Clinical Implications, Risk Factors And Predictors with Mixed Candida/bacterial Bloodstream Infection (BSI), Especially in Cadiovascular Patients

Clinical Implications, Risk Factors And Predictors with Mixed Candida/bacterial Bloodstream Infection (BSI), Especially in Cadiovascular Patients

Clinical Implications, Risk Factors And Predictors with Mixed Candida/bacterial Bloodstream Infection (BSI), Especially in Cadiovascular Patients

Data analysis

Patient characteristics

Abstract

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Introduction

Methods

Data analysis

Results

Patient characteristics

Discussion

Conclusion

Declarations

References

Additional Declarations

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Study Design And Setting

Study population

Definition

Data collection

Species distribution

Predictive factors

Clinical outcome

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Version 1

Study Design And Setting

Study population

Definition

Data collection

Species distribution

Predictive factors

Clinical outcome

Status:

Version 1

doi:10.21203/rs.3.rs-2443276/v1

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Background. To identify the clinical implications, risk factors and predictors with mixed candida/bacterial bloodstream infection (BSI) of cadiovascular patients in Guangdong Provincial People’s Hospital, Guangzhou, Guangdong, China (a third-class hospital with a strong focus on cardiovascular disease). We conducted a retrospective case-control study of patients complicated with candidaemia over the past 10-year period to identify the risk factors and clinical implications of mixed candidia/bacterial BSIs vs. monobacterial candidiasis.

Method. We searched all discharged patients' diagnoses for icd codes related to candida bloodstream infection. We have made two sets of comparisons:1. Two groups of patients were compared: all cadiovascular patients with mixed candida/bacterial BSI (cases1 n=86), and all no cadiovascular patients with mixed candida/bacterial BSI (control 2 n=45); 2. Two groups of patients were compared: all patients with mixed candida/bacterial BSI (cases1 n=69), and all patients with mono candida BSI (control 2 n=62). Statistical analysis was performed using SPSS 25.0 statistical software. The independent sample t-test and chi-square analysis was used.

Result. The median age of the patients who have mixed candida / bacterial BSI was 63 years old, and 70.42% of these patients were male. Cardiovascular disease was the most common underlying disease of mixed candida / bacterial BSI, followed by neurological disease, and followed by tumors and diabetes. In cases of mono candida bloodstream infection, infection with Candida tropicalis and Candida albicans dominated. In cases of mixed bloodstream infection with bacterial candida, the highest proportion is Candida albicans. In the cases of candida bloodstream infection without cardiovascular underlying disease, it is Candida tropicalis, followed by Candida albicans. Opposite, in the cases with an underlying cardiovascular disease, the highest proportion is Candida albicans.

Conclusion. Our data show that older adults（age＞65 years）, men are more susceptible to candida bloodstream infections. Bacterial candida mixed bloodstream infections mostly led by staphylococcus sp. Procalcitonin（PCT）, white blood cell（WBC）, neutrophilicgranulocyte（N） were predictive for mixed bloodstream infection with bacterial candida species. Among the cases in our hospital, patients with underlying cardiovascular disease were associated with mixed bacterial candida infections.

Bloodstream infection

Candida

Mixed candida/bacterial bloodstream infection

Cadiovascular diseases.

It has been reported that the incidence of mixed candida/bacterial blood infections (BSIs) accounts for about 20% of all cases of candidaemia ^[1–3].Some existing studies have reported on the Candida bloodstream infection and haematological disease / granulocyte deficiency / diabetes / neurological disease association studies^{[4, 5]}. Nevertheless, most of these existing literatures regarding such polymicrobial BSIs are old, and very few studies have focused specifically on the patients with cadiovascular diseases. Statistics the data of the past decade, we found that candida bloodstream infection in our hospital may have some correlation with cardiovascular disease. However, in the last decade, the general management of cadiovascular diseases has greatly improved, including the application of new surgery, changes of bacterial and fungal prevention, and so on. The above-mentioned innovations may influence the clinical characteristics of BSIs in cadiovascular patients. Therefore, the retrospective, case-control research was performed to explore the incidence, clinical characteristics, risk factors, etiology, and clinical outcomes of mixed candida/bacterial BSIs in the cadiovascular patients in the new era.

The single-center retrospective observational, case-control study was conducted at the Guangdong Provincial People’s Hospital, a 2852-bed tertiary care teaching hospital with approximately 113,000 admissions per year, located in Guangzhou, Guangdong, China. There are 3 comprehensive intensive care units (ICUs) with 42 beds. It is the major medical center in South China for critical patients such as serious cardiac condition, severe pneumonia, cancer, malignant hematologic diseases and septic shock. Relative information on baseline characteristics, clinical features, etiology, empirical antibiotic therapy, and clinical outcomes were retrospectively collected. We also compared the clinical characteristics of patients to determine the factors influencing mortality. The study was approved by Guangdong Provincial People.

We identified all patients who had at least one positive blood culture for candida. Exclusion criteria are as follows: 1) patients with missing important clinical date; 2) a blood culture was considered to be contaminated. We reviewed all episodes of BSI that occurred in our clinical microbiology laboratory from 1 January 2011 to 30 September 2022. Finally,1. patients with mixed candida/ bacterial BSI (n = 71), and all patients with mono-candida BSI (n = 59). 2. patients with cadiovascular diseases(n = 86), and patients without cadiovascular diseases(n = 44) were included. The patients who were separated into two groups were all clinically diagnosed and confirmed with microbiology laboratory examinations.

Candida BSIs were defined as blood cultures that are positive of candida species one or more times from patients with relevant clinical manifestation. Mixed candida/bacterial BSIs were confirmed by candida species growing concomitantly with bacterial species from the same or different sets of blood cultures obtained within 72 hours. Neutropenia was defined as absolute neutrophil count less than 0.5 × 10E9/L. Central venous catheter (CVC)-related BSIs were defined as one of the following: (1) culture of the same candida from both the catheter tips and at least one percutaneous blood culture or (2) culture of the same candida from at least two blood samples (one from a catheter hub and the other from a peripheral vein) and growth detected from the catheter hub sample at least 2 h before growth were detected from the peripheral vein sample.

We searched all discharged patients' diagnoses for icd codes related to candida bloodstream infection from 1 January 2011 to 31 September 2022, and 130 were eligible after completing the screening. We have made two sets of comparisons:1. Two groups of patients were compared: all cadiovascular patients with mixed candida/bacterial BSI (cases1 n = 86), and all no cadiovascular patients with mixed candida/bacterial BSI (control 2 n = 45); 2.Two groups of patients were compared: all patients with mixed candida/bacterial BSI (cases1 n = 69), and all patients with mono candida BSI(control 2 n = 62).

For all eligible patients, the clinical data were retrieved from the patients’ electronic medical records. The following data were collected: sex, age, admitting department, underlying disease, sample sites, date of blood collection, date of the first positive blood culture, date of admission and discharge, medical history, treatment record, laboratory test results, final discharge diagnosis, all invasive procedures, length of hospital stay, length of ICU stay, prior hospital stay before onset of bacterial organism or candida spp BSI.

Statistical analysis was performed using SPSS 25.0 statistical software. The independent sample t-test and chi-square analysis was used.

All patients in 4 groups were included in the analysis, the characteristics of patients were shown in Table 1. The median age of the mixed candida / bacterial BSI was 63 years, and 70.42% (50 / 71) of the patients were male. Cardiovascular disease was the most common underlying disease of mixed candida / bacterial BSI (74.65%, 53 / 71), followed by neurological disease (36.62%, 26 / 71), followed by tumors (19.72%, 14 / 71) and diabetes (18.31%, 13 / 71). Compared with candida BSI, cardiovascular disease, tumor, blood disease and granulocyte deficiency neurological disease in patients with mixed candida / bacterial BSI(p < 0.05). Patients with mixed candida / bacterial BSI all had longer icu hospital stay, and higher icu occupancy rates before the onset of bacterial microorganisms or candida BSI.

Table 1

Characteristics of patients
Characteristic	mono candida BSI(n = 59)	mixed candida/bacterial BSI(n = 71)	no cadiovascular patients with candida BSI (n = 44)	cadiovascular patients with candida BSI(n = 86)
Male sex	41	50	33	58
Age, median years (IQR)	51.5	63	62	61.5
Underlying disease
None	5	10	15	0
solid tumor	27	14	26	15
DM	10	13	1	22
Chronic nephrosis	5	7	0	12
Chronic liver disease	8	1	0	9
COPD	2	9	1	10
Cardiovascular disease	35	53	0	86
Neurological disease	14	26	6	34
Haematological disease	21	6	13	14
Neutroprnia	15	3	14	4
Surgery in previous 30 days	18	31	16	33
Picc	52	59	37	79
^bPrior hospital stay, median	22	25	24.5	24
ICU residence	26	51	12	65
Length of ICU stay, median	0	7.5	6	6.5
Length of hospital stay, median (	44.5	49	46	46.5

The median age of the patients without the underlying cardiovascular disease was 62 years old, and 75% (33 / 44) of the patients were male. Tumor was the most common underlying disease among such patients (59.09%, 26 / 44); the median age of patients with underlying cardiovascular disease was 61.5 years, and 67.44% (58 / 86) were male and the most diabetic (22 / 86,25.58%).

In addition, we classified the species of bsi with the results shown below (Table 2; Fig. 1). Based on the data that we count here, as shown in the table below, in cases of C. monororis bloodstream infection, infection with Candida tropicalis and Candida albicans dominated (n = 26, n = 23). In cases of mixed bloodstream infection with bacterial candida, the highest proportion is Candida albicans (n = 29). This was followed by near-smooth Candida (n = 17). Candida tropicalis was followed by others (n = 13); In addition, the species of Candida infected with or without cardiovascular underlying disease also showed significant differences: in the cases of candida bloodstream infection without cardiovascular underlying disease it is Candida tropicalis (n = 24), followed by Candida albicans (n = 12). Opposite, in the cases with an underlying cardiovascular disease, the highest proportion is Candida albicans (n = 40). This was followed by near-smooth Candida (n = 19). Then came Candida tropicalis (n = 15). In the cases of mixed bacterial candida infections, the most common bacteria were Staphylococcus bacteria (n = 27), with the most surface Staphylococcus bacteria (n = 14), followed by Staphylococcus gold bacteria (n = 5). The second most bacteria is Enterococcus faecium (n = 14), the third most is Klebsiella pneumoniae (n = 12), and the fourth most is Paratyphoid C (n = 7). Although staphylococci are the first, the overall bacteria is gram-negative bacteria, which is consistent with the conclusion of previous studies.

We collected the serological indicators from all patients, and analyzed the relevant indicators after infection, as illustrated in following figure. Since the collected pct, fungal D experiments, leukocyte counts, and neutrophil counts were analyzed did not satisfy the normal distribution and homogeneity of variance, we could not use ANOVA to analyze the data. Therefore, we chose the statistical method of independent sample T test, and after analysis, pct, neutrophils, leukocytes were significantly different between groups 1 and 2, that is, pct, neutrophils, leukocytes may be the index used to predict the blood stream infection of mixed Candida bacteria (Fig. 2).

According to our data, the prognosis of these infected cases is usually very poor, with very few patients being discharged from hospital. In our statistics, 51.54% (67 / 130), with Candida mono 32 (54.24%, 32 / 59) and mixed bacterial Candida 35 (49.30%, 35 / 71). There were 50 patients (58.14%, 50 / 86%) of infected patients with uninfected cardiovascular diseases, and 17 patients (38.64%, 17 / 44%) were all uninfected patients. According to the statistical results (Table 3–6), the clinical prognosis of mono candida and mixed bacterial candida infections were not significantly different, and the clinical prognosis of infected patients with and those without basic cardiovascular disease was 0.

Table 3．The chi-square test of whether bacterial Candida is mixed bloodstream infection in patients with cardiovascular vs patients without cardiovascular

Crosstab
Count
		group		Total
		Mono	Mixed
cardiovascular	Without	26	18	44
	With	33	53	86
Total		59	71	130

Chi-Square Tests
	Value	df	Asymptotic Significance (2-sided)	Exact Sig. (2-sided)	Exact Sig. (1-sided)
Pearson Chi-Square	5.041^a	1	.025
Continuity Correction^b	4.240	1	.039
Likelihood Ratio	5.047	1	.025
Fisher's Exact Test				.027	.020
Linear-by-Linear Association	5.002	1	.025
N of Valid Cases	130
a. 0 cells (0.0%) have expected count less than 5. The minimum expected count is 19.97.
b. Computed only for a 2x2 table

Table 4．The chi-square test of whether bacterial Candida is mixed bloodstream infection in patients with hematopathy vs patients without hematopathy

Crosstab
Count
		hematopathy		Total
		without	with
group	mono	48	25	73
	mixed	64	5	69
Total		112	30	142

Chi-Square Tests
	Value	df	Asymptotic Significance (2-sided)	Exact Sig. (2-sided)	Exact Sig. (1-sided)
Pearson Chi-Square	15.519a	1	.000
Continuity Correctionb	13.941	1	.000
Likelihood Ratio	16.736	1	.000
Fisher's Exact Test				.000	.000
Linear-by-Linear Association	15.409	1	.000
N of Valid Cases	142
a. 0 cells (0.0%) have expected count less than 5. The minimum expected count is 14.58.
b. Computed only for a 2x2 table

Table 5．The chi-square test of whether bacterial Candida is mixed bloodstream infection in patients with agranulocytic vs patients without agranulocytic

Crosstab
Count
		agranulocytic		Total
		without	with
group	mono	65	8	73
	mixed	68	1	69
Total		133	9	142

Chi-Square Tests
	Value	df	Asymptotic Significance (2-sided)	Exact Sig. (2-sided)	Exact Sig. (1-sided)
Pearson Chi-Square	5.404a	1	.020
Continuity Correctionb	3.921	1	.048
Likelihood Ratio	6.153	1	.013
Fisher's Exact Test				.034	.021
Linear-by-Linear Association	5.366	1	.021
N of Valid Cases	142
a. 2 cells (50.0%) have expected count less than 5. The minimum expected count is 4.37.
b. Computed only for a 2x2 table

Table 6．The chi-square test of whether bacterial Candida is mixed bloodstream infection in patients with tumor vs patients without tumor

Crosstab
Count
		group		Total
		mono	mixed
tumor	with	31	57	88
	without	27	14	41
Total		58	71	129

Chi-Square Tests
	Value	df	Asymptotic Significance (2-sided)	Exact Sig. (2-sided)	Exact Sig. (1-sided)
Pearson Chi-Square	10.601a	1	.001
Continuity Correctionb	9.400	1	.002
Likelihood Ratio	10.679	1	.001
Fisher's Exact Test				.001	.001
Linear-by-Linear Association	10.519	1	.001
N of Valid Cases	129
a. 0 cells (0.0%) have expected count less than 5. The minimum expected count is 18.43.
b. Computed only for a 2x2 table

Mixed C/B-BSIs occupied a high proportion of 54.6% among candidemia in the current study, which was consistent with previous studies that 18–56% of nosocomial candidemia are polymicrobial^[³^,⁴^,^6-9^]. A 30.8% (20/65) frequency of mixed C/B-BSIs in patients with hematological diseases was reported in a national key hematologic center in China^[⁴^]. These studies suggest that the proportion of polymicrobial candidemia is not rare, which deserves the attention of clinicians.

As mentioned by other researchers, Gram-negative organisms were most frequently isolated bacteria in mixed candida/ bacterial BSIs^[⁸^,¹⁰^,¹¹^]. In line with it, we found that Enterococcus faecium, surface Staphylococcus, Klebsiella pneumoniae were the three most common bacterias in case group. Recent literature suggests that, among non-fermenting Gram-negative bacilli, Stenotrophomonas maltophilia is the third commonest pathogen after Pseudomonas aeruginosa and Acinetobacter baumannii^[¹²^]. Compare with this, it seems higher incidence of Enterococcus faecium in our study. We consider this may be related to the particularity of the population in our study.

Furthermore, our data do not appear identical to the results of some previous studies. But some new conclusions can be drawn from our data. In the current study, many factors were associated with mixed C/B-BSIs. By multinomial regression analysis, cardiovascular diseases were found to be independent factors for mixed C/B-BSIs which is different from the conclusions of previous literature, possibly because our data are obtained from many critical / difficult patients with cardiovascular diseases in Guangdong Provincial People's Hospital (strong discipline: cardiovascular). It might be associated with prolonged hospitalization, and invasive diagnostic/therapeutic procedures. Peripherally Inserted Central Catheter (PICC) was an independent risk factor of mixed C/B-BSIs in our research, which was consistent with the previous study, showing that PICC was associated with the onset of secondary bacterial infection^[¹³^]. It may because of repeated hemodialysis access to the vascular system through a venous catheter, resulting in frequent episodes of bloodstream infection.

We found that cardiovascular basic disease, chronic liver disease, tumor, blood disease, granulocyte deficiency and the presence of mixed bacterial Candida infection: cardiovascular disease and significant positive correlation with mixed bacterial candida blood stream infection, tumor, blood disease, granulocyte deficiency with candida monophyte infection. In addition, we also conducted an analysis of the relevant indicators after the infection. These conclusions are roughly the same as in previous studies^[⁹^,¹⁴^]. In addition, we also found some serological index associations with them, which have not been found in the previous literature. Since the collected pct, fungal D experiments, leukocyte counts, and neutrophil counts were analyzed did not satisfy the normal distribution and homogeneity of variance, we could not use ANOVA to analyze the data. Therefore, we chose the statistical method of independent sample T test, and after analysis, pct, neutrophils, leukocytes were significantly different between groups 1 and 2, that is, pct, neutrophils, leukocytes may be the indicator used to predict the blood stream infection of mixed candida bacteria.

We therefore performed a second analysis, the second analysis of candida BSI with cardiovascular disease VS without cardiovascular disease. It is not difficult to see, cardiovascular basic disease of BSI accounted for the majority (86 / 130), back to the medical history of these patients, found that 33 patients have surgery within a month, most of them are in-heart / cardiac surgery: such as valve replacement, stenting, etc., these operations have one thing in common, is the trauma, and a foreign body implantation, picc tube. (The picc catheterization is considered as a high-risk factor for bsi. This has been mentioned several times in previous studies)^[¹³^]. It is worth mentioning that most of these patients also have diabetes mellitus (22 / 86), which is also one of the high-risk factors for fungal infections^[⁹^,¹⁴^]. The prognosis is usually poor if attention is not monitored for bloodstream infection.

In addition, if candida patients have no underlying cardiovascular disease, what are their clinical risk factors? According to our statistics, blood diseases and tumors account for the vast majority (13 / 44; 26 / 44), and the leukocyte and neutrophil counts of these patients are usually below normal values, and even many patients are in granulocyte deficiency. Combined with the previous Xiao’s article^[⁴^], we analyzed that the immunosuppression caused by tumor / chemotherapy puts the body in a low immune state, so it is more prone to fungal bloodstream infection. So we need further precautions against this, which is currently the most important problem to be solved.

All in all, our data show that older adults（age＞65 years, men are more susceptible to candida bloodstream infections. Bacterial candida mixed bloodstream infections led by staphylococcus sp. PCT, WBC, N were predictive for mixed bloodstream infection with bacterial Candida species. Among the cases in our hospital, patients with underlying cardiovascular disease were associated with mixed bacterial candida infections.

However, this study has several limitations. First, because of the retrospective study itself, some data such as patient characteristics or comorbidities were obtained based on medical records rather than interviews or clinical examination at the time of infection, which may cause some important information or variables that could not be accurately accessed. Second, the current study was conducted from a center with a relatively small number of patients, although it reviewed the records of candidemia in our hospital for over 10 years. In addition, because our hospital enjoys a high reputation in the field of cardiovascular treatment nationwide, the number of cardiovascular patients involved in this study is relatively large, and there may be a selection bias. Third, some important confounding variables of the mixed C / B-BSI may not be included and analyzed, an inherent flaw of the retrospective study. Therefore, multicenter studies with large samples are necessary to further investigate the characteristics and risk factors of the mixed C / B-BSI.

Our data show that older adults(age༞65 years), men are more susceptible to candida bloodstream infections. Bacterial candida mixed bloodstream infections mostly led by staphylococcus sp. PCT, WBC, N were predictive for mixed bloodstream infection with bacterial Candida species. Among the cases in our hospital, patients with underlying cardiovascular disease were associated with mixed bacterial candida infections.

Ethics approval and consent to participate: The study was performed in accordance with Research Ethics Committee of Guangdong Provincial People’s Hospital. (Number: GDREC2019451H) and conducted according to the principles of the Declaration of Helsinki. Our data does not involve patients’ privacy and therefore does not require the consent of participants.

Consent for publication: Not applicable

Availability of data and materials: The data that support the findings of this study are available from Guangdong Provincial People’s Hospital, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Guangdong Provincial People’s Hospital.

Competing interests: The authors declare that they have no competing interests

Funding: Not applicable

Authors' contributions: Y.Z contributed to the conception of the study. TY.H contributed to the design of the study. YR.Q analyzed the data. YR.Q, DD.Z and MQ.S wrote the first draft on the manuscript. SF.W, YF.L, and D.L contributed significantly to the discussion of the clinical presentation of sepsis. JX.H and F.H produced the figures. All authors contributed to manuscript revision, read, and approved the submitted version.

Acknowledgements: Thank Jieliang Liu for her constant encouragement.

Wargo MJ, Hogan DA. Fungal–bacterial interactions: a mixed bag of mingling microbes[J]. Curr Opin Microbiol. 2006;9(4):359–64.
Tortorano AM, Peman J, Bernhardt H, et al. Epidemiology of candidaemia in Europe: results of 28-month European Confederation of Medical Mycology (ECMM) hospital-based surveillance study[J]. Eur J Clin Microbiol Infect Dis. 2004;23(4):317–22.
Pulimood S, Ganesan L, Alangaden G, et al. Polymicrobial candidemia[J]. Diagn Microbiol Infect Dis. 2002;44(4):353–7.
Chen XC, Xu J, Wu DP. Clinical characteristics and implications of mixed candida/bacterial bloodstream infections in patients with hematological diseases[J]. Eur J Clin Microbiol Infect Dis. 2020;39(8):1445–52.
Smyth J, Mullen CC, Jack L, et al. Diabetes, malignancy and age as predictors of Candida glabrata bloodstream infection: A re-evaluation of the risk factors[J]. J Mycol Med. 2018;28(3):547–50.
Kim SH, Yoon YK, Kim MJ, et al. Risk factors for and clinical implications of mixed Candida/bacterial bloodstream infections[J]. Clin Microbiol Infect. 2013;19(1):62–8.
Bouza E, Burillo A, Muñoz P, et al. Mixed bloodstream infections involving bacteria and Candida spp[J]. J Antimicrob Chemother. 2013;68(8):1881–8.
Klotz SA, Chasin BS, Powell B, et al. Polymicrobial bloodstream infections involving Candida species: analysis of patients and review of the literature[J]. Diagn Microbiol Infect Dis. 2007;59(4):401–6.
Zhong L, Zhang S, Tang K, et al. Clinical characteristics, risk factors and outcomes of mixed Candida albicans/bacterial bloodstream infections[J]. BMC Infect Dis. 2020;20(1):810.
Wisplinghoff H, Seifert H, Wenzel RP, et al. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States[J]. Clin Infect Dis. 2003;36(9):1103–10.
Mikulska M, Viscoli C, Orasch C, et al. Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients[J]. J Infect. 2014;68(4):321–31.
Kim EJ, Kim YC, Ahn JY, et al. Risk factors for mortality in patients with Stenotrophomonas maltophilia bacteremia and clinical impact of quinolone-resistant strains[J]. BMC Infect Dis. 2019;19(1):754.
Chopra V, Ratz D, Kuhn L, et al. PICC-associated bloodstream infections: prevalence, patterns, and predictors[J]. Am J Med. 2014;127(4):319–28.
Zhong L, Dong Z, Liu F, et al. Incidence, clinical characteristics, risk factors and outcomes of patients with mixed Candida/bacterial bloodstream infections: a retrospective study[J]. Ann Clin Microbiol Antimicrob. 2022;21(1):45.

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mono candida BSI(n = 59)

mixed candida/bacterial BSI(n = 71)

no cadiovascular patients with candida BSI(n = 44)

cadiovascular patients with candida BSI(n = 86)