What is the recommended dose of Fluconazole (an antifungal medication) in the Intensive Care Unit (ICU)?

From the Guidelines

Fluconazole dosing in the ICU should start at 800 mg (12 mg/kg) loading dose on day 1, followed by 400 mg (6 mg/kg) daily for most invasive Candida infections. This recommendation is based on the most recent and highest quality study available, which suggests that fluconazole is an acceptable alternative for patients who have had no recent azole exposure and are not colonized with azole-resistant Candida species 1. For critically ill patients with normal renal function, this higher dosing is recommended to ensure adequate drug concentrations at the infection site. Dose adjustment is necessary for patients with renal impairment: reduce to 50% of the normal dose if creatinine clearance is 11-50 mL/min, and to 25% if clearance is below 10 mL/min.

Key Considerations

• ICU patients often have altered pharmacokinetics due to fluid shifts, hypoalbuminemia, and organ dysfunction, which may affect drug distribution 1.
• Therapeutic drug monitoring may be beneficial in complex cases.
• Duration of therapy depends on the specific infection but typically continues for 14 days after the first negative blood culture for candidemia.
• Fluconazole has excellent bioavailability and tissue penetration, including the central nervous system, making it effective for treating susceptible Candida species, though resistance in C. glabrata and intrinsic resistance in C. krusei limit its use in some cases 1.

Important Factors to Consider

• Recent azole exposure and colonization with azole-resistant Candida species should be taken into account when deciding on empiric antifungal therapy 1.
• Echinocandins are preferred empiric therapy for suspected candidiasis in nonneutropenic patients in the ICU, but fluconazole is an acceptable alternative in certain cases 1.

From the FDA Drug Label

Dosage and Administration in Adults: ... In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. Systemic Candida infections: For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used

The recommended fluconazole dose in ICU patients is not explicitly stated, but for systemic Candida infections, doses of up to 400 mg daily have been used.

• The daily dose should be based on the infecting organism and the patient’s response to therapy.
• A loading dose of twice the daily dose is recommended on the first day of therapy 2

From the Research

Fluconazole Dosing in ICU

• The optimal fluconazole dose in ICU patients is a subject of ongoing research, with several studies suggesting that higher doses may be necessary to achieve adequate drug concentrations 3, 4, 5.
• A study published in 2020 found that fluconazole clearance is highly variable in ICU patients and is strongly dependent on renal function and continuous renal replacement therapy (CRRT) 3.
• The same study recommended the following fluconazole doses:
  • 400 mg for patients with poor to moderate renal function
  • 600 mg for patients with adequate renal function
  • 800 mg for patients treated with CRRT
• Another study published in 2021 found that current fluconazole treatment regimens often result in under-dosing of critically ill adults during early therapy, particularly in those who are overweight or have higher creatinine clearance 4.
• A study published in 2006 found that a daily dose of 800 mg fluconazole is necessary to achieve fungicidal drug concentrations in ICU patients undergoing continuous veno-venous haemofiltration (CVVHF) 5.
• The importance of accurate Candida species identification and minimum inhibitory concentration (MIC) determination is highlighted in a study published in 2020, which found varied antifungal MIC values among different Candida species 6.
• A study published in 2012 compared the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin B for the treatment of HIV-associated cryptococcal meningitis, and found that amphotericin B plus fluconazole (800-1200 mg/day) represents an immediately implementable alternative to amphotericin B plus flucytosine 7.