Continuing Education Activity

This activity delves into the pharmacological intricacies of antifungal ergosterol synthesis inhibitors, commonly called "azoles." These medications, encompassing miconazole, ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole, and oteseconazole, play a crucial role in managing diverse fungal infections. The primary mechanism of action involves the inhibition of ergosterol biosynthesis, leading to the disruption of fungal cell membrane integrity. Exploring these azole antifungal agents involves covering indications, contraindications, drug interactions, and adverse event profiles. Notably, the potential for hepatotoxicity necessitates vigilant monitoring and interprofessional communication. These agents' scientific and medical examination includes in-depth discussions on pharmacokinetics, monitoring protocols, clinical toxicology, and elucidating significant box warnings.

By imparting insights into absorption, distribution, metabolism, and elimination, healthcare professionals will be equipped to make informed decisions, ensuring optimal patient outcomes. The emphasis on adverse drug reactions, such as QT interval prolongation and hepatotoxicity, along with a thorough exploration of contraindications, empowers clinicians with the knowledge essential for safe prescribing practices, ultimately enhancing collaborative patient care.

Objectives:

• Identify the mechanism of action of azole antifungal drugs.

• Identify the potential adverse effects of the azole antifungal drugs.

• Select the necessary patient monitoring when prescribing azole antifungal drugs.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from azole therapy.

Indications

The incidence of invasive fungal infections is increasing, leading to 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 is an inviting target for antifungal drugs. There has been an increase in systemic and nosocomial fungal infections in recent years, with a corresponding rise in treatment-resistant cases. 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. Due to improved efficacy and safety, the triazole family has largely replaced early azoles, such as ketoconazole. Each member of the triazole family, including fluconazole, itraconazole, voriconazole, isavuconazole, and posaconazole, possesses distinct characteristics that make them practical for specific indications.[3] Ketoconazole is a common topical antifungal medication for cutaneous fungal infections, including cutaneous candidiasis, seborrheic dermatitis, tinea infections, and certain types of dandruff.[4] Itraconazole absorption is influenced by food, leading to unpredictable plasma levels of itraconazole. The FDA has approved a novel formulation called SUper BioAvailable SUBA-itraconazole.[5] Oteseconazole received FDA approval in April 2022 for the indication of recurrent vulvovaginal candidiasis in females with a history of RVVC who are not of reproductive potential.[6]

FDA-approved Indications

• 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: Severe fungal infections, including invasive aspergillosis and candidemia in non-neutropenic patients
• Posaconazole: Prophylaxis for invasive fungal infections in immunocompromised patients and invasive aspergillosis
• Efinaconazole: Onychomycosis of the toenails [7]
• Isavuconazonazole: Aspergillosis and mucomycosis [8][9]
• Oteseconazole: Recurrent vulvovaginal candidiasis [10]

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.[11] 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.

Clinical Pharmacokinetics

All azole antifungals are involved in drug-drug interactions via cytochrome P450 enzyme metabolism.[12] Each family member is metabolized by and 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 is not 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.[13] Drugs that induce the CYP enzymes cause faster metabolism of the antifungals, the most potent being rifampin.[14] 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 to prevent toxicity when using other medications, such as warfarin. The other relevant pharmacokinetics is summarized in the table below.[15][16]

Administration

(a) Available Dosage Forms, Strengths and Adult Dosage

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 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 formulations. The 1% ketoconazole shampoo can be purchased over-the-counter (OTC). Oteseconazole is available in an oral formulation.

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 2 weeks.

Esophageal candidiasis therapy includes a loading dose followed by daily dosing for up to 3 weeks. Certain azole treatments, including ketoconazole tablets, itraconazole capsules, and posaconazole solution, rely on gastric acid for optimal absorption. Therefore, antacids, histamine-2 blockers, and proton pump inhibitors decrease the absorption of these dosing types.[19] Dosage and administration vary depending on the type of infection. Please see articles on the individual agents for specific dosing based on indication. Below is an overview of the administration.

• Miconazole: 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 2 weeks. Dosages come in 200 mg tablets or 0.5 mg tablets for prevention of vaginal infections. The 1% ketoconazole shampoo can be purchased over the counter.

• Fluconazole: The dosage 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 has weight-based dosing for most infections.

• Posaconazole: Available as a suspension, IV, and delayed-release tablet. Doses range from 200 mg to 400 mg daily, depending on the type of infection. It does not require dose adjustment for hepatic insufficiency.

• Efinaconazole: This agent is available as a topical solution for use on toenail fungus. It is applied once daily for 48 weeks.

• Isavuconazole: Administer 324 mg orally or intravenously every 24 hours. 

• Oteseconazole: Oteseconazole is prescribed for recurrent vulvovaginal candidiasis with an initial dose of 600 mg orally on day 1, followed by a 450 mg dose on day 2. Subsequently, starting on day 14, a maintenance dose of 150 mg is administered weekly for 11 weeks.

(b) Specific Patient Populations

(i) Hepatic impairment: According to a study, drug-induced liver injury is most commonly reported with voriconazole, fluconazole, and itraconazole. Use with caution in hepatic impairment. Consider dose reduction of itraconazole in hepatic impairment.[20][16]

(ii) Renal impairment: In the intravenous formulation of itraconazole, the carrier hydroxypropyl-β-cyclodextrin is excreted via glomerular filtration, potentially leading to accumulation in individuals with impaired renal function. Similarly, the intravenous formulation of voriconazole includes a cyclodextrin carrier that is eliminated in the urine, with potential accumulation in patients with renal impairment.[21] According to the available literature, therapeutic drug monitoring (TDM) with itraconazole, voriconazole, and posaconazole is advised for individuals undergoing treatment for invasive fungal infections.[22]

(iii) Pregnancy considerations: Prenatal exposure to azole antifungals correlates with a shorter anogenital distance in male offspring due to the anti-androgenic properties of the drugs.[23] Superficial fungal infections, such as vaginal candidiasis, pose a risk for adverse pregnancy and perinatal outcomes. The use of oral azoles in pregnant individuals may lead to potential maternal complications, including spontaneous abortions. Fetal malformations reported in association with oral azoles include congenital heart anomalies and eye defects. For mild cases during pregnancy, it is safe and preferred to use topical agents to reduce the risks.[24]

(iv) Breastfeeding considerations: Fluconazole is often prescribed in breastfeeding mothers.[25] However, topical antifungal agents like clotrimazole or miconazole result in minimal maternal serum concentrations, posing little risk to the nursing infant. Miconazole, with poor absorption from the skin and vagina and low oral bioavailability, is unlikely to affect breastfed infants adversely. Any excess cream should be removed before nursing, and water-miscible cream or gel products of miconazole and cotrimazole are recommended to avoid exposing the infant to high levels of mineral paraffin.[26][27]

(v) Pediatric patients: The safety and effectiveness of oteseconazole have not been established or approved for use in pediatric patients.

(vi) Older patients:  Pharmacokinetic changes associated with age are observed in older patients for azoles. Fluconazole's half-life increases in older patients, particularly those with renal impairment, necessitating a dose reduction.[28]

Adverse Effects

The azole family of drugs is usually well tolerated but may have some adverse effects:[29]

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

(a) Drug-Drug Interactions

Azoles can increase the toxicity of other drugs when combined with drugs that are also metabolized by the CYP enzymes. A summary of the drug interactions is given below.[16]

Ketoconazole

• Ketoconazole exerts inhibitory effects on cytochrome P450 enzyme CYP3A4, increasing plasma concentrations of drugs such as cyclosporine A, clarithromycin, and telithromycin.
• Ketoconazole should not be administered with dofetilide, quinidine, pimozide, lurasidone, cisapride, methadone, disopyramide, dronedarone, and ranolazine due to the potential for QT prolongation. Ketoconazole's interference with the metabolism of these drugs heightens the risk of serious cardiac arrhythmias, specifically torsades de pointes, necessitating caution and avoidance of concurrent use.

Fluconazole

• Fluconazole is a strong inhibitor of CYP3A4 and CYP2C9.
• Transplant recipients undergoing immunosuppression with CYP3A4 substrates like cyclosporine A, tacrolimus, or sirolimus face an elevated risk of adverse effects, including nephrotoxicity and over-immunosuppression, requiring dose reduction and vigilant therapeutic drug monitoring.[30]
• The combination of fluconazole with warfarin extends the prothrombin time, elevating the risk of bleeding.[31]
• Fluconazole's inhibition of phenytoin metabolism via CYP2C poses risks of hepatic and neurological adverse effects.
• Concurrent use of fluconazole with midazolam leads to a markedly prolonged sedative effect.[32]
• Levonorgestrel and ethinyl estradiol levels experience a moderate enhancement of 40% and 24% under fluconazole treatment.
• The Concomitant use of rifampicin (CYP3A inducer) and fluconazole resulted in significant alterations in fluconazole's pharmacokinetic parameters. Continuous monitoring is essential to evaluate the clinical relevance of this interaction in terms of recurrence rates in cryptococcal meningitis.[33]

Itraconazole

• Contraindicated coadministration with lovastatin, atorvastatin, simvastatin, or quinidine.[34]
• The coadministration of itraconazole can result in increased plasma levels of various CYP3A4 substrates, including midazolam, triazolam, cyclosporine A, tacrolimus, sirolimus, everolimus, methylprednisolone, warfarin, digoxin, carbamazepine, rifabutin, and anti-retroviral drugs like ritonavir, indinavir, and saquinavir.[35][36]

Voriconazole

• Potent inhibitor of CYP2C19, CYP2C9, and a moderate inhibitor of CYP3A4.
• Coadministration with immunosuppressants like sirolimus, cyclosporine A, and tacrolimus requires dose reduction and monitoring.[37]
• Voriconazole also interacts with vitamin K antagonists, benzodiazepines, opioids, sulfonylureas, and St. John's wort.

Posaconazole

• Strong CYP3A4 inhibitor, causing increased levels of tacrolimus, cyclosporine A, glipizide, and midazolam. An interaction between posaconazole and digoxin resulted in atrial fibrillation and deteriorated into polymorphic ventricular tachycardia, mediated via P-glycoprotein.[38]

Isavuconazole:

• Acting as a moderate CYP3A4 inhibitor, it elevates plasma levels when co-administered with cyclosporine A, tacrolimus, sirolimus, and mycophenolate mofetil; it requires dose modification and vigilant monitoring.

Oteseconazole

• Oteseconazole is a BCRP inhibitor, impacting drug transport mechanisms. When co-administered with BCRP substrates such as rosuvastatin, there exists a potential for increased exposure to the substrate. This exposure raises the risk of adverse reactions associated with BCRP substrates, underscoring the importance of careful monitoring during concurrent administration.

     

Contraindications

Contraindications of azole include hypersensitivity reactions and anaphylaxis.[39] 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

(a) Box Warnings

Risk of ventricular arrhythmias: Ketoconazole is contraindicated with methadone, quinidine, pimozide, lurasidone, ranolazine, dronedarone, or cisapride due to the risk of QT prolongation and torsades de pointes and life-threatening ventricular dysrhythmias. Ketoconazole tablets are contraindicated for onychomycosis, cutaneous dermatophyte, or Candida infections. Use when alternative antifungal therapy is unavailable, weighing potential benefits against risks. Drug-induced liver injuries that have resulted in fatalities or the need for liver transplantation have been reported as a result of hepatotoxicity.[40]

Congestive heart failure: In the context of itraconazole therapy, a reevaluation is warranted if signs or symptoms of congestive heart failure appear. The use of itraconazole is not recommended for patients exhibiting ventricular dysfunction or with a history of congestive heart failure, except in cases of severe or life-threatening infections.[41]

Monitoring

Most azole 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.[42] The impaired renal function requires dose adjustment of fluconazole.[16]

Toxicity

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.[43] 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 global issue, and research is directing its efforts to answer this problem, especially as antimicrobial resistance increases.[44] 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 (MDs, DOs, PAs, NPs) will prescribe or order appropriate medication for various infections, including cutaneous fungal infections such as athlete's foot, dandruff, and tinea versicolor. It is also helpful for invasive fungal infections such as blastomycosis, histoplasmosis, and coccidioidomycosis.[45] Infectious disease physicians should be consulted for invasive and life-threatening fungal infections. 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.[43] 

Antifungal stewardship (AFS) was investigated in a study assessing its role in improving the appropriateness of antifungal therapy. The study comprised 3 periods: an observation phase for baseline measurement, a feedback/education phase with monthly meetings for physicians, and a final phase involving daily AFS activities with a clinical pharmacist participating in ward rounds. The overall appropriateness of antifungal use, including prevention and treatment, showed significant improvement with the integration of AFS, demonstrating the potential for team-based evaluations and pharmacist involvement in enhancing the quality of antifungal therapy.[46]

Due to interactions with many other drugs metabolized by CYP enzymes, physicians and pharmacists need to communicate about the patient's medications to ensure that there will be little or no adverse events due to drug-drug interactions. Nurses will coordinate with the clinician and pharmacy staff, provide patient counseling, answer questions, and refer the patient to the pharmacist if necessary. Using an interprofessional team approach is vital to ensuring patient safety. Therefore, all healthcare professionals should coordinate their activities and share information to monitor the patient for the most beneficial health outcomes.