Antimicrobials · Antifungals
The facts most likely to be tested
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Fluconazole functions by inhibiting the fungal cytochrome P450 enzyme 14-alpha-demethylase, preventing the conversion of lanosterol to ergosterol.
It is the first-line treatment for vulvovaginal candidiasis and oropharyngeal candidiasis in immunocompromised patients.
Fluconazole is the drug of choice for the consolidation and maintenance therapy of Cryptococcal meningitis following initial induction with amphotericin B and flucytosine.
It is highly effective against Candida species and Cryptococcus neoformans but lacks activity against Aspergillus and Candida krusei.
The drug is a potent CYP450 inhibitor, leading to significant drug-drug interactions with medications like warfarin, phenytoin, and statins.
Fluconazole is teratogenic and strictly contraindicated in pregnancy, particularly during the first trimester, due to risks of craniofacial and skeletal abnormalities.
It is the preferred prophylactic agent for invasive candidiasis in high-risk patients, such as those undergoing bone marrow transplantation.
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A 34-year-old female with a history of HIV presents with white, curd-like plaques on her tongue and buccal mucosa that bleed when scraped. She reports odynophagia and a metallic taste in her mouth. Her CD4 count is 140 cells/mm³. She is currently taking antiretroviral therapy and a statin for hyperlipidemia. Physical examination reveals erythematous patches on the soft palate.
What is the most appropriate initial pharmacologic treatment for this patient's condition?
Oral fluconazole
The patient presents with classic oropharyngeal candidiasis (thrush), for which oral fluconazole is the first-line treatment; clinicians must monitor for potential interactions with her statin therapy due to CYP450 inhibition.
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Classification
Triazole antifungal. Inhibits fungal cytochrome P450.
Indications
Candidiasis (mucocutaneous/systemic) and Cryptococcal meningitis.
Mechanism of Action
Inhibits 14-alpha-demethylase, blocking ergosterol synthesis.
Side Effects
GI upset, QT prolongation, hepatotoxicity.
Contraindications / Monitoring
Pregnancy (teratogenic), CYP3A4 inhibitors. Monitor LFTs.
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Mechanism of Action
Fluconazole binds to the fungal 14-alpha-demethylase enzyme, a member of the cytochrome P450 system. This inhibition prevents the conversion of lanosterol to ergosterol, the essential component of the fungal cell membrane. Depletion of ergosterol leads to membrane instability and inhibition of fungal growth, exerting a fungistatic effect.
Unique Properties
Unlike other azoles, fluconazole has excellent CSF penetration, making it the drug of choice for Cryptococcal meningitis. It is highly water-soluble and exhibits high bioavailability with oral administration, often allowing for easy transition from IV to PO therapy.
Indications
It is the first-line treatment for esophageal candidiasis and vulvovaginal candidiasis. It is also used for the consolidation phase of Cryptococcal meningitis and as prophylaxis in immunocompromised patients. It is ineffective against Aspergillus species.
Pharmacokinetics
Fluconazole is primarily excreted unchanged by the kidneys, requiring dose adjustments in patients with renal impairment. It is a potent inhibitor of CYP2C9 and CYP3A4, leading to significant drug-drug interactions with agents like warfarin and phenytoin.
Side Effects & Adverse Events
Common side effects include nausea, vomiting, and abdominal pain. Clinically significant risks include QT interval prolongation leading to Torsades de Pointes and dose-dependent hepatotoxicity. Rare but severe Stevens-Johnson syndrome has been reported.
Contraindications
Pregnancy is a major contraindication due to potential teratogenicity and congenital anomalies with high-dose chronic use. It is also contraindicated in patients with known hypersensitivity to azoles or those taking drugs that prolong the QT interval.
Monitoring
Baseline and periodic LFTs are required, especially in patients with pre-existing liver disease. In patients on long-term therapy, monitor renal function (CrCl) to adjust dosing. Obtain an ECG if the patient is on other medications that affect cardiac conduction.
Clinical Pearls
Remember that fluconazole is the answer for thrush in HIV patients. Always check the medication list for CYP450 interactions before prescribing. If a patient fails fluconazole for Candida, consider Candida glabrata or Candida krusei, which are often fluconazole-resistant.