Azole antifungals

• Definition

• Azole antifungals are a broad class of synthetic or semi-synthetic agents that inhibit fungal growth by targeting ergosterol biosynthesis, an essential component of fungal cell membranes

• They are used in the prevention and treatment of a wide spectrum of superficial, subcutaneous, and systemic fungal infections

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• Classification

1. Imidazoles – contain two nitrogen atoms in the azole ring; typically used topically but some have systemic applications

   • Examples: Clotrimazole, miconazole, ketoconazole, econazole, tioconazole, sulconazole, oxiconazole, bifonazole, sertaconazole

2. Triazoles – contain three nitrogen atoms in the azole ring; generally have improved potency, broader spectrum, and better pharmacokinetics than imidazoles, often used systemically

   • Examples: Fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole

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• Mechanism of Action

• Inhibit fungal cytochrome P450-dependent enzyme lanosterol 14α-demethylase

• This blocks conversion of lanosterol to ergosterol, disrupting fungal cell membrane structure and function

• Result: Increased membrane permeability, leakage of intracellular contents, inhibition of fungal growth and replication

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• Spectrum of Activity

• Imidazoles: Effective against dermatophytes (Trichophyton, Microsporum, Epidermophyton), yeasts (Candida spp., Malassezia furfur), some dimorphic fungi

• Triazoles: Broader coverage including dermatophytes, yeasts, dimorphic fungi (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis), and molds (Aspergillus spp. – especially with itraconazole, voriconazole, posaconazole)

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• Therapeutic Uses

1. Superficial Mycoses

   • Tinea pedis, tinea cruris, tinea corporis, tinea versicolor

   • Cutaneous candidiasis

   • Onychomycosis (itraconazole, fluconazole, ketoconazole topical)

2. Mucosal Candidiasis

   • Oral thrush, esophageal candidiasis (fluconazole, itraconazole)

   • Vaginal candidiasis (fluconazole single oral dose, clotrimazole/miconazole topical)

3. Systemic Mycoses

   • Itraconazole: histoplasmosis, blastomycosis, sporotrichosis, onychomycosis

   • Voriconazole: invasive aspergillosis, serious infections by Fusarium spp., Scedosporium spp.

   • Posaconazole: prophylaxis in immunocompromised patients, mucormycosis salvage therapy

   • Isavuconazole: invasive aspergillosis, mucormycosis

4. Prophylaxis

   • Posaconazole or fluconazole in high-risk immunosuppressed patients (e.g., post-hematopoietic stem cell transplant)

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• Dosage Considerations

• Dosing varies significantly between agents due to differences in absorption, half-life, and formulation

• Fluconazole: excellent oral bioavailability, once-daily dosing

• Itraconazole: capsule absorption enhanced by food/acidic beverage; solution better absorbed fasting

• Voriconazole: non-linear pharmacokinetics, requires therapeutic drug monitoring in some patients

• Posaconazole: delayed-release tablets and IV forms have improved bioavailability over suspension

• Isavuconazole: available as prodrug isavuconazonium sulfate; once-daily dosing after loading

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• Contraindications

• Known hypersensitivity to azoles

• Concomitant use with certain drugs metabolized by CYP3A4 that may cause QT prolongation (e.g., quinidine, cisapride)

• Ketoconazole oral use avoided for superficial infections due to hepatotoxicity risk and drug interactions

• Caution in pregnancy: most azoles are category C; fluconazole high-dose/long-term linked to birth defects

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• Adverse Effects

1. Common

   • Nausea, vomiting, abdominal pain, diarrhea

   • Headache, dizziness

2. Serious

   • Hepatotoxicity: elevated liver enzymes to severe hepatic failure

   • QT prolongation (except isavuconazole, which shortens QT interval)

   • Visual disturbances and hallucinations (voriconazole)

   • Adrenal suppression (ketoconazole, high doses of other azoles)

   • Rash, including Stevens-Johnson syndrome (rare)

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• Precautions

• Monitor liver function before and during prolonged therapy

• Dose adjustment in renal impairment for fluconazole (predominantly renal clearance)

• Consider therapeutic drug monitoring for itraconazole, voriconazole, posaconazole in long-term or serious infections

• Avoid prolonged sun exposure with voriconazole due to photosensitivity risk

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• Drug Interactions

• Potent inhibitors of CYP3A4 (especially ketoconazole, itraconazole, voriconazole), CYP2C9 (fluconazole, voriconazole), CYP2C19 (fluconazole, voriconazole)

• Increase plasma concentrations of drugs metabolized by these enzymes (e.g., warfarin, statins, calcineurin inhibitors, benzodiazepines, certain antiretrovirals)

• Inducers of CYP3A4 (e.g., rifampicin, phenytoin, carbamazepine) reduce azole levels, risking treatment failure

• PPIs and H2 antagonists reduce absorption of ketoconazole, itraconazole capsules

• Coadministration with drugs that prolong QT may increase risk of arrhythmia (except isavuconazole)

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• Resistance Mechanisms

• Alterations in target enzyme (lanosterol 14α-demethylase)

• Overexpression of efflux pumps

• Changes in membrane sterol composition

• Biofilm formation in Candida spp. reducing drug penetration

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• Clinical Considerations

• Drug selection guided by infecting organism, site of infection, patient comorbidities, and susceptibility patterns

• For systemic and invasive infections, azole choice often based on spectrum and patient-specific PK/PD factors

• Long-term use requires vigilance for hepatotoxicity and drug-drug interactions

• In immunocompromised hosts, prophylaxis with broad-spectrum triazoles may be lifesaving but increases resistance pressure