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Australian Candidemia Study, Australasian Society for Infectious Diseases: Candidaemia in adult cancer patients: risks for fluconazole-resistant isolates and death


Abstract and Figures

Candidaemia in cancer patients is associated with increasing fluconazole resistance. Models for predicting such isolates and their clinical impact are required. Clinical, treatment and outcome data from a population-based candidaemia survey (2001-2004) were collected at 5 and 30 days after diagnosis. Speciation and antifungal susceptibility testing was performed. There were 138 candidaemia episodes (33% Candida albicans) in adults with haematological malignancies and 150 (51% C. albicans) in adults with solid organ malignancies. Thirty-nine isolates had fluconazole MICs of >or=64 mg/L and 40 had MICs of 16-32 mg/L (predominantly Candida glabrata and Candida krusei). By multivariate analysis, triazole therapy, gastrointestinal tract (GIT) surgery in the 30 days before candidaemia and age >65 years were predictive of fluconazole-resistant candidaemia. Thirty day crude mortality was 40% in haematology patients and 45% in oncology patients. Fluconazole-resistant isolates were associated with increased risk of mortality by univariate (P = 0.04) and Kaplan-Meier survival analyses. By Cox proportional hazards modelling, the strongest predictors of mortality at onset of candidaemia were invasive ventilation, elevated creatinine, intensive care unit (ICU) admission and receipt of systemic triazoles or corticosteroids in the previous 30 days. Removal of a central venous access device (CVAD) at or within 5 days of onset was associated with decreased mortality. Risk factors for fluconazole-resistant candidaemia in adults with cancer include fluconazole/triazole exposure and GIT surgery. ICU admission, invasive ventilation, renal impairment, age >65 years and prior exposure to corticosteroids and triazoles are risk factors for death. CVAD removal reduced mortality. These findings should be integrated into surveillance and treatment algorithms.
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Candidaemia in adult cancer patients: risks for fluconazole-resistant
isolates and death
Monica A. Slavin1*, Tania C. Sorrell2, Deborah Marriott3, Karin A. Thursky 1, Quoc Nguyen 3, David H. Ellis 4,
C. Orla Morrissey5and Sharon C.-A. Chen 2on behalf of the Australian Candidemia Study, Australasian Society
for Infectious Diseases†
Peter MacCallum Cancer Centre and the Centre for Research Excellence in Infectious Diseases, Royal Melbourne Hospital, Parkville,
VIC 3050, Australia;
Centre for Infectious Diseases and Microbiology and the University of Sydney, Camperdown, NSW 2006, Australia;
Department of Microbiology, St Vincent’s Hospital, Darlinghurst, NSW 2010, Australia;
The Mycology Unit, Women’s and Children’s
Hospital, Adelaide, SA 5006, Australia;
Infectious Diseases Unit, Department of Medicine, Alfred Hospital and Monash University,
Prahran, VIC 3004, Australia
*Corresponding author. Department of Infectious Diseases, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, Victoria, Australia,
3002. Tel: þ61-396561707; Fax: þ61-396561185; E-mail:
†Members are listed in the Acknowledgements section.
Received 15 October 2009; returned 13 November 2009; revised 2 February 2010; accepted 2 February 2010
Background: Candidaemia in cancer patients is associated with increasing fluconazole resistance. Models for
predicting such isolates and their clinical impact are required.
Methods: Clinical, treatment and outcome data from a population-based candidaemia survey (20012004)
were collected at 5 and 30 days after diagnosis. Speciation and antifungal susceptibility testing was performed.
Results: There were 138 candidaemia episodes (33% Candida albicans) in adults with haematological malig-
nancies and 150 (51% C. albicans) in adults with solid organ malignancies. Thirty-nine isolates had fluconazole
MICs of 64 mg/L and 40 had MICs of 16 –32 mg/L (predominantly Candida glabrata and Candida krusei). By
multivariate analysis, triazole therapy, gastrointestinal tract (GIT) surgery in the 30 days before candidaemia
and age .65 years were predictive of fluconazole-resistant candidaemia. Thirty day crude mortality was
40% in haematology patients and 45% in oncology patients. Fluconazole-resistant isolates were associated
with increased risk of mortality by univariate (P¼0.04) and KaplanMeier survival analyses. By Cox proportional
hazards modelling, the strongest predictors of mortality at onset of candidaemia were invasive ventilation,
elevated creatinine, intensive care unit (ICU) admission and receipt of systemic triazoles or corticosteroids in
the previous 30 days. Removal of a central venous access device (CVAD) at or within 5 days of onset was associ-
ated with decreased mortality.
Conclusions: Risk factors for fluconazole-resistant candidaemia in adults with cancer include fluconazole/tria-
zole exposure and GIT surgery. ICU admission, invasive ventilation, renal impairment, age .65 years and prior
exposure to corticosteroids and triazoles are risk factors for death. CVAD removal reduced mortality. These find-
ings should be integrated into surveillance and treatment algorithms.
Keywords: mortality, Candida, triazoles, susceptibility
Candidaemia is a complication of cancer and its treatment, and
results in mortality rates of 30%50%, prolonged hospital stay
and substantial healthcare costs.
Recent studies of candidae-
mia in patients with haematological malignancy describe a shift
in epidemiology towards non-albicans Candida spp., particularly
Candida glabrata and Candida krusei.
This shift is clinically rel-
evant as these species are frequently fluconazole resistant.
There are fewer comprehensive data for patients with solid
tumours, although it appears that the species distribution is
more consistent with that of general hospital patients.
trends have important implications for the selection of antifungal
therapy. Timely and appropriate antifungal therapy reduces mor-
whereas fluconazole resistance has been associated
with increased mortality in general hospital patients with candi-
Whether these factors are as important in cancer
patients is unknown.
#The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail:
J Antimicrob Chemother 2010; 65: 10421051
doi:10.1093/jac/dkq053 Advance publication 4 March 2010
by guest on August 7, 2016 from
We therefore analysed the data from a contemporary, nation-
wide study of candidaemia in all adult patients with cancer to
determine: first, the clinical risk factors for candidaemia due to
a fluconazole-resistant isolate at presentation; and, secondly,
whether bloodstream infection (BSI) with fluconazole-resistant
Candida adversely affects clinical outcome and/or is associated
with cross-resistance to other triazoles. These data are needed
to inform strategies for prevention, risk predictive models and
treatment guidelines.
Study design and data collection
Cases of candidaemia were prospectively identified by blood culture sur-
veillance at public and private microbiology laboratories over a 3 year
period (August 2001July 2004) as previously described.
Approval for
the study was obtained from Human Ethics Review Committees at parti-
cipating institutions. Information collected from each case included age,
gender, co-morbidities and risk factors over the 30 days prior to onset of
candidaemia [recent surgery, central venous access devices (CVADs),
neutropenia, hyperalimentation, and administration of corticosteroids
and antimicrobial or systemic antifungal agents], clinical signs of
results of diagnostic studies, antifungal therapy and outcome.
Data were collected at 5 and 30 days following the date of the initial
positive blood culture.
A case was the incident isolation of any Candida species from blood
during the study period. Adults were those aged .14 years. Relapses
were positive blood cultures within 30 days of the first positive blood
culture after an initial clinical and microbiological response. Polycandidal
candidaemia was an episode caused by more than one Candida species.
Haematological malignancy was classified according to the International
Statistical Classification of Diseases and Related Health Problems, 10th
revision, Australian modification.
Solid tumours were not further classi-
fied. Patients undergoing stem cell transplantation (SCT) were grouped by
their underlying condition: haematological malignancy or solid tumour.
Neutropenia was an absolute neutrophil count (ANC) of ,1.010
and impaired renal function was a serum creatinine .0.17 mmol/L.
Sepsis and severe sepsis were according to international definitions.
Treatment was the antifungal drug received on the day of or after the
date the blood culture positive for Candida was drawn. Death was attrib-
uted to candidaemia, or not, by the treating physician, and overall mor-
tality determined at day 30 after diagnosis.
Microbiological methods
Candida isolates were speciated using standard phenotypic methods.
Candida albicans and Candidadubliniensis were differentiatedby PCR finger-
Isolates were forwarded to a reference laboratory (Women’s
and Children’s Hospital, Adelaide) for susceptibility testing as follows: for
amphotericin B, fluconazole, itraconazoleand voriconazole, the Sensititre
YO3 microdilution test panel (Trek Diagnostic Systems, Dutec
Diagnostics, Australia) was used. Posaconazole pure substance was
supplied by Schering-Plough (Schering-Plough Pty Ltd, North Ryde,
New South Wales, Australia). Tests were performed according to the
CLSI (formerly NCCLS) broth microdilution M27-A2 protocol
MICs were defined using CLSI methodology.
Resistance was defined
as: MIC64 mg/L [and susceptible dose-dependent (S-DD) as an MIC of
16–32 mg/L] for fluconazole; MIC1 mg/L for itraconazole; and
MIC4 mg/L for voriconazole.
For posaconazole, MICs of 2 mg/L were
interpreted as non-susceptible, although no breakpoints have been
Candida parapsilosis ATCC 22019 and C. krusei ATCC 6258 were
used as quality control strains.
Statistical analysis
Data were analysed using Stata software, version 9 (Statacorp, Texas).
Continuous variables were compared using Student’s t-test and pro-
portions compared using the x
or Fisher’s exact test. A Pvalue of
,0.05 was considered to be significant. Univariate analyses were per-
formed to identify risk factors associated with overall mortality and iso-
lation of a species with fluconazole resistance or S-DD. Candidate
variables with a univariate significance of P,0.15 or those found to be
significant in other publications were entered into the model for multi-
variate analysis using stepwise logistic regression. No adjustments were
made for multiple comparisons. The KaplanMeier method was used
to examine the probability of survival with fluconazole resistance. The
log rank test was used to test the null hypothesis between the two
groups. Cox proportional hazards regression with the day of onset of can-
didaemia as failure was also applied.
Incidence and patient demographics
A total of 1095 incident cases of candidaemia were identified;
288 (26%) episodes occurred in 288 adults with cancer—138
with haematological malignancies (haematology patients) and
150 with solid organ malignancies (oncology patients). Demo-
graphic and clinical data were available for all 288 episodes,
and clinical and microbiological outcome data for 262/288
(91%) and 235/288 (82%), respectively. All percentages are of
number of episodes with data available. Species identity was
established for 280 (97%) isolates. There were no relapses and
69/288 episodes were breakthrough cases after prior antifungal
therapy. The median age of haematology and oncology patients
was 57 and 64 years, respectively (Table 1).
Co-morbidities and established risk factors
Haematology patients were more likely to have received che-
motherapy and corticosteroids, to have been neutropenic and to
have a CVAD in place at the time of candidaemia, but were less
likely to have undergone major surgery or to have received hyper-
alimentation than oncology patients. CVADs were removed more
often in oncology patients than in haematology patients.
Fifty-eight of 127 (45.7%) haematology patients had received
a systemic antifungal agent compared with 11/150 (7.3%)
(P,0.001) oncology patients (Table 1). Forty-four of 58 haema-
tology patients had received fluconazole prior to candidaemia
(73% for prophylaxis, 27% for treatment/empirical therapy).
The median daily dose of fluconazole was 200 mg. One or
more other antifungals was given in 18 haematology patients:
amphotericin B (n¼13); itraconazole (n¼9); voriconazole
(n¼5); posaconazole (n¼2); and caspofungin (n¼2). Eight of
the 11 oncology patients who received a systemic antifungal
agent prior to candidaemia received fluconazole.
Candida species and antifungal susceptibility (Figure 1)
C. albicans was the most common species in both haematology
patients (32.7% of episodes) and oncology patients (51% of
Fluconazole-resistant Candida in cancer
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episodes). In haematology patients, C. albicans was followed in
frequency by C. parapsilosis (n¼27 episodes, 19.5%), C. krusei
(n¼23, 16.6%) and C. glabrata (n¼17, 12.3%), whilst in oncol-
ogy patients the second most common species was C. glabrata
(n¼29, 19.3%) and then C. parapsilosis (n¼24, 16%). C. krusei
candidaemia occurred in only one oncology patient. Additionally,
three haematology and four oncology patients had polycandidal
candidaemia, which included C. krusei in two and three of these
episodes, respectively.
No C. albicans isolate was resistant to triazoles. There were 39
fluconazole-resistant isolates (26 C. krusei,12C. glabrata and 1
C. parapsilosis) and 40 that tested S-DD (32 C. glabrata, 2 each of
C. krusei,C. dubliniensis and C. parapsilosis, and 1 each of
Candida guilliermondii and Candida rugosa). The one (of 60)
fluconazole-resistant C. parapsilosis isolate was cross-resistant
to itraconazole but not to voriconazole or posaconazole. Thirty-six
of 44 (82%) C. glabrata isolates that tested fluconazole resistant or
S-DD were cross-resistant to itraconazole and 4 (9%) were also
resistant to voriconazole. Twenty-eight of the 29 C. krusei isolates
which were tested were resistant (92%) or S-DD (8%) to flucona-
zole but none was cross-resistant to itraconazole or voriconazole.
Of four isolates each of C. parapsilosis,C. glabrata and C. krusei
tested for posaconazole susceptibility, none was resistant.
Candida species and relationship to prior antifungal
C. albicans caused 21% of episodes in the 58 haematology
patients receiving antifungal agents prior to onset of candidae-
mia and 41.5% in those who were not (P,0.01). For C. glabrata
the proportions were 16.1% and 7.3%, respectively (P¼0.02), for
C. krusei the proportions were 29.0% and 4.9%, respectively
Table 1. Demographics: adults with candidaemia in Australia 2001– 2004
Patient characteristic Haematological malignancy, N¼138 Solid tumour, N¼150
Median age (range) 57 (1583) 64 (2888)
Gender male, n(%) 77 (55.8) 87 (58.0)
diabetes, n(%) 13 (8.2) 23 (14.6)
ANC ,0.510
/L, n(%) 89 (64.4) 13 (8.7)
ANC ,0.110
/L, n(%) 79 (59.9) 7 (5.0)
Median duration of neutropenia (days) 10 5
Corticosteroid use, n(%) 43 (34.4) 108 (76.1)
Cytotoxic chemotherapy, n(%) 80 (71.4) 28 (25)
Presence of sepsis at diagnosis, n(%) 103 (83.1) 124 (87.9)
Diagnosis in ICU, n(%) 19 (13.8) 38 (25.3)
CVAD in place at diagnosis, n(%) 123 (97.6) 112 (77.2)
Median duration of CVAD insertion, days (range) 17 (2625) 11 (1446)
Use of antimicrobials, n(%) 121 (87.7) 125 (83.3)
3 antibiotic classes 51 (42.1) 47 (37.6)
4 antibiotic classes 66 (47.9) 78 (62.4)
Concomitant bacteraemia, n(%) 14 (10.1) 23 (15.3)
Systemic antifungals, n(%) 58 (45.7) 11 (7.7)
Surgery, n(%) 14 (10.1) 74 (49.3)
Surgical site infection, n(%) 4 (2.9) 41 (27.3)
TPN, n(%) 36 (26.1) 59 (39.3)
died due to candidaemia, n(%) 17 (13.2) 19 (12.1)
30 day mortality, n(%) 44 (40) 61 (45)
ANC, absolute neutrophil count; ICU, intensive care unit; CVAD, central venous access device; TPN, total parenteral
Demographics were determined in the 30 days before onset of candidaemia unless otherwise specified.
Slavin et al.
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(P,0.001), and for C. parapsilosis the proportions were 29.0%
and 19.5%, respectively (P¼0.04). Duration of prior fluconazole
also affected the species recovered. Of those receiving ,6 days
of fluconazole before onset of candidaemia, 56% of episodes
were due to C. albicans and 11% to C. krusei, compared with
14% and 44%, respectively, for patients receiving at least
6 days of fluconazole before candidaemia. With other antifungal
agents, duration of prior treatment (,6 days versus 6 days) did
not affect the proportion of episodes due to C. albicans (25% and
22%, respectively). All 13 candidaemia episodes in patients
receiving fluconazole for .14 days before candidaemia were
due to a species other than C. albicans. Only 11 oncology
patients received prior systemic antifungals (8 were prescribed
fluconazole) at onset of candidaemia and there was no effect
of antifungal therapy on the causative species (data not
shown, P¼0.15).
Risk factors for infection with fluconazole-resistant
By univariate analysis, variables associated with the recovery of a
fluconazole-resistant Candida isolate included duration of neu-
tropenia (P¼0.02), prior receipt of any systemic antifungal drug
including a triazole and fluconazole (both P,0.001), acquisition
in the state of Victoria (P¼0.02) and prior gastrointestinal tract
(GIT) surgery (P¼0.04) (Table 2). Multivariate analysis revealed
that receipt of triazoles was the strongest independent predictor
for a fluconazole-resistant isolate [odds ratio (OR) 2.9, 95% con-
fidence interval (CI) 1.336.1; P¼0.007] followed by acquisition
of candidaemia in the state of Victoria (OR 2.0, 95% CI 1.1
3.5; P¼0.02), recent GIT surgery (OR 2.0, 95% CI 1.1 4.2;
P¼0.05) and use of fluconazole within 14 days prior to onset
of candidaemia (OR 3.4, 95% CI 1.011.3; P¼0.05). There was
a trend towards significance for recovery of a fluconazole-
resistant Candida and age .65 years (OR 1.7, 95% CI 0.9 –3.1;
Mortality and risks for death
Forty-four (40%) haematology patients and 61 (45%) oncology
patients died within 30 days of onset of candidaemia, with
68% and 61% of these, respectively, within the first 10 days.
Variables associated with 30 day mortality by univariate analysis
are summarized in Table 3. The risk of death was reduced in
patients who had their CVAD removed within 5 days of onset of
candidaemia (P¼0.01) and in those treated with fluconazole
after diagnosis (P¼0.004). Table 4shows the risk factors for
death at day 30 in the Cox proportional hazards model, which
were: invasive ventilation at onset of candidaemia, receipt of a
systemic triazole in the 30 days prior to candidaemia, corticos-
teroids in the 30 days prior to candidaemia and onset of candi-
daemia in the intensive care unit (ICU). Removal of a CVAD
within 5 days of onset of candidaemia was protective, and this
is also shown in Figure 2(a) where the KaplanMeier survival
curve shows improved survival with catheter removal, log rank
Antifungal treatment and outcome associated with
a fluconazole-resistant isolate
Ninety-five percent of haematology patients and 86% of oncol-
ogy patients with candidaemia were treated with an antifungal
after diagnosis (P¼0.01). Fluconazole was used in 22% of
MIC < 16 MIC 16–32 MIC 64 (mg/L)
40 60 80
C. albicans
C. dubliniensis
C. glabrata
C. krusei
C. parapsilopsis
C. tropicalis
Polycandidal inf.
Other Candida spp.*
Figure 1. Species responsible for candidaemia and fluconazole susceptibility in adults with haematological malignancy (Haem) or solid tumours
(Solid), Australia 2001– 2004. Polycandidal inf., infection with more than one Candida species; MIC, MIC of fluconazole. *Other Candida spp
included three each of C. guilliermondii,C. kefyr and C. lusitanae, two of C. famata and one each of C. rugosa and C. sake.
Fluconazole-resistant Candida in cancer
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haematology patients and in 64% of oncology patients. The
median time to initiation of therapy was 1 day after the onset
of candidaemia (range: day 0 to 12 days after blood was
drawn) for haematology patients and 2 days (range day 0 to
43 days after blood was drawn) for oncology patients. Of the
39 patients with a fluconazole-resistant isolate, 19 were initially
treated with fluconazole and 6 (32%) died by day 30. A further
15 received other antifungal agents (9 amphotericin B-based
products, 3 caspofungin, 2 itraconazole and 1 voriconazole)
and 8/15 (53%) died by day 30. Outcome data were not available
for two patients, and three others received no antifungal
Kaplan– Meier survival analysis showed that survival was
reduced in patients with candidaemia caused by a fluconazole-
resistant or S-DD isolate (Figure 2b), log rank test P¼0.0082.
These patients were alsomore likely toremain blood culture positive
at day 30 (P¼0.01) and there was a trend to poorer clinical resol-
ution (P¼0.07) and more deaths at day 30 (P¼0.05) (Table 5).
This population-based description of candidaemia in cancer
patients is the first to identify independent risk factors for isolation
of fluconazole-resistant isolates in this population. Analysis of
comprehensive data from multiple institutions throughout
Australia revealed that most fluconazole-resistant or S-DD
Candida BSIs were due to either C. krusei or C. glabrata (91%). Clini-
cal risk factors identified for isolation of a fluconazole-resistant
isolate included prior triazole (all) as well as fluconazole receipt,
age .65 years and, for the first time, prior GIT surgery. Further-
more, clinical outcomes and survival were less favourable in
patients infected with fluconazole-resistant isolates. Although
the association between C. glabrata and C. krusei and prior fluco-
nazole exposure has been reported in cancer patients,
association between fluconazole receipt and infection with a
fluconazole-resistant or S-DD C. glabrata and other species such
as C. dubliniensis,C. parapsilosis,C. rugosa and C. guilliermondii
has not.
There were significant epidemiological differences between
haematological patients and those with solid organ cancer. In
both groups, C. albicans was susceptible to fluconazole but
C. albicans caused a substantially smaller proportion of episodes
in patients with haematological malignancy compared with
those with solid organ cancer (33% versus 64%). Conversely,
C. glabrata (32% of which were fluconazole susceptible) and
C. krusei (all fluconazole resistant) caused 11% and 15% of epi-
sodes in haematology patients, respectively and 20% and 0.7%
of episodes in oncology patients, respectively. Most of this differ-
ence is attributable to prior use of fluconazole which was ident-
ified in almost half of haematology patients but only 5% of
oncology patients. Not only was receipt of prior fluconazole (or
triazoles in general, but not other antifungal classes) a risk
factor for infection with a fluconazole-resistant Candida in hae-
matology patients, but the risk was increased significantly with
prior fluconazole therapy of .14 days duration (OR 3.35,
The identification of C. glabrata as the second most common
cause of candidaemia in oncology patients is of interest. Its
recent emergence was reported in a population-based study
that included patients without malignancy
and a series in
cancer patients.
In both studies C. glabrata infection was associ-
ated with fluconazole prophylaxis.
Although only a minority
(8 of 150) of oncology patients in our study had received fluco-
nazole, age .65 years and prior GIT surgery predisposed to
recovery of fluconazole-resistant isolates. The association of
C. glabrata candidaemia with older age was observed in an
Australian multicentre study of candidaemia in general hospital
Table 2. Risk factors for candidaemia with a fluconazole-resistant or
susceptible dose-dependent isolate in adults with cancer (univariate
Variable OR 95% CI Pvalue
Male 0.78 0.46– 1.32 0.36
Age .65 years 1.54 0.91– 2.63 0.11
Haematological malignancy 1.60 0.95– 2.69 0.08
Solid organ malignancy 0.74 0.44– 1.25 0.26
Cytotoxic chemotherapy 1.50 0.89– 2.56 0.13
Neutropenia at diagnosis 1.25 0.73– 2.15 0.42
Days of neutropenia (as logarithm) 1.79 1.09– 2.94 0.02
ANC ,0.510
/L 1.31 0.76– 2.23 0.33
Systemic antifungal drugs 2.99 1.68– 5.36 0.00
Systemic triazoles 3.30 1.80– 6.08 0.00
fluconazole 2.96 1.57– 5.59 0.001
.14 days of fluconazole 3.27 0.95– 11.24 0.06
itraconazole 3.52 0.92– 13.5 0.06
voriconazole 4.16 0.68 25.3 0.12
posaconazole 2.71 0.17 43.93 0.48
Conventional amphotericin B 1.36 0.24– 7.55 0.73
Candidaemia acquired in Victoria 1.87 1.10– 3.12 0.02
Gastrointestinal surgery 1.91 1.02– 3.54 0.04
Surgery 1.44 0.82– 2.52 0.20
Ventilated at diagnosis of candidaemia 1.42 0.74– 2.73 0.29
Corticosteroid use 1.39 0.92– 2.35 0.22
Heparin use 1.38 0.67– 2.82 0.37
TPN 1.32 0.76 2.31 0.32
Community-acquired candidaemia 0.61 0.14– 2.61 0.51
Diagnosis of candidaemia in ICU 1.31 0.79– 2.47 0.39
Use of antimicrobial agents 1.79 0.65– 4.90 0.26
Antimicrobial-impregnated CVAD 0.89 0.24– 3.39 0.87
OR, odds ratio; CI, confidence interval; ANC, absolute neutrophil count;
TPN, total parenteral nutrition; ICU, intensive care unit; CVAD, central
venous access device.
Risk factors were determined in the 30 days prior to the diagnosis of can-
didaemia unless otherwise specified.
Slavin et al.
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Table 3. Univariate analysis for 30 day mortality in adult cancer patients with candidaemia
OR 95% CI Pvalue Proportional hazards 95% CI Pvalue
Male 1.55 0.91– 2.64 0.11 1.29 0.86 1.95 0.22
Age .65 years 2.17 1.27 –3.69 0.00 1.24 0.83–1.85 0.28
Haematological malignancy 1.05 0.63 1.77 0.84 1.20 0.91 1.79 0.38
allogeneic SCT 1.32 0.42 4.16 0.64 1.47 0.64 3.37 0.36
autologous SCT 0.22 0.03 1.78 0.16 1.74 0.43 7.09 0.44
leukaemia 0.84 0.46– 1.56 0.59 0.88 0.54 1.42 0.27
lymphoma 1.53 0.80–2.94 0.20 1.66 1.02– 2.67 0.042
Solid organ malignancy 0.95 0.57 1.60 0.85 0.82 0.55–1.24 0.35
Community-acquired candidaemia 0.83 0.830.16 4.36 0.75 0.18– 3.03 0.69
Neutropenia at diagnosis 1.05 0.60 1.84 0.86 1.12 0.731.74 0.59
ANC ,0.510
/L 2.47 1.27– 4.81 0.01 1.23 0.81 1.89 0.32
Cytotoxic chemotherapy 0.92 0.54– 1.57 0.77 0.92 0.61 1.40 0.71
Corticosteroid use 1.71 1.02– 2.89 0.04 1.51 1.012.26 0.04
Prior systemic antifungal drugs 1.43 0.80 2.55 0.23 1.37 0.88 2.12 0.17
prior fluconazole 0.67 0.23 1.94 0.46 1.15 0.68 1.95 0.60
Candida parapsilosis 0.52 0.25–1.11 0.09 0.69 0.37– 1.29 0.25
Candida glabrata 1.45 0.74 2.85 0.28 1.33 0.83 2.15 0.24
Candida krusei 1.31 0.52– 3.29 0.57 1.38 0.67 2.87 0.38
Candida albicans 1.10 0.65– 1.85 0.73 0.91 0.61 1.36 0.65
Fluconazole resistance (MIC.64 mg/L) 1.77 1.00 –3.14 0.05 1.55 1.02– 2.38 0.04
Surgery 0.90 0.52– 1.57 0.71 0.75 0.49 1.15 0.19
Gastrointestinal surgery 1.65 0.62 4.35 0.31 0.85 0.52–1.39 0.52
TPN 1.54 0.90– 2.63 0.11 1.12 0.74 1.68 0.58
Antibiotics 4.06 1.18– 13.93 0.03 1.42 0.62– 3.26 0.4
Sepsis at diagnosis 1.20 0.57– 2.56 0.63 0.79 0.44 1.43 0.45
Onset of candidaemia in ICU 5.50 2.9110.37 0.00 2.07 1.363.13 0.001
Serum creatinine .0.17 mmol/L 1.82 1.023.27 0.04 1.84 0.89– 3.81 0.1
Ventilated at diagnosis of candidaemia 5.47 2.70 11.09 0.00 2.47 1.64 3.14 ,0.001
CVAD removed after diagnosis 0.43 0.22 0.84 0.01 0.52 0.35 0.77 0.001
Treatment given after diagnosis
amphotericin B (n¼66) 0.62 0.33– 1.17 0.15 0.86 0.54 1.39 0.54
lipid amphotericin B (n¼48) 1.05 0.54– 2.04 0.88 0.82 0.49 1.37 0.45
fluconazole (n¼190) 0.44 0.25– 0.77 0.004 0.59 0.390.89 0.013
itraconazole (n¼9) 1.04 0.25– 4.27 0.95 1.29 0.41 4.13 0.66
voriconazole (n¼24) 0.52 0.18– 1.44 0.21 0.54 0.24 1.23 0.14
caspofungin (n¼31) 1.37 0.62 2.96 0.43 1.35 0.772.35 0.29
combination (n¼99) 0.79 0.52 1.19 0.26
Time to starting antifungal treatment (days) 1.00 0.99 1.00 0.73
OR, odds ratio; CI, confidence interval; SCT, stem cell transplant; ANC, absolute neutrophil count; ICU, intensive care unit; CVAD, central venous access
Variables were determined in the 30 days prior to candidaemia unless otherwise specified.
Treatments given after diagnosis do not equal the number of patients as the number receiving each agent includes those receiving combination
Fluconazole-resistant Candida in cancer
by guest on August 7, 2016 from
patients and in a large European study,
and with GIT surgery
within a non-neutropenic intensive care cohort of patients.
Komshian et al.
further reported C. glabrata candidaemia to
be associated with surgery in patients with solid tumours.
Antifungal treatment guidelines universally recommend an
agent other than a triazole as initial therapy in a patient who
has received fluconazole prophylaxis.
27 29
Our data suggest
that recent GIT surgery and age .65 years should also be
explored as indications for a non-triazole-based empirical treat-
ment regimen of candidaemia in cancer patients (Table 2).
The over-representation of fluconazole-resistant isolates of
C. glabrata and C. krusei causing candidaemia in one large hospi-
tal in Victoria was responsible for the appearance of this state as
an independent risk factor for fluconazole-resistant isolates,
emphasizing the importance of monitoring local hospital epide-
miology to guide treatment. Whilst there was no difference in
antifungal policy at this hospital, its case mix may differ from
that of other hospitals surveyed as it is a referral centre for
burns, trauma, critical care and organ transplantation.
Key findings from our study included a delay in clearance of
blood cultures, a more severe clinical course and reduced survival
in patients with fluconazole-resistant candidaemia (Table 5and
Figure 2b). Two recent studies of candidaemia, in mostly
non-neutropenic patients, reported an association between
fluconazole resistance (best expressed in AUC/MIC
or weight-
normalized daily fluconazole dose/MIC
) and patient mortality
in patients treated for the first 3 days or more with flucona-
Neither included many patients with cancer
the generalizability of these findings is uncertain. Our data
support an impact of fluconazole resistance in cancer patients.
They are also consistent with results from an experimental
model of disseminated candidiasis where the absence of neutro-
penia and timely initiation of active antifungal agents were the
important determinants of outcome.
Few modifiable predictors of mortality were identified. It is
likely that the prompt commencement of appropriate antifungal
treatment in cancer patients will also improve clinical outcomes.
Studies in general hospital patients, most of whom did not
receive antifungal prophylaxis, showed a mortality benefit
when antifungal therapy was commenced within 12 24 h of
onset of candidaemia.
A limitation of our study was the
inability to analyse the effect on mortality of initiating antifungal
therapy within 12 h of onset of candidaemia, as only the date of
commencement of antifungals was recorded in relation to the
date the positive blood culture was drawn. However, the
median day of starting antifungal treatment in haematology
patients was day 1 after onset of candidaemia, and was day 2
Survivor function for removal of CVAD
Survivor function for fluconazole resistance
Analysis time
CVAD not removed after diagnosis
CVAD removed after diagnosis
FLC susceptible FLC resistant
Figure 2. (a) Survival of cancer patients with candidaemia according to
whether the central venous access device (CVAD) was removed within
5 days of first positive culture or not. (b) Survival estimates for adult
cancer patients with candidaemia according to the presence of a
fluconazole-susceptible isolate (‘FLC susceptible’) or a fluconazole-
resistant or susceptible dose-dependent isolate (grouped as ‘FLC
Table 4. Cox proportional hazards regression predicting 30 day mortality in adult cancer patients with candidaemia
Variable Cox proportional hazards 95% CI Pvalue
Voriconazole given after diagnosis 0.42 0.18– 0.99 0.045
Removal of CVAD after diagnosis 0.42 0.28–0.64 ,0.001
Fluconazole given after diagnosis 0.58 0.390.90 0.015
Use of corticosteroids within 30 days of onset 1.55 1.02 2.40 0.048
Onset in ICU 1.76 0.98 3.15 0.055
Prior systemic triazole use 1.80 1.06 3.06 0.031
Ventilation at onset of candidaemia 2.26 1.28 4.00 0.005
Serum creatinine .17 mmol/L at onset of candidaemia 2.62 1.195.74 0.016
CVAD, central venous access device; ICU, intensive care unit; CI, confidence interval.
Slavin et al.
by guest on August 7, 2016 from
after onset in oncology patients, compared with a median time
to initiation of 2448 h in the published studies.
Another potentially modifiable factor is CVAD removal, which
was the only independent predictor of improved survival in our
study, although it was performed less frequently in haematology
patients than in oncology patients. Whilst another population-
based study also showed a survival benefit with CVAD
a prospective cohort study in cancer patients did
The issue of CVAD removal in neutropenic haematology
patients with candidaemia remains controversial. It is possible
that candidaemia originates from the GIT rather than the
further, removal of CVADs may be impractical in severely
ill patients and in those with significant intravenous access pro-
blems. Survival benefit was suggested in three studies,
32 34
one of which comprised both solid tumour and haematology
patients, almost half of whom were neutropenic.
In the
latter study the greatest clinical benefit was seen at day 0 of
candidaemia, persisted to day 4, but was only modest when
compared with the much greater impact of visceral dissemina-
tion, APACHE (Acute Physiology and Chronic Health Evaluation)
score and neutrophil recovery.
Notably, only 18% of patients
received antifungal prophylaxis and only 15% of episodes were
due to C. glabrata or C. krusei.
Since antifungal prophylaxis is
now common in haematology patients, a reappraisal of the
value of CVAD removal in managing candidaemia is required. It
is possible that the epidemiological shift away from C. albicans
to other species brings with it an increased propensity to form
In the interim, removal of the CVAD should be con-
sidered for both haematology and oncology patients.
Other predictors of mortality were largely unmodifiable and
included onset of candidaemia in the ICU, invasive ventilation
at onset, elevated serum creatinine and prior corticosteroid
and triazole receipt. These variables are largely markers of under-
lying co-morbidity and disease severity, captured in some series
by APACHE II scores, although these have not been validated for
use outside of the ICU setting.
In conclusion, this nationwide, contemporary survey of candi-
daemia in adult cancer patients highlights differences in epide-
miology between patients with haematological malignancies
and solid organ cancers, risk factors for infection with a
fluconazole-resistant isolate and the impact of fluconazole
resistance on clinical outcome. Removal of the CVAD was the
only readily modifiable predictor of mortality. These findings
warrant evaluation in other populations and may form the
basis of more targeted treatment algorithms for cancer patients.
This work was presented in part at the Forty-ninth Interscience
Conference on Antimicrobial Agents and Chemotherapy, San Francisco,
CA, USA, 2009 (Abstract M-1010).
The Australian Candidemia Study consists of the following members
and acknowledges all infectious diseases physicians, clinical
microbiologists and hospital scientists that have contributed to the study:
Queensland: Cairns Base Hospital (J. McBride); Calboolture Hospital
(C. Coulter); Mater Adult Hospital (J. McCormack and K. Walmsley);
Princess Alexandra Hospital (D. Looke, B. Johnson, G. Nimmo and
G. Playford); Queensland Medical Laboratories (D. Drummond);
Rockhampton Hospital (E. Preston); Royal Brisbane Hospital (A. Allworth
and J. Faoagali); Sullivan and Nicolaides Pathology (J. Botes and
J. Robson); Townsville Hospital (R. Norton); and The Prince Charles
Hospital (C. Coulter).
New South Wales: Albury Base Hospital (D. Robb); Concord Hospital
(T. Gottlieb); Douglass Hanly Moir Pathology (I. Chambers); Gosford
Hospital (D. DeWit); Hunter Area Pathology Service (J. Ferguson and
L. Tierney); Liverpool Hospital (F. Jozwiak and R. Munro); Manning Base
Hospital (R. Pickles); Mayne Health (J. Holland); Narrabri District Hospital
(F. Groenwald); New Children’s Hospital (K. Hale); Orange Base Hospital
(R. Vaz); Prince of Wales Hospital (R. Hardiman and C. Baleriola); Royal
North Shore Hospital (R. Pritchard and K. Weeks); Royal Prince Alfred
Hospital (R. Benn and N. Adams); St George Hospital (R. Lawrence and
P. Taylor); St Vincent’s Private and St Vincent’s Public Hospital
(J. Harkness, D. Marriott and Q. Nguyen); Sydney Children’s Hospital
(P. Palasanthrian); Sydney Adventist Hospital (R. Grant); Westmead
Hospital (S. Chen, C. Halliday, O. C. Lee and T. Sorrell); and Wollongong
Hospital (P. Newton and N. Dennis).
Victoria: Alfred Hospital (C. Franklin, O. Morrisey, M. Slavin and
D. Spelman); Austin and Repatriation Hospital (B. Speed); Bendigo
Health Care Group (J. Hellsten and R. Russell); Melbourne Pathology
(S. Coloe); Melbourne Private Hospital (A. Sherman); Monash Medical
Centre (T. Korman); PathCare Consulting Pathologists (S. Graves); Peter
MacCallum Cancer Institute (M. Slavin and M. Huysmans); and Royal
Melbourne Hospital (M. Slavin and A. Sherman).
South Australia: Flinders Medical Centre (D. Gordon); Royal Adelaide
Hospital (K. Rowlands, D. Shaw and W. Ferguson); and Women’s and
Children’s Hospital (D. Ellis, R. Handke and S. Davis).
Western Australia: Fremantle Hospital (M. Beaman and J. McCarthy);
Royal Perth Hospital (C. Heath); and Sir Charles Gairdner Hospital
(S. Altmann, I. Arthur and D. Speers).
Tasmania: Launceston General (E. Cox); and Royal Hobart Hospital
(L. Cooley and A. McGregor).
Northern Territory: Royal Darwin Hospital (B. Currie, G. Lum and D. Fisher).
Australian Capital Territory: The Canberra Hospital (P. Collignon and
A. Watson).
Table 5. Outcomes for adult patients with candidaemia with fully fluconazole-susceptible isolates (no fluconazole resistance)
compared with those with fluconazole-resistant or susceptible dose-dependent isolates (fluconazole resistance present)
Outcome variable No fluconazole resistance Fluconazole resistance present Pvalue
Presence of sepsis at day 5 n(%) 71/151 (47.0) 31/54 (57.4) 0.21
Clinical resolution at day 30 n(%) 53/191 (27.8) 12/69 (17.4) 0.068
Persistently positive blood cultures at day 30 n(%) 3/109 (2.8) 6/39 (15.4) 0.011
Mortality at day 5 n(%) 19/193 (9.8) 10/69 (14.5) 0.37
Mortality at day 30 n(%) 56/193 (29.0) 40/69 (58.0) 0.053
Relapses after day 5 n(%) 17/162 (10.5) 9/49 (18.4) 0.145
Median length of stay (days) 30 33
Fluconazole-resistant Candida in cancer
by guest on August 7, 2016 from
The work was supported by an unrestricted educational grant from Pfizer.
Pfizer had no role in study design, analysis or writing of the manuscript.
Transparency declarations
M. A. S., T. C. S. and D. H. E. serve/have served on Advisory Boards for
Pfizer, Merck, Gilead and Schering-Plough and have received investigator
initiated grants from Pfizer, Merck and Gilead Sciences. D. M. has been a
consultant to Schering-Plough, Pfizer and Merck, Australia. C. O. M. has
been a consultant to, received grant support from and given lectures
for Gilead Sciences, Pfizer, Merck, Schering-Plough and Orphan
Australia. S. C.-A. C. has been a consultant to Pfizer Australia and
Gilead Sciences. Other authors: none to declare.
Author contributions
M. A. S. was part of the study design and management group, analysed
data and led the writing of the manuscript. T. C. S. was part of the study
design and management group, and contributed to writing of the
manuscript. D. M. was part of the study design and management
group, and contributed to writing of the manuscript. K. A. T. performed
the statistical analysis and contributed to writing of the
manuscript. Q. N. was the study coordinator and data manager, designed
the database and contributed to statistical analysis. D. H. E. was part of
the study design and management group, performed the antifungal
susceptibility testing and contributed to writing of the
manuscript. C. O. M. contributed to the data analysis and writing of the
manuscript. S. C.-A. C. was part of the study design and management
group, and contributed to writing of the manuscript.
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Fluconazole-resistant Candida in cancer
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... However, in the multivariate analysis, the diagnostic group (HR 1.72; p = 0.04) and ICU admission (HR 3.08; p =< 0.01) were the variables that maintained their association with statistical significance as risk factors for mortality in patients with fungemia. Septic shock and ICU admission have been widely described as a risk factors associated with mortality [10,14,15,33,50,58]; however, there is little information in the literature regarding the study of mortality according to the type of hematologic neoplasia [34]. ...
... Interestingly, advanced age, the presence of organ dysfunction, kidney failure, and neutropenia were not related to mortality, as previously described in different studies [2,10,14,58,59]. Similarly, protective factors for mortality, such as antifungal prophylaxis and remission of oncological pathology as described in other studies, were not found [3]. ...
Full-text available
Fungemia in hematologic malignancies (HM) has high mortality. This is a retrospective cohort of adult patients with HM and fungemia between 2012 and 2019 in institutions of Bogotá, Colombia. The epidemiological, clinical, and microbiological characteristics are described, and risk factors related to mortality are analyzed. One hundred five patients with a mean age of 48 years (SD 19.0) were identified, 45% with acute leukemia and 37% with lymphomas. In 42%, the HM was relapsed/refractory, 82% ECOG > 3, and 35% received antifungal prophylaxis; 57% were in neutropenia, with an average duration of 21.8 days. In 86 (82%) patients, Candida spp. was identified, and other yeasts in 18%. The most frequent of the isolates were non-albicans Candida (61%), C. tropicalis (28%), C. parapsilosis (17%), and C. krusei (12%). The overall 30-day mortality was 50%. The survival probability at day 30 in patients with leukemia vs. lymphoma/multiple myeloma (MM0 group was 59% (95% CI 46–76) and 41% (95% CI 29–58), p = 0.03, respectively. Patients with lymphoma or MM (HR 1.72; 95% CI 0.58–2.03) and ICU admission (HR 3.08; 95% CI 1.12–3.74) were associated with mortality. In conclusion, in patients with HM, non-albicans Candida species are the most frequent, and high mortality was identified; moreover, lymphoma or MM and ICU admission were predictors of mortality.
... Additionally, owing to selection pressure, prior fluconazole exposure increased the risk of invasive non-C. albicans infections, especially in patients with hematologic malignancies, bone marrow transplants, and critical illnesses [25][26][27]. Although detailed clinical characteristics were not examined in our study, we speculate that these risk factors likely remain applicable among our complex patient population. ...
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The prevalence of invasive candidiasis caused by non-Candida albicans has rapidly increased. Candida glabrata (Nakaseomyces glabrata) is an important pathogen associated with substantial mortality. Our study examined the antifungal temporal susceptibility of C. glabrata and cross-resistance/non-wild-type patterns with other azoles and echinocandins. Laboratory data of all adult patients with C. glabrata isolated from clinical specimens at the Mayo Clinic, Rochester, from 2012 to 2022 were collected. Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were used. We obtained 1046 C. glabrata isolates from 877 patients. Using CLSI and EUCAST breakpoints, 187 (17.9%) isolates and 256 (24.5%) isolates were fluconazole-resistant, respectively. Focusing on C. glabrata bloodstream infections, fluconazole-resistance ranged from 16 to 22%. Among those 187 fluconazole-resistant isolates, 187 (100%) and 184 (98.4%) isolates were also voriconazole and posaconazole non-wild-type, respectively, with 97 (51.9%) isolates deemed non-wild type for itraconazole. The fluconazole susceptibility pattern has not changed over the past decade. The proportion of fluconazole-resistant C. glabrata is relatively high, which could be due to the complexity of patients and fluconazole exposure. Itraconazole appears to be a compelling step-down therapy for fluconazole-resistant C. glabrata, given the high proportion of wild-type isolates. Further research to examine clinical outcomes is warranted.
... Azole exposure was the only similarity shared with the Rauseo et al [1] model. This is a well described risk factor supported by in vitro, retrospective, and prospective cohort studies around the world [4][5][6]. In contrast, hematological factors (HSCT, MDS) were not significant predictors. ...
... Recent FLZ exposure may increase the potential for colonization and subsequent infection from FLZresistant Candida species [27]. Specifically, prior FLZ therapy, at any dose, has been associated with candidemia due to FLZ-resistant Candida isolates, including C. glabrata, C. krusei, and C. tropicalis [28][29][30]. Globally, C. krusei candidemia is an uncommon infection both in adults and pediatrics [2]; however, several outbreaks were reported due to the species in neonatal units [2,31]. Nevertheless, an unexpected increase was reported in the number of C. krusei candidemia cases from 4.93% in 2012 to 44.09% in 2014 [31]. ...
Full-text available
Background and purpose: This study aimed to evaluate the species distribution and susceptibility pattern of the strains isolated from Candida colonization in pediatric patients staying at pediatric intensive care unit (ICU) and infant ICU of Children's Medical Center in Tehran, Iran. Materials and methods: This study was conducted in the Children's Medical Center in Tehran, Iran. In total, 440 samples from 56 patients with oral cavity, skin surrounded catheters, and ear, throat, nasal, and urine cultures were collected. All patients were evaluated in terms of Candida colonization on the admission day as well as the days 7, 14, and 28 according to the previous studies. CHROMagar Candida medium was applied for primary/multiple species identification and the isolates were identified by using polymerase chain reaction-based methods to the species-specific complex level. The antifungal susceptibility test was performed according to the Clinical and Laboratory Standards protocol published as M27-A3 and M60 documents. Results: In total, 136 yeast samples from 26 individuals (30.9%) out of 440 samples were considered colonization. The most prevalent species in IICU was C. albicans (27%, n=20) followed by C. krusei (24 %, n=18) and C. parapsilosis (16%, n=12). In PICU, the predominant species was C. krusei (40%, n=24) followed by C. parapsilosis (18%, n=11) and C. dubliniensis (16%, n=10). Among the 40 tested isolates from both units, fluconazole-resistant isolates (n=11, 8.15%) were determined according to the new breakpoints. In the case of echinocandins, 2 isolates, including C. albicans (n=1) and C. krusei (n=1) were resistant against both caspofungin and anidulafungin (totally 1.48%). Conclusion: In the present study, since C. krusei is intrinsically-resistance against fluconazole, emphasizing the importance of species-level identification of Candida isolates is outstanding. However, according to the antifungal susceptibility testing results, only 7.2% of the strains were resistant to fluconazole. It would be beneficial to monitor the ICU patients who are at high risk of invasive Candida infection.
... The choice of antifungal agents for candidemia should be based on microbiology, susceptibility, presence of endophthalmitis, and general condition. In recent decades, because the microbiology of candidemia has shifted to non-albicans Candida and fluconazole-resistant strains [4,5,19,33]. In candidemia without organ involvement, the duration of systemic antifungal therapy should be up to 14 days after a negative blood culture for Candida spp. ...
Full-text available
Purpose Candidemia is a bloodstream infection (BSI) by Candida spp. and is associated with high mortality. However, there have been few reports about BSI in head and neck cancer (HNC). We aimed to evaluate the impact of candidemia in patients with HNC and compared it with bacteremia. Study design A multicenter retrospective study. Methods We retrospectively analyzed 83 BSI episodes in HNC (2011 to 2020) and divided them into the candidemia and bacteremia groups. We then compared the survival rate and risk factors for candidemia between the groups. Results The overall cumulative incidence (risk) of candidemia in BSI was 12 out of 83 episodes (14.5%). The 1-year mortality for the bacteremia and candidemia groups was 33.3% and 58.3%, respectively (log-rank p = 0.041). Broad-spectrum antibiotics (odds ratio [OR]: 29.5; 95% confidence interval [CI], 2.49–350), mucositis (OR 11.0; 95% CI, 1.52–80.1), and malignant wounds (OR 79.5; 95% CI 1.33–4737) were significant risk factors for candidemia in HNC. Conclusions Candidemia causes high mortality in patients with HNC. To our knowledge, malignant wounds have not been previously reported as a risk factor for candidemia. For early diagnosis and treatment of candidemia, risk factors should be considered, and antifungal therapy started earlier.
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Purpose of Review Corticosteroids have a complex relationship with fungal disease — risk for many, benefit for others. This systematic review aims to address the effect of corticosteroids on mortality and visual outcome in different fungal diseases. Recent Findings Corticosteroids are a risk factor of aspergillosis for patients who have COVID-19, and they also led to a worse outcome. Similarity, corticosteroids are a risk factor for candidemia and mucormycosis. Some researchers reported that using topical corticosteroid in keratitis was associated with worse visual outcome if fungal keratitis. Some studies showed that corticosteroids are linked to a negative outcome for non-HIV patients with Pneumocystis jirovecii pneumonia (PCP), in contrast to those with HIV and PCP. Summary In 59 references, we found that corticosteroid therapy showed a worse clinical outcome in invasive aspergillosis (IA) (HR: 2.50, 95%CI: 1.89–3.31, p < 0.001) and chronic pulmonary aspergillosis (CPA) (HR: 2.74, 95%CI: 1.48–5.06, p = 0.001), PCP without HIV infection (OR: 1.29, 95%CI: 1.09–1.53, p = 0.003), invasive candidiasis and candidaemia (OR: 2.13, 95%CI: 1.85–2.46, p < 0.001), mucormycosis (OR: 4.19, 95%CI: 1.74–10.05, p = 0.001) and early in the course of fungal keratitis (OR: 2.99, 95%CI: 1.14–7.84, p = 0.026). There was equivocal outcome in cryptococcal meningoencephalitis in AIDS and primary coccidioidomycosis, while corticosteroid therapy showed a better outcome in PCP in HIV-infected patients (RR: 0.62, 95%CI: 0.46–0.83, p=0.001) and fungal keratitis patients after keratoplasty surgery (OR: 0.01, 95%CI: 0.00–0.41, p = 0.041) and probably in cryptococcal meningoencephalitis in non-immunocompromised patients. A sub-analysis in invasive aspergillosis and CPA showed that use of more than 2 mg/kg/day of prednisolone equivalents per day is a significant factor in increasing mortality (HR: 2.94, 95%CI: 2.13–4.05, p < 0.001). Corticosteroid therapy during invasive fungal disease was usually associated with a slightly or greatly increased mortality or worse visual outcome (in fungal keratitis), with two disease exceptions. Avoiding the addition of corticosteroids, or minimising dose and duration in those who require them, is likely to improve the outcome of most life- and vision-threatening fungal diseases. This review provides a cornerstone for further research in exploring the accuracy of suitable dose and duration of corticosteroids treatment in fungal diseases.
Candida türleri hastanede yatan hastalarda özellikle hematolojik maligniteli hastalarda önde gelen invazif fungal enfeksiyon etkenidir. Bu çalışma, hematolojik maligniteli hastalarda kandidemi prevalansını, mortalite ile ilişkili kontrol edilebilir risk faktörlerini ve antifungal direnci belirlemeyi, ampirik antifungal tedaviye rehberlik edecek ve enfeksiyon kontrol stratejilerinin geliştirilmesine katkıda bulunacak bilgiler elde etmeyi amaçlamaktadır. Uludağ Üniversitesi Tıp Fakültesi Hastanesi Hematoloji Kliniğinde 2009-2016 yılları arasında Candida kan kültürü pozitif saptanan hematolojik maligniteli hastaların demografik verileri, laboratuvar sonuçları, antifungal duyarlılıkları ve tedavi sonuçları geriye dönük olarak incelendi. Hematolojik maligniteleri olan 2489 hastanın 45’inde 45 kandidemi atağı saptandı. Bu hastaların büyük çoğunluğu akut lösemi hastalarıydı (%75.5). Çalışmamızda hematolojik malignitesi olan hastalarda kandidemi insidansını %1.8 bulduk; akut lösemili hastalarda ise bu oran %2.3 idi. Hastaların tür dağılımında C. albicans dışı türler hakimdi (38/45, %84,4). Genel olarak yatan hastalara kıyasla hematolojik malignitesi olan hastalarda C. krusei ve C. tropicalis daha yaygındı. C. parapsilosis her iki grupta da kandidemi için yaygın bir etkendi. Antifungal direnç, flukonazole karşı sadece iki C. parapsilosis izolatında antifungal direnç gözlendi. Toplam 30 günlük ölüm oranı %55,5 idi. Mortalite ile ilişkili bağımsız risk faktörleri hipoalbuminemi, aktif hastalık, septik şok ve monoterapi almaktı. Sonuç olarak, Tedavisindeki gelişmelere rağmen, ilişkili mortalitede önemli bir azalma sağlanamamıştır. Kandidemi tedavisinde lokal epidemiyolojik çalışmalar hala önemini korumaktadır. C. parapsilosis, kötü kateter yönetiminin bir göstergesi olarak kabul edilir. Çalışmamızda C. parapsilosis yüksek oranda tespit edilmiş ve antifungale direnç gösteren tek tür olmuştur. Bu, kandidemi ile mücadelede iyi kateter yönetiminin öneminin yanı sıra ampirik antifungal tedavi stratejilerinde epidemiyolojik çalışmaların önemini vurgulamaktadır.
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Objective: To evaluate the prevalence of Candida species in cancer patients with candidemia around the world, and to identify related risk factors and their antifungal resistance, with an emphasis on non-albicans Candida species (NACs). Methods: The published papers related to the subject were systematically searched in databases of MEDLINE (including PubMed), Web of Science, Scopus, Science Direct, and Google Scholar between the 1st January 2000 and 21st April 2021. Results: Among the 4 546 records, 69 studies met the inclusion criteria. The pooled prevalence of NACs in cancer patients with candidemia was 62% (95% CI 58%-67%; I2=94.85%, P=0.00). Based on type of cancer, the pooled prevalence of NACs in hematologic and solid cancer patients were 68% (95% CI 65%- 70%) and 52% (95% CI 49%-54%), respectively. Among NACs, Candida (C.) parapsilosis was the most frequently isolated organism followed by C. tropicalis and C. glabrata. In addition, the therapeutic usage of antibiotics was found as the most common risk factor, accounting for 85% (95% CI 81%-89%) and central venous catheter accounting for 69% (95% CI 62%-77%). Conclusions: The incidence of Candida bloodstream infections among cancer patients is a growing concern, especially when the etiologic agents of candidemia tend to shift towards NACs.
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Background IDSA guidelines on candidemia recommend fluconazole as first-line therapy when the risk of fluconazole-resistance (fluc-R) is low. There is no method to estimate risk of resistance resulting in extended use of echinocandins and prolonged hospitalization. This study aimed to develop a clinical predictive model to identify patients at low risk for fluc-R where initial use of fluconazole or early step-down would be appropriate. Methods We performed a retrospective analysis of all hospitalized adult patients with positive blood culture for Candida spp. from 2013 to 2019. We performed a multivariable logistic regression model to identify factors associated with fluc-R. Stepwise regression was performed on bootstrapped samples to test individual variable stability and estimate confidence intervals. We used receiver operator curves to assess performance across the probability spectrum. Results 539 adults with candidemia were identified. 13.4% (72/539) of Candida isolates were fluc-R. Increased risk of fluc-R was associated with older age, prior bacterial bloodstream infection (2.02 [1.13, 3.63]), myelodysplastic syndrome (3.09 [1.13, 8.44]) and receipt of azole therapy (5.42 [2.90, 10.1]) within 1 year prior to index blood culture, as well as history of bone marrow or stem cell transplant (2.81 [1.41, 5.63]). The model had good discrimination (optimism corrected c-statistic 0.771) and all the selected variables were stable. The prediction model had a negative predictive value of 95.7% for the selected sensitivity cut-off of 90.3%. Conclusions This model is a potential tool for identifying patients at low risk for fluc-R candidemia to receive fluconazole as initial therapy or early stepdown.
Patients with haematological malignancies, haemopoietic stem cell transplant recipients and patients requiring admission to intensive care settings are at high risk for invasive candidiasis (IC). Over the past decade, there has been increased reporting of non-albicans species and fluconazole resistance in Australia. These guidelines provide updated evidence-based recommendations for the diagnosis and management of IC in adult and paediatric haematology, oncology and intensive care settings. Optimal pharmacological and non-pharmacological management are discussed. Recent studies strengthen the recommendation for an echinocandin agent as first-line therapy for high-risk patients with IC. Mortality benefit has also been demonstrated for non-pharmacological management, including removal of central venous catheters, infectious diseases consultation and use of care bundles. Healthcare facilities managing immunocompromised patient populations should therefore adopt implementation strategies for these multimodal interventions.
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This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases.When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
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Most cases of candidiasis have been attributed to C. albicans, but recently, non- Candida albicans Candida (NCAC) species have been identified as common pathogens. The ability of Candida species to form biofilms has important clinical repercussions due to their increased resistance to antifungal therapy and the ability of yeast cells within the biofilms to withstand host immune defenses. Given this clinical importance of the biofilm growth form, the aim of this study was to characterize biofilms produced by three NCAC species, namely C. parapsilosis, C. tropicalis and C. glabrata. The biofilm forming ability of clinical isolates of C. parapsilosis, C. tropicalis and C. glabrata recovered from different sources, was evaluated by crystal violet staining. The structure and morphological characteristics of the biofilms were also assessed by scanning electron microscopy and the biofilm matrix composition analyzed for protein and carbohydrate content. All NCAC species were able to form biofilms although these were less extensive for C. glabrata compared with C. parapsilosis and C. tropicalis. It was evident that C. parapsilosis biofilm production was highly strain dependent, a feature not evident with C. glabrata and C. tropicalis. Scanning electron microscopy revealed structural differences for biofilms with respect to cell morphology and spatial arrangement. Candida parapsilosis biofilm matrices had large amounts of carbohydrate with less protein. Conversely, matrices extracted from C. tropicalis biofilms had low amounts of carbohydrate and protein. Interestingly, C. glabrata biofilm matrix was high in both protein and carbohydrate content. The present work demonstrates that biofilm forming ability, structure and matrix composition are highly species dependent with additional strain variability occurring with C. parapsilosis.
Two randomized, placebo-controlled trials previously showed that fluconazole (400 mg/d) administered prophylactically decreases the incidence of candidiasis in blood and marrow transplant (BMT) recipients. However, there exists conflicting data regarding the optimal duration of fluconazole administration, specifically whether prophylaxis through acute graft-versus-host disease (GVHD) results in improved survival in allograft recipients. Reported here are the results of long-term follow-up and a detailed analysis of invasive candidiasis and candidiasis-related death in 300 patients who received fluconazole (400 mg/d) or placebo for 75 days after BMT at the Fred Hutchinson Cancer Research Center. Patients in both treatment arms were compared for survival, causes of death, and the incidence of invasive fungal infections early (less than 110 days) and late (more than 110 days) after BMT. After 8 years of follow-up, survival is significantly better in fluconazole recipients compared with placebo recipients (68 of 152 vs 41 of 148,P = .0001). The overall incidence of invasive candidiasis was increased in patients who received placebo compared with fluconazole (30 of 148 vs 4 of 152, P < .001). More patients who received placebo died with candidiasis early (13 of 148 vs 1 of 152, P = .001) and late (8 of 96 vs 1 of 121,P = .0068) after BMT. The incidence of severe GVHD involving the gut was higher in patients who did not receive fluconazole (20 of 143 vs 8 of 145, P = .02), and fewer patients who received fluconazole died with this complication. Thus, administration of fluconazole (400 mg/d) for 75 days after BMT appears to be associated with decreased gut GVHD, a persistent protection against disseminated candidal infections and candidiasis-related death, resulting in an overall survival benefit in allogeneic BMT recipients.
• Between 1977 and 1984, estimates of hospital-acquired bloodstream infections caused by Candida species increased in the United States from 0.5 to 1.5 per 10000 admissions (National Nosocomial Infection Study data). We examined crude and attributable mortality rates and excess length of stay in 88 closely matched pairs of cases and controls with illnesses occurring between July 1983 and December 1986. The crude mortality rates for cases and controls were 57% and 19%, respectively; thus the attributable mortality rate was 38% with a 95% confidence interval of 26% to 49%. The risk ratio was 2.94 with a 95% confidence interval of 1.95 to 4.43. The median length of stay was 48 days for all cases and 40 days for all controls. An analysis of the length of stay for the 34 matched pairs that survived showed a median of 70 days for cases and 40 days for controls. Candida bloodstream infections represented 10% of all nosocomial bloodstream infections in the period studied at our University Hospital; they are associated with a significant medical and economic burden well above that expected of the underlying diseases alone. (Arch Intern Med 1988;148:2642-2645)
An increasing incidence of invasive fungal infections is observed in most immunocompro- mised patients, and especially leukaemia patients. In order to decrease the mortality due to these infections, the clinicians need to optimise their treatment choices for the most com- mon fungal infections observed in this population: invasive aspergillosis and candidiasis. These recommendations have been developed by an expert panel following an evidence- based search of the literature assessing the role of antifungal therapies in the treatment of patients with acute leukaemia or bone marrow transplantation and invasive candi- diasis - including candidaemia - and aspergillosis. We present results from a questionnaire on the current practice among experts in Europe, show results of the literature search and provide the panel's recommendations.
BACKGROUND.The objective of the current retrospective study was to compare the epidemiology of candidemia and its risk factors in patients who had hematologic malignancies(HM) with those in patients who had solid tumors (ST).METHODS.The medical and electronic records of all patients with cancer who had candidemia at the authors' institution from 1993 to 2003 were reviewed for demographic data and clinical information, including the use of prophylactic fluconazole, the infecting Candida species, and the source of candidemia (catheter-related vs other apparent sources).RESULTS.Six hundred thirty-five patients with candidemia were analyzed. C. glabrata and C. krusei were the leading causes of candidemia in 31% and 24% of patients with HM, respectively, and in 18% and 2% of patients with ST, respectively (P < .001). A catheter was the source of candidemia in 36% of the patients with ST and in 12% of the patients with HM (P < .001). Response to antifungal therapy occurred in 73% of the ST group compared with 49% of the HM group (P < .001). Multivariate logistic regression analysis revealed that fluconazole prophylaxis was a risk factor for both C. glabrata and C. krusei candidemia. The analysis also identified neutropenia as a risk factor for all candidemia and catheter-related infection as a risk factor for C. parapsilosis candidemia.CONCLUSIONS.The results of this study indicated that C. glabrata and C. krusei were the leading causes of candidemia in patients with HM. Neutropenia was the leading risk factor for all candidemia, whereas the catheter was the leading risk factor for C. parapsilosis candidemia. Cancer 2008. © 2008 American Cancer Society.
Many factors, including severity of illness, neutropenia, intravenous catheter management, and drug therapy may affect the outcome of candidemia in cancer patients. The records of all patients at M. D. Anderson Cancer Center who developed one or more positive blood cultures for Candida spp between January 1, 1988, and December 31, 1992, were retrospectively reviewed. Four hundred ninety-one episodes of candidemia were identified, for which 476 had complete medical records, which were reviewed in detail. By 3-month follow-up, 52% of the patients had died. Neutropenia, higher APACHE III score, and visceral dissemination were associated with poor prognosis. Cure rates, adjusted for severity of illness, were similar for fluconazole and amphotericin B treatment. Exchange of central venous catheters was associated with a modest improvement in prognosis. Several factors that influence the outcome of candidemia in cancer patients have been identified. These factors may be relevant for the clinical management of cancer patients with candidemia, and for the design of therapeutic trials.