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Antifungal Ergosterol Synthesis Inhibitors

Editor: Muhammad F. Hashmi Updated: 2/19/2023 2:13:14 PM


Invasive infections with fungi are continuing to increase and cause significant morbidity and mortality.[1] Ergosterol is a sterol present in the cell membranes of fungi, serving many of the same cell membrane functions as cholesterol in humans. Since ergosterol is not a component of animal cells, it serves as an inviting target for antifungal drugs. Systemic and nosocomial fungal infections have been increasing in recent years, and the number of treatment-resistant infections has also increased. Therefore newer therapies that can overcome this resistance are necessary; triazole antifungals have demonstrated some of the most potent antifungal properties.[2]

Miconazole and ketoconazole were among the first triazoles synthesized, but safety profile concerns limitations associated with their use. Subsequent generations of triazoles such as voriconazole, posaconazole, efinaconazole, ravuconazole, and isavuconazole all derive from second-generation conazoles itraconazole or fluconazole. They are designed to alleviate the deficiencies of their parent drugs and generally have a broader spectrum of activity.[2]

The azole family of antifungal agents has indications for many fungal pathogens. They have relatively few adverse effects compared with older agents such as amphotericin B. The triazole family has largely supplanted the use of early azoles, such as ketoconazole, due to improved safety and efficacy. Each of the five members of the triazole family (fluconazole, voriconazole, itraconazole, posaconazole, and isavuconazole) has different characteristics that prove each one effective for specific cases.[3] Ketoconazole is a common topical antifungal for cutaneous fungal infections, including cutaneous candidiasis, seborrheic dermatitis, tinea infections, and certain types of dandruff.[4]

FDA-approved indications for the various agents in this class of drugs:

  • Miconazole: oropharyngeal, vulvovaginal, and cutaneous candidiasis, tinea corporis, tinea cruris, tinea pedis, tinea versicolor
  • Ketoconazole: tinea infections, cutaneous candidiasis, pityriasis versicolor, seborrheic dermatitis
  • Fluconazole: esophageal, oropharyngeal, and vulvovaginal candidiasis, systemic candidiasis, cryptococcal meningitis, and fungal prophylaxis for bone marrow transplant patients
  • Itraconazole: onychomycosis of the toenails and fingernails, oropharyngeal and esophageal candidiasis, blastomycosis, histoplasmosis, invasive aspergillosis
  • Voriconazole: various severe fungal infections, invasive aspergillosis, candidemia in non-neutropenic patients
  • Posaconazole: prophylaxis for invasive fungal infections in immunocompromised patients and invasive aspergillosis
  • Efinaconazole: onychomycosis of the toenails[5]
  • Isavuconazonazole: aspergillosis and mucomycosis[6]

Mechanism of Action

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Mechanism of Action

The general mechanism of action by which the azole antifungal family works is by inhibiting lanosterol 14-alpha-demethylase, which converts lanosterol to ergosterol in fungus cellular membranes.[7] The inability to produce ergosterol increases the membrane's permeability, which results in cell lysis and death. Although these drugs cause cell death, they are still considered fungistatic in their actions.


All azole antifungals are involved in drug-drug interactions via cytochrome P450 enzyme metabolism.[8] Each family member is metabolized by and also affects this oxidative drug metabolism to a certain extent. Fluconazole strongly inhibits CYP2C19 and moderately inhibits CYP2C9 and CYP3A4, but it is only a weak substrate. Itraconazole is a potent inhibitor and a substrate of CYP3A4. Voriconazole is a potent inhibitor of CYP3A4, a moderate inhibitor of CYP2C19, a weak inhibitor of CYP2C9, and has not been shown to be a substrate. Posaconazole inhibits CYP3A4 but does not get metabolized by cytochrome P450. Isavuconazole moderately inhibits CYP3A4 and cannot be cleared if combined with other drugs that either induce or inhibit CYP3A4. Ketoconazole strongly inhibits and is metabolized by CYP3A4.[9] Drugs that induce the CYP enzymes cause faster metabolism of the antifungals - the most potent being rifampin.[10] Other examples include rifabutin, phenobarbital, carbamazepine, phenytoin, chronic alcohol use, and St. John's wort. Due to the inhibitory effects of azoles on the CYP enzymes, dose reductions may be needed for other substrates such as warfarin to prevent toxicity.


Fluconazole is available in oral and intravenous dosing. Oral doses are available in both suspension and tablets as either brand name or generic. Both suspensions are available as either 10 mg/mL or 40 mg/mL doses. Both tablets are available as 50 mg, 100 mg, 150 mg, or 200 mg tablets. The intravenous dosing is available in generic 100 mg/50 mL in NaCl 0.9% or 200 mg/100 mL in NaCl 0.9%. Ketoconazole is popular in topical cream, foam, gel, and shampoo forms. The 1% ketoconazole shampoo can be purchased over-the-counter (OTC).

The dosing of the azole medications varies due to the presenting condition. The presence of severe diseases, such as CNS blastomycosis, initial candidemia therapy, infections of cardiac valves, intra-abdominal infections, and endophthalmitis, requires loading doses of 800 mg once daily for several weeks or months followed by step-down dosing of 400 mg once daily for at least two weeks.

Esophageal candidiasis therapy includes a loading dose followed by daily dosing for up to 3 weeks. Some of the azole treatments - such as ketoconazole tablets, itraconazole capsules, and posaconazole solution - need gastric acid to be absorbed. Therefore antacids, histamine-2 blockers, and proton pump inhibitors decrease the absorption of these dosing types.[11] 

For specific dosing based on indication, please see articles on the individual agents.

Doses vary depending on the type of infection and the drug of choice.

  • Miconazole: Is administered topically, vaginally, and buccally for oropharyngeal infections.
  • Ketoconazole: For oral administration, dosing is 3.3 to 6.6 mg/kg body weight per day for two weeks. Dosages come in 200 mg tablets, and two 200 mg tablets or 0.5 mg tablets are the dosing options for prophylaxis of vaginal infections. The 1% ketoconazole shampoo can be purchased over-the-counter.
  • Fluconazole: The dose is between 3 and 8 mg/kg body weight per day for 1 to 8 weeks. Doses are shorter for cutaneous infections and longer for mycoses. Doses come in 50, 100, and 200 mg tablets. There is a 150 mg tablet for vaginal infections. 150 mg can be used weekly or monthly for prophylaxis. It is also available and administered intravenously.
  • Itraconazole: Dosing is 5 mg/kg body weight for 1 to 6 weeks; dose regimens are shorter for cutaneous infections and longer for mycoses. Dosing can be in pulses or continuous. The drug comes in 100 mg capsules.
  • Voriconazole: This drug is available in tablets and as a suspension. It can also be administered IV, and it has weight-based dosing for most infections.
  • Posaconazole: Available as a suspension, IV, and delayed-release tablets. Doses range from 200 mg to 400 mg daily for a period of weeks, depending on the type of infection. It does not require dose adjustment for hepatic insufficiency.
  • Efinaconazole: This agent comes as a topical solution only for use on toenail fungus. It is applied once daily for 48 weeks.
  • Isavuconazole: Dosed 324 mg orally or IV every 24 hours.

Adverse Effects

The conazole family of drugs usually is well tolerated but may have some adverse effects [12]:

  • Drug-induced hepatitis
  • Pruritus
  • Allergic rashes
  • Diarrhea
  • Nausea and vomiting
  • Lethargy
  • Anorexia

Prenatal exposure to conazole antifungals correlates with a shorter anogenital distance in male offspring due to the anti-androgenic properties of the drugs.[13]

Conazoles can increase the toxicity of other drugs when combined with drugs that are also metabolized by the CYP enzymes.


The adverse effects of topical conazole drugs are mild. Therefore contraindications include:

  • Hypersensitivity reaction
  • Anaphylaxis

Systemic ingestion of the conazole drugs available for systemic administration is either contraindicated or merits extreme caution in the following situations:

  • Abnormal liver function tests
  • Chronic kidney disease stage 3A or worse
  • Hypokalemia
  • Hypomagnesemia
  • Prolonged QTc interval
  • QTc abnormalities
  • Torsades de pointes
  • Pregnancy


Most conazole drugs require hepatic monitoring and even discontinuation of therapy if liver enzymes increase above normal limits in response to systemic therapy. Elevated ALT above baseline requires interruption of therapy due to the risk of drug-induced hepatitis. Patients may resume treatment when the liver function returns to baseline.[14] Impaired renal function does not require dosing adjustments.


The patient should discontinue any conazole drug if a hypersensitivity reaction or anaphylaxis occurs. An analysis of 204 studies of ketoconazole-associated hepatotoxicity concluded an incidence of 3.6% to 4.2%. The dose and duration of treatment did not show a significant difference between study groups. Oral therapy had a higher incidence of hepatotoxicity than topical treatment.[15] The patient should be monitored for hepatotoxicity and should discontinue the drug if liver enzymes start to rise above the baseline. Ketoconazole has a higher incidence of hepatotoxicity than fluconazole. The physician and patient should consider if the benefits outweigh the risks.

Enhancing Healthcare Team Outcomes

Fungal infections have become a much more significant issue globally, and research is accordingly directing its efforts to answer this problem, especially as antimicrobial resistance increases.[16] Ergosterol synthesis inhibiting drugs are a mainstay, and newer-generation agents offer better safety and adverse event profiles than their earlier counterparts. The most significant adverse event when administered systemically is hepatotoxicity for most agents.

Overseeing and managing antifungal therapy with conazole drugs requires an interprofessional team approach. Clinicians (physicians, PAs, NPs) will prescribe or order the medication as appropriate for various infections, including cutaneous fungal infections such as athlete’s foot, dandruff, and tinea versicolor. It is also useful for more invasive fungal infections such as blastomycosis, histoplasmosis, and coccidioidomycosis.[17] While these agents are generally safe with only mild adverse effects, some agents like ketoconazole carry a risk of severe adverse effects such as hepatotoxicity, and this requires discussion before the initiation of treatment.[15]

Due to interactions with many other drugs metabolized by CYP enzymes, physicians and pharmacists need to communicate about the patient’s medications to be certain that there will be little or no adverse events due to drug-drug interactions. Nursing will coordinate with the clinician and pharmacy staff and provide patient counsel and answer questions, referring the patient to the pharmacist if necessary. Using an interprofessional team approach is vital to ensuring the safety of the patient. Therefore all healthcare workers need to coordinate their activities and share information to monitor the patient to get the most beneficial health outcomes. [Level 5]



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