Fluconazole

Article Author:
Ameish Govindarajan
Article Editor:
Ayham Aboeed
Updated:
12/29/2018 7:05:33 PM
PubMed Link:
Fluconazole

Indications

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, Candida urinary tract infections, 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 and/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 anti-fungal treatments, particularly with infections caused by coccidioidomycosis.[1]

Mechanism of Action

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.[2] As ergosterol forms a critical part of the fungal cell membrane, fluconazole inhibits the synthesis of ergosterol to increase the 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 has been found to be 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.

Administration

Fluconazole is available in both oral (suspension and tablets) and intravenous preparations. The pharmacokinetic properties are similar following administration by the intravenous or oral routes; the intravenous preparation 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.[3] 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, while it excretes about 11% of the dose in the urine as metabolites.

The half-life of the long serum is approximately 24 hours, allowing for once-daily dosing; however, the daily dose of fluconazole to treat infections other than vaginal candidiasis should be based on the organism and the response to therapy. Treatment should be continued until clinical parameters oshow 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 to12 weeks after the cerebrospinal fluid becomes culture negative. Suppression dose of 200 mg once daily is recommended in patients with AIDS.

Higher daily doses of 600-100 mg have been used in treating some endemic fungal infection like coccidioidomycosis especially in disseminated disease for a duration of months or even years.

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.

Adverse Effects

Although the use of fluconazole is well tolerated among patients, gastrointestinal symptoms are most frequently reported. These can include but are not limited to nausea, abdominal pain, vomiting, and diarrhea, especially in children[3].

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[4].

Contraindications

Fluconazole is contraindicated if there is hypersensitivity. 

It is recommended that one use caution when administering fluconazole to patients with these potentially proarrhythmic conditions. Coadministration of other drugs known to prolong the QT interval, which are metabolized via the enzyme CYP3A4 are contraindicated in patients receiving fluconazole.

Additionally, the administration of fluconazole must be applied with caution to patients with liver and renal dysfunction. The dose of fluconazole should be reduced in patients with impaired renal function, and if there is an inverse relationship between the elimination half-life and creatinine clearance.

The oral suspension of fluconazole powder contains sucrose; therefore, it is important to use caution with patients with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency[3]. It is important to note that When driving vehicles or operating machines, occasional dizziness or seizures may occur. Patients are warned to use caution when driving or operating machinery.

The U.S. Food and Drug Administration (FDA) stated that chronic, high doses (400-800 mg/day) of fluconazole can be associated with a rare and distinct set of birth defects 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[5].

Based on this information, the pregnancy category for fluconazole indications, other than treatment of vaginal candidiasis, is Category D; however, for a single dose of fluconazole 150 mg to treat vaginal candidiasis is Category C.

Monitoring

In rare cases, serious hepatic toxicity has been associated with the use of fluconazole. The spectrum of hepatic reactions ranges from mild transient elevations in transaminases to clinical hepatitis, cholestasis to fulminant hepatic failure. 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 age of the patient observed.

Fluconazole hepatotoxicity has typically, but not always, been reversible on discontinuation of therapy. It is recommended to monitor patients who develop abnormal liver function tests during fluconazole therapy closely, 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%.[3]

Enhancing Healthcare Team Outcomes

Healthcare workers including nurse practitioners who prescribe fluconazole should be aware of its indications and contraindications. While fluconazole is generally well tolerated, it should be used with caution in patients with prolonged QT syndrome. An ECG is recommended prior to initiating drug therapy. Additionally, liver and renal function monitoring are in order because drug dosage modification is necessary in the presence of dysfunction.


References

[1] Galgiani JN,Ampel NM,Blair JE,Catanzaro A,Geertsma F,Hoover SE,Johnson RH,Kusne S,Lisse J,MacDonald JD,Meyerson SL,Raksin PB,Siever J,Stevens DA,Sunenshine R,Theodore N, 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2016 Sep 15     [PubMed PMID: 27470238]
[2] Spampinato C,Leonardi D, Candida infections, causes, targets, and resistance mechanisms: traditional and alternative antifungal agents. BioMed research international. 2013     [PubMed PMID: 23878798]
[3] Amichai B,Grunwald MH, Adverse drug reactions of the new oral antifungal agents--terbinafine, fluconazole, and itraconazole. International journal of dermatology. 1998 Jun     [PubMed PMID: 9646122]
[4] Pappas PG,Kauffman CA,Perfect J,Johnson PC,McKinsey DS,Bamberger DM,Hamill R,Sharkey PK,Chapman SW,Sobel JD, Alopecia associated with fluconazole therapy. Annals of internal medicine. 1995 Sep 1     [PubMed PMID: 7625624]
[5] Alsaad AM,Kaplan YC,Koren G, Exposure to fluconazole and risk of congenital malformations in the offspring: A systematic review and meta-analysis. Reproductive toxicology (Elmsford, N.Y.). 2015 Apr     [PubMed PMID: 25724389]