A one-year survey of candidemia in Belgium in 2002.

Abstract

A total of 211 episodes of bloodstream yeast infections in 207 patients, hospitalized in 28 Belgian hospitals participating in a National Surveillance Program, were evaluated. A total of 81% of the patients were more than 50 years of age. Candida albicans was the cause of infections in 55% of patients, 22% were due to C. glabrata and 13% to C. parapsilosis. The most common predisposing factors were antibacterial therapy (42%), residence in an intensive care unit (32.9%) and presence of an intravascular catheter (29.7%). Most patients had more than one predisposing factor. Fluconazole alone or in association with another antifungal agent was the treatment of choice for 89.7% of the cases. In vitro susceptibility testing of the isolates revealed that 99% were susceptible to amphotericin B, 95% to 5-fluorocytosine, 82% to fluconazole and 69% to itraconazole. Resistance to azoles was more common among C. glabrata isolates in the elderly. We conclude that the frequency of C. albicans infection is decreasing in Belgium and this is associated with the emergence of other species, most notably, C. glabrata.

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A one-year survey of candidemia in Belgium in 2002
D. SWINNE1*, M. WATELLE1, C. SUETENS2, K. MERTENS2, P.-A. FONTEYNE1
AND N. NOLARD1
1Mycology Section, Scientific Institute of Public Health, Brussels, Belgium
2Epidemiology Section, Scientific Institute of Public Health, Brussels, Belgium
(Accepted 1 July 2004)
SUMMARY
A total of 211 episodes of bloodstream yeast infections in 207 patients, hospitalized in 28 Belgian
hospitals participating in a National Surveillance Program, were evaluated. A total of 81% of the
patients were more than 50 years of age. Candida albicans was the cause of infections in 55% of
patients, 22% were due to C. glabrata and 13% to C. parapsilosis. The most common
predisposing factors were antibacterial therapy (42%), residence in an intensive care unit (32.9%)
and presence of an intravascular catheter (29.7%). Most patients had more than one predisposing
factor. Fluconazole alone or in association with another antifungal agent was the treatment of
choice for 89.7% of the cases. In vitro susceptibility testing of the isolates revealed that 99% were
susceptible to amphotericin B, 95% to 5-fluorocytosine, 82% to fluconazole and 69% to
itraconazole. Resistance to azoles was more common among C. glabrata isolates in the elderly.
We conclude that the frequency of C. albicans infection is decreasing in Belgium and this is
associated with the emergence of other species, most notably, C. glabrata.
INTRODUCTION
Yeasts are emerging as important aetiological agents
of nosocomial infections, the most frequent being
Candida spp. These are now the fourth most common
cause of hospital-acquired bloodstream infection in
the United States [1]. Candida albicans has historically
been the most predominant Candida spp. associated
with infections and remains the most common cause
of candidemia today. However, the proportion of
bloodstream infections due to other Candida spp. has
increased in the last two decades [2]. The rise in the
number of immunocompromised patients, linked to
the use of prophylactic antifungal agents, are thought
to have played a major role in these changes. Indeed,
whereas C. albicans is generally susceptible to all
antifungal drugs, other species, such as C. glabrata,
may exhibit reduced susceptibility to antifungals [3].
Nevertheless, the reasons for the rise in non-C. albi-
cans species remain unclear and are probably multi-
factorial [4].
Suetens et al. [5] performed a preliminary survey on
bloodstream infections in Belgium in 2001 and found
that 7.6% were due to Candida spp. with an associ-
ated mortality of 48.1%.
Owing to the lack of information on the incidence
and epidemiology of candidemia in Belgium and
sparse data on the susceptibility of clinical isolates
to antifungal drugs, we organized the first mycologi-
cal multicentre study in this country. The aims
of the study were to document the distribution of
species among bloodstream Candida isolates, to test
* Author for correspondence: Dr D. Swinne, Scientific Institute of
Public Health, Mycology Section, Wytsmanstreet, 14, 1050 Brus-
sels, Belgium.
(Email: d.swinne@iph.fgov.be)
Epidemiol. Infect. (2004), 132, 1175–1180.
DOI: 10.1017/S095026880400295X
f 2004 Cambridge University Press
Printed in the United Kingdom

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the susceptibilities of the isolates to antifungal agents,
and to compile clinical and therapeutic data to inform
patient management.
The 150 Belgian medical centres, registered with the
Ministry of Public Health were asked to participate
in the study on a voluntary basis. All bloodstream
yeast isolates collected between 1 January and 31
December 2002 were requested and 28 centres con-
tributed isolates and data to the study. Isolates were
identified at the participating centre using the routine
methodology in the local laboratory. On receipt, iso-
lates were subcultured on Sabouraud’s agar for 24 h
at 35 xC and the identification confirmed using stan-
dard methods [6].
For susceptibility testing, isolates were assayed
using the Sensititre YeastOne panels according to the
manufacturer’s instructions (Trek Diagnostics Sys-
tems Ltd, East Grinstead, UK). The inoculum con-
centration ranged from 1.5r103to 8r103cells/ml
and colorimetric minimum inhibitory concentration
(MIC) end-points were read visually after incubation
at 35 xC for 24 h. For amphotericin B, the MIC
was recorded as the lowest drug concentration that
prevented a discernible colour change whereas for
itraconazole, fluconazole and flucytosine, the MIC
was taken as the lowest concentration that showed a
slight colour change compared to the positive growth
control. Isolates were categorized as susceptible (S),
susceptible-dose-dependent (SDD), intermediate sus-
ceptible (I), and fully resistant (R), according to the
NCCLS breakpoints [7].
A total of 211 yeast isolates were collected from 207
patients hospitalized in 28 different medical centres.
A single yeast species was isolated from 203 patients
and four patients were infected by two different
species. In total, 189 (95.6%) isolates were from
patients >15 years, 30 patients (14.5%) were aged
16–49 years, 73 patients (35%) were aged 50–64
years, and 86 patients (41.5%) were o65 years. Data
on gender were available for 205 cases: 107 were male
and 98 female (47.8%). Table 1 shows that more than
half of the isolates were C. albicans and with C. glab-
rata and C. parapsilosis these species accounted for
approximately 90% of all isolates. The remaining
isolates were distributed among eight other species.
The four mixed infections were due to two combina-
tions of C. albicans and C. glabrata and two of
C. albicans and C. tropicalis.
Information on risk factors for candidemia were
provided for 188 cases and are listed in Table 2. Most
patients had more than one risk factor but the most
common single factors were previous antimicrobial
therapy (79 patients, 42%), residence in an intensive
care unit (62 patients, 33%), the presence of an in-
dwellingcatheter(51patients,27%)andanunderlying
cancer (49 patients, 26%). Steroid therapy, parenteral
nutrition, pneumonia and organ transplantation were
Table 1. Yeast strains isolated from blood cultures in
Belgium in 2002
Species No. isolates (%)
Candida albicans
Candida glabrata
Candida parapsilosis
Candida tropicalis
Candida krusei
Saccharomyces cerevisiae
Pichia anomala
Candida lusitaniae
Candida guilliermondii
Candida norvegensis
Trichosporon mucoı¨des
115 (55)
47 (22)
26 (13)
6 (2.8)
5 (2.3)
4 (1.8)
3 (1.4)
2 (0.9)
1 (0.4)
1 (0.4)
1 (0.4)
Total 211
Table 2. Potential risk factors for 188 episodes of
candidemia
Potential risk factor
No. (%) of
patients
Antimicrobial therapy
Hospitalization in ICU
Indwelling catheters
Underlying cancer
Major surgery
Steroid therapy
Parenteral nutrition
Pneumonia
Transplant patient
Cutaneous abscess
Alcoholism
Biotherapy
Colitis
Colon perforation
Down syndrome
Drug abuse
Mucoviscidosis
Osteomyelitis
Pancreatitis
Prematurity
Prostatitis
Renal failure
Traffic accident
79 (42)
62 (33)
51 (27.1)
49 (25.9)
18 (9.6)
10 (5.3)
5 (2.6)
4 (2.1)
4 (2.1)
3 (1.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
1 (0.5)
Total 298
1176 D. Swinne and others

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the less common factors identified in a minority of
patients.
Data on the initial antifungal treatment was avail-
able for 156 cases. Fluconazole monotherapy was
prescribed for 132 (84.6%) patients; amphotericin B
and itraconazole were used singly for 15 patients and
one patient respectively. Eight patients received
sequential monotherapies: six received amphotericin
B followed by fluconazole, one fluconazole and itra-
conazole and the last amphotericin B, fluconazole
and voriconazole.
The susceptibilities to antifungal agents by NCCLS
criteria are presented in Table 3. All but two out of
211 isolates were fully susceptible to amphotericin B
(MICs <1 mg/ml). Only one isolate of C. tropicalis
and one of C. krusei had higher MIC values for
amphotericin B. A total of 201 isolates were suscep-
tible to flucytosine (MICs <4 mg/ml). Seven isolates
(5 C. krusei, 1 C. norvegensis and 1 Trichosporon mu-
co€ ? ?des) showed intermediate susceptibilities to this
agent with MICs between 8 and 16 mg/ml and three
(1 C. lusitaniae and 2 C. albicans) were resistant
(MICs >32 mg/ml). In total, 145 isolates (69%) were
susceptible to itraconazole (MICs <0.125 mg/ml), 51
(24%) were susceptible-dose-dependent with MICs
between 0.25 and 0.5 mg/ml and 15 (13 C. glabrata and
2 C. albicans, 7%) were resistant (MICs >1 mg/ml).
One hundred and seventy-two isolates (82%) were
susceptibletofluconazole(MICs<8 mg/ml),32(15%)
were susceptible-dose-dependent with MICs between
16 and 32 mg/ml and seven isolates (4 C. glabrata, 2
C. krusei and 1 C. albicans) were resistant (MICs
>64 mg/ml).
Four C. glabrata and one C. albicans isolates were
resistant to both itraconazole and fluconazole. Three
C. glabrata and one C. albicans isolate resistant to
itraconazole were susceptible-dose-dependent to flu-
conazole.
The MIC50 and MIC90 of the four antifungal
agents for the three most prevalent Candida spp. are
presented in Table 4. For amphotericin B, similar
MIC50and MIC90values were found for the three
species. C. glabrata was the most susceptible of the
speciestoflucytosine.The highest MIC90forthis agent
were found with C. albicans and C. parapsilosis. Full
susceptibilitytoitraconazolewasshownbyC.albicans
(MIC90=0.125 mg/ml) but C. glabrata isolates had the
highest resistance to this agent. C. glabrata isolates
weregenerallynotsusceptibletofluconazole(MIC90=
32 mg/ml) followed by C. parapsilosis. Almost all
C. albicans were susceptible.
The first objective was to document the distribution
of yeast species responsible for candidemia in Belgium
in 2002 and this was the first time that such a study
had been performed in that country. The low rate
(18.6%)ofvoluntaryparticipationbyregisteredmedi-
cal centres was disappointing. Centres were asked to
send all their bloodstream isolates over the test period
but no checking occurred to establish that this was the
case. Nevertheless we obtained sufficient samples to
allow us to establish the relative frequency of species
of yeasts causing bloodstream infections.
C. albicans remains the most common cause of
candidemia accounting for 55% of the cases. This is
less than the 64% reported from the National Sur-
veillance in Belgian Hospitals from October 1992 to
the end of June 2001 [5] and leads us to conclude that
the proportion of non-C. albicans candidemia is also
increasing in Belgium as observed elsewhere [2, 8, 9].
It is, however, difficult to compare our isolation rate
for C. albicans with those reported from other
European countries and which vary considerably be-
tween countries. For example,in Hungary afrequency
of C. albicans of 73.5% over a 5-year period (1996–
2000) was reported [10], in Norway, 66% (1991–1996)
[11], in Iceland, 64.4% (1980–1999) [12], in France,
53% in 1995 [13]; the lowest rate (41.4%) was re-
ported from Italy in a 10-year survey completed in
1997 [14]. The reasons for these differences are prob-
ably multifactorial but our rate of 55% is very close
to that (58%) observed by Pfaller et al. [2] who gath-
ered results from different European countries.
C. glabrata was the second most common species
overall causing 22% of the bloodstream infections
followed by C. parapsilosis in 13% of the cases. In
most published studies C. glabrata has emerged as the
second more frequent species responsible for blood-
stream infections [11, 12, 14, 15]. This rise occurs with
increasing patient age, an observation supported by
our results where 81% of patients with this organism
were older than 50 years. The higher incidence of this
Table 3. Susceptibilities of 211 yeast isolates from
blood cultures to antifungal agents
Antifungal
agentsSusceptible
Susceptible dose-
dependent/
Intermediate Resistant
Amphotericin B 209 (99%)
Flucytosine
Itraconazole
Fluconazole
—
7
51 (24%)
32 (15%)
2
3 201 (95%)
145 (69%)
172 (82%)
15 (7%)
7
Candidemia in Belgium 1177

Page 4

endosaprophytic species may be the result of modifi-
cation of the flora of the gastrointestinal and genital
mucosa [16]. Further, as fluconazole alone or in as-
sociation with another agent was the primary thera-
peutic choice in almost 90% of our patients, the rise
of C. glabrata may be related to its decreased suscep-
tibility to this drug [15, 17]. On the other hand,
C. parapsilosis, which was isolated from 13% of the
cases studied here, is an exogenously acquired yeast
pathogen which is horizontally transmitted and has
the propensity to adhere to implantable or semi-
implantable synthetic materials, including indwelling
central venous catheters [18]. Indeed, the rise of
C. parapsilosis candidemia is known to be associated
with invasive procedures involving the implantation
of prosthetic devices [8, 18, 19]. C. parapsilosis also
affects more frequently paediatric and neonatal
patients [20, 21] as well as critically ill individuals with
haematological malignancies [22]. In all those groups,
C. parapsilosis can become the most common species
after C. albicans and supplant C. glabrata with inci-
dence rates as high as 36% [22].
The frequency of C. parapsilosis (13%) isolates in
our study is low, considering that indwelling catheters
were present in 27% of the patients. This may be ex-
plained by the age distribution of our population that
is favourable to C. glabrata. If this hypothesis is veri-
fied, it suggests that the impact of age is more im-
portant than the presence of indwelling catheters.
All the other isolates belonged to species commonly
found as aetiological agents of candidemia.
The other main objective of the study was to evalu-
ate the susceptibilities of the isolates to commonly
used antifungal drugs. Our results show that the sus-
ceptibility of different species to amphotericin B was
excellent. Indeed, the two C. lusitaniae isolates, a
species frequently resistant to amphotericin B, were
both susceptible to the agent [23]. The responses to
flucytosine were also favourable with only 1.5% of
resistance and if only the 96 non-C. albicans isolates
were considered, the frequency of resistant isolates
diminishes to 1.1%. This is very low compared to
previously published data, i.e. 7.3% in Italy [24], 6%
in the United States [25] and 3% in Brazil [26]. In
contrast, the profiles of susceptibilities to triazole-
derived antifungal drugs were less favourable and
C. glabrata was the most frequently encountered
speciesexhibitingeitherlowsusceptibilityorresistance
to them: four were resistant to fluconazole (8.5%) and
13 to itraconazole (27.6%). The occurrence of cross-
resistances between the two triazoles was also more
frequently observed among C. glabrata isolates. Seven
isolates, either susceptible-dose-dependent or resistant
to fluconazole were also resistant to itraconazole.
In the SENTRY study mentioned above, Pfaller
et al. [16] found that isolates of Candida spp. showed a
trend of decreasing susceptibility to antifungal drugs
and more especially to azoles with increasing patient
age. In that study, none of the C. glabrata isolates
from individuals f1 year old were resistant to fluco-
nazole whereas they made up 9% of isolates from
individuals aged o65 years. This may partly explain
our results as 46% of our patients were elderly.
In conclusion, the frequency of occurrence of
C. albicans as a cause of bloodstream infections is
decreasing in Belgium. This is associated with the
Table 4. Antifungal susceptibility profile of 188 Candida bloodstream
isolates
Species (no.)Antifungal agents Range
MICs (mg/ml)
MIC 50% MIC 90%
C. albicans
(115)
Amphotericin B
Flucytosine
Itraconazole
Fluconazole
0.125–1.0
<0.03–>64
0.008–>16
0.06–>256
0.03–1.0
<0.03–16
0.06–>16
0.5–128
0.125–1.0
<0.03–1.0
0.03–0.25
0.5–16
0.5
0.06
0.06
0.5
0.5
0.03
0.5
16
0.5
0.12
0.125
2
1.0
0.25
0.125
1.0
1.0
0.03
1.0
32
1.0
0.25
0.25
4
C. glabrata
(47)
Amphotericin B
Flucytosine
Itraconazole
Fluconazole
C. parapsilosis
(26)
Amphotericin B
Flucytosine
Itraconazole
Fluconazole
1178D. Swinne and others

Page 5

emergence of other species, C. glabrata being the most
frequent. Decreased susceptibilities to azoles was also
observed and this is more prominent among C. glab-
rata isolates from individuals in the adult age group.
ACKNOWLEDGEMENTS
WethanktheBelgianinstitutionsthatcontributediso-
lates to the study: M. Andre ´ (CH Ardennes, Libra-
mont), J. Brouillard (RHMS, Ath), E. Christiaens
(RHMS, Tournai), G. Claeys/G. Verschraegen (UZ,
Gent), J. Colaert (AZ Groeninge, Kortrijk), G. Cop-
pens (ZOL, Genk), A. Dediste (CHU St-Pierre,
Bruxelles), M. De Weer/C. Vanhenterijck (H. Hart-
ziekenhuis, Leuven), D. Famere ´ e (CHU, Charleroi),
P. Gabrie ¨ ls (RZ St-Trudo, St-Truiden), M. G. Gar-
rino (CHR St-Camille, Namur), J. Gigi (UCL St-Luc,
Bruxelles), D. Govaerts (CHU Ve ´ sale, Montigny-le-
Tilleul), I. Grosjean (CH Peltzer-La-Tourelle, Ver-
viers), S. Lauwers/D. Pierard (AZ VUB, Brussel),
K. Magerman (Virga Jesse Ziekenhuis, Hasselt),
J. Moreaux (Cl. St-Joseph, Lie ` ge), M. F. Parmentier
(Centre de Sante ´ des Fagnes, Chimay), C. Potvliege
(CH Tivoli, La Louvie ` re), C. Sion (CHR, Huy),
M.Struelens/H.Rodriguez-Villalobos
Erasme, ULB, Bruxelles), I. Surmont/A. Verlinde (H.
Hartziekenhuis, Roeselare), N. Thys (CHR, Namur),
Ch. Trolin (CH Ixelles, Bruxelles), P. Vandecande-
laere (J. Ypermanziekenhuis, Ieper), A-M. Van Den
Abeele (AZ St-Lucas, Gent), H. Van Landuyt (AZ
St-Jan, Brugge), Ch. Verdonckt (St-Andrieszieken-
huis, Tielt), M. Wegge (Cl. St-Jean, Bruxelles). We
also thank Marc Van Der Flaes, Isabelle Seel and
Fre ´ de ´ ric Fauche for excellent technical help as well
as Genevie ` ve Ducoffre for the administrative organ-
ization.
(Ho ˆ pital
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