Drugs 2011; 71 (18): 2405-2419

REVIEW ARTICLE 0012-6667/11/0018-2405/$55.55/0

ª 2011 Adis Data Information BV. All rights reserved.

Triazole Antifungal Agents in

Invasive Fungal Infections
A Comparative Review
Cornelia Lass-Flörl
Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2405
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2406
2. Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2406
3. In Vitro and In Vivo Antifungal Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2407
4. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2407
4.1 Absorption and Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2407
4.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2408
4.3 Metabolism and Elimination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2409
5. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2410
6. Practical Approaches and Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2411
7. Therapeutic Drug Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2412
8. Invasive Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2413
8.1 Fluconazole and Invasive Candidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2413
8.2 Voriconazole and Invasive Candidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2414
8.3 Triazoles and Invasive Aspergillosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2414
9. Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2414
10. Cost Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2414
11. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2415

Abstract Invasive fungal disease continues to be a problem associated with signif-

icant morbidity and high mortality in immunocompromised and, to a lesser
extent, immunocompetent individuals. Triazole antifungals have emerged as
front-line drugs for the treatment and prophylaxis of many systemic mycoses.
Fluconazole plays an excellent role in prophylaxis, empirical therapy, and the
treatment of both superficial and invasive yeast fungal infections. Vori-
conazole is strongly recommended for pulmonary invasive aspergillosis. Posa-
conazole shows a very wide spectrum of activity and its primary clinical
indications are as salvage therapy for patients with invasive aspergillosis and
prophylaxis for patients with neutropenia and haematopoietic stem-cell
transplant recipients. Itraconazole also has a role in the treatment of fungal
skin and nail infections as well as dematiaceous fungi and endemic mycoses.
Fluconazole and voriconazole are well absorbed and exhibit high oral
bioavailability, whereas the oral bioavailability of itraconazole and posaco-
nazole is lower and more variable. Posaconazole absorption depends on
2406 Lass-Flörl

administration with a high-fat meal or nutritional supplements. Itraconazole

and voriconazole undergo extensive hepatic metabolism involving the cyto-
chrome P450 system. The therapeutic window for triazoles is narrow, and
inattention to their pharmacokinetic properties can lead to drug levels too
low for efficacy or too high for good tolerability or safety. This makes these
agents prime candidates for therapeutic drug monitoring (TDM). Target
drug concentrations for voriconazole and itraconazole should be >1 mg/mL
and for posaconazole >1.5 mg/mL for treatment. Blood should be drawn once
the patient reaches steady state, which occurs after 5 and 7 days of triazole
therapy. Routine TDM of fluconazole is not required given its highly fa-
vourable pharmacokinetic profile and wide therapeutic index. The aim of this
review is to provide a brief update on the pharmacology, activity, clinical
efficacy, safety and cost of triazole agents (itraconazole, fluconazole, vori-
conazole and posaconazole) and highlight the clinical implications of simi-
larities and differences.

1. Introduction who have failed or who are intolerant of itraco-

The triazoles available for routine clinical use
include fluconazole, itraconazole, voriconazole and
posaconazole, with isavuconazole currently in
development. Triazole antifungals have emerged
as front-line drugs for the treatment and prophy-
laxis of many systemic mycoses (table I). Fluco-
nazole has an excellent long-term safety and
efficacy record, with an established role for pro-
phylaxis, empirical therapy and the treatment of
both superficial and invasive yeast fungal infec-
tions.[5,6] Fluconazole is remarkably well tolerated,
even at higher dosages. Itraconazole has demon-
strated efficacy for the prophylaxis[7-10] and treat-
ment of acute[11-14] and chronic aspergillosis,[15]
and allergic bronchopulmonary aspergillosis.[16]
Itraconazole also has a role in the treatment of
fungal skin and nail infections as well as dematiac-
eous fungi and endemic mycoses, such as cocci-
dioidomycosis, histoplasmosis, blastomycosis and
sporotrichosis.[2] Voriconazole has demonstrated
safety and efficacy for the treatment of dissemi-
nated candidiasis[17] and is a first-line agent for
the treatment of invasive aspergillosis.[18] Fur-
thermore, voriconazole has a specific role in the
treatment of cerebral aspergillosis[19] and Asper-
gillus osteomyelitis,[20] in which tissue penetra-
tion may be an important determinant of efficacy.
Voriconazole has a role in the treatment of chronic
pulmonary aspergillosis, especially for patients
nazole.[21] Voriconazole may also be used for in-
fections due to Scedosporium and Fusarium species.
Posaconazole has a very wide spectrum of anti-
fungal activity and its primary clinical indications
are for salvage therapy for patients with invasive
aspergillosis and for prophylaxis for patients with
neutropenia and for haematopoietic stem-cell
transplant recipients.[22,23] Posaconazole has ac-
tivity against zygomycetes, but studies are needed
to place posaconazole in the management of zygo-
mycosis, as either primary or salvage therapy.
2. Mechanism of Action
Triazole antifungals inhibit the synthesis of
ergosterol from lanosterol in the fungal cell mem-
brane;[24,25] the target is the cytochrome P450
(CYP)-dependent 14-a-demethylase (CYP51 or
Erg11p), which catalyses this reaction. Thereby,
ergosterol is depleted and methylsterols accumu-
late within the cell membrane and lead to either
inhibition of fungal cell growth or death, depen-
ding on the species and antifungal compound
involved. Triazoles are generally fungistatic, with
itraconazole and voriconazole being fungicidal
against Aspergillus spp.[24] The various azoles
have different affinities for the CYP-dependent
14-a-demethylase, which in return result in var-
ious antifungal activities, side effects and drug-
drug interactions.[26]

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (18)
Triazole Antifungal Agents 2407

Table I. Detailed indications of fluconazole, itraconazole, voriconazole and posaconazole (European Medicines Agency and US FDA)[1-4]
Indication
Fluconazole
Vaginal, oropharyngeal and oesophageal
candidiasis; urinary tract infection; systemic
Candida infections; cryptococcosis, including
cryptococcal meningitis and infections of other
sites; prophylaxis for candidiasis
Itraconazole
Blastomycosis; histoplasmosis; aspergillosis in
pts with disease refractory to/intolerant of
amphotericin B; aspergillosis, candidiasis and
cryptococcosis, including cryptococcal meningitis
Voriconazole
Invasive aspergillosis; oesophageal candidiasis;
candidaemia in non-neutropenic pts; serious
fluconazole-resistant invasive Candida infections;
significant cross-resistance with fluconazole can
occur; serious fungal infections caused by
Scedosporium apiospermum and Fusarium spp.
in pts with disease refractory to/intolerant of other
therapy
Posaconazole
Prophylaxis of IFI in HSCT recipients with GVHD
and pts with haematological malignancy with
prolonged neutropenia from chemotherapy;
oropharyngeal candidiasis, including infections
refractory to itraconazole or fluconazole or as first-
line therapy for severe disease or in
immunocompromised pts; refractory invasive
aspergillosis, fusariosis, coccidioidomycosis
CLCR = creatinine clearance; GVHD = graft versus host disease; HSCT = haemopoietic stem cell transplant; IFI = invasive fungal infections;
pt(s) = patient(s).
Spectrum of activity
Spectrum limited to yeast; reduced
susceptibility of Candida glabrata;
resistance in Candida krusei
Broad spectrum of activity (i.e.
Candida, Cryptococcus spp.),
dermatophytes and some moulds
(e.g. Aspergillus, dimorphic fungi);
resistance in C. glabrata (46–53%)
and C. krusei (31%); cross-
resistance with fluconazole
Extended spectrum of activity;
active against a variety of fungal
pathogens, including Candida,
Aspergillus, Cryptococcus spp. and
dimorphic fungi (e.g. Blastomyces
dermatitidis, Coccidioides immitis
and Histoplasma capsulatum);
lacks activity against the
Zygomycetes
Extended spectrum of activity;
active against Candida,
Aspergillus, Cryptococcus and
Fusarium spp. and the
Zygomycetes
Special considerations
Well tolerated; hepatotoxicity (rare); dose
reduction in renal failure
Poor tolerance with oral solution; capsules display
wide variability in plasma concentrations and low
bioavailability; oral cyclodextrin solution is better
absorbed than capsule; monitoring of plasma
concentrations recommended; significant drug
interactions; hepatotoxicity with
cyclophosphamide
Significant drug interactions with many agents;
variable inter-subject plasma concentration; visual
disturbances during infusion, hallucinations;
cyclodextrin in intravenous formulation may
accumulate and be nephrotoxic in pts with renal
dysfunction; breakthrough zygomycosis has been
reported; intravenous formulation: use oral if CLCR
<50 mL/min
Safety profile generally comparable to that of
fluconazole; lower potential for drug-drug
interactions than voriconazole or itraconazole; oral
formulation only; bioavailability is significantly
enhanced by concomitant ingestion of high-fat
meal, any meal, a nutritional supplement, a low pH
beverage or with 4 · daily dosing

3. In Vitro and In Vivo Antifungal Activities
Fluconazole has no activity against Candida
krusei, Aspergillus spp., Fusarium spp., Scedo-
sporium spp. or zygomycetes, and no activity
against some strains of Candida glabrata.[25]
Itraconazole activity includes most Candida
spp. and Aspergillus spp., with limited activity
against zygomycetes. Voriconazole has activity
against Candida krusei, some but not all fluco-
nazole-resistant C. glabrata, Fusarium spp. and
Scedosporium apiospermum, yet with varying ac-
tivity against Scedosporium prolificans.[27] Posa-
conazole appears to have the broadest spectrum,
including Candida spp., Aspergillus spp. and ac-
tivity against many zygomycetes.[25] Table II
gives an overview of the spectrum of antifungal
activities for fluconazole, itraconazole, vori-
conazole and posaconazole.
4. Pharmacokinetics
4.1 Absorption and Bioavailability
Fluconazole, itraconazole and voriconazole
are available as intravenous and oral formula-
tions (capsules or suspension) and posaconazole
only orally (tables II and III).[31,32] Intravenous
itraconazole has been withdrawn in some coun-
tries, therefore differences in the availability may
occur.

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (18)
2408 Lass-Flörl

Table II. Spectrum of in vitro and in vivo antifungal activity for fluconazole, itraconazole, voriconazole and posaconazole[28-30]
Pathogens Triazoles
fluconazole itraconazole voriconazole posaconazole
Candida species
C. albicans +, R ++ ++ ++
C. glabrata +/- +/- +/- +/-
C. tropicalis ++ ++ ++ ++
C. parapsilosis ++ ++ ++ ++
C. krusei - +/- + +
Aspergillus species
A. fumigatus - +, R ++, R ++, R
A. terreus - + ++ ++
Cryptococcus neoformans + + ++ ++
Histoplasma species + + + +
Coccidioides species +/- +/- +/- +/-
Blastomyces dermatitidis +/- +/- +/- +/-
Scedosporium species
S. apiospermum - +/- + +
S. prolificans - ? +/- +/-
Fusarium species - - + +
Zygomycetes - +/- - +/-
R = in principle good activity, yet resistance might occur; - indicates no activity; +/- indicates slight activity; + indicates modest activity;
++ indicates good activity; ? indicates unknown.

Voriconazole is structurally related to fluco-
nazole; both drugs are well absorbed and display
excellent bioavailability following oral adminis-
tration.[25,31,32] Fluconazole exhibits linear phar-
macokinetics and the bioavailability is independent
of food or gastric acidity.[33,35-37] Voriconazole
shows nonlinear pharmacokinetics[1,25] and the
bioavailability is independent of gastric acidity,
but is modestly decreased when administered
with high-fat foods.[1] In general, drug exposure
of voriconazole following oral administration is
lower than following intravenous administration.
Oral bioavailability of itraconazole and the
structurally related posaconazole is lower than
that of fluconazole and voriconazole, and is more
variable. The bioavailability of itraconazole (oral
solution) is about 55% under fed conditions, and
can be improved if the drug is administered with-
out food under fasting conditions.[2,28] The ab-
sorption of the itraconazole capsule is generally
lower and negatively affected by low gastric acidity
and fasting state.[38-40] The bioavailability of po-
saconazole depends on dosing and fatty food.
Compared with a single 800 mg dose, 400 mg twice
daily or 200 mg four times increased bioavaila-
bility by 98% and 220%, respectively.[41] Posaco-
nazole pharmacokinetics are linear and no further
increases in exposure are observed with higher
dosages.[3] Coadministration of a high-fat meal,
high-fat liquid nutritional supplement or carbo-
nated acidic beverage[3,42-45] increases posacona-
zole absorption.
4.2 Distribution
Fluconazole is highly water soluble, exhib-
its limited plasma protein binding (11–12%)
[table III],[4,46] and the volume of distribution
(Vd) approximates that of total body water.[4]
This azole achieves excellent levels in the cere-
brospinal fluid (CSF),[47,48] which are approxi-
mately 50–60% of those in serum.[48] Itraconazole,
voriconazole and posaconazole display moderate
water solubilities (table III).[46] The apparent Vd
for itraconazole, voriconazole and posaconazole
range from 5 to 25 L/kg after oral administration,[32]

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (18)
 Triazole Antifungal Agents 2409

Faecal - renal (66% unchanged in faeces;

bid = twice daily; CYP = cytochrome P450; IV = intravenous; PO = per oral; tmax = time to maximum plasma concentration (h); UGT = uridine diphosphate-glucuronosyltransferases;
with wide distributions. Itraconazole and posa-

<1% unchanged, 13% changed in urine)

conazole are highly protein bound in plasma
<45% variable (depending on dosing

(>98%);[2,3] voriconazole only moderately (58%).[1]

Voriconazole appears to demonstrate similar CSF
and CNS penetration as fluconazole.[49]

Glucuronidation; UGT1A4
frequency and food)

4.3 Metabolism and Elimination

PO (suspension)
Posaconazole

Triazoles display clinically relevant concentra-

400 mg bid

CYP3A4
tion-effect and concentration-toxicity relation-
15–35

ships (tables III and IV). Fluconazole undergoes

7–25
3–6
99

minimal hepatic CYP-mediated metabolism at

standard dosages of 200–400 mg/day (11%). Flu-
metabolites (<2% unchanged in urine)
Renal - faecal; primarily as inactive
IV 4 mg/kg bid; PO 200 mg bid (dose

conazole is excreted in urine in unchanged form

Extensive hepatic (CYP 2C19, 3A4)

(80%)[4] and elimination depends on renal excre-

<90% (decreased by fatty food)
IV, PO (capsules and solution)

adjustment might be needed)

tion. Therefore, dose modifications are required

in patients with impaired renal function. Studies
CYP3A4, 2C19 > 2C9

showed that the elimination half-life may increase

up to 98 hours in patients with a creatinine clearance
(CLCR) of <20 mL/min, whereas it is ~30 hours in
Voriconazole

patients with normal renal function. Dosage re-

duction of fluconazole is mandatory in patients
6–24
1–2

with renal impairment (i.e. CLCR of <60 mL/min).[4]

4.6
58

In patients whose CLCR is between 10 and

metabolites (<1% unchanged in urine)

60 mL/min, a 50% reduction of fluconazole main-

tenance doses, by halving the unitary dose or by
doubling the dosing interval, is recommended. In
<55% variable (depending on

Extensive hepatic (CYP 3A4)

Table III. Pharmacokinetic properties of currently approved triazoles[24-26,31-34]

Faecal - renal; primarily as

PO (capsules and solution)

formulation, gastric acidity)

patients on chronic haemodialysis, fluconazole

should be administered at doses ranging from 100
to 400 mg after each haemodialysis session, thrice
IV and PO 200 mg

a week, after a loading dose of 100–800 mg (ad-

CYP3A4 > 2C9
Itraconazole

ministered after a haemodialysis session and de-

pending on the indication).[4] Fluconazole is a
35–64

moderate inhibitor of CYP3A4, CYP2C8/9 and

4–5
99
11

CYP2C19, and interacts with several drugs me-

tabolized by these enzymes.[46,51] Fluconazole is
CYP2C9 > 3A4 > 2C19
IV, PO (capsules and

Renal (80% excreted

also an inhibitor of uridine diphosphate (UDP)-

unchanged in urine)
IV and PO 400 mg

glucuronosyltransferases (UGTs), which drive drug

metabolism by glucuronidation.[51]
Fluconazole

Itraconazole is metabolized in the liver by

solution)

Minimal
0.7–0.8

22–31
>90%

CYP3A4, which results in the formation of meta-

Vd = volume of distrubution.
2–4
12

bolites, including the pharmacologically active

hydroxyitraconazole.[2] Forty percent of itraco-
Protein binding (%)
Maintenance dose

nazole is excreted as inactive metabolites in urine,

CYP inhibition
bioavailability)
Absorption (%

with another 3–18% excreted in faeces. Itraco-

Formulations

Metabolism
Half-life (h)
Parameter

nazole is a strong inhibitor of CYP3A4[46] and

Excretion
tmax (h)

has a great potential for drug-drug interactions

Vd

when co-administered with drugs metabolised via

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (18)
2410 Lass-Flörl

Table IV. Potential drug interactions encountered with triazole antifungal drugs[24-26,31-34,50]
Drug Fluconazole Itraconazole Voriconazolea Posaconazolea
Ciclosporin ++ ++ +++ ++
Sirolimus ++ ++ ++++ ++
Tacrolimus ++ ++ +++ ++
Calcium channel blockers ++ ++ ++ ++
Busulfan None ++ ++
Vinca alkaloids ++ ++ ++
Midazolam › fluconazole ++ ++ ++
Simvastatin + ++++ ++++ +++
Rifampicin fl fluconazole fl fl itraconazole fl fl fl voriconazole fl posaconazole
Phenytoin +++ +++ +++ +++
fl fl fluconazole fl fl itraconazole fl fl voriconazole fl posaconazole
Omeprazole None fl fl itraconazole › voriconazole fl posaconazole
a Voriconazole and/or posaconazole therapy plus sirolimus and itraonazole, voriconazole and/or posaconazole treatment plus pregnancy
might display major contraindications.
+ indicates mild effects; ++ indicates moderate effects; +++ indicates high effects; ++++ indicates very high effects; fl indicates decreased
plasma concentrations; › indicates increased plasma concentrations.

CYP3A4.[46] Itraconazole should be administered
with caution in patients with renal or hepatic
impairment. Limited data are available on the use
of oral itraconazole in patients with renal im-
pairment.[2] Caution is recommended when ad-
ministering this drug to patients with CLCR of
30–80 mL/min, and the drug is contraindicated in
those with CLCR of <30 mL/min.[2]
Voriconazole is primarily metabolized by
CYP2C19 and to a lesser extent by CYP2C9 and
CYP3A4.[1,25,46] Excretion is via several metabo-
lites in urine, with <2% in unchanged form. None
of the voriconazole metabolites exhibit antifungal
activity. Due to genetically determined differences
in CYP2C19, any dose of voriconazole can be
associated with inter-patient variability in serum
drug concentrations. CYP3A4 can be a source of
drug-drug interactions.[46] The voriconazole dose
should be halved in patients with mild-to-moderate
hepatic cirrhosis. No dose adjustment is necessary
in patients with mild-to-severe renal impairment,
although cyclodextrin in the intravenous drug
has been shown to accumulate in patients with se-
vere renal dysfunction,[1] including those receiving
haemodialysis for end-stage renal failure.[52]
Posaconazole is primarily metabolized by UGTs
in the liver[3,51,53] and is not a substrate for
CYP3A4, CYP2C9 or CYP2C19.[46,54] Posaco-
nazole is excreted in faeces (66%) and in urine
(14%),[3,55] and may be associated with fewer drug-
drug interactions than voriconazole or itracona-
zole. However, posaconazole inhibits the clearance
of drugs metabolized by CYP3A4. Overall, no
dose adjustment is recommended in renally im-
paired patients[3] or in patients with mild-to-
severe hepatic insufficiency.
5. Pharmacodynamics
The ratio of the area under the concentration-
time curve (AUC) at 24 hours to the minimum
inhibitory concentration (MIC) is the pharma-
codynamic parameter that best predicts triazole
efficacy in preclinical animal models of dissem-
inated candidiasis.[56-60] Preclinical animal stud-
ies have shown that a total drug 24-hour AUC :
MIC of approximately 25 (range 12–25) is nec-
essary to achieve 50% of the maximal effect with
triazole treatment.[34,57-59,61] An AUC : MIC of
25–50 is required to maintain an average drug
concentrations one to two times the MIC.[61]
Two recent studies evaluating voriconazole[62]
and posaconazole[63] in a murine model of asper-
gillosis suggest that the same AUC : MIC para-
meter and value may be important for controlling
disseminated Aspergillus fumigatus infections.

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (18)
Triazole Antifungal Agents
A higher 24-hour AUC : MIC is required for
maximal posaconazole effect in animals infected
with mutated A. fumigatus with reduced suscep-
tibility and CYP51A mutations.[63]
6. Practical Approaches and Side Effects
The therapeutic window for triazoles is nar-
row,[64-70] and non-observance of their pharmaco-
kinetic properties can lead to drug levels too low
for efficacy or too high for tolerability or safety.
Therapeutic drug monitoring (TDM) may be use-
ful to ensure adequate levels when using a given
dose in a particular patient.[50] This necessitates
individualized treatment decisions based on a risk
versus benefit analysis for a particular patient.
Hepatic metabolism and clearance of vori-
conazole from plasma is highly dependent on
CYP2C19 genotype. Genetically determined poly-
morphisms of CYP2C19 result in poor and ex-
tensive metabolizers, subdivided as homozygous
or heterozygous.[71] Poor metabolizers are over-
represented in Asian populations relative to White
or Black populations. Studies in healthy volun-
teers reported voriconazole oral bioavailability
was substantially higher in poor metabolizers
than in extensive metabolizers (94% vs 75%).[72]
Outcomes might be improved by modifying in-
itial voriconazole doses based on CYP2C19 sta-
tus: 7.2–8.9 mg/kg/day for CYP2C19 wild-type
and 4.4–6.5 mg/kg/day for CYP2C19 nonwild-
type. However, other factors such as the patient
population have been linked to treatment out-
come. Trifilio et al.[73] observed a wide inter- and
intra-patient variability of voriconazole levels in
haematopoietic stem-cell transplant (HSCT) re-
cipients. There was no clinically relevant correla-
tion between the dose of voriconazole administered
and plasma trough concentrations. One study sug-
gested that the therapeutic range for voriconazole
trough levels should be 2–4 mg/L,[74] whereas others
suggest a range of approximately 1–6 mg/L.[75]
Pascual et al.[75] provided evidence for the wide
intra-dose, intra-patient and inter-patient vari-
ability in voriconazole levels, coupled with a link
between underexposure and limited efficacy. Lack
of treatment response was significantly more
common in patients with levels of £1 mg/L than
ª 2011 Adis Data Information BV. All rights reserved.
2411
in those with levels >1 mg/L, 46% versus 12%,
respectively. Other studies have also pointed to a
relationship between voriconazole blood level or
exposure and either treatment response[76-78] or
neurological,[77,79] hepatic[80-82] or visual adverse
events.[81] For example, a study of voriconazole
in paediatric patients reported a 6.3-fold increased
relative risk of death for each trough serum
voriconazole level <1 mg/L.[76] This is consistent
with the importance of trough level for treatment
response in adults.[75]
Absorption-related factors are important for
posaconazole, and reduced levels are more likely
in allogeneic HSCT recipients than in non-HSCT
patients,[83] particularly those with chemothera-
py-related mucositis and reduced food intake;[84]
diarrhoea;[85] or concomitant treatment with ri-
fabutin, phenytoin, efavirenz,[3,86] metoclopra-
mide[44] and gastric acid suppressors.[3,44,87] Jang
et al.[88] analysed the exposure-response profile
for posaconazole prophylaxis based on the data
from the trials by Ullmann et al.[22] and Cornely
et al.[23] The analysis showed failure rates of
44%, 21%, 18% and 18% with posaconazole val-
ues of 0.29 mg/mL, 0.74 mg/mL, 1.24 mg/mL and
2.61 mg/mL, respectively.[88] No significant re-
lationship was observed between posaconazole
concentration and major drug-related adverse
events. There was a 5–24% incidence of nausea,
vomiting, diarrhoea and hepatoxicity in patients
receiving triazoles (table V).
Azoles play a critical role in the management
of invasive fungal disease, for prophylaxis and
treatment, but a number of questions arise con-
cerning the extensive use of extended-spectrum
triazoles.[89,90] Although more than 90% of
Candida species are susceptible to fluconazole
and newer triazoles, increased resistance has been
noted for less common Candida species. The past
decade has seen an increase in the incidence of
candidiasis due to C. glabrata or C. krusei, both
of which are among the most commonly recovered
Candida species from clinical isolates. There have
also been reports of A. fumigatus isolates with
reduced susceptibility to the broad-spectrum
triazoles. It is extremely important that every ef-
fort is made to ensure Aspergillus resistance to
broad-spectrum triazoles remains low.[89,90]
Drugs 2011; 71 (18)
2412 Lass-Flörl

Table V. Adverse events associated with the various triazoles[1-4,24-26,31,32]

Clinical signs and symptoms Adverse events (%)
fluconazole itraconazole voriconazole posaconazole
Nausea, vomiting, diarrhoea 5 24 (oral solution) NA 8–18
Hepatotoxicity 5–20 8.5 10–23 2–3
Skin rash <3 5–19 5 NA
Visual disturbance NA NA 1–30 NA
Headache <3 <3 NA 5–17
Psychiatric symptoms NA NA <1 NA
NA = not applicable.

7. Therapeutic Drug Monitoring true for itraconazole, voriconazole and posacona-

A large number of factors can lead to treat-
ment ineffectiveness in fungal infections, includ-
ing drug susceptibility/resistance, location of the
infection and several host-specific factors that are
often beyond the control of the clinician, includ-
ing immune deficiency due to neutropenia, or
malignancy, sepsis and other co-morbidities.[50,91]
TDM may be a useful adjunct to therapy (table VI)
in the following circumstances: (i) intra- or inter-
patient pharmacokinetic variability that cannot
be predicted or reasonably overcome within the
therapeutic window of drug dosing; (ii) ceiling effect
of dosing escalation because of drug toxicity or
suboptimal absorption; (iii) lack of a more im-
mediate alternative endpoint useful for assessing
drug response, as is true for all invasive fungal in-
fections; (iv) availability of a rapid, sensitive and
specific assay with a quick turnaround time; and
(v) clinically validated therapeutic/toxic ranges for
the antifungals.[50] Among these, both (i) and (ii) are
zole. High-performance liquid chromatography or
liquid chromatography-mass spectroscopy assays
have been validated for each of the triazoles.[50,91]
Routine TDM of fluconazole is not required
given its highly favourable pharmacokinetic profile
and wide therapeutic index. The target blood
concentrations are presented in terms of trough
levels[91,92] and blood should be drawn once the
patient reaches steady state, which occurs after
5 and 7 days of therapy for triazole drugs. For
this reason, a sampling 4–7 days after initiating
itraconazole, voriconazole or posaconazole ther-
apy is recommended. For agents with nonlinear
pharmacokinetics, such as itraconazole and po-
saconazole, additional sampling later in therapy
may also be useful. For itraconazole, capsule dos-
ing can be increased from 200 mg twice daily to
300 mg twice daily or changed to itraconazole
suspension 200 mg twice daily.[91,92] Further in-
creases in dosage directed by serum levels may
be appropriate but are often limited by gastro-

Table VI. Tentative recommendations for monitoring of blood levels during triazole therapy (adapted from Andes et al.[50] with permission)
Drug Indications After initiation Target blood concentrationa
of treatment (mg/mL)
(days)
Itraconazole Routine during first week of therapy; lacking response; 4–7 Prophylaxis: trough > 0.5
breakthrough infections; GI dysfunction; co-medication Treatment: trough > 1–2
Voriconazole Lack of response; breakthrough infections; GI 4–7 Prophylaxis: trough > 0.5
dysfunction; co-medication; IV-to-oral switch; severe Treatment: trough > 1–2
hepatology; unexplained neurological symptoms
Posaconazole Lack of response; breakthrough infections; GI 4–7 Prophylaxis: trough > 0.5
dysfunction; therapy with proton pump inhibitors; Treatment: trough > 0.5–1.5
co-medication
a Total or bound and unbound drug concentration.
GI = gastrointestinal; IV = intravenous.

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (18)
Triazole Antifungal Agents
intestinal intolerance induced by the cyclodextrin
excipient. To achieve voriconazole therapeutic
concentrations as quickly as possible, a loading
dose should be administered; this can be achieved
orally (400 mg twice daily for two dosages) or
intravenously (6 mg/kg for two dosages, followed
by 4 mg/kg for one dose). The dosage may be in-
creased from 200 mg twice daily to 300 mg twice
daily if clinically indicated, and a recent study
suggests that dosage escalation is frequently re-
quired to achieve therapeutic targets.[91,92] For
patients with high levels, dose reduction may pre-
vent toxicity. Voriconazole can either be tem-
porarily stopped or the dose reduced to 150 mg
twice daily.[91,92] For patients with low posaco-
nazole levels, an assessment should be made as to
whether the drug is being administered with food
(and preferably high-fat food). Dosage escalation
beyond 800 mg/day is unlikely to be useful, but an
attempt may be made to fractionate the total
dosage.[91,92]
8. Invasive Fungal Infections
Fungal infections can be caused by several
different types of fungi. Invasive candidiasis is the
most frequently encountered invasive fungal in-
fection and, although C. albicans remains the
most common causative species (40–50% candi-
daemias), clinicians should be alert to the rise
in infections due to azole-resistant Candida spp.
A. fumigatus and other Aspergillus spp. are common
pathogenic moulds and cause major morbidity,
especially in neutropenic and organ-transplant
patients.[93] Other moulds, such as Scedosporium
spp. and the Zygomycetes, albeit less common,
are associated with high mortality depending
on site of infection and host factors. Given the
drug resistance of emerging fungal pathogens,
accurate identification of the pathogen is critical
for selecting an appropriate antifungal therapy.
Common fungi in breakthrough infection in
neutropenic and transplant patients during anti-
fungal prophylaxis with fluconazole and itraco-
nazole are Aspergillus spp. and azole-resistant
Candida spp., and with voriconazole, it is the zygo-
mycetes, C. glabrata and others (e.g. Acremonium
and Scedosporium spp.).[29]
ª 2011 Adis Data Information BV. All rights reserved.
2413
General management strategies include (i) di-
rected treatment of established infections re-
quiring microbiological identification of the
pathogen; (ii) pre-emptive antifungal therapy for
high-risk patients whose signs and symptoms are
suggestive for invasive disease; (iii) empirical
therapy for at-risk patients with persistent fever
despite broad-spectrum antibacterial therapy;
and (iv) prophylaxis, in which antifungal treat-
ment is designed to prevent infection in at-risk
populations.
8.1 Fluconazole and Invasive Candidiasis
Gafter-Gvili et al.[94] performed a systematic
review and meta-analysis of randomized con-
trolled trials that compared different antifungal
agents for the treatment of candidaemia and
other forms of invasive candidiasis. Fifteen trials
were included in the meta-analysis: nine compar-
ing fluconazole with other drugs (amphotericin B
deoxycholate, itraconazole or a combination of
fluconazole and amphotericin B deoxycholate),
four comparing echinocandins with other drugs
(fluconazole, amphotericin B deoxycholate and
liposomal amphotericin B), one comparing mi-
cafungin and caspofungin, and one comparing
amphotericin B deoxycholate plus fluconazole
and voriconazole. No difference in mortality was
observed with fluconazole versus amphotericin
B; however, the rate of microbiological failure
was higher in the fluconazole arm (relative risk
1.52; 95% CI 1.12, 2.07). Anidulafungin de-
creased the rate of microbiological failure com-
pared with fluconazole (relative risk 0.50; 95% CI
0.29, 0.86) with fewer adverse events. The authors
concluded from the evidence that all antifungal
agents have a similar efficacy, but the rate of
microbiological failure was higher with flucona-
zole than with amphotericin B or anidulafungin.
Amphotericin B is associated with a higher rate
of adverse events than fluconazole and the echi-
nocandins. Triazoles are generally fungistatic
compounds, although some are associated with
fungicidal activity in particular fungi, such as
itraconazole or vorocionazole in Aspergillus spp.
Whether this mode of action has any clinical im-
plication needs to be investigated in more detail.
Drugs 2011; 71 (18)
2414
8.2 Voriconazole and Invasive Candidiasis
A large randomized study investigated the ef-
ficacy of voriconazole versus amphotericin B
deoxycholate followed by fluconazole after species
identification and antifungal susceptibility testing
in non-neutropenic patients with candidaemia
and showed an equal efficacy of both treatment
regimens.[17] Success rate, defined as clinical cure
and mycological eradication, was equal in both
treatment regimens (41%), with significantly fewer
serious adverse events in the voriconazole group
(46% vs 57%). The compassionate use programme
of voriconazole as salvage therapy for invasive can-
didiasis included 13 neutropenic patients, of whom
six (46%) experienced a favourable response.[95]
8.3 Triazoles and Invasive Aspergillosis
Only limited data are available on itraconazole
in invasive aspergillosis. Denning et al.[13] reported
the results of oral itraconazole in 76 patients with
various underlying conditions. Overall objective
response rate was 39%. A strategy using intra-
venous itraconazole followed by the oral formula-
tion was assessed in 31 patients, with a successful
response rate of 48%.[12]
Voriconazole was assessed in two open-labelled
studies, and response rates of 44% and 48% were
reported.[80,96] Superiority of voriconazole over
amphotericin B deoxycholate was demonstrated
for efficacy, safety and survival in a randomized
trial.[18] Voriconazole proved to be superior to
amphotericin B deoxycholate, irrespective of the
host group, site of lesion and neutropenic status.
Voriconazole is strongly recommended for pul-
monary invasive aspergillosis.[1] Analysis of a
series of 81 cases of cerebral aspergillosis treated
with voriconazole showed a 35% response rate,
with a 31% survival rate,[19] and underscored the
critical role of surgical resection of the lesion. The
role of voriconazole in bone or joint aspergillosis
has also been investigated in a retrospective anal-
ysis of 20 patients, with a 55% response rate.[20]
Very limited data are available on other extra-
pulmonary Aspergillus infections. Aspergillus terreus,
poorly sensitive to amphotericin B, is susceptible
in vitro and in vivo to voriconazole.[97] There are
ª 2011 Adis Data Information BV. All rights reserved.
Lass-Flörl
insufficient data for recommendations on when
to initiate oral voriconzole treatment, and oral
dosing not adapted to weight may lead to sub-
optimal therapy. Intravenous voriconazole admin-
istration is contraindicated in renal insufficiency.
Oral posaconazole has been assessed in salvage
therapy of various invasive fungal infections, in-
cluding a cohort of 107 patients with aspergillo-
sis.[98] A total of 86 cases showed a 42% favourable
response rate in posaconazole-treated patients and
a significant improved survival compared with
the external control group.
9. Combination Therapy
The most common rationales for combination
therapy are an expected synergy with complemen-
tary targets within the fungal cells, an increase of
the spectrum of action and complementary phar-
macokinetic or pharmacodynamic character-
istics.[99] While most data demonstrated synergy
or additive effects in both in vitro and in vivo ex-
perimental models, no prospective comparative
clinical trial has so far been published on combi-
nation therapy in first-line or salvage therapy. Non-
comparative studies provide controversial results.
10. Cost Effectiveness
The cost effectiveness of posaconazole, fluco-
nazole or itraconazole for preventing invasive
fungal infection in neutropenic patients was com-
pared using a model based on clinical trial data
from patients with acute myelogenous leukaemia
or myelodysplastic syndromes and chemotherapy-
induced neutropenia.[100] Posaconazole was found
to be cost effective for preventing invasive fungal
infection in neutropenic patients, with a 73% prob-
ability that posaconazole is cost saving compared
with fluconazole and itraconazole, and a 96% prob-
ability that the incremental cost-effectiveness ratio
for posaconazole compared with the other two
drugs was $US50 000 or less per life-year saved, a
threshold commonly used to determine whether
an expenditure is worthwhile for society. Other
pharmacoeconomic studies have similarly con-
cluded that posaconazole prophylaxis was a cost-
effective alternative to prophylaxis with standard
Drugs 2011; 71 (18)
Triazole Antifungal Agents
azoles for patients in the Netherlands,[101,102]
Switzerland[103] and Canada.[104] A major random-
ized controlled trial evaluated voriconazole versus
liposomal amphotericin B as empirical therapy in
febrile neutropenia. Compared with voriconazole,
liposomal amphotericin B was associated with a
net cost saving of Australian dollars ($A)1422
(2.9%) per patient. A similar trend was observed
with the cost per death prevented and success-
ful treatment.[105] By contrast, 18 peer-reviewed
publications on the pharmacoeconomics of vori-
conazole suggest that voriconazole is a more
cost-effective option for antifungal treatment of
invasive aspergillosis.[106] Another study analysed
the cost effectiveness of micafungin and flucona-
zole for prophylaxis of invasive fungal in-
fections in patients undergoing HSCT in a Korean
healthcare setting. Micafungin was a cost-effective
prophylactic antifungal strategy, producing lower
medical costs and longer life expectancy than
fluconazole.[107]
Due to wide heterogeneity in patient char-
acteristics, underlying diseases, hospital settings
and study methods in these various economic
studies, as well as the lack of ‘head-to-head’ trials,
it is difficult to find clear evidence of the economic
advantages of using a single agent in all settings.[108]
Another study by Menzin et al.[109] provides
support for the theory that costs vary more by
underlying patient diagnosis and/or disease state.
Wilson et al.[110] observed that the highest costs
and invasive fungal infections occurred in
patients with HSCT or bone marrow transplan-
tation ($US117 087) or solid organ transplants
($US71 116), followed by those with solid or blood
cancer ($US55 092 and $US51 538, respectively),
diabetes mellitus ($US37 698), chronic obstruc-
tive pulmonary disease ($US33 849) and HIV
($US29 442). Determining the best strategy for a
given patient includes a careful analysis of local
epidemiology and drug use trends in addition to in-
formation from the published literature in order to
make the most appropriate evidence-based decision.
11. Conclusion
Triazole antifungals have emerged as front-
line drugs for the treatment and prophylaxis of
ª 2011 Adis Data Information BV. All rights reserved.
2415
many systemic mycoses. Voriconazole is structu-
rally related to fluconazole, and both drugs are
well absorbed and display excellent bioavaila-
bility following oral administration. Oral bio-
availability of itraconazole and the structurally
related posaconazole is lower than that for flu-
conazole and voriconazole, and is more variable.
Fluconazole has an excellent long-term safety
and efficacy record, with an established role for
prophylaxis, empirical therapy and the treatment
of both superficial and invasive yeast fungal in-
fections, although its spectrum of activity is lim-
ited. Voriconazole has demonstrated safety and
efficacy and is strongly recommended for pul-
monary invasive aspergillosis. Posaconazole has
a very wide spectrum of antifungal activity and its
primary clinical indications are as for salvage
therapy for patients with invasive aspergillosis
and for prophylaxis for patients with neutropenia
and for HSCT recipients.
The various azoles have different affinities for
the CYP-dependent 14-a-demethylase, which in
turn result in various antifungal activities and
different amounts of drug-drug interactions and
adverse events. Consequently, itraconazole, vori-
conazole and posaconazole are associated with
adverse events, and drug interactions might fre-
quently occur – particularly in cancer patients –
since the triazoles and many drugs used in cancer
chemotherapy are metabolized via the hepatic CYP
enzyme systems. Therefore, TDM represents an
important aspect in the management of patients
receiving triazoles, and tentative guidelines recom-
mend sampling 4–7 days after initiating itracona-
zole, voriconazole or posaconazole therapy.
Acknowledgements
No sources of funding were used in the preparation of this
review. In the past 5 years, the author has received grant
support from the Austrian Science Fund (FWF) P174840,
MFF Tirol, Astellas Pharma, Gilead Sciences, Pfizer, Scher-
ing Plough and Merck Sharp and Dohme. She has been an
advisor/consultant to Gilead Sciences, Merck Sharp and
Dohme, Pfizer and Schering Plough. She has been paid for
talks on behalf of Gilead Sciences, Merck Sharp and Dohme,
Pfizer, Astellas Pharma and Schering Plough.
References
1. Vfend [package insert]. New York: Pfizer Inc., 2010
Drugs 2011; 71 (18)
2416
2. Sporanox oral solution [package insert]. Raritan (NJ): Orth
Biotech Products, L.P., 2003
3. Noxafil [package insert]. Kenilworth (NJ): Schering-
Plough, 2009
4. Diflucan [package insert]. New York: Pfizer Inc., 2010
5. Slavin MA, Osborne B, Adams R, et al. Efficacy and safety
of fluconazole prophylaxis for fungal infections after
marrow transplantation: a prospective, randomized,
double-blind study. J Infect Dis 1995; 171: 1545-52
6. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial
comparing fluconazole with amphotericin B for the
treatment of candidemia in patients without neutropenia.
Candidemia Study Group and the National Institute.
N Engl J Med 1994; 331: 1325-30
7. Glasmacher A, Cornely O, Ullmann AJ, et al. An open-
label randomized trial comparing itraconazole oral solu-
tion with fluconazole oral solution for primary prophy-
laxis of fungal infections in patients with haematological
malignancy and profound neutropenia. J Antimicrob
Chemother 2006; 57: 317-25
8. Glasmacher A, Prentice A, Gorschluter M, et al. Itraco-
nazole prevents invasive fungal infections in neutropenic
patients treated for hematologic malignancies: evidence
from a meta-analysis of 3,597 patients. J Clin Oncol 2003;
21: 4615-26
9. Marr KA, Crippa F, Leisenring W, et al. Itraconazole
versus fluconazole for prevention of fungal infections in
patients receiving allogeneic stem cell transplants. Blood
2004; 103: 1527-33
10. Winston DJ, Maziarz RT, Chandrasekar PH, et al. In-
travenous and oral itraconazole versus intravenous and
oral fluconazole for long-term antifungal prophylaxis in
allogeneic hematopoietic stem-cell transplant recipients: a
multicenter, randomized trial. Ann Intern Med 2003; 138:
705-13
11. Caillot D. Intravenous itraconazole followed by oral itra-
conazole for the treatment of amphotericin-B-refractory
invasive pulmonary aspergillosis. Acta Haematol 2003;
109: 111-8
12. Caillot D, Bassaris H, McGeer A, et al. Intravenous itra-
conazole followed by oral itraconazole in the treatment of
invasive pulmonary aspergillosis in patients with hema-
tologic malignancies, chronic granulomatous disease, or
AIDS. Clin Infect Dis 2001; 33: e83-90
13. Denning DW, Lee JY, Hostetler JS, et al. NIAID Mycoses
Study Group multicenter trial of oral itraconazole ther-
apy for invasive Aspergillosis. Am J Med 1994; 97: 135-44
14. Dupont B. Itraconazole therapy in aspergillosis: study in 49
patients. J Am Acad Dermatol 1990; 23: 607-14
15. Denning DW, Riniotis K, Dobrashian R, et al. Chronic
cavitary and fibrosing pulmonary and pleural aspergillo-
sis: case series, proposed nomenclature change, and re-
view. Clin Infect Dis 2003; 37 Suppl. 3: S265-80
16. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial
of itraconazole in allergic bronchopulmonary aspergillo-
sis. N Engl J Med 2000; 342: 756-62
17. Kullberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole
versus a regimen of amphotericin B followed by flucona-
zole for candidaemia in nonneutropenic patients: a ran-
domised noninferiority trial. Lancet 2005; 366: 1435-42
ª 2011 Adis Data Information BV. All rights reserved.
Lass-Flörl
18. Herbrecht R, Denning DW, Patterson TF, et al. Vori-
conazole versus amphotericin B for primary therapy of
invasive aspergillosis. N Engl J Med 2002; 347: 408-15
19. Schwartz S, Ruhnke M, Ribaud P, et al. Improved outcome
in central nervous system aspergillosis, using voriconazole
treatment. Blood 2005; 106: 2641-5
20. Mouas H, Lutsar I, Dupont B, et al. Voriconazole for
invasive bone aspergillosis: a worldwide experience of
20 cases. Clin Infect Dis 2005; 40: 1141-7
21. Jain LR, Denning DW. The efficacy and tolerability of
voriconazole in the treatment of chronic cavitary pul-
monary aspergillosis. J Infect 2006; 52: e133-7
22. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or
fluconazole for prophylaxis in severe graft-versus-host
disease. N Engl J Med 2007; 356: 335-47
23. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole
vs. fluconazole or itraconazole prophylaxis in patients
with neutropenia. N Engl J Med 2007; 356: 348-59
24. Mohr J, Johnson M, Cooper T, et al. Current options in
antifungal pharmacotherapy. Pharmacotherapy 2008; 28:
614-45
25. Groll AH, Gea-Banacloche JC, Glasmacher A, et al. Clin-
ical pharmacology of antifungal compounds. Infect Dis
Clin North Am 2003; 17: 159-91
26. Warrilow AG, Martel CM, Parker JE, et al. Azole binding
properties of Candida albicans sterol 14-alpha demethy-
lase (CaCYP51). Antimicrob Agents Chemother 2010; 54:
4235-45
27. Lass-Flörl C, Mayr A, Perkhofer S, et al. Activities of
antifungal agents against yeasts and filamentous fungi:
assessment according to the methodology of the European
Committee on Antimicrobial Susceptibility Testing. An-
timicrob Agents Chemother 2008; 52: 3637-41
28. Van de Velde VJ, Van Peer AP, Heykants JJ, et al. Effect of
food on the pharmacokinetics of a new hydroxypropyl-
beta-cyclodextrin formulation of itraconazole. Pharma-
cotherapy 1996; 16: 424-8
29. Lass-Flörl C. The changing face of epidemiology of invasive
fungal diseases in Europe. Mycoses 2009; 52 (3): 197-205
30. Denning DW, Hope WW. Therapy for fungal diseases:
opportunities and priorities. Trends Microbiol 2010; 18:
195-204
31. Lipp HP. Clinical pharmacodynamics and pharmacokine-
tics of the antifungal extended-spectrum triazole posaco-
nazole: an overview. Br J Clin Pharmacol 2010; 70: 471-80
32. Li Y, Theuretzbacher U, Clancy CJ, et al. Pharmacokine-
tic/pharmacodynamic profile of posaconazole. Clin
Pharmacokinet 2010; 49: 379-96
33. Purkins L, Wood N, Kleinermans D, et al. Effect of food
on the pharmacokinetics of multiple-dose oral vori-
conazole. Br J Clin Pharmacol 2003; 56 Suppl. 1: 17-23
34. Andes D. Clinical utility of antifungal pharmacokinetics
and pharmacodynamics. Curr Opin Infect Dis 2004; 17:
533-40
35. Purkins L, Wood N, Kleinermans D, et al. Histamine H2-
receptor antagonists have no clinically significant effect
on the steady-state pharmacokinetics of voriconazole.
Br J Clin Pharmacol 2003; 56 Suppl. 1: 51-5
36. Zimmermann T, Yeates RA, Laufen H, et al. Influence of
concomitant food intake on the oral absorption of two
Drugs 2011; 71 (18)
Triazole Antifungal Agents
triazole antifungal agents, itraconazole and fluconazole.
Eur J Clin Pharmacol 1994; 46: 147-50
37. Zimmermann T, Yeates RA, Riedel KD, et al. The influ-
ence of gastric pH on the pharmacokinetics of flucona-
zole: the effect of omeprazole. Int J Clin Pharmacol Ther
1994; 32: 491-6
38. Sporanox capsules [package insert]. Raritan (NJ): PriCara,
2009
39. Barone JA, Koh JG, Bierman RH, et al. Food interaction
and steady-state pharmacokinetics of itraconazole cap-
sules in healthy male volunteers. Antimicrob Agents
Chemother 1993; 37: 778-84
40. Van Peer A, Woestenborghs R, Heykants J, et al. The ef-
fects of food and dose on the oral systemic availability of
itraconazole in healthy subjects. Eur J Clin Pharmacol
1989; 36: 423-6
41. Ezzet F, Wexler D, Courtney R, et al. Oral bioavailability
of posaconazole in fasted healthy subjects: comparison
between three regimens and basis for clinical dosage
recommendations. Clin Pharmacokinet 2005; 44: 211-20
42. Courtney R, Radwanski E, Lim J, et al. Pharmacokinetics
of posaconazole coadministered with antacid in fasting or
nonfasting healthy men. Antimicrob Agents Chemother
2004; 48: 804-8
43. Courtney R, Wexler D, Radwanski E, et al. Effect of food
on the relative bioavailability of two oral formulations of
posaconazole in healthy adults. Br J Clin Pharmacol 2004;
57: 218-22
44. Krishna G, Moton A, Ma L, et al. Pharmacokinetics and
absorption of posaconazole oral suspension under various
gastric conditions in healthy volunteers. Antimicrob
Agents Chemother 2009; 53: 958-66
45. Sansone-Parsons A, Krishna G, Calzetta A, et al. Effect of
a nutritional supplement on posaconazole pharmaco-
kinetics following oral administration to healthy volun-
teers. Antimicrob Agents Chemother 2006; 50: 1881-3
46. Dodds-Ashley E. Management of drug and food interac-
tions with azole antifungal agents in transplant recipients.
Pharmacotherapy 2010; 30: 842-54
47. Arndt CA, Walsh TJ, McCully CL, et al. Fluconazole pe-
netration into cerebrospinal fluid: implications for treat-
ing fungal infections of the central nervous system. J In-
fect Dis 1988; 157: 178-80
48. Foulds G, Brennan DR, Wajszczuk C, et al. Fluconazole
penetration into cerebrospinal fluid in humans. J Clin
Pharmacol 1988; 28: 363-6
49. Lutsar I, Roffey S, Troke P. Voriconazole concentrations
in the cerebrospinal fluid and brain tissue of guinea pigs
and immunocompromised patients. Clin Infect Dis 2003;
37: 728-32
50. Andes D, Pascual A, Marchetti O. Antifungal therapeutic
drug monitoring: established and emerging indications.
Antimicrob Agents Chemother 2009; 53: 24-34
51. Nivoix Y, Ubeaud-Sequier G, Engel P, et al. Drug-drug
interactions of triazole antifungal agents in multimorbid
patients and implications for patient care. Curr Drug
Metab 2009; 10: 395-409
52. Hafner V, Czock D, Burhenne J, et al. Pharmacokinetics of
sulfobutyletherbeta-cyclodextrin and voriconazole in
patients with end-stage renal failure during treatment with
ª 2011 Adis Data Information BV. All rights reserved.
2417
two hemodialysis systems and hemodiafiltration. Anti-
microb Agents Chemother 2010; 54: 2596-602
53. Keating GM. Posaconazole. Drugs 2005; 65 (11): 1553-67;
discussion 1568-9
54. Wexler D, Courtney R, Richards W, et al. Effect of posa-
conazole on cytochrome P450 enzymes: a randomized,
open-label, two-way crossover study. Eur J Pharm Sci
2004; 21: 645-53
55. Krieter P, Flannery B, Musick T, et al. Disposition of posa-
conazole following single-dose oral administration in healthy
subjects. Antimicrob Agents Chemother 2004; 48: 3543-51
56. Andes D, Marchillo K, Conklin R, et al. Pharmaco-
dynamics of a new triazole, posaconazole, in a murine
model of disseminated candidiasis. Antimicrob Agents
Chemother 2004; 48: 137-42
57. Andes D, Marchillo K, Stamstad T, et al. In vivo pharm-
acokinetics and pharmacodynamics of a new triazole,
voriconazole, in a murine candidiasis model. Antimicrob
Agents Chemother 2003; 47: 3165-9
58. Andes D, Marchillo K, Stamstad T, et al. In vivo
pharmacodynamics of a new triazole, ravuconazole, in a
murine candidiasis model. Antimicrob Agents Chemother
2003; 47: 1193-9
59. Andes D, van Ogtrop M. Characterization and quantita-
tion of the pharmacodynamics of fluconazole in a neu-
tropenic murine disseminated candidiasis infection model.
Antimicrob Agents Chemother 1999; 43: 2116-20
60. Louie A, Drusano GL, Banerjee P, et al. Pharmacodynamics
of fluconazole in a murine model of systemic candidiasis.
Antimicrob Agents Chemother 1998; 42: 1105-9
61. Andes D. Pharmacokinetics and pharmacodynamics of
antifungals. Infect Dis Clin North Am 2006; 20: 679-97
62. Mavridou E, Bruggemann RJ, Melchers WJ, et al. Impact
of cyp51A mutations on the pharmacokinetic and phar-
macodynamic properties of voriconazole in a murine
model of disseminated aspergillosis. Antimicrob Agents
Chemother 2010; 54: 4758-64
63. Mavridou E, Bruggemann RJ, Melchers WJ, et al. Efficacy
of posaconazole against three clinical Aspergillus fumi-
gatus isolates with mutations in the cyp51A gene. Anti-
microb Agents Chemother 2010; 54: 860-5
64. Eiden C, Peyriere H, Tichit R, et al. Inherited long QT
syndrome revealed by antifungals drug-drug interaction.
J Clin Pharm Ther 2007; 32: 321-4
65. Esch JJ, Kantoch MJ. Torsades de Pointes ventricular
tachycardia in a pediatric patient treated with flucona-
zole. Pediatr Cardiol 2008; 29: 210-3
66. Justo D, Zeltser D. Torsade de pointes induced by systemic
antifungal agents: lessons from a retrospective analysis of
published case reports. Mycoses 2006; 49: 463-70
67. Owens Jr RC, Nolin TD. Antimicrobial-associated QT in-
terval prolongation: points of interest. Clin Infect Dis
2006; 43: 1603-11
68. Pham CP, de Feiter PW, van der Kuy PH, et al. Long QTc
interval and torsade de pointes caused by fluconazole.
Ann Pharmacother 2006; 40: 1456-61
69. Prosser JM, Mills A, Rhim ES, et al. Torsade de pointes
caused by polypharmacy and substance abuse in a patient
with human immunodeficiency virus. Int J Emerg Med
2008; 1: 217-20
Drugs 2011; 71 (18)
2418
70. Tatetsu H, Asou N, Nakamura M, et al. Torsades de pointes
upon fluconazole administration in a patient with acute
myeloblastic leukemia. Am J Hematol 2006; 81: 366-9
71. Desta Z, Zhao X, Shin JG, et al. Clinical significance of the
cytochrome P450 2C19 genetic polymorphism. Clin
Pharmacokinet 2002; 41: 913-58
72. Scholz I, Oberwittler H, Riedel KD, et al. Pharmacokine-
tics, metabolism and bioavailability of the triazole anti-
fungal agent voriconazole in relation to CYP2C19 geno-
type. Br J Clin Pharmacol 2009; 68: 906-15
73. Trifilio S, Pennick G, Pi J, et al. Monitoring plasma vori-
conazole levels may be necessary to avoid subtherapeutic
levels in hematopoietic stem cell transplant recipients.
Cancer 2007; 109: 1532-5
74. Matsumoto K, Ikawa K, Abematsu K, et al. Correlation
between voriconazole trough plasma concentration and
hepatotoxicity in patients with different CYP2C19 geno-
types. Int J Antimicrob Agents 2009; 34: 91-4
75. Pascual A, Calandra T, Bolay S, et al. Voriconazole ther-
apeutic drug monitoring in patients with invasive mycoses
improves efficacy and safety outcomes. Clin Infect Dis
2008; 46: 201-11
76. Neely M, Rushing T, Kovacs A, et al. Voriconazole
pharmacokinetics and pharmacodynamics in children.
Clin Infect Dis 2010; 50: 27-36
77. Pascual A, Nieth V, Calandra T, et al. Variability of vori-
conazole plasma levels measured by new high-performance
liquid chromatography and biomass methods. Antimicrob
Agents Chemother 2007; 51: 137-43
78. Smith J, Safdar N, Knasinski V, et al. Voriconazole ther-
apeutic drug monitoring. Antimicrob Agents Chemother
2006; 50: 1570-2
79. Imhof A, Schaer DJ, Schanz U, et al. Neurological adverse
events to voriconazole: evidence for therapeutic drug
monitoring. Swiss Med Wkly 2006; 136: 739-42
80. Denning DW, Ribaud P, Milpied N, et al. Efficacy and
safety of voriconazole in the treatment of acute invasive
aspergillosis. Clin Infect Dis 2002; 34: 563-71
81. Tan K, Brayshaw N, Tomaszewski K, et al. Investigation of
the potential relationships between plasma voriconazole
concentrations and visual adverse events or liver function
test abnormalities. J Clin Pharmacol 2006; 46: 235-43
82. Trifilio S, Ortiz R, Pennick G, et al. Voriconazole ther-
apeutic drug monitoring in allogeneic hematopoietic stem
cell transplant recipients. Bone Marrow Transplant 2005;
35: 509-13
83. Ullmann AJ, Cornely OA, Burchardt A, et al. Pharmaco-
kinetics, safety, and efficacy of posaconazole in patients with
persistent febrile neutropenia or refractory invasive fungal
infection. Antimicrob Agents Chemother 2006; 50: 658-66
84. Gubbins PO, Krishna G, Sansone-Parsons A, et al.
Pharmacokinetics and safety of oral posaconazole in
neutropenic stem cell transplant recipients. Antimicrob
Agents Chemother 2006; 50: 1993-9
85. Kohl V, Muller C, Cornely A, et al. Factors influencing
pharmacokinetics of prophylactic posaconazole in
patients undergoing allogeneic stem cell transplantation.
Antimicrob Agents Chemother 2010; 54: 207-12
86. Krishna G, Parsons A, Kantesaria B, et al. Evaluation of
the pharmacokinetics of posaconazole and rifabutin fol-
ª 2011 Adis Data Information BV. All rights reserved.
Lass-Flörl
lowing coadministration to healthy men. Curr Med Res
Opin 2007; 23: 545-52
87. Jain R, Pottinger P. The effect of gastric acid on the ab-
sorption of posaconazole [letter]. Clin Infect Dis 2008; 46
(10): 1627; author reply 1627-8
88. Jang SH, Colangelo PM, Gobburu JV. Exposure-response
of posaconazole used for prophylaxis against invasive
fungal infections: evaluating the need to adjust doses
based on drug concentrations in plasma. Clin Pharmacol
Ther 2010; 88: 115-9
89. Mayr A, Lass-Flörl C. Epidemiology and antifungal resis-
tance in invasive Aspergillosis according to primary disease:
review of the literature. Eur J Med Res 2011; 16: 153-7
90. Binder U, Lass-Flörl C. Epidemiology of invasive fungal
infections in the mediterranean area. Mediterr J Hematol
Infect Dis. Epub 2011 Mar 31
91. Lewis RE. Antifungal drug monitoring. Curr Fungal Infect
Rep 2010; 4: 158-67
92. Hope WW, Billaud EM, Lestner J, et al. Therapeutic drug
monitoring for triazoles. Curr Opin Infect Dis 2008; 21:
580-6
93. Perkhofer S, Lass-Flörl C, Hell M, et al. The Nationwide
Austrian Aspergillus Registry: a prospective data collec-
tion on epidemiology, therapy and outcome of invasive
mould infections in immunocompromised and/or im-
munosuppressed patients. Int J Antimicrob Agents 2010;
36: 531-6
94. Gafter-Gvili A, Vidal L, Goldberg E, et al. Treatment of
invasive candidal infections: systematic review and meta-
analysis. Mayo Clin Proc 2008; 83: 1011-21
95. Ostrosky-Zeichner L, Oude Lashof AM, Kullberg BJ, et al.
Voriconazole salvage treatment of invasive candidiasis.
Eur J Clin Microbiol Infect Dis 2003; 22: 651-5
96. Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treat-
ment for less-common, emerging, or refractory fungal
infections. Clin Infect Dis 2003; 36: 1122-31
97. Steinbach WJ, Benjamin Jr DK, Kontoyiannis DP, et al.
Infections due to Aspergillus terreus: a multicenter retro-
spective analysis of 83 cases. Clin Infect Dis 2004; 39: 192-8
98. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive
aspergillosis with posaconazole in patients who are refrac-
tory to or intolerant of conventional therapy: an externally
controlled blinded trial. Clin Infect Dis 2007; 44: 2-12
99. Mukherjee PK, Sheehan DJ, Hitchcock CA, et al. Combi-
nation treatment of invasive fungal infections. Clin Micro-
biol Rev 2005; 18: 163-94
100. Lyseng-Williamson KA. Posaconazole: a pharm-
acoeconomic review of its use in the prophylaxis of in-
vasive fungal disease in immunocompromised hosts.
Pharmacoeconomics 2011 Mar 1; 29 (3): 251-68
101. Jansen JP, O’Sullivan AK, Lugtenburg E, et al. Economic
evaluation of posaconazole versus fluconazole prophy-
laxis in patients with graft-versus-host disease (GVHD) in
the Netherlands. Ann Hematol 2010; 89: 919-26
102. Stam WB, O’Sullivan AK, Rijnders B, et al. Economic
evaluation of posaconazole vs. standard azole prophy-
laxis in high risk neutropenic patients in the Netherlands.
Eur J Haematol 2008; 81: 467-74
103. Greiner RA, Meier Y, Papadopoulos G, et al. Cost-
effectiveness of posaconazole compared with standard
Drugs 2011; 71 (18)
Triazole Antifungal Agents
azole therapy for prevention of invasive fungal infections
in patients at high risk in Switzerland. Oncology 2010; 78:
172-80
104. Dranitsaris G, Khoury H. Posaconazole versus fluconazole
or itraconazole for prevention of invasive fungal infec-
tions in patients undergoing intensive cytotoxic therapy
for acute myeloid leukemia or myelodysplasis: a cost ef-
fectiveness analysis. Support Care Cancer 2010; 19 (11):
1807-13
105. Al-Badriyeh D, Liew D, Stewart K, et al. Cost-effectiveness
evaluation of voriconazole versus liposomal amphotericin
B as empirical therapy for febrile neutropenia in Aus-
tralia. J Antimicrob Chemother 2009; 63: 197-208
106. Al-Badriyeh D, Heng SC, Neoh CF, et al. Pharmacoeco-
nomics of voriconazole in the management of invasive
fungal infections. Expert Rev Pharmacoecon Outcomes
Res 2010; 10: 623-36
107. Sohn HS, Lee TJ, Kim J, et al. Cost-effectiveness analysis
of micafungin versus fluconazole for prophylaxis of in-
vasive fungal infections in patients undergoing hemato-
ª 2011 Adis Data Information BV. All rights reserved.
2419
poietic stem cell transplantation in Korea. Clin Ther 2009;
31: 1105-15
108. Pechlivanoglou P, Vries RD, Daenen SM, et al. Cost ben-
efit and cost effectiveness of antifungal prophylaxis in
immunocompromised patients treated for haematological
malignancies: reviewing the available evidence. Pharma-
coeconomics 2011; 29 (9): 737-51
109. Menzin J, Meyers JL, Friedman M, et al. Mortality, length
of hospitalization, and costs associated with invasive
fungal infections in high-risk patients. Am J Health Syst
Pharm 2009; 66: 1711-7
110. Wilson LS, Reyes CM, Stolpman M, et al. The direct cost
and incidence of systemic fungal infections. Value Health
2002; 5: 26-34
Correspondence: Professor Dr Cornelia Lass-Flörl, Division
of Hygiene and Medical Microbiology, Innsbruck Medical
University, Fritz Pregl Str 3/III, Innsbruck, Austria.
E-mail: cornelia.lass-floerl@i-med.ac.at
Drugs 2011; 71 (18)