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been replaced by an oral solution.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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