What Does 5 Fluorocytosine Do? Unpacking Its Antifungal Action

October 11, 2025 •

4 min read

First synthesized in 1957, flucytosine—also known as 5-fluorocytosine (5-FC)—is an antifungal agent primarily used for serious infections. But what does 5 fluorocytosine do to combat these fungal pathogens, and what makes its mechanism so specific?

Quick Summary

5-fluorocytosine is an antifungal prodrug that inhibits fungal DNA and RNA synthesis by converting to 5-fluorouracil inside fungal cells, a process human cells lack.

Key Points

Fungal-Specific Action: 5-FC is a prodrug converted to its active, toxic form inside fungal cells by enzymes like cytosine deaminase, which human cells lack.
Dual Inhibitory Effect: Its active metabolite, 5-fluorouracil, blocks both DNA and RNA synthesis within fungal cells, halting their growth and replication.
Combination Therapy: Due to rapid resistance development, 5-FC is typically used in combination with other antifungals, most notably amphotericin B, for serious infections.
Treatment of Serious Infections: It is indicated for severe infections caused by susceptible strains of Candida and Cryptococcus, including meningitis and septicemia.
Renal Excretion: The drug is predominantly eliminated unchanged by the kidneys, necessitating careful dose monitoring and adjustment in patients with impaired renal function.
Potential Toxicity: Serious dose-dependent side effects can include bone marrow suppression (e.g., leukopenia, anemia) and hepatotoxicity.
Good CNS Penetration: 5-FC is highly water-soluble and achieves excellent concentrations in the cerebrospinal fluid, making it valuable for treating meningitis.

Mechanism of Action: The Fungal-Specific Attack

5-fluorocytosine (5-FC) is a pro-drug, meaning it is inactive until converted into its toxic form inside fungal cells, which possess specific enzymes for this conversion. This selective activation minimizes harm to human cells. The process involves:

Entry into Fungal Cells

5-FC enters fungal cells via the enzyme cytosine permease, which is not found in human cells.

Conversion to 5-Fluorouracil (5-FU)

Inside fungal cells, cytosine deaminase, another enzyme absent in human cells, converts 5-FC to the active metabolite 5-fluorouracil (5-FU). A small amount of this conversion may occur in the human gut due to bacteria, potentially causing some toxicity.

Disruption of RNA Synthesis

5-FU is further metabolized to 5-fluorouridine triphosphate (FUTP), which is incorporated into fungal RNA, leading to miscoding and impaired protein synthesis.

Inhibition of DNA Synthesis

5-FU is also converted to 5-fluorodeoxyuridine monophosphate (FdUMP), which inhibits thymidylate synthase. This enzyme is crucial for DNA synthesis, effectively halting fungal DNA production and repair.

Clinical Uses and Combination Therapy

Due to the rapid development of resistance, 5-FC is rarely used alone for serious fungal infections. It is typically combined with other antifungals, such as amphotericin B, for synergistic effects and to prevent resistance.

5-FC is primarily used for serious systemic infections caused by susceptible Candida and Cryptococcus strains. Conditions treated with combination therapy include:

Cryptococcal Meningitis: Often treated with amphotericin B and 5-FC, particularly in immunocompromised patients.
Systemic Candidiasis: Including bloodstream, heart, and urinary system infections.
Pulmonary Infections: Serious lung infections caused by Candida or Cryptococcus.

For less severe cases like uncomplicated Candida cystitis, monotherapy might be considered, especially if the strain is resistant to other drugs. 5-FC's excellent penetration into cerebrospinal fluid and urine makes it useful for CNS and urinary tract infections.

The Problem of Resistance

Rapid resistance development is a major limitation of 5-FC monotherapy. Fungi can develop resistance through mechanisms such as:

Decreased Uptake: Mutations affecting cytosine permease.
Defective Metabolism: Mutations in enzymes like cytosine deaminase (FCY1) or uracil phosphoribosyltransferase (FUR1).
Increased Pyrimidine Production: Fungi producing more normal pyrimidines to outcompete 5-FC metabolites.

Combination therapy with drugs like amphotericin B can help overcome these resistance mechanisms.

Comparing 5-Fluorocytosine and Amphotericin B

This table highlights the differences between 5-FC and amphotericin B, a common partner in combination therapy.


Feature	5-Fluorocytosine (5-FC)	Amphotericin B
Mechanism	Inhibits fungal DNA and RNA synthesis inside the fungal cell.	Binds to ergosterol in the fungal cell membrane, creating pores and leading to cell death.
Drug Class	Antimetabolite, fluorinated pyrimidine analogue.	Polyene macrolide.
Administration	Typically oral capsules, though IV formulations exist.	Historically intravenous infusion due to poor oral absorption.
Use as Monotherapy	Not recommended for serious infections due to rapid resistance; effective for minor infections like urinary candidiasis.	Effective as monotherapy but often combined to reduce toxicity and enhance efficacy.
Synergy	Synergistic with amphotericin B for improved efficacy against serious infections.	Synergistic with 5-FC, helping to facilitate its uptake into the fungal cell.
Primary Resistance	Relatively low initial resistance rates for some species, but resistance develops quickly during monotherapy.	Resistance rates vary but are generally lower than for 5-FC.
Toxicity Profile	Dose-dependent side effects include bone marrow suppression and hepatotoxicity; also gastrointestinal issues.	Associated with significant nephrotoxicity (kidney damage) and infusion-related reactions.
CNS Penetration	Achieves excellent concentrations in the cerebrospinal fluid (CSF).	Penetration into the CSF can be less reliable.

Pharmacokinetics and Side Effects

Pharmacokinetics

5-FC is well-absorbed orally, with 75%–90% bioavailability. It distributes well into body fluids, including CSF, and is primarily excreted unchanged by the kidneys. Renal impairment requires dose adjustment, and therapeutic drug monitoring is often used to manage levels.

Side Effects

Side effects can resemble those of the chemotherapy drug 5-FU due to some gut bacterial conversion. Serious dose-related toxicities include bone marrow suppression (anemia, leukopenia, thrombocytopenia) and hepatotoxicity (liver injury). Gastrointestinal issues like nausea, vomiting, and diarrhea are common. Neurological effects have also been reported. Monitoring blood counts and liver function is important, especially when combined with other potentially toxic drugs.

Conclusion

In summary, what does 5 fluorocytosine do? It acts as a selective antifungal prodrug that targets fungal metabolism. By converting to 5-fluorouracil inside fungal cells, it disrupts DNA and RNA synthesis, inhibiting growth. While rapid resistance prevents single use for severe infections, its synergy with antifungals like amphotericin B makes it crucial for treating serious Candida and Cryptococcus infections. Careful monitoring is necessary due to potential dose-related toxicities, particularly in patients with kidney issues. Understanding its mechanism is vital for optimal use.

For more detailed information on antifungal drugs and infectious diseases, consult a reliable medical resource like the National Institutes of Health.

Frequently Asked Questions

5-fluorocytosine (5-FC) is a prodrug that is absorbed by fungal cells and converted into the toxic antimetabolite 5-fluorouracil (5-FU) by the enzyme cytosine deaminase. 5-FU then blocks both DNA and RNA synthesis within the fungal cell, which stops the fungus from growing and kills it.

Using 5-fluorocytosine as a single agent can lead to rapid development of resistance in fungi. Combining it with another antifungal, most commonly amphotericin B, prevents resistance and creates a synergistic effect that enhances the overall antifungal activity.

Common side effects include gastrointestinal issues such as nausea, vomiting, and diarrhea. More serious side effects, which are dose-dependent, can include bone marrow suppression (leading to anemia or leukopenia), liver toxicity, and some neurological effects.

In most serious systemic infections, 5-fluorocytosine is not recommended as a standalone treatment due to the high risk of resistance developing rapidly. It may be used alone for minor, non-systemic infections, such as uncomplicated urinary candidiasis.

5-Fluorocytosine is a prodrug that is converted to 5-fluorouracil (5-FU) exclusively inside fungal cells by the enzyme cytosine deaminase, which human cells lack. In contrast, 5-FU is a direct chemotherapy agent used to treat cancer, and it is highly toxic to human cells.

5-Fluorocytosine is primarily used to treat serious systemic infections caused by susceptible strains of Candida and Cryptococcus, including septicemia, endocarditis, and meningitis.

Because 5-fluorocytosine is mainly excreted by the kidneys, patients with kidney problems will need a dose reduction to avoid drug accumulation. Close monitoring of blood levels and renal function is necessary to prevent toxicity.