Fluconazole

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Fluconazole
Fluconazole skeletal formula.svg
Fluconazole ball-and-stick model.png
Clinical data
Trade names Diflucan, others
AHFS/Drugs.com Monograph
MedlinePlus a690002
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth, intravenous, topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability >90% (oral)
Protein binding 11–12%
Metabolism Liver 11%
Elimination half-life 30 hours (range 20–50 hours)
Excretion Kidney 61–88%
Identifiers
  • 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.156.133 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C13H12F2N6O
Molar mass 306.277 g·mol−1
3D model (JSmol)
Melting point 139 [4]  °C (282 °F)
  • OC(Cn1cncn1)(Cn1cncn1)c1ccc(F)cc1F
  • InChI=1S/C13H12F2N6O/c14-10-1-2-11(12(15)3-10)13(22,4-20-8-16-6-18-20)5-21-9-17-7-19-21/h1-3,6-9,22H,4-5H2 Yes check.svgY
  • Key:RFHAOTPXVQNOHP-UHFFFAOYSA-N Yes check.svgY
   (verify)

Fluconazole is an antifungal medication used for a number of fungal infections. [5] This includes candidiasis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and tinea versicolor. [5] It is also used to prevent candidiasis in those who are at high risk such as following organ transplantation, low birth weight babies, and those with low blood neutrophil counts. [5] It is given either by mouth or by injection into a vein. [5]

Contents

Common side effects include vomiting, diarrhea, rash, and increased liver enzymes. [5] Serious side effects may include liver problems, QT prolongation, and seizures. [5] During pregnancy it may increase the risk of miscarriage while large doses may cause birth defects. [6] [5] Fluconazole is in the azole antifungal family of medication. [5] It is believed to work by affecting the fungal cellular membrane. [5]

Fluconazole was patented in 1981 and came into commercial use in 1988. [7] It is on the World Health Organization's List of Essential Medicines. [8] Fluconazole is available as a generic medication. [5] In 2021, it was the 165th most commonly prescribed medication in the United States, with more than 3 million prescriptions. [9] [10]

Medical uses

Fluconazole is a first-generation triazole antifungal medication. It differs from earlier azole antifungals (such as ketoconazole) in that its structure contains a triazole ring instead of an imidazole ring. While the imidazole antifungals are mainly used topically, fluconazole and certain other triazole antifungals are preferred when systemic treatment is required because of their improved safety and predictable absorption when administered orally. [11]

Fluconazole's spectrum of activity includes most Candida species (but not Candida krusei or Candida glabrata ), Cryptococcus neoformans , some dimorphic fungi, and dermatophytes, among others.[ medical citation needed ] Common uses include: [2] [11] [12] [13] [14]

Resistance

Antifungal resistance to drugs in the azole class tends to occur gradually over the course of prolonged drug therapy, resulting in clinical failure in immunocompromised patients (e.g., patients with advanced HIV receiving treatment for thrush or esophageal Candida infection). [15]

In C. albicans , resistance occurs by way of mutations in the ERG11 gene, which codes for 14α-demethylase. These mutations prevent the azole drug from binding, while still allowing binding of the enzyme's natural substrate, lanosterol. Development of resistance to one azole in this way will confer resistance to all drugs in the class. Another resistance mechanism employed by both C. albicans and C. glabrata is increasing the rate of efflux of the azole drug from the cell, by both ATP-binding cassette and major facilitator superfamily transporters. Other gene mutations are also known to contribute to development of resistance. [15] C. glabrata develops resistance by up regulating CDR genes, and resistance in C. krusei is mediated by reduced sensitivity of the target enzyme to inhibition by the agent. [2]

The full spectrum of fungal susceptibility and resistance to fluconazole can be found in the product data sheet. [16] According to the US Centers for Disease Control and Prevention, fluconazole resistance among Candida strains in the US is about 7%. [17]

Combating Resistance

The rising fungal resistance to fluconazole and related azole drugs spurs the need to find effective combative solutions swiftly. Rising resistance raises concerns since fluconazole is commonly used due to its inexpensiveness and ease of administration, according to the World Health Organization. [18]

One possible solution to counter the increasing prevalence of Candida infections–fungal infections caused by the yeast Candida–is combination antifungal therapy, combining natural components with commercial antifungal drugs to combat resistance. [19] Research shows that natural substances can have specified interactions with cell components, increasing the intracellular concentration of associated antifungal drugs and their effectiveness. For example, Brazilian red propolis, an organic bee liquid, synergizes with fluconazole to combat common yeast infections such as C. parapsilosis and C. glabrata. The essential oil from Nectandra lanceolata, a tree species native to wet tropical biomes, plays a similar role in ciclopirox, another common antifungal. [18]

While combination therapy offers the benefits of faster and more extensive fungal eradication, including a reduced risk of resistance or tolerance, it also presents challenges. These include potential increases in toxicity, costs, and the need for standardized practices to test the efficacy of the combination. Therefore, it is crucial to critically evaluate the role of combination therapy.

Echinocandin Rezafungin.svg
Echinocandin

An alternative to combination therapy for those who had prior exposure to Azoles is antifungal drugs of class echinocandins, recommended as the first method of treatment against invasive candidiasis. The three echinocandins currently licensed for medical use, namely anidulafungin, caspofungin, and micafungin, are potent against candidiasis, which has grown resistant to fluconazole because of the differences in their action mechanism. However, resistance to echinocandins can still develop through point mutations within highly conserved regions of the FKS1 and FKS2 genes through the exposure of members of this class. These genes encode for an enzyme called β-1,3-glucan synthase, responsible for building the yeast’s cell wall. Mutations in this enzyme reduce resistance to antifungal medications that target this enzyme and affect the yeast’s ability to construct its cell wall.

Another promising avenue is the integration of phage therapy, which has shown successive results in functional therapies. Phages, viruses that infect microbes including fungi, exhibit potent antimicrobial effects against various resistant fungal strains, demonstrating remarkable specificity and efficacy. [20] These viruses are integral components of diverse ecosystems, including the human microbiome. Their unique attributes, such as specificity, potency, compatibility with biological systems, and ability to kill fungi, make them attractive candidates for therapeutic interventions. However, challenges remain in terms of their production scalability, formulation, stability, and the emergence of fungal resistance, which hinders their widespread adoption. Prior to clinical use, phages intended for therapy require thorough purification, characterization, and validation of their virulence. While further research is needed, phage therapy holds promise in the fight against antifungal resistance that other therapies struggle to address.

Contraindications

Fluconazole is contraindicated in patients who: [14]

Side effects

Adverse drug reactions associated with fluconazole therapy include: [14]

If taken during pregnancy it may result in harm. [22] [23] These cases of harm, however, were only in women who took large doses for most of the first trimester. [22]

Fluconazole is secreted in human milk at concentrations similar to plasma. [2]

Fluconazole therapy has been associated with QT interval prolongation, which may lead to serious cardiac arrhythmias. Thus, it is used with caution in patients with risk factors for prolonged QT interval, such as electrolyte imbalance or use of other drugs that may prolong the QT interval (particularly cisapride and pimozide). [24]

Some people are allergic to azoles, so those allergic to other azole drugs might be allergic to fluconazole. [25] That is, some azole drugs have adverse side-effects. Some azole drugs may disrupt estrogen production in pregnancy, affecting pregnancy outcome. [26]

Oral fluconazole is not associated with a significantly increased risk of birth defects overall, although it does increase the odds ratio of tetralogy of Fallot, but the absolute risk is still low. [27] Women using fluconazole during pregnancy have a 50% higher risk of spontaneous abortion. [28]

Fluconazole should not be taken with cisapride (Propulsid) due to the possibility of serious, even fatal, heart problems. [24] In rare cases, severe allergic reactions including anaphylaxis may occur. [29]

Powder for oral suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption or sucrase-isomaltase deficiency. Capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption [30]

Interactions

Fluconazole is an inhibitor of the human cytochrome P450 system, particularly the isozyme CYP2C19 (CYP3A4 and CYP2C9 to lesser extent) [31] In theory, therefore, fluconazole decreases the metabolism and increases the concentration of any drug metabolised by these enzymes. In addition, its potential effect on QT interval increases the risk of cardiac arrhythmia if used concurrently with other drugs that prolong the QT interval. Berberine has been shown to exert synergistic effects with fluconazole even in drug-resistant Candida albicans infections. [32] Fluconazole may increase the serum concentration of Erythromycin (Risk X: avoid combination). [31]

Pharmacology

Pharmacodynamics

Like other imidazole- and triazole-class antifungals, fluconazole inhibits the fungal cytochrome P450 enzyme 14α-demethylase. Mammalian demethylase activity is much less sensitive to fluconazole than fungal demethylase. This inhibition prevents the conversion of lanosterol to ergosterol, an essential component of the fungal cytoplasmic membrane, and subsequent accumulation of 14α-methyl sterols. [33] Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus. [34]

Pharmacokinetics

Following oral dosing, fluconazole is almost completely absorbed within two hours. [35] Bioavailability is not significantly affected by the absence of stomach acid. Concentrations measured in the urine, tears, and skin are approximately 10 times the plasma concentration, whereas saliva, sputum, and vaginal fluid concentrations are approximately equal to the plasma concentration, following a standard dose range of between 100 mg and 400 mg per day. [36] The elimination half-life of fluconazole follows zero order, and only 10% of elimination is due to metabolism, the remainder being excreted in urine and sweat. Patients with impaired renal function will be at risk of overdose. [24]

In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. [37]

History

Fluconazole was patented by Pfizer in 1981 in the United Kingdom and came into commercial use in 1988. [7] Patent expirations occurred in 2004 and 2005. [38]

Related Research Articles

<span class="mw-page-title-main">Candidiasis</span> Fungal infection due to any type of Candida

Candidiasis is a fungal infection due to any species of the genus Candida. When it affects the mouth, in some countries it is commonly called thrush. Signs and symptoms include white patches on the tongue or other areas of the mouth and throat. Other symptoms may include soreness and problems swallowing. When it affects the vagina, it may be referred to as a yeast infection or thrush. Signs and symptoms include genital itching, burning, and sometimes a white "cottage cheese-like" discharge from the vagina. Yeast infections of the penis are less common and typically present with an itchy rash. Very rarely, yeast infections may become invasive, spreading to other parts of the body. This may result in fevers, among other symptoms.

<span class="mw-page-title-main">Antifungal</span> Pharmaceutical fungicide or fungistatic used to treat and prevent mycosis

An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others. Such drugs are usually obtained by a doctor's prescription, but a few are available over the counter (OTC). The evolution of antifungal resistance is a growing threat to health globally.

<span class="mw-page-title-main">Itraconazole</span> Medication used to treat fungal infections

Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mouth or intravenously.

<span class="mw-page-title-main">Ketoconazole</span> Antifungal chemical compound

Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candidiasis, pityriasis versicolor, dandruff, and seborrheic dermatitis. Taken by mouth it is a less preferred option and only recommended for severe infections when other agents cannot be used. Other uses include treatment of excessive male-patterned hair growth in women and Cushing's syndrome.

<i>Coccidioides immitis</i> Species of fungus

Coccidioides immitis is a pathogenic fungus that resides in the soil in certain parts of the southwestern United States, northern Mexico, and a few other areas in the Western Hemisphere.

<span class="mw-page-title-main">Caspofungin</span> Antifungal medication

Caspofungin is a lipopeptide antifungal drug from Merck & Co., Inc.. It is a member of a class of antifungals termed the echinocandins. It works by inhibiting the enzyme (1→3)-β-D-glucan synthase and thereby disturbing the integrity of the fungal cell wall.

<span class="mw-page-title-main">Terconazole</span> Chemical compound

Terconazole is an antifungal drug used to treat vaginal yeast infection. It comes as a lotion or a suppository and disrupts the biosynthesis of fats in a yeast cell. It has a relatively broad spectrum compared to azole compounds but not triazole compounds. Testing shows that it is a suitable compound for prophylaxis for those that suffer from chronic vulvovaginal candidiasis.

<span class="mw-page-title-main">Fungemia</span> Internal, blood-borne infection by fungi, including yeasts.

Fungemia is the presence of fungi or yeast in the blood. The most common type, also known as candidemia, candedemia, or systemic candidiasis, is caused by Candida species. Candidemia is also among the most common bloodstream infections of any kind. Infections by other fungi, including Saccharomyces, Aspergillus and Cryptococcus, are also called fungemia. It is most commonly seen in immunosuppressed or immunocompromised patients with severe neutropenia, cancer patients, or in patients with intravenous catheters. It has been suggested that otherwise immunocompetent patients taking infliximab may also be at a higher risk.

<span class="mw-page-title-main">Anidulafungin</span> Antifungal medication

Anidulafungin (INN) is a semisynthetic echinocandin used as an antifungal drug. It was previously known as LY303366. It may also have application in treating invasive Aspergillus infection when used in combination with voriconazole. It is a member of the class of antifungal drugs known as the echinocandins; its mechanism of action is by inhibition of (1→3)-β-D-glucan synthase, an enzyme important to the synthesis of the fungal cell wall.

<span class="mw-page-title-main">Flucytosine</span> Chemical compound

Flucytosine, also known as 5-fluorocytosine (5-FC), is an antifungal medication. It is specifically used, together with amphotericin B, for serious Candida infections and cryptococcosis. It may be used by itself or with other antifungals for chromomycosis. Flucytosine is used by mouth and by injection into a vein.

<span class="mw-page-title-main">Posaconazole</span> Pharmaceutical drug

Posaconazole, sold under the brand name Noxafil among others, is a triazole antifungal medication.

<span class="mw-page-title-main">Echinocandin</span> Group of chemical compounds

Echinocandins are a class of antifungal drugs that inhibit the synthesis of β-glucan in the fungal cell wall via noncompetitive inhibition of the enzyme 1,3-β glucan synthase. The class has been termed the "penicillin of antifungals," along with the related papulacandins, as their mechanism of action resembles that of penicillin in bacteria. β-glucans are carbohydrate polymers that are cross-linked with other fungal cell wall components, the fungal equivalent to bacterial peptidoglycan. Caspofungin, micafungin, and anidulafungin are semisynthetic echinocandin derivatives with limited clinical use due to their solubility, antifungal spectrum, and pharmacokinetic properties.

<span class="mw-page-title-main">Sterol 14-demethylase</span> Class of enzymes

In enzymology, a sterol 14-demethylase (EC 1.14.13.70) is an enzyme of the cytochrome P450 (CYP) superfamily. It is any member of the CYP51 family. It catalyzes a chemical reaction such as:

<span class="mw-page-title-main">Clotrimazole</span> Chemical compound

Clotrimazole, sold under the brand name Lotrimin, among others, is an antifungal medication. It is used to treat vaginal yeast infections, oral thrush, diaper rash, tinea versicolor, and types of ringworm including athlete's foot and jock itch. It can be taken by mouth or applied as a cream to the skin or in the vagina.

<span class="mw-page-title-main">Isavuconazonium</span> Chemical compound

Isavuconazonium, sold under the brand name Cresemba, is a systemic antifungal medication of the triazole class which is used to treat invasive aspergillosis and mucormycosis. It is used as the sulfate. It is taken by mouth or given via injection into a vein.

<span class="mw-page-title-main">Vaginal yeast infection</span> Medical condition

Vaginal yeast infection, also known as candidal vulvovaginitis and vaginal thrush, is excessive growth of yeast in the vagina that results in irritation. The most common symptom is vaginal itching, which may be severe. Other symptoms include burning with urination, a thick, white vaginal discharge that typically does not smell bad, pain during sex, and redness around the vagina. Symptoms often worsen just before a woman's period.

Invasive candidiasis is an infection (candidiasis) that can be caused by various species of Candida yeast. Unlike Candida infections of the mouth and throat or vagina, invasive candidiasis is a serious, progressive, and potentially fatal infection that can affect the blood (fungemia), heart, brain, eyes, bones, and other parts of the body.

<i>Candida tropicalis</i> Species of fungus

Candida tropicalis is a species of yeast in the genus Candida. It is a common pathogen in neutropenic hosts, in whom it may spread through the bloodstream to peripheral organs. For invasive disease, treatments include amphotericin B, echinocandins, or extended-spectrum triazole antifungals.

Topical antifungaldrugs are used to treat fungal infections on the skin, scalp, nails, vagina or inside the mouth. These medications come as creams, gels, lotions, ointments, powders, shampoos, tinctures and sprays. Most antifungal drugs induce fungal cell death by destroying the cell wall of the fungus. These drugs inhibit the production of ergosterol, which is a fundamental component of the fungal cell membrane and wall.

<span class="mw-page-title-main">Oteseconazole</span> Chemical compound

Oteseconazole, a novel orally bioavailable and selective inhibitor of fungal cytochrome P450 enzyme 51 (CYP51), has shown promising efficacy in the treatment of recurrent vulvovaginal candidiasis (RVVC) in patients.

References

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