Antifungal p.4

Flucytosine: Antifungal Agent

• Category: Pyrimidine analog antifungal agent.
• Primary Function: Narrow-spectrum antifungal agent, most effective against Candida and Cryptococcus neoformans.
• Unique Feature: Often used in combination with amphotericin B due to common resistance development.
• Mechanism of Action: Converted to 5-fluorouracil (5-FU) by fungal cells, interfering with DNA and RNA synthesis. Human cells are relatively unaffected due to lacking cytosine deaminase.

Therapeutic Uses

• Systemic Fungal Infections: Treats candidiasis and cryptococcosis, especially severe forms like systemic candidiasis and cryptococcal meningitis, often in combination with amphotericin B.

Side Effects

• Hematologic: Bone marrow suppression, reversible neutropenia or thrombocytopenia, rare risk of fatal agranulocytosis.
• Hepatic: Mild and reversible hepatic dysfunction is common, severe injury is rare.

Precautions & Contraindications

• Renal Impairment: Use caution due to prolonged half-life, adjust dosage for renal insufficiency.
• Hematologic Disorders: Use caution in clients with pre-existing hematologic disorders or bone marrow suppression.
• Black Box Warning: Extreme caution in clients with renal impairment due to prolonged half-life.

Drug Interactions

• Amphotericin B: Can cause nephrotoxicity. Combined use requires adequate kidney function to prevent flucytosine toxicity.
• Cisapride, Pimozide, Dofetilide, Quinidine: Flucytosine can inhibit CYP450 enzymes, increasing plasma levels of these drugs, posing a risk of fatal dysrhythmias.

Dosing & Administration

• Dosing: Varies based on condition, severity, and client response. Often combined therapy with amphotericin B.
• Dosage: Flucytosine capsules (250mg & 500mg). For clients with normal renal function: 50-150mg/kg/day in four divided doses every 6 hours. Reduced dosage for renal insufficiency.
• Administration: Oral administration.
• Client Teaching: Monitor for hematologic and hepatic adverse effects.

Labs to Monitor

• Basic Metabolic Panel (BMP): Monitor renal function (BUN/Creatine, Creatine Clearance).
• Complete Blood Count (CBC): Monitor platelet and leukocyte count weekly.
• Liver Function Tests (LFTs): Monitor weekly for hepatotoxicity.
• Serum Drug Levels: Monitor flucytosine levels in clients receiving concomitant amphotericin B therapy.

Flucytosine - Pyrimidine Analog Antifungal

• Flucytosine is a narrow-spectrum antifungal agent effective against susceptible strains of Candida and Cryptococcus neoformans.
• Flucytosine is typically used in combination with amphotericin B due to the high risk of developing fungal resistance.
• Flucytosine is taken up by fungal cells and converted to 5-fluorouracil (5-FU), which disrupts fungal DNA and RNA synthesis.
• Human cells lack cytosine deaminase, preventing the conversion of flucytosine to 5-FU and rendering it relatively harmless to humans.

Indications and Therapeutic Uses

• Flucytosine is indicated for treating candidiasis and cryptococcosis.
• For severe infections like systemic candidiasis and cryptococcal meningitis, flucytosine should be combined with amphotericin B.

Side Effects and Adverse Reactions

• Hematologic Effects: Bone marrow suppression is the most serious side effect, including reversible neutropenia or thrombocytopenia, and a rare risk of fatal agranulocytosis.
• Hepatotoxicity: Mild and reversible hepatic dysfunction is common, but severe hepatic injury is rare.

Precautions and Contraindications

• Clients with renal impairment: Reduced dosage is required due to a prolonged half-life of flucytosine.
• Clients with hematologic disorders and bone marrow suppression: Use with caution.

Black Box Warning

• Use with extreme caution in clients with renal impairment due to the prolonged half-life of flucytosine.

Drug Interactions

• Amphotericin B: Can cause nephrotoxicity, requiring adequate kidney function to prevent flucytosine toxicity.
• Cisapride, pimozide, dofetilide, or quinidine: Concomitant use can increase their plasma levels, increasing the risk of fatal dysrhythmias.

Dosing, Administration, & Client Teaching

• Dosing: Varies based on the condition, severity, and client response.
• Administration: Oral administration.
• Client Teaching: Monitor for hematologic and hepatic adverse effects.

Labs to Monitor

• Basic Metabolic Panel (BMP): Monitor renal function (BUN/Creatinine and Creatine Clearance) during therapy.
• Complete Blood Count (CBC): Monitor weekly for platelet and leukocyte counts.
• Liver Function Tests (LFTs): Monitor weekly for hepatotoxicity.
• Serum Drug Levels: Monitor flucytosine levels in clients concomitantly using amphotericin B.

Overview of the Drug Class

• Flucytosine is a narrow-spectrum antifungal agent in the Pyrimidine Analog Antifungal Agent category
• It is primarily effective against Candida and Cryptococcus neoformans
• Flucytosine is often used in combination with amphotericin B due to the high likelihood of developing resistance

Mechanism of Action

• Flucytosine is taken up by fungal cells and converted into 5-fluorouracil (5-FU)
• 5-FU disrupts fungal DNA and RNA synthesis
• Mammalian cells lack the enzyme, cytosine deaminase, which converts flucytosine to 5-FU making flucytosine relatively safe for humans

Indications & Therapeutic Uses

• Flucytosine is used for treating candidiasis and cryptococcosis
• For severe infections, flucytosine should be combined with amphotericin B

Side Effects and Adverse Reactions

• Bone marrow suppression is the most serious side effect leading to neutropenia or thrombocytopenia, and, rarely, agranulocytosis
• Hepatotoxicity is common with flucytosine, presenting as mild and reversible hepatic dysfunction, but severe hepatic injury is rare.

Precautions and Contraindications

• Use with caution in patients with renal impairment because of the prolonged half-life
• Dosage must be reduced in patients with renal insufficiency
• Use with caution in patients with hematologic disorders and bone marrow suppression

Drug Interactions

• Amphotericin B can cause nephrotoxicity and may increase flucytosine toxicity.
• Flucytosine can inhibit CYP450 enzymes, increasing the risk of fatal dysrhythmias when used with cisapride, pimozide, dofetilide, or quinidine

Dosing, Administration, & Client Teaching

• Dosage varies depending on the condition, severity, and patient response
• Flucytosine is available in 250 mg and 500 mg capsules for oral administration
• The typical dose for patients with normal renal function is 50 - 150 mg/kg/day administered in four divided doses at 6-hour intervals
• Dosage must be reduced for patients with renal insufficiency

Labs to Monitor

• Basic metabolic panel (BMP) to monitor renal function
• Complete blood count (CBC) to monitor platelet and leukocyte counts weekly
• Liver function tests (LFTs) to monitor for hepatotoxicity
• Serum drug levels in patients concomitantly using amphotericin B

Flucytosine Overview

• Flucytosine is a pyrimidine analog antifungal agent with narrow-spectrum activity.
• Its primary function is to inhibit fungal DNA and RNA synthesis.
• Flucytosine is primarily effective against susceptible strains of Candida and Cryptococcus neoformans.
• Due to developing resistance, flucytosine is usually used in combination with amphotericin B.

Mechanism of Action

• Flucytosine is taken up by fungal cells and converted into 5-fluorouracil (5-FU), a potent antimetabolite.
• 5-FU disrupts fungal DNA and RNA synthesis.
• Mammals lack cytosine deaminase, the enzyme responsible for converting flucytosine to 5-FU, making the drug relatively harmless to humans.

Indications and Therapeutic Uses

• Flucytosine is indicated for treating candidiasis and cryptococcosis.
• In treating severe systemic infections like candidiasis and cryptococcal meningitis, flucytosine should be combined with amphotericin B.

Side Effects and Adverse Reactions

• Hematologic Effects: The most severe complication is bone marrow suppression, which can lead to reversible neutropenia or thrombocytopenia, and in rare cases, fatal agranulocytosis.
• Hepatotoxicity: Mild and reversible hepatic dysfunction commonly occurs with flucytosine use. Severe hepatic injury is rare.

Precautions and Contraindications

• Use caution in clients with renal impairment because of the drug's prolonged half-life. Dosage reduction is necessary for clients with renal insufficiency.
• Exercise caution in patients with hematologic disorders or bone marrow suppression.

Black Box Warning

• Flucytosine has a black box warning for extreme caution in clients with renal impairment due to the long half-life.

Drug Interactions

• When combined with Amphotericin B, which causes nephrotoxicity, adequate kidney function is crucial to prevent flucytosine toxicity.
• As flucytosine can inhibit CYP450 enzymes, concurrent use with cisapride, pimozide, dofetilide, or quinidine can increase their plasma levels, raising the risk of fatal dysrhythmias.

Dosing, Administration, & Client Teaching

• Dosing varies based on the condition, severity, and patient response. Consult drug dosing guidelines for individualized dosing.
• Flucytosine is often administered in combination with amphotericin B.
• Oral administration is the preferred method for the drug.
• Dosing for clients with normal renal function is 50–150 mg/kg/day, administered in four divided doses at 6-hour intervals.
• Dosage must be reduced for clients with renal insufficiency.

Labs to Monitor

• Monitor renal function using a Basic Metabolic Panel (BMP), including BUN/Creatine and Creatinine Clearance.
• Monitor platelet and leukocyte counts weekly using a Complete Blood Count (CBC).
• Monitor liver function tests (LFTs) weekly to assess for hepatotoxicity.
• Monitor flucytosine levels in clients using amphotericin B concurrently.