Continuing Education Activity

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, urinary tract infections, peritonitis, and systemic Candida infections, including candidemia, disseminated candidiasis, 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. This activity outlines the indications, mechanism of action, dosing, significant adverse effects, contraindications, monitoring, and toxicity of fluconazole, so providers can direct patient therapy to optimal outcomes in combating fungal infections.

Objectives:

• Identify the mechanism of action of fluconazole.
• Review the indications for fluconazole therapy.
• Outline the adverse event profile and necessary monitoring when using fluconazole.
• Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving fluconazole treatment.

Indications

Fluconazole is a member of the triazole family, one of the most widely used antifungal agents.[1] It is an FDA-approved drug to treat vaginal candidiasis, oropharyngeal and esophageal candidiasis, peritonitis, and systemic Candida infections, including candidemia, disseminated candidiasis, pneumonia, and cryptococcal meningitis. Prophylaxis is also known to decrease candidiasis incidence in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy or radiation therapy.[2]

Non-FDA-approved uses for fluconazole include blastomycosis, histoplasmosis, and coccidioidomycosis. Recently, there has been an increase in fluconazole administration 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.[2]

Recent studies have proven that fluconazole is more effective at treating soft tissue and pulmonary infections than other azole antifungal treatments, mainly with infections caused by coccidioidomycosis.[2]

Invasive candidiasis has been reported in patients with severe COVID-19 infection. Fluconazole or other azoles can be used in combination with echinocandins and liposomal amphotericin B. Similarly, cryptococcal meningoencephalitis has been reported in immunocompromised patients, which requires aggressive treatment with the induction phase for amphotericin B and flucytosine, followed by fluconazole followed by consolidation and secondary prophylaxis with fluconazole.[3]

Mechanism of Action

Fluconazole interacts with 14-demethylase, a cytochrome P-450 enzyme responsible for catalyzing the conversion of lanosterol to ergosterol.[4] 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, using fluconazole helps the body counteract the causative agents of fungal infection. However, triazoles are considered fungistatic against Candida species despite this mechanism of action.

Microbiologically, fluconazole has activity limited to yeasts and some clinical activity against the endemic fungi, Histoplasma, Blastomyces, and Coccidioides. In addition, fluconazole has excellent activity against Candida and Cryptococcus species but has less activity against C. glabrata and no activity against C. krusei.

Mechanism of Resistance

Mutation in the ERG11 gene decreases the binding of the drug target enzyme, lanosterol C14-alpha demethylase, to fluconazole leading to drug resistance. Efflux pumps coded by two carrier gene families include CDR-1 and CDR-2 genes belonging to the ATP-binding cassette superfamily (ABC) and MDR-1 genes. Efflux pumps encoded by CDR-1 can cause resistance to all azole drugs, while efflux pumps encoded by MDR are selective for fluconazole. Resistance in C. glabrata usually includes upregulation of CDR genes.[5]

Administration

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; intravenous administration is useful in patients with impaired 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.[6] 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 as the unchanged drug in the urine. 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.

Adult Dosing

Fluconazole administration 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 to prevent 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 an initial therapy duration of 10 to 12 weeks after the cerebrospinal fluid becomes culture negative. In addition, 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 diseases.

Pediatric Patients

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.

Hepatic Impairment

Fluconazole use requires caution in patients with liver dysfunction, given its hepatotoxic potential. 

Renal Impairment

The pharmacokinetics of fluconazole is affected by the reduction in renal function. Therefore, the dose of fluconazole needs to be reduced in patients with impaired renal function. If creatinine clearance is ≤ 50 ml/min, the clinician must reduce the dose to 50%. Patients on hemodialysis should be given 100% of the recommended dose after each dialysis session. On non-dialysis days, the clinician should administer the dose according to the patient's creatinine clearance.

Pregnancy Considerations

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 former FDA Category D. According to a meta-analysis, there is a risk of cleft palate, bowed tibia and femur, brachycephaly, and increased risk of musculoskeletal malformations and congenital heart defects in patients exposed to high dose fluconazole therapy during pregnancy. Hence, healthcare providers should avoid fluconazole in pregnant mothers except in patients with life-threatening fungal infections. However, fluconazole may be used if the expected benefit outweighs the possible risk to the fetus.[7]

Breastfeeding Considerations

According to the manufacturer's labeling, clinicians should be cautious when prescribing fluconazole to a nursing woman. Fluconazole is acceptable in nursing mothers because doses excreted into breastmilk are less than the neonatal fluconazole dosage. Therefore, clinicians frequently prescribe fluconazole to treat recurrent breast candidiasis in nursing mothers. The regimen for breast candidiasis is 400 mg once, followed by 200 mg daily for at least two weeks.[8]

Adverse Effects

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.[6]

Other adverse effects may include anaphylaxis, hepatotoxicity, asthenia, myalgia, fatigue, fever, malaise, QT prolongation, torsade de 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.[9][10]

Fluconazole inhibits human adrenocortical steroidogenesis, and reversible adrenal insufficiency has been observed with fluconazole.[11] Fluconazole therapy can cause transient mild-to-moderate serum aminotransferase elevations and is a known cause of clinically apparent acute drug-induced liver injury with a likelihood score of B (likely cause of clinically apparent liver injury). DILI (Drug-Induced Liver Injury) pattern is usually hepatocellular and occurs within the initial few weeks of therapy. Hepatotoxicity can be associated with hypersensitivity reactions, including eosinophilia, fever, and rash. Most patients recover after discontinuing fluconazole, but clinical recovery may require 3 to 4 months. Rechallenge with the fluconazole may lead to the recurrence of hepatotoxicity, so it should be avoided.[12]

Contraindications

Fluconazole is contraindicated if the patient has hypersensitivity to the drug or any formulation components. Caution is recommended when administering fluconazole to patients with proarrhythmic conditions. In addition, coadministration of other drugs known to prolong the QT interval or those metabolized via the enzyme CYP3A4 is contraindicated in patients receiving fluconazole.

The oral suspension of fluconazole powder contains sucrose; therefore, caution is essential for patients with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency.[6] It is important to note that occasionally dizziness or seizures may occur, so caution is recommended when driving vehicles or operating machines. Patients should exercise caution when driving or operating machinery.

Monitoring

In rare cases, hepatic toxicity has correlated with the use of fluconazole. Hepatic reactions range from mild transient elevations in transaminases to clinical hepatitis. There have been 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 patient's age.

Fluconazole hepatotoxicity has typically, but not always, been reversible on discontinuation of therapy. Therefore, 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. Patients on warfarin therapy who have been prescribed fluconazole need monitoring of INR, as a bleeding manifestation has been reported.[13]

Toxicity

In a case report, acute toxicity of fluconazole has been described with peripheral nervous system involvement. In addition, the patient developed polyneuropathy, a confusional state, acute kidney injury, and thrombotic thrombocytopenic purpura.[14] Reports exist of fluconazole overdose accompanied by hallucinations and paranoid behavior. If there is an overdose, symptomatic treatment with supportive measures and gastric lavage should be instituted. As fluconazole excretes in urine, a 3-hour hemodialysis session decreases plasma levels by approximately 50%.[6]

Enhancing Healthcare Team Outcomes

Healthcare professionals 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 EKG is a strong recommendation before initiating drug therapy in these patients. Additionally, liver and renal function monitoring are essential to adjust dosages. An interprofessional healthcare team, including clinicians (MDs, DOs, NPs, and PAs), infectious disease specialists, nurses, and pharmacists, operating as a cohesive unit and using open communication can optimize patient outcomes with fluconazole therapy and minimize adverse events and interactions. Given the potential adverse events and drug-drug interactions of fluconazole, it is incumbent on all interprofessional team members to monitor the patient and document any changes in status, including signs of therapy failure, and report these to other team members as appropriate. [Level 5]