Flucytosine

Antimetabolite antifungals (Flucytosine (5-FC) ) Flucytosine (5-FC) was originally investigated as an oncology drug, but it was found to be significantly more active against fungi than against human cancer cells.

It is used in combination with amphotericin B. - Never used alone due to resistance for the treatment of systemic mycoses and for meningitis caused by: Cryptococcus neoformans , Candida albicans.

Note: Amphotericin B increases cell permeability, allowing more 5-FC to penetrate the cell and leading to synergistic effects.

Mechanism of action :

5-FC enters the fungal cell via a cytosine specific permease, an enzyme not found in mammalian cells. *It is subsequently converted to a series of compounds, including 5-fluorouracil and 5- fluorodeoxyuridine 5′monophosphate, which interfere with both protein and DNA synthesis. *

Antifungal spectrum:5-FC is fungistatic. It is effective:Y

1. in combination with itraconazole for treating chromoblastomycosis (chronic skin and subcutaneous infections)
2. in combination with amphotericin B for treating candidiasis and cryptococcosis (potentially fatal fungal disease caused by Cryptococcus neoformans or Cryptococcus gattii).
3. for Candida urinary tract infections when fluconazole is not appropriate.

Resistance to (5-FC) may be due to :

Resistance is the primary reason that 5-FC is not used as a single antimycotic drug:

1. Decreased levels of any of the enzymes in the conversion of 5-FC to 5-fluorouracil (5-FU).
2. Increased synthesis of cytosine can develop during therapy.

Pharmacokinetics-

Well absorbed by the oral route. It distributes throughout the body water and penetrates well into the CSF. Excretion of both the parent drug and its minimal metabolites is by glomerular filtration and, The dose must be adjusted in patients with compromised renal function.

Adverse effects:Z

Conversion flucytosine to 5-FU may occur outside fungal cells, potentially via:

1. Gut microflora, and expose patients to side effects similar to those of this cytotoxic chemotherapy agent. 2
2. Bone marrow suppression is the primary adverse effect of concern, particularly in higher doses or during prolonged courses.
3. Hepatotoxicity is another reversible adverse effect to be cautious of.