Clinical Features, Strain Distribution, Antifungal Resistance and Prognosis of Patients with Non-albicans Candidemia: A Retrospective Observational Study

Figures & data

Figure 1 Flow diagram of patient recruitment.

Table 1 Baseline Characteristics of Patients with C. albicans and NAC Candidemia

Characteristics	Total (n=301)	C. albicans (n=140)	NAC (n=161)	P-value
Age, median years (IQR)	66.0(53.0,75.5)	68.0(58.2,75.0)	64.0(49.0,77.5)	0.338
Age (≥60years), n(%)	200(66.4%)	102(72.9%)	98(60.9%)	0.028*
Male sex, n(%)	193(64.1%)	82(58.6%)	111(68.9%)	0.061
Ward
Medical ward, n(%)	44(14.6%)	14(10.0%)	30(18.6%)	0.034*
Surgical ward, n(%)	63(20.9%)	37(26.4%)	26(16.1%)	0.029*
ICU, n(%)	194(64.5%)	89(63.6%)	105(65.2%)	0.766
Nosocomial infection, n(%)	274(91.0%)	130(92.9%)	144(89.4%)	0.301
Baseline comorbidities
Chronic pulmonary disease, n(%)	18(6.0%)	8(5.7%)	10(6.2%)	0.856
Haematological malignancy, n(%)	12(4.0%)	1(0.7%)	11(6.8%)	0.007*
Chronic cardiac insufficiency, n(%)	49(16.3%)	29(20.7%)	20(12.4%)	0.052
Neurological disease, n(%)	51(16.9%)	18(12.9%)	33(20.5%)	0.078
Diabetes mellitus, n(%)	55(18.3%)	34(24.5%)	21(13.0%)	0.012*
Solid tumor, n(%)	71(23.6%)	40(28.6%)	31(19.3%)	0.058
Solid organ transplant recipient, n(%)	5(1.7%)	4(2.9%)	1(0.6%)	0.288
Chronic kidney disease, n(%)	28(9.3%)	11(7.9%)	17(10.6%)	0.421
Chronic liver disease, n(%)	30(10.0%)	17(12.1%)	13(8.1%)	0.240
Gastrointestinal disease, n(%)	96(31.9%)	54(38.6%)	42(26.1%)	0.020*
Severe burn, n(%)	15(5.0%)	4(2.9%)	11(6.8%)	0.114
CCI, median (IQR)	4.0(3.0,6.0)	5.0(3.0,7.0)	4.0(3.0,6.0)	0.119
APACHE II score, median (IQR)	17.0(12.0,22.5)	17.0(11.2,23.7)	16.0(12.0,22.0)	0.711
SOFA score, median (IQR)	6.0(3.0,9.0)	6.0(3.0,9.0)	6.00(3.0,9.5)	0.670
Risk factors
Current and former smoker, n(%)	99(32.9%)	41(29.3%)	58(36.0%)	0.215
Septic shock on admission, n(%)	32(10.6%)	20(14.3%)	12(7.5%)	0.055
Surgery, n(%)	171(56.8%)	95(67.9%)	76(47.2%)	0.000**
Abdominal surgery, n(%)	71(23.6%)	48(34.3%)	23(14.3%)	0.000**
Steroid therapy, n(%)	15(5.0%)	9(6.4%)	6(3.7%)	0.283
Immunosuppressive therapy, n(%)	8(2.7%)	6(4.3%)	2(1.2%)	0.201
Chemotherapy/radiation, n(%)	23(7.6%)	7(5.0%)	16(9.9%)	0.108
Blood transfusion, n(%)	115(38.2%)	60(42.9%)	55(34.2%)	0.121
Prior antifungal exposure^a, n(%)	26(8.6%)	6(4.3%)	20(12.4%)	0.012*
Prior antibiotics exposure^a, n(%)	259(86.0%)	121(86.4%)	138(85.7%)	0.858
TPN, n(%)	198(65.8%)	97(69.3%)	101(62.7%)	0.232
Neutropenia, n(%)	17(5.6%)	5(3.6%)	12(7.5%)	0.146
Invasive devices
Mechanical ventilation, n(%)	171(56.8%)	77(55.0%)	94(58.4%)	0.554
Presence of CVC, n(%)	226(75.1%)	118(84.3%)	108(67.1%)	0.001*
Presence of PICC, n(%)	55(18.3%)	15(10.7%)	40(24.8%)	0.002*
Presence of arterial catheter, n(%)	98(32.6%)	55(39.3%)	43(26.7%)	0.020*
Presence of urethral catheter, n(%)	267(88.7%)	129(92.1%)	138(85.7%)	0.079
Presence of gastric tube, n(%)	246(77.4%)	110(80.9%)	119(73.9%)	0.137
Presence of abdominal drainage tube, n(%)	67(22.3%)	45(32.1%)	22(13.7%)	0.000**
Blood purification, n(%)	79(26.2%)	38(27.1%)	41(25.5%)	0.724
Prior hospital stay, median days (IQR)	15.0(6.0,31.0)	14.5(5.2,31.7)	16.0(6.0,31.0)	0.654
Prior ICU stay, median days (IQR)	5.0(0.0,19.5)	5.0(0.0,15.5)	6.0(0.0,21.0)	0.213

Notes: *P<0.05, **P<0.001. ^aAll patients received systemic drug therapy for ≥3 days within 2 weeks before onset of candidemia.

Abbreviations: C. albicans, Candida albicans; NAC, non-albicans Candida; IQR, interquartile range; ICU, intensive care unit; CCI, Charlson Comorbidity Index; APACHE, acute physiology and chronic health evaluation; SOFA, sequential organ failure assessment; TPN, total parenteral nutrition; CVC, central venous catheter; PICC, peripherally inserted central catheter.

Table 2 Biological Parameters of Patients with C. albicans or NAC Candidemia

Variables	Total (n=301)	C. albicans (n=140)	NAC (n=161)	P-value
Temperature>38°C, n(%)	222(73.8%)	97(69.3%)	125(77.6%)	0.100
Temperature<36°C, n(%)	9(3.0%)	3(2.1%)	6(3.7%)	0.642
Laboratory data
WBC(×10^9 /L), n(%)
<4	34(11.3%)	7(5.0%)	27(16.8%)	0.001*
>10	127(42.2%)	65(46.4%)	62(38.5%)	0.165
NC(×10^9 /L), median(IQR)	7.8(4.8,11.9)	8.6(5.4,17.8)	7.0(4.0,10.7)	0.005*
LC(×109 /L), median(IQR)	0.7(0.3,1.1)	0.7(0.4,1.0)	0.7(0.3,1.1)	0.585
NLR, median(IQR)	11.4(6.3,19.9)	12.3(8.2,23.0)	9.2(5.5,17.5)	0.003*
Anaemia, n(%)	267(88.7%)	124(88.6%)	143(88.8%)	0.946
Thrombocytopaenia, n(%)	152(50.5%)	71(50.7%)	81(50.3%)	0.944
Hypoproteinemia, n(%)	127(42.2%)	56(40.0%)	71(44.1%)	0.473
TB(μmol/L), median(IQR)	16.0(11.0,31.0)	18.5(11.0,35.6)	15.0(10.0,28.0)	0.029*
AST(U/L), median(IQR)	39.0(26.0,65.5)	43.0(27.0,75.5)	36.0(25.0,57.5)	0.080
ALT(U/L), median(IQR)	32.0(21.0,64.0)	33.5(21.0,64.8)	30.0(19.5,63.0)	0.356
Renal failure, n(%)	64(21.3%)	36(25.7%)	28(17.4%)	0.078
PCT (ng/mL),n(%)
≥0.5, <2	90(29.9%)	44(31.4%)	46(28.6%)	0.589
≥2	90(29.9%)	49(35.0%)	41(25.5%)	0.072

Note: *P<0.05.

Abbreviations: C. albicans, Candida albicans; NAC, non-albicans Candida; WBC, white blood count; NC, neutrophil count; IQR, interquartile range; LC, Lymphocyte count; NLR, neutrophil to lymphocyte ratio; TB, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PCT, procalcitonin.

Table 3 Multivariable Logistic Regression of Risk Factors Caused by C. albicans vs NAC Candidemia

Variables	Unadjusted OR (95% CI)	P-value	Adjusted OR (95% CI)	P-value
Age (≥60 years)	1.726(1.058,2.813)	0.029*	1.522(0.878,2.638)	0.135
Medical ward	0.485(0.246,0.958)	0.037*	1.825(0.688,4.841)	0.226
Surgical ward	1.865(1.062,3.276)	0.030*	1.853(0.929,3.694)	0.080
Haematological malignancy	0.098(0.013,0.770)	0.027*	0.318(0.034,2.964)	0.315
Diabetes mellitus	2.138(1.174,3.895)	0.013*	2.267(1.186,4.334)	0.013*
Gastrointestinal disease	1.779(1.091,2.902)	0.021*	0.834(0.417,1.669)	0.608
Surgery	2.361(1.475,3.780)	0.000**	1.621(0.915,2.872)	0.098
Abdominal surgery	3.130(1.783,5.495)	0.000**	1.468(0.614,3.513)	0.388
Prior antifungal exposure	0.316(0.123,0.810)	0.016*	0.312(0.113,0.859)	0.024*
Presence of CVC	2.632(1.501,4.615)	0.001*	1.882(0.872,4.061)	0.107
Presence of PICC	0.363(0.191,0.691)	0.002*	0.696(0.321,1.507)	0.358
Presence of arterial catheter	1.776(1.091,2.889)	0.021*	1.600(0.904,2.832)	0.107
Presence of abdominal drainage tube	2.993(1.688,5.307)	0.000**	1.594(0.679,3.744)	0.284

Notes: *P<0.05, **P<0.001.

Abbreviations: C. albicans, Candida albicans; NAC, non-albicans Candida; CVC, central venous catheter; PICC, peripherally inserted central catheter; OR, odds ratio; CI, confidence interval.

Table 4 Distribution of Candida spp., Cross-Resistance and Prior Antifungal Exposure of Patients with Hematological Malignancy

Candida Species	Prior Antifungal Exposure n(%)	Cross-Resistance^a n(%)
C. albicans (n=1)	0(0.0%)	0(0.0%)
NAC (n= 11)	4(36.4%)	10(90.9%)
C. tropicalis (n= 10)	3(30.0%)	9(90.0%)
C. krusei (n = 1)	1(100.0%)	1(100.0%)

Notes: ^aCross-resistance was defined as resistance to any two or more azoles in the drug sensitivity tests in this study.

Abbreviations: C. albicans, Candida albicans; NAC, non-albicans Candida; C. tropicalis, Candida tropicalis; C. krusei, Candida krusei.

Figure 2 Distribution of different Candida spp. during this candidemia study period.

Table 5 Comparison of Antifungal Susceptibilities of Different Candida spp. in vitro

Species (n)	Antifungal Agent	S, n(%)	I, n(%)	R, n(%)
C. albicans (n= 140)	5-fluorocytosine	64(98.5%)	0(0.0%)	1(1.5%)
	Fluconazole	123(96.1%)	4(3.1%)	1(0.8%)
	Amphotericin B	134(100.0%)	0(0.0%)	0(0.0%)
	Voriconazole	124(99.2%)	0(0.0%)	1(0.8%)
	Itraconazole	128(95.6%)	3(2.2%)	3(2.2%)
	Clotrimazole	66(98.5%)	0(0.0%)	1(1.5%)
	Ketoconazole	25(42.4%)	21(35.6%)	13(22.0%)
	Nystatin	66(98.5%)	0(0.0%)	1(1.5%)
NAC (n=161)
C. tropicalis (n= 72)	5-fluorocytosine	36(100.0%)	0(0.0%)	0(0.0%)
	Fluconazole	31(44.3%)	4(5.7%)	35(50.0%)
	Amphotericin B	71(98.6%)	0(0.0%)	1(1.4%)
	Voriconazole	27(43.5%)	0(0.0%)	35(56.5%)
	Itraconazole	29(42.6%)	8(11.8%)	31(45.6%)
	Clotrimazole	12(23.5%)	4(7.8%)	35(68.6%)
	Ketoconazole	9(26.5%)	13(38.2%)	12(35.3%)
	Nystatin	32(97.0%)	1(3.0%)	0(0.0%)
C. parapsilosis (n=47)	5-fluorocytosine	24(100.0%)	0(0.0%)	0(0.0%)
	Fluconazole	42(93.3%)	2(4.4%)	1(2.2%)
	Amphotericin B	24(100.0%)	0(0.0%)	0(0.0%)
	Voriconazole	41(97.6%)	0(0.0%)	1(2.4%)
	Itraconazole	38(92.7%)	3(7.3%)	0(0.0%)
	Clotrimazole	19(90.5%)	1(4.8%)	1(4.8%)
	Ketoconazole	10(50.0%)	6(30.0%)	4(20.0%)
	Nystatin	20(100.0%)	0(0.0%)	0(0.0%)
C. glabrata (n= 31)	5-fluorocytosine	9(100.0%)	0(0.0%)	0(0.0%)
	Fluconazole	24(80.0%)	4(13.3%)	2(6.7%)
	Amphotericin B	31(100.0%)	0(0.0%)	0(0.0%)
	Voriconazole	25(96.2%)	0(0.0%)	1(3.8%)
	Itraconazole	14(56.0%)	6(24.0%)	5(20.0%)
	Clotrimazole	14(73.7%)	3(15.8%)	2(10.5%)
	Ketoconazole	8(42.1%)	4(21.1%)	7(36.8%)
	Nystatin	22(100.0%)	0(0.0%)	0(0.0%)
Other Candida spp.^a (n= 11)	5-fluorocytosine	3(100.0%)	0(0.0%)	0(0.0%)
	Fluconazole	7(70.0%)	1(10.0%)	2(20.0%)
	Amphotericin B	11(100.0%)	0(0.0%)	0(0.0%)
	Voriconazole	8(100.0%)	0(0.0%)	0(0.0%)
	Itraconazole	9(90.0%)	1(10.0%)	0(0.0%)
	Clotrimazole	8(100.0%)	0(0.0%)	0(0.0%)
	Ketoconazole	6(75.0%)	1(12.5%)	1(12.5%)
	Nystatin	8(100.0%)	0(0.0%)	0(0.0%)

Notes: Not all agents listed have been tested in all isolated species. ^aIncluded Candida famata (n = 4), Candida guilliermondii (n = 3), Candida (n = 2), Candida portuguese (n = 1), and Candida krusei (n = 1).

Abbreviations: S, susceptible; I, intermediate; R, resistant; C. albicans, Candida albicans; NAC, non-albicans Candida; C. tropicalis, Candida tropicalis; C. parapsilosis, Candida parapsilosis; C. glabrata, Candida glabrata.

Table 6 Clinical Features and Treatments of Patients with C. albicans or NAC at the Onset of Candidemia

Clinical Features and Treatments	Total (n=301)	C. albicans (n=140)	NAC (n=161)	P-value
Septic shock, n(%)	111(36.8%)	51(36.4%)	60(37.3%)	0.880
Fluid resuscitation, n(%)	70(23.3%)	30(21.4%)	40(24.8%)	0.484
Vasopressor therapy, n(%)	96(31.9%)	45(32.1%)	51(31.7%)	0.931
RRT, n(%)	22(7.3%)	5(3.6%)	17(10.6%)	0.020*
Hydrocortisone treatment, n(%)	4(1.3%)	1(0.7%)	3(1.9%)	0.385
Concomitant bacterial infection, n(%)	58(19.3%)	25(17.9%)	33(20.5%)	0.562
Source of candidemia
Catheter-related candidemia, n(%)	100(33.2%)	45(32.1%)	55(34.2%)	0.711
Pulmonary infection, n(%)	14(4.7%)	9(6.4%)	5(3.1%)	0.172
Urinary tract infection, n(%)	13(4.3%)	7(5%)	6(3.7%)	0.588
Intra-abdominal infection, n(%)	39(13.0%)	24(17.1%)	15(9.3%)	0.044*
Others^a, n(%)	129(42.9%)	52(37.1%)	77(47.8%)	0.062
Remove the catheters (≤48h) (45 vs 55)^b, n(%)	73(73.0%)	36(80.0%)	37(67.3%)	0.154
Adequate antifungal treatment, n(%)	99(32.9%)	48(34.1%)	51(31.7%)	0.631
Antifungal therapy + catheter removal (≤48h) (36 vs 37)^c, n(%)	38(52.1%)	21(58.3%)	17(45.9%)	0.290
Antifungal agents
Pyrroles, n(%)	167(55.5%)	72(51.4%)	95(59.0%)	0.187
Echinocandins, n(%)	141(46.8%)	66(47.1%)	75(46.6%)	0.923
Duration of antifungal therapy, median days (IQR)	9.0(4.0,16.5)	9.0(4.0,16.0)	10.0(4.0,17.0)	0.544
Antifungal resistance^d
5-fluorocytosine (65 vs 72)^e, n(%)	1(0.7%)	1(1.5%)	0(0.0%)	0.959
Fluconazole (128 vs 155)^e, n(%)	41(14.5%)	1(0.8%)	40(25.8%)	0.000**
Amphotericin B (134 vs 138)^e, n(%)	1(0.4%)	0(0.0%)	1(0.7%)	1.000
Voriconazole (125 vs 138)^e, n(%)	38(14.4%)	1(0.8%)	37(26.8%)	0.000**
Itraconazole (134 vs 144)^e, n(%)	39(14.0%)	3(2.2%)	36(25.0%)	0.000**
Clotrimazole (67 vs 99)^e, n(%)	39(23.4%)	1(1.5%)	38(38.4%)	0.000**
Ketoconazole (59 vs 81)^e, n(%)	37(26.4%)	13(22.0%)	24(29.6%)	0.314
Nystatin (67 vs 83)^e, n(%)	2(1.3%)	1(1.5%)	1(1.2%)	0.914

Notes: *P<0.05, **P<0.001. ^aThe source of infection could not be identified or primary infection. ^bThe numbers in parentheses represented the total numbers of Candida spp. with intravascular catheters. ^cThe numbers in parentheses represented the total numbers of Candida spp. with catheter removal. ^dNot all agents listed have been tested in all isolates. ^eThe numbers in parentheses represented the total numbers of Candida species performed susceptibility test.

Abbreviations: C. albicans, Candida albicans; NAC, non-albicans Candida; RRT, renal replacement therapy; IQR, interquartile range.

Table 7 In vitro Drug Resistance of Candida spp. to Azoles

Species (n)	Fluconazole	Voriconazole	Itraconazole	Clotrimazole	Ketoconazole	Cross-Resistance^a
	R, n(%)	R, n(%)	R, n(%)	R, n(%)	R, n(%)	n(%)
C. albicans (n= 140)	1(0.8%)	1(0.8%)	3(2.2%)	1(1.5%)	13(22.0%)	3(2.1%)
NAC (n= 161)
C. tropicalis (n= 72)	35(50.0%)	35(56.5%)	31(45.6%)	35(68.6%)	12(35.3%)	36(50.0%)
C. parapsilosis (n=47)	1(2.2%)	1(2.4%)	0(0.0%)	1(4.8%)	4(20.0%)	1(2.1%)
C. glabrata (n= 31)	2(6.7%)	1(3.8%)	5(20.0%)	2(10.5%)	7(36.8%)	3(9.7%)
Other species^b (n= 11)	2(20.0%)	0(0.0%)	0(0.0%)	0(0.0%)	1(12.5%)	1^c(9.1%)
Total (n=301)	41(14.5%)	38(13.1%)	11(4.0%)	39(23.5%)	37(26.6%)	44(14.6%)

Notes: Not all agents listed have been tested in all isolated species. ^aCross-resistance was defined as resistance to any two or more of the above azoles. ^bIncluded Candida famata (n = 4), Candida guilliermondii (n = 3), Candida (n = 2), Candida portuguese (n = 1), and Candida krusei (n = 1). ^cOnly one case of Candida krusei had cross-resistance in other Candida species.

Abbreviations: R, resistant; C. albicans, Candida albicans; NAC, non-albicans Candida; C. tropicalis, Candida tropicalis; C. parapsilosis, Candida parapsilosis; C. glabrata, Candida glabrata.

Table 8 Outcomes of Patients with C. albicans and NAC Candidemia

Outcomes	Total (n=301)	C. albicans (n=140)	NAC (n=161)	P -value
Length of ICU stay (M) (IQR)	14.0(1.0,38.0)	14.0(2.0,33.8)	15.0(0.5,46.0)	0.406
Length of hospital stay (M) (IQR)	35.0(19.3,65.0)	34.0(19.0,60.0)	37.5(20.2,70.0)	0.303
Crude 14-day mortality, n(%)	87(28.9%)	44(31.4%)	43(26.7%)	0.368
Crude 28-day mortality, n(%)	104(34.6%)	53(37.9%)	51(31.7%)	0.261
Crude 60-day mortality, n(%)	114(37.9%)	58(41.4%)	56(34.8%)	0.236
Crude in-hospital mortality, n(%)	122(40.5%)	62(44.3%)	60(37.3%)	0.216

Abbreviations: C. albicans, Candida albicans; NAC, non-albicans Candida; ICU, intensive care unit; M, median; IQR, interquartile range.

Figure 3 Kaplan-Meier estimates of survival in patients with C. albicans candidemia and NAC candidemia.