The clinical significance of Candida colonization of respiratory tract secretions in critically ill patients B

Journal of Critical Care (2008) 23, 11–17

The clinical significance of Candida colonization of
respiratory tract secretions in critically ill patientsB
Marie-Soleil Delisle a , David R. Williamson b,c , Marc M. Perreault c,d ,
Martin Albert b,c , Xuran Jiang e , Daren K. Heyland e,⁎
 Hôpital de l'Enfant-Jésus, Québec, Québec, Canada
  Hôpital du Sacré-Cœur de Montréal, Montréal, Québec, Canada
 Université de Montréal, Montréal, Québec, Canada
  Centre Universitaire de Santé McGill, Montréal, Québec, Canada
 Queens University, Kingston, Ontario, Canada

                                         Purpose: Clinical uncertainty exists regarding the significance of colonization confined to respiratory
                                         tract secretions with Candida sp in critically ill patients. Our objectives were to describe such
    Candida airway
                                         colonization, its associated risk factors, and to examine the clinical outcomes in patients with a
                                         clinical suspicion of ventilator-associated pneumonia with isolated Candida colonization compared to
                                         those without.
                                         Materials and Methods: In a retrospective analysis of the Canadian ventilator-associated pneumonia
                                         study, patients were divided into 2 groups according to the isolated presence or absence of Candida
    Critical care
                                         in the respiratory tract enrollment culture. We compared length of mechanical ventilation, intensive
                                         care unit and hospital stay, and mortality outcomes between groups. We used multiple logistic
                                         regression analysis to determine factors independently associated with Candida colonization and
                                         hospital mortality.
                                         Results: Of the 639 eligible patients, 114 (17.8%) were colonized with Candida in the enrollment
                                         culture. A multivariate analysis identified female sex (odds ratio [OR], 1.65; 95% confidence interval
                                         [CI], 1.02-2.65), number of comorbidities (OR, 1.35; 95% CI, 1.08-1.71), worsening or persistent
                                         infiltrate at randomization (OR, 1.92; 95% CI, 1.09-1.38), antibiotics started within 3 days of
                                         randomization (OR, 3.16; 95% CI, 1.71-5.83), and on antibiotics at randomization but all started
                                         more than 3 days before randomization (OR, 3.04; 95% CI, 1.68-5.50) as variables associated with
                                         Candida respiratory tract colonization. A significant increase in median hospital stay (59.9 vs 38.6 days,
                                         P = .006) and hospital mortality (34.2% vs 21.0%, P = .003) was observed in patients with Candida
                                         colonization. In a multivariate model, Candida colonization of the respiratory tract was independently
                                         associated with hospital mortality (OR, 2.47; 95% CI, 1.39-4.37).
                                         Conclusion: Respiratory tract Candida colonization is associated with worse clinical outcomes and is
                                         independently associated with increased hospital mortality. However, it is unclear whether Candida

       This study was supported by grants from the Canadian Institutes of Health Research and Physicians' Services Incorporated of Ontario, and by unrestricted
grants from AstraZeneca, Bayer, and Merck Frosst.
   ⁎ Corresponding author. Tel.: +613 549 6666x3339, fax: +1 613 548 1351.
   E-mail address: (D.K. Heyland).

0883-9441/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
12                                                                                                               M.-S. Delisle et al.

                                   colonization is causally related to poor outcomes or whether it is a marker for increased morbidity
                                   and mortality.
                                   © 2008 Elsevier Inc. All rights reserved.

1. Introduction                                                       using a 2 × 2 factorial design to either bronchoscopy or
                                                                      endotracheal aspirate (ETA) groups and to receive treatment
    Fungal infection and colonization are becoming major              with either 2 broad-spectrum antibiotics or a single broad-
clinical challenges in patients in the intensive care unit (ICU)      spectrum antibiotic. Subjects were followed prospectively
[1-12]. Candida colonization from various sites has been              for 28 days or until death or hospital discharge.
associated with prolonged ICU and hospital stays as well as
increased health care costs in mixed medical, surgical, and           2.2. Population
trauma populations [10]. Although some studies address
Candida colonization mainly in surgical ICU patients, few                 Adult patients were included in the VAP trial if they were
examine other ICU populations. Wey et al [13] identified              admitted to an ICU for more than 96 hours, if they were
Candida colonization at one or multiple sites as an                   mechanically ventilated for more than 48 hours, and if they
independent risk factor for candidemia. Although numerous             fulfilled criteria for a clinical suspicion of VAP. The criteria
risk factors for candidemia have been reported, none of these         for clinical suspicion of pneumonia had to be met within
risk factors have been studied for association with an                48 hours of enrollment [22]. Immunocompromised patients,
increased risk of Candida colonization at any site [13-16].           defined as post–organ transplantation, HIV or neutropenic
    Isolation of Candida sp from respiratory tract secretions is      (b1000 absolute neutrophils) patients, or those receiving
frequent in mechanically ventilated, non-immunocompro-                corticosteroids more than 20 mg/d of prednisone or
mised patients [9,11,17-20]. Studies assessing the signifi-           equivalent for more than 6 months, were excluded, as well
cance of colonization of respiratory tract secretions                 as patients infected or colonized with Pseudomonas species
specifically are scarce and leave the matter unclear                  or methicillin-resistant Staphylococcus aureus, and those
[9,11,17-20]. The clinical relevance of isolated respiratory          unlikely to be discharged from ICU within 3 weeks. The
tract secretion Candida colonization in contrast to coloniza-         complete VAP study design and results have been published
tion of multiple sites has also not been established. Recently,       elsewhere [22].
in a mixed medical and surgical population, Azoulay et al [21]            Within 12 hours of randomization, respiratory tract cultures
found an association between Candida colonization of the              (either bronchoalveolar lavage [BAL] or ETA) were obtained.
respiratory tract secretions and a prolonged period of                For this analysis, we divided patients in 2 groups according to
mechanical ventilation (MV), longer ICU and hospital stay,            whether Candida was present or not in the enrollment
and an increased risk for Pseudomonas VAP but no difference           specimen. Because we focused on Candida colonization
in mortality. Of note, 39.7% of patients in that study had            confined to respiratory tract secretions, patients with a positive
extrapulmonary Candida colonization. No studies have                  Candida culture at any site in the 7-day period preceding
described the risk factors and outcomes of patients with              randomization and from any site other than the respiratory tract
isolated Candida colonization of respiratory tract secretions         on day of randomization were excluded from this analysis.
in a North American setting.                                          Cultures other than respiratory samples obtained at randomi-
    The primary objective of this study of patients with a            zation were performed according to clinicians' judgment.
clinical suspicion of a VAP was to describe the characteristics           Sample procurement and laboratory processing were
of patients with isolated Candida colonization (confined to           standardized. The BAL and ETA were performed in a
the respiratory tract secretions only) and to determine the risk      standardized manner according to conventional techniques.
factors associated with Candida colonization. Our secondary           Both ETA and BAL specimens were transported immedi-
objectives were to compare patients with and without Can-             ately to the laboratory.
dida colonization in terms of duration of MV, ICU and
hospital stay; and ICU, hospital, and 28-day mortality.               2.3. Data collection

2. Materials and methods                                                 Upon enrollment in the VAP trial, demographics such as
                                                                      age, sex, height, weight, primary admission diagnosis
2.1. Design                                                           category, number of comorbid diseases, APACHE (Acute
                                                                      physiology and chronic health evaluation) II score, type of
    We conducted a retrospective cohort study on a subset of          ICU, date and time of randomization, admission to the
patients from the Canadian randomized, multicenter VAP                hospital, admission to the ICU, and start of MV were
trial [22]. In this trial, ICU patients with a clinical suspicion     recorded for all patients [23]. Daily monitoring was then
of a VAP from 28 participating centers were randomized                performed on all patients for signs and symptoms of
Significance of Candida colonization of respiratory tract secretions                                                             13

infection, organ dysfunction, and other ICU-acquired                 MV, length of stay, and mortality are described using Kaplan-
complications [24]. During hospitalization, newly acquired           Meier estimates of the median and quartiles and were
diagnoses, duration of MV, need for vasopressors, and                compared between groups using the log-rank test. To identify
hemodialysis were recorded. Culture results from all sites           factors independently associated with Candida colonization
and antibiotic use for the 7 days before enrollment and              and increased mortality in colonized patients vs noncolonized
throughout the study period were recorded. We recorded               patients, we used logistic regression including patient
secondary outcome measures of days of MV, in the ICU and             characteristics with a univariate model significance level of
in the hospital, as well as occurrence of fungemia and ICU,          0.20: age, sex, APACHE II score, number of comorbidities,
in-hospital, and 28-day mortality.                                   presence vs absence of Candida in respiratory tract secre-
                                                                     tions, admission diagnosis category (sepsis, trauma, and
                                                                     neurologic condition assessed independently), BAL vs ETA
2.4. Statistical analysis                                            diagnostic method, antibiotic monotherapy vs combination
                                                                     therapy, use of vasopressors during hospitalization, anti-
   Baseline patient characteristics were compared between            biotics started within 3 days before randomization vs no
patients with and without the presence of Candida in the             antibiotic, antibiotics started prior to 3 days before randomi-
respiratory tract enrollment culture. Categorical variables are      zation vs no antibiotics, multiple organ dysfuncfion score on
described as counts and percentages and were tested using the        day 1, and PaO2/FiO2 ratio also on day 1. Variables identified
χ2 test. Continuous variables are described as means with            from the univariate model with a significance level of 0.20 or
SDs and compared using independent t test. Mortality                 less were included in a multivariate analysis, in addition to
outcomes between the colonized patients vs noncolonized              age, sex, APACHE II score, bronchoscopy vs ETA groups,
patients were compared using Fisher exact test. Length of            and combination antibiotic therapy vs monotherapy to

                                                     Fig. 1   Patient flowchart.
14                                                                                                           M.-S. Delisle et al.

determine relevant risk factors. All tests are two-sided, and a    sample within 7 days before randomization, or had Candida-
P value of less than .05 was considered statistically              positive culture from other sites within that same period or on
significant. Analyses were completed with SAS Version 9.1          day of randomization; 21 were excluded because of Candida
(SAS Institute, Cary, NC).                                         found in their respiratory tract secretions on the day of
                                                                   randomization and a positive Candida culture from other
                                                                   sites within 7 days before or on the day of randomization.
3. Results                                                             We found Candida colonization confined to respiratory
                                                                   tract secretions on the day of randomization in 114 (17.8%)
   Of the 740 patients enrolled in the VAP study between           of 639 patients (Fig. 1). The proportion of patients whose
May 2000 and February 2005, we included 639 for analysis.          positive Candida cultures were isolated via the ETA or BAL
One patient withdrew consent and was not considered                arms of the VAP trial were 15.6% (n = 49) and 20.0%
further. We excluded an additional 100 patients: 79 had            (n = 65), respectively (P = .15).
Candida-negative respiratory tract secretions sample on                Various types of Candida sp were isolated from res-
randomization day, but positive respiratory tract secretion        piratory tract secretion specimens collected at randomization.

 Table 1    Baseline patient characteristics
                                                     Colonized           Noncolonized              Total                    P
                                                     n = 114             n = 525                   N = 639
 Age                                                 59.6 ± 16.8          58.9 ± 18.4               59.0 ± 18.1             .71
 Male sex (n [%])                                    71 (62.3)           377 (71.8)                448 (70.1)               .04
 Admission category (n [%])                                                                                                 .69
  Medical                                            72 (63.2)           321 (61.1)                393 (61.5)
  Surgical                                           42 (36.8)           204 (38.9)                246 (38.5)
 Primary diagnosis system (n [%])                                                                                           .007
  Cardiovascular                                     33 (28.9)           128 (24.2)                161 (25.2)               .31
  Gastrointestinal                                    9 (7.9)             44 (8.4)                  53 (8.3)                .87
  Neurologic                                          7 (6.1)             80 (15.2)                 87 (13.6)               .01
  Renal                                               1 (0.9)              3 (0.6)                   4 (0.6)                .68
  Respiratory                                        25 (21.9)            75 (14.3)                100 (15.6)               .71
  Sepsis                                              8 (7.0)             11 (2.1)                  19 (3.0)                .04
  Trauma                                             24 (21.1)           146 (27.8)                170 (26.6)               .005
  Other condition                                     7 (6.1)             38 (7.2)                  45 (7.0)                .14
 No. of comorbidities                                                                                                       .04
  0                                                  24 (21.1)           174 (33.1)                198 (31.0)
  1                                                  28 (24.6)           136 (25.9)                164 (25.7)
  2                                                  28 (24.6)            95 (18.1)                123 (19.2)
  3                                                  34 (29.8)           120 (22.9)                154 (24.1)
 APACHE II                                           20.4 ± 6.4           19.8 ± 6.2                19.9 ± 6.3              .37
 PaO2/Fio2                                          201.1 ± 77.0         221.4 ± 84.5              217.6 ± 83.5             .02
 Day 1 MODS                                           6.0 ± 2.7            5.5 ± 3.0                 5.6 ± 2.9              .11
 Days on MV                                           7.7 ± 4.5            7.5 ± 5.6                 7.5 ± 5.4              .82
 Days in ICU                                          8.0 ± 4.3            7.6 ± 5.6                 7.6 ± 5.3              .37
 CXR at enrollment (n [%])                                                                                                  .001
  New infiltrate                                      20 (17.5)          172 (32.8)                192 (30.0)
  Worsening or                                        94 (82.5)          353 (67.2)                447 (70.0)
 On antibiotics at randomization (n [%])                                                                                  b.001
  Not on an any within 3 d                            21 (18.4)          227 (43.2)                248 (38.8)
  Yes but none started                                53 (46.5)          155 (29.5)                208 (32.6)
   within 3 d
  New antibiotics started                             40 (35.1)          143 (27.2)                183 (28.6)
   within 3 d
 On antifungal agents                                  8 (7.0)            14 (2.7)                  22 (3.4)                .02
 On vasopressors                                      32 (28.1)          112 (21.3)                144 (22.5)               .12
 MODS indicates multiple organ dysfunction score.
Significance of Candida colonization of respiratory tract secretions                                                                     15

                                                                              secretion Candida colonization: female sex (odds ratio
 Table 2 Mortality outcomes of patients with and without
                                                                              [OR], 1.65; 95% confidence interval [CI], 1.02-2.65; P =
 Candida colonization of respiratory tract secretions
                                                                              .04), number of comorbidities (OR, 1.35; 95% CI, 1.08-
                Colonized Noncolonized RR (95% CI)               P            1.71; P = .01), worsening or persistent infiltrate at
                n = 114        n = 525         (Colonized/                    randomization (OR, 1.92; 95% CI, 1.09-1.38; P = .02),
                                               noncolonized)                  antibiotics started within 3 days of randomization (OR,
 28-d        27 (23.7)          86 (16.4)      1.45 (0.99-2.12) .08           3.16; 95% CI, 1.71-5.83; P = .02), and on antibiotics at
   mortality                                                                  randomization but all started more than 3 days before
 ICU         24 (21.1)          73 (13.9)      1.51 (1.00-2.29) .06           randomization (OR, 3.04; 95% CI, 1.68-5.50; P = .02).
   mortality                                                                  Candida colonization of respiratory tract secretions was
 Hospital    39 (34.2)         110 (21.0)      1.63 (1.20-2.21) .003          less common in patients admitted for neurologic reasons
   mortality                                                                  (OR, 0.35; 95% CI, 0.14-0.87; P = .02).
 RR indicates relative risk.                                                      We present mortality data in Table 2, whereas results for
                                                                              other clinical outcomes are outlined in Table 3. A
                                                                              significant increase in hospital mortality (34.2% vs 21.0%
Candida albicans was accounted for in 65.3% of                                P = .003) was observed in the colonized group. Hospital
samples. Torulopsis glabrata was isolated in 1.3% of                          stay was also significantly longer (59.9 vs 38.6 days, P =
samples, whereas other non-albicans sp were found in                          .006) in this group. All other outcomes tended to be worse
6.7% of airway specimen. One specimen (0.7%) was iden-                        in the colonized group but were not significantly different
tified to have non–Candida albicans yeast species, and                        between groups. Candidemia subsequently developed in 1
finally, 26% of samples grew yeast not further speciated                      and 4 patients from the colonized and noncolonized groups,
by the local laboratory. All non–albicans sp were isolated                    respectively. Of note, 34 patients (29.8%) in the colonized
in colonized patients who were on antifungals at time                         group and 72 (13.7%) in the noncolonized group received
of randomization.                                                             antifungals at some point during the course of the VAP trial
    Patients with and without isolated Candida colonization                   (P b .001). Fluconazole was the most commonly used
of respiratory tract secretions at randomization are                          agent. Mortality in colonized patients who received
compared in Table 1. Male patients were more frequently                       antifungals was not significantly different from patients
found in the noncolonized group (71.8% vs 62.3%, P =                          who did not receive such treatment (38.2% vs 32.5%, P =
.04). Patients in the colonized group were more frequently                    .67). In addition, no significant difference in mortality was
admitted for sepsis (7.0% vs 2.1%, P = .005) and                              found in patients excluded from the study because of
respiratory conditions (21.9% vs 14.3%, P = .04) but                          multiple sites Candida colonization compared with patients
less often for neurologic conditions (6.1% vs 15.2%, P =                      with respiratory tract Candida colonization only (41.9% vs
.01). A significantly lower PaO2/FiO2 ratio was observed in                   34.2%, P = .33).
the colonized group (201.1 vs 221.4, P = .02). More                               Logistic regression showed a significant association
patients in the colonized group had worsening or persistent                   between Candida colonization of respiratory tract secretions
infiltrate as opposed to a new infiltrate at the time that                    and hospital mortality (OR, 2.38; 95% CI, 1.38-4.11). Other
VAP was suspected. They were also more frequently on                          factors significantly independently associated with increased
antibiotics (81.6% vs 56.7%, P b .001) and antifungal                         hospital mortality were older age (OR, 1.06; 95% CI, 1.04-
agents (7.0% vs 2.7%, P = .02) at randomization. Those                        1.08), increased number of comorbidities (OR, 1.38; 95% CI,
with colonization had greater number of comorbid                              1.11 -1.70), and admission for neurologic disorders (OR,
conditions (P = .04). Bacterial VAP was documented                            2.48; 95% CI, 1.28-4.78).
through BAL or ETA culture results in 72 (63.2%)                                  Although patients with pseudomonal colonization or
colonized patients compared to 417 (79.4%) patients in                        infection at randomization were excluded from the VAP
the noncolonized group (P b .001).                                            trial, 1.8% (n = 2) of patients in the colonized group and
    A multivariate analysis identified the following variables                1.3% (n = 7) of patients in the noncolonized group developed
as carrying a significantly higher risk of respiratory tract                  subsequent pseudomonal superinfection (P = .67).

 Table 3     Clinical outcomes of patients with and without Candida colonization of respiratory tract secretions
                                            Colonized                                   Noncolonized                                 P
                                            n (%)              Median (IQR)             n (%)              Median (IQR)
 Time on ventilator (d)                     91 (79.8)          10.9 (3.9, 32.7)         447 (85.1)          8.1 (3.8, 18.1)          .06
 ICU length of stay (d)                     88 (77.2)          14.1 (6.2, 43.2]         439 (83.6)         11.6 (6.1, 25.2)          .07
 Hospital length of stay (d)                73 (64.0)          59.9 (24.2, –)           407 (77.5)         38.6 (21.0, 111.0)        .006
 IQR indicates interquartile range.
16                                                                                                            M.-S. Delisle et al.

4. Discussion                                                       possibly numerous contributing factors. However, when
                                                                    multivariate logistic regression was performed, only Can-
   We conducted a retrospective analysis of data from a large       dida colonization of respiratory tract secretions, number of
randomized trial of diagnostic strategies and empiric               comorbidities, and admission for neurologic reasons were
antibiotics in patients with a clinical suspicion of VAP to         found to be associated with increased hospital mortality.
assess whether isolated Candida colonization of respiratory             A multivariate analysis suggests that patients who develop
tract secretions impacts on patient outcomes. Our main              Candida colonization of respiratory tract secretions are
finding is that isolated Candida colonization of respiratory        generally sicker and have recently received antibiotics than
tract secretions is associated with a longer hospital length of     those who do not. Further prospective trials are required to
stay and increased hospital mortality.                              confirm which patient characteristics are risk factors for
   Previous studies have suggested that Candida coloniza-           respiratory tract secretions Candida colonization and whether
tion without Candida infection or candidemia is associated          such colonization is independently associated with worse
with worse clinical outcomes in nonsurgical populations.            clinical outcomes. The question also remains as to whether
Olaechea et al demonstrated that critically ill patients with       isolated Candida colonization of respiratory tract secretions
Candida colonization, defined as the presence of Candida            carries a different burden of illness than multiple-site Can-
sp in nonsignificant samples obtained from the urine,               dida colonization. In our study, mortality between these 2
stomach, oropharynx, or tracheal aspirates, experienced a           groups of patients did not differ significantly, but this would
prolonged ICU stay by 6.2 days (OR, 1.69; 95% CI, 1.53-             need to be further explored in future trials, along with
1.87, P b.001) and an extended hospital stay by 8.6 days (OR,       comparison of other outcomes such as length of ICU or
1.27; 95% CI, 1.16-1.40, P b .001), resulting in increased          hospital stay, length of MV, or incidence of subsequent
health care costs [10]. This interesting finding left unan-         pseudomonal VAP.
swered the question of whether Candida colonization at a                The issue as to whether respiratory tract secretions Can-
specific site was significantly associated with worse clinical      dida colonization is associated with or responsible for an
outcomes. Recently, Azoulay et al [21] have observed that           increased burden of illness remains unclear. The retro-
patients with Candida airway colonization, defined as               spective design of our analysis does not provide an answer.
recovery of Candida from the respiratory tract, had a               However, the fact that few patients in either study group
significantly longer period of MV (13 vs 6 days, P b .0001),        developed candidemia possibly indicates that it may not be a
ICU stay (17 vs 9 days, P b.0001), and hospital stay (36 vs 22      major cause of death in this population. The published
days, P b .0001) as compared to patients not colonized with         literature suggests that isolation of Candida from the
Candida from the respiratory tract. However, they found no          respiratory tract correlates poorly with candidiasis [18,19].
difference in ICU or hospital mortality. Our results show a         This further raises the question as to whether initiating
trend for longer duration of MV and length of ICU stay, as          antifungal treatment would be beneficial, which can only be
well as for increased ICU and 28-day mortality. Though not          addressed with rigorous randomized trials.
significant, these results are in keeping with those obtained by        An association between Pseudomonas and the presence
Azoulay et al. Furthermore, 39.7% of patients with Candida          of Candida sp has been suggested previous trials [21,25]. In
airway colonization in that study had extrapulmonary                our study, a comparable proportion of patients in each group
colonization, raising the issue of different findings depending     developed subsequent pseudomonal pneumonia superinfec-
on patient populations. To our knowledge, no previous study         tion. The fact that patients with pseudomonal colonization
has demonstrated a relationship between respiratory tract           and infection were excluded from the VAP trial by design
Candida colonization and increased mortality.                       and the small number of patients prevents firm conclusions
   Admission characteristics other than respiratory tract           to be drawn on the matter.
secretion colonization by Candida also identify patients with           The strengths of our study include the large number of
a worse outcome. Colonized patients were more often admitted        patients enrolled, the prospective data collection in a
with pulmonary conditions, were more often on antibiotics,          multicenter, randomized controlled setting, and airway
tended to have more comorbid diseases, have a lower PaO2/           specimen collection done by protocol. We collected data on
FiO2 ratio, and were more often identified as having a persistent   both invasive and noninvasive techniques to obtain micro-
or worsening infiltrate. These conditions suggest that              biological specimens on mechanically ventilated patients.
colonized patients were sicker upon admission to ICU, yet               There are several limitations to this analysis including the
APACHE II score calculated at that time was similar between         assumption that isolation of Candida from respiratory tract
groups. This is similar to findings by Azoulay et al, which         culture specimens indicates colonization and not infection.
observed that patients colonized in the respiratory tract have      However, this is in concordance with similar studies [10,21].
been more often admitted for acute respiratory failure, were        As a normal colonizer of the gastrointestinal tract and oral
more infected at admission, yet were less often admitted for        cavity, Candida spreads along the respiratory tract after
coma and less often directly admitted to ICU. These common          intubation or aspiration of gastric content [12,21]. It is then
findings suggest that patients with Candida colonization of         usually observed in small number in respiratory tract
respiratory tract secretions are at risk of worse outcome with      quantitative cultures without clinical evidence of pneumonia
Significance of Candida colonization of respiratory tract secretions                                                                                      17

[12,21]. It was not possible in this study to examine the risk of              [4] Rangel-Frausto MS, Wiblin T, Blumberg HM, Saiman L, Patterson J,
aspiration pneumonia or other respiratory conditions asso-                         Rinaldi M, et al. National epidemiology of mycoses survey (NEMIS):
                                                                                   variations in rate of bloodstream infections due to Candida sp. in
ciated with Candida colonization of the respiratory tract                          seven surgical intensive care units and six neonatal intensive care units.
because these were not documented in the VAP trial. Candidal                       Clin Infect Dis 1999;29:253-8.
invasion of the lung parenchyma after hematogenous                             [5] Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP. Hospital-
dissemination would be frequently associated with real                             acquired candidemia: the attributable mortality and excess length of
                                                                                   stay. Arch Intern Med 1988;148:2642-5.
clinical pneumonia but unlikely to have happened in the
                                                                               [6] Wenzel RP. Nosocomial candidemia: risk factors and attributable
course of our trial as only 5 patients developed documented                        mortality. Clin Infect Dis 1995;20:1531-4.
candidemia [12,18,19,21]. Clinical suspicion of VAP was                        [7] Rentz AM, Halpern MT, Bowden R. The impact of candidemia on
generally attributed to bacterial causative agents. We did not                     length of hospital stay, outcome and overall cost of illness. Clin Infect
routinely perform surveillance cultures of all other sites to be                   Dis 1998;27:781-8.
sure that patients were truly only colonized in the respiratory                [8] Charles PE, Doise JM, Quenot JP, Aube H, Dalle F, Chavanet P, et al.
                                                                                   Candidemia in critically ill patients : difference of outcome between
tract. This study was done in the context of a clinical                            medical and surgical patients. Intern Care Med 2003;29:2162-9.
suspicion of VAP and does not generalize to patients without                   [9] Pittet D, Monod MM, Suter PM, Frenk E, Auckenthaler R. Candida
such a suspicion. Moreover, a proportion of patients in each                       colonization and subsequent infections in critically ill surgical patients.
group received antifungal treatment. The decision to initiate                      Ann Surg 1994;220(6):751-8.
or stop treatment was at clinicians' discretion and could be                  [10] Olaechea PM, Palomar M, Léon-Gil C, Álvarez-Lerma F, Jordá R,
                                                                                   Nolla-Salas J, et al. Economic impact of Candida colonization and
done at any time during the 28-day study period. Therefore,                        Candida infection in the critically ill patient. Eur J Clin Microbiol
the impact of antifungal treatment on patient outcomes and on                      Infect Dis 2004;23:323-30.
our results could not be adequately measured within this                      [11] Charles PE, Dalle F, Aube H, Doise JM, Quenot JP, Aho LS. Candida
study, or controlled for as a confounding variable.                                spp. colonization significance in critically ill medical patients: a
                                                                                   prospective study. Intensive Care Med 2005;31:393-400.
                                                                              [12] Azoulay E, Cohen Y, Zahar JR, Garrouste-Orgeas M, Adrie C, Moine
5. Conclusion                                                                      P, et al. Practices in non neutropenic ICU patients with Candida-
                                                                                   positive airway specimens. Intensive Care Med 2004;30:1384-9.
   Our study demonstrates an association between isolated                     [13] Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP. Risk factors
                                                                                   for hospital-acquired candidemia. A matched case-control study. Arch
Candida colonization of respiratory tract secretions and
                                                                                   Intern Med 1989;149:2349-53.
increased hospital mortality and hospital length of stay.                     [14] Fraser VJ, Jones M, Dunkel J, Storfer S, Medoff G, Dunagan WC.
Whether Candida colonization of respiratory tract secretions                       Candidemia in a tertiary care hospital: epidemiology, risk factors and
is a marker of disease severity or contributes directly to                         predictors of mortality. Clin Infect Dis 1992;15:414-21.
mortality and prolonged hospital stay requires further                        [15] Jarvis WR. Epidemiology of nosocomial fungal infections, with
                                                                                   emphasis on Candida species. Clin Infect Dis 1995;20:1526-30.
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                                                                                   of Candida sp isolates from bronchoscopic samples in nonneutropenic
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centers, and research coordinators of the Canadian Critical                   [20] Wood C, Mueller EW, Croce MA, et al. Candida sp. isolated from
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article [22].                                                                      patients. Intensive Care Med 2006;32(4):599-603.
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