**3. Distribution of Candida blodostream infections**

During the 12-month study period a total of 984 Candida BSIs were reported. The calculated overall incidence was 1.09 cases per 1,000 admissions, however the incidence rate changed a lot between the 40 centers enrolled in this study and ranged from 0.76 to 1.49 cases per 1,000 admissions.

Epidemiology of Bloodstream *Candida* spp. Infections

Median no. of days (range) until

No. of cases of underlying diseases

Chronic Obstructive Pulmonary disease

No. of patients with characteristic Previous or actual corticosteroid

Immunosuppressive therapy and/or

June 2009.

Variable Value for all total

No. of males 577 (58.64) <sup>273</sup>

candidemia 20 (0–385) 20 (0–

Cancer 311 (31.61) <sup>127</sup>

neutropenia 265 (26.93) <sup>102</sup>

In the ICU at diagnosis 252 (25.61) <sup>120</sup>

Mechanical ventilation 265 (26.93) <sup>133</sup>

Previous surgery 311 (31.61) <sup>148</sup>

Central venous catheter 659 (66.79) <sup>295</sup>

Urinary catheter 450 (45.73) <sup>207</sup>

Prior antibiotic therapy 747 (75.91) <sup>337</sup>

Overall mortality 237 (24.10) <sup>108</sup>

Observed During a Surveillance Study Conducted in Spain 19

Value for species

(56.52) 182 (89.21) 51 (48.11) <sup>62</sup>

114) 19 (0–385) 19 (0–47) 19 (0–

(26.29) 86 (42.16) 34 (32.07) <sup>26</sup>

(21.12) 75 (36.76) 28 (26.41) <sup>28</sup>

(24.84) 68 (33.33) 21 (19.81) <sup>25</sup>

(27.54) 71 (34.80) 15 (14.15) <sup>26</sup>

(30.64) 82 (40.20) 19 (17.92) <sup>36</sup>

(61.07) 187 (91.66) 52 (49.06) <sup>61</sup>

(42.86) 112 (54.90) 31 (29.25) <sup>52</sup>

(69.77) 106 (51.96) 60 (56.60) <sup>71</sup>

(22.36) 56 (27.45) 20 (18.87) <sup>29</sup>

*C. tropicalis*

*C. glabrata*

(46.27)

115)

(19.40)

(14.93)

(15.67)

(20.90)

(18.66)

(19.40)

(26.87)

(45.52)

(38.81)

(52.98)

(11.19)

(10.45)

(21.64)

*C. parapsilosis*

*C. albicans*

cases

Average age (range) 41 (0–96) 46 (0–92) 48 (0–96) 33 (0–89) 52 (0–88)

No. of outpatients 7 (0.71) 3 (0.62) 1 (0.49) 3 (2.83) 0 (0.00)

Hematological malignancy 20 (2.03) 5 (1.04) 6 (2.94) 1 (0.94) 1 (0.75) Coronary artery disease 82 (8.33) 33 (6.83) 23 (11.27) 5 (4.72) 8 (5.97)

(COPD) 71 (7.21) 40 (8.28) 11 (5.39) 5 (4.72) 9 (6.71) Neurological disease 35 (3.55) 14 (2.80) 12 (5.88) 2 (1.89) 2 (1.49) Diabetes 120 (12.20) 53 (10.97) 22 (10.78) 8 (7.55) <sup>20</sup>

Organ transplantation 45 (4.57) 14 (2.90) 21 (10.29) 2 (1.89) 3 (2.23) HIV infection 33 (3.35) 18 (3.73) 3 (1.47) 3 (2.83) 3 (2.24) Parenteral drug abusers 22 (2.23) 10 (2.07) 4 (1.96) 2 (1.89) 1 (0.75)

therapy 180 (18.29) 80 (16.56) 50 (24.50) 13 (12.26) <sup>21</sup>

Hemodialysis at diagnosis 12 (1.22) 2 (0.41) 4 (1.96) 1 (0.94) 3 (2.24)

Prior fluconazole use 78 (7.93) 29 (6.00) 10 (4.90) 12 (11.32) 9 (6.71) Death attributed to candidemia 134 (13.62) 60 (12.42) 20 (9.80) 13 (12.26) <sup>15</sup>

Mortality due to other conditions 103 (10.47) 48 (9.94) 36 (17.65) 7 (6.60) <sup>14</sup>

Table 3. Demographics, clinical characteristics, and mortality for *Candida* spp. BSI episodes identified during prospective sentinel surveillance conducted in Spain from June 2008 to

Among the invasive Candida BSIs, 45.3 % occurred in patients in an medical service, 23.5% in patients hospitalized in an intensive care unit, 17.6% in patients in a surgical ward, 7.41% in a pediatric ward and finally 4.06% in other services. Most of the patients (98.7%) were hospitalized and only nine of them were outpatients at the time of diagnosis.

Candidemia incidence was slightly higher in males (64.02% of the case patients) and the global average age at the onset of the episode was 41 years with a median age was 53 years among adult patients and 7 months among children.

The frequency of BSIs due to the most frequently isolated species of *Candida* in the study sites are presented in Table 2.


a Species with less than 10 isolates are included in this category. This category includes *C. famata*, *C. lusitaniae*, *C. pelliculosa* and *Candida spp*.

Table 2. Species distribution and incidence among 984 cases of candidemia detected during prospective sentinel surveillance in Spain from June 2008 to June 2009

Overall, the 49.08% of the cases were attributable to *C. albicans*, 20.73% were attributable to *C. parapsilosis*, 13.61% were attributable to *C. glabrata*, 10.77% were attributable to *C. tropicalis*, 2,13% to *C. krusei* and the rest of the cases (3.65%) were attributable to other species. The distribution of Candida species among adult population was similar to the one found in pediatric cases, however, the distribution of species varied considerably when analyzed between centers as it has been reflected in the ranges specified in Table 2. The species distribution among our study isolates is similar to that described by Pfaller et al. (Pfaller et al., 1998) in Latin America with data collected by the Sentry Antimicrobial Surveillance Program. As Pfaller and colleagues described previously, the proportion of species isolated varies considerably among medical centers beign unclear the reasons for such differences and they could be attributed to many different influences.

Table 3 summarizes the overall clinical characteristics and outcome of the 984 candidemia cases identified.

At the time of candidemia diagnosis, neoplasia was documented for 195 (19.84%) patients, 35 of which (17.94%) were affected with hematologic malignancies Prior surgery was recorded from 311 (31.6%) patients (311 of a total of 984), being most of them abdominal surgeries (64% of total surgical patients). Two third of the patients (66.97%) had a central venous catheter and one quarter (26.93%) of them were under mechanical ventilation. Neutropenia and dialysis were rare conditions which was only documented in only 35 case patients (3.55%) and 12 patients (1.21%) respectively. Invasive *Candida* spp. infection complications such as endocarditis or endophalmitis were infrequent and with 17 cases documented for the former complication (2%) and 3 patients for the later.

#### Epidemiology of Bloodstream *Candida* spp. Infections Observed During a Surveillance Study Conducted in Spain 19

18 Epidemiology Insights

Among the invasive Candida BSIs, 45.3 % occurred in patients in an medical service, 23.5% in patients hospitalized in an intensive care unit, 17.6% in patients in a surgical ward, 7.41% in a pediatric ward and finally 4.06% in other services. Most of the patients (98.7%) were

Candidemia incidence was slightly higher in males (64.02% of the case patients) and the global average age at the onset of the episode was 41 years with a median age was 53 years

The frequency of BSIs due to the most frequently isolated species of *Candida* in the study

Species No. (%) of cases Range (in %) between clinical settings

a Species with less than 10 isolates are included in this category. This category includes *C. famata*, *C.* 

Table 2. Species distribution and incidence among 984 cases of candidemia detected during

Overall, the 49.08% of the cases were attributable to *C. albicans*, 20.73% were attributable to *C. parapsilosis*, 13.61% were attributable to *C. glabrata*, 10.77% were attributable to *C. tropicalis*, 2,13% to *C. krusei* and the rest of the cases (3.65%) were attributable to other species. The distribution of Candida species among adult population was similar to the one found in pediatric cases, however, the distribution of species varied considerably when analyzed between centers as it has been reflected in the ranges specified in Table 2. The species distribution among our study isolates is similar to that described by Pfaller et al. (Pfaller et al., 1998) in Latin America with data collected by the Sentry Antimicrobial Surveillance Program. As Pfaller and colleagues described previously, the proportion of species isolated varies considerably among medical centers beign unclear the reasons for

Table 3 summarizes the overall clinical characteristics and outcome of the 984 candidemia

At the time of candidemia diagnosis, neoplasia was documented for 195 (19.84%) patients, 35 of which (17.94%) were affected with hematologic malignancies Prior surgery was recorded from 311 (31.6%) patients (311 of a total of 984), being most of them abdominal surgeries (64% of total surgical patients). Two third of the patients (66.97%) had a central venous catheter and one quarter (26.93%) of them were under mechanical ventilation. Neutropenia and dialysis were rare conditions which was only documented in only 35 case patients (3.55%) and 12 patients (1.21%) respectively. Invasive *Candida* spp. infection complications such as endocarditis or endophalmitis were infrequent and with 17 cases

hospitalized and only nine of them were outpatients at the time of diagnosis.

*C. albicans* 483 (49.08%) 27 – 54 *C. parapsilosis* 204 (20.73%) 7 – 40 *C. glabrata* 134 (13.61%) 2 – 14 *C. tropicalis* 106 (10.77%) 16 – 29 *C. krusei* 21 (2.13%) 0 – 9 Other species a 36 (3.65 %) 0 – 4

prospective sentinel surveillance in Spain from June 2008 to June 2009

such differences and they could be attributed to many different influences.

documented for the former complication (2%) and 3 patients for the later.

among adult patients and 7 months among children.

sites are presented in Table 2.

*lusitaniae*, *C. pelliculosa* and *Candida spp*.

cases identified.


Table 3. Demographics, clinical characteristics, and mortality for *Candida* spp. BSI episodes identified during prospective sentinel surveillance conducted in Spain from June 2008 to June 2009.

Epidemiology of Bloodstream *Candida* spp. Infections

studies. (Messer et al., 2009, Pemán et al., 2011).

resistant to fluconazole.

vs. resistant or SDD ones

(Table 6).

0.06 µg/ml, respectively; *P* ≤ 0.05

using univariate statistical techniques.

Observed During a Surveillance Study Conducted in Spain 21

When we considered the *C. glabrata* isolates obtained during the study only the 81.33% of them were were susceptible to fluconazole and 97.76% were susceptible to voriconazole, but on the contrary, 97.93% and 98.96% of the isolates of *C. albicans* were susceptible to fluconazole and voriconazole respectively. The proportion of isolates that was resistant to the studied azole drugs was comparable with that observed in the other recently published

The antifungal activities of voriconazole, fluconazole, amphotericin B, caspofungin and anidulafungin against the 984 *Candida spp* isolated during the study period are summarized in Table 4. Among the azole compounds, voriconazole was the most active drug overall with an MIC90 of 0.25 µg/ml. Against *C. albicans*, *C. parapsilosis* and *C. tropicalis* isolates, voriconazole (MIC90 range 0.03-0.25 µg/ml) was much more active than fluconazole (MIC90, 2-4). Although these differences in the drug activity, both azole compounds showed lower MICs for fluconazole and voriconazole for the species mentioned before when compared to *C. glabrata* and *C. krusei* isolates. Despite this good susceptibility profile, we found five *Candida albicans* isolates with a MIC greater than 4 µg/ml to voriconazole and two *C. krusei* isolates that had a voriconazole MIC of 2 ug/ ml. All these isolates were also

We found that there was a statistically significant moderate linear correlation between fluconazole and voriconazole MICs (*r* = 0.574; *P* ≤ 0.01). having higher voriconazole MICs those isolates from patients who received fluconazole before the candidemia episode when compared to those without previous exposure to fluconazole (MIC90s of 0.25 µg/ml and

Table 5 summarize the risk factors we identified during the study with a candidemia episode due to an isolate with decreased susceptibility (SDD or resistant) to fluconazole

Neoplasia 27 (2.95) 6 (8.70) ≤ 0.01 Neutropenia 37 (4.04) 11(15.94) ≤ 0.01 Prior fluconazole use 27 (2.95) 10 (14.49) ≤ 0.01

Table 5. Summary of univariate statistical analysis between fluconazole susceptible isolates

We found that this condition was associated with neoplasia (9% versus 3%; *P* ≤ 0.01), current neutropenia (16% versus 4%; *P* ≤ 0.01), and prior fluconazole use (14% versus 3%; *P* ≤ 0.001). These independent factors identified using the univariate statistical approach, were analyzed more deeply using a repeated measures logistic regression model. We obtained significant results for neoplasia (odds ratio, 2.9; 95% confidence interval, 1.4 to 5.9; *P* ≤ 0.05) and prior use of fluconazole (odds ratio, 3.8; 95% confidence interval, 1.7 to 8.2; *P* ≤ 0.01).

No. of isolates (%) with decreased susceptibility or resistant to fluconazole

P - value

No of isolates (%) susceptible to fluconazole

a Only statistically significant variables are summarized in the table

There were no statistically significant differences when the risk mentioned above were analyzed for the pediatric population of patients.
