342 FUNGAL AND NON-HIVVIRAL INFECTIONS
Ketoconazolewas the first imidazole to be used therapeut-
ically but it has been superseded by newer group members
because of its hepatotoxicity, its incomplete specificity (it
inhibits testosterone and cortisol synthesis) and because it
interacts adversely with many drugs. It is still used to treat
metastatic prostate cancer and adrenocortical carcinoma (see
Chapter 48).
The use and properties of more commonly used imidazoles
are listed in Table 45.2.
TRIAZOLES
This group of drugs (e.g. fluconazole, itraconazole and
voriconazole) is derived from the imidazoles. Triazole drugs
work by the same mechanism as imidazoles but have a wider
antifungal spectrum and are more specific for fungal CYP450.
FLUCONAZOLE
Uses
Fluconazoleis a potent and broad-spectrum antifungal agent.
It is active against many Candidaspecies,Cryptococcus neofor-
mansandHistoplasma capsulatum. However, Aspergillusspecies
are resistant and resistant Candidaspecies are problematic in
immunocompromised patients. Fluconazoleis used clinically
to treat superficial Candidainfections and oesophageal Candida,
for the acute therapy of disseminated Candida, systemic therapy
for blastomycosis and histoplasmosis, for dermatophytic fun-
gal infections and, in low doses, for prophylaxis in neutropenic
and immunocompromised patients. It is administered orally or
intravenously as a once daily dose.
Adverse effects
Adverse effects include:
- nausea, abdominal distension, diarrhoea and flatulence;
- rashes, including erythema multiforme;
- hepatitis (rarely, hepatic failure).
Contraindications
Fluconazoleis contraindicated in pregnancy because of fetal
defects in rodents and humans. Breast milk concentrations are
similar to those in plasma and fluconazoleshould not be used
by nursing mothers.Pharmacokinetics
Fluconazoleis well absorbed after oral administration and is
widely distributed throughout the body. CSF concentrations
reach 50–80% of those in the plasma. About 80% is excreted by
the kidney and dose reduction is required in renal failure. The
fluconazolemean elimination t1/2is 30 hours in patients with
normal renal function. Fluconazoleis a weaker inhibitor than
ketoconazoleof human CYP3A.Drug interactions
Fluconazole reduces the metabolism of several drugs by
inhibiting CYP3A, including benzodiazepines, calcium chan-
nel blockers, ciclosporin,docetaxeland, importantly, war-
farin. The plasma concentrations and toxicity of these drugs
will increase during concomitant treatment with fluconazole.
Rifampicinenhances the metabolism of fluconazole.ITRACONAZOLE AND VORICONAZOLE
Itraconazoleandvoriconazoleare available as oral and par-
enteral formulations. Oral bioavailability is good for both
agents, but intravenous use is indicated for severe fungal infec-
tions. The antifungal spectrum is similar to that of fluconazole
and is broad. They are fungicidal at high concentrations. Both
are metabolized by hepatic CYP450s and are inhibitors of
hepatic CYP450s. The mean itraconazolet1/2is 30–40 hours and
that for voriconazoleis six hours. For intraconazole, once dailyTable 45.2:Properties of other commonly used imidazolesDruga Use (other specific Standard formulation Side effects Pharmacokinetics
comments)
Clotrimazole Topical therapy for 1% cream or powder Local irritation Poorly absorbed
dermatophytes and not used from gastro-intestinal
systemically for Candida tract. Induces its own
infections metabolism
Miconazole Oral Candida(topical therapy for Oral gel, four times daily Nausea and Systemic absorption is
ringworm,Candidaand pityriasis 2% cream or powder vomiting, rashes. very poor, undergoes
applied twice daily Local irritation extensive hepatic
metabolism
Tiaconazole Topical treatment for nail Apply 28% solution to Minor local irritation Systemic absorption is
infections with dermatophytes nails and local skin twice negligible
and yeasts daily for 6 months
aOther drugs in this group that are used topically include butoconazole, econazole, fenticonazole, isoconazole and sulconazole (see also Chapter 50).