Bassetti et al. Critical Care (2020) 24:117 https://doi.org/10.1186/s13054-020-2793-y RESEARCH Open Access Factors associated with the development of septic shock in patients with candidemia: a post hoc analysis from two prospective cohorts Matteo Bassetti1,2,3* , Antonio Vena1,2,3, Marco Meroi1, Celia Cardozo4, Guillermo Cuervo5, Daniele Roberto Giacobbe2,3, Miguel Salavert6, Paloma Merino7, Francesca Gioia8, Mario Fernández-Ruiz9, Luis Eduardo López-Cortés10, Benito Almirante11, Laura Escolà-Vergé11, Miguel Montejo12, Manuela Aguilar-Guisado13, Pedro Puerta-Alcalde4, Mariona Tasias6, Alba Ruiz-Gaitán6, Fernando González7, Mireia Puig-Asensio11, Francesc Marco4, Javier Pemán6, Jesus Fortún8, Jose Maria Aguado9, Alejandro Soriano4, Jordi Carratalá5, Carolina Garcia-Vidal4, Maricela Valerio14,15, Assunta Sartor16, Emilio Bouza14,15,17,18 and Patricia Muñoz14,15,17,18 Abstract Background: Almost one third of the patients with candidemia develop septic shock. The understanding why some patients do and others do not develop septic shock is very limited. The objective of this study was to identify variables associated with septic shock development in a large population of patients with candidemia. Methods: A post hoc analysis was performed on two prospective, multicenter cohort of patients with candidemia from 12 hospitals in Spain and Italy. All episodes occurring from September 2016 to February 2018 were analyzed to assess variables associated with septic shock development defined according to The Third International Consensus Definition for Sepsis and Septic Shock (Sepsis-3). Results: Of 317 candidemic patients, 99 (31.2%) presented septic shock attributable to candidemia. Multivariate logistic regression analysis identifies the following factors associated with septic shock development: age > 50 years (OR 2.57, 95% CI 1.03–6.41, p = 0.04), abdominal source of the infection (OR 2.18, 95% CI 1.04–4.55, p = 0.04), and admission to a general ward at the time of candidemia onset (OR 0.21, 95% CI, 0.12–0.44, p = 0.001). Septic shock development was independently associated with a greater risk of 30-day mortality (OR 2.14, 95% CI 1.08–4.24, p = 0.02). Conclusions: Age and abdominal source of the infection are the most important factors significantly associated with the development of septic shock in patients with candidemia. Our findings suggest that host factors and source of the infection may be more important for development of septic shock than intrinsic virulence factors of organisms. Keywords: Candidemia, Septic shock, Intra-abdominal candidiasis, Risk factors * Correspondence: matteo.bassetti@unige.it 1 Infectious Diseases Clinic, Department of Medicine, University of Udine and Azienda Sanitaria Universitaria Integrata, Piazzale Santa Maria della Misericordia 15, 33010 Udine, Italy 2 Department of Health Sciences, University of Genoa, Genoa, Italy Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Bassetti et al. Critical Care (2020) 24:117 Page 2 of 9 Introduction The following variables were explored as possibly asso- Candida species has been reported as the most common ciated with septic shock development: cause of fungal disease in septic shock, affecting 8–10% of these patients [1–3]. Moreover, among patients devel- i. For patient variables, we considered age, sex, oping septic shock, candidemia is actually considered hospital ward stay at the time of infection, Charlson the clinical condition with the highest attributable mor- comorbidity index [8]),underlying diseases, tality, ranging from 54 to 66% [4–6]. The survival of immunosuppressive therapy, history of previous these patients is strictly related to a timely control of the abdominal surgery (30 days preceding candidemia source and appropriate antifungal treatment [4, 5]. onset), presence of central venous catheter (CVC) While candidemia has long been recognized as a trig- at the time of candidemia, total parenteral nutrition, ger for septic shock development, our understanding of and prior exposure to antimicrobial or antifungal why patients with candidemia develop or not septic therapy (within previous 30 days). shock has not been well addressed [7]. Literature on the ii. For infection variables, we considered source of topic is very limited and difficult to interpret due to the infection, pathogen species, and antifungal low number of patients included and the inconclusive resistance. results reported [7]. Therefore, the aim of our study was to assess factors All patients were followed until discharge or death and associated with the development of septic shock in the were assessed for survival on day 30. context of two large multicenter studies of patients with candidemia. Definitions An episode of candidemia was defined as at least one Materials and methods peripheral blood culture positive for Candida spp. Can- Study design, setting, and population didemia onset was defined as the date of collection of In the present report, we included data coming from the first blood culture yielding the study isolate. two separate studies. First is a prospective cohort assem- Septic shock was determined according to The Third bled within a quasi-experimental study aimed at asses- International Consensus Definition for Sepsis and Septic sing the impact of an evidence-based intervention Shock (Sepsis-3) [9]. All clinical and laboratory data de- bundle to improve the clinical management of candide- fining septic shock were assessed within 24 h of the first mia (the CANDI-Bundle Study) that was conducted positive blood culture yielding Candida spp. Patients from September 2016 to February 2018 in 11 hospitals were classified as having septic shock attributable to from Spain. Second is a prospective observational study Candida infection if vasopressors were required to on candidemia that was conducted during the same maintain a mean arterial pressure of ≥ 65 mmHg and period at the University Hospital Santa Maria della Mis- serum lactate level greater than 2 mmol/L [9]. Patients ericordia in Udine, Italy. The full results from both co- who required vasopressors ≥ 24 h prior to the collection horts are currently undergoing detailed analysis. of a blood culture subsequently positive for Candida In order to ensure comparability, the same inclusion species were included in the non-septic shock group. and exclusion criteria, study definitions, patient follow- As for the source of infection, CVC-related candide- up, and data collection procedures were applied in both mia was defined according to current guidelines [10, 11]. studies. However, for this post hoc analysis, we excluded The urinary tract was considered to be the portal of patients aged < 18 years old and those who had mixed entry in patients with urological predisposing conditions infection (concomitant blood culture positive for a bac- (i.e., manipulation or obstruction of the urinary tract) terial pathogen). and evidence of urinary tract infection caused by the The study was approved by the local institutional re- same Candida spp. [12]. The abdomen was considered view boards, and written patient consent was not re- to be the origin of the candidemia when a patient had quired because of observational nature of this study. evidence of abdominal infection and (i) a positive culture from the intra-abdominal space was obtained during Clinical data and definitions surgery or by needle aspiration or (ii) no other apparent Data were collected from patients’ hospital charts and sources of candidemia were detected [13–15]. When a the laboratory database, which contains complete pro- source of candidemia could not be identified, candide- files for all candidemic patients. The main outcome mia was defined as “primary.” measured was development of septic shock attributable Initial antifungal therapy was considered as adequate if to candidemia. Septic shock patients and non-septic at least one active drug according to in vitro susceptibil- shock subgroups were compared to identify variables as- ity results was initiated at an appropriate dosage [10] sociated with septic shock development. within the first 24 h after blood culture was obtained. Bassetti et al. Critical Care (2020) 24:117 Page 3 of 9 Source control included CVC withdrawal and invasive blood culture was drawn, and 34.3% of them died in 30 procedures to resolve urinary tract obstruction and days. intra-abdominal abscess drainage, depending on the source of candidemia. Source control was considered ad- Clinical characteristics of study population equate when performed within 24 h from candidemia Demographics and baseline clinical features of study onset. population are shown in Table 1. Mean age was 65.4 Neutropenia was defined as an absolute neutrophil years, and 184 patients were men (58.0%). Overall, 63 count< 500 cells/mm3 at the onset of candidemia. out of 317 (19.9%) episodes of candidemia occurred in intensive care unit (ICU), and 254 (80.1%) occurred in Microbiological studies patients hospitalized in general wards, including 150 Candida specie identification and in vitro antifungal ac- (47.3%) in internal medicine and 104 (32.8%) in surgical tivity were assessed at participating hospitals using local wards. routine methods. Currently, two sets of two blood sam- The most common underlying condition was solid ples were collected from patients with a suspected tumor (35.9%) followed by cardiovascular disease bloodstream infection. The blood samples were proc- (32.2%) and diabetes mellitus (28.4%). Almost all pa- essed using a BACTEC 9240 system (Becton– Dickinson tients had recently received antibiotic therapy (within Microbiology Systems, Franklin Lakes, NJ, USA) or the previous 1 month). A CVC was in place in 225 out BACTE 860 system or BacTAlert (BioMérieux SA, of 317 patients (71.0%), with 158 of them receiving total Marcy L’Etoile, France) with an incubation period of 5 parenteral nutrition at the time of candidemia onset. days. If yeast cells were observed after microscopic The most prevalent source of infection was the CVC examination of a Gram stain, blood bottles were subcul- (44.5%) followed by the abdomen that was detected in tured into Sabouraud agar plates (BD BBL StrackerTM 39 patients (12.3%). Source of candidemia remained un- PlatesTM, Heidelberg, Germany) and chromogenic known in 98 (30.9%) patients. media (ChromAgar BioMerieux SA, Paris, France). In As for species, C. albicans was the most frequent one vitro antifungal activity was studied by a commercial (42.3%) followed by C. glabrata (18.3%), C. parapsilosis microdilution method (YeastOne®Sensitre®, TREK Diag- (17.4%), and C. tropicalis (9.1%). nostic Systems Ltd., East Grinstead, UK) or E test (Bio- Mérieux SA, Paris, France), in accordance with the Variables associated with septic shock attributable to manufacturer’s instructions. candidemia Patients with septic shock attributable to candidemia (99 Statistical analysis patients) and without septic shock (218 patients) were Categorical variables are expressed as absolute numbers compared (Table 1). There were no significant differ- and relative frequencies. Quantitative variables are pre- ences regarding sex, Charlson comorbidity index, under- sented as means and standard deviation (SD) if normally lying disease, and risk factors for candidemia and distributed or as median and interquartile range (IQR) if Candida species. However, at univariate analysis, factors non-normally distributed. We compared continuous var- associated with development of septic shock were as fol- iables between patients with or without septic shock lows: age older than 50 years (92.9% vs 83.9%; p = 0.03), using the Student t test for normally distributed vari- hospitalization in ICU at the time of candidemia (37.4% ables and the Mann-Whitney U test for non-normally vs 11.9%, p = 0.001), and an abdominal source of the in- distributed variables. Categorical variables were evalu- fection (20.2% vs 8.7%; p = 0.006). A multivariate analysis ated by using the chi-square or the two-tailed Fisher (Table 2) showed that older age (OR 2.57, 95% CI 1.03– exact test. 6.41, p = 0.04) and an abdominal source of the infection Variables associated with septic shock due to candidemia (OR 2.18, 95% CI 1.04–4.55, p = 0.04) were independ- in univariate analysis (p ≤ 0.20) were included in a logistic ently associated with the development of septic shock in regression analysis, and a backward stepwise approach was candidemic patients. By contrast, being admitted to a used to identify those independently associated with septic general ward at the time of candidemia onset was con- shock development (p < 0.05). All statistical analyses were sidered as a protective factor (OR 0.21, 95% CI 0.12– performed by using SPSS Statistics for MAC, Version 22.0 0.44, p = 0.001). (SPSS Inc., Chicago, IL, USA). Comparison between patients with and without intra- abdominal origin of the infection is reported in Supple- Results mentary material 1. As for infection management, echi- A total of 317 episodes of candidemia were included in nocandin was the most frequent initial antifungal agent, the study. Overall, 99 of the 317 patients (31.2%) fulfilled prescribed in 57.7% of cases, followed by azoles in 35.3% the criteria for septic shock within the first 24 h after of patients. Although rates of initial echinocandin Bassetti et al. Critical Care (2020) 24:117 Page 4 of 9 Table 1 Comparison of the main demographic and clinical characteristics of study population Variable All episodes, N = 317 (%) Non-septic shock, N = 218 (%) Septic shock, N = 99 (%) p value Demographics Sex, male 184 (58.0) 141 (64.7) 43 (43.4) 0.17 Mean age (± SD), years 65.4 ± 17.0 65.2 ± 18.6 66.9 ± 15.2 0.77 Age ≥ 50 years 275 (86.4) 183 (83.9) 92 (92.9) 0.03 Median hospital stay until Candida BSI (IQR), days 16 (7–31) 17 (6–32) 14 (8–28) 0.18 Hospital ward stay at the time of candidemia onset General ward 254 (80.1) 192 (88.1) 62 (62.6) 0.001 Intensive care unit 63 (19.9) 26 (11.9) 37 (37.4) Charlson comorbidity index 3.4 ± 2.7 3.4 ± 2.6 3.3 ± 2.8 0.71 Underlying condition Solid tumor 114 (35.9) 77 (35.3) 37 (37.4) 0.80 Cardiovascular disease 102 (32.2) 69 (31.7) 33 (33.3) 0.79 Diabetes mellitus 90 (28.4) 57 (26.1) 33 (33.3) 0.22 Chronic Lung disease 51 (16.1) 35 (16.1) 16 (16.2) 1 Chronic kidney failure 50 (15.8) 32 (14.7) 18 (18.2) 0.50 Chronic liver disease 41 (12.9) 27 (12.4) 14 (14.1) 0.74 Solid organ transplantation 27 (8.5) 19 (8.7) 8 (8.1) 1 Hematological malignancy 20 (6.3) 16 (7.3) 4 (4.0) 0.32 Hematopoietic stem cell transplantation 9 (2.8) 8 (3.7) 1 (1.0) 0.28 Risk factors for candidemia Previous antibiotic therapy 297 (93.6) 202 (92.7) 95 (96.0) 0.32 Central venous catheter 225 (71.0) 150 (68.8) 75 (75.8) 0.23 TPN during candidemia 158 (49.8) 101 (46.3) 57 (57.6) 0.07 Previous corticosteroid therapy 72 (22.7) 51 (23.4) 21 (22.1) 0.77 Abdominal surgery 85 (26.8) 52 (23.9) 33 (33.3) 0.10 Immunosuppressive therapy 47 (14.8) 36 (16.5) 11 (11.1) 0.23 Neutropenia 10 (3.2) 9 (4.1) 1 (1.0) 0.18 Previous antifungal treatment 49 (15.4) 37 (17.0) 12 (12.1) 0.32 Source of infection Central venous catheter 141 (44.5) 101 (46.3) 40 (40.4) 0.33 Primary 98 (30.9) 73 (33.5) 25 (25.3) 0.15 Abdomen 39 (12.3) 19 (8.7) 20 (20.2) 0.006 Urinary tract 23 (7.3) 18 (8.3) 5 (5.1) 0.36 Infective endocarditis 3 (0.9) 1 (0.5) 2 (2.0) 0.23 Other 13 (4.1) 6 (2.8) 7 (7.1) 0.12 Candida species C. albicans 134 (42.3) 91 (41.7) 43 (43.4) 0.80 C. glabrata 58 (18.3) 38 (17.4) 20 (20.2) 0.63 C. parapsilosis 55 (17.4) 40 (18.3) 15 (15.2) 0.52 C. tropicalis 29 (9.1) 22 (10.1) 7 (7.1) 0.52 C. krusei 6 (1.9) 4 (1.8) 2 (2.0) 1 C. lusitaniae 4 (1.3) 2 (0.9) 2 (2.0) 0.59 C. auris 27 (8.5) 18 (8.3) 9 (9.1) 0.86 Other 13 (4.1) 11 (5.0) 2 (2.0) 0.35 Bassetti et al. Critical Care (2020) 24:117 Page 5 of 9 Table 1 Comparison of the main demographic and clinical characteristics of study population (Continued) Variable All episodes, N = 317 (%) Non-septic shock, N = 218 (%) Septic shock, N = 99 (%) p value Resistant strains Fluconazole 45 (14.1) 29 (13.3) 16 (16.2) 0.73 Echinocandins 3 (0.9) 2 (0.9) 1 (1.0) 1 BSI bloodstream infection, IQR interquartile range, SD standard deviation, TPN total parenteral nutrition therapy (65.3% vs 60.9%) or initial azole therapy (32.7% vs The incidence of septic shock is only collaterally men- 39.1%) were comparable, patients with an intra-abdominal tioned in reports on candidemia in the general popula- origin received an adequate initial antifungal treatment tions and it ranges from 12.9 to 49.0% in recent studies more often (38.1 vs 61.5, p = 0.008). No differences regard- [16–18]. However, only three series have specifically fo- ing the rates of adequate source control (43.4% vs 40.5%, cused on the incidence of septic shock among candi- p = 0.86) were observed between groups. demic patients. Patel et al. [19] in a single center retrospective study that ended in 2007 documented sep- Prognostic factors for 30-day mortality tic shock in 23% of patients with candidemia. The preva- We compared candidemic patients who died at 30 days lence was higher in two cohorts of critically ill patients (70 patients) with those who survived (247 patients). with candidemia in which septic shock developed in ~ Septic shock attributable to candidemia was present in 35% of them [7, 20]. Ours is the first study to analyze 48.6% of patients who died (34/70) in comparison to the prevalence of septic shock attributable to candide- 26.3% (65/247 patients) who survived (p = 0.001) mia, in the light of the new Sepsis-3 definition [9]. With (Table 3). The Kaplan-Meier curves in Fig. 1 demon- these new criteria, we found that septic shock occurred strate that patients with septic shock attributable to can- in almost one third of unselected candidemic patients. didemia had a significantly greater likelihood of dying We also found a significant difference in term of compared to patients not developing septic shock at prevalence between ICU patients and those admitted to candidemia onset. internal medicine and surgical ward, with a nearly two Variables examined as risk factors for 30-day mortality times greater proportion of septic shock in ICU patients. are presented in Table 3. Multivariate logistic regression Although such difference was not unexpected, an analysis demonstrated that a higher Charlson comorbid- underestimation of the number of cases of septic ity index and septic shock attributable to candidemia shock outside ICU should not be excluded. Regarding and requiring hemodialysis after candidemia onset were this aspect, new Sepsis-3 definitions showed low sen- independently associated with greater 30-day mortality, sitivity in non-critically ill patients and performed while CVC-related candidemia was independently asso- poorly as a screening tool for early identification of ciated with a lower risk of 30-day mortality (Table 3). sepsis outside ICU [21–23] Moreover, many patients admitted to internal medicine and surgical ward are Discussion frequently affected by multiple pre-existing underlying To the best of our knowledge, the current multicenter diseases [24–28]. In such circumstance, worsening of study is the largest one to identify variables associated clinical conditions can be often misled to the progres- with development of septic shock among patients with sion of the underlying disease rather than to infec- Candida bloodstream infection. We found a significant tion, as suggested by the low number of patients who rate of septic shock among patients with candidemia were admitted to ICU after candidemia onset in our (30%), and we also demonstrated that age more than study (~ 7%). 50 years old and an intra-abdominal origin of the infec- Factors predisposing candidemic patients to develop tion are the most important independent factors associ- septic shock have been reported in just one retrospective ated with septic shock development. study including only 15 patients with septic shock [7]. Table 2 Risk factors for development of septic shock at candidemia onset. Multivariate analysis Variable Odds ratio 95% confidence interval p value Age > 50 years 2.57 1.03–6.41 0.04 Intra-abdominal source of the infection 2.18 1.04–4.55 0.04 Male sex 1.33 0.78–2.26 0.29 Charlson comorbidity index 0.99 0.91–1.10 0.92 General ward stay at the time of candidemia onset 0.21 0.12–0.44 0.001 Bassetti et al. Critical Care (2020) 24:117 Page 6 of 9 Table 3 Risk factors for 30-day mortality (univariate and multivariate analysis) Variable All episodes, N = 317 (%) Alive, N = 247 (%) Died, N = 70 (%) p OR 95% CI p Demographics Sex, male 184 (58.0) 154 (62.3) 46 (61.4) 0.89 – – – Age ≥ 50 years 275 (86.8) 212 (85.8) 63 (90.0) 0.43 – – – Mean age (± SD), years 65.4 ± 17.0 64.8 ± 16.8 67.2 ± 17.7 0.30 – – – Median hospital stay until 16 (7–31) 15 (6–29) 20 (10–34) 0.09 – – Candida BSI (IQR), days Hospital ward General ward 254 (80.1) 201 (84.1) 47 (67.1) 0.003 1.9 0.93–4.30 0.78 Intensive care unit 63 (19.9) 38 (15.9) 23 (32.9) Charlson comorbidity index 3.4 ± 2.7 3.0 ± 2.4 4.6 ± 3.1 < 0.001 1.28 1.13–1.45 < 0.001 Underlying condition Solid tumor 114 (35.9) 91 (36.8) 23 (32.9) 0.57 – – – Cardiovascular disease 102 (32.2) 72 (29.1) 30 (42.9) 0.04 – – – Diabetes mellitus 90 (28.4) 68 (27.5) 22 (31.4) 0.55 – – – Chronic lung disease 51 (16.1) 36 (14.6) 15 (21.4) 0.20 – – – Chronic kidney failure 50 (15.8) 36 (14.6) 14 (20.0) 0.27 – – – Chronic liver disease 41 (12.9) 26 (10.5) 15 (21.4) 0.02 – – – Solid organ transplantation 27 (8.5) 22 (8.9) 5 (7.1) 0.81 – – – Hematological malignancy 20 (6.3) 15 (6.1) 5 (7.1) 0.78 – – – Hematopoietic stem cell transplantation 9 (2.8) 6 (2.4) 3 (4.3) 0.41 – – – Risk factors for candidemia Previous antibiotic therapy 297 (93.6) 232 (93.9) 65 (92.9) 0.78 – – – Central venous catheter 225 (71.0) 171 (69.2) 54 (77.1) 0.23 – – – TPN during candidemia 158 (49.8) 118 (47.8) 40 (57.1) 0.17 – – – Previous corticosteroid therapy 72 (22.7) 53 (21.5) 19 (27.1) 0.33 – – – Abdominal surgery 85 (26.8) 65 (26.3) 20 (28.6) 0.76 – – – Immunosuppressive therapy 47 (14.8) 39 (15.8) 8 (11.4) 0.45 – – – Neutropenia 10 (3.2) 7 (2.8) 3 (4.3) 0.46 – – – Previous antifungal treatment 49 (15.4) 37 (15.0) 12 (17.1) 0.71 – – – Source of infection Central venous catheter 141 (44.5) 122 (49.9) 19 (27.1) 0.001 0.42 0.20–0.88 0.02 Primary 98 (30.9) 71 (28.7) 27 (38.6) 0.14 – – Abdomen 39 (12.3) 22 (8.9) 17 (24.3) 0.001 1.89 0.76–4.66 0.17 Urinary tract 23 (7.3) 22 (8.9) 1 (1.4) 0.03 0.11 0.12–1.02 0.05- Infective endocarditis 3 (0.9) 3 (1.2) 0 (0) 1 – – – Other 13 (4.1) 7 (2.8) 6 (8.6) 0.05 – – – Septic shock 99 (31.2) 65 (26.3) 34 (48.6) 0.001 2.14 1.08–4.24 0.02 Initial adequate antifungal therapy 130 (41.0) 95 (38.5) 35 (50.0) 0.09 1.41 0.71–2.81 0.32 Adequate source control of the infection* 124/288 (43.1) 94/225 (41.8) 30/63 (47.6) 0.47 1.68 0.84–3.35 0.14 Hemodialysis after candidemia onset 7 (2.2) 2 (0.8) 5 (7.1) 0.007 8.55 1.35–53.95 0.02 *The source of the infection was susceptible of control in 288 patients BSI bloodstream infection, IQR interquartile range, SD standard deviation, TPN total parenteral nutrition Bassetti et al. Critical Care (2020) 24:117 Page 7 of 9 Fig. 1 Thirty-day mortality of candidemic patients according to the development or not of septic shock, log rank ≤ 0.001 Reflecting this weakness, this study identified no conven- results, thus suggesting that host factors may be more tional factors associated with septic shock development important than intrinsic factors of organisms. Antifungal other than the time spent in ICU before candidemia onset. resistance was not an issue predisposing to septic shock Our data suggest that, apart from older age, the only in our study, since only 14.1% of the patients had flucon- variable associated with septic shock in candidemic pa- azole resistant strains and half of them received ad- tient was an intra-abdominal origin of the infection. This equate definitive antifungal treatment. result supports recent experimental observations that in- Of interest, in the present report, the overall 30-day testinal abundance of Candida may be associated with an mortality rate in patients with septic shock attributable increased sepsis severity, perhaps through cytokine storm to candidemia was 34.3%, which is significantly lower induction and/or decreased macrophage killing activity than that observed in two previous studies performed in [29–31]. The fact that patients with other source of the in- Europe and St. Louis, where mortality rate remained fection (i.e., CVC or urinary tract) received a similar rate around 50–60% [4, 5]. The difference in septic shock of adequate source control of candidemia (43.4% vs 40.5%, definitions [9], improvements in fungal diagnosis [33, p = 0.86) and even a lower rate of adequate antifungal 34], and the widespread implementation of sepsis bundle treatment (38.1% vs 61.5%, p = 0.008) is further consistent in recent years [38–40] may explain the lower incidence with this intriguing explanation. Although we do not have of mortality observed in this study. clear answer regarding to the best approach for reducing As for risk factors for mortality, our findings are consist- the incidence of septic shock in candidemic patients, we ent with those recently reported by other investigators believe that new diagnostic strategies investigating the role [41] who found increased severity of the underlying condi- of serological biomarkers such as β-D-glucan or T2MR tions (higher Charlson comorbidity index), clinical presen- [32–35] should be applied in order to early identify pa- tation of candidemia (septic shock), and signs of organ tients at risk of intra-abdominal candidiasis. Future studies dysfunction (hemodialysis after candidemia onset) as risk addressing risk factors for developing intra-abdominal factors for late mortality (30 days after candidemia onset). candidiasis are also needed to better clarify the best em- Although ours is the largest study published to date re- piric or pre-emptive therapeutic approach. garding variables associated with septic shock in candi- With regard to Candida species as predisposing factor, demic patients, it has some limitations that should be Guzman et al. did [36] not find any significant differ- addressed. We only examine patients who develop septic ences [7]. Despite our study including 27 episodes of C. shock within the first 24 h from the first positive blood auris candidemia (8.5%) that is typically associated with culture for Candida. Therefore, we cannot rule out that a high degree of virulence [37], we confirm previous some patients presented with a septic shock in a later Bassetti et al. Critical Care (2020) 24:117 Page 8 of 9 stage of the infection. Furthermore, we did not include, in Competing interests the risk factors analysis for mortality, other core elements MB has participated in advisory boards and/or received speaker honoraria from Achaogen, Angelini, Astellas, AstraZeneca, Bayer, Basilea, Cidara, Gilead, of general supportive care that are crucial for an adequate Menarini, MSD, Paratek, Pfizer, Roche, The Medicine Company, Shionogi, septic shock management (need for mechanical ventila- Tetraphase, VenatoRx, and Vifor. CGV has received honoraria for talks on tion, use of intravenous fluids and oxygen therapy). There- behalf of Gilead Science, Merck Sharp and Dohme, Novartis, Pfizer, Jannsen, as well as a grant from Gilead Science. JC has received honoraria for lectures fore, additional studies specifically designed to investigate from Gilead and Merck Sharp and Dohme. MS has received honoraria for risk factors predicting septic shock development in pa- participating in meetings, forums and consultancies, as well as for having tients with candidemia may be useful to assess the repro- given conferences for MSD, Pfizer, Janssen, Angelini, ERN, Gilead, and Astellas Ph. He has also received grants and scholarships for research and teaching, ducibility of our results. which were administered through La Fe Sanitary Research Institute (IIS-LA FE) and companies such as ViiV, Janssen, MSD. LELC has served as speaker Conclusions for Merck, Sharp, and Dohme. Angelini has received research support from Novartis and served as trainer for Merck, Sharp, and Dohme. PM is a An abdominal source of the infection is the most important consultant and/or speaker for Astellas, Gilead, Merck, Novartis, and Pfizer, and factor significantly associated with the development of sep- T2 Biosystems. JF has been advisor/consultant and has received honoraria for tic shock attributable to candidemia. In view of the prog- talks on behalf of Gilead Sciences, Merck, Sharp, and Dohme, Pfizer, and Astellas Pharma; MFR has received honoraria for talks on behalf of Gilead nostic implication of septic shock development, our results Science, Astellas, and Pfizer. JMA has received honoraria for speaking at lead us to consider an appropriate stratification of candi- symposia organized on behalf of Pfizer, Astellas, Merck, Sharp, & Dohme demic patients on the basis of the source of the infection. (MSD). Angelini has sat on advisory boards for antifungal agents on behalf of Pfizer, Astellas, MSD, Angelini, and Gilead Science. Supplementary information Author details 1 Supplementary information accompanies this paper at https://doi.org/10. Infectious Diseases Clinic, Department of Medicine, University of Udine and 1186/s13054-020-2793-y. Azienda Sanitaria Universitaria Integrata, Piazzale Santa Maria della Misericordia 15, 33010 Udine, Italy. 2Department of Health Sciences, University of Genoa, Genoa, Italy. 3Clinica Malattie Infettive, Ospedale Additional file 1. Comparison between patients with and without intra- Policlinico San Martino-IRCCS, Genoa, Italy. 4Hospital Clínic, IDIBAPS (Institut abdominal origin of candidemia. d’Investigacions biomèdiques Agust Pi i Sunyer), Universitat de Barcelona, Barcelona, Spain. 5Hospital Universitari de Bellvitge, IDIBELL (Institut Abbreviations D’Investigació Biomèdica de Bellvitge), Universitat de Barcelona, Barcelona, CVC: Central venous catheter; ICU: Intensive care unit; OR: Odds ratio Spain. 6Hospital Universitari I Politecnic “La Fe”, Valencia, Spain. 7Hospital Universitario Clínico “San Carlos”, Madrid, Spain. 8Hospital Universitario Acknowledgements “Ramón y Cajal”, Madrid, Spain. 9Hospital Universitario “12 de Octubre”, Not applicable Instituto de Investigación Hospital “12 de Octubre” (i+12), Universidad Complutense de Madrid, Madrid, Spain. 10Unidad Clínica de Enfermedades Endorsement Infecciosas y Microbiología Clínica, Hospital Universitario Virgen Macarena/ The study was endorsed by the Critically Ill Patients Study Group (ESGCIP) of Instituto de Biomedicina de Sevilla (IBiS)/Universidad de Sevilla/Centro the European Society of Clinical Microbiology and Infectious Diseases Superior de Investigaciones Científicas, Seville, Spain. 11Hospital Universitari (ESCMID), by the Grupo de Estudio de Micología Médica (GEMICOMED) Vall d’Hebron, VHIR (Vall d’Hebron Institut de Recerca), Universitat Autònoma dentro de la SEIMC (Sociedad Española de Enfermedades infecciosas y de Barcelona, Barcelona, Spain. 12Hospital Universitario “Cruces”, Bilbao, Spain. Microbiología Clinica) and by Società Italiana di Terapia Antinfettiva (SITA). 13 Hospital Universitario “Virgen del Rocío”, Sevilla, Spain. 14Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 15Instituto de Investigación Sanitaria, Hospital Authors’ contributions Gregorio Marañón, Madrid, Spain. 16Microbiology Unit, Azienda Sanitaria MB, PM, CGV, EB, MM, and AV made substantial contributions to the study Universitaria Integrata Santa Maria della Misericordia, Udine, Italy. 17Medicine concept and design, acquisition of data, analysis and interpretation of data, first Department School of Medicine, Universidad Complutense de Madrid, drafting of the manuscript, and critical revision of the manuscript for important Madrid, Spain. 18CIBER Enfermedades Respiratorias-CIBERES (CB06/06/0058), intellectual content. 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