Continuing Education Activity

Flucytosine is a medication used in the management and treatment of systemic and severe candida and cryptococcus infections. It is in the antimetabolite, antifungal class of drugs. This activity outlines the indications, action, and contraindications for flucytosine as a valuable agent in treating and managing severe fungal infections. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to members of the healthcare team in the care of patients with candida and cryptococcus infections and related conditions.

Objectives:

• Identify the mechanism of action of flucytosine.
• Describe the potential adverse effects of flucytosine.
• Summarize the indications for using flucytosine.
• Outline some interprofessional team strategies for improving care coordination and communication to advance flucytosine and improve outcomes.

Indications

Flucytosine (5-fluorocytosine) is an antimetabolite agent, classified as a systemic antifungal. It was first made in 1957 and FDA approved in 1971 for the treatment of severe candida and cryptococcus infections.[1] Once administered, flucytosine's pharmacologic effect only takes place in the presence of fungal cells, and the action does not act on mammalian cells.[2] The use of flucytosine as monotherapy is not advised due to the high risk of drug resistance to its use individually. It may be used without the addition of a second medication when treating non-systemic, non-life-threatening conditions such as candida infections that affect the lower urinary tract and vagina.[3] The recommended use is alongside another antifungal medication. A standard sequence of flucytosine use is along with amphotericin B, which serves a synergistic effect when used together for systemic infections.[4] The combination therapy can treat cryptococcosis meningitis and candidosis causing endocarditis, meningitis, endophthalmitis, peritonitis, cystitis, and systemic infection.[5] The use of this medication must be on a case-by-case basis as this drug is heavily reliant on an individual's kidney function. The drug does not undergo metabolism within the human body, and by 24 hours, 85 to 95% of flucytosine is excreted in the urine without changing from its original form.[2][6]

FDA Approved Use

Clinicians use flucytosine in combination with amphotericin B for invasive cryptococcal (meningitis) and candida infections.

Other Use[7]

• Chromoblastomycosis
• Aspergillosis

Mechanism of Action

Flucytosine (5-FC) action takes effect when it comes in contact with the fungus and is taken up by an enzyme known as cytosine permease. Once the drug has entered the fungus, it is then converted to its active form 5-fluorouracil(5-FU) by the enzyme cytosine deaminase within the cell.[8] 5-fluorouracil incorporates itself into the RNA strand by competing with uracil, disrupting the RNA synthesis, and impairing protein synthesis within the fungus.[6] 5-fluorouracil also further inhibits DNA synthesis through its conversion into fluoro-deoxyuridylic acid and inhibiting thymidylate synthase, which causes DNA damage within fungal cells.[6] The enzyme cytosine deaminase is not present in mammalian cells, which explains its inactivity in bacteria and human cells.[8]

Administration

[9]Flucytosine is available in oral capsules and comes in the following dosages[1]:

• 250 mg
• 500 mg

The medication can be started on an oral dosage of 50 mg to 150 mg/kg/day every six hours.[1] Once orally administered, the medication is well absorbed in the gastrointestinal tract with a 75 to 90% bioavailability and is eliminated by glomerular filtration of the kidneys and excreted in the urine.[2][6][9]

Flucytosine is available as a solution and is available in the following dosages[10]:

• 2.5 g/250 ml

Flucytosine administered by infusion should maintain concentrations of 50 mg/L.

The FDA has not approved flucytosine for intrathecal administration.

Black Box Warnings: flucytosine's use requires monitoring and extreme caution in patients with hepatic, renal, and hematologic insufficiency.[11][9]

Adverse Effects

Common Adverse Effects [1][12]

• Gastrointestinal: nausea, emesis, abdominal pain, diarrhea
• Skin: rash, pruritus
• Acute hepatitis
• Nephrotoxicity

There are also reports of more severe hematologic adverse effects such as bone marrow suppression, pancytopenia, aplastic anemia, and agranulocytosis. Inflammatory bowel disease such as ulcerative colitis and perforation of the bowel are among the more severe but rare gastrointestinal adverse effects of flucytosine.[13][2]

Contraindications

Flucytosine is contraindicated in patients who have a hypersensitivity to the medication. During pregnancy, flucytosine use is not indicated during the first trimester as anatomic irregularities have appeared during aborted pregnancies. There have been no evidenced reports of toxicity during the second and third trimesters.[14] It should only be administered to the mother once the benefits outweigh the uncertainties, as the drug can readily cross the placenta. The FDA has labeled flucytosine as risk category C during pregnancy.[14] Breastfeeding is also not recommended during flucytosine use.

Monitoring

It is vital to monitor the liver enzymes, CBC, and kidney functions regularly for patients taking flucytosine. The serum drug concentrations require thorough monitoring for patients receiving high dosages or extended durations of the treatment. The drug concentration is considered non-toxic and adequate at a level below 100 mg/L. With levels above 100 mg/L, toxicity may occur.[15][9] The onset of action and half-life of this medication is dependent on the individual and their kidney function.[15] The half-life of flucytosine in healthy individuals is 2 to  5 hours. It can be notably lengthened in subjects who have an insufficient organ function.[9] The onset of peak levels is usually 2 hours in a healthy person with normal kidney function.[9] In individuals with compromised renal function, peak onset can be 4 to 5 hours due to decreased elimination of the drug.[9]

Toxicity

Flucytosine toxicity can present with hepatitis and gastrointestinal symptoms such as diarrhea, nausea, and vomiting.[1] More severe symptoms, such as leukopenia and thrombocytopenia, can also develop.[1] The adverse effects and toxicity of flucytosine are concentration-dependent and can be managed by decreasing the dosage or discontinuing the medication if complications arise. In the event severe toxicity does pursue, the drug is manageable through hemodialysis, or peritoneal dialysis, as 97% of the drug is excreted through glomerular filtration of the kidneys.[9]

Enhancing Healthcare Team Outcomes

Flucytosine (5-fluorocytosine) is an FDA-approved medication indicated for the treatment of severe candida and cryptococcus infections. Administering care to patients prescribed flucytosine requires excellent interaction between the patient and an interprofessional team of healthcare providers. These providers can include a primary care clinician, mid-level practitioners, an infectious disease specialist, a nurse, and a pharmacist. The primary care physician and infectious disease specialist must establish exceptional patient rapport so that the patient thoroughly comprehends the significance of medication compliance and is educated on the treatment of flucytosine for the illness and its complications.

The patient should receive routine checkups to monitor if the flucytosine is in an optimal range and the patient is not experiencing any toxicities and harm to the liver, kidneys, or bone marrow. The primary care and specialist should be up to date with the latest management guidelines with flucytosine, its implications, and adverse effects. Recommendations are not to use flucytosine as monotherapy due to likely drug resistance and its frequent use with nephrotoxic medication amphotericin B. If toxicity and organ damage does pursue, it is vital to dialyze the patient as 85 to 95% of the medication is excreted through the urine. Joint decision-making between the interprofessional team is essential to improve patient-centered care and reach the coveted outcome. Nursing staff can provide additional counseling on proper administration and potential adverse effects, and the pharmacist can reinforce those points and check for medication interactions. This type of interprofessional interaction will lead to better patient outcomes with flucytosine therapy. [Level 5]