Intensive Care Med (2014) 40:839–845 DOI 10.1007/s00134-014-3310-z
Matteo Bassetti Elda Righi Filippo Ansaldi Maria Merelli Trucchi Cecilia Gennaro De Pascale Ana Diaz-Martin Roberto Luzzati Chiara Rosin Leonel Lagunes Enrico Maria Trecarichi Maurizio Sanguinetti Brunella Posteraro Jose Garnacho-Montero Assunta Sartor Jordi Rello Giorgio Della Rocca Massimo Antonelli Mario Tumbarello Received: 4 March 2014 Accepted: 15 April 2014 Published online: 8 May 2014 Ó Springer-Verlag Berlin Heidelberg and ESICM 2014 Take-home message: High mortality rates were confirmed in patients with Candidainduced septic shock. In this group, the administration of an adequate antifungal therapy along with adequate source control are key factors to improve clinical outcomes.
M. Bassetti E. Righi M. Merelli Infectious Diseases Division, Santa Maria Misericordia University Hospital, Udine, Italy F. Ansaldi T. Cecilia Department of Health Sciences, IRCCS San Martino IST, University of Genoa, Genoa, Italy G. De Pascale M. Antonelli Critical Care Department, Universita` Cattolica del Sacro Cuore, Rome, Italy A. Diaz-Martin J. Garnacho-Montero Critical Care and Emergency Clinical Unit, Virgen del Rocio University Hospital, Seville, Spain R. Luzzati C. Rosin Infectious Diseases Unit, University Hospital of Trieste, Trieste, Italy
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A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality
L. Lagunes J. Rello Critical Care Department, Vall d’Hebron University Hospital, CIBERES, Universitat autonoma de Barcelona, Barcelona, Spain
Abstract Purpose: Candida is the most common cause of severe yeast infections worldwide, especially in critically ill patients. In this setting, septic shock attributable to Candida E. M. Trecarichi M. Tumbarello is characterized by high mortality Institute of Infectious Diseases, rates. The aim of this multicenter Universita` Cattolica del Sacro Cuore, study was to investigate the determiRome, Italy nants of outcome in critically ill patients with septic shock due to M. Sanguinetti candidemia. Methods: This was a ` Institute of Microbiology, Universita retrospective study in which patients Cattolica del Sacro Cuore, Rome, Italy with septic shock attributable to B. Posteraro Candida who were treated during Institute of Public Health (Section of the 3-year study period at one or Hygiene), Universita` Cattolica del Sacro more of the five participating Cuore, Rome, Italy teaching hospitals in Italy and Spain were eligible for enrolment. Patient A. Sartor characteristics, infection-related Microbiology Unit, Santa Maria Misericordia University Hospital, Udine, variables, and therapy-related feaItaly tures were reviewed. Multiple logistic regression analysis was perG. D. Rocca formed to identify the risk factors Critical Care Department, Santa Maria significantly associated with 30-day Misericordia University Hospital, Udine, mortality. Results: A total of 216 Italy patients (mean age 63.4 ± 18.5 M. Bassetti ()) years; 58.3 % males) were included Clinica Malattie Infettive, Azienda in the study. Of these, 163 (75 %) Ospedaliera Universitaria Santa Maria della were admitted to the intensive care Misericordia, Piazzale Santa Maria della unit. Overall 30-day mortality was Misericordia 15, 33100 Udine, Italy 54 %. Significantly higher Acute e-mail: [email protected] Physiology and Chronic Health Tel.: ?39-4-32559355
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Evaluation (APACHE) II scores, dysfunctional organs, and inadequate antifungal therapy were compared in nonsurvivors and survivors. No differences in survivors versus nonsurvivors were found in terms of the time from positive blood culture to initiation of adequate antifungal
therapy. Multivariate logistic regression identified inadequate source control, inadequate antifungal therapy, and 1-point increments in the APACHE II score as independent variables associated with a higher 30-day mortality rate.
Introduction Candida spp. are a significant cause of bloodstream infections, leading to high rates of mortality, especially in the nosocomial setting [1, 2]. In the past decade, a fivefold increase in candidemia incidence has been registered across European and U.S. hospitals, placing Candida spp. as the fifth most common isolates in nosocomial bloodstream infections [3, 4]. Risk factors associated to candidemia include severe comorbidities (i.e., acute leukemia, leukopenia), burns, and gastrointestinal disease [2]. A constant increase in the number of high-risk patients and surgical technique complexity contribute to the critical increase of Candidaspp.-related infections. Overall, the impact of candidemia has been estimated to be a 15 % increase in mortality and a mean increase in hospital stay of 10 days [1]. The crude and attributable mortality attributable to Candida ranges between 30 and 50 % and can reach up to 80 and 70 %, respectively, especially in critically ill patients [1, 5–7]. In a 1-day, point-prevalence study (Extended Prevalence of Infection in Intensive Care, EPIC II) which involved more than 7,000 infected intensive care unit (ICU) patients from 75 countries, Candida was the third most common pathogen, with an infection rate of 17 % [8]. Septic shock is a major cause of death in ICUs, with hospital mortality rates of between 30 and 50 % [8]. In this setting, Candida is the most frequent cause of fungal severe sepsis or septic shock, ranging from 8 to 30 % and from 23 to 38 %, respectively [9–14]. When complicated by septic shock, candidemia is a severe condition with mortality rates that can exceed 60 % [11, 14–16]. Increasing mortality attributable to candidemia has driven research into the role of early diagnosis and prompt treatment initiation to improve outcomes [7]. Inadequate initial antifungal treatment has been associated with increased mortality in patients with invasive candidiasis [17–19]. A retrospective study involving 224 patients with septic shock attributable to Candida infection identified delayed antifungal treatment and failure to achieve timely source control as risk factors for 30-day mortality in the multivariate logistic regression [16]. Recent guidelines no longer consider fluconazole as the drug of choice for the treatment of invasive candidiasis in severely ill patients [20]. The rationale is based on the
Keywords Candidemia Septic shock Fluconazole Echinocandins Catheter Source control
increasing prevalence of Candida spp. with decreased susceptibility to fluconazole and the lower clinical efficacy of fluconazole compared with anidulafungin in patients with candidemia and invasive candidiasis [21]. Nevertheless, larger studies with the aim to analyze the determinants of outcome in critically ill patient with septic shock and candidemia are still lacking. Here we report the results of a multicenter multinational study that includes patients with septic shock attributable to Candida infection. Our aim was to identify the influence and effect of various determinants on patient outcome.
Materials and methods Patient population and study design A retrospective multicenter cohort study was conducted at five teaching hospitals across Italy and Spain over a 3-year period (2009–2011). The sites included: Trieste University Hospital (700 beds) in Trieste, Italy; Santa Maria Misericordia University Hospital (1,200 beds) in Udine, Italy; Policlinico Gemelli (1,500 beds) in Rome, Italy; Val d’Hebron Hospital (1,150 beds) in Barcelona, Spain; Virgen Del Rocio University Hospital (851 beds) in Seville, Spain. The study was approved by the local institutional review boards, and written patient consent was not required because of the observational nature of this study. All hospitalized patients whose need for vasopressors began within 24 h of the blood culture testing positive for Candida spp. with no other concomitant infections were classified as having septic shock attributable to Candida and included in the study. Organ dysfunction and definitions of septic shock have been previously reported [16]. Patients on vasopressors for [24 h prior to the collection of a blood culture that subsequently yielded a Candida species were excluded. Vasopressors included norepinephrine, vasopressin, dopamine, and epinephrine. Patient baseline characteristics and infection-related variables were obtained from the automated hospital medical record, microbiology database, and pharmacy database of the participating centers. The baseline
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characteristics collected included age, gender, comorbidities, previous surgery, use of immunosuppressants, acute physiology and chronic health evaluation [Acute Physiology and Chronic Health Evaluation (APACHE) II scores], number of acquired organ dysfunctions, and need of ICU admission. The APACHE II score was calculated based on clinical data collected during the 24 h after the positive blood cultures were obtained. Infection and therapy-related characteristics examined were infection source, Candida species, prior antibiotic exposure, adequate source control, timing of antifungal therapy relative to blood culture positivity, and type of antifungal used. The primary outcome variable was all-cause 30-day mortality. Initial treatment was considered adequate when the infecting organism was ultimately shown to be susceptible, and the dosage of antifungal used was adequate within the first 24 h of the determination of culture positivity. Source control measures were considered within the first 48 h from the determination of blood culture positivity. These included the removal of central vein catheters or surgical or radiologic procedures to drain abscesses or fluid collections thought to be the source of Candida infection. The following antifungal dosages were considered to be adequate: (1) fluconazole 800 mg loading dose followed by a daily dosage of at least 400 mg liposomal amphotericin B 3 mg/kg/day; (2) amphotericin lipid complex 5 mg/kg/day; (3) caspofungin 70 mg loading dose followed by 50 mg/ day; micafungin 100 mg/day; (4) anidulafungin 200 mg loading dose followed by 100 mg/day. During the study period there were no changes in microbiological laboratory techniques in the five hospitals. Candida species were isolated from blood using the BACTEC 860 system (Becton–Dickinson Inc., Sparks, MD). The species were identified using the API ID 32C system (bioMe´rieux, Marcy l’Etoile, France) or the Vitek 2 system (bioMe´rieux). In the case of inconclusive results by both the systems, isolates were definitively identified using supplemental tests, such as the presence/absence of well-formed pseudohyphae on cornmeal-Tween 80 agar and growth at 42–45 °C. The last test was also required to differentiate isolates of Candida albicans from those of C. dubliniensis. Antifungal susceptibility testing to amphotericin B, caspofungin, fluconazole, itraconazole, and voriconazole was performed using the Sensititre YeastOne colorimetric plate (Trek Diagnostic Systems, Cleveland, OH). Statistical analysis Continuous and categorical data were reported as the median, 25th and 75th percentile (interquartile range, IQR), and frequency distributions, respectively. The Wilcoxon and chi-square tests were used to determine whether significant differences existed between groups
for continuous and categorical variables, respectively. The Kaplan–Meier Wilcoxon test was used to compare survival in patients who received adequate therapy or/and source control (45 and 97 patients, respectively) and neither adequate therapy nor source control (5 patients). Multiple logistic regression analysis was performed to identify risk factors that were associated with 30-day mortality (JMP; SAS Institute, Cary, NC). Covariates that were significant at 0.10 in the univariate analysis were further evaluated for inclusion in multivariable regression models, using a stepwise algorithm. All tests were twotailed, and a P value of \0.05 was determined to represent statistical significance.
Results A total of 216 patients with septic shock attributable to candidemia were included in the study. The median age was 66 years [interquartile range (IQR; 25th to 75th percentile) 54.25–76], and the mean age (± standard deviation) was 63.4 ± 18.5 years; there were 126 (58.3 %) males and 90 (41.6 %) females. Overall, 75 % of the patients (163/216) were hospitalized in ICUs and 53 (25 %) in medical and surgical wards. Previous surgery was documented in 132 (61 %) patients. Overall, 66 (30.6 %) patients had an underlying malignancy, and 14 (6 %) were recipients of solid organ transplantation. The median APACHE II score was 20 (IQR 15–25; mean score 20.2 ± 9.0). Of the 216 patients, 116 (53.7 %) died within 30 days from the onset of candidemia. Median time from the first positive blood culture to death was 9.5 (IQR 4.25–18.75; mean 12.08 ± 9.49) days. Patients who died had significant higher APACHE II scores and number of organ dysfunctions than survivors (Table 1). Candida albicans (CA) was the most common species isolated from our patient cohort, being identified in 131 (61 %) patients. Among non-albicans (NAC) species, C. parapsilosis was the most frequently species isolated (16 %), followed by C. glabrata (12 %), C. tropicalis (10 %), and others (1 %). No significant differences in mortality were detected between CA and NAC or among Candida species. Although not statistically significant, nonsurvivors had higher rates of candidemia due to C. tropicalis and lower rates due to C. parapsilosis compared to survivors (12.9 vs. 7 % and 12.9 vs. 20 %, respectively). No significant differences in infectious source distribution were detected between survivors and nonsurvivors (Table 2). Among cases where an infectious source was recognized, central vascular catheter (CVC)associated candidemia was the most common (40 %). In this group, significantly higher mortality was noted for patients without CVC removal than in those undergoing CVC removal [26/64 (41 %) vs. 14/19 (74 %),
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Table 1 Comparison of the characteristics of patients with candidemia who died within 30 days of the first positive blood culture compared with those of survivors Characteristics
Alive (n = 100)
Deceased (n = 116)
P value
Age, (years) Males Previous surgery Solid organ transplantation Hematological malignancy Solid tumors HIV positive ESRD COPD Trauma Diabetes mellitus APACHE II scorea Number of acquired organ dysfunctionb
64 (53–76) 58 (58) 62 (62) 8 (8) 5 (5) 26 (26) 1 (1) 23 (23) 16 (16) 9 (9) 23 (23) 17 (13–22.25) 2 (1–3)
68 (57–76) 68 (58.6) 70 (60.3) 6 (5.2) 7 (6) 28 (24.1) 4 (3.5) 25 (21.6) 25 (21.6) 8 (6.9) 38 (32.8) 23 (16–28.25) 3 (2–4)
0.239 1 0.888 0.421 0.776 0.756 0.376 0.87 0.385 0.619 0.13 \0.001* 0.005*
Values are expressed as a number with the percentage in paren- * Significant at P \ 0.05 thesis, or as the median with the interquartile range (IQR; 25th to a During the 24 h after positive blood cultures were obtained b 75th percentile) in parenthesis, as appropriate At the time of positivity of blood culture HIV Human immunodeficiency virus, ESRD end-stage renal disease, COPD chronic obstructive pulmonary disease, APACHE Acute Physiology and Chronic Health Evaluation score Table 2 Species distribution, infectious source, and treatment-related characteristics between survivors and nonsurvivors Characteristics Candida species C. albicans C. parapsilosis C. glabrata C. tropicalis Other Infection source Vascular catheter-associated Gastrointestinal Surgical site Central nervous system Unknown Prior antibiotic exposure ICU admission ICU stay (days)a Adequate antifungal therapy Time from culture positivity to adequate treatment (h) Initial antifungal agents Fluconazole Echinocandin Amphotericin B Inadequate antifungal therapy Fluconazole resistance/SDD Treatment within 24 h Adequate source control
Alive (n = 100)
Deceased (n = 116)
P value
61 (61) 20 (20) 10 (10) 7 (7) 2 (2)
70 15 16 15 0
(60.3) (12.9) (13.8) (12.9)
0.921 0.184 0.393 0.142 0.104
46 (46) 11 (11) 2 (2) 1 (1) 40 (40) 94 (94) 69 (69) 8 (1–25.5) 98 (98) 48 (24–72)
40 (34.5) 17 (14.7) 3 (2.6) 0 56 (48.3) 110 (94.8) 94 (81) 5 (1–13) 92 (79.3) 48 (24–96)
0.113 0.554 0.863 0.353 0.987 0.057 0.1 \0.001* 0.10
46 (46) 49 (49) 3 (3) 2 (2) 8 (8) 60 (64.5)b 67 (75.3)c
41 (35) 45 (39) 6 (5) 24 (20.7) 11 (9.4) 60 (69)b 43 (47.8)c
0.150 0.181 0.566 \0.0001* 0.783 0.635 \0.001*
Values are expressed as a number with the percentage in parenthesis, or as the median with the IQR in parenthesis, as appropriate ICU Intensive care unit,SDD susceptible dose-dependent * Significant at P \ 0.05
a
respectively; P = 0.006]. Although not significant, a higher number of patients admitted to the ICU died during hospitalization compared to patients in the medical and surgical wards (81 vs. 69 %; P = 0.06). The majority of patients received either an echinocandin (41.7 %) or
fluconazole (40 %) as antifungal therapy. No difference in mortality was detected between the two treatment groups or among patients with a reduced susceptibility to fluconazole. One hundred and ninety patients (88 %) received adequate antifungal therapy in terms of dosage
b c
At the time of first positive blood culture Data available on 93 living patients and 87 deceased patients Data available on 89 living patients and 90 deceased patients
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Patients receiving adequate therapy and adequate source control Patients receiving adequate therapy and no adequate source control Patients receiving no adequate therapy and no adequate source control
Surviving
Fig. 1 Kaplan–Meier curves comparing patients who received adequate therapy and adequate source control, adequate therapy and inadequate source control, and neither adequate therapy nor adequate source control (P \ 0.001, log-rank test)
Time from positive blood culture to death in days
and species of Candida causing the infection; 26 patients (12 %) did not receive adequate antifungal therapy. Mortality in this latter group was significantly higher (92 %) than that in patients receiving adequate therapy (P \ 0.001). Nonsurvivors were statistically less likely to have received adequate therapy or source control when compared to survivors (98 vs. 79.3 % and 75.3 vs. 47.8 %, respectively; Table 2). Eleven patients received adequate source control but inadequate antifungal therapy; of these, four died and seven survived. No differences in mortality were found for the time from positive blood culture to the initiation of antifungal therapy start (P = 0.10; Table 2). The Kaplan–Meier curve shows how patients receiving adequate antifungal therapy and/or source control had a significantly greater likelihood of survival than patients who received inadequate antifungal therapy and inadequate source control (Fig. 1). Median time to death for patients receiving adequate treatment and adequate source control was significantly longer than that for patients receiving adequate treatment without source control [16 (IQR 7–23) vs. 9 (IQR 4–10.7) days, respectively; P = 0.019]. Figure 2 shows that patients with both inadequate antifungal therapy and inadequate source control had significantly higher mortality than those receiving adequate therapy with or without source control (P \ 0.001). The APACHE II score was higher in patients treated with echinocandins (22; IQR 15–27) than in patients treated with fluconazole (18; IQR 13–23). Nevertheless, adjustment for the APACHE II score did not result in any difference on mortality towards fluconazole or echinocandins, with or without adjustment for adequate source control (odds ratio 1.08; P = 0.36). Multivariate logistic regression analysis demonstrated that inadequate source control, inadequate antifungal therapy, and increments of 1 point in the APACHE II score were independently associated with a higher 30-day mortality (Table 3).
Fig. 2 Thirty-day mortality according to adequate antifungal therapy and/or source control in patients with septic shock due to candidemia (univariate analysis, P \ 0.001 for patients not receiving adequate antifungal therapy and source control compared to the other two groups) Numbers to the right of the bars Number of patients who had died by day 30 of the follow-up Table 3 Multivariate analysis of risk factors for hospital survival Risk factor
Chisquare
Odds ratio
P value
APACHE II score (1-point increments) Adequate antifungal therapy Source control
12.79
0.93
\0.001*
3.9 10.38
5.99 2.99
0.048* 0.001*
* Significant at P \ 0.05
Discussion Our study is the largest multicenter, multinational investigation of candidemia episodes in septic shock patients reported to date. We collected patient data from five large medical centers in two different countries, including data
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on patients admitted to both ICUs and medical/surgical wards. Candidemia is a life-threatening condition in critically ill patients and is associated with a crude 30-day mortality ranging from 50 up to 70 % [14, 22–24]. In our study cohort, mortality rates were around 53 %, with a higher, although nonstatistically significant number of patients dying within 30 days of being isolated in the ICU for candidemia compared to those in surgical/medical wards, thereby confirming the high severity of the disease in the former setting. Our results confirm that Candida-induced septic shock is a severe condition with high mortality rates. Our data do allow us to estimate the true incidence of Candida-induced septic shock, although the percentage of patients with shock [22] is similar to the frequency previously reported (20 %) [10]. We noted that patients’ severity and organ dysfunction had an impact on the outcome, although only APACHE score increments were significantly correlated to 30-day mortality in multivariate analysis. Our study also shows how inadequate source control and inadequate antifungal therapy significantly impact survival in patients with septic shock attributable to candidemia, thereby supporting the recent observation of Kollef et al. [16]. Patients with inadequate antifungal therapy were more likely to die within 30 days of the isolation of Candida from blood samples than patients treated with an adequate antifungal treatment. Nevertheless, we did not observe a clear effect of the timing of antifungal administration on mortality rates, as demonstrated in previous studies [16, 18, 19]. Given the importance of an adequate therapy of septic shock attributable to Candida infection as an outcome determinant, clinical strategies facilitating the attainment of this goal are needed. The appropriateness of the chosen antifungal therapy has a crucial impact on the outcome of invasive candidiasis. Several studies have shown that inadequate empirical therapy is associated with an increased mortality in patients with candidemia or septic shock due to Candida [16, 18, 19]. At face value, these data suggest a role for empirical or preemptive therapy in the management of invasive candidiasis. However, to date criteria for initiating empirical antifungal therapy in fungal sepsis remain poorly defined and should be balanced against the potential risks of toxicity, selection of resistance, and treatment costs. Published guidelines have expressed a preference for an echinocandin over fluconazole as initial therapy for severely ill patients [20]. Also, although most trials have shown that triazoles and echinocandins are equally efficacious and equally well tolerated, one study found that anidulafungin achieved significantly faster clearance of blood cultures and fewer persistent infections compared to fluconazole [21]. Conversely, in a recent study involving ventilated patients with candidemia, those receiving fluconazole as initial monotherapy were significantly more likely to survive than those treated with an echinocandin [24].
In our study the majority of patients received either an echinocandin (41.7 %) or fluconazole (40 %), but we did not observe any difference in mortality between the two treatment groups. One possible reason for this result is that echinocandins are more frequently used in the more severely ill patients; however, adjustment for APACHE II score did not show any difference between fluconazole and echinocandins on mortality. Furthermore, fluconazole dosage was adequate ([400 mg/day) in the majority of patients. Finally, we did detect a low prevalence of fluconazole-resistant species. Our results differ from a recent patient-level review of a candidemia trial that reported improved clinical outcomes in patients receiving an echinocandin. However, in the subgroup analysis of this trial, this benefit was restricted to the half of the analyzed population who were less severely ill [25]. The results of our study support the importance of a source control in septic patients. Source control has shown to be an important determinant of outcome for patients with serious infections attributed to Candida species [16]. Although the need to remove all CVCs in candidemia patients remains controversial [26], recent European guidelines support catheter removal [20]. The distribution of Candida species among our patients was similar that which we previously observed, with C. albicans being the most frequently isolated species [22]. Although not significant, we observed a trend for lower mortality rates in patients with candidemia due to C. parapsilosis and higher mortality rates in patients infected with C. tropicalis compared with other Candida species. We did not observe an impact of fluconazole resistance or doserelated susceptibility on patient mortality. There are a number of important limitations to our study that should be noted. We did not examine all aspects of hospital care that may have influenced the clinical outcomes, and we could not capture the reasons for the choice of the different antifungals. Also, prescription and source control practices may have varied from one site to the other. In conclusion, our study is the largest multicenter investigation of candidemia in patients with septic shock published to date. We identified that inadequate antifungal therapy and inadequate source control combined with the disease severity were the most important determinants of outcome among patients with septic shock attributable to Candida infection with positive blood cultures. Acknowledgments This research was conducted in collaboration with the Critically Ill Patients Study Group (CIPSG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Conflicts of interest MB serves on scientific advisory boards for Pfizer Inc, Merck Serono, and Astellas Pharma Inc. and has received funding for travel or speaker honoraria from Pfizer Inc., Merck Serono, Gilead Sciences, Teva Inc and Astellas Pharma Inc. The other authors declare no conflict of interest.
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Matteo Bassetti Elda Righi Filippo Ansaldi Maria Merelli Trucchi Cecilia Gennaro De Pascale Ana Diaz-Martin Roberto Luzzati Chiara Rosin Leonel Lagunes Enrico Maria Trecarichi Maurizio Sanguinetti Brunella Posteraro Jose Garnacho-Montero Assunta Sartor Jordi Rello Giorgio Della Rocca Massimo Antonelli Mario Tumbarello Received: 4 March 2014 Accepted: 15 April 2014 Published online: 8 May 2014 Ó Springer-Verlag Berlin Heidelberg and ESICM 2014 Take-home message: High mortality rates were confirmed in patients with Candidainduced septic shock. In this group, the administration of an adequate antifungal therapy along with adequate source control are key factors to improve clinical outcomes.
M. Bassetti E. Righi M. Merelli Infectious Diseases Division, Santa Maria Misericordia University Hospital, Udine, Italy F. Ansaldi T. Cecilia Department of Health Sciences, IRCCS San Martino IST, University of Genoa, Genoa, Italy G. De Pascale M. Antonelli Critical Care Department, Universita` Cattolica del Sacro Cuore, Rome, Italy A. Diaz-Martin J. Garnacho-Montero Critical Care and Emergency Clinical Unit, Virgen del Rocio University Hospital, Seville, Spain R. Luzzati C. Rosin Infectious Diseases Unit, University Hospital of Trieste, Trieste, Italy
ORIGINA L
A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality
L. Lagunes J. Rello Critical Care Department, Vall d’Hebron University Hospital, CIBERES, Universitat autonoma de Barcelona, Barcelona, Spain
Abstract Purpose: Candida is the most common cause of severe yeast infections worldwide, especially in critically ill patients. In this setting, septic shock attributable to Candida E. M. Trecarichi M. Tumbarello is characterized by high mortality Institute of Infectious Diseases, rates. The aim of this multicenter Universita` Cattolica del Sacro Cuore, study was to investigate the determiRome, Italy nants of outcome in critically ill patients with septic shock due to M. Sanguinetti candidemia. Methods: This was a ` Institute of Microbiology, Universita retrospective study in which patients Cattolica del Sacro Cuore, Rome, Italy with septic shock attributable to B. Posteraro Candida who were treated during Institute of Public Health (Section of the 3-year study period at one or Hygiene), Universita` Cattolica del Sacro more of the five participating Cuore, Rome, Italy teaching hospitals in Italy and Spain were eligible for enrolment. Patient A. Sartor characteristics, infection-related Microbiology Unit, Santa Maria Misericordia University Hospital, Udine, variables, and therapy-related feaItaly tures were reviewed. Multiple logistic regression analysis was perG. D. Rocca formed to identify the risk factors Critical Care Department, Santa Maria significantly associated with 30-day Misericordia University Hospital, Udine, mortality. Results: A total of 216 Italy patients (mean age 63.4 ± 18.5 M. Bassetti ()) years; 58.3 % males) were included Clinica Malattie Infettive, Azienda in the study. Of these, 163 (75 %) Ospedaliera Universitaria Santa Maria della were admitted to the intensive care Misericordia, Piazzale Santa Maria della unit. Overall 30-day mortality was Misericordia 15, 33100 Udine, Italy 54 %. Significantly higher Acute e-mail: [email protected] Physiology and Chronic Health Tel.: ?39-4-32559355
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Evaluation (APACHE) II scores, dysfunctional organs, and inadequate antifungal therapy were compared in nonsurvivors and survivors. No differences in survivors versus nonsurvivors were found in terms of the time from positive blood culture to initiation of adequate antifungal
therapy. Multivariate logistic regression identified inadequate source control, inadequate antifungal therapy, and 1-point increments in the APACHE II score as independent variables associated with a higher 30-day mortality rate.
Introduction Candida spp. are a significant cause of bloodstream infections, leading to high rates of mortality, especially in the nosocomial setting [1, 2]. In the past decade, a fivefold increase in candidemia incidence has been registered across European and U.S. hospitals, placing Candida spp. as the fifth most common isolates in nosocomial bloodstream infections [3, 4]. Risk factors associated to candidemia include severe comorbidities (i.e., acute leukemia, leukopenia), burns, and gastrointestinal disease [2]. A constant increase in the number of high-risk patients and surgical technique complexity contribute to the critical increase of Candidaspp.-related infections. Overall, the impact of candidemia has been estimated to be a 15 % increase in mortality and a mean increase in hospital stay of 10 days [1]. The crude and attributable mortality attributable to Candida ranges between 30 and 50 % and can reach up to 80 and 70 %, respectively, especially in critically ill patients [1, 5–7]. In a 1-day, point-prevalence study (Extended Prevalence of Infection in Intensive Care, EPIC II) which involved more than 7,000 infected intensive care unit (ICU) patients from 75 countries, Candida was the third most common pathogen, with an infection rate of 17 % [8]. Septic shock is a major cause of death in ICUs, with hospital mortality rates of between 30 and 50 % [8]. In this setting, Candida is the most frequent cause of fungal severe sepsis or septic shock, ranging from 8 to 30 % and from 23 to 38 %, respectively [9–14]. When complicated by septic shock, candidemia is a severe condition with mortality rates that can exceed 60 % [11, 14–16]. Increasing mortality attributable to candidemia has driven research into the role of early diagnosis and prompt treatment initiation to improve outcomes [7]. Inadequate initial antifungal treatment has been associated with increased mortality in patients with invasive candidiasis [17–19]. A retrospective study involving 224 patients with septic shock attributable to Candida infection identified delayed antifungal treatment and failure to achieve timely source control as risk factors for 30-day mortality in the multivariate logistic regression [16]. Recent guidelines no longer consider fluconazole as the drug of choice for the treatment of invasive candidiasis in severely ill patients [20]. The rationale is based on the
Keywords Candidemia Septic shock Fluconazole Echinocandins Catheter Source control
increasing prevalence of Candida spp. with decreased susceptibility to fluconazole and the lower clinical efficacy of fluconazole compared with anidulafungin in patients with candidemia and invasive candidiasis [21]. Nevertheless, larger studies with the aim to analyze the determinants of outcome in critically ill patient with septic shock and candidemia are still lacking. Here we report the results of a multicenter multinational study that includes patients with septic shock attributable to Candida infection. Our aim was to identify the influence and effect of various determinants on patient outcome.
Materials and methods Patient population and study design A retrospective multicenter cohort study was conducted at five teaching hospitals across Italy and Spain over a 3-year period (2009–2011). The sites included: Trieste University Hospital (700 beds) in Trieste, Italy; Santa Maria Misericordia University Hospital (1,200 beds) in Udine, Italy; Policlinico Gemelli (1,500 beds) in Rome, Italy; Val d’Hebron Hospital (1,150 beds) in Barcelona, Spain; Virgen Del Rocio University Hospital (851 beds) in Seville, Spain. The study was approved by the local institutional review boards, and written patient consent was not required because of the observational nature of this study. All hospitalized patients whose need for vasopressors began within 24 h of the blood culture testing positive for Candida spp. with no other concomitant infections were classified as having septic shock attributable to Candida and included in the study. Organ dysfunction and definitions of septic shock have been previously reported [16]. Patients on vasopressors for [24 h prior to the collection of a blood culture that subsequently yielded a Candida species were excluded. Vasopressors included norepinephrine, vasopressin, dopamine, and epinephrine. Patient baseline characteristics and infection-related variables were obtained from the automated hospital medical record, microbiology database, and pharmacy database of the participating centers. The baseline
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characteristics collected included age, gender, comorbidities, previous surgery, use of immunosuppressants, acute physiology and chronic health evaluation [Acute Physiology and Chronic Health Evaluation (APACHE) II scores], number of acquired organ dysfunctions, and need of ICU admission. The APACHE II score was calculated based on clinical data collected during the 24 h after the positive blood cultures were obtained. Infection and therapy-related characteristics examined were infection source, Candida species, prior antibiotic exposure, adequate source control, timing of antifungal therapy relative to blood culture positivity, and type of antifungal used. The primary outcome variable was all-cause 30-day mortality. Initial treatment was considered adequate when the infecting organism was ultimately shown to be susceptible, and the dosage of antifungal used was adequate within the first 24 h of the determination of culture positivity. Source control measures were considered within the first 48 h from the determination of blood culture positivity. These included the removal of central vein catheters or surgical or radiologic procedures to drain abscesses or fluid collections thought to be the source of Candida infection. The following antifungal dosages were considered to be adequate: (1) fluconazole 800 mg loading dose followed by a daily dosage of at least 400 mg liposomal amphotericin B 3 mg/kg/day; (2) amphotericin lipid complex 5 mg/kg/day; (3) caspofungin 70 mg loading dose followed by 50 mg/ day; micafungin 100 mg/day; (4) anidulafungin 200 mg loading dose followed by 100 mg/day. During the study period there were no changes in microbiological laboratory techniques in the five hospitals. Candida species were isolated from blood using the BACTEC 860 system (Becton–Dickinson Inc., Sparks, MD). The species were identified using the API ID 32C system (bioMe´rieux, Marcy l’Etoile, France) or the Vitek 2 system (bioMe´rieux). In the case of inconclusive results by both the systems, isolates were definitively identified using supplemental tests, such as the presence/absence of well-formed pseudohyphae on cornmeal-Tween 80 agar and growth at 42–45 °C. The last test was also required to differentiate isolates of Candida albicans from those of C. dubliniensis. Antifungal susceptibility testing to amphotericin B, caspofungin, fluconazole, itraconazole, and voriconazole was performed using the Sensititre YeastOne colorimetric plate (Trek Diagnostic Systems, Cleveland, OH). Statistical analysis Continuous and categorical data were reported as the median, 25th and 75th percentile (interquartile range, IQR), and frequency distributions, respectively. The Wilcoxon and chi-square tests were used to determine whether significant differences existed between groups
for continuous and categorical variables, respectively. The Kaplan–Meier Wilcoxon test was used to compare survival in patients who received adequate therapy or/and source control (45 and 97 patients, respectively) and neither adequate therapy nor source control (5 patients). Multiple logistic regression analysis was performed to identify risk factors that were associated with 30-day mortality (JMP; SAS Institute, Cary, NC). Covariates that were significant at 0.10 in the univariate analysis were further evaluated for inclusion in multivariable regression models, using a stepwise algorithm. All tests were twotailed, and a P value of \0.05 was determined to represent statistical significance.
Results A total of 216 patients with septic shock attributable to candidemia were included in the study. The median age was 66 years [interquartile range (IQR; 25th to 75th percentile) 54.25–76], and the mean age (± standard deviation) was 63.4 ± 18.5 years; there were 126 (58.3 %) males and 90 (41.6 %) females. Overall, 75 % of the patients (163/216) were hospitalized in ICUs and 53 (25 %) in medical and surgical wards. Previous surgery was documented in 132 (61 %) patients. Overall, 66 (30.6 %) patients had an underlying malignancy, and 14 (6 %) were recipients of solid organ transplantation. The median APACHE II score was 20 (IQR 15–25; mean score 20.2 ± 9.0). Of the 216 patients, 116 (53.7 %) died within 30 days from the onset of candidemia. Median time from the first positive blood culture to death was 9.5 (IQR 4.25–18.75; mean 12.08 ± 9.49) days. Patients who died had significant higher APACHE II scores and number of organ dysfunctions than survivors (Table 1). Candida albicans (CA) was the most common species isolated from our patient cohort, being identified in 131 (61 %) patients. Among non-albicans (NAC) species, C. parapsilosis was the most frequently species isolated (16 %), followed by C. glabrata (12 %), C. tropicalis (10 %), and others (1 %). No significant differences in mortality were detected between CA and NAC or among Candida species. Although not statistically significant, nonsurvivors had higher rates of candidemia due to C. tropicalis and lower rates due to C. parapsilosis compared to survivors (12.9 vs. 7 % and 12.9 vs. 20 %, respectively). No significant differences in infectious source distribution were detected between survivors and nonsurvivors (Table 2). Among cases where an infectious source was recognized, central vascular catheter (CVC)associated candidemia was the most common (40 %). In this group, significantly higher mortality was noted for patients without CVC removal than in those undergoing CVC removal [26/64 (41 %) vs. 14/19 (74 %),
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Table 1 Comparison of the characteristics of patients with candidemia who died within 30 days of the first positive blood culture compared with those of survivors Characteristics
Alive (n = 100)
Deceased (n = 116)
P value
Age, (years) Males Previous surgery Solid organ transplantation Hematological malignancy Solid tumors HIV positive ESRD COPD Trauma Diabetes mellitus APACHE II scorea Number of acquired organ dysfunctionb
64 (53–76) 58 (58) 62 (62) 8 (8) 5 (5) 26 (26) 1 (1) 23 (23) 16 (16) 9 (9) 23 (23) 17 (13–22.25) 2 (1–3)
68 (57–76) 68 (58.6) 70 (60.3) 6 (5.2) 7 (6) 28 (24.1) 4 (3.5) 25 (21.6) 25 (21.6) 8 (6.9) 38 (32.8) 23 (16–28.25) 3 (2–4)
0.239 1 0.888 0.421 0.776 0.756 0.376 0.87 0.385 0.619 0.13 \0.001* 0.005*
Values are expressed as a number with the percentage in paren- * Significant at P \ 0.05 thesis, or as the median with the interquartile range (IQR; 25th to a During the 24 h after positive blood cultures were obtained b 75th percentile) in parenthesis, as appropriate At the time of positivity of blood culture HIV Human immunodeficiency virus, ESRD end-stage renal disease, COPD chronic obstructive pulmonary disease, APACHE Acute Physiology and Chronic Health Evaluation score Table 2 Species distribution, infectious source, and treatment-related characteristics between survivors and nonsurvivors Characteristics Candida species C. albicans C. parapsilosis C. glabrata C. tropicalis Other Infection source Vascular catheter-associated Gastrointestinal Surgical site Central nervous system Unknown Prior antibiotic exposure ICU admission ICU stay (days)a Adequate antifungal therapy Time from culture positivity to adequate treatment (h) Initial antifungal agents Fluconazole Echinocandin Amphotericin B Inadequate antifungal therapy Fluconazole resistance/SDD Treatment within 24 h Adequate source control
Alive (n = 100)
Deceased (n = 116)
P value
61 (61) 20 (20) 10 (10) 7 (7) 2 (2)
70 15 16 15 0
(60.3) (12.9) (13.8) (12.9)
0.921 0.184 0.393 0.142 0.104
46 (46) 11 (11) 2 (2) 1 (1) 40 (40) 94 (94) 69 (69) 8 (1–25.5) 98 (98) 48 (24–72)
40 (34.5) 17 (14.7) 3 (2.6) 0 56 (48.3) 110 (94.8) 94 (81) 5 (1–13) 92 (79.3) 48 (24–96)
0.113 0.554 0.863 0.353 0.987 0.057 0.1 \0.001* 0.10
46 (46) 49 (49) 3 (3) 2 (2) 8 (8) 60 (64.5)b 67 (75.3)c
41 (35) 45 (39) 6 (5) 24 (20.7) 11 (9.4) 60 (69)b 43 (47.8)c
0.150 0.181 0.566 \0.0001* 0.783 0.635 \0.001*
Values are expressed as a number with the percentage in parenthesis, or as the median with the IQR in parenthesis, as appropriate ICU Intensive care unit,SDD susceptible dose-dependent * Significant at P \ 0.05
a
respectively; P = 0.006]. Although not significant, a higher number of patients admitted to the ICU died during hospitalization compared to patients in the medical and surgical wards (81 vs. 69 %; P = 0.06). The majority of patients received either an echinocandin (41.7 %) or
fluconazole (40 %) as antifungal therapy. No difference in mortality was detected between the two treatment groups or among patients with a reduced susceptibility to fluconazole. One hundred and ninety patients (88 %) received adequate antifungal therapy in terms of dosage
b c
At the time of first positive blood culture Data available on 93 living patients and 87 deceased patients Data available on 89 living patients and 90 deceased patients
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Patients receiving adequate therapy and adequate source control Patients receiving adequate therapy and no adequate source control Patients receiving no adequate therapy and no adequate source control
Surviving
Fig. 1 Kaplan–Meier curves comparing patients who received adequate therapy and adequate source control, adequate therapy and inadequate source control, and neither adequate therapy nor adequate source control (P \ 0.001, log-rank test)
Time from positive blood culture to death in days
and species of Candida causing the infection; 26 patients (12 %) did not receive adequate antifungal therapy. Mortality in this latter group was significantly higher (92 %) than that in patients receiving adequate therapy (P \ 0.001). Nonsurvivors were statistically less likely to have received adequate therapy or source control when compared to survivors (98 vs. 79.3 % and 75.3 vs. 47.8 %, respectively; Table 2). Eleven patients received adequate source control but inadequate antifungal therapy; of these, four died and seven survived. No differences in mortality were found for the time from positive blood culture to the initiation of antifungal therapy start (P = 0.10; Table 2). The Kaplan–Meier curve shows how patients receiving adequate antifungal therapy and/or source control had a significantly greater likelihood of survival than patients who received inadequate antifungal therapy and inadequate source control (Fig. 1). Median time to death for patients receiving adequate treatment and adequate source control was significantly longer than that for patients receiving adequate treatment without source control [16 (IQR 7–23) vs. 9 (IQR 4–10.7) days, respectively; P = 0.019]. Figure 2 shows that patients with both inadequate antifungal therapy and inadequate source control had significantly higher mortality than those receiving adequate therapy with or without source control (P \ 0.001). The APACHE II score was higher in patients treated with echinocandins (22; IQR 15–27) than in patients treated with fluconazole (18; IQR 13–23). Nevertheless, adjustment for the APACHE II score did not result in any difference on mortality towards fluconazole or echinocandins, with or without adjustment for adequate source control (odds ratio 1.08; P = 0.36). Multivariate logistic regression analysis demonstrated that inadequate source control, inadequate antifungal therapy, and increments of 1 point in the APACHE II score were independently associated with a higher 30-day mortality (Table 3).
Fig. 2 Thirty-day mortality according to adequate antifungal therapy and/or source control in patients with septic shock due to candidemia (univariate analysis, P \ 0.001 for patients not receiving adequate antifungal therapy and source control compared to the other two groups) Numbers to the right of the bars Number of patients who had died by day 30 of the follow-up Table 3 Multivariate analysis of risk factors for hospital survival Risk factor
Chisquare
Odds ratio
P value
APACHE II score (1-point increments) Adequate antifungal therapy Source control
12.79
0.93
\0.001*
3.9 10.38
5.99 2.99
0.048* 0.001*
* Significant at P \ 0.05
Discussion Our study is the largest multicenter, multinational investigation of candidemia episodes in septic shock patients reported to date. We collected patient data from five large medical centers in two different countries, including data
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on patients admitted to both ICUs and medical/surgical wards. Candidemia is a life-threatening condition in critically ill patients and is associated with a crude 30-day mortality ranging from 50 up to 70 % [14, 22–24]. In our study cohort, mortality rates were around 53 %, with a higher, although nonstatistically significant number of patients dying within 30 days of being isolated in the ICU for candidemia compared to those in surgical/medical wards, thereby confirming the high severity of the disease in the former setting. Our results confirm that Candida-induced septic shock is a severe condition with high mortality rates. Our data do allow us to estimate the true incidence of Candida-induced septic shock, although the percentage of patients with shock [22] is similar to the frequency previously reported (20 %) [10]. We noted that patients’ severity and organ dysfunction had an impact on the outcome, although only APACHE score increments were significantly correlated to 30-day mortality in multivariate analysis. Our study also shows how inadequate source control and inadequate antifungal therapy significantly impact survival in patients with septic shock attributable to candidemia, thereby supporting the recent observation of Kollef et al. [16]. Patients with inadequate antifungal therapy were more likely to die within 30 days of the isolation of Candida from blood samples than patients treated with an adequate antifungal treatment. Nevertheless, we did not observe a clear effect of the timing of antifungal administration on mortality rates, as demonstrated in previous studies [16, 18, 19]. Given the importance of an adequate therapy of septic shock attributable to Candida infection as an outcome determinant, clinical strategies facilitating the attainment of this goal are needed. The appropriateness of the chosen antifungal therapy has a crucial impact on the outcome of invasive candidiasis. Several studies have shown that inadequate empirical therapy is associated with an increased mortality in patients with candidemia or septic shock due to Candida [16, 18, 19]. At face value, these data suggest a role for empirical or preemptive therapy in the management of invasive candidiasis. However, to date criteria for initiating empirical antifungal therapy in fungal sepsis remain poorly defined and should be balanced against the potential risks of toxicity, selection of resistance, and treatment costs. Published guidelines have expressed a preference for an echinocandin over fluconazole as initial therapy for severely ill patients [20]. Also, although most trials have shown that triazoles and echinocandins are equally efficacious and equally well tolerated, one study found that anidulafungin achieved significantly faster clearance of blood cultures and fewer persistent infections compared to fluconazole [21]. Conversely, in a recent study involving ventilated patients with candidemia, those receiving fluconazole as initial monotherapy were significantly more likely to survive than those treated with an echinocandin [24].
In our study the majority of patients received either an echinocandin (41.7 %) or fluconazole (40 %), but we did not observe any difference in mortality between the two treatment groups. One possible reason for this result is that echinocandins are more frequently used in the more severely ill patients; however, adjustment for APACHE II score did not show any difference between fluconazole and echinocandins on mortality. Furthermore, fluconazole dosage was adequate ([400 mg/day) in the majority of patients. Finally, we did detect a low prevalence of fluconazole-resistant species. Our results differ from a recent patient-level review of a candidemia trial that reported improved clinical outcomes in patients receiving an echinocandin. However, in the subgroup analysis of this trial, this benefit was restricted to the half of the analyzed population who were less severely ill [25]. The results of our study support the importance of a source control in septic patients. Source control has shown to be an important determinant of outcome for patients with serious infections attributed to Candida species [16]. Although the need to remove all CVCs in candidemia patients remains controversial [26], recent European guidelines support catheter removal [20]. The distribution of Candida species among our patients was similar that which we previously observed, with C. albicans being the most frequently isolated species [22]. Although not significant, we observed a trend for lower mortality rates in patients with candidemia due to C. parapsilosis and higher mortality rates in patients infected with C. tropicalis compared with other Candida species. We did not observe an impact of fluconazole resistance or doserelated susceptibility on patient mortality. There are a number of important limitations to our study that should be noted. We did not examine all aspects of hospital care that may have influenced the clinical outcomes, and we could not capture the reasons for the choice of the different antifungals. Also, prescription and source control practices may have varied from one site to the other. In conclusion, our study is the largest multicenter investigation of candidemia in patients with septic shock published to date. We identified that inadequate antifungal therapy and inadequate source control combined with the disease severity were the most important determinants of outcome among patients with septic shock attributable to Candida infection with positive blood cultures. Acknowledgments This research was conducted in collaboration with the Critically Ill Patients Study Group (CIPSG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Conflicts of interest MB serves on scientific advisory boards for Pfizer Inc, Merck Serono, and Astellas Pharma Inc. and has received funding for travel or speaker honoraria from Pfizer Inc., Merck Serono, Gilead Sciences, Teva Inc and Astellas Pharma Inc. The other authors declare no conflict of interest.
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