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AZOLES FOR THE TREATMENT OF INVASIVE
FUNGAL INFECTIONS
Authored by Dr. Daniel Thirion
FLUCONAZOLE
Azoles used for invasive fungal infections include two Fluconazole, an imidazole, is well absorbed when given classes, the imidazoles (ketoconazole) and the triazoles
orally, distributes widely throughout the body and is (itraconazole, fluconazole, voriconazole, posaconazole).
mostly eliminated through the kidneys. It has very good A number of agents are available for topical use in different activity against Candida spp. and is used as first line agent indications but this is beyond the paper’s focus. Azoles are for treatment and prevention of most infections. For usually recognized according to spectrum of activity and treatment of severe infections or in patients with an safety profiles. The imidazole ring is the synthetic component immune dysfunction, amphotericin B or an echinocandin is that confers activity to azoles. Triazoles are obtained by usually preferred. Fluconazole is also indicated for treatment a slight modification of this ring and present similar or of cryptococcal meningitis. Regarding safety, fluconazole is improved activity and less adverse effects. Azoles inhibit very well tolerated. Short term side effects include mostly an enzyme required for the production of ergosterol an headache, nausea, and vomiting. If used chronically, essential component of the fungal cytoplasmic membrane. uncommon side effects include hair loss, anorexia, and However, since this enzyme is similar to one found in the slight increase in liver enzymes. Fluconazole inhibits human human liver, drug interactions due to metabolism do occur. CYP450 3A4 in a dose dependant manner which may lead Because of important differences in activity and safety it is to drug interactions. Monitoring for efficacy and safety easier to understand each azole separately.
is warranted when fluconazole is administered with a KETOCONAZOLE
Ketoconazole was among the first antifungal agents ITRACONAZOLE
available for use. However, because oral absorption Itraconazole is a highly lipophilic imidazole. Oral absorption varies significantly between individuals according to the of the capsule formulation is improved with food. Since level of acidity in the stomach and because of its anti- absorption is sometimes poor with the capsule it has androgenic properties it is uncommonly used in the fungal been replaced by an oral solution. Its absorption is more world. Ketoconazole remains pertinent in some cases for predictable and improved when taken on an empty stomach. Itraconazole is mostly used for treatment use oral and parenteral formulations of voriconazole offer of dimorphic fungi (blastomycosis, histoplasmosis, some advantages for patients and from a cost perspective. sporothricosis, coccidioimycosis, paracoccidioidomycosis) The parenteral formulation should not be used in patients and the mold Aspergillus spp. The most important adverse with moderate to severe renal dysfunction. Also, it is effect is the dose limiting nausea and vomiting. In more important to monitor clinical efficacy and adverse effects severe infections, a balance is required between the level given the high potential for drug interactions. of discomfort of the patient and response to therapy. POSACONAZOLE
Dividing the dose into twice daily administration and certain antiemetic medication such as prochlorperazine can help Posaconazole is a highly lipophilic triazole with a broad attenuate this side effect. Itraconazole is a more potent spectrum of activity which includes yeast (fluconazole resistant strains as well), dimorphic fungi (Histoplasma inhibitor of CYP450 3A4 than fluconazole and therefore has capsulatum, Blastomyces dermatidis, Coccidioides more drug interactions. Expertise in this matter should be immitis, Sporothrix schenckii), and molds (Aspergillus spp, considered when concomitant medications are used. zygomycetes). Posaconazole has a major role as prophylaxis VORICONAZOLE
in patients at high risk of filamentous fungal infections and for therapy of zygomycoses. It is only available in oral Voriconazole is considered as a second generation formulation which should be taken with fatty meals to triazole with very good activity against yeast, dimorphic ensure appropriate absorption. Posaconazole is mostly fungi and opportunistic molds including Aspergillus spp. eliminated through the feces as unchanged drug. However, Since it has certain affinity for several target sites, it has like other azoles, it does inhibit hepatic CYP450 3A4 and demonstrated good clinical efficacy in patients with therefore has the potential for significant interactions with fluconazole resistant Candida spp infection. However, its drugs metabolized by this pathway. Tolerability is similar to non-linear pharmacokinetic profile complicates dosing for that of fluconazole with gastro-intestinal disturbances and different populations and patient conditions. Interpatient headaches being the most frequent observed side effects.
variability and more importantly intrapatient variability Selected references:
of serum concentrations have been associated with decreased efficacy and increased side effects and warrants 1. Zonios DI, Bennett JE. Update on azole antifungals. Semin concentration monitoring in selected patients. The easy to Respir Crit Care Med. 2008;29(2):198-210.

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