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Intensive Care Medicine

, Volume 40, Issue 10, pp 1489–1498 | Cite as

Prognostic factors and historical trends in the epidemiology of candidemia in critically ill patients: an analysis of five multicenter studies sequentially conducted over a 9-year period

  • Arnaldo L. Colombo
  • Thais Guimarães
  • Teresa Sukienik
  • Alessandro C. Pasqualotto
  • Ricardo Andreotti
  • Flavio Queiroz-Telles
  • Simone A. Nouér
  • Marcio Nucci
Open Access
Original

Abstract

Purpose

To describe temporal trends in the epidemiology, clinical management and outcome of candidemia in intensive care unit (ICU) patients.

Methods

This study was a retrospective analysis of 1,392 episodes of candidemia in 647 adult ICU patients from 22 Brazilian hospitals. The characteristics of candidemia in these ICU patients were compared in two periods (2003–2007, period 1; 2008–2012, period 2), and the predictors of 30-day mortality were assessed.

Results

The proportion of patients who developed candidemia while in the ICU increased from 44 % in period 1 to 50.9 % in period 2 (p = 0.01). Prior exposure to fluconazole before candidemia (22.3 vs. 11.6 %, p < 0.001) and fungemia due to Candida glabrata (13.1 vs. 7.8 %, p = 0.03) were more frequent in period 2, as was the proportion of patients receiving an echinocandin as primary therapy (18.0 vs. 5.9 %, p < 0.001). The 30-day mortality rate decreased from 76.4 % in period 1 to 60.8 % in period 2 (p < 0.001). Predictors of 30-day mortality by multivariate analysis were older age, period 1, treatment with corticosteroids and higher APACHE II score, while treatment with an echinocandin were associated with a higher probability of survival.

Conclusions

We found a clear change in the epidemiology and clinical management of candidemia in ICU patients over the 9-year period of the study. The use of echinocandins as primary therapy for candidemia appears to be associated with better outcomes.

Keywords

Candidemia Mortality Antifungal therapy Echinocandin Invasive candidiasis 

Introduction

Despite the best efforts of the medical community, the morbidity and mortality associated with candidemia remains elevated, with crude mortality rates of ≥40 % [1, 2, 3]. In addition, population-based studies conducted in the USA and Europe suggest that the incidence of candidemia has increased during the last decade [4, 5, 6]. Patients admitted to intensive care units (ICUs) are at high risk of developing candidemia, with recent multicenter studies reporting that 30–40 % of candidemic patients were in ICUs at the time of the diagnosis. Delays in initiating antifungal therapy may increase mortality rates in patients with candidemia [7, 8]. Consequently, serious attempts have been directed to validating predictive guidelines based on risk factors and/or the presence of fungal biomarkers in order to assist clinicians in their decision to provide early antifungal therapy to patients at high risk [9, 10, 11, 12].

In Latin America, overall mortality rates of patients with candidemia are usually higher than those observed in the Northern Hemisphere [13, 14, 15]. However, it should be noted that data on the epidemiology and prognostic factors associated with candidemia in patients admitted to ICUs in Latin America are scarce. Therefore, the main objective of this study was to evaluate historical trends in the epidemiology and clinical management of patients admitted to ICUs in tertiary care hospitals in Brazil, as well as to identify the prognostic factors of candidemia.

Patients and methods

Patient selection and data collection

This is a retrospective analysis of a collection of candidemia cases created by merging the databases of five prospective laboratory-based surveillance cohorts conducted in 22 tertiary care medical centers in Brazil between March 2003 and February 2012. Only tertiary care hospitals providing medical care in most medical specialties participated in these five studies, and they can be categorized as public hospitals (n = 13), which provide medical assistance to low-income patients, and private hospitals (n = 9), which are for-profit medical institutions that provide care mostly to patients covered by private insurance plans. These hospitals are representative of public and private reference medical centers located in 12 large cities in Brazil. In the first two cohorts, only patients from public hospitals were enrolled, while in the latter three cohort studies, the patients were from a mixture of public and private hospitals.

An investigator at each medical center was assigned the specific task of contacting the microbiology laboratory of the hospital on a weekly basis in order to collect clinical and epidemiological data of all incident cases of candidemia. This investigator was trained to record such data on a standard case report form using a dictionary of terms that included all definitions of underlying conditions and medical exposures collected during the study. The case report form, dictionary of terms and strategy for data collection were the same in all five surveillance studies. Patients were followed up to 30 days after the incident candidemia or death. A case of candidemia was defined as the incident isolation of Candida spp. from a blood culture. The date of the incident candidemia was defined as the date of the collection of the blood culture that became positive for Candida species. Candidemia occurring >30 days after the incident isolation was defined as a new case. Fever was defined as an axillary temperature of ≥37.8 °C and neutropenia as an absolute neutrophil count of <500/mm3. Cardiac and lung diseases were considered if the patient presented any cardiac or lung condition requiring active treatment. Such conditions included (but were not restricted to) congestive heart failure, coronary arterial disease, hypertension and cardiac arrhythmias (cardiac diseases), as well as chronic obstructive pulmonary disease, asthma, emphysema, bronchiectasis or chronic pneumonia or interstitial disease of any etiology (lung disease). Renal failure was defined as any documented serum creatinine value of >1.5 g/dL.

With the exception of invasive medical procedures and antibiotic use, we considered all these manifestations documented up to 30 days before the date of the incident candidemia as conditions associated with candidemia. Data on central venous catheters, dialysis and antibiotic use were captured up to 15 days before the onset of candidemia. Data on surgery requiring general anesthesia was captured up to 3 months before candidemia. All medical records were reviewed and monitored by a central data collection system for the analysis of completeness and consistency. In cases of uncompleted or inconsistent clinical forms, queries were generated and sent back to the investigators for corrections or completion.

Yeast identification

All Candida bloodstream isolates were sent to a central laboratory (Special Mycology Laboratory, Escola Paulista de Medicina, UNIFESP) for further species identification based on the micromorphologic characteristics of the colonies and biochemical tests (ID 32C system; BioMérieux, Marcy l’Etoile, France).

Data analysis

For this analysis we excluded patients aged <18 years. We compared candidemia occurring in ICU patients versus non-ICU patients in terms of baseline characteristics, clinical manifestations, species distribution, treatment and outcome. In addition, we arbitrarily defined two 5-year periods (2003–2007, period 1; 2008–2012, period 2) and compared the epidemiological characteristics of ICU patients admitted in these two periods. Additional analyses included comparison of the epidemiology of candidemia in ICU patients from public versus private institutions. Finally, prognostic factors for ICU patients with candidemia were identified by comparing patients who died versus those who survived for 30 days after the candidemia episode.

Categorical variables were analyzed using chi-square or Fisher’s exact tests, as appropriate, and continuous variables were compared using the Wilcoxon test. A p value of <0.05 was considered to be statistically significant. Variables significant at p < 0.1 by univariate analysis were included in a multivariate model (backward and forward). Statistical analyses were performed using SPSS version 15.0 (SPSS, Inc., Chicago, IL).

Results

A total of 1,392 episodes of candidemia were collected for analysis. The median age of the patient cohort was 62 (range 18–97) years, and 718 were males. C. albicans was the leading etiologic agent of candidemia (42 %), followed by C. tropicalis (20 %), C. parapsilosis (19 %) and C. glabrata (9 %). The 30-day crude mortality rate was 62.4 %.

In 647 episodes (46.5 %) the patient was in an ICU at the time candidemia was diagnosed. Comparison between these patients and those who were not in an ICU is shown in Table 1 where it can be seen that ICU patients were older (median of 66 vs. 58 years, p < 0.001) and more likely to present comorbidities such as renal failure and neurologic, cardiac or lung disease. Likewise, ICU patients were more likely to have been exposed to surgery, dialysis, mechanical ventilation, central venous catheterization and antibiotics. However, non-ICU patients with candidemia were more likely to have cancer (especially hematologic malignancies), organ transplantation and auto-immune diseases. Non-ICU patients were also more likely to have neutropenia and to have received anticancer chemotherapy and immunosuppressive drugs. The 30-day crude mortality rate was 70.3 % in ICU patients and 52.6 % in non-ICU patients (p < 0.001). In terms of species distribution, the only significant difference was a lower proportion of C. parapsilosis among ICU patients (17.2 vs. 21.7 %, p = 0.03). Of note, both the proportion of C. glabrata candidemia and prior exposure to azoles were similar among ICU and non-ICU patients.
Table 1

Characteristics of patients admitted to an intensive care unit (ICU) versus those of patients not in an ICU at the time of candidemia diagnosis

Variable

In the ICU (N = 647)

Outside the ICU (N = 745)

p

Gender (N, male:female)

328:319

390:355

0.54

Age (years)

66 (18–97)

58 (18–97)

<0.001

Time (days) from admission to candidemia diagnosis

20 (0–188)

20 (0–159)

0.83

Cancer

174 (26.9)

283 (38.0)

<0.001

  Hematologic

29 (4.5)

95 (12.8)

<0.001

  Solid tumor

145 (22.4)

188 (25.2)

0.22

Diabetes

154 (24.4)

170 (22.8)

0.48

Renal failure

262 (40.5)

217 (29.1)

<0.001

Chronic renal failure

81 (12.5)

113 (15.2)

0.15

Dialysis

183 (28.3)

118 (15.8)

<0.001

Liver disease

74 (11.4)

91 (12.2)

0.65

Auto-immune disease

28 (4.3)

52 (7.0)

0.03

Neurologic disease

160 (24.7)

141 (18.9)

0.009

Transplant

3 (0.5)

27 (3.6)

<0.001

Cardiac disease

227 (35.1)

163 (21.9)

<0.001

Lung disease

185 (28.6)

120 (16.1)

<0.001

Surgery

336 (51.9)

328 (44.0)

0.003

Abdominal surgery

194 (30.0)

189 (25.4)

0.05

Mechanical ventilation

480 (74.2)

120 (16.1)

<0.001

Total parenteral nutrition

140 (21.6)

157 (21.1)

0.80

Central venous catheter

605 (93.5)

591 (79.3)

<0.001

Neutropenia

16 (2.5)

51 (6.8)

<0.001

Prior drug/treatment exposure

  Antibiotics

622 (96.1)

653 (87.7)

<0.001

  Corticosteroids

338 (52.2)

223 (29.9)

<0.001

  Other immunosuppressive drugs

38 (5.9)

67 (9.0)

0.03

  Chemotherapy

22 (3.4)

76 (10.2)

<0.001

  Fluconazole prior to candidemia

102 (15.8)

108 (14.5)

0.51

Candida spp.

  C. albicans

285 (44.0)

300 (40.3)

0.15

  C. parapsilosis

111 (17.2)

162 (21.7)

0.03

  C. tropicalis

141 (21.8)

140 (18.8)

0.16

  C. glabrata

64 (9.9)

68 (9.1)

0.63

  C. krusei

16 (2.5)

21 (2.8)

0.69

  C. guilliermondii

12 (1.9)

22 (3.0)

0.19

Treatment received

482 (74.5)

577 (77.4)

0.20

  Fluconazole

295/482 (61.2)

395/577 (68.5)

0.01

  Deoxycholate AMB

106/482 (22.0)

106/577 (18.4)

0.14

  Lipid AMB

21/482 (4.4)

8/577 (1.4)

0.003

  Echinocandins

52/482 (10.8)

33/577 (5.7)

0.002

30-day crude mortality

450/640 (70.3)a

389/740 (52.6)b

<0.001

AMB, Amphotericin B

Data are presented as a number with the percentage given in parenthesis, or as the median with the range given in parenthesis, unless specified otherwise

aStatus on day 30 was not known in 7 patients

bStatus on day 30 was not known in 5 patients

The proportion of patients who developed candidemia while in the ICU increased from 44 % in period 1 to 50.9 % in period 2 (p = 0.01). Table 2 shows the comparisons of episodes in the two periods. As expected, the proportion of patients in private hospitals was higher in period 2, as was the proportion of patients with liver or neurologic diseases. Prior exposure to fluconazole (22.3 vs. 11.6 %, p < 0.001) and candidemia due to C. glabrata (13.1 vs. 7.8 %, p = 0.03) were also more frequent in period 2. Of note, the increase in the proportion of C. glabrata over the entire study period was mostly driven by a change in the proportion of public institutions [5.1 (period 1) vs. 10.5 % (period 2), p = 0.07] compared to private centers [11.1 (period 1) vs. 15.1 % (period 2), p = 0.29].
Table 2

Characteristics of ICU patients with candidemia in the two study periods, 2003–2007 (period 1) and 2008–2012 (period 2)

Variable

Period 1 (N = 396)

Period 2 (N = 251)

p

Gender (N, male:female)

206:190

122:129

0.40

Age (years)

67 (18–97)

63 (19–97)

0.67

Time (days) from admission to candidemia diagnosis

21 (0–142)

16 (0–188)

0.01

Private hospital

340 (37.8)

242 (49.3)

<0.001

APACHE II score, median (range)a

27 (0–46)

22 (3–42)

0.08

Cancer

102 (25.8)

72 (28.7)

0.41

  Hematologic

14 (3.5)

15 (6.0)

0.14

  Solid tumor

88 (22.2)

57 (22.7)

0.88

Diabetes

96 (24.2)

62 (24.7)

0.89

Renal failure

162 (40.9)

100 (39.8)

0.79

Chronic renal failure

57 (14.4)

24 (9.6)

0.07

Dialysis

112 (28.3)

71 (28.3)

1.00

Liver disease

32 (8.1)

42 (16.7)

0.001

Auto-immune disease

18 (4.5)

10 (4.0)

0.73

Neurologic disease

83 (21.0)

77 (30.7)

0.005

Transplant

2 (0.5)

1 (0.4)

1.00

Cardiac disease

142 (35.9)

85 (33.9)

0.60

Lung disease

106 (26.8)

79 (31.5)

0.20

Surgery

205 (51.8)

131 (52.2)

0.92

Abdominal surgery

129 (32.6)

66 (25.9)

0.07

Mechanical ventilation

296 (74.7)

184 (73.3)

0.68

Total parenteral nutrition

83 (21.0)

57 (22.7)

0.60

Central venous catheter

364 (91.9)

241 (96.0)

0.04

Neutropenia

9 (2.3)

7 (2.8)

0.68

Prior drug/treatment exposure

  Antibiotics

377 (95.2)

245 (97.6)

0.12

  Corticosteroids

202 (51.0)

136 (54.2)

0.43

  Other immunosuppressive drugs

23 (5.8)

15 (6.0)

0.93

  Chemotherapy

7 (1.8)

15 (6.0)

0.004

  Fluconazole prior to candidemia

46 (11.6)

56 (22.3)

<0.001

Candida spp.

  C. albicans

177 (44.7)

108 (43.0)

0.68

  C. parapsilosis

72 (18.2)

39 (15.5)

0.38

  C. tropicalis

90 (22.7)

51 (20.3)

0.47

  C. glabrata

31 (7.8)

33 (13.1)

0.03

  C. krusei

5 (1.3)

11 (4.4)

0.01

  C. guilliermondii

9 (2.3)

3 (1.2)

0.38

Treatment received

288 (72.7)

194 (77.3)

0.19

  Fluconazole

174/288 (60.4)

121/194 (62.4)

0.67

  Deoxycholate AMBb

80/288 (27.8)

26/194 (13.4)

<0.001

  Lipid AMBb

9/288 (3.1)

12/194 (6.2)

0.11

  Echinocandin

17/288 (5.9)

35/194 (18.0)

<0.001

30-day crude mortality

298/390 (76.4)c

152/250 (60.8)d

<0.001

Data are presented as a number with the percentage given in parenthesis, or as the median with the range given in parenthesis, unless specified otherwise

aAPACHE, Acute physiologic and chronic health evaluation (Data available for 261 patients only)

bAMB, amphotericin B

cStatus on day 30 was not known in 6 patients

dStatus on day 30 was not known in 1 patient

Antifungal treatment was given to 72.7 % of patients in period 1 and 77.3 % in period 2 (p = 0.19). During the study period the antifungal drugs prescribed for the primary treatment of candidemia changed, with a decrease in the use of deoxycholate amphotericin B (27.8 vs. 13.4 %, p < 0.001) and an increase in the use of echinocandins (5.9 vs. 18.0 %, p < 0.001). The use of lipid formulations of amphotericin B also increased from period 1 to period 2 (3.1 vs. 6.2 %, p = 0.11), but the difference was not statistically significant. Of interest, the 30-day crude mortality rate decreased from 76.4 % in period 1 to 60.8 % in period 2 (p < 0.001).

The main characteristics of candidemic patients according to admission to ICUs of public or private hospitals are shown in Table 3. Patients in public hospitals were significantly younger, and a higher proportion had autoimmune and lung diseases; in private hospitals, a higher number of patients had neutropenia and received cancer chemotherapy. In terms of species distribution, C. albicans was more frequently isolated in public institutions (48.6 vs. 39.6 %, p = 0.02), whereas C. glabrata (12.9 vs. 6.9 %, p = 0.01) and C. krusei (3.7 vs. 1.2 %, p = 0.05) were more prone to be isolated in private medical centers. In terms of antifungal therapy, echinocandins (2.9 vs. 18.5 %, p < 0.001) and lipid formulations of amphotericin B (1.3 vs. 7.4 %, p = 0.001) were more likely to be used for the treatment of candidemia in private institutions, whereas deoxycholate amphotericin B was more frequently used in the public institutions (31.8 vs. 12.3 %, p < 0.001). The 30-day crude mortality rate was 75.3 % in the public hospitals and 65.3 % in private institutions (p = 0.006).
Table 3

Characteristics of patients with candidemia according to admission to ICUs of public and private hospitals

Variable

Public (N = 321)

Private (N = 326)

p

Gender (N, male:female)

169:152

159:167

0.32

Age (years)

60 (18–97)

64 (18–97)

<0.001

Time (days) from admission to candidemia

20 (0–188)

19 (0–159)

0.62

Cancer

79 (24.6)

95 (29.1)

0.19

  Hematologic

10 (3.1)

19 (5.8)

0.09

  Solid tumor

69 (21.5)

76 (23.3)

0.58

Diabetes

69 (21.5)

89 (27.3)

0.09

Renal failure

126 (39.3)

136 (41.7)

0.52

Chronic renal failure

45 (14.0)

36 (11.0)

0.25

Dialysis

88 (27.4)

95 (29.1)

0.63

Liver disease

34 (10.6)

40 (12.3)

0.50

Auto-immune disease

20 (6.2)

8 (2.5)

0.02

Neurologic disease

75 (23.4)

85 (25.1)

0.42

Transplant

1 (0.3)

2 (0.6)

1.00

Cardiac disease

113 (35.2)

114 (35.0)

0.95

Lung disease

106 (33.0)

79 (24.2)

0.01

Surgery

164 (51.1)

172 (52.8)

0.67

Abdominal surgery

96 (29.9)

98 (30.1)

0.97

Mechanical ventilation

247 (76.9)

233 (71.5)

0.11

Total parenteral nutrition

68 (21.2)

72 (22.1)

0.78

Central venous catheter

297 (92.5)

308 (94.5)

0.31

Neutropenia

3 (0.9)

13 (4.0)

0.01

Prior drug/treatment exposure

  Antibiotics

310 (96.6)

312 (95.7)

0.57

  Corticosteroids

173 (53.9)

165 (50.6)

0.40

  Immunosuppressive drugs

18 (5.6)

20 (6.1)

0.77

  Chemotherapy

4 (1.2)

18 (5.5)

0.003

  Fluconazole prior to candidemia

43 (13.4)

59 (18.1)

0.10

Candida spp.

  C. albicans

156 (48.6)

129 (39.6)

0.02

  C. parapsilosis

61 (19.0)

50 (15.3)

0.22

  C. tropicalis

64 (19.9)

77 (23.6)

0.26

  C. glabrata

22 (6.9)

42 (12.9)

0.01

  C. krusei

4 (1.2)

12 (3.7)

0.05

  C. guilliermondii

7 (2.2)

5 (1.5)

0.54

Treatment received

239 (74.5)

243 (74.5)

0.98

  Fluconazole

147/239 (61.5)

148/243 (60.9)

0.89

  Deoxycholate AMB

76/239 (31.8)

30/243 (12.3)

<0.001

  Lipid AMB

3/239 (1.3)

18/243 (7.4)

0.001

  Echinocandin

7/239 (2.9)

45/243 (18.5)

<0.001

30-day crude mortality

241/320 (75.3)a

209/320 (65.3)b

0.006

Data are presented as a number with the percentage given in parenthesis, or as the median with the range given in parenthesis, unless specified otherwise

aStatus on day 30 was not known in 1 patient

bStatus on day 30 was not known in 6 patients

As shown in Table 4, the following variables were associated with higher 30-day mortality by univariate analysis: older age, period 1, public hospital, higher acute physiologic and chronic health evaluation (APACHE) II score, cancer, lung disease, renal failure, dialysis, mechanical ventilation, receipt of corticosteroids, no treatment for candidemia and treatment with deoxycholate amphotericin B. Infection due to C. parapsilosis and treatment with an echinocandin were associated with lower mortality.
Table 4

Factors associated with 30-day mortality among 640 ICU patientsa with candidemia by univariate analysis

Variable

Alive (N = 190)

Dead (N = 450)

p value

Gender (N, male:female)

94:96

233:217

0.59

Age (years)

60 (19–97)

68 (18–97)

<0.001

Time (days) from admission to candidemia

17 (0–151)

20.5 (0–188)

0.10

Period 2 (2008–2012)

98 (51.6)

152 (33.8)

<0.001

Private hospital

111 (58.4)

79 (41.6)

0.006

APACHE II scoreb

19 (3–37)

27 (0–46)

<0.001

Cancer

31 (16.3)

140 (31.1)

<0.001

  Hematologic

7 (3.7)

21 (4.7)

0.58

  Solid tumor

24 (12.6)

119 (26.4)

<0.001

Cardiac disease

62 (32.6)

161 (35.8)

0.44

Lung disease

42 (22.1)

141 (31.3)

0.02

Diabetes

49 (25.8)

107 (23.8)

0.59

Renal failure

61 (32.1)

199 (44.2)

0.004

Chronic renal failure

20 (10.5)

60 (13.3)

0.33

Dialysis

32 (16.8)

149 (33.1)

<0.001

Liver disease

13 (8.9)

56 (12.4)

0.20

Auto-immune disease

4 (2.1)

24 (5.3)

0.07

Neurologic disease

53 (27.9)

104 (23.1)

0.20

Transplant

0

3 (0.7)

0.56

Surgery

108 (56.8)

226 (50.2)

0.13

Abdominal surgery

54 (28.4)

139 (30.9)

0.53

Mechanical ventilation

117 (61.6)

378 (79.6)

<0.001

Total parenteral nutrition

42 (22.1)

97 (21.6)

0.88

Central venous catheter

176 (92.6)

422 (93.8)

0.59

Neutropenia

2 (1.1)

14 (3.1)

0.17

Prior drug/treatment exposure

  Antibiotics

181 (95.3)

436 (96.9)

0.31

  Corticosteroids

74 (38.9)

259 (57.6)

<0.001

  Other immunosuppressive drugs

9 (4.7)

29 (6.4)

0.40

  Chemotherapy

6 (3.2)

16 (3.6)

0.80

  Fluconazole prior to candidemia

36 (18.9)

65 (14.4)

0.15

Candida spp.

  C. albicans

73 (38.4)

210 (46.7)

0.055

  C. parapsilosis

43 (22.6)

67 (14.9)

0.02

  C. tropicalis

39 (20.5)

99 (22.0)

0.68

  C. glabrata

23 (12.1)

40 (8.9)

0.21

  C. krusei

5 (2.6)

11 (2.4)

1.00

  C. guilliermondii

2 (1.1)

10 (2.2)

0.52

Treatment received

176 (92.6)

301 (66.9)

<0.001

  Fluconazole

106/176 (60.2)

185/301 (61.5)

0.79

  Deoxycholate AMB

27/176 (15.3)

78/301 (25.9)

0.007

  Lipid AMB

8/176 (4.5)

13/301 (4.3)

0.91

  Echinocandin

31/176 (17.6)

21/301 (7.0)

<0.001

Time (days) from candidemia to treatment

2 (0–11)

2 (0–18)

0.12

Data are presented as a number with the percentage given in parenthesis, or as the median with the range given in parenthesis, unless specified otherwise

aStatus on day 30 was not known in 7 patients

bData available for 258 patients only

By multivariate analysis (Table 5), older age [odds ratio (OR) 1.03, 95 % confidence interval (CI) 1.01–1.05], period 1 (OR 2.49, 95 % CI 1.22–5.08), corticosteroid treatment (OR 4.00, 95 % CI 1.98–8.13) and higher APACHE II score (OR 1.05, 95 % CI 1.01–1.09) were associated with an increased risk of death. By contrast, treatment with an echinocandin (OR 0.20, 95 % CI 0.07–0.58) was associated with a higher probability of survival. Prognostic factors were also evaluated in the 745 patients who were not in an ICU (Electronic Supplementary Material Table A). Among these patients, the variables associated with 30-day mortality were period 1(OR 2.67, 95 % CI 1.33–5.33, p = 0.005), mechanical ventilation (OR 3.87, 95 % CI 1.46–10.31, p = 0.007) and antibiotic treatment (OR 5.87, 95 % CI 1.71–18.18, p = 0.004).
Table 5

Factors associated with 30-day mortalitya among 640 ICU patients with candidemia by multivariate analysis

Variable

Odds ratio

95 % Confidence interval

p value

Receipt of corticosteroids

4.00

1.98–8.13

<0.001

Period 1

2.49

1.22–5.08

0.01

APACHE II scoreb

1.05

1.01–1.09

0.03

Age

1.03

1.01–1.05

0.003

Treatment with an echinocandin

0.20

0.07–0.58

0.003

aThe factors associated with 30-day mortality were: age [odds ratio (OR) 1.02, 95 % confidence interval (CI) 1.01–1.03, p < 0.001), period 1 (OR 2.07, 95 % CI 1.36–1.16, p = 0.001), public hospital (OR 1.68, 95 % CI 1.09–2.58, p = 0.02), solid tumor (OR 2.45, 95 % CI 1.39–4.31, p = 0.002), receipt of dialysis (2.07, 95 % CI 1.28–3.33, p = 0.003), mechanical ventilation (OR 1.60, 95 % CI 1.01–2.55, p = 0.04), corticosteroids (OR 2.31, 95 % CI 1.52–3.52, p < 0.001), while treatment with an echinocandin was protective (OR 0.45, 95 % CI 0.22–0.89, p = 0.02)

bSince the APACHE II score was available in only approximately 40 % of patients, we ran the multivariate analysis without this variable

Discussion

In this study we observed that while the 30-day crude mortality rate of patients with candidemia admitted to an ICU was very high, it decreased from 76.4 % in period 1 (2003–2007) to 60.8 % in period 2 (2008–2012). We also observed that among the predictors of outcome identified by multivariate analysis, the use of an echinocandin as primary therapy for candidemia was associated with a better outcome and that echinocandins were increasingly being used as primary therapy for candidemia in period 2.

Critically ill patients still represent a large proportion of patients who develop candidemia in tertiary care hospitals. In the present study, the proportion of candidemic patients in an ICU was 46.5 % over the entire study period and increased in period 2. As expected, compared to non-ICU patients, patients already admitted to an ICU when candidemia was diagnosed were more likely to have received antibiotics and invasive medical procedures, while cancer and transplantation were more frequent in non-ICU patients.

An interesting finding of our study relates to changes in the epidemiology and clinical management of candidemia over the 9-year period covered by this study. In parallel with the observed increase in the proportion of candidemic patients who had been exposed to fluconazole prior to being diagnosed with candidemia, we found a substantial rise in the proportion of candidemia due to C. glabrata. The association between previous exposure to fluconazole and candidemia due to C. glabrata has been extensively reported [16, 17, 18, 19]. While epidemiologic studies of candidemia in Latin America still show a relatively low proportion of candidemia caused by species that exhibit a lower susceptibility to fluconazole [14], the emergence of C. glabrata has been documented in other studies from the region [20, 21, 22].

A dramatic finding in our study was the unacceptably high 30-day crude mortality of candidemic ICU patients, both in public and private hospitals. Indeed, two large studies published in the USA reported a decrease in the mortality rate of patients with candidemia during the last 10 years [5, 18]. The crude mortality rate in the EPIC study evaluating candidemia in ICUs was 42 % [23], and two European studies reported 30-day mortality of 47 % [24, 25]. The high mortality rate observed in our series may be multifactorial and include poor general clinical conditions of sick patients (especially from public hospitals), delays in making a diagnosis and the choice of treatment.

Interestingly, we observed a significant decrease in the crude mortality rate of patients with candidemia in the second period of the analysis. When we compared the clinical characteristics of patients from both periods, we found that age distribution and underlying conditions were similar, with the exception of neurologic and liver diseases, which were more common in period 2. In addition, the APACHE II score was slightly lower in period 2, although the difference was not statistically significant. We do not believe that these differences explain the significant reduction in the death rate in period 2—rather, important differences in the clinical management of candidemia did occur in period 2. Patients from the latter period were more likely to have been treated with echinocandins and less likely to have received deoxycholate amphotericin B. Various studies, including a randomized clinical trial [26] and a patient-level pooled analysis of randomized clinical trials [27], have shown that the outcome of candidemia is better when an echinocandin is used as primary therapy. Therefore, it is reasonable to assume that the observed decrease in 30-day crude mortality in period 2 may have been, at least in part, due to the increase in the use of echinocandins as primary therapy, especially since treatment with an echinocandin was an independent predictor of better outcome by the multivariate analysis.

As already reported in other studies, older age, treatment with corticosteroids and higher APACHE II score were associated with an increased risk of death [2, 25, 28, 29, 30, 31]. In addition, period 1 was also associated with a higher risk of death. It is possible that differences in factors related to patient care not captured in the present study contributed to the better survival observed in period 2.

Our study has a number of limitations related to its retrospective nature. For example, we did not have data to calculate incidence rates of candidemia in and outside the ICU. Likewise, data on trends in susceptibility of Candida bloodstream isolates could not be provided because of changing standards in reading the test over time. Nevertheless, according to the standards in each period, fluconazole resistance occurred in <10 % of isolates and was almost exclusively limited to C. glabrata and C. krusei (data not shown). Another limitation of our study is that the APACHE II score was not available in a significant proportion of cases, limiting the number of patients analyzed in the multivariate analysis. Likewise, since the time of central venous catheter removal is critical to an analysis of its impact on the outcome [32], we were not able to do such an analysis because the date of catheter removal was not available for the majority of patients.

In conclusion, we found a clear change in the epidemiology and clinical management of candidemia in ICU patients during the 9-year period of this study. The incorporation of echinocandins as primary therapy for candidemia in critically ill patients seems to be associated with better outcomes.

Notes

Acknowledgments

The authors express their sincere gratitude to all investigators who collected data for the original studies. The original studies were partially sponsored by MSD, Pfizer and United Medical.

Conflicts of interest

None.

Ethical standard

Our study was approved by the respective ethics committees of the participating hospitals and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The ethics committees granted waiver for informed consent due to the observational nature of the study.

References

  1. 1.
    Delaloye J, Calandra T (2014) Invasive candidiasis as a cause of sepsis in the critically ill patient. Virulence 5:161–169. doi: 10.4161/viru.26187 PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Bassetti M, Righi E, Ansaldi F, Merelli M, Cecilia T, De Pascale G, Diaz-Martin A, Luzzati R, Rison C, Lagunes L, Trecarichi EM, Sanguinetti M, Posteraro B, Garnacho-Montero J, Sartor A, Rello J, Rocca GD, Antoneiil M, Tumbarello M (2014) A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality. Intensive Care Med 40:839–845. doi: 10.1007/s00134-014-3310-z PubMedCrossRefGoogle Scholar
  3. 3.
    Leon C, Ostrosky-Zeichner L, Schuster M (2014) What’s new in the clinical and diagnostic management of invasive candidiasis in critically ill patients. Intensive Care Med 40:808–819. doi: 10.1007/s00134-014-3281-0 PubMedCrossRefGoogle Scholar
  4. 4.
    Asmundsdottir LR, Erlendsdottir H, Gottfredsson M (2013) Nationwide study of candidemia, antifungal use, and antifungal drug resistance in Iceland, 2000–2011. J Clin Microbiol 51:841–848. doi: 10.1128/JCM.02566-12 PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Cleveland AA, Farley MM, Harrison LH, Stein B, Hollick R, Lockhart SR, Magill SS, Derado G, Park BJ, Chiller TM (2012) Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011. Clin Infect Dis 55:1352–1361. doi: 10.1093/cid/cis697 PubMedCrossRefGoogle Scholar
  6. 6.
    Playford EG, Nimmo GR, Tilse M, Sorrell TC (2010) Increasing incidence of candidaemia: long-term epidemiological trends, Queensland, Australia, 1999–2008. J Hosp Infect 76:46–51. doi: 10.1016/j.jhin.2010.01.022 PubMedCrossRefGoogle Scholar
  7. 7.
    Garey KW, Rege M, Pai MP, Mingo DE, Suda KJ, Turpin RS, Bearden DT (2006) Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 43:25–31. doi: 10.1086/504810 PubMedCrossRefGoogle Scholar
  8. 8.
    Morrell M, Fraser VJ, Kollef MH (2005) Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 49:3640–3645. doi: 10.1128/AAC.49.9.3640-3645.2005 PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Ostrosky-Zeichner L, Kullberg BJ, Bow EJ, Hadley S, Leon C, Nucci M, Patterson TF, Perfect JR (2011) Early treatment of candidemia in adults: a review. Med Mycol 49:113–120. doi: 10.3109/13693786.2010.512300 PubMedCrossRefGoogle Scholar
  10. 10.
    Leon C, Ruiz-Santana S, Saavedra P, Galvan B, Blanco A, Castro C, Balasini C, Utande-Vazquez A, Gonzalez de Molina FJ, Blasco-Navalproto MA, Lopez MJ, Charles PE, Martin E, Hernandez-Viera MA (2009) Usefulness of the “Candida score” for discriminating between Candida colonization and invasive candidiasis in non-neutropenic critically ill patients: a prospective multicenter study. Crit Care Med 37:1624–1633. doi: 10.1097/CCM.0b013e31819daa14 PubMedCrossRefGoogle Scholar
  11. 11.
    Bassetti M, Marchetti M, Chakrabarti A, Colizza S, Garnacho-Montero J, Kett DH, Munoz P, Cristini F, Andoniadou A, Viale P, Rocca GD, Roilides E, Sganga G, Walsh TJ, Tascini C, Tumbarello M, Menichetti F, Righi E, Eckmann C, Viscoli C, Shorr AF, Leroy O, Petrikos G, De Rosa FG (2013) A research agenda on the management of intra-abdominal candidiasis: results from a consensus of multinational experts. Intensive Care Med 39:2092–2106. doi: 10.1007/s00134-013-3109-3 PubMedCrossRefGoogle Scholar
  12. 12.
    Leon C, Ruiz-Santana S, Saavedra P, Castro C, Ubeda A, Loza A, Martin-Mazuelos E, Blanco A, Jerez V, Ballus J, Alvarez-Rocha L, Utande-Vazquez A, Farinas O (2012) Value of beta-d-glucan and Candida albicans germ tube antibody for discriminating between Candida colonization and invasive candidiasis in patients with severe abdominal conditions. Intensive Care Med 38:1315–1325. doi: 10.1007/s00134-012-2616-y PubMedCrossRefGoogle Scholar
  13. 13.
    Colombo AL, Thompson L, Graybill JR (2008) The north and south of candidemia: issues for Latin America. Drugs Today (Barc) 44[Suppl A]:1–34Google Scholar
  14. 14.
    Nucci M, Queiroz-Telles F, Alvarado-Matute T, Tiraboschi IN, Cortes J, Zurita J, Guzman-Blanco M, Santolaya ME, Thompson L, Sifuentes-Osornio J, Echevarria JI, Colombo AL (2013) Epidemiology of candidemia in Latin America: a laboratory-based survey. PLoS ONE 8:e59373. doi: 10.1371/journal.pone.0059373 PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Santolaya ME, Alvarado T, Queiroz-Telles F, Colombo AL, Zurita J, Tiraboschi IN, Cortes JA, Thompson L, Guzman M, Sifuentes J, Echevarria JI, Nucci M (2014) Active surveillance of candidemia in children from Latin America: a key requirement for improving disease outcome. Pediatr Infect Dis J 33:e40–e44. doi: 10.1097/INF.0000000000000039 PubMedCrossRefGoogle Scholar
  16. 16.
    Garnacho-Montero J, Diaz-Martin A, Garcia-Cabrera E, de Ruiz Perez PM, Hernandez-Caballero C, Aznar-Martin J, Cisneros JM, Ortiz-Leyba C (2010) Risk factors for fluconazole-resistant candidemia. Antimicrob Agents Chemother 54:3149–3154. doi: 10.1128/AAC.00479-10 PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Slavin MA, Sorrell TC, Marriott D, Thursky KA, Nguyen Q, Ellis DH, Morrissey CO, Chen SC (2010) Candidaemia in adult cancer patients: risks for fluconazole-resistant isolates and death. J Antimicrob Chemother 65:1042–1051. doi: 10.1093/jac/dkq053 PubMedCrossRefGoogle Scholar
  18. 18.
    Diekema D, Arbefeville S, Boyken L, Kroeger J, Pfaller M (2012) The changing epidemiology of healthcare-associated candidemia over three decades. Diagn Microbiol Infect Dis 73:45–48. doi: 10.1016/j.diagmicrobio.2012.02.001 PubMedCrossRefGoogle Scholar
  19. 19.
    Lortholary O, Desnos-Ollivier M, Sitbon K, Fontanet A, Bretagne S, Dromer F (2011) Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving 2,441 patients. Antimicrob Agents Chemother 55:532–538. doi: 10.1128/AAC.01128-10 PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Colombo AL, Garnica M, Aranha Camargo LF, Da Cunha CA, Bandeira AC, Borghi D, Campos T, Senna AL, Valias Didier ME, Dias VC, Nucci M (2013) Candida glabrata: an emerging pathogen in Brazilian tertiary care hospitals. Med Mycol 51:38–44. doi: 10.3109/13693786.2012.698024 PubMedCrossRefGoogle Scholar
  21. 21.
    Moretti ML, Trabasso P, Lyra L, Fagnani R, Resende MR, de Oliveira Cardoso LG, Schreiber AZ (2013) Is the incidence of candidemia caused by Candida glabrata increasing in Brazil? Five-year surveillance of Candida bloodstream infection in a university reference hospital in southeast Brazil. Med Mycol 51:225–230. doi: 10.3109/13693786.2012.708107 PubMedCrossRefGoogle Scholar
  22. 22.
    Pasqualotto AC, Zimerman RA, Alves SH, Aquino VR, Branco D, Wiltgen D, do AA, Cechinel R, Colares SM, Rocha IG, Severo LC, Sukiennik TC (2008) Take control over your fluconazole prescriptions: the growing importance of Candida glabrata as an agent of candidemia in Brazil. Infect Control Hosp Epidemiol 29:898–899. doi: 10.1086/590191 PubMedCrossRefGoogle Scholar
  23. 23.
    Kett DH, Azoulay E, Echeverria PM, Vincent JL (2011) Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study. Crit Care Med 39:665–670. doi: 10.1097/CCM.0b013e318206c1ca PubMedCrossRefGoogle Scholar
  24. 24.
    Bassetti M, Taramasso L, Nicco E, Molinari MP, Mussap M, Viscoli C (2011) Epidemiology, species distribution, antifungal susceptibility and outcome of nosocomial candidemia in a tertiary care hospital in Italy. PLoS ONE 6:e24198. doi: 10.1371/journal.pone.0024198 PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Puig-Asensio M, Peman J, Zaragoza R, Garnacho-Montero J, Martin-Mazuelos E, Cuenca-Estrella M, Almirante B (2014) Impact of therapeutic strategies on the prognosis of candidemia in the ICU. Crit Care Med 42:1423–1432. doi:  10.1097/CCM.0000000000000221
  26. 26.
    Reboli AC, Rotstein C, Pappas PG, Chapman SW, Kett DH, Kumar D, Betts R, Wible M, Goldstein BP, Schranz J, Krause DS, Walsh TJ (2007) Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 356:2472–2482. doi: 10.1056/NEJMoa066906 PubMedCrossRefGoogle Scholar
  27. 27.
    Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, Sobel JD, Pappas PG, Kullberg BJ (2012) Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis 54:1110–1122. doi: 10.1093/cid/cis021 PubMedCrossRefGoogle Scholar
  28. 28.
    Leroy O, Gangneux JP, Montravers P, Mira JP, Gouin F, Sollet JP, Carlet J, Reynes J, Rosenheim M, Regnier B, Lortholary O (2009) Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005-2006). Crit Care Med 37:1612–1618. doi: 10.1097/CCM.0b013e31819efac0 PubMedCrossRefGoogle Scholar
  29. 29.
    Marriott DJ, Playford EG, Chen S, Slavin M, Nguyen Q, Ellis D, Sorrell TC (2009) Determinants of mortality in non-neutropenic ICU patients with candidaemia. Crit Care 13:R115. doi: 10.1186/cc7964 PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Munoz P, Giannella M, Fanciulli C, Guinea J, Valerio M, Rojas L, Rodriguez-Creixems M, Bouza E (2011) Candida tropicalis fungaemia: incidence, risk factors and mortality in a general hospital. Clin Microbiol Infect 17:1538–1545. doi: 10.1111/j.1469-0691.2010.03338.x PubMedCrossRefGoogle Scholar
  31. 31.
    Tortorano AM, Biraghi E, Astolfi A, Ossi C, Tejada M, Farina C, Perin S, Bonaccorso C, Cavanna C, Raballo A, Grossi A (2002) European Confederation of Medical Mycology (ECMM) prospective survey of candidaemia: report from one Italian region. J Hosp Infect 51:297–304. doi: 10.1053/jhin.2002.1261 PubMedCrossRefGoogle Scholar
  32. 32.
    Nucci M, Anaissie E, Betts RF, Dupont BF, Wu C, Buell DN, Kovanda L, Lortholary O (2010) Early removal of central venous catheter in patients with candidemia does not improve outcome: analysis of 842 patients from 2 randomized clinical trials. Clin Infect Dis 51:295–303. doi: 10.1086/653935 PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2014

Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Authors and Affiliations

  • Arnaldo L. Colombo
    • 1
    • 7
  • Thais Guimarães
    • 2
  • Teresa Sukienik
    • 3
  • Alessandro C. Pasqualotto
    • 4
  • Ricardo Andreotti
    • 1
  • Flavio Queiroz-Telles
    • 5
  • Simone A. Nouér
    • 6
  • Marcio Nucci
    • 6
  1. 1.Escola Paulista de MedicinaUniversidade Federal de São PauloSão PauloBrazil
  2. 2.Hospital do Servidor Público Estadual de São PauloSão PauloBrazil
  3. 3.Irmandade da Santa Casa de Misericórdia de Porto AlegrePorto AlegreBrazil
  4. 4.Universidade Federal de Ciências da Saúde de Porto AlegrePorto AlegreBrazil
  5. 5.Universidade Federal do ParanáCuritibaBrazil
  6. 6.Universidade Federal do Rio de JaneiroRio de JaneiroBrazil
  7. 7.São PauloBrazil

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