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Flucytosine

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Flucytosine, Ancoban

  • See Also
  1. Antifungal
  • Indications
  1. Systemic Fungal Infections (used with Amphotericin; risk of induced resistance when used alone)
    1. Cryptococcal Meningitis (e.g. HIV Infection, transplant recipient)
    2. Severe, Invasive Candida infections
      1. CNS Candidiasis (HIV Infection)
      2. Candida Pyelonephritis
      3. Candida endocarditis
  • Contraindications
  1. Flucytosine Hypersensitivity
  2. Severe Bone Marrow suppression (relative)
  • Mechanism
  1. Flucytosine is a Fluorouracil prodrug, a fluorinated cytosine analog with Antifungal activity
  2. Transported into fungal cells via cytosine permease
  3. Within fungal cells, Flucytosine is deaminated to the active metabolite 5-Fluorouracil
    1. 5-Fluorouracil substitutes for the Pyrimidine uracil during RNA synthesis
    2. Inhibits fungal Protein synthesis
  4. Fluorouracil is also metabolized to the active 5-Fluorodeoxyuridine monophosphate (FdUMP)
    1. FdUMP inhibits thymidylate synthetase
    2. Blocks Nucleotide metabolism, and secondarily DNA synthesis and Protein synthesis
  • Medications
  1. Capsules: 250 mg, 500 mg
  • Dosing
  1. Typically combined with Amphotericin B
    1. Induced resistance may occur rapidly when Flucytosine is used alone
    2. Duration varies, but typically 2 weeks during induction phase
  2. Dose: 100 mg/kg/day orally divided four times daily for >=14 days
    1. Although not FDA approved in children, it is used off-label (not in renal dysfunction)
    2. Decrease dose to 75 mg/kg/day in weight <2 kg or age <60 days
    3. Consider Ideal Body Weight dosing in Obesity, when treating non-life threatening infections
    4. In Meningitis, consider using adjusted body weight and monitoring serum concentrations
  3. Renal Dosing: Adults
    1. Creatinine Clearance 20 to 40 ml/min: Take 25 mg/kg every 12 hours
    2. Creatinine Clearance 10 to 20 ml/min: Take 25 mg/kg every 24 hours
    3. Creatinine Clearance <10 ml/min: Take 25 mg/kg every 48 hours
    4. Hemodialysis: 25 mg/kg every 24 to 48 hours (dosing after Hemodialysis run)
  • Adverse Effects
  1. Serious Adverse Effects
    1. Enterocolitis
    2. Hepatotoxicity
    3. Peripheral Neuropathy
    4. Myelosuppression (esp. peak levels >100 mcg/ml)
      1. Bone Marrow toxicity due to its antimetabolite mechanism
      2. Leukopenia
      3. Thrombocytopenia
  2. Common Adverse Effects
    1. Nausea and Vomiting
      1. Spread capsule doses out over 15 minutes
    2. Diarrhea
    3. Headache
  3. Induced resistance
    1. Primarily used in combination with Amphotericin B
    2. Not recommended for single agent therapy
  • Safety
  1. Avoid in Lactation
  2. Avoid in pregnancy (esp. first trimester)
    1. Teratogenicity reported in animal studies
    2. Although listed as Pregnancy Category C
  • Pharmacokinetics
  1. Target peak level (2 hours after dose, after 3-5 days): 70 to 80 mcg/ml
    1. Peak serum concentrations >100 mcg/ml risk increased toxicity
  • Monitoring
  1. Therapeutic drug levels (see Pharmacokinetics above)
  2. Liver function
  3. Complete Blood Count
  4. Renal Function
  • Efficacy
  1. When Flucytosine is added to Amphotericin B therapy
    1. More rapid CSF sterilization in Cryptococcal Meningitis
    2. Decreases relapse rates and improves survival
  • Resources
  1. Flucytosine Capsule (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9b386823-8b36-4bf3-b627-3814fae931cf
  • References
  1. (2012) Med Lett Drugs Ther 10(120): 61-8
  2. Hamilton (2020) Tarascon Pocket Pharmacopoeia
  3. LoVecchio and Murugan (2026) Crit Dec Emerg Med 40(3): 42