txo antimicotico precoz en uci, curr opin crit care 2
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Early antifungal intervention strategies in ICU patientsPhilippe Eggimanna and Luis Ostrosky-Zeichnerb
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 determi-nants 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 con-
tinuous 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 associ-
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 ICUpatientsEarly antifungal treatments, such as prophylaxis, pre-
emptive, or empiric therapies have progressively
emerged; however, most of these strategies lack an evi-dence 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
[5–11]. However, this effectively requires targeting very
specific subgroups of patients with a risk above 10%. A
lower underlying risk of approximately 1–2%, which is
aDepartment of Intensive Care Medicine and BurnCenter, Centre Hospitalier Universitaire Vaudois,Lausanne, Switzerland and bDivision of InfectiousDiseases, University of Texas Health Science Center at
Houston, Houston, Texas, USA
Correspondence to Luis Ostrosky-Zeichner, Division ofInfectious Diseases, University of Texas HealthScience Center at Houston, TX 77030, USAE-mail: [email protected]
Current Opinion in Critical Care 2010,16:465–469
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 andmortality. 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.
SummaryTo 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 16:465–469 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins1070-5295
1070-5295 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MCC.0b013e32833e0487
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more typical of open ICU populations, would require
exposing approximately 100–200 patients to antifungal
prophylaxis to prevent one case [6]. Antifungal prophy-
laxis 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 resultsare 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’ anti-
fungal 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 risk-predictive models that will be discussed in this review
[16–23,24,25]. (Table 1).
Colonization indexIt 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 beforedocumented 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 anti-
fungals, showed that only one developed invasive candi-
diasis 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 startingat 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 ¼ 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 ¼ 0.016) and the thresholdof 0.5 was reached in 36 patients (39.1%). Invasive
candidiasis developed in six patients, in whom the colo-
nization 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] pro-
spectively 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 random-
ized by Normand et al. [34] to receive prophylaxis with
oral nystatin or placebo. No invasive candidiasis devel-
oped in these low-risk patients, but prophylaxis signifi-cantly 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 fol-
lowed 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
466 Infectious diseases
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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
ReferencePopulation and method of derivationof the model Parameters included in the model Accuracy of IC prediction
Pittetet al. [16]
29 patients (11 with IC) heavily colonizedwith Candida spp. in single Swiss ICU.Quantitative colonization only considered.Nonstandardized specimen collection.
Colonization index (distinct body sitescolonized/distinct body sitescultured). Threshold¼0.5.
PPV¼66%, NPV¼100%.
Dupontet al. [17]
231 and 57 surgical patients in singleFrench ICU with peritonitis in the
derivation and validation cohort,respectively. Clinical risk factors onlyconsidered.
Risk score for the presence of yeast inthe peritoneal fluid based on the
combination of four independent risk factors (female sex, upper gastrointestinaltract origin of peritonitis, peroperativecardiovascular failure, previousantimicrobial therapy at least 48 h beforethe onset of peritonitis), Score: gradeA: 1 risk factor, B 2, C 3, D¼4.
For a grade C score,sensitivity¼84%,
specificity¼50%,PPV¼67%, NPV¼72%.
Paphitouet al. [18]
327 patients (23 with proven/probableIC rate¼11%) with length of stay4 days in single US ICU. Clinicalrisk factor only considered.
One of: diabetes, total TPN prior ICU stay,new onset haemodialysis, or use of broadspectrum antibiotics.
Captured 52% of IC,sensitivity¼83%,specificity¼50%,PPV¼11%, NPV¼98%.
Montraverset al. [19]
91 patients with peritonitis and yeastisolated from the peritoneal fluidmatched with 168 controls free ofyeast from 17 French ICUs. Clinicalrisk factor only considered.
Increased mortality rate only in nosocomialperitonitis with fungal isolates (48 vs. 28%in controls, P <0.01). Upper gastrointestinalorigin of the peritonitis (OR 4.9; 95% CI1.6–14.8) and isolation of Candida species(OR 3.0; 95% CI 1.3 –6.7) independently
predicted mortality in patients withnosocomial peritonitis.
Upper GI tract ? Sensitivity¼,Specificity¼, PPV¼, NPV¼.
Leon et al. [20] 1669 patients (97 with IC rate¼6%)staying 7 days in 73 mixed medical/surgical Spanish ICUs. Clinical risk factors and quantitative colonizationconsidered.
‘Candida score’ to predict IC: sum of: Sepsis(2 points), surgery (1), TPN (1), multifocalCandida colonization (1).Threshold¼2.5 points.
Captured 81% of IC,sensitivity¼81%,specificity¼74%,PPV¼16%, NPV¼98%,would expose 13% of thepatients from the cohort.
Ostrosky-Zeichneret al. [21]
2890 patients (88 with proven/probableIC rate¼3%) with length of stay4 days in nine US/Brazilian ICUs.Clinical risk factor parameters onlyconsidered.
Both (day 1–3 of ICU stay: systemic antibioticsand CVC) and two of [TPN (d1-3), dialysis(d1-3), major surgery (d-7-0), pancreatitis(d-7-0), steroids (d-7-3), otherimmunosuppressive agents (d-7-0)].
Captured 34% of IC,sensitivity¼34%,specificity¼90%,PPV¼10%, NPV¼97%,would expose 10% of thepatients from the cohort.
Ostrosky-Zeichneret al. [22]
649 patients from mixed ICUs fromSwitzerland, France, US, and Australia(12 cases of proven IC rate¼1.8%).Clinical risk factor parameters as
above combined with the presence ofCandida in the microbiologicalspecimens available outside of anysystemic screening for Candida
colonization.
All of (day 1–3 of ICU stay mechanicalventilation, broad spectrum antibiotics andCVC) and one of [TPN (d1-3), dialysis (d1-3),major surgery (d-7-0), pancreatitis (d-7-0),
steroids (d-7-3), other immunosuppressiveagents (d-7-0)] and presence of Candida
spp. in any clinical specimen send formicrobiological examination.
Captured 66% of IC,sensitivity¼66%,specificity¼87%,PPV¼9%, NPV¼99%,
would expose 13% ofpatients from the cohort.
Charles et al. [23] 136 patients without bacterial infections(20 with IC rate¼15%) staying7 days in 36 mixed ICUs fromSpain, Argentina and France. Clinicalrisk factors, quantitative colonizationand biological parameters considered(procalcitonin weakly).
Candida score 3points at day 7 [sum of:Sepsis (2 points), surgery (1), TPN (1),multifocal Candida colonization (1)] andprocalcitonin 0.3 ng/ml.
Captured 80% of IC,sensitivity¼80%,specificity¼74%,PPV¼59%, NPV¼89%.
Ostrosk y-Zeichneret al. [24]
597 patients (22 with proven/probableIC rate¼4%) with length of stay4 days in six US ICUs. Clinical risk factor only considered.
All of [(day 1–3 of ICU stay): mechanicalventilation, broad spectrum antibiotics andCVC] and one of [TPN (d1-3), dialysis(d1-3), major surgery (d-7-0), pancreatitis(d-7-0), steroids (d-7-3), otherimmunosuppressive agents (d-7-0)].
Captured 90% of IC,sensitivity¼90%,specificity¼48%,PPV¼6%, NPV¼99%.
Shorr et al. [25] 64 019 patients admitted withbloodstream infection (738candidemia, rate 1.2%) and 24 685patients (321 candidemia, 1.3%) from176 US acute care hospitals, in aderivation and validation cohort,respectively. Clinical risk factor onlyconsidered.
Recursive partitioning analysis identified6 variables as the best discriminators:age <65 years; T8 > 988F or severealtered mental status; cachexia; previoushospitalization within 30 day; admitted fromother healthcare facility; need for mechanicalventilation. The prevalence of with 0through 6 risk factors in the derivationcohort was 28.7, 38.8, 21.8, 8.3, 2.1, 0.3,and <0.1%, respectively. Correspondingcandidemia rates were 0.4% (69/18 355),0.8% (196/24811), 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).
Score 1,sensitivity¼90.7%,NPPV¼99.6%.
NPV, negative predictive value; PPV, positive predictive value.
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caspofungin therapy [36]. Invasive candidiasis devel-
oped in only one out of 19 patients (one breakthrough
invasive candidiasis 5 days after inclusion). The coloniza-
tion 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 imple-ment in daily clinical practice.
Clinical prediction rulesClinicians 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 e t 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 dia-betes, 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, Ostrosky-
Zeichner 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%, captur-
ing 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). How-
ever, 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 con-
cerned 2.6% of all patients admitted and significantly
decreased the rate of fungal catheter-related bloodstreaminfections from 3.4 to 0.79 episodes per 1000 catheter-
days. 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 pro-
phylaxis and preemptive therapy in ICU patients (MSG-
01, 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 colo-
nization, 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 aspecificity of 87%. This new rule is being investigated in
a randomized, placebo-controlled, pilot study on empiri-
cal therapy with caspofungin in high-risk ICU patients
(MSG-04, www.clinicaltrials.gov).
Candida scoreThe 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%) devel-oped an invasive candidiasis. Only 13/565 (2.3%) patients
with a ‘Candida score’ below 3 points developed an
invasive candidiasis (sensitivity¼ 78%, specificity¼ 66%,
66%, PPV¼ 14%, NPV¼ 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) 1.8–7.7]. A linear
progression of the risk of invasive candidiasis and higher
score was further observed. The incidence rates of inva-
sive 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 3.28–10.92) was lower than Candida score of at least 3
(RR was 5.98, 95% CI 3.28–10.92).
ConclusionTo date, clinical models targeted at early identification of
patients at risk of developing invasive candidiasis remain
limited by suboptimal performance, and a lack of vali-
dation 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 predictiverules have either been completed or just started (MSG-
01, MSG-04, and INTENSE, www.clinicaltrials.gov).
They may not only potentially confirm the usefulness
of these approaches but strongly influence the manage-
ment of these patients in the near future.
AcknowledgementsDisclosures: Pertinent to this article, P.E. has received researchfunding and/or consulting and speaking honoraria from the followingcompanies: Astellas, Merck, and Pfizer. L.O. has received researchfunding and/or consulting and speaking honoraria from the followingcompanies: Merck, Astellas, Pfizer, and Associates of Cape Cod.
468 Infectious diseases
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