed orally. Food slows the rate, but not the extent, of absorption; if vomiting occurs, give it with food or a small treat.
• Renal elimination: Excreted largely unchanged in urine; dose adjustments may be necessary in patients with reduced renal function.
• Low protein binding: Flucytosine is widely distributed and only about 2% to 4% is protein bound. In healthy humans, the volume of distribution is approximately 0.7 L/kg.
• Short plasma half-life with prolonged effect: The elimination half-life is approximately 2.7 hours in dogs. In humans it is approximately 3 to 6 hours with normal renal function and may be significantly prolonged with renal dysfunction.
• Monitoring requirements: Check renal function at least twice weekly while amphotericin B is being given as well, a complete blood count with platelets, and hepatic enzymes at least monthly.
• Owner-reportable signs: Tell owners to report abnormal bleeding or bruising promptly, as these may indicate haematologic toxicity.
• Antigen titre monitoring: For cryptococcosis, monitor capsular antigen titres every 1 to 2 months during treatment and after discontinuation; ideally treat until the titre reaches zero, which may take more than 2 years.
• Storage: Store the capsules in a tight, light-resistant container at about 25°C, with brief excursions between 15°C and 30°C permitted. Flucytosine may decompose to fluorouracil if stored warmer than this – and cats develop a severe, potentially fatal neurotoxicity when given fluorouracil.
• Compounded oral liquid: A 10 mg/mL oral suspension can be compounded from the capsules and retains more than 95% of its potency for 60 days, whether refrigerated or kept at room temperature – useful when a capsule is too large a dose unit for a cat.
• Laboratory interference: Flucytosine may cause falsely elevated serum creatinine results when creatinine is measured with an Ektachem® analyser; interpret an unexpected increase with this assay limitation in mind.
• Availability: There is no veterinary-licensed flucytosine product; human capsules are used, and in some markets tablets are obtainable only through special-order manufacturers or specialist importers. Confirm supply before starting a course that may run for months.