Candida Colonization Index in the Management of Critically Ill Patients
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Candida Colonization Index in the Management of Critically Ill Patients P. Eggimann and D. Pittet z Introduction Invasive candidiasis, which includes candidemia and severe Candida infections, re- mains a dreadful complication in hospitalized patients with a prognosis comparable to septic shock [1±3]. With incidences around 5 to 10 per 1000 intensive care unit (ICU) admissions, invasive candidiasis represents 5 to 10% of all nosocomial infec- tions [4]. Difficult to diagnose, except for candidemia, which manifests only late in the course of the disease, early pre-emptive or empirical antifungal treatment has been shown to improve prognosis [5]. The high proportion of bone marrow transplant recipients developing invasive candidiasis has stimulated extensive clinical research, which has established the value of systematic prophylaxis with triazole compounds and early empirical or pre-emp- tive antifungal therapy for persisting fever of unknown origin. These aggressive strat- egies have progressively been imposed as a standard of care in severely neutropenic patients [6], as well as in solid organ transplant recipients [5]. However, they have been repeatedly implicated in the epidemiological shift, from Candida albicans to in- creasing proportions of non-albicans Candida in many cancer centers [7, 8]. This has generated considerable debate, and guidelines have been modified accordingly [9]. The situation is, fortunately, not the case in immunocompetent patients, in whom international surveillance programs have shown that Candida albicans re- mains the predominant strain in most countries [10]. More specifically, this is also the case in all recent series on candidiasis in ICU patients [11±16]. Many ICU pa- tients present risk factors for invasive candidiasis, and a large proportion of them become colonized with Candida species during their stay, but only a minority will develop an invasive candidiasis [11, 12, 15, 17±19]. However, it is difficulty to iden- tify subgroups of patients likely to benefit from prophylaxis and a majority of clini- cians systematically treat all colonized patients [20, 21]. With the experience ac- quired from immunocompromised patients, such practice may have a strong nega- tive impact on the ecology of Candida species by selecting resistant strains, and it should be avoided [22]. The majority of risk factors for invasive candidiasis are directly linked to an un- derlying disease or to its treatments and it is not possible to target them for pre- vention [4]. However, a progressive increase in colonization almost invariably pre- dicts the development of invasive candidiasis [11±13, 18, 23±26]. This dynamic may be taken into account by determination of the colonization index, and we proposed to integrate this index in a clinical pathway to help in the early identification of cri- tically ill patients likely to benefit from early empirical antifungal treatment [27]. This chapter reviews the rationale for using the colonization index.
Candida Colonization Index in the Management of Critically Ill Patients 605
z Pathophysiology of Invasive Candidiasis
Candida species are part of the endogenous flora and may be found in the diges-
tive tract of nearly half the population. Colonization, which is a prerequisite for the
development of candidiasis, develops following alterations of the endogenous flora
promoting Candida overgrowth on mucosal and skin surfaces [18]. Repetitive and/
or continuous exposure to risk factors promotes further invasion (Fig. 1). Care-
fully-designed studies using genotyping techniques for the identification of strains
of Candida confirmed that colonization from an endogenous source is responsible
for a large majority of cases of severe candidiasis [28]. Nosocomial exogenous
cross-transmission of Candida species has also been described, but infection con-
trol measures should control this source [29].
Many risk factors predicting the development of a candidiasis have been identi-
fied over the last three decades (Table 1) [18, 25, 30, 31]. Colonization by Candida
species independently predicts candidiasis [17, 18, 24, 32, 33]. Sequential spread
from the abdominal cavity to other body sites before candidemia occurs was dem-
onstrated early in the 1980s, and heavy and/or increasing growth of Candida spe-
cies in fluids obtained from the peritoneal cavity is predictive of subsequent inva-
sive candidiasis [11, 14, 17, 32, 34].
In critically ill patients, it may, however, be difficult to differentiate colonization
from invasive candidiasis. At ICU entry, only 5 to 15% of patients are colonized by
Candida species, but this proportion may increase up to 50 to 80% with time and
exposure to risk factors [11, 14, 33, 34]. However, only 5 to 30% of these patients
will develop true invasive candidiasis [11±13]. Thus, the clinical significance of sur-
veillance cultures positive for Candida species is difficult to assess.
Fig. 1. Pathophysiology of invasive candidiasis. From [4] with permission606 P. Eggimann and D. Pittet
Table 1. Risk factors predisposing to the development of severe candidiasis
High risk factors Non-specific risk factors
z Colonization of several body sites z Young and old ages
z Broad-spectrum antibiotics z Diabetes
z Immunosuppression z Renal failure
z Neutropenia z Recent surgery
z Burns (> 50%) z Urinary catheter
z Perforation of the digestive tract z Vascular access
z Major abdominal surgery z Prolonged ICU stay (> 7 days)
z Surgery on the urinary tract (if candiduria) z Multiple transfusion
z Major trauma (ISS > 20)
z Parenteral nutrition
z Hemodialysis
z APACHE Score II > 20
z Central venous catheter
z Candiduria > 105 cfu/ml
z Diagnosis of Candidiasis in Critically Ill Patients
Except for candidemia, invasive candidiasis is difficult to diagnose. Clinical signs
are identical to those of any other nosocomial infection, and more specific manifes-
tations, such as retinal emboli or hepato-splenic involvement are rare [35]. Cultures
other than blood, or from normally sterile body sites, are nonspecific and may be-
come positive only late in the course of infection. In contrast to Aspergillus species,
and despite recent advances in experience with mannan antigens and anti-mannan
antibodies, biological tools have not helped with the diagnosis of candidiasis [36].
In addition, using clinical and microbiological criteria currently available, the
threshold between colonization and infection may be difficult to distinguish [4]. In
contrast, this is not the case for colonization by Candida species. As assessed by
the colonization index proposed by Pittet et al. in 1994 and recently confirmed by
others, increasing growth of Candida species from multiple body sites is predictive
of subsequent invasive candidiasis [12±15, 18, 37]. By restricting this evaluation of
the dynamics of colonization to the subset of critically ill patients with persistence
of other risk factor for invasive candidiasis, this approach may help to select criti-
cally ill patients likely to benefit from early empirical antifungal treatment. This
may also avoid overexposure of ICU patients to antifungal agents [27].
z Colonization Index in Critically Ill Patients
Some experts have suggested that in cases of clinical suspicion of candidiasis, the
presence of Candida species in more than two body sites may be sufficient to justi-
fy the initiation of antifungal therapy [32, 38]. In a prospective cohort study of cri-
tically-ill, surgical patients, Pittet et al. showed that the dynamics of Candida colo-
nization are better evaluated by a colonization index [18]. This index was deter-Candida Colonization Index in the Management of Critically Ill Patients 607
Fig. 2. The colonization index is defined as the ratio of the number of non-blood distinct body sites colo-
nized by Candida species to the total number of distinct body sites tested. It was recorded for each pa-
tient from the first day of colonization until discharge from the ICU among non-infected patients and un-
til time of severe candidiasis among infected patients. Black circles: patients who developed severe candi-
diasis. White circles: patients who remained colonized. From [18] with permission
mined daily as the ratio of the number of distinct body sites colonized with geno-
typically identical strains of Candida species over the total number of sites tested
(Fig. 2) [39]. Twenty-nine of 650 patients admitted in the surgical ICU were colo-
nized at several distinct body sites. Eleven of 29 patients developed severe Candida
infection, including candidemia in eight. The other 18 patients remained colonized
but did not develop candidiasis. The severity of illness and the degree of coloniza-
tion independently predicted the development of invasive candidiasis among colo-
nized patients. The average Candida colonization index was 0.47 in colonized vs.
0.70 in infected patients, respectively (p < 0.01). A threshold of ³ 0.5 correctly iden-
tified all infected patients, and this value was reached at an average of 6 days before
documented candidiasis. This delay may open the door for early empirical antifun-
gal treatment.
The predictive value of this index has never been tested in a large prospective
clinical trial, but at least seven studies suggest that it may be clinically useful. Du-
bau et al. determined the colonization index in 89 of 669 consecutive patients stay-
ing for more than 7 days in a surgical ICU, or in whom the protein C level was
greater than 100 mg/ml [37]. Of the 35 patients with an index above 0.5 empirically
treated with antifungals, only one developed candidiasis and the degree of coloniza-
tion rapidly decreased in the 34 other patients. In a survey on candiduria per-
formed in French ICUs, Chabasse found a correlation between quantitative cultures
above 104 cfu/ml and a colonization index ³ 0.5 [40]. Garbino et al. prospectively
determined the colonization index in all patients included in a double-blind, place-
bo-controlled study on antifungal prophylaxis in critically ill patients mechanically
ventilated for at least 5 days [13]. Candida colonization developed in 53% (29/55)
of patients free of colonization at study entry in the fluconazole group compared to
78% (40/51) of patients in the placebo group. Colonization increased over time in
the latter group but decreased in the former. Candida infection occurred less fre-
quently in patients in the fluconazole group and 90% of candidemias developed in
patients in the placebo group. Moreover, candidemia developed only in patients
heavily colonized with Candida species. In a ten-year retrospective cohort study on
51 cases of candidemia in the ICU, Charles et al. reported a prior high-density of
colonization by Candida species with a colonization index ³ 0.5 in 21 (45.6%) of608 P. Eggimann and D. Pittet
the 46 assessed patients (0.56 Ô 0.31). At the onset of candidemia, the colonization
index was significantly higher in medical patients compared to surgical patients,
(0.74 Ô 0.31 versus 0.45 Ô 0.40, p = 0.01) [41]. In a further prospective study on 92
non-neutropenic patients consecutively admitted on a medical ICU for more than 7
days, the same group evaluated the dynamics of colonization by performing the
colonization index weekly [42]. The colonization index increased significantly by
0.10 over the ICU stay (p = 0.016) and the threshold of 0.5 was reached in 36 pa-
tients (39.1%). Invasive candidiasis developed in six patients, in whom the coloni-
zation index was ³ 0.5, compared to three in whom it was < 0.5 (p value non signif-
icant). However, significantly more patients with a colonization index ³ 0.5 received
antifungal therapy for more than 2 days: 14/36 (61.1%) versus 7/56 (12.5%), respec-
tively. Hematological malignancy, duration of exposure to broad-spectrum antibiot-
ics, fungal colonization at entry and candiduria predicted an increase in the coloni-
zation index. In contrast, the duration of exposure to antifungals was significantly
associated with a decrease in the index. In a before/after trial, Piarroux et al. pro-
spectively screened 478 surgical ICU patients for Candida species colonization.
These patients received preemptive antifungal treatment if the corrected coloniza-
tion index was > 0.4 [15]. Compared to a historical cohort of 455 controls, invasive
candidiasis decreased from 7.0 to 3.6%, respectively. Moreover, this strategy com-
pletely prevented the development of ICU-acquired invasive candidiasis. Finally, in
an open-label study, 98 patients mechanically ventilated for more than 48 hours
were randomized by Normand et al. to receive prophylaxis with oral nystatin or a
placebo. No invasive candidiasis developed in these low-risk patients, but prophy-
laxis significantly reduced the colonization index and prevented colonization [43].
z Pre-emptive Empirical Antifungal Treatment in Critically Ill Patients
Pre-emptive therapy is early antifungal treatment given to patients with risk factors
for infection and significant Candida species colonization. However, overexposure
of critically ill patients to antifungals may promote the emergence of resistant
strains and empirical treatment must be strictly limited to patients likely to benefit
from it [7, 8]. As discussed in the previous section, periodic determination of the
colonization index is currently the best way to adequately select these patients [22].
z Management Strategy for Immunocompetent Patients
A large proportion of critically ill patients have several risk factors for Candida in-
fection. A high proportion of such patients may become colonized with Candida
species during their hospital stay, but only a minority will develop severe candidia-
sis.
Review of the indications for antifungal prophylaxis is beyond the scope of this
paper. The reader can find extensive reviews elsewhere [27, 44, 45]. In brief, despite
a series of at least 11 clinical studies suggesting a benefit of antifungal prophylaxis
in critically ill immunocompetent patients, none of them reached sufficient power
and this approach is considered as insufficiently validated. Accordingly, antifungal
prophylaxis is not included in most published guidelines [5, 38, 46]. However, anti-
fungal prophylaxis should nevertheless be considered for selected groups of patientsCandida Colonization Index in the Management of Critically Ill Patients 609
Fig. 3. Candida colonization index in the management of clinical suspicion of candidia-
sis. Adapted from [27] with permission
in whom the incidence of candidemia is sufficiently high to be beneficial [11±13,
47±50]. In any case, prospective surveillance of the proportion of strains of non-al-
bicans Candida should be organized.
Apart from a positive fundoscopic examination, which is relatively infrequent
during candidemia, the clinical manifestations of invasive candidiasis are non-spe-
cific, and, the diagnosis is made only late in the course of the disease [7]. Never-
theless, pre-emptive antifungal therapy should be restricted to unstable critically ill
patients with well-established risk factors, such as those with a septic shock of in-
tra-abdominal origin [49]. For patients in whom the immediate start of antifungal
treatment is not justified by their severe clinical condition, considering the dy-
namics of colonization using the colonization index will allow early detection of
those patients who might also benefit from pre-emptive antifungal treatment.
Although not tested in prospective multicenter trials, we propose a strategy for the
clinical diagnosis and practical management of critically ill patients suspected, or
at risk, of severe candidiasis, which distinguishes prophylactic from pre-emptive
therapy (Fig. 3) [27].
z Conclusion
In conclusion, invasive candidiasis is a severe complication with mortality rates
comparable to those of septic shock (40% to 60%), and represents 5 to 10% of all
nosocomial infections. Many ICU patients cumulate risk factors for invasive candi-
diasis, and a large proportion become colonized with Candida species, although
only a minority will develop invasive candidiasis [11, 12, 15, 18, 19]. However, it is
difficulty to identify subgroups of patients likely to benefit from preemptive treat-610 P. Eggimann and D. Pittet
ment and a majority of clinicians will systematically treat all colonized patients
[21]. Following lessons leaned in immunocompromised patients, such practice
should be avoided. As biological tools are currently unavailable at the bedside, em-
pirical treatment relies on clinical strategies aimed at identifying the subgroup of
patients likely to benefit from it. A progressive increase in Candida colonization
predicts the development of an invasive infection and the colonization index takes
these dynamics into account. Starting empirical antifungals only when the coloniza-
tion index reaches a threshold value that predicts subsequent candidiasis will avoid
overexposure of critically ill patients to antifungal drugs.
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