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.
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:
Systemic ingestion is contraindicated, or merits extreme caution, in the following situations:
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.[10] The renal function does not require dosing adjustments.
The patient should discontinue the 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.[11] 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.
Ketoconazole is a common conazole family member used on an everyday basis for the treatment of 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.[12] Ketoconazole is considered safe and may be accompanied only by mild adverse effects, but the risk of severe adverse effects such as hepatotoxicity requires discussion before the initiation of treatment. Due to interactions with many other drugs that are metabolized by CYP enzymes, physicians and pharmacists need to communicate with each other 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. Reports of ketoconazole causing hepatotoxicity are common.[11] Therefore all healthcare workers need to work together to monitor the patient to get the most beneficial health outcomes.
[1] | Gallagher JC,Dodds Ashley ES,Drew RH,Perfect JR, Antifungal pharmacotherapy for invasive mould infections. Expert opinion on pharmacotherapy. 2003 Feb; [PubMed PMID: 12562305] |
[2] | Poojary S,Miskeen A,Bagadia J,Jaiswal S,Uppuluri P, A Study of {i}In vitro{/i} Antifungal Susceptibility Patterns of Dermatophytic Fungi at a Tertiary Care Center in Western India. Indian journal of dermatology. 2019 Jul-Aug; [PubMed PMID: 31516136] |
[3] | Zonios DI,Bennett JE, Update on azole antifungals. Seminars in respiratory and critical care medicine. 2008 Apr; [PubMed PMID: 18366001] |
[4] | Nivoix Y,Levêque D,Herbrecht R,Koffel JC,Beretz L,Ubeaud-Sequier G, The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clinical pharmacokinetics. 2008; [PubMed PMID: 19026034] |
[5] | Albengres E,Le Louët H,Tillement JP, Systemic antifungal agents. Drug interactions of clinical significance. Drug safety. 1998 Feb; [PubMed PMID: 9512916] |
[6] | Tucker RM,Denning DW,Hanson LH,Rinaldi MG,Graybill JR,Sharkey PK,Pappagianis D,Stevens DA, Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1992 Jan; [PubMed PMID: 1315160] |
[7] | Alffenaar JW,van Assen S,van der Werf TS,Kosterink JG,Uges DR, Omeprazole significantly reduces posaconazole serum trough level. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2009 Mar 15; [PubMed PMID: 19220151] |
[8] | Mayer UK,Glos K,Schmid M,Power HT,Bettenay SV,Mueller RS, Adverse effects of ketoconazole in dogs--a retrospective study. Veterinary dermatology. 2008 Aug; [PubMed PMID: 18547382] |
[9] | Mogensen DM,Pihl MB,Skakkebæk NE,Andersen HR,Juul A,Kyhl HB,Swan S,Kristensen DM,Andersen MS,Lind DV,Jensen TK, Prenatal exposure to antifungal medication may change anogenital distance in male offspring: a preliminary study. Environmental health : a global access science source. 2017 Jun 21; [PubMed PMID: 28637461] |
[10] | Bhat VS,Hester SD,Nesnow S,Eastmond DA, Concordance of transcriptional and apical benchmark dose levels for conazole-induced liver effects in mice. Toxicological sciences : an official journal of the Society of Toxicology. 2013 Nov; [PubMed PMID: 23970803] |
[11] | Yan JY,Nie XL,Tao QM,Zhan SY,Zhang YD, Ketoconazole associated hepatotoxicity: a systematic review and meta- analysis. Biomedical and environmental sciences : BES. 2013 Jul; [PubMed PMID: 23895707] |
[12] | Kajfasz P,Basiak W, Outbreak of pulmonary histoplasmosis involving a group of four Polish travellers returning from Ecuador. International maritime health. 2012; [PubMed PMID: 22669814] |