JOURNAL OF CLINICAL MICROBIOLOGY, Sept. 2011, p. 3300–3308
Copyright © 2011, American Society for Microbiology. All Rights Reserved.
Vol. 49, No. 9
Diagnostic Issues, Clinical Characteristics, and Outcomes
for Patients with Fungemia?
Maiken Cavling Arendrup,1* Sofia Sulim,2Anette Holm,3Lene Nielsen,4Susanne Dam Nielsen,5
Jenny Dahl Knudsen,5Niels Erik Drenck,6Jens Jørgen Christensen,7and Helle Krogh Johansen8
Unit of Mycology, Department of Microbiological Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark1;
Department of Clinical Microbiology, Skejby Hospital, Aarhus University Hospital, Aarhus, Denmark2; Department of
Clinical Microbiology, Odense University Hospital, Odense, Denmark3; Department of Clinical Microbiology, Herlev
University Hospital, Herlev, Denmark4; Department of Clinical Microbiology, Hvidovre University Hospital,
Hvidovre, Denmark5; Department of Intensive Care, Roskilde University Hospital, Roskilde, Denmark6;
Unit of Clinical Microbiology, Statens Serum Institut, Copenhagen, Denmark7; and
Department of Clinical Microbiology, Rigshospitalet, Copenhagen
University Hospital, Copenhagen, Denmark8
Received 28 January 2011/Returned for modification 18 April 2011/Accepted 20 June 2011
This study investigated microbiological, clinical, and management issues and outcomes for Danish fungemia
patients. Isolates and clinical information were collected at six centers. A total of 334 isolates, 316 episodes, and
305 patients were included, corresponding to 2/3 of the national episodes. Blood culture positivity varied by
system, species, and procedure. Thus, cases with concomitant bacteremia were reported less commonly by
BacT/Alert than by the Bactec system (9% [11/124 cases] versus 28% [53/192 cases]; P < 0.0001), and cultures
with Candida glabrata or those drawn via arterial lines needed longer incubation. Species distribution varied
by age, prior antifungal treatment (57% occurrence of C. glabrata, Saccharomyces cerevisiae, or C. krusei in
patients with prior antifungal treatment versus 28% occurrence in those without it; P ? 0.007), and clinical
specialty (61% occurrence of C. glabrata or C. krusei in hematology wards versus 27% occurrence in other wards;
P ? 0.002). Colonization samples were not predictive for the invasive species in 11/100 cases. Fifty-six percent
of the patients had undergone surgery, 51% were intensive care unit (ICU) patients, and 33% had malignant
disease. Mortality increased by age (P ? 0.009) and varied by species (36% for C. krusei, 25% for C. parapsilosis,
and 14% for other Candida species), severity of underlying disease (47% for ICU patients versus 24% for others;
P ? 0.0001), and choice but not timing of initial therapy (12% versus 48% for patients with C. glabrata infection
receiving caspofungin versus fluconazole; P ? 0.023). The initial antifungal agent was deemed suboptimal upon
species identification in 15% of the cases, which would have been 6.5% if current guidelines had been followed.
A large proportion of Danish fungemia patients were severely ill and received suboptimal initial antifungal
treatment. Optimization of diagnosis and therapy is possible.
Surveillance of fungemia was initiated in Denmark in 2003
and has demonstrated a high incidence of this condition and an
increasing proportion of isolates belonging to the not fully
susceptible species Candida glabrata and C. krusei from a
Nordic as well as a global perspective (4, 9–11, 16, 23, 27, 40,
41, 46, 52).
A number of recent surveys have provided important infor-
mation on underlying diseases and host factors in patients with
fungemia. The most important factors are (i) critical illness
with a prolonged stay in the intensive care unit (ICU); (ii)
abdominal surgery, especially if it is complicated or repeated;
(iii) low birth weight; (iv) acute necrotizing pancreatitis; (v)
malignant disease; (vi) organ transplantation, especially of the
liver; (vii) Candida colonization; and (viii) use of antibiotics,
central venous catheters, steroids, dialysis, and total parenteral
The crude 30-day mortality was 30 to 40% in most popula-
tion-based studies enrolling patients until the turn of the mil-
lennium (2, 4, 12, 14, 16, 29, 41, 42, 49, 52) but was lower in
recent studies (16, 17, 36) and higher for ICU patients (7, 33),
patients infected with C. glabrata (54), and patients with de-
layed initiation of appropriate antifungal treatment (20, 34).
Because timing and diagnostic sensitivity are still major issues
in the management of fungemia, an understanding of diagnos-
tic features, risk groups, and epidemiology is of utmost impor-
tance for selection of patients who may benefit from early
antifungal treatment and for selection of the most appropriate
antifungal agent before species identification is available.
On this background, the Danish surveillance scheme was
continued, and information on underlying host factors, diag-
nostic procedures, and antifungal treatment was collected pro-
spectively over a 1-year period for patients admitted to six
major centers participating in the national surveillance of
fungemia in order to provide a better understanding of the epi-
demiology and possible areas for improved diagnostics or man-
agement. The six participating centers covered half of the
Danish population and included two-thirds of the national
fungemia cases, with a species distribution mirroring the na-
tional data, suggesting that this study provides a representative
picture of the national situation.
* Corresponding author. Mailing address: Unit of Mycology, 43/117,
Department of Microbiological Surveillance and Research, Statens
Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark. Phone:
(45) 32 68 32 23. Fax: (45) 32 68 30 33. E-mail: firstname.lastname@example.org.
?Published ahead of print on 29 June 2011.
MATERIALS AND METHODS
Surveillance and population. During a 1-year period from January to Decem-
ber 2006, fungal blood isolates were collected at the six major Danish depart-
ments of clinical microbiology, at Rigshospitalet and Hvidovre Hospital (serving
Copenhagen City hospitals and the island of Bornholm since 1 January 2005),
Herlev Hospital (serving hospitals in the County of Copenhagen), Statens Serum
Institut (serving hospitals in the County of Roskilde), Odense University Hos-
pital (serving hospitals in the County of Funen), and Skejby Hospital (serving
hospitals in the County of Aarhus). Together, the six departments served 11
university and 20 district hospitals in the municipality of Copenhagen and the
respective counties. The total number of admissions was 609,850, or 53% of the
total number of nonpsychiatric hospital beds in Denmark. Altogether, these
hospitals served a total population of 2,636,027 patients (1,294,166 males [49.1%]
and 1,341,861 females [50.9%]), or 49% of the Danish population. Besides
serving the populations of their respective catchment areas, the university hos-
pitals are secondary or tertiary care centers for all of Denmark. In particular, all
solid organ transplantations and autologous bone marrow transplantations in
Denmark are performed at the participating hospitals, and all allogeneic bone
marrow transplantations and liver transplantations are performed at Rigshospi-
talet. However, it was not feasible to determine the contributions of referred
cases from other hospitals in Denmark. Information on the number of nonpsy-
chiatric admissions was retrieved at the Denmark National Board of Health
website (www.sundhedsdata.sst.dk). During the study period, two departments
used the BacT/Alert blood culture system (bioMe ´rieux, Marcy l’Etoile, France),
and four used the Bactec blood culture system (Becton Dickinson, Franklin
Lakes, NJ). Surveillance cultures were performed systematically at only one
department of intensive care (at Rigshospitalet).
Information on the total number of bloodstream isolates was retrieved from
the departments’ laboratory information systems. Successive blood cultures with
fungi from a patient were considered to be distinct episodes if they occurred at
least 21 days apart or were caused by different species. Three hundred of the 334
isolates were sent to the reference laboratory, the Unit of Mycology and Para-
sitology at Statens Serum Institut, Copenhagen, Denmark, for verification of
species identification and susceptibility testing. The isolates not referred from the
participating hospital to the reference laboratory comprised 34 isolates (7.2%).
A pro forma document was provided to collect data on each patient with a
fungus-positive blood culture and on the time course of the mycological diag-
nosis. The clinical information requested included the patient’s age, sex, and
underlying conditions, the hospital department at the time of positive blood
culture, the presence or absence of an indwelling catheter, and whether or not
the patient was receiving total parenteral nutrition, corticosteroid therapy, or
mechanical ventilation or had undergone surgery. Other documented infections
were noted, as well as any antibacterial or antifungal therapy given in the 2 weeks
before blood culture, the therapy given for the present episode of fungemia, and
whether or not the intravenous (i.v.) catheter was removed as part of antifungal
treatment. Day 30 mortality was recorded and, whenever possible, classified as
either related to the fungemia or not, based on a clinical and microbiological
evaluation. Information regarding the diagnosis of the fungemia included the
number of positive blood culture bottles and the number of samples taken,
whether the blood culture was drawn peripherally or via a catheter, time to
positivity, time to species identification, and presence of Candida colonization
within the week before blood culture. While full information was not available
for all patients, the cooperation and enthusiasm of the participating physicians
and laboratories were very high, and data were obtained for 314 of the 316
Species identification. Species identification at the reference laboratory was
based on colony morphology on chromogenic agar (CHROMagar Co., Paris,
France), microscopic morphology on corn meal agar and rice plus Tween agar
(SSI Diagnostika, Hillerød, Denmark), growth at 35°C and 43°C, and use of a
commercial system (ATB ID32C; bioMe ´rieux, Marcy l’Etoile, France). In addi-
tion, commercial rapid tests for the identification of C. dubliniensis and C.
glabrata were used increasingly over the study period (Bichro-Dubli and Glabrata
RTT, respectively; Fumouze Diagnostics, Simoco, Denmark).
Susceptibility testing. Susceptibility testing was performed according to the
protocol in EUCAST definitive document EDef 7.1 (45). Manufacturers and
stock concentrations of reagents were as follows: dimethyl sulfoxide (DMSO)
(D8779), Sigma-Aldrich; fluconazole, Pfizer A/S, Ballerup, Denmark (10,000
?g/ml); amphotericin B (A2411), Sigma-Aldrich, Vallensbaek Strand, Denmark
(5,000 ?g/ml in DMSO); caspofungin, Merck, Sharp and Dohme, Glostrup,
Denmark (5,000 ?g/ml in DMSO); itraconazole, Janssen-Cilag, Birkerød, Den-
mark (5,000 ?g/ml in DMSO); and voriconazole, Pfizer A/S, Ballerup, Denmark
(5,000 ?g/ml in DMSO). Twofold dilutions of drugs in RPMI medium supple-
mented to a final concentration of 2% glucose were prepared in microtiter plates
and stored at ?80°C until use. Microtiter plates were read spectrophotometri-
cally at 490 nm. The MIC was defined as the lowest drug dilution giving 100%
growth inhibition for amphotericin B and 50% growth inhibition for the other
compounds. C. krusei ATCC 6862 was included as a control in each run, and the
MIC determinations were accepted if they were within the published ranges for
amphotericin B, fluconazole, itraconazole, and voriconazole (18) and within 0.25
to 2 ?g/ml for caspofungin, for which no quality control range has yet been
Statistics. Fisher’s exact test and the chi-square test for independence were
used. P values of ?0.05 were considered statistically significant.
Epidemiological and microbiological findings. (i) Epidemi-
ology. During the 1-year study period, a total of 334 isolates
from 316 episodes of fungemia were registered for 305 pa-
tients. Overall, the rates of fungemia were 0.5 case/1,000 ad-
missions and 11.9 cases/100,000 somatic admissions (Table 1).
The majority of patients were male (57.6%) and between 61
and 80 years of age (55.7%) (Table 1). Age-specific incidences
(per 100,000 persons) were 25.1 cases among those aged ?1
year, 1.7 cases among 1- to 9-year-olds, and the following for
each 10-year age group between 10 and 89 years: 0.3, 2.2, 1.7,
7.8, 13.4, 35.6, 53.2, and 30.9 cases. Finally, the incidence was
28.8 cases/100,000 persons among those aged ?90 years.
The most common species were C. albicans (53.1% [178/335
cases]), C. glabrata (21.8% [73/335 cases]), and C. krusei (7.8%
[26/335 cases]). C. parapsilosis and C. tropicalis both accounted
for 4.8% (16/335 cases) of cases, C. dubliniensis accounted for
3.3% (11/335 cases) of cases, and 2.4% (8/335 cases) of cases
involved other Candida species, including two each involving
C. pelliculosa and C. kefyr and one each involving C. guillier-
mondii, C. inconspicua/norvegensis, C. lusitaniae, and C. inter-
media. Finally, 2.1% (7/335 cases) of the isolates were other
fungi, including Saccharomyces cerevisiae (3/335 cases) and one
each of Cryptococcus neoformans, Fusarium solani, and Rho-
dotorula sp. The species distribution varied by age and clinical
specialty. For example, the C. glabrata proportion increased by
age, from 0% (0/14 cases) in patients below 20 years of age to
42% in patients older than 80 years (11/26 cases), and the C.
parapsilosis proportion decreased from 14% (2/14 cases) to 0%
(0/26 cases) for the same age groups. Furthermore, C. albicans
accounted for 92% (11/12 cases) of cases in neonatal and
pediatric wards and 61.2% (93/152 cases) of cases in ICU
departments, excluding hematological ICUs, but for only 6%
(1/18 cases) of cases in hematological units (including hema-
tological ICUs) (Table 2), whereas C. glabrata and C. krusei
were significantly more common in the hematological wards
(61% of episodes [11/18 cases]) than in other wards (29% of
episodes [83/289 cases]) (P ? 0.002) (Table 2). Polyfungal
infections were found more often in patients in medical wards
(9/93 cases [10%]) than in patients in surgical wards (4/159
cases [3%]) (P ? 0.018) and most often (12/14 cases) involved
at least one species with an inherently low susceptibility to
fluconazole (C. glabrata, C. krusei, Saccharomyces cerevisiae, or
Rhodotorula sp.) (Table 2).
(ii) Microbiological details for positive blood cultures. Con-
comitant bacteremia was observed for 64 fungemia episodes
(20%) and was reported significantly more often at centers
using the Bactec blood culture system (53/192 episodes [28%])
than at those using the BacT/Alert system (11/124 episodes
VOL. 49, 2011 FUNGEMIA: DIAGNOSTICS AND OUTCOME3301
[9%]) (P ? 0.0001 by Fisher’s exact test) (Table 1). The epi-
sodes involved coagulase-negative staphylococci in 15 cases (14
of which were detected at centers using the Bactec system),
Gram-negative rods in 14 cases (13 of which were detected at
centers using the Bactec system), enterococci in 11 cases (8 of
which were detected at centers using the Bactec system),
Staphylococcus aureus in 5 cases (4 of which were detected at
centers using the Bactec system), Lactobacillus or Bacillus spp.
in 5 cases (all of which were detected at centers using the
Bactec system), streptococci in 4 cases (2 of which were de-
tected at centers using the Bactec system), and polybacterial
bacteremia in 10 cases (7 of which were detected at centers
using the Bactec system).
Information regarding the origin of blood culture and incu-
TABLE 1. Characteristics of the six participating centers, rates of fungemia, and selected demographic factors for patients with fungemia
Value or description
Characteristics of participating centers
No. of hospitals (no. of university
hospitals/no. of district hospitals)
Population served in the catchment
area in 2006
No. of admissions in 2006
Blood culture system
9 (1/8) 3 (1/2)4 (3/1)1 (1/0) 8 (3/5)6 (1/5) 30 (10/20)
478,347241,523 618,529 NAa
No. of patients
No. of episodes
No. of isolates
No. (%) of polyfungal episodes
No. (%) of episodes including bacteria
No. of episodes/1,000 admissions
No. of episodes/100,000 patient daysc
0 6 (8)
No. (%) of females
No. (%) of males
No. (%) of patients at age (yr):
aRigshospitalet has a variable uptake area depending on specialty and additionally receives an extensive number of patients referred from other parts of Denmark
due to the tertiary function of this hospital.
bUse of a mycosis bottle in addition to aerobic and anaerobic bottles was introduced for high-risk patients, starting from November 2006.
cSomatic patient days only.
TABLE 2. Species distribution overall and by clinical specialty for 307 episodes of fungemiaa
No. (%) of episodes
Surgical wards (159)Medical wards (93)
ICU-S-GEICU-SS-GES HematologybICU-MM M-GE Cardiology
C. albicans (161)
C. dubliniensis (7)
C. glabrata (65)
C. krusei (18)
C. tropicalis (13)
Candida spp. (8)
Other fungi (4)
10 (53) 17 (52)
4 (100) 17 (50)
1 (6) 5 (20)
2 (17) 1 (3)
7 (21) 13 (52)
3 (21)5 (28)
1 (8) 1 (14)
1 (5)1 (3) 1 (7)
1 (5) 3 (9)1 (7) 2 (11)
1 (14) 8 (3)
4 (1)1 (1) 2 (6)
aData for dominating species are highlighted in bold. ICU, intensive care unit; S, surgical; GE, gastroenterology; M, medical.
bIncludes 5 patients in the ICU (2 C. glabrata, 1 C. krusei, and 1 polyfungal episode, as well as an episode with 1 other fungus).
cIncludes one patient in the ICU (with C. albicans).
3302ARENDRUP ET AL. J. CLIN. MICROBIOL.
bation time before positivity was available for 313 episodes.
The median (range) incubation time before positivity was 2
days (0 to 10 days) but varied by species and by origin of blood
culture (Fig. 1). Thus, blood cultures from episodes due to
C. tropicalis or C. krusei were positive after a median incuba-
tion time of only 1 day (ranges of 1 to 3 days and 1 to 4 days,
respectively), whereas blood cultures from episodes due to
C. albicans, C. glabrata, or C. parapsilosis were positive after a
median incubation time of 3 days, with 25% of the episodes
due to C. glabrata being positive on day 4 or later (ranges of 0
to 10 days, 0 to 8 days, and 0 to 4 days, respectively) (Fig. 1a).
Blood cultures obtained via an arterial line were positive later
than blood cultures obtained via an i.v. line or by venipuncture
(Fig. 1b). The necessary incubation times for the two blood
culture systems were similar, i.e., 48.8% of samples turned
positive by the BacT/Alert system and 51.6% did so by the
Bactec system after 2 days of incubation (Fig. 1c). Finally,
times to positivity were comparable for patients receiving an-
tifungal agents and those not receiving these agents at the time
of collection of blood culture (Fig. 1d).
FIG. 1. Time to blood culture positivity overall and by species. Numbers of episodes per species are indicated in parentheses. AF, antifungal;
BC, blood culture.
VOL. 49, 2011 FUNGEMIA: DIAGNOSTICS AND OUTCOME3303
One center (Copenhagen County) introduced the use of a
Bactec mycosis blood culture bottle for selected high-risk pa-
tients in the last two study months. In five episodes (none with
ongoing antifungal treatment), a mycosis bottle was used si-
multaneously with aerobic and anaerobic bottles. In three of
these episodes, the mycosis bottle was the only one that was
positive (positive for C. albicans, C. glabrata, or C. parapsilosis),
whereas in two episodes, the mycosis bottle and at least one of
the two to four traditional bottles were positive (for C. albicans
or C. glabrata).
(iii) Yeast colonization. Colonization with yeast within the
last 7 days before the day of blood culture was documented in
149/316 episodes (47.1%), and the isolate(s) was identified in
100 episodes. For the remaining episodes, samples either were
not taken or were culture negative for yeast. The species caus-
ing the fungemia was different from the colonizing flora in
11/100 cases. These included 9/70 cases with C. albicans as the
only colonizing fungal species but with fungemia with C. dub-
liniensis (2 cases), C. tropicalis (1 case), C. glabrata (3 cases), C.
albicans plus S. cerevisiae (1 case), C. krusei (1 case), or S.
cerevisiae (1 case). Furthermore, in 2/10 cases, C. glabrata was
the only colonizing fungus detected, whereas the invasive dis-
ease was polyfungal, i.e., C. glabrata was present in combina-
tion with C. albicans or C. dubliniensis. The invasive organism
was part of the colonizing flora in all other cases, including the
14 cases with polyfungal colonization, and infection was mono-
fungal in all of these cases.
Clinical and outcome characteristics. (i) Underlying host
factors. More than half of the patients had undergone surgery
(177 episodes [56%]), the majority of which were abdominal
surgeries (81%), and half of the patients were in the ICU
(Table 3). One-third of the patients had underlying malignant
disease, including solid cancer (24%) and hematological dis-
ease (9%), and only 5% were neutropenic (Table 3). Solid
organ transplantation had been performed in seven patients
(2%; 3 kidney, 3 liver, and 1 combined lung and kidney trans-
plantation), five of whom survived, and 3 patients were autol-
ogous stem cell transplant recipients, all of whom survived.
Thirty-five patients had underlying diabetes mellitus (12%),
three were premature infants (1%), and six were burn patients
(2%). Ninety-two percent of the patients had a central venous
catheter in place (288/304 patients), 67/294 (23%) patients
were on renal replacement therapy, and 73/277 (26%) patients
had received corticosteroid therapy in the preceding 2 weeks.
The majority of the patients had received antibiotic treatment
within the preceding 2 weeks (85.7% [269/314 patients]),
and cephalosporins, penicillins, metronidazole, and quinolones
were the most commonly prescribed drug classes (data not
shown). In a univariate analysis, mortality was significantly
higher in patients in the ICU and in patients with leukocytosis,
whereas no difference in mortality was observed for the other
underlying diseases and host factors (Table 3).
(ii) Antifungal treatment. Antifungal agents had been given
as prophylactic, empirical, or preemptive therapy at least 1 day
before the blood culture was drawn in 49 episodes. Flucona-
zole was prescribed in 33 cases (67.3%), an amphotericin B
formulation was used in 6 cases (12.2%), caspofungin was used
in 3 cases (6.1%), voriconazole was used in 2 cases (4.1%), and
several antifungal compounds were prescribed in 5 cases
(10.2%). Subsequent candidemia due to C. glabrata, C. krusei,
or S. cerevisiae was significantly more common in patients who
had received antifungal agents for at least 1 week before be-
coming blood culture positive (57.1% [16/28 patients]) than in
patients with no or shorter exposure (28.3% [73/258 patients]
and 28.6% [6/21 patients], respectively) (P ? 0.007 by the
chi-square test for independence).
In 278 episodes, antifungal treatment was given after the
blood culture was obtained. Fluconazole was prescribed most
often (Table 4). There was a noticeable difference in choice of
antifungal agent by age group. Thus, the proportion of epi-
TABLE 3. Underlying conditions, host factors, and mortality for
314 patients with fungemia
(no. of patients with
P value for
Solid cancer (314)
Leukocyte count (286)
Total314 100115 37
aOther surgeries included 6 orthopedic surgeries, 5 neurosurgeries, 1 urologic
surgery, and 1 percutaneous coronary angiography.
bComparing this surgery with no surgery.
cComparing “yes” and “no” groups.
dComparing patients with leukocyte counts of ?10 with patients with leuko-
cyte counts of ?10.
eSolid cancers involved the gastrointestinal tract in 38 cases, were of urogen-
ital origin in 19 cases, and were other cancers in 19 cases. Hematological disease
included 19 cases of acute leukemia, 2 cases of chronic leukemia, 3 cases of
lymphoma, and 4 other hematological diseases.
fNS, not significant.
3304 ARENDRUP ET AL.J. CLIN. MICROBIOL.
sodes initially treated with fluconazole increased by age, from
36% in the pediatric setting to 85% for the elderly population,
whereas the opposite was true for amphotericin (Fig. 2). The
initial antifungal treatment was considered suboptimal in 15%
of cases, involving fluconazole for episodes with C. glabrata, C.
krusei, S. cerevisiae, or Trichosporon spp., caspofungin for those
with C. parapsilosis or Fusarium spp., and voriconazole for
those with C. glabrata or C. krusei (Table 4). Overall, antifungal
therapy was changed in 99 cases (35%). Seventy-four changes
involved fluconazole, i.e., a step-down to fluconazole in 9 cases
and a change from initial fluconazole treatment to a broad-
spectrum agent in 65 cases. For C. albicans episodes specifi-
cally, a step-down to fluconazole therapy was performed in
19% (9/48 cases) of the cases initially treated with a broader
agent. For patients with C. glabrata episodes who initially re-
ceived fluconazole, this was changed to amphotericin (4 epi-
sodes) or caspofungin (11 episodes) in 56% of cases (Table 4).
(iii) Outcomes. The 30-day mortality was 37% (113/305 pa-
tients) overall, 37% (18/49 patients) for patients who received
at least 1 day of antifungal treatment before blood culture, and
28% (80/278 patients) among patients who received antifungal
treatment after the blood culture was obtained. In 44/113 fatal
cases, the death was related primarily or in part to the funge-
mia (38.9% of deaths; 14.4% of all patients) (Fig. 3a). In
30/113 cases (26.5% of deaths; 9.8% of all patients), it was
classified as unrelated to the fungemia, while in 39/113 cases
the cause of death was not available (34.5%; 12.8% of all
patients) (Fig. 3a). Hence, the attributable mortality was at
least 14.4% and was 22.0% if unclassified cases were excluded.
The overall as well as attributable mortality was highest for
patients older than 80 years of age and lowest for 1- to 20-
year-old patients (Fig. 3a), with a significant trend for an in-
crease with age (P ? 0.009). Finally, the overall, attributable,
and unrelated mortality rates (47%, 20%, and 13%, respec-
tively) were all higher in the ICU setting than for patients in
other wards (26%, 8%, and 6%, respectively) (Fig. 3a). For 261
episodes, information was available regarding the timing of
TABLE 4. Antifungal treatment of patients with fungemia
No. (%) of cases or % of cases (no. of cases with change/total no. of cases)b
Suboptimal initial therapya
Antifungal modifications upon species identification
Step-down for C. albicans infection
Change of fluconazole for C. glabrata infection
NA 1/2 19 (9/48)
56 (15/27) 56 (15/27)NA
aInitial antifungal therapy was considered suboptimal for the following drug-bug combinations: fluconazole and C. glabrata (27), C. krusei (3), S. cerevisiae (1), or
Trichosporon spp. (1); caspofungin and C. parapsilosis (2) or Fusarium spp. (1); and voriconazole and C. glabrata (1) or C. krusei (5).
bNA, not applicable.
FIG. 2. Initial antifungal compound by age group. Solid squares,
fluconazole; open triangles, amphotericin B formulation; gray circles,
caspofungin; ?, voriconazole.
FIG. 3. Thirty-day mortality according to age (a) and according to
timing of initiation of therapy for 261 patients receiving at least 1 day
of antifungal treatment (b). Numbers on bars indicate the number of
patients in each group. We calculated the days to the start of therapy
by subtracting the start date of antifungal therapy from the culture
date of the first blood sample that was positive for yeast growth.
Negative values indicate the number of days the patient had been on
antifungal treatment at the time the blood culture was drawn.
VOL. 49, 2011 FUNGEMIA: DIAGNOSTICS AND OUTCOME3305
therapy and outcome (Fig. 3b). Overall mortality rates ranged
from 20 to 44%, with no difference depending on timing of
treatment for either overall mortality or the cases classified as
attributable to the fungemia. Numerically, mortality was high-
est for cases involving C. krusei (36%) and lowest for cases
involving C. parapsilosis (25%) or other Candida spp. (14%)
(P ? 0.183) (Table 5). For episodes involving C. glabrata, the
mortality was significantly lower for patients receiving caspo-
fungin than for those receiving fluconazole as initial antifungal
therapy (12% versus 48%; P ? 0.023). For the other species,
no significant difference depending on initial antifungal agent
was observed (Table 5).
This study has revealed several important issues concerning
the epidemiology, diagnostics, and treatment of fungemia, with
implications for a better understanding and improved manage-
ment of this disease.
The species distribution varied by age, as previously de-
scribed (4, 11, 23, 46), but also by specialty. Thus, C. glabrata
and C. krusei together accounted for half of the cases in pa-
tients with underlying hematological disease and in patients at
departments of medical gastroenterology. The association be-
tween hematology and fungal species has been addressed by
others (1, 32, 56). Thus, C. albicans and C. krusei were involved
in 14 to 35% and 12 to 24% of cases, respectively, in hema-
tology patients in Australia, Europe, and the United States (22,
47, 48, 51). On this background, our low rates of C. albicans
and high rates of C. krusei infection were expected. However,
to our knowledge, the large proportion of C. glabrata infections
among medical gastroenterology patients has not been re-
ported previously. The median age of the medical gastroenter-
ology patients with fungemia was 61 years, which is lower than
that of the total patient population (66 years), and only three
of these patients had received azoles before the blood culture
was taken. Thus, apparently, neither older age nor azole pro-
phylaxis explains the high C. glabrata rate in this setting.
Polyfungal episodes were significantly more common in
medical than in surgical patients. Nace et al. also reported a
trend toward more underlying medical diseases among 40
cases of poly-Candida sp. candidemia, but the difference did
not reach statistical significance in that study (35).
Yeast colonization was registered in half of the patients but
was identified to the species level in only two-thirds of these.
The invasive species had been detected in the colonizing flora
in all cases with either polyfungal colonization or colonization
including less common species. In contrast, the blood isolate
belonged to a species different from the colonizing one in 13%
of the cases with either C. albicans or C. glabrata monofungal
colonization. In half of these cases, treatment guided by the
colonizing flora would have been suboptimal. Several studies
have previously shown a strong genetic association between the
colonizing flora and invasive isolates (15, 19, 28) and have
reported that invasive infection rarely arises without prior col-
onization (30, 39). Our findings suggest that results for colo-
nization samples should be evaluated with caution unless such
samples are given high priority (including systematic surveil-
lance culture sampling, the use of chromogenic agars, and
species identification of all isolates) in the decision process
regarding choice of antifungal compound.
We previously demonstrated a differential performance of
the two major automated blood culture systems for the detec-
tion of C. glabrata and therefore recommended that a mycosis
bottle be included when the Bactec blood culture system is
used (11). This was done at one of the centers during the last
two study months, with promising results, though the numbers
are too small for us to draw any firm conclusions. Moreover, in
the present study, we found a difference in the detection rates
of episodes with concomitant bacteremia. Thus, significantly
fewer such cases were detected at centers using the BacT/Alert
system than at those using the Bactec system. Whereas the
sensitivity issue for detection of C. glabrata by the Bactec sys-
tem has also been shown in vitro (26) and the use of fungal
selective agars is recommended in order not to miss detection
of fungi in polymicrobial specimens (8), we are not aware of
studies systematically evaluating the performance of detection
of fungi and bacteria simultaneously in blood culture systems.
However, a mycosis bottle taken at the same time may increase
the diagnostic sensitivity of both systems due to a possible
negative influence of concomitant bacteremia in the BacT/
TABLE 5. Mortality by species and initial antifungal treatment for the 278 patients receiving antifungal treatment
No. of deaths/no. of treated patients (% mortality) with initial antifungal compound
C. krusei (22)
C. tropicalis (15)
C. glabrata (58)
C. parapsilosis (15)
Candida spp. (9)
Other fungi (5)
Total (278)29 13/48 (27)15/63 (24) 50/159 (31)2/8 0.327d
aComparing mortality rates for patients with C. glabrata receiving caspofungin or fluconazole as the first antifungal compound.
bFigures are for C. albicans (148 isolates) and C. dubliniensis (6 isolates).
cComparing mortality rates for patients with C. albicans receiving caspofungin or amphotericin B as the first antifungal compound.
dComparing mortality rates for all patients receiving caspofungin or fluconazole as the first antifungal compound.
3306ARENDRUP ET AL. J. CLIN. MICROBIOL.
Alert system or low sensitivity for C. glabrata infections in the
Bactec system. This should be explored further.
More patients in our study had undergone surgery or were in
the ICU than was the case in similar studies (16, 17, 23, 36, 52).
In the most recent studies, which included patients from Aus-
tralia and Spain who were enrolled after the millennium, only
a quarter of the patients were in the ICU, whereas this was the
case for half of the patients in our cohort (16, 17, 36). ICU stay
was significantly associated with mortality in our study, as ex-
pected (33). Hence, the overall mortality of 38%, which may
seem high compared to that in postmillennium reports (22 to
25% mortality), was likely due to this larger proportion of
patients with severe underlying disease (16, 17, 36, 38). In
agreement with this, the attributable mortality was between
14.4 and 22% and thus in the lower half of the values reported
in the literature (10%, 14.5%, 21.5%, 34.7%, and 49%) (21, 24,
57), and the attributable as well as unrelated mortality was
higher in the ICU setting in our study.
Antifungal compounds were used prophylactically/empiri-
cally in a subset of patients, without an apparent impact on
survival or on diagnostics as evaluated by time to blood culture
positivity. A larger proportion of infections due to species with
intrinsically reduced susceptibility to fluconazole was seen in
these patients, in accordance with previous observations (13,
31, 48, 53). However, previous studies have suggested that this
reflects a decrease in the number of fluconazole-susceptible
infections rather than an increase in the number of flucona-
zole-resistant infections (25, 31, 53).
Several studies have shown that early treatment improves
overall survival (20, 34, 50). To our surprise, we were not able
to detect any difference in outcome dependent on the timing of
therapy. Either timing had a lesser impact on overall mortality
due to the patient population being more severely ill or mor-
tality was driven to a large extent by the underlying disease (7,
44). However, we also observed that attributable mortality was
not affected by the timing of therapy. Alternatively, our obser-
vations may reflect the fact that the patients most likely to
receive early treatment were those with the highest a priori risk
of poor outcomes due to being those with the most risk factors
and severe underlying disease or those with the highest fungal
loads, leading to an earlier blood culture positivity.
The mortality was significantly lower for patients with
C. glabrata candidemia receiving caspofungin than for those
receiving fluconazole as the first antifungal agent. Several re-
ports have suggested that echinocandins are superior to flu-
conazole for candidemia not due to C. parapsilosis. Thus, a
significantly better outcome was seen overall, and specifically
for infections due to C. albicans or C. tropicalis, in a clinical
trial comparing anidulafungin and fluconazole (43). Similarly,
a significantly better outcome was demonstrated for patients
receiving echinocandin in a laboratory-based candidemia sur-
veillance program, and a numerically better response was seen
for echinocandin monotherapy for each species except C.
parapsilosis (36). In agreement with this, the Infectious Dis-
eases Society of America (IDSA) recommends an echinocan-
din as first-line therapy, with a subsequent step-down to flu-
conazole if the organism is susceptible (37). Due to the very
low prevalence of C. glabrata and C. krusei but the higher
prevalence of C. parapsilosis in the neonatal and pediatric
setting in Denmark, the Danish recommendations suggest the
use of fluconazole as a first-line agent only in the neonatal and
pediatric setting for patients not previously exposed to flucona-
zole but the use of an echinocandin in the adult population
before species identification is obtained. This recommendation
was not followed, as the proportion of patients receiving flu-
conazole as a first-line agent increased by age, leading to as
many as 15% of patients initially receiving suboptimal treat-
ment. This number would have been 6.5%, the vast majority of
which would have been cases of C. parapsilosis in adults treated
with an echinocandin, if the recommendations had been fol-
lowed. C. parapsilosis is lowly virulent and, in general, associ-
ated with a higher survival rate (6). Thus, not only would fewer
patients have received suboptimal treatment, but these cases
might also have been less grave (3, 6, 20, 23, 38, 54, 55).
In conclusion, the take-home messages in this study are as
follows. First, the outcomes for patients with C. glabrata infec-
tions were significantly better if the patients received caspo-
fungin, not fluconazole, treatment. Second, not only is Den-
mark a high-incidence area, but the overall mortality is also
high in comparison with that in other surveys conducted after
the millennium. The high mortality may be explained in part by
a larger proportion of patients with severe underlying diseases
but might have been reduced if an echinocandin was given
more often as first-line treatment in the adult population, as
recommended in official guidelines (5, 37, 43). Third, we have
shown that significantly fewer cases with concomitant bacter-
emia are diagnosed with the BacT/Alert system, suggesting a
low sensitivity for fungemia in this important setting. This
finding may suggest that a mycosis medium is also recommend-
able for this blood culture system to ensure maximal sensitivity
for diagnosing fungemia.
M.C.A. has received research support grants and honorariums for
talks from Astellas, Gilead, Merck, and Pfizer and has received travel
grants from Astellas, Merck, Pfizer, and Schering-Plough. S.S. has
received a travel grant from Merck. L.N. has received travel grants
from Astellas, Merck, and Gilead. J.D.K. has received funds for speak-
ing, consultancy, advisory board membership, or travel from Gilead,
Merck Sharp & Dohme, Pfizer, and Swedish Orphan.
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