Background {#Sec1}
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*Candida* is an important cause of bloodstream infections (BSIs) and it is the main agent of invasive fungal infection in hospitalized patients \[[@CR1], [@CR2]\]. Although *Candida albicans* is the most common cause of invasive candidiasis, infections due to *Candida* species other than *C. albicans* are rising \[[@CR3], [@CR4]\]. In particular, *Candida parapsilosis* complex, which includes *C. parapsilosis* sensu strictu (the most frequent), *Candida orthopsilosis* and *Candida metapsilosis*, has emerged as an important fungal pathogen and became one of the main causes of fungemia in tertiary-care hospitals \[[@CR5]--[@CR9]\]. Although the mortality rate due to this species is generally lower than that reported for other *Candida* species, *C. parapsilosis* complex possesses several distinct features, such as its ability to develop biofilms on intravascular devices, high affinity for parenteral nutrition, and an intrinsic low susceptibility to echinocandins \[[@CR10]--[@CR12]\].

The aim of this study was to analyze the factors related to outcome of candidemia due to *C. parapsilsosis* complex in a single institution over a five-year period.

Methods {#Sec2}
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Study population and data collection {#Sec3}
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A retrospective observational study of all cases of candidemia was carried out from January 1, 2010 to December 31, 2014 (5-year period) in a single 980-bedded referral University Hospital in Ancona, Italy. A case of *Candida* BSI was defined as a peripheral isolation of *Candida* species from blood culture in a patient with temporally related clinical signs and symptoms of infection. All *Candida* BSIs were identified through the microbiological laboratory database. Data regarding demographic characteristics and clinical risk factors were collected from the patient's medical records. Appropriate antifungal therapy was considered when an appropriate drug (based on subsequent in vitro susceptibility testing results) with adequate dosage was started within 72 h from the first blood culture performed. Adequate dosage of an antifungal agent was defined according to IDSA 2009 guidelines \[[@CR13]\]. Early central venous catheter (CVC) removal was defined a removal of the line within 48 h from drawing blood culture. Mortality was calculated after 7 and 30 days from the occurrence of the episode of *Candida* BSI.

*Candida* species were isolated from blood samples using BacT/ALERT (bioMérieux) and identified with standard techniques. Each of the three species of *C. parapsilosis* sensu lato was identified using the MALDI-TOF Biotyper™ \[[@CR14]\]. Antifungal susceptibility testing was performed using the SensitreYeastOne colorimetric plate (SYO) (Trek Diagnostic System) and MIC results were interpreted according to latest species-specific CBPs as established by the CLSI \[[@CR15]\].

The present research has been performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendements. The Institutional Review Board of the Azienda Ospedaliero-Universitaria Ospeadali Riuniti Umberto I°-Lancisi-Salesi granted retrospective access to the data without need for individual informed consent.

Statistical analysis {#Sec4}
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Quantitative data were shown as the median with interquartile ranges (Q1--Q3). Qualitative variables were expressed as absolute and relative frequencies. Categorical variables were compared using the χ2 test, whereas Mann--Whitney U test or Fisher exact test were applied for continuous variables. Variables with a *p* ≤0.05 at the descriptive analysis were analyzed by Cox regression. All statistical analyses were performed using the statistical package SPSS for Windows v. 20 (SPSS Inc., Chicago, IL, USA). A *P* value of ≤0.05 was considered to represent statistical significance and all statistical tests were two-tailed.

Results {#Sec5}
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Of 270 patients diagnosed with *Candida* BSIs during the study period, 63 (23 %) were infected with isolates of *C. parapsilosis* complex (95 *C. parapsilosis* sensu lato, 3 *C. orthopsilsosis* and 2 % *C. metapsilosis*). This species represented the second most frequently isolated yeast after *C. albicans* (146 \[54 %\]). The remaining infections were due to *C. tropicalis* (23 \[9\]), *C. glabrata* (10 \[4\]) and other *Candida species* (10 \[4 %\]). Although C. *albicans* represented the most commonly isolated species, its percentage significantly decreased from 68 % to 48 % in the time period considered (*p* = 0.040). On the opposite, there was a significant increase of the percentage of *C. parapsilosis* isolation from 8 % (2010) to 30 % (2014) (*p* = 0.036). The overall incidence rate of BSIs due to *C. parapsilosis* was 0.4 episodes/1000 hospital admissions.

Demographics and clinical characteristics of 63 patients infected with isolates of *C. parapsilosis* complex were compared with those of 146 patients infected with isolates of *C. albicans* and the results are shown in Table [1](#Tab1){ref-type="table"}. Median patients age was 67 years. Male accounted for 56 % of the population. Twenty-five isolates were recovered from patients hospitalized in medical wards, 21 from patients hospitalized in ICUs and 17 from patients hospitalized in surgical wards. The majority of patients (90 %) suffered from multiple comorbidities (range 2 to 4) being the most common cardiovascular (43) and gastrointestinal (33 %) diseases. A total of 51 % of patients underwent a surgical intervention within 30 days from the onset of candidemia. In comparison with *C. albicans*, BSIs due to *C. parapsilosis* were significantly more often associated with the use of CVC (*p* = 0.015). The overall crude mortality at 30 days was higher in patients infected with *C. albicans* than *C. parapsilosis* (42 % *vs* 27 %, respectively, *p* = 0.042).Table 1Comparison of epidemiological, clinical characteristics and outcome of patients with BSIs due to *Candida parapsilosis* and *Candida albicans*VariablesPatients with BSIs due to:*C. parapsilosis* (*n* = 63)*C. albicans* (*n* = 146)*P* value^*a*^Age (years), median (IQR)^*b*^67 (43--76)51 (66--77)0.133Neonates (\<3 months)1 (2)5 (3)0.465Elderly (\>65 years)32 (51)72 (49)0.844Male sex, *n (%)*35 (56)91 (63)0.358Ward Internal Medicine, *n (%)*25 (40)52 (36)0.448 Surgery, *n (%)*17 (27)32 (22) Intensive Care Unit, *n (%)*21 (33)62 (43)Comorbidities, *n (%)*57 (90)137 (94)0.387 Chronic pulmonary diseases, *n (%)* ^*c*^9 (14)11 (8)0.127 Haematological malignancy, *n (%)*1 (2)8 (5)0.203 Cardiovascular diseases, *n (%)* ^*d*^27 (43)67 (46)0.685 Neurological diseases, *n (%)* ^*e*^10 (16)24 (16)0.919 Gastrointestinal diseases, *n (%)* ^*f*^21 (33)43 (29)0.576 Diabetes mellitus, *n (%)*8 (13)28 (19)0.254 Solid tumors, *n (%)*15 (24)43 (30)0.403 Chronic renal failure, n (%)7 (11)12 (8)0.504Previous surgery (\<30 days)*, n (%)*32 (51)67 (46)0.514 Gastrointestinal surgery, *n (%)*8 (13)19 (13)0.950 Cardiovascular surgery, *n (%)*13 (21)28 (19)0.807 Other surgery, *n (%)* ^*g*^12 (19)24 (16)0.646Central venous catheter, *n (%)*56 (89)127 (87)0.702 BSI CVC-related, *n (%)*36 (64)57 (45)0.015Other devices, *n (%)* ^*h*^57 (90)129 (88)0.653Previous invasive procedures (\<72 h), *n (%)* ^*i*^16 (25)44 (30)0.486Parenteral nutrition, *n (%)*43 (68)105 (72)0.592Immunosuppressive therapy, *n (%)* ^*j*^18 (29)56 (34)0.174Neutropenia, *n (%)*4 (6)7 (5)0.644Septic shock, *n (%)*2 (3)12 (8)0.180Prior antibiotic therapy, *n (%)*58 (92)139 (95)0.370Previous antifungal therapy (\<30 days), *n (%)*5 (8)21 (14)0.195Concomitant bacteriemia, *n (%)*15 (24)40 (27)0.588Other coinfections, *n (%)* ^*k*^39 (62)89 (61)0.897Appropriate antifungal therapy*, n (%)* ^*l*^38 (60)92 (63)0.712 Primary azole therapy41 (65)77 (53)0.098 Primary echinocandin therapy7 (11)34 (23)0.041 Primary polyene therapy1 (2)3 (2)0.820 None14 (22)32 (22)0.961Overall mortality, *n (%)*17 (27)61 (42)0.042 Early mortality (days 1--7)*, n (%)*4 (6)24 (17)0.049 Late mortality (days 8--30), *n (%)*13 (21)37 (25)0.464^a^Comparisons between groups were performed using Wilcoxon rank sum test for quantitative variables and Chi-Square test (or Fisher Exact Test when expected frequencies were less than five) for qualitative variables^b^IQR, Interquartile range^c^Chronic pulmonary diseases include asthma, chronic bronchitis, emphysema and lung fibrosis^d^Cardiovascular diseases include heart failure, ischemic heart disease, endocarditis and arrhythmia^e^Neurological diseases include Parkinson's disease, Alzheimer's disease and paralysis^f^Gastrointestinal diseases include Crohn's disease, ulcerative colitis, chronic pancreatitis and gallbladder stones^g^ Other surgery includes plastic surgery, thoracic surgery, orthopaedic surgery, urological surgery and neurosurgery^h^ Other devices include urinary catheter, surgical drainage, cutaneous gastrostomy and tracheostomy tube^i^Previous invasive procedures include endoscopy and positioning of any device^j^Immunosuppressive therapy include corticosteroids, calcineurin inhibitors and monoclonal antibodies^k^Other coinfections include bacterial and/or fungal infections in sites other than blood^l^Appropriate antifungal therapy was considered when the appropriate drug with adequate dosage was started ≤ 72 h from the first blood culture performed

Factors related to outcome of 63 patients with BSIs due to *C. parapsilosis* are reported in Table [2](#Tab2){ref-type="table"}. Older age (*p* = 0.046), being hospitalized in ICU or in medical wards rather than in surgical wards (*p* = 0.033), being recently diagnosed with a cardiovascular disease (*p* = 0.006), and the lack of an early CVC removal (*p* = 0.003) were all factors associated with a significant higher probability of death at the descriptive analysis. On multivariate analysis, being hospitalized in ICU resulted independently associated with a significant higher risk of mortality (HR 4.625 \[CI95% 1.015--21.080\], *p* = 0.048). Conversely, early CVC removal was confirmed to be significantly associated with a lower risk of mortality (HR 0.299 \[CI95% 0.102--0.874\], *p* = 0.027).Table 2Outcome of 63 patients with BSIs due to *Candida parapsilosis* complex considered in this studyCharacteristics30-day outcomeSurvival (*n* = 46)Death (*n* = 17)*P* value^*a*^Age (years), median (IQR)^*b*^62 (31--75)76 (63--78)0.046Male sex, *n (%)*24 (52)11 (65)0.374Ward Internal Medicine, *n (%)*21 (46)4 (24)0.033 Surgery, *n (%)*14 (30)3 (18) Intensive Care Unit, *n (%)*11 (24)10 (59)Comorbidities, *n (%)*40(87)17(100)0.117 Chronic pulmonary diseases, *n (%)* ^*c*^5(11)4 (24)0.235 Haematological malignancy, *n (%)*1 (2)0 (0)0.540 Cardiovascular diseases, *n (%)* ^*d*^15 (33)12(71)0.006 Neurological diseases, *n (%)* ^*e*^9 (20)1(6)0.263 Gastrointestinal diseases, *n (%)* ^*f*^16 (35)5 (29)0.688 Diabetes mellitus, *n (%)*4 (9)4 (24)0.195 Solid tumors, *n (%)*9 (20)6 (35)0.193 Chronic renal failure, *n (%)*5 (11)2 (12)1.000Previous surgery (\<30 days)*, n (%)*23(50)9(53)0.835 Gastrointestinal surgery, *n (%)*5(11)3(18)0.671 Cardiovascular surgery, *n (%)*7(15)6(35)0.080 Other surgery, *n (%)* ^*g*^11(24)1 (6)0.154Central venous catheter, *n (%)*41(89)15 (88)0.920 BSI CVC-related, *n (%)*25 (61)11 (73)0.460 Early central venous catheter removal, *n (%)* ^*h*^41 (100)11 (73)\<0.0001Other devices, *n (%)* ^*i*^40 (87)17(100)0.178Previous invasive procedures (\<72 h), *n (%)* ^*j*^9 (20)7 (41)0.080Parenteral nutrition, *n (%)*29 (63)14 (82)0.143Immunosuppressive therapy, *n (%)* ^*k*^13(28)5(29)0.920Neutropenia, *n (%)*3 (7)1 (6)1.000Septic shock, *n (%)*1(2)1(6)0.470Prior antibiotic therapy, *n (%)*42 (91)16 (94)0.713Previous antifungal therapy, *n (%)*4 (9)1 (6)0.713Concomitant bacteriemia, *n (%)*12(26)3(18)0.487Other coinfections, *n (%)* ^*l*^28 (61)11(65)0.780Appropriate antifungal therapy^*m*^30 (65)8 (47)0.190 Primary azole therapy32 (70)9 (53)0.219 Primary echinocandin therapy5 (11)2 (12)1.000 Primary polyene therapy1 (2)0 (0)1.000 None8 (17)6 (35)0.129^a^Comparisons between groups were performed using Wilcoxon rank sum test for quantitative variables and Chi-Square test (or Fisher Exact Test when expected frequencies were less than five) for qualitative variables^b^ IQR, Interquartile range^c^Chronic pulmonary diseases include asthma, chronic bronchitis, emphysema and lung fibrosis^d^Cardiovascular diseases include heart failure, ischemic heart disease, endocarditis and arrhythmia^e^Neurological diseases include Parkinson's disease, Alzheimer's disease and paralysis^f^Gastrointestinal diseases include Crohn's disease, ulcerative colitis, chronic pancreatitis and gallbladder stones^g^Other surgery includes plastic surgery, thoracic surgery, orthopaedic surgery, urological surgery and neurosurgery^h^ Early CVC removal was considered occurring within 48 h from blood cultures drawing^i^ Other devices include urinary catheter, surgical drainage, cutaneous gastrostomy and tracheostomy tube^j^ Previous invasive procedures include endoscopy and positioning of any device^k^Immunosuppressive therapy include corticosteroids, calcineurin inhibitors and monoclonal antibodies^l^ Other coinfections include bacterial and/or fungal infections in sites other than blood^m^Appropriate antifungal therapy was considered when the appropriate drug with adequate dosage was started within 72 h the first blood culture performed

Table [3](#Tab3){ref-type="table"} shows the results of antifungal susceptibility testing to nine antifungal agents as routinely performed by the SYO method which was developed to provide an easy alternative to the CLSI procedure. With the exception of one isolate that showed to be susceptible dose dependent to fluconazole (MIC 4 μg/ml) and two isolates which were found to have non-wild type phenotype for flucytosine (MIC 1 μg/ml), all isolates showed to be fully susceptible to all antifungals according to the CLSI interpretation \[[@CR15]\].Table 3In vitro susceptibilities of *Candida parapsilosis* complex isolates considered in this studyAntifungal agentsMIC range (μg/ml)MIC~50~ (μg/ml)MIC~90~ (μg/ml)% of isolates in the indicated category according to CLSI^*a*^SSDDIRWTNon-WTAmphotericin B≤0.12--10.50.5\-\-\--1000Flucytosine≤0.06--1≤0.060.25\-\-\--973Fluconazole≤0.12--40.25198.41.6-0\--Itraconazole≤0.015--0.250.060.12\-\-\--1000Voriconazole≤0.008--0.06≤0.0080.0151000-0\--Posaconazole≤0.008--0.120.030.06\-\-\--100-Caspofungin0.06--10.250.5100-00\--Anidulafungin0.12--20.52100-00\--Micafungin0.12--212100-00\--^*a*^Category was interpreted according to CLSI breakpoints as reported in ref. 15. S, susceptible; *SDD* susceptible dose dependent, *I* intermediate, *R* resistant, *WT* wild type

Discussion and conclusions {#Sec6}
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Although *C. albicans* remains the most common fungal isolate from blood, longitudinal studies showed a trend toward an increased prevalence of other *Candida* spp. with a larger proportion of *C. glabrata* in the United States and *C. parapsilosis* in some European (i.e.: Italy or Spain) and Latin American countries \[[@CR3]--[@CR9]\]. As far, few studies focused on the specific predictors influencing the outcome of BSIs due to *C. parapsilosis* \[[@CR16]--[@CR18]\].

First, we confirmed that the mortality due to this species is somewhat lower than that reported for *C. albicans*, having found a rate of 27 % at 30 days. This figure is consistent with literature data in which the 30-day mortality due to this species ranges from 23 % to 30 % \[[@CR14], [@CR19]--[@CR21]\].

Second, hospitalization in ICU showed to be independently associated with higher risk of mortality. Our data are in agreement with a large study showing a mortality rate increasing from 29 % to 47 % in patients with BSIs due to *Candida* spp. hospitalized, respectively, in non-ICU and ICU wards \[[@CR22]\]. ICU stay would represent a surrogate marker of illness severity thereby facilitating the poor outcome of this population group.

Third, we showed that early CVC removal is protective in BSIs due to *C. parapsilosis.* Although the impact of CVC management has been extensively investigated on the outcome of patients with candidemia, few studies have examined this issue across individual *Candida* species. Two recent studies showed that CVC removal exerted a protective effect on the outcome of candidemia due to *C. parapsilosis* \[[@CR14], [@CR20]\]. Since this species is characterized by a high propensity to develop biofilms on intravascular devices, their early removal play a fundamental role in determining the outcome of infection.

Fourth, we found that the outcome was not influenced by an appropriate antifungal therapy. Despite this finding is somewhat divergent from that reported by the current literature \[[@CR23]--[@CR25]\], there is a paucity of data considering the infection outcome of individual *Candida* species. In this regard, there are two important factors to consider. First, being *C. parapsilosis* less pathogenic than other *Candida* species (i.e.: *C. albicans* and *C. tropicalis*) \[[@CR17]\], BSIs due to this entity could be more deeply affected by a correct general management (i.e.: prompt removal of any central line) rather than an early therapeutic intervention. Second, we defined appropriate antifungal therapy as the appropriate drug with adequate dosage started within 72 h from the first blood culture performed. Since *C. parapsilosis* has a time to positivity of blood cultures longer than those reported for *C. albicans* and *C. tropicalis* \[[@CR26]\], preliminary blood culture showing the growth of yeast-like fungal pathogen could be delayed thereby determining an initial, although adequate, antifungal treatment after this time interval.

Interestingly, we found that primary antifungal treatment (i.e.: triazoles or echinocandins) did not influence the outcome of *C. parapsilosis* BSIs. Although, this *Candida* species possesses a natural low susceptibility profile to echinocandins \[[@CR12]\] and there is still a debate on the use of these molecules in infections caused by this species, either randomized or not-randomized clinical trials have shown not significant differences in the success rates between arms \[[@CR27]--[@CR30]\]. Our data, although with a limited number of patients, corroborated these findings.

The present study have some limitations. First, being a single-center study, the number of patients considered is low. This feature has certainly weakened the statistical power of the study. Nevertheless, we have made all attempts to collect and analyze as many as clinical data as possible to reveal useful information for the management of patients infected with this *Candida* species. Second, being a retrospective study encompassing several departments and medical disciplines over a five years period, there was not a univocal management of each individual case. In this respect, serial follow-up blood cultures were not systematically performed and we were unable to include important parameters, other then 30-day mortality, such as the persistence of positive blood cultures after the initiation of antifungal therapy.

In conclusion, our study shows that candidemia due to *C. parapsilosis* complex, the second most commonly causative agent of yeast BSIs in our center, is characterized by a non-negligible mortality at 30 days. While an early CVC removal is associated with significant reduced mortality, the type of primary antifungal therapy does not influence the outcome. Further prospective studies including higher number of patients are needed to corroborate these findings.

Abbreviations {#Sec7}
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BSIs, bloodstream infections; CBP, clinical breakpoints; CLSI, Clinical and Laboratory Standards Institute; CVC, central venous catheter; HR, hazard ratio; ICUs, Intensive Care Units; IDSA, Infectious Disease Society of America; MALDI-TOF, Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry; MICs, minimum inhibitory concentrations; Q1-Q3, interquartile range; spp, species; h, hours.; SPSS, Statistical Package for the Social Sciences; SYO, SensitreYeastOne colorimetric plate

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Availability of data and materials {#FPar1}
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The data cannot be shared as local Institutional Review Board has no policy to share the data without prior permission.

Authors' contributions {#FPar2}
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FB designed the study, analyzed data and wrote the article. EO, performed the acquisition of data, analyzed data and wrote the article. PO, CC, and FS, provided the clinical data. EM, provided the laboratory data. All authors drafted the article, revised it critically for important intellectual content, and approved the final article.

Competing of interests {#FPar3}
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The authors declare that they have no competing interests. The authors alone are responsible for the content and the writing of the paper.

Consent for publication {#FPar4}
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Not applicable.

Ethics approval and consent to participate {#FPar5}
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The present research has been performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendements. The Institutional Review Board of the Azienda Ospedaliero-Universitaria Ospeadali Riuniti Umberto I°-Lancisi-Salesi granted retrospective access to the data without need for individual informed consent.
