Flucytosin: Pyrimidine analog in combination therapy of systemic mycoses

Flucytosin (5 fluorocytosine, abbreviated 5 FC) is a synthetic antifungal agent from the class of pyrimidine analogues. It was approved in 1968 and is used today almost exclusively in combination with other antifungal agents, particularly amphotericin B, for the treatment of life-threatening systemic fungal infections. Known brand names are Ancotil and generics.

The most important indication is cryptococcal meningitis, especially in HIV-positive or otherwise immunosuppressed patients, where the combination of amphotericin B plus flucytosin as induction significantly improves outcomes. Because of rapid resistance development with monotherapy, flucytosin is practically never used alone.

Mechanism of action

Flucytosin is a selective antifungal agent because it is selectively taken up and activated in fungal cells. In the fungal cell, flucytosin is converted by the enzyme cytosine deaminase to 5 fluorouracil (5 FU). Cytosine deaminase is absent in mammalian cells, which explains the selectivity. Subsequently, 5 FU is further phosphorylated to 5 fluorouridine triphosphate, which is incorporated into mycotic RNA and disrupts protein synthesis. A parallel metabolic pathway leads to inhibition of thymidylate synthase and thus inhibition of DNA synthesis.

This dual effect on RNA and DNA synthesis leads to inhibition of fungal growth (Cryptococcus neoformans, Candida species, some other yeasts). Filamentous fungi such as Aspergillus are largely resistant. The effect is concentration and time dependent, fungistatic.

Pharmacokinetically, flucytosin is well absorbed orally (bioavailability approximately 80 percent), but the oral form is not commercially available in Germany, only the intravenous form. Half-life approximately 4 hours, elimination renal in unchanged form, which is why dose adjustment in renal insufficiency is essential. The substance penetrates well into cerebrospinal fluid (60 to 80 percent of plasma concentration), which is important for the treatment of cryptococcal meningitis.

Indications

• Cryptococcal meningitis in HIV-positive and immunosuppressed patients: in combination with amphotericin B as induction, then maintenance with fluconazole
• Systemic candidiasis: in combination with amphotericin B or echinocandins in severe cases
• Candida endocarditis and meningitis: as combination partner
• Chromoblastomycosis: oral use in some countries
• Aspergillosis and mucormycosis: not or only limited effectiveness

Dosage and administration

Standard intravenous dose: 100 to 150 mg/kg/day divided into four individual doses every 6 hours. Duration of therapy depends on indication and course, usually 1 to 6 weeks.

For cryptococcal meningitis: 100 mg/kg/day as induction over 2 weeks combined with amphotericin B liposomal or deoxycholate, then maintenance with fluconazole.

Renal insufficiency: mandatory dose adjustment based on creatinine clearance, as accumulation leads to bone marrow toxicity. Additional dose after dialysis during hemodialysis.

Therapeutic drug monitoring (TDM): Trough levels should be 25 to 50 mg/L, peak concentrations should remain below 100 mg/L. Excessively high levels lead to bone marrow suppression, excessively low levels lead to treatment failure and resistance development.

Adverse effects

Frequent: nausea, vomiting, diarrhea, abdominal pain, skin rash, elevation of liver transaminases, photosensitivity.

Serious: bone marrow suppression with neutropenia, thrombocytopenia and anemia (often dose-dependent and reversible); hepatotoxicity up to fulminant liver failure; nephrotoxicity (especially with accumulation); deterioration of function of inflamed intestinal mucosa, severe diarrhea and in individual cases colitis. Severe skin reactions such as Stevens Johnson syndrome are rare.

Important: bone marrow suppression is the most important toxicity and can become life-threatening. Close blood count monitoring is mandatory (at least twice per week), therapeutic drug monitoring should be performed if possible, especially in renal insufficiency or concurrent medication with other myelotoxic agents.

Drug interactions

• Amphotericin B: synergistic antifungal effect (clinically desired combination), but additive nephrotoxicity with risk of flucytosin accumulation and bone marrow suppression
• Other myelotoxic agents (cytostatics, linezolid, cotrimoxazole): additive bone marrow suppression
• Cytosine arabinoside: may antagonize effect of flucytosin
• Antacids: reduced absorption with oral form
• Other nephrotoxic agents: additive nephrotoxicity, thereby accumulation of flucytosin

Special precautions

Pregnancy and lactation: contraindicated. Flucytosin is teratogenic and mutagenic, especially in the first trimester. In life-threatening mycoses, risk-benefit assessment is performed by the interdisciplinary team.

Before therapy: blood count, liver transaminases, creatinine, electrolytes. With eGFR below 50 ml/min dose adjustment, with eGFR below 20 ml/min special caution.

Monitoring during therapy: blood count twice per week, liver transaminases weekly, creatinine daily in renal insufficiency or amphotericin B concurrent medication. Therapeutic drug monitoring trough level 25 to 50 mg/L.

Combination mandatory: flucytosin should practically never be used as monotherapy, as resistance develops rapidly. Combination with amphotericin B or fluconazole is standard.

You might also be interested in

• Amphotericin B, standard combination partner
• Fluconazole, maintenance therapy after cryptococcal meningitis
• Voriconazole, triazole for aspergillosis
• Caspofungin, echinocandin for systemic candidiasis
• Posaconazole, broad-spectrum triazole

Frequently asked questions

Sources

• Gelbe Liste, Flucytosin active substance profile
• WHO Guidelines on HIV opportunistic infections
• IDSA Guidelines Cryptococcosis and Candidiasis
• BfArM, Federal Institute for Drugs and Medical Devices