Fluconazole is a member of the triazole family, one of the most widely used antifungal agents. It is an FDA-approved drug to treat vaginal candidiasis, oropharyngeal and esophageal candidiasis, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, and cryptococcal meningitis. Prophylaxis is also known to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy or radiation therapy.
Non-FDA-approved uses for fluconazole include blastomycosis, histoplasmosis, and coccidioidomycosis. Recently, there has been an increase in the administration of fluconazole to treat coccidioidomycosis inflicted bone and joint infection, meningitis, pneumonia in immunocompromised patients, and pneumonia as a primary infection in HIV positive or severely debilitated patients.
Recent studies have proven that fluconazole is more effective at the treatment of soft tissue and pulmonary infections compared to other azole antifungal treatments, mainly with infections caused by coccidioidomycosis.
As a way of counteracting yeast infection, fluconazole interacts with 14- demethylase, a cytochrome P-450 enzyme responsible for catalyzing the conversion of lanosterol to ergosterol. As ergosterol forms a critical part of the fungal cell membrane, fluconazole inhibits the synthesis of ergosterol to increase cellular permeability. Other functions of the medication are to prevent endogenous respiration and the formation of yeasts. It is also noteworthy to reiterate that the loss of sterols goes parallel with the accumulation of 14—methyl sterols found in fungi and is the primary cause of the perceived fungistatic activity of fluconazole.
Mammalian demethylation is less sensitive to fluconazole inhibition; therefore, the usage of fluconazole helps the body in counteracting the causative agents of fungal infection. Despite this mechanism of action, triazoles are considered to be fungistatic against Candida species.
Microbiologically, fluconazole has activity limited to yeasts and some clinical activity against the endemic fungi, Histoplasma, Blastomyces, and Coccidioides. Fluconazole has excellent activity against Candida species and Cryptococcus species but has less activity against C. glabrata and no activity against C. krusei.
Fluconazole is available in both oral (suspension and tablet form) and intravenous preparations. The pharmacokinetic properties are similar following administration by the intravenous or oral routes; the intravenous way of administration is useful in patients with impairment of gastrointestinal absorption or motility. Fluconazole's absorption is unaffected by food or gastric pH. The bioavailability of oral fluconazole is over 90% compared with intravenous administration. The daily dose of fluconazole does not change based on the mode of administration.
Fluconazole clearance is primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. In comparison, it excretes about 11% of the medication in the urine as metabolites.
The serum half-life is approximately 24 hours, allowing for once-daily dosing; however, the daily dose of fluconazole to treat infections other than vaginal candidiasis should depend on the organism and the response to therapy. Treatment should continue until clinical parameters show that active fungal infection has subsided.
The administration of fluconazole usually requires multiple doses except in vaginal candidiasis, where the recommended dosage is 150 mg as a single oral dose.
The doses range from 200 mg on the first day, followed by 100 mg once daily as in oropharyngeal and esophageal candidiasis, to daily doses of 50 to 200 mg in the treatment of Candida peritonitis and urinary tract infections. However, doses of up to 400 mg daily have been used in systemic candida infections and for the prevention of candidiasis in patients undergoing a bone marrow transplantation.
The recommended dosage for treating acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily, with a duration of initial therapy is ten to 12 weeks after the cerebrospinal fluid becomes culture negative. A suppression dose of 200 mg once daily is recommended in patients with AIDS.
Higher daily doses of 600 to 100 mg have been necessary for treating some endemic fungal infections like coccidioidomycosis, especially in disseminated disease.
The following daily doses in adults (100, 200, and 400 mg) should be equivalent to the following doses (3, 6, and 12 mg/kg), respectively, in pediatric patients, but doses exceeding 600 mg/day are not recommended.
Although most patients tolerate the use of fluconazole well, gastrointestinal symptoms are a frequently reported adverse event. These can include but are not limited to nausea, abdominal pain, vomiting, and diarrhea, especially in children.
Other adverse effects may include anaphylaxis, hepatotoxicity, asthenia, myalgia, fatigue, fever, malaise, QT prolongation, torsade des pointes, seizures, dizziness, vertigo, insomnia, paresthesia, somnolence, tremor, leukopenia including neutropenia and agranulocytosis, thrombocytopenia, hypercholesterolemia, hypertriglyceridemia, hypokalemia, cholestasis, dry mouth, dyspepsia, taste perversion, acute exanthematous pustulosis, drug eruption, excessive sweating, exfoliative skin disorders such as Stevens-Johnson syndrome and toxic epidermal necrolysis, alopecia and chapped lips.
Fluconazole is contraindicated if there is hypersensitivity.
Caution is recommended when administering fluconazole to patients with proarrhythmic conditions. Coadministration of other drugs known to prolong the QT interval or those metabolized via the enzyme CYP3A4 is contraindicated in patients receiving fluconazole.
Additionally, fluconazole use requires caution to patients with liver and renal dysfunction. Reduce the dose of fluconazole in patients with impaired renal function.
The oral suspension of fluconazole powder contains sucrose; therefore, caution is essential for patients with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency. It is important to note that when driving vehicles or operating machines, occasional dizziness or seizures may occur. Patients should exercise caution when driving or operating machinery.
The U.S. Food and Drug Administration (FDA) stated that chronic, high doses (400 to 800 mg/day) of fluconazole could be associated with a rare and distinct set of congenital disabilities in infants whose mothers received the drug during the first trimester of pregnancy. This risk does not appear to be related to a single low dose.
Based on this information, fluconazole's pregnancy category is Category D.
In rare cases, hepatic toxicity has correlated with the use of fluconazole. The spectrum of hepatic reactions ranges from mild transient elevations in transaminases to clinical hepatitis. There have been cases of fatalities, primarily in patients with severe underlying medical conditions, predominantly AIDS, malignancy, or chronic liver disease, and often while taking multiple concomitant medications. There is no apparent relationship to the total daily dose, duration of therapy, sex, or the age of the patient observed.
Fluconazole hepatotoxicity has typically, but not always, been reversible on discontinuation of therapy. The recommendation is to carefully monitor patients who develop abnormal liver function tests during fluconazole therapy, to check for the development of more severe hepatic injury. Fluconazole should be discontinued if clinical signs and symptoms consistent with liver disease develop.
Reports exist of fluconazole overdose accompanied by hallucinations and paranoid behavior. If there is an overdose, symptomatic treatment, with supportive measures and gastric lavage if clinically showed, should be instituted. As fluconazole excretes in urine, a 3-hour hemodialysis session decreases plasma levels by approximately 50%.
Healthcare workers who prescribe fluconazole should be aware of its indications and contraindications. While fluconazole is generally well tolerated, its use requires caution in patients with prolonged QT syndrome. An ECG is a strong recommendation before initiating drug therapy in these patients. Additionally, liver and renal function monitoring are essential to adjust dosages.
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