3.1 Incidence and clinical features of Candida BSI episodes
Data on a total of 393 consecutive episodes of Candida BSI were collected from 370 inpatients during the 11-year study period. The demographic characteristics of the patients are summarized in Table 1. The mean age of the patients was 57.6 ± 19.0 years, and 74.3% were male. Candida BSI incidence was 0.39 episodes/1000 admissions. The incidence increased steadily from 0.21 (2008), to 0.59 (2017), to 0.33 episodes per 1,000 admissions (2018) (Fig. 1[A]). Among the 393 Candida BSI episodes, 148 (37.7%), 167 (42.5%), and 78 (19.8%) occurred in the surgical ward, intensive care units (ICUs), and internal medicine ward, respectively (Fig. 1[B]).
Table 1
Demographic and clinical data for patients with Candida bloodstream infection
|
C. albicans
|
C. parapsilosis
|
C. tropicalis
|
C. glabrata
|
C. guilliermondii
|
C.
sake
|
C.
krusei
|
Other Candida spp.
|
Total
|
|
(n = 141)
|
(n = 87)
|
(n = 69)
|
(n = 48)
|
(n = 20)
|
(n = 8)
|
(n = 5)
|
(n = 15)
|
(n = 393)
|
Age, y
|
65.2 ± 14.5
|
53.2 ± 20.3
|
50.5 ± 19.5
|
60.7 ± 17.5
|
50.5 ± 19.4
|
52 ± 20.6
|
40.8 ± 27.1
|
52.6 ± 20.0
|
57.6 ± 19.0
|
Male
|
102(73.4)
|
60(69.0)
|
51(73.9)
|
44(91.7)
|
14(70)
|
8(100)
|
2(40)
|
11(73.3)
|
292(74.3)
|
Origin
|
|
|
|
|
|
|
|
|
|
Internal medicine ward
|
15(10.6)
|
19(21.8)
|
27(39.1)
|
7(14.6)
|
3(15)
|
0(0)
|
3(60)
|
4(26.7)
|
78(19.8)
|
Surgical ward
|
61(43.3)
|
32(36.8)
|
16(23.2)
|
15(31.3)
|
10(50)
|
6(75)
|
0(0)
|
8(53.3)
|
148(37.7)
|
ICU
|
65(46.1)
|
36(41.4)
|
26(37.7)
|
26(54.1)
|
7(35)
|
2(25)
|
2(40)
|
3(20)
|
167(42.5)
|
Time from admission to infection, d
|
30.6 ± 35.3
|
48.4 ± 56.2
|
37.7 ± 32.4
|
27.5 ± 19.1
|
35.9 ± 52.5
|
120.6 ± 242.7
|
64.2 ± 68.6
|
21.5 ± 13.6
|
37.6 ± 53.1
|
Length of hospital stay, d
|
56.0 ± 54.9
|
83.2 ± 78.1
|
71.5 ± 56.1
|
67.1 ± 72.7
|
97.7 ± 142.6
|
178.5 ± 281.7
|
92.4 ± 88.5
|
52.7 ± 101.5
|
71.1 ± 82.8
|
Turnaround Time, d
|
4.3 ± 1.9
|
4.5 ± 1.1
|
3.8 ± 1.1
|
4.8 ± 1.3
|
4.3 ± 1.2
|
4.5 ± 1.6
|
4.4 ± 1.5
|
5.9 ± 1.8
|
4.4 ± 1.5
|
Underlying disease
|
|
|
|
|
|
|
|
|
|
Solid tumor
|
47(33.3)
|
26(29.9)
|
13(18.8)
|
17(35.4)
|
6(30)
|
2(25)
|
0(0)
|
7(46.7)
|
118(30)
|
Hematologic malignancy
|
8(5.7)
|
6(6.9)
|
24(34.8)
|
2(4.2)
|
2(10)
|
1(12.5)
|
3(60)
|
2(13.3)
|
48(12.2)
|
Diabetes mellitus
|
33(23.4)
|
21(24.1)
|
8(11.6)
|
9(18.8)
|
1(5)
|
1(12.5)
|
0(0)
|
4(26.7)
|
77(19.6)
|
Chronic cardiac disease
|
55(39)
|
22(25.3)
|
16(23.2)
|
18(37.5)
|
6(30)
|
3(37.5)
|
2(40)
|
2(13.3)
|
124(31.6)
|
Chronic pulmonary disease
|
26(18.4)
|
9(10.3)
|
5(7.2)
|
6(12.5)
|
1(5)
|
1(12.5)
|
1(20)
|
3(20)
|
52(13.2)
|
Chronic renal failure
|
18(12.8)
|
6(6.9)
|
6(8.7)
|
5(10.4)
|
5(25)
|
0(0)
|
0(0)
|
2(13.3)
|
42(10.7)
|
Skin barrier compromised
|
5(3.5)
|
9(10.3)
|
5(7.2)
|
1(2.1)
|
3(15)
|
3(37.5)
|
0(0)
|
0(0)
|
26(6.6)
|
Prior surgical intervention (< 1 month)
|
97(68.8)
|
48(55.2)
|
36(52.2)
|
30(62.5)
|
15(75)
|
6(75)
|
2(40)
|
10(66.7)
|
244(62.1)
|
Corticosteroid use
|
11(7.8)
|
13(14.9)
|
12(17.4)
|
9(18.8)
|
4(20)
|
0(0)
|
3(60)
|
2(13.3)
|
54(13.7)
|
Prior use of antifungal agents (< 6 months)
|
20(14.2)
|
19(21.8)
|
24(34.8)
|
11(22.9)
|
8(40)
|
1(12.5)
|
4(80)
|
1(6.7)
|
88(22.4)
|
Severity of clinical feature
|
|
|
|
|
|
|
|
|
Fever (T > 38.2˚C)
|
114(80.9)
|
63(72.4)
|
60(87)
|
34(70.8)
|
16(80)
|
6(75)
|
3(60)
|
13(86.7)
|
309(78.6)
|
Parenteral nutrition
|
71(50.4)
|
42(48.3)
|
28(40.6)
|
23(47.9)
|
5(25)
|
3(37.5)
|
2(40)
|
6(40)
|
180(45.8)
|
Mechanical ventilation
|
58(41.1)
|
31(35.6)
|
23(33.3)
|
25(52.1)
|
5(25)
|
2(25)
|
2(40)
|
1(6.7)
|
147(37.4)
|
Renal replacement therapy
|
17(12.1)
|
10(11.5)
|
9(13)
|
7(14.6)
|
5(25)
|
0(0)
|
1(20)
|
0(0)
|
49(12.5)
|
Central venous catheter
|
121(85.8)
|
67(77)
|
49(71)
|
43(89.6)
|
17(85)
|
5(62.5)
|
4(80)
|
10(66.7)
|
316(80.4)
|
Severe neutropenia
|
4(2.8)
|
8(9.2)
|
22(31.9)
|
1(2.1)
|
2(10)
|
0(0)
|
3(60)
|
2(13.3)
|
42(10.7)
|
28-day mortality
|
54(38.3)
|
16(18.4)
|
19(27.5)
|
13(27.1)
|
3(15)
|
1(12.5)
|
1(20)
|
5(33.3)
|
112(28.5)
|
Other Candida spp. Includes C. gum (4 cases), C. lusitaniae (3 cases), C. intermedia (2 cases), C. lipolytica (2cases), C. theae (2 cases), C.famata (1case), and C. haemulonii (1 case). |
Data were expressed as mean ± SD for continuous variables and n (%) for categorical variables. ICU, intensive care unit; SD, standard deviation |
C. albicans was isolated in 19.3%, 41.2% and 38.9%, of cases in internal medicine wards, surgery wards, and the ICU, respectively (P = 0.003). A higher proportion of C. tropicalis (34.7%) was found in internal medicine wards than in the surgery wards (21.6%) and ICUs (21.6%).
Most patients with Candida BSI had at least one comorbidity. These included 118 (30%) patients with solid tumors, 48 (12.2%) had hematological malignancies, 77 (19.6%) had diabetes mellitus, 124 (31.6%) had chronic cardiac disease, 52 (13.2%) had chronic pulmonary disease, 42 (10.7%) had chronic renal failure, in 26 (6.6%) patients, the skin barrier was considered compromised, 244 (62.1%) had prior surgical intervention, 54 (13.7%) used corticosteroid, 88 (22.4%) used prior antifungal agents, and 255 (64.9%) received antibiotics prior Candida BSI onset. A total of 244 (72%) patients had at least two comorbidities. Regarding the severity, 309 (78.6%) patients had fever, 180 (45.8%) received parenteral nutrition, 147 (37.4%) received mechanical ventilation, 49 (12.5%) received renal replacement therapy, and 42 (10.7%) had severe neutropenia. The clinical characteristics of patients by Candida species are shown in Table 1.
3.2 Antifungal susceptibility of Candida isolates
A total of 393 Candida spp. were isolated, including 141 (35.9%), C. albicans, 87, C. parapsilosis (22.1%); 69, C. tropicalis (17.6%); 48, C. glabrata (12.2%); 20, C. guilliermondii (5.1%); 8, C. sake (2.0%); 5, C.krusei (1.3%); and 15, other species (4, C. gum; 3, C. lusitaniae; 2, C. intermedia; 2, C. theae; 2, C. lipolytica; 1, C. famata; and 1, C. haemulonii).
Among the 393 Candida species, 378 were subjected to antifungal susceptibility testing, on the basis of 2012 CLSI breakpoints (CBPs). As shown in Table 2, the susceptibility of C. albicans, C. parapsilosis to fluconazole and voriconazole were quite high, compared to that to itraconazole (94%, 93.3% vs. 82.1%). The susceptibility of C. tropicalis to triazoles fluconazole, voriconazole, and itraconazole was unsatisfactory. Amphotericin B and 5-flucytosine remained superior against common Candida spp., except for C. krusei and C. guilliermondii, with 95% susceptibility.
3.3 Antifungal therapy and outcome of patients with Candida BSI
Antifungal therapy was administered to 299 (76.1%) patients, whereas 94 (23.9%) patients did not receive antifungal therapy. Among those who received antifungal therapy, 247 (62.8%) received early appropriate antifungal therapy, and 52 (13.2%) received targeted antifungal therapy. Fluconazole was most frequently used as an empirical therapy, followed by echinocandins and voriconazole. Eighteen (4.6%) patients with Candida BSI received combination therapy.
The overall, 28-day mortality rate was 28.5%, and the rate was significantly higher in internal medicine wards and ICUs than in surgical wards (37.2% and 34.7% vs. 16.9%, respectively, P < 0.001). The mortality rates among those who received early appropriate or targeted antifungal therapy was 26.8% and 25.1% (P = 0.012 or P = 0.046), compared to 39.3% for those who did not receive any antifungal therapy, with no significant difference between those who received early appropriate antifungal therapy and those who received targeted antifungal therapy.
On univariate analysis, age, solid tumor, diabetes mellitus, chronic cardiac disease, chronic renal failure, skin disease, prior surgical intervention, mechanical ventilation, severe neutropenia, and antifungal therapy were found to be associated with 28-day mortality. On multivariate Cox regression analysis, advanced age (HR = 1.025; 95%CI, 1.013–1.037; P < 0.001), chronic renal failure (HR = 2.018; 95%CI 1.234–3.299; P = 0.005), mechanical ventilation (HR = 1.950; 95%CI 1.307–2.912; P = 0.001), and severe neutropenia (HR = 4.347; 95%CI 2.462–7.675; P < 0.001), were found to be independent risk factors for 28-day mortality. However, antifungal therapy (HR = 0.570; 95%CI 0.382–0.849; P = 0.006) was an independent protective factor for 28-day mortality (Table 3).
Table 3
Multivariable Cox regression analysis for 393 Candida bloodstream infection episodes
28-day outcome
|
Multivariable analysis
|
|
|
|
|
Survival (n = 281)
|
Death (n = 112)
|
P-value
|
|
HR (95%CI)
|
P-value
|
Male
|
|
216(76.9)
|
76(67.9)
|
0.065
|
|
-
|
|
-
|
Age, y
|
|
55.2(19.5)
|
63.6(16.2)
|
< 0.01
|
|
1.025(1.013–1.037)
|
|
< 0.001
|
Underlying disease
|
|
|
|
|
|
-
|
|
-
|
Solid tumor
|
|
91(32.4)
|
27(24.1)
|
0.106
|
|
-
|
|
-
|
Hematologic malignancy
|
|
32(11.4)
|
16(14.3)
|
0.428
|
|
-
|
|
-
|
Diabetes mellitus
|
|
49(17.4)
|
28(25)
|
0.088
|
|
-
|
|
-
|
Chronic Cardiac disease
|
|
72(25.6)
|
52(46.4)
|
< 0.01
|
|
-
|
|
0.105
|
Chronic Pulmonary disease
|
|
34(12.1)
|
18(16.1)
|
0.294
|
|
-
|
|
-
|
Chronic renal failure
|
|
20(7.1)
|
22(19.6)
|
< 0.01
|
|
2.018(1.234–3.299)
|
|
0.005
|
Skin barrier compromised
|
|
24(8.5)
|
2(1.8)
|
0.015
|
|
-
|
|
0.308
|
Prior surgical intervention (< 1month)
|
182(64.8)
|
62(55.4)
|
0.083
|
|
-
|
|
-
|
Corticosteroid use
|
|
40(14.2)
|
14(12.5)
|
0.652
|
|
-
|
|
-
|
Prior antifungal agents use (< 6month)
|
64(22.8)
|
24(21.4)
|
0.772
|
|
-
|
|
-
|
Severity of clinical feature
|
|
|
|
|
|
-
|
|
-
|
Fever (T > 38.2℃)
|
|
220(78.3)
|
89(79.5)
|
0.798
|
|
-
|
|
-
|
Parenteral nutrition
|
|
124(44.1)
|
56(50)
|
0.292
|
|
-
|
|
-
|
Mechanical ventilation
|
|
89(31.7)
|
58(51.8)
|
< 0.01
|
|
1.950(1.307–2.912)
|
|
0.001
|
Renal replacement therapy
|
|
32(11.4)
|
17(15.2)
|
0.305
|
|
-
|
|
-
|
Central venous catheter
|
|
227(80.8)
|
89(79.5)
|
0.766
|
|
-
|
|
-
|
Severe neutropenia
|
|
24(8.5)
|
18(16.1)
|
0.029
|
|
4.347(2.462–7.675)
|
|
< 0.001
|
Antifungal therapy
|
|
224(74.9)
|
75(25.1)
|
0.007
|
0.502(0.294–0.857)
|
0.006
|
No treatment
|
|
57(60.6)
|
37(39.4)
|
Data were expressed as mean ± SD for continuous variables and n (%) for categorical variables. SD, standard deviation. |