An observational efficacy and safety analysis of the treatment of acute invasive aspergillosis using voriconazole.

Abstract

The purpose of this study was to evaluate efficacy and safety of voriconazole in patients with acute invasive aspergillosis (IA) in a real-life, clinical setting. This was a multicenter observational study in adult patients treated with voriconazole for invasive mycosis. The study evaluated clinical response, mortality, use of other licensed antifungal therapy (OLAT), and treatment duration. This sub-analysis evaluated treatment and outcome data specifically from adult patients with proven/probable IA, while safety data were assessed in patients with proven/probable/possible IA. Of the 141 patients enrolled, 113 were adults with proven/probable IA and six had possible IA. Voriconazole treatment duration ranged from 1 to 183 days (median, 49.5 days). Voriconazole was used exclusively in 64% (72/113) of patients and in combination/sequentially with OLAT in 36%. Overall successful treatment response was 50% (57/113 patients). Twelve percent (14/113) of patients were switched to OLAT, either because of insufficient response (four patients) or for safety reasons (10 patients). Overall and attributable (entirely or partially due to fungal infection) mortality rates were 52% (59/113) and 17%, respectively. Treatment-related adverse events were reported for 18% (22/119) of patients. This observational study confirms the results of previous clinical trials demonstrating voriconazole as an effective and safe agent for treatment of confirmed acute IA.

Full text

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ARTICLE
An observational efficacy and safety analysis of the treatment
of acute invasive aspergillosis using voriconazole
F. Jacobs & D. Selleslag & M. Aoun & A. Sonet &
A. Gadisseur
Received: 31 March 2011 /Accepted: 12 September 2011 /Published online: 5 October 2011
# The Author(s) 2011. This article is published with open access at Springerlink.com
efficacy and safety of voriconazole in patients with acute
invasive aspergillosis (IA) in a real-life, clinical setting.
This was a multicenter observational study in adult patients
treated with voriconazole for invasive mycosis. The study
evaluated clinical response, mortality, use of other licensed
antifungal therapy (OLAT), and treatment duration. This
sub-analysis evaluated treatment and outcome data specif-
ically from adult patients with proven/probable IA, while
safety data were assessed in patients with proven/probable/
possible IA. Of the 141 patients enrolled, 113 were adults
with proven/probable IA and six had possible IA. Vorico-
nazole treatment duration ranged from 1 to 183 days
(median, 49.5 days). Voriconazole was used exclusively in
64% (72/113) of patients and in combination/sequentially
with OLAT in 36%. Overall successful treatment response
was 50% (57/113 patients). Twelve percent (14/113) of
insufficient response (four patients) or for safety reasons
(10 patients). Overall and attributable (entirely or partially
due to fungal infection) mortality rates were 52% (59/113)
and 17%, respectively. Treatment-related adverse events
were reported for 18% (22/119) of patients. This observa-
tional study confirms the results of previous clinical trials
demonstrating voriconazole as an effective and safe agent
for treatment of confirmed acute IA.
Introduction
The incidence of severe systemic fungal infections has
increased over the past decade [1, 2], mainly due to the
increasing number of immunosuppressed patients surviving
with underlying disease (e.g., hematologic/non-hematologic
malignancies, HIV) and those undergoing hematopoietic
stem cell or solid organ transplantation [2–4]. Such
infections represent a serious cause of morbidity and
mortality in these patient populations [1, 5, 6].
Voriconazole is a broad-spectrum triazole antifungal
agent approved in the European Union and the United
States for the treatment of invasive aspergillosis (IA),
candidemia in non-neutropenic patients, specific types of
invasive Candida infections, and serious fungal infections
caused by Scedosporium and Fusarium spp. [7, 8]. Of note,
this agent is not active against the zygomycetes [9]. The
efficacy of voriconazole was demonstrated in several
clinical studies [10–12] and in a randomized, open-label,
comparative trial of 277 patients with acute IA [13]. In that
trial, voriconazole showed superior efficacy and tolerance
compared with conventional amphotericin B in all patient
populations [13]. Voriconazole is now generally recom-
mended as first-line therapy of IA [14–17], and in Belgium
F. Jacobs (*)
Hôpital Erasme, Université Libre de Bruxelles (ULB),
Brussels, Belgium
e-mail: frederique.jacobs@erasme.ulb.ac.be
D. Selleslag
AZ Sint-Jan Hospital,
Brugge, Belgium
M. Aoun
Institut Bordet,
Brussels, Belgium
A. Sonet
Hôpital Universitaire de Mont-Godinne,
Yvoir, Belgium
A. Gadisseur
Antwerp University Hospital,
Edegem, Belgium
Eur J Clin Microbiol Infect Dis (2012) 31:1173–1179
DOI 10.1007/s10096-011-1425-5
Abstract The purpose of this study was to evaluate
patients were switched to OLAT, either because of

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it is reimbursed for the treatment of proven or probable IA
(according to international consensus criteria), among other
conditions.
While voriconazole has demonstrated efficacy in clinical
trials, data from observational studies prospectively con-
ducted in a real-life setting are sparse. Observational
evidence may add relevant information to the totality of
clinical evidence [18], and can thus be regarded as
complementary to randomized clinical trials. Such real-life
data are important not only to clinicians faced with
selecting appropriate antifungal treatment, but also to
healthcare payers making reimbursement decisions. For
instance, observational studies can help to assess the
predictive and external validity of pharmacoeconomic
models, such as the model used to support the reimburse-
ment submission of voriconazole in Belgium [19]. We
therefore conducted a study to evaluate the use of
voriconazole in daily clinical practice for the treatment of
invasive mycoses in Belgian hospitals, with a specific focus
on adult patients with acute IA. Treatment and outcome
data were evaluated in patients with proven/probable IA,
while safety was assessed in patients with proven/probable/
possible IA.
Materials and methods
Study design and population
This was a prospective, multicenter, observational, non-
interventional study in adult patients treated for serious
invasivefungalinfections.Thestudywasconductedinvarious
clinical-care settings (hematology, infectious disease, pulmo-
nary medicine, and intensive care) in Belgian hospitals. Ten
centers (mainly major academic hospitals), which routinely
treat patients with IA, initially participated in this study.
Each participating investigational site was asked to
collect data from 15 to 20 successive eligible patients over
a period of approximately 18 months. Patients were eligible
for inclusion into the study if they received intravenous
(IV) or oral voriconazole for first-line treatment of acute
invasive aspergillosis, candidiasis, or scedosporiosis. Of
note, the type of antifungal therapy (including dosing and
duration) was selected entirely at the local investigator's
discretion. Diagnosis and classification (i.e., as proven,
probable, or possible) of invasive mycoses was carried out
by the investigator according to generally accepted standard
criteria developed by the European Organization for
Research and Treatment of Cancer (EORTC) together with
the National Institute of Allergy and Infectious Diseases
Mycosis Study Group (MSG) [20], and was based on a
combination of histologic, microbiologic, and radiologic
evidence.
Each site acquired Institutional Review Board/Indepen-
dent Ethics Committee approval of the study design. The
study was performed in accordance with the ethical stand-
ards laid down in the Declaration of Helsinki. All patients
gave their written informed consent. In seriously ill patients
who were unable to make properly informed decisions,
consent was obtained from the next of kin or legal
representative.
Treatment and outcome evaluations
Data collection started on day 1 of voriconazole therapy
and continued for a maximum duration of 182 days.
Patients were followed until the end of antifungal therapy
or day 182; treatment durations of more than 182 days were
recorded as 183 days. The primary clinical endpoint was
the patient’s response to antifungal therapy, assessed either
at 12 weeks of treatment or at the end of therapy. Outcomes
were categorized by the investigator as complete response
(i.e., resolution of all clinical signs and symptoms and most
of the radiologic lesions), partial response (i.e., major
improvement), stable (i.e., minor or no improvement, but
no deterioration), or failure, based on the change in status
of symptoms, signs, and/or diagnostic abnormalities attrib-
utable to invasive mycosis that had been present at baseline.
Failure was defined as deterioration in attributable symp-
toms, signs, and/or diagnostic abnormalities present at
baseline. Complete or partial clinical responses, but not
stable disease, were considered successful treatment
responses. Use of other licensed antifungal therapy (OLAT)
was not considered a failure if the patient had a successful
response at 12 weeks. These definitions of outcomes and
treatment response are identical to those used in the pivotal
randomized clinical trial of voriconazole in IA [13]. Other
endpoints were survival at the end of the observational
period, number of patients who also received OLAT, and
treatment duration. In terms of treatment and outcome
evaluations, this sub-analysis focuses exclusively on adult
patients with proven/probable, acute IA. Patients aged
<18 years who received oral voriconazole 200 mg twice
daily (i.e., the same dosage recommended for adults) [7, 8]
were classified as adults for the purposes of this study and
were consequently included in these analyses; patients aged
<18 years who received <200 mg oral voriconazole twice
daily were excluded.
Safety evaluations
Adverse events (AEs) were monitored throughout the study
across all enrolled patients and were reported spontaneously
by the physician. Laboratory values of aspartate amino-
transferase, alanine aminotransferase, bilirubin, alkaline
phosphatase, and serum creatinine were considered abnor-
1174Eur J Clin Microbiol Infect Dis (2012) 31:1173–1179

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mal when they exceeded five times the upper limit of
normal (or 2.5 mg/dl for serum creatinine). Treatment-
emergent laboratory abnormalities were defined as those
that worsened (i.e., new abnormality or change in severity)
during treatment compared with baseline levels. In terms of
safety evaluations, this paper focuses exclusively on adult
(according to the definition above) patients with proven/
probable/possible acute IA.
Statistical methods and sample size
The study was designed to prospectively collect data from
120 to 150 eligible patients. All analyses were based on the
intent-to-treat population, defined as those patients who
received at least one dose of study medication. Descriptive
statistics were used to explore the collected data.
Results
Patients
The number of patients enrolled (between 10 March 2004
and 12 September 2005) per study center ranged from three
to 32. Some centers were unable to recruit a sufficient
number of patients; therefore, four additional centers were
contacted, leading to 14 investigational sites participating in
this study overall. A total of 141 patients were enrolled,
including 113 adult patients with a diagnosis of proven or
probable IA. Of note, six of these 113 patients were
diagnosed with concurrent invasive Candida infections.
Twenty-eight patients were excluded from the present
analysis for the following reasons: invasive Candida
infection only (n=10; i.e. patients without concurrent IA);
possible IA (n=6); children (n=5); other invasive fungal
infection (Microsporum canis, n=1; Phaeoacremonium sp,
n=1; Saccharomyces cerevisae, n=1); use of voriconazole
for prophylaxis only (n=2); non-invasive Aspergillosis
(n=1); and Scedosporium fusarium infection (n=1).
Baseline data for patients with proven/probable IA are
summarized in Table 1. Of note, neutropenia (absolute
neutrophil count <500/mm3) was reported in 35.3% of
patients, and 91.3% were immunocompromised. The
average duration of hospitalization due to IA was 9.6 days
(median 3.5 days; range 0–94 days).
Treatment duration and OLAT use
Ninety-six patients were initially treated with voriconazole
alone(85%);14patients wereswitchedtoOLATfollowing an
average duration of 26 days of voriconazole therapy (median
15 days; range 3–83 days) because of either insufficient
response (n=4 patients) or for safety reasons (n=10 patients;
Table 2). Four patients with a shift from voriconazole to
OLAT were treated again later with voriconazole. In ten
patients, OLAT was added to voriconazole after an average
of 12 days (range 3–35 days), either because of insufficient
response (nine patients) or due to safety reasons (one patient,
who received 3 days of fluconazole following “pyrexia”; the
Table 1 Baseline data for 113 patients with acute invasive aspergil-
losis treated with voriconazole (intravenous or oral)
Baseline characteristics Value
Mean age, years (range)
Male, n (%)
Mean weight, kg (±SD)
Underlying condition, n (%)a
Allogeneic hematopoietic stem cell transplantation
Autologous hematopoietic stem cell transplantation
Leukemia
Other hematologic malignancy
Solid tumour
Solid organ transplantation
AIDS
Pulmonary diseasesb
Autoimmune diseasesc
Liver cirrhosis
55.6 (14–85)
67 (59)
65.4±14.4
21 (18.6)
4 (3.5)
51 (45.1)
23 (20.3)
8 (7.0)
10 (8.8)
2 (1.8)
8 (7.0)
3 (2.6)
1 (0.9)
aPatients could have multiple underlying conditions
bChronic obstructive pulmonary disease (n=7); tuberculosis (n=1)
cWegener's granulomatosis (n=1); agranulocytosis (n=1); autoim-
mune skin disease (n=1)
Table 2 Treatment characteristics for 113 adult patients with invasive
aspergillosis
Treatment characteristicValue
Voriconazole treatment duration, mean, days (range)
Treatment duration in voriconazole-only patients, mean, days (range)
All (n=72)
IV only (n=24)
Oral only (n=24)
IV and oral (n=24)
Course of antifungal treatment, n (%)
Voriconazole only
Voriconazole→OLAT
Voriconazole→combination therapya, b
Combination therapya
Combination therapya→ OLATc
63 (1–183)
56 (1–183)
12 (1–36)
73 (6–183)
83 (13–183)
72 (63.7)
14 (12.4)
10 (8.8)
13 (11.5)
4 (3.5)
IV intravenous, OLAT other licensed antifungal therapy
aVoriconazole plus OLAT
bThree of these patients subsequently treated with voriconazole alone
cOne of these patients subsequently treated with voriconazole alone
Eur J Clin Microbiol Infect Dis (2012) 31:1173–11791175

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voriconazole dose was not changed). Seventeen patients
were initially treated with a combination of voriconazole and
OLAT; in four of the 17, voriconazole was subsequently
stopped.
In the overall population (N=113), voriconazole treat-
ment duration ranged from 1 to 183 days (median duration
49.5 days), keeping in mind that all durations >182 days
were recorded as 183 days. Most patients (41.6%) received
only oral formulations of voriconazole, 32 patients (28.3%)
were only treated intravenously, and 34 (30.1%) received
both IV and oral therapy. Among the latter, 29/34 patients
(85.3%) underwent step down from IV to oral therapy after
an average IV treatment duration of 11 days (range 1–61).
Oral voriconazole doses ranged from 400 to 600 mg/d.
Voriconazole dosages were generally in line with those
recommended in prescribing guidelines [7, 8].
Most patients (63.7%) were treated with voriconazole
only (Table 2), with a median total treatment duration of
32 days; mean treatment durations in patients receiving
only voriconazole were considerably longer in patients
given oral or both IV and oral formulations than in those
receiving just IV voriconazole (Table 2).
Caspofungin was the most frequent OLAT employed in
this study, given to 23 of the 41 patients who received a
systemic antifungal other than only voriconazole. Other
antifungal agents used by smaller numbers of patients
included various amphotericin B formulations (n=12
patients), itraconazole (n=3), and fluconazole (n=8).
Fluconazole is not active against Aspergillus spp. but was
nevertheless administered to some patients with IA only,
mostly for antifungal prophylaxis or as part of salvage
combination therapy.
Treatment response
Successful outcomes were observed in 50.4% (57/113) of
patients: 41 experienced a complete and 16 a partial
response. Stable response was reported in 13 patients and
failure in 43 patients. Among those patients who received
only voriconazole, 58.3% had a successful treatment
outcome (Table 3), which was higher than in patients
receiving combination therapy (48.1%) or those switched to
OLAT (14.4%).
The crude mortality rate at the end of the observational
period (12 weeks) was 52.2%; crude mortality at days 14,
42, and 84 was 14.2%, 27.4%, and 41.6%, respectively.
The majority of all deaths were attributed to underlying
disease and/or other causes rather than fungal infection.
Only 19 deaths were attributable (wholly or in part) to
invasive fungal disease, corresponding to an attributable
mortality rate of 16.8% (Table 4). The mortality rate was
lower in patients who received voriconazole monotherapy
or voriconazole-based combination therapy than in those
who were switched to OLAT (Table 4). Crude mortality at
the end of the observational period in patients receiving
exclusively IV voriconazole was 75.0% (18/24), following
an average of 12 days of voriconazole treatment. The cause
of death was attributable to fungal infection in three of
these patients and to a combination of fungal infection and
underlying disease in four others; the remaining patients
died due to underlying disease (n=10) or sepsis (n=1).
Safety
Safety was assessed in all 119 adult IA patients, including
those with possible IA (n=6). Treatment-related AEs were
reported for 22/119 patients (18.5%), with some patients
experiencing more than one such event.
Hepatic AEs and renal toxicity were reported in 12 and
four patients, respectively. Ten patients reported other AEs:
confusion or hallucinations (five patients), neutropenia,
dysphagia, an unspecified neurologic AE, dysuria, gastric
pain, and encephalopathy (one patient each). A shift from at
least one normal laboratory test value at baseline to an
abnormal value during treatment was recorded for 34 of
119 patients (28.6%), depending on the specific laboratory
test: 13 patients for alanine aminotransferase, 12 patients
for aspartate aminotransferase, 14 patients for alkaline
phosphatase, ten patients for bilirubin, and six patients for
serum creatinine.
Table 3 Clinical response
by type of treatment
OLAT other licensed
antifungal therapy
Clinical response All patients
(n=113)
Voriconazole
only (n=72)
Voriconazole switched
to OLAT (n=14)
Combination
therapy (n=27)
Successful
response
Complete
response
Partial
response
Unsuccessful
response
Stable
Failure
57 422 13
4131010
161123
56 30 1214
13
43
8
22
1
11
4
10
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Three patients (all with probable/proven IA) experienced
serious AEs that were considered related to voriconazole
treatment, and voriconazole was discontinued in all three.
The serious AEs that resulted in treatment discontinuation
were as follows: (1) hallucinations on day 3 (recovered on
day 4, when voriconazole was discontinued); (2) toxic
nephropathy, neurotoxicity, and hepatotoxicity on day 16 in
a solid organ transplant recipient with hematologic malig-
nancy (this patient eventually died from underlying
disease); and (3) confusion with encephalopathy on day
183 in a patient receiving combination therapy with
voriconazole, caspofungin, and conventional amphotericin
B (recovered completely).
In total, 22 of 119 (18.5%) patients discontinued
voriconazole treatment because of safety issues, i.e., all
patients for whom an AE was reported. Among the
remaining patients, 43 (36.1%) discontinued voriconazole
treatment following therapeutic failure, 53 (44.5%) because
the patient responded to treatment (not broken down by
type of treatment), and one for “other” reasons (not
specified by the investigator).
Discussion
This observational study supports the results from previous
clinical trials indicating the efficacy and good tolerability of
voriconazole in the treatment of IA. Investigators were not
bound to adhere to a specific protocol of antifungal therapy.
The results of this study thus reflect a range of available
treatment options and strategies.
About half of all adult patients given voriconazole as
first-line therapy for proven/probable IA in a real-life
setting recorded a successful treatment outcome. Of note,
more than 40% of all patients received only oral voricona-
zole, and an additional 25% of patients were stepped down
from IV to oral voriconazole after an average of 11 days’
therapy. These findings support previous suggestions that a
large number of patients can be effectively treated with oral
voriconazole [21]. However, current guidelines of the
Infectious Diseases Society of America (IDSA) recommend
initial use of parenteral therapy where feasible in patients
with IA [16], reflecting the design of the original
randomized clinical trial of voriconazole versus amphoter-
icin B [13]. The majority of patients who were switched to
OLAT did so because of safety concerns about voricona-
zole, rather than presumed lack of response. Almost three
quarters of those switched to other antifungals had died by
the end of the observational period, most of them from their
underlying disease; this does not necessarily indicate lack
of efficacy of OLAT, since it is possible that these patients
had more severe underlying disease than those who
continued taking voriconazole.
About 25% of all patients received voriconazole-based
antifungal combination therapy at some point during the
study, mostly with other mould-active agents. Mortality in
these patients was similar to that observed in patients
treated with voriconazole only, but clinical success rates
were 10% lower, possibly reflecting more severe fungal
disease. Among patients given only voriconazole, treatment
durations were shorter in those administered just the IV
formulation; the data suggest that those who received only
IV voriconazole died earlier, before step down to an oral
formulation could take place.
Overall, voriconazole was found to be well tolerated.
Since all patients for whom an AE was reported
discontinued the study, it is probable that AEs that did
not lead to treatment discontinuation were not reported
by the investigators.
Observational studies are a key complement to clinical
trials in the same setting, and can verify that treatment
outcomes observed under the highly controlled environ-
ment of a clinical study are reproducible in real-life
situations. The pivotal clinical trial conducted by Herbrecht
et al. [13] supports the use of voriconazole as the gold
standard for first-line treatment of IA [14–17]. Of note,
Table 4 Death rate and causes of death by type of treatment in the 113 patients with invasive aspergillosis over the course of the observational
period (12 weeks)
All patients
(n=113)
Voriconazole
only (n=72)
Voriconazole switched
to OLAT (n=14)
Combination therapy
(n=27)
Total number of deaths, n (%)
Cause of death, n (%)
Underlying disease
Fungal infection
Mixed (underlying disease and fungal infection)
Mixed (underlying disease plus other causesa)
59 (52.2)35 (48.6)10 (71.4) 14 (51.9)
34 (57.6)
8 (13.6)
11 (18.6)
6 (10.2)
20 (57.1)
3 (8.6)
6 (17.1)
6 (17.1)
6 (60.0)
1 (10.0)
3 (30.0)
0 (−)
8 (57.1)
4 (28.6)
2 (14.3)
0 (−)
OLAT other licensed antifungal therapy
aSeptic shock/septicemia (×2), multiple organ failure, chronic respiratory failure, cerebral tumor, bowel ischemia
Eur J Clin Microbiol Infect Dis (2012) 31:1173–1179 1177

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clinical outcomes (i.e., treatment success at 12 weeks) for
proven/probable IA were almost identical between our
observational study and the clinical trial [13, 22]. The
results of our study, including clinical outcomes, frequency
of combination therapy, and mortality, are also similar to
those from observational studies assessing the treatment of
invasive fungal disease in critically ill patients and
hematology patients undergoing intensive chemotherapy
[23, 24].
On the other hand, the mortality rate of 52% in our study
was much higher than the 29% in the clinical trial reported
by Herbrecht et al. [13]. However, different cut-off points
were used in the observational study and clinical trial (i.e.,
an observational period of a maximum of 182 days vs. day
84, respectively); when extrapolating the results to day 84,
the crude mortality rate in this observational study was only
42%. Mortality rates were 27% and 20% on day 42 in our
observational study and the clinical trial, respectively, and
14% and 9% on day 14. Survival was therefore somewhat
lower at all time points than in the clinical trial. However,
this may not come as a surprise, given that our observa-
tional study included patients with poor prognosis at
baseline, who would have been excluded from enrollment
in the trial. A systematic comparison of observational
studies and randomized clinical trials found that mortality
rates can be higher in the former, due to differences in
mortality risk of the enrolled patients [25]. The higher
mortality rate observed in our study may also explain why
the median total treatment duration in patients remaining on
voriconazole monotherapy (50 days) was lower than that
reported by Herbrecht et al. (77 days) [26]. It should be
noted that successful treatment response in our study was
observed almost exclusively in patients receiving vorico-
nazole monotherapy or voriconazole-based combination
therapy. Treatment failed in all but two of the 14 patients
switched to OLAT.
The good tolerability of voriconazole observed in our
study is in line with the known safety profile of this
antifungal [7, 8]. However, except for the incidence of
hallucinations (∼5%), the frequency of AEs observed was
somewhat higher than that reported in clinical trials; this
was particularly the case for abnormal liver function tests
(∼5%) and increased creatinine levels (∼1%). This discrep-
ancy may be due to differences in the definitions of
abnormal laboratory parameters and differences in the
patient populations. On the other hand, only severe or
unexpected AEs were reported in our study and AEs may
thus actually have been underreported. Of note, none of the
laboratory abnormalities required treatment or management
other than the discontinuation of voriconazole.
While observational studies are important complements
to randomized clinical trials [18], they also have certain
weaknesses, including selection and information bias. Our
study allowed the inclusion of patients with very poor
prognosis, thus complicating comparison of the results with
those from clinical trials. Unfortunately, the specific type of
IA (i.e., pulmonary, extrapulmonary, disseminated, or
cerebral) was not recorded. Another potential limitation is
the difficulty in accurately assessing clinical response in
patients who received only a few days of treatment.
Furthermore, the study did not use well-defined criteria
for the evaluation of treatment response. Since response
was assessed on a case-by-case basis by the investigator,
possibly using somewhat different principles and methods
of evaluation, survival may be a more meaningful outcome
measure in our study than clinical response. On the other
hand, the study design closely mimics clinical reality,
which constitutes a considerable strength. Due to the nature
of IA, which is a severe and life-threatening infection,
management is based on generally accepted recommenda-
tions. Therefore, it is unlikely that participation in an
observational study would have influenced the treatment of
the patients enrolled. The assessment and diagnosis of IA
was carried out in strict accordance with the standard
criteria defined by the EORTC-MSG [20], as was also done
in the pivotal clinical trial [13]. Despite the inherent
shortcoming of any observational study, our data allow
robust conclusions on the usage of voriconazole in a real-
life setting.
This observational study confirms the findings of
previous clinical trials, which demonstrated voriconazole
to be an effective agent for the treatment of IA. Adverse
events observed in this study were also consistent with the
known safety profile of voriconazole.
Acknowledgements
the other investigators of the study group: Prof. A. Bosly, Cliniques
Universitaires UCL, Godinne; Dr. G. Bries, Virga Jesse Ziekenhuis,
Hasselt; Prof. P. Damas, CHU Sart-Tilman, Liège; Prof. A. Ferrant
and Prof. P.- F. Laterre, Cliniques Universitaires St-Luc, Bruxelles; Dr.
M. Lambrechts, AZ St Maarten, Mechelen; Dr. J. Maertens, UZ
Gasthuisberg, Leuven; Dr. A. Van Hoof and Dr. J. Van Droogen-
broeck, AZ St Jan, Brugge; Prof. H. Spapen, AZ VUB, Jette; Dr. A.
Vergison, HUDERF, Laeken; Prof. P. Zachée, Alg Centrumziekenhuis
Antwerpen, Stuivenbergh. The authors also wish to thank Dr. Vincent
De Mees for his contribution to the study design and analysis,
Katelyne Capiau, Pfizer, for her input as study coordinator, Annelies
Decoster for the monitoring and field work, Dr. Marie-Paule Derde,
Veeda Clinical Research, for the data management and statistical
analysis, and Hilde Van Campenhout, Pfizer, for the overall study
management.
The study was sponsored by Pfizer. Editorial support was provided by
Dominik Wolf, MSc, of PAREXEL and funded by Pfizer International
Operations.
The authors wish to express their gratitude to
Potential conflicts of interest
from Pfizer and other pharmaceutical companies that market antifungal
agents.D.SelleslagreceivedhonorariaforpublicspeakingfromPfizerand
MSD, and research grants from Pfizer, Basilea, and MSD. M. Aoun, A.
Sonet, and A. Gadisseur have no relevant conflicts of interest to declare.
F. Jacobs has received consultancy fees
1178Eur J Clin Microbiol Infect Dis (2012) 31:1173–1179

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medium, provided the original author(s) and source are credited.
This article is distributed under the terms of the
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