Invasive infections with fungi are continuing to increase and cause significant morbidity and mortality.[1] The azole family of antifungal agents has indications for many fungal pathogens. They have few adverse effects compared with amphotericin B. The triazole family has mostly replaced 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. Ketoconazole is a common topical antifungal for cutaneous fungal infections, including cutaneous candidiasis, seborrheic dermatitis, tinea infections, and dandruff.[2]

The azole antifungal family works by inhibiting lanosterol 14-alpha-demethylase, which converts lanosterol to ergosterol in fungus cellular membranes.[3] The inability to produce ergosterol increases the permeability of the membrane, which causes 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.[4] Each family member is both metabolized by and affect this oxidative drug metabolism to a certain extent. Fluconazole strongly inhibits CYP2C19 and moderately inhibits CYP2C9 and CYP3A4, but 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 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.[5] Drugs that induce the CYP enzymes cause faster metabolism of the antifungals - the most potent being rifampin.[6] Other examples include rifabutin, phenobarbital, carbamazepine, phenytoin, chronic alcohol use, and St. Johns 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 illness present. 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 of 400 mg, followed by 200 to 400 mg once daily dosing for up to 3 weeks. For less invasive infections such as cystitis and pyelonephritis, 200 mg once daily for two weeks is sufficient. For vaginal candidiasis, 150 mg single dose or every 72 hours for up to 2 weeks for severe or recurrent cases. 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.[7] 

Doses vary depending on the type of infection and the drug of choice. Fluconazole: The dose of 3 to 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. Ketoconazole: The dose of 3.3 to 6.6 mg/kg body weight per day for two weeks. Dosages come in 200 mg tablets. 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. Itraconazole: The dose of 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.

The conazole family of drugs usually is well tolerated but may have some adverse effects [8]:

Increase the toxicity of other drugs when combined with drugs that are also metabolized by CYP.

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

Prenatal exposure to conazole antifungals has correlations with a shorter anogenital distance in male offspring due to the anti-androgenic properties of the drugs.[9]

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

• Hypersensitivity reaction
• Anaphylaxis

Systemic ingestion is contraindicated, or merits extreme caution, in the following situations:

• Abnormal LFTs
• Chronic kidney disease stage 3A or worse
• Hypokalemia
• Hypomagnesemia
• Prolonged QTc interval
• QTc abnormalities
• Torsades de Pointes
• Pregnancy