Early antifungal intervention strategies in ICU patients

Philippe Eggimanna and Luis Ostrosky-Zeichnerb

a

Department of Intensive Care Medicine and Burn

Center, Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland and bDivision of Infectious
Diseases, University of Texas Health Science Center at
Houston, Houston, Texas, USA
Correspondence to Luis Ostrosky-Zeichner, Division of
Infectious Diseases, University of Texas Health
Science Center at Houston, TX 77030, USA
E-mail: Luis.Ostrosky-Zeichner@uth.tmc.edu
Current Opinion in Critical Care 2010,
16:465469

Purpose of review
Despite progress in the understanding of the pathophysiology of invasive candidiasis,
and the development of new classes of well tolerated antifungals, invasive candidiasis
remains a disease difficult to diagnose, and associated with significant morbidity and
mortality. Early antifungal treatment may be useful in selected groups of patients who
remain difficult to identify prospectively. The purpose of this review is to summarize the
recent development of risk-identification strategies targeting early identification of ICU
patients susceptible to benefit from preemptive or empirical antifungal treatment.
Recent findings
Combinations of different risk factors are useful in identifying high-risk patients. Among
the many risk factors predisposing to invasive candidiasis, colonization has been
identified as one of the most important. In contrast to prospective surveillance of the
dynamics of colonization (colonization index), integration of clinical colonization status in
risk scores models significantly improve their accuracy in identifying patients at risk of
invasive candidiasis.
Summary
To date, despite limited prospective validation, clinical models targeted at early
identification of patients at risk to develop invasive candidiasis represent a major
advance in the management of patients at risk of invasive candidiasis. Moreover, large
clinical studies using such risk scores or predictive rules are underway.
Keywords
antifungals, early therapy, empirical treatment, ICU, invasive candidiasis
Curr Opin Crit Care 16:465469
2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1070-5295

Introduction
Repetitive observations support the evidence that
delayed initiation of antifungal therapy in patients
developing invasive candidiasis is associated with worse
outcomes. In a cohort of 157 patients with Candida
bloodstream infection, Morrell et al. [1] showed that
APACHE II score, prior antibiotic treatment and start
of antifungal treatment more than 12 h after having the
first positive blood culture were independent determinants of hospital mortality. A similar and significant
mortality benefit associated with early antifungal
initiation within 24 h was reported in another cohort of
230 candidemic patients by Garey et al. [2] with continuous mortality increase correlating with increasing
delays in initiation. Further, Parkins et al. [3] reported
that among a cohort of 199 patients developing invasive
candidiasis, the initiation of adequate empiric therapy
after culture draw but before growth was associated with
a significantly reduced mortality. These studies also
emphasize the relative insensitivity and delays associ1070-5295 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins

ated with microbiological cultures, therefore resulting in

a minority of the patients who experience the disease
that receive early treatment.

Early antifungal intervention strategies in ICU

patients
Early antifungal treatments, such as prophylaxis, preemptive, or empiric therapies have progressively
emerged; however, most of these strategies lack an evidence base that would establish them as standard of care
[4
].
Antifungal prophylaxis with fluconazole has been
assessed in diverse groups of ICU and surgical patients.
Despite clinical and methodological heterogeneity,
meta-analyses of these trials consistently indicated
approximately 50% reduction in invasive candidiasis
[511]. However, this effectively requires targeting very
specific subgroups of patients with a risk above 10%. A
lower underlying risk of approximately 12%, which is
DOI:10.1097/MCC.0b013e32833e0487

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466 Infectious diseases

more typical of open ICU populations, would require

exposing approximately 100200 patients to antifungal
prophylaxis to prevent one case [6]. Antifungal prophylaxis fails in unselected ICU populations, or surgical
patients at lower risk, such as those with uncomplicated
peritonitis [12,13]. A clinical trial exploring antifungal
prophylaxis with caspofungin (vs. placebo) in high-risk
ICU patients has just been completed and results
are expected later this year. This trial is also interesting
as it used a serum marker (1,3-b-D-glucan) to asses
breakthrough infections and trigger preemptive antifungal therapy for prophylaxis failures (MSG-01,
www.clinicaltrials.gov).
Combination of many of the well established risk factors
for invasive candidiasis may help to promptly identify
patients with a risk of invasive candidiasis higher than
10%, making these selected populations more likely to
benefit from early preemptive antifungal treatment
[14,15]. Such strategies have been integrated into riskpredictive models that will be discussed in this review
[1623,24

,25]. (Table 1).

Colonization index
It has been suggested that in cases of suspicion of
invasive candidiasis, the colonization of more than two
body sites may be sufficient to justify the initiation of
antifungal therapy [26,27]. In a prospective cohort study
of critically ill surgical patients, Pittet et al. [16] assessed
the degree of colonization. A daily colonization index was
determined as the ratio of the number of distinct body
sites colonized with identical strains of Candida spp. over
the total number of sites tested. Twenty-nine of 650
patients admitted were colonized at several distinct body
sites. Eleven of 29 patients developed severe Candida
infection, including candidemia in eight. The 18 other
patients remained colonized but did not develop invasive
candidiasis. The severity of illness and the degree of
colonization independently predicted the development
of a candidiasis among colonized patients. The average
Candida colonization index was 0.47 in colonized vs. 0.70
in infected patients, respectively (P < 0.01). A threshold
of at least 0.5 correctly identified all infected patients, and
this value was reached at an average of 6 days before
documented invasive candidiasis. Such delay opened the
door for early empirical antifungal treatment.
The predictive value of this index has never been tested
in a large prospective clinical trial, but at least nine
studies suggest that it may be clinically useful. In one
study, 35/39 of patients at risk (ICU stay >7 days) with an
index above 0.5 who were empirically treated with antifungals, showed that only one developed invasive candidiasis and the degree of colonization rapidly decreased in
the 34 other patients [28]. In French ICU patients,

Chabasse [29] found a correlation between quantitative

cultures above 104 cfu/ml and a colonization index at least
0.5. Garbino et al. [30] prospectively followed it in all
patients included in a double-blind, placebo-controlled
study on antifungal prophylaxis in patients mechanically
ventilated for at least 5 days. The colonization index
increased over time in the placebo group, but decreased in
the fluconazole group with significant differences starting
at the 7th day. In a 10-year retrospective cohort study on
51 ICU patients having invasive candidiasis, Charles et al.
[31] reported a prior high-density of colonization by
Candida spp. with a colonization index of at least 0.5 in
21 (45.6%) of the 46 assessed patients (0.56  0.31).
Colonization index was significantly higher in medical
patients than surgical patients (P 0.01) [31]. In a further
prospective study on 92 nonneutropenic patients staying
more than 7 days in a medical ICU, the dynamics of
colonization were assessed by weekly colonization index
[32]. The index increased significantly by 0.10 every
week over the ICU stay (P 0.016) and the threshold
of 0.5 was reached in 36 patients (39.1%). Invasive
candidiasis developed in six patients, in whom the colonization index was at least 0.5 as compared to three in
those in whom it was below 0.5 (P value nonsignificant).
However, significantly more patients with a colonization
index of at least 0.5 received antifungal therapy for more
than 2 days, 14/36 (61.1%) vs. 7/56 (12.5%), respectively.
Hematological malignancy, duration of exposure to
broad-spectrum antibiotics, fungal colonization at entry
and candiduria predicted an increase in the colonization
index. In contrast, the duration of exposure to antifungals
was significantly associated with colonization index
decrease. In a before/after trial, Piarroux et al. [33] prospectively screened 478 surgical ICU patients for Candida
spp. colonization. These patients received preemptive
antifungal treatment if the corrected colonization index
was greater than 0.4 [33]. Compared to an historical
cohort of 455 controls, invasive candidiasis decreased
from 7.0 to 3.6%, respectively. Moreover, this strategy
completely prevented the development of ICU-acquired
invasive candidiasis. In an open-label study, 98 patients
mechanically ventilated for more than 48 h were randomized by Normand et al. [34] to receive prophylaxis with
oral nystatin or placebo. No invasive candidiasis developed in these low-risk patients, but prophylaxis significantly reduced the colonization index and prevented
colonization [34]. In a prospective evaluation of 59
ICU patients, Agvald-Ohman et al. [35] showed that
increased values of colonization index after major
abdominal surgery were significantly correlated with
the development of an invasive candidiasis. Candida
colonization index and corrected index (CCI) were followed twice weekly in a prospective noncomparative
single-center study in consecutive adult surgical patients
with recurrent gastrointestinal perforation/anastomotic
leakage or acute necrotizing pancreatitis with preventive

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Early antifungal intervention strategies Eggimann and Ostrosky-Zeichner 467

Table 1 Published risk predictive models for invasive candidiasis (IC) among critically ill patients
Reference
Pittet
et al. [16]
Dupont
et al. [17]

Paphitou
et al. [18]
Montravers
et al. [19]

Population and method of derivation

of the model
29 patients (11 with IC) heavily colonized
with Candida spp. in single Swiss ICU.
Quantitative colonization only considered.
Nonstandardized specimen collection.
231 and 57 surgical patients in single
French ICU with peritonitis in the
derivation and validation cohort,
respectively. Clinical risk factors only
considered.

327 patients (23 with proven/probable

IC rate 11%) with length of stay
4 days in single US ICU. Clinical
risk factor only considered.
91 patients with peritonitis and yeast
isolated from the peritoneal fluid
matched with 168 controls free of
yeast from 17 French ICUs. Clinical
risk factor only considered.

Parameters included in the model

Accuracy of IC prediction

Colonization index (distinct body sites

colonized/distinct body sites
cultured). Threshold 0.5.

PPV 66%, NPV 100%.

Risk score for the presence of yeast in

the peritoneal fluid based on the
combination of four independent risk
factors (female sex, upper gastrointestinal
tract origin of peritonitis, peroperative
cardiovascular failure, previous
antimicrobial therapy at least 48 h before
the onset of peritonitis), Score: grade
A: 1 risk factor, B 2, C 3, D 4.
One of: diabetes, total TPN prior ICU stay,
new onset haemodialysis, or use of broad
spectrum antibiotics.

For a grade C score,

sensitivity 84%,
specificity 50%,
PPV 67%, NPV 72%.

Increased mortality rate only in nosocomial

peritonitis with fungal isolates (48 vs. 28%
in controls, P < 0.01). Upper gastrointestinal
origin of the peritonitis (OR 4.9; 95% CI
1.614.8) and isolation of Candida species
(OR 3.0; 95% CI 1.36.7) independently
predicted mortality in patients with
nosocomial peritonitis.
Candida score to predict IC: sum of: Sepsis
(2 points), surgery (1), TPN (1), multifocal
Candida colonization (1).
Threshold 2.5 points.

Leon et al. [20]

1669 patients (97 with IC rate 6%)

staying 7 days in 73 mixed medical/
surgical Spanish ICUs. Clinical risk
factors and quantitative colonization
considered.

Ostrosky-Zeichner
et al. [21]

2890 patients (88 with proven/probable

IC rate 3%) with length of stay
4 days in nine US/Brazilian ICUs.
Clinical risk factor parameters only
considered.

Both (day 13 of ICU stay: systemic antibiotics

and CVC) and two of [TPN (d1-3), dialysis
(d1-3), major surgery (d-7-0), pancreatitis
(d-7-0), steroids (d-7-3), other
immunosuppressive agents (d-7-0)].

Ostrosky-Zeichner
et al. [22]

649 patients from mixed ICUs from

Switzerland, France, US, and Australia
(12 cases of proven IC rate 1.8%).
Clinical risk factor parameters as
above combined with the presence of
Candida in the microbiological
specimens available outside of any
systemic screening for Candida
colonization.
136 patients without bacterial infections
(20 with IC rate 15%) staying
7 days in 36 mixed ICUs from
Spain, Argentina and France. Clinical
risk factors, quantitative colonization
and biological parameters considered
(procalcitonin weakly).
597 patients (22 with proven/probable
IC rate 4%) with length of stay
4 days in six US ICUs. Clinical risk
factor only considered.

All of (day 13 of ICU stay mechanical

ventilation, broad spectrum antibiotics and
CVC) and one of [TPN (d1-3), dialysis (d1-3),
major surgery (d-7-0), pancreatitis (d-7-0),
steroids (d-7-3), other immunosuppressive
agents (d-7-0)] and presence of Candida
spp. in any clinical specimen send for
microbiological examination.

Charles et al. [23]

Ostrosky-Zeichner
et al. [24

]

Shorr et al. [25]

64 019 patients admitted with

bloodstream infection (738
candidemia, rate 1.2%) and 24 685
patients (321 candidemia, 1.3%) from
176 US acute care hospitals, in a
derivation and validation cohort,
respectively. Clinical risk factor only
considered.

Captured 52% of IC,

sensitivity 83%,
specificity 50%,
PPV 11%, NPV 98%.
Upper GI tract ? Sensitivity,
Specificity, PPV, NPV.

Captured 81% of IC,

sensitivity 81%,
specificity 74%,
PPV 16%, NPV 98%,
would expose 13% of the
patients from the cohort.
Captured 34% of IC,
sensitivity 34%,
specificity 90%,
PPV 10%, NPV 97%,
would expose 10% of the
patients from the cohort.
Captured 66% of IC,
sensitivity 66%,
specificity 87%,
PPV 9%, NPV 99%,
would expose 13% of
patients from the cohort.

Candida score 3points at day 7 [sum of:

Sepsis (2 points), surgery (1), TPN (1),
multifocal Candida colonization (1)] and
procalcitonin 0.3 ng/ml.

Captured 80% of IC,

sensitivity 80%,
specificity 74%,
PPV 59%, NPV 89%.

All of [(day 13 of ICU stay): mechanical

ventilation, broad spectrum antibiotics and
CVC] and one of [TPN (d1-3), dialysis
(d1-3), major surgery (d-7-0), pancreatitis
(d-7-0), steroids (d-7-3), other
immunosuppressive agents (d-7-0)].
Recursive partitioning analysis identified
6 variables as the best discriminators:
age <65 years; T8 > 988F or severe
altered mental status; cachexia; previous
hospitalization within 30 day; admitted from
other healthcare facility; need for mechanical
ventilation. The prevalence of with 0
through 6 risk factors in the derivation
cohort was 28.7, 38.8, 21.8, 8.3, 2.1, 0.3,
and <0.1%, respectively. Corresponding
candidemia rates were 0.4% (69/18 355),
0.8% (196/24 811), 1.6% (229/13 984),
3.2% (168/5330), 4.2% (58/1371), 9.6%
(15/157), and 27.3% (3/11),
respectively (P < 0.0001).

Captured 90% of IC,

sensitivity 90%,
specificity 48%,
PPV 6%, NPV 99%.
Score 1,
sensitivity 90.7%,
NPPV 99.6%.

NPV, negative predictive value; PPV, positive predictive value.

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468 Infectious diseases

caspofungin therapy [36

]. Invasive candidiasis developed in only one out of 19 patients (one breakthrough
invasive candidiasis 5 days after inclusion). The colonization index decreased significantly during study therapy,
and the CCI remained below 0.4 in all patients.
The colonization index, however, remains time- and
resource-consuming and is particularly difficult to implement in daily clinical practice.

Clinical prediction rules

Clinicians and researchers have been interested in
creating a prediction rule based on risk factors and
clinical parameters to identify patients at high risk of
invasive candidiasis in the critical care setting. In
preliminary work, Paphitou et al. [18] performed a
retrospective analysis of 327 surgical ICU patients,
identifying individual risk factors that increased the
risk of invasive candidiasis. These factors were diabetes, parenteral nutrition, hemodialysis, and use of
broad-spectrum antibiotics. Identifying patients at risk
through the presence of any of those risk factors
captured 52% of all cases of invasive candidiasis in
the unit; however, it would also have the potential for
massive exposure to antifungals (if used as an early
therapy strategy) due to the commonality of these
events in critically ill patients.
In a second multicenter retrospective study, OstroskyZeichner et al. [21] found that a combination of risk
factors (Table 1) was sufficient to identify a population
with a risk of invasive candidiasis of at least 10%, capturing 34% of cases of invasive candidiasis in the study
population. This prediction rule was subsequently used
to launch a randomized multicenter clinical trial of
caspofungin prophylaxis in ICU patients (BAMSG-01,
www.clinicaltrials.gov). The trial had to be discontinued
due to low enrolment, since the rule proved to be too
restrictive (applying to <8% of eligible patients). However, the usefulness of this risk factor-based predictive
rule has further been demonstrated in a medical ICU
[37
]. Prescription of antifungals based on the rule concerned 2.6% of all patients admitted and significantly
decreased the rate of fungal catheter-related bloodstream
infections from 3.4 to 0.79 episodes per 1000 catheterdays. The rule was subsequently modified to be more
inclusive [22], while maintaining an incidence of invasive
candidiasis of at least 10%. This iteration of the clinical
prediction rule was used for inclusion into the recently
completed multicenter clinical trial of caspofungin prophylaxis and preemptive therapy in ICU patients (MSG01, www.clinicaltrials.gov).
In a final validation of this clinical prediction rule,
researchers felt it was important to investigate if the

clinical prediction rule, coupled with clinical signs and

symptoms of infection in the presence of Candida colonization, was indicative of early invasive candidiasis and
could be used as a trigger of preemptive or empirical
antifungal therapy. In a multicenter, multinational study,
Ostrosky-Zeichner et al. [22] investigated this coupling
and found that the new rule captured 66% of patients
with invasive candidiasis, with a sensitivity of 66% and a
specificity of 87%. This new rule is being investigated in
a randomized, placebo-controlled, pilot study on empirical therapy with caspofungin in high-risk ICU patients
(MSG-04, www.clinicaltrials.gov).

Candida score
The usefulness of the risk-factor based Candida score
has further been demonstrated to rule out the probability
of invasive candidiasis [20,38

]. In a prospective cohort
of 1007 patients staying for more than 7 days in 36 mixed
ICUs from Spain, Argentina and France, 58 (5.4%) developed an invasive candidiasis. Only 13/565 (2.3%) patients
with a Candida score below 3 points developed an
invasive candidiasis (sensitivity 78%, specificity 66%,
66%, PPV 14%, NPV 98%), as compared to 45/327
(13.8%) of those with a score at least 3 [relative risk (RR)
3.7, 95% confidence interval (CI) 1.87.7]. A linear
progression of the risk of invasive candidiasis and higher
score was further observed. The incidence rates of invasive candidiasis according to the colonization index were
3.9% (16 of 411 patients) in the group of less than 0.5 and
8.7% (42 of 481 patients) in the group of at least 0.5. The
accuracy of the colonization index at least 0.5 (5.98, 95%
CI 3.2810.92) was lower than Candida score of at least 3
(RR was 5.98, 95% CI 3.2810.92).

Conclusion
To date, clinical models targeted at early identification of
patients at risk of developing invasive candidiasis remain
limited by suboptimal performance, and a lack of validation on prospective and independent ICU patient
cohorts. However, such approaches represent a major
advance in our continued progression to improve the
management of patients at risk of invasive candidiasis.
Large clinical studies using such risk scores or predictive
rules have either been completed or just started (MSG01, MSG-04, and INTENSE, www.clinicaltrials.gov).
They may not only potentially confirm the usefulness
of these approaches but strongly influence the management of these patients in the near future.

Acknowledgements
Disclosures: Pertinent to this article, P.E. has received research
funding and/or consulting and speaking honoraria from the following
companies: Astellas, Merck, and Pfizer. L.O. has received research
funding and/or consulting and speaking honoraria from the following
companies: Merck, Astellas, Pfizer, and Associates of Cape Cod.

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Early antifungal intervention strategies Eggimann and Ostrosky-Zeichner 469

References and recommended reading

Papers of particular interest, published within the annual period of review, have
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of special interest


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