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

mailto:[email protected]

http://dx.doi.org/10.1097/MCC.0b013e32833e0487

http://dx.doi.org/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

http://www.clinicaltrials.gov/




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.


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)].


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.



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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Early antifungal intervention strategies Eggimann and Ostrosky-Zeichner 469

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