Usage
Flucytosine is an antifungal medication primarily used in combination with other antifungals, such as amphotericin B or fluconazole, for the treatment of serious systemic fungal infections. These infections include:
- Cryptococcal meningitis: A severe infection of the brain and spinal cord caused by the fungus Cryptococcus neoformans.
- Systemic candidiasis (Candidemia): A bloodstream infection caused by Candida species.
- Other severe Candida infections: Including endocarditis, pneumonia, and urinary tract infections.
Pharmacological Classification: Antifungal, Antimetabolite
Mechanism of Action: Flucytosine enters fungal cells and is converted into 5-fluorouracil, which disrupts fungal RNA and DNA synthesis, leading to fungal cell death. It is typically used in combination therapy as resistance can quickly develop with Flucytosine monotherapy.
Alternate Names
- 5-fluorocytosine (5-FC)
- 4-amino-5-fluoro-1,2-dihydropyrimidin-2-one
Brand Name: Ancobon
How It Works
Pharmacodynamics: Flucytosine’s antifungal activity stems from its conversion to 5-fluorouracil within the fungal cell. 5-fluorouracil interferes with fungal RNA and DNA synthesis, ultimately causing cell death. Human cells lack the enzyme to convert flucytosine to 5-fluorouracil limiting its toxicity to human cells. Combination therapy with other antifungals is generally necessary to prevent the emergence of resistance.
Pharmacokinetics:
- Absorption: Flucytosine is well-absorbed orally (75% to 90%). Food may delay, but does not substantially reduce absorption.
- Distribution: It distributes widely throughout the body, including the cerebrospinal fluid (CSF), achieving therapeutically relevant concentrations.
- Metabolism: Limited metabolism occurs in the human body; most of the drug remains unchanged. Primarily metabolized by the fungal enzyme cytosine deaminase into 5-fluorouracil.
- Elimination: Primarily excreted unchanged by the kidneys (renal excretion), with a half-life of 3-6 hours in patients with normal renal function. This half-life significantly increases with renal impairment.
Mode of Action: At the cellular level, Flucytosine is converted to 5-fluorouracil in the fungal cell. It gets incorporated into fungal RNA and disrupts protein synthesis. It inhibits fungal DNA synthesis by interfering with the enzyme thymidylate synthetase.
Receptor Binding/Enzyme Inhibition: The primary mechanism involves inhibition of thymidylate synthetase, a key enzyme in DNA synthesis. Cytosine permease is needed for entry into the fungal cell.
Elimination Pathways: Primarily renal excretion.
Dosage
Standard Dosage
Adults:
50-150 mg/kg/day orally, divided every 6 hours. The dose should be individualized based on patient weight, infection severity, and renal function.
Children:
Same as adult dosing (50-150 mg/kg/day orally, divided every 6 hours). Neonates may require higher doses (80-160 mg/kg/day divided every 6 hours). Pediatric dosages should be carefully determined by a physician, considering renal function and age.
Special Cases:
- Elderly Patients: Initiate at lower doses and monitor renal function closely.
- Patients with Renal Impairment: Dosage adjustments are crucial. Reduce dose according to creatinine clearance (CrCl):
CrCl 20-40 ml/min: 50 mg/kg every 12 hours.
CrCl 10-20 ml/min: 50 mg/kg every 24 hours.
CrCl < 10 ml/min: 50 mg/kg as a single dose, with subsequent doses adjusted according to serum levels. Monitor serum levels regularly. For hemodialysis, administer post-dialysis with subsequent dose adjustments based on serum levels. For peritoneal dialysis, 500 to 1000 mg every 24 hours with dose adjustments according to levels.
- Patients with Hepatic Dysfunction: Use with caution; no specific dosage adjustments are universally defined, but close monitoring is recommended.
- Patients with Comorbid Conditions: Use with caution in patients with bone marrow suppression or receiving myelosuppressive medications. Close monitoring is also recommended for patients with HIV infection.
Clinical Use Cases
Flucytosine is not typically used in isolation for clinical cases involving intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. It is usually used in combination with other antifungal medications to treat severe fungal infections, in the instances mentioned, it would be treating an underlying fungal infection but is not specifically used for these conditions.
Dosage Adjustments
Adjustments are made based on renal function, hepatic function, and hematologic parameters. Therapeutic drug monitoring (TDM) to maintain serum levels within a therapeutic range (25-100 mcg/mL) is recommended to optimize efficacy and prevent toxicity.
Side Effects
Common Side Effects:
Nausea, vomiting, diarrhea, abdominal pain, headache, rash.
Rare but Serious Side Effects:
Bone marrow suppression (leukopenia, thrombocytopenia, pancytopenia, anemia, agranulocytosis), hepatotoxicity (jaundice, elevated liver enzymes), renal impairment, hallucinations, confusion, seizures, cardiac arrest.
Long-Term Effects: Bone marrow suppression and hepatotoxicity can occur with prolonged use. Close monitoring is required.
Contraindications
- Hypersensitivity to flucytosine.
- Known complete dihydropyrimidine dehydrogenase (DPD) deficiency. Patients with DPD deficiency are unable to metabolize 5-fluorouracil, this could result in dangerously elevated levels.
- Co-administration with antiviral nucleoside drugs and their analogs.
Drug Interactions
- Cytarabine: Antagonizes the antifungal activity of flucytosine.
- Nephrotoxic drugs (e.g., amphotericin B): Increase the risk of flucytosine toxicity due to reduced renal clearance. Close monitoring is recommended.
- Myelosuppressive drugs: Additive bone marrow suppression.
Pregnancy and Breastfeeding
Flucytosine is generally not recommended during pregnancy due to potential teratogenic effects. Its use should only be considered if the benefits clearly outweigh the risks. Its excretion in breast milk is unknown, but breastfeeding is generally not recommended during treatment.
Drug Profile Summary
- Mechanism of Action: Converted to 5-fluorouracil in fungal cells, disrupting RNA and DNA synthesis.
- Side Effects: Nausea, vomiting, diarrhea, bone marrow suppression, hepatotoxicity, renal impairment.
- Contraindications: Hypersensitivity to flucytosine, DPD deficiency.
- Drug Interactions: Cytarabine, nephrotoxic drugs.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: 50-150 mg/kg/day divided every 6 hours; adjustments needed for renal impairment.
- Monitoring Parameters: Renal function (BUN, serum creatinine, CrCl), liver function tests (AST, ALT, alkaline phosphatase, bilirubin), complete blood count (CBC), and flucytosine serum levels.
Popular Combinations
- Amphotericin B + Flucytosine: For cryptococcal meningitis and severe systemic candidiasis.
- Fluconazole + Flucytosine: Alternative for cryptococcal meningitis in patients who cannot tolerate amphotericin B.
Precautions
- General Precautions: Monitor renal, hepatic, and hematological parameters throughout treatment.
- Specific Populations: As described above, use with caution and adjust dosages in renal impaired, hepatic impaired, pregnant women, and breastfeeding mothers. Use caution and monitor closely in neonates with hyperbilirubinemia. Use with caution and monitor closely in geriatric patients. Consider weight-based dosing and monitor closely in pediatric patients.
- Lifestyle Considerations: No specific lifestyle considerations are typically associated with flucytosine.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Flucytosine?
A: The standard dose is 50-150 mg/kg/day orally, divided every 6 hours, adjusted for renal function and other patient-specific factors.
Q2: What are the most common side effects?
A: Nausea, vomiting, diarrhea, and headache are the most common side effects.
Q3: What are the serious adverse effects of Flucytosine?
A: Bone marrow suppression, hepatotoxicity, and renal impairment are potentially life-threatening side effects.
Q4: What are the contraindications for Flucytosine use?
A: Known hypersensitivity to flucytosine and complete DPD deficiency. Coadministration with antiviral nucleoside drugs and their analogs.
Q5: How is Flucytosine administered?
A: Flucytosine is available in oral capsules and as a solution for IV infusion. It is almost always co-administered with another anti-fungal medication.
Q6: How does renal impairment affect Flucytosine dosing?
A: Flucytosine dosage must be reduced in patients with renal impairment to prevent drug accumulation and toxicity. Dose reductions are based on creatinine clearance (CrCl).
Q7: Does Flucytosine interact with other medications?
A: Yes, Flucytosine can interact with other medications, especially those that are nephrotoxic or myelosuppressive. It also interacts with cytarabine, which can reduce its effectiveness.
Q8: Is Flucytosine safe to use during pregnancy or breastfeeding?
A: Flucytosine is generally not recommended during pregnancy and breastfeeding due to potential risks to the fetus or infant.
Q9: What monitoring parameters are essential during Flucytosine therapy?
A: Renal function tests, liver function tests, complete blood counts, and flucytosine serum levels should be monitored regularly during treatment.
