Epidemiology, clinical characteristics, and outcome of candidemia in critically ill patients in Germany: a single-center retrospective 10-year analysis

Bloodstream infections (BSI) caused by Candida spp. have become a major concern in critical care medicine due to the increasing number of immunocompromised patients [1, 2]. Yeast-related BSI are usually healthcare-associated infections with a high mortality of up to 60% in critically ill patients [1, 3‐5]. Importantly, BSI caused by Candida spp., central-line-associated BSI in particular, have been increasing over the past decades [6]. The international EPIC II study including more than 14,000 patients showed that Candida was the third most common cause of infection and was second in both North America and Western Europe [7]. Importantly, mortality was found to be substantially higher in patients with Candida BSI compared with patients suffering from Gram-positive or Gram-negative BSI [5, 7].

In the past years, a shift in Candida spp. towards non-albicans Candida spp. has been observed. The proportion of candidemia caused by non-albicans Candida spp. was 59.8% in an Italian multicenter survey [8]. An analysis from a North American prospective registry showed similar rates with 57.9% of non-albicans Candida spp.[9]. The shift in species distribution may reflect selection pressure induced by prior azole prescription [9‐11].

Current recommendations on the management of invasive candidiasis in nonneutropenic patients suggest that adequate source control including catheter removal, should be performed early, if clinically feasible [12]. Although there is strong evidence that a delay in treatment negatively affects outcome, the optimal time point of intervention, such as central venous catheter (CVC) removal, is under debate [13, 14].

The aim of this retrospective study was to identify risk factors for mortality 28 and 180 days after Candida BSI. We hypothesized that survival would mainly be determined by appropriate antifungal treatment, such as adequate antifungal substance and timely source control, and yeast spp. Therefore, we analyzed clinical characteristics, antifungal management, and patterns of Candida spp. distribution in a mixed population of critically ill patients at 12 multidisciplinary intensive care units (ICUs) over a 10-year period.

In this single-center retrospective study, including 391 critically ill patients with Candida BSI, we observed a high mortality 28 and 180 days after culture positivity. We identified higher age, a history of liver cirrhosis, high SOFA and Candida scores, increased length of ICU stay, and the presence of septic shock as risk factors for mortality after Candida BSI. Patients, who had abdominal surgery, and patients receiving any empirical antifungal agent had a reduced risk of mortality compared to medical admission type and no antifungal treatment, respectively. Throughout the study period of 10 years, we did not observe a significant change in the distribution pattern of yeast species and no multidrug-resistant Candida auris spp. was identified.

We found a mortality rate of 47% 28 days after diagnosis of Candida BSI. Our results are in line with findings from previous studies. In one of the largest European multicenter trials on the epidemiology of ICU-acquired candidiasis, the 30-day mortality rate was 42% [1]. Similarly, a 30-day-mortality of 45% has been reported after candidemia in internal medicine wards [19]. The French Mycoses study group observed 50% survival in a mixed ICU population 30 days after candidemia [11], which is similar to the findings of a retrospective observation by Ghanem-Zoubi and colleagues [3]. An analysis from prospectively collected data in the French REA-RAISIN network showed a mortality rate of 52% among patients with ICU-acquired candidemia in 213 ICUs [20].

We found that adequate antifungal management, defined by the start of antifungal medication, susceptibility of Candida spp., and time point of CVC removal, was a predictor of survival after 28 and 180 days. Interestingly, multivariable analysis showed that also non-adequate antifungal treatment including delayed administration of antifungal medication or resistant drugs was associated with an increased probability of survival. By contrast, adequate antifungal treatment, does not seem to be superior with regard to survival after 28 or 180 days when compared to non-adequate antifungal management. Several factors may be accountable for the non-superiority of adequate antifungal treatment over non-adequate antifungal management with regard to survival in our study population. First, there are no detailed uniform criteria for adequate antifungal treatment. We used a rather strict definition that has been proposed previously [18]. Following a more liberal definition, 21 (7.1%) more patients would have fulfilled the criteria for adequate treatment, which may have altered the results of our analysis.

The influence of different definitions of appropriate antifungal treatment on the strength of association with mortality after candidemia has been reported by another retrospective trial. Three definitions of appropriate empiric treatment and their association with 30-day mortality were compared in a cohort of 302 critically ill patients [3]. Interestingly, statistical associations varied by definition, which underlines the impact of treatment criteria on outcome prediction.

Second, the susceptibility of Candida spp. to specific antifungal drugs may not necessarily correlate with outcome. Ghrenassia and colleagues observed that Candida susceptibility was not associated with survival after candidemia in immunocompromised patients [21]. Neither was the choice of antifungal agent in favor of echinocandins. As opposed to the treatment regimen in our study, antifungal prophylaxis was used by Ghenrassia et al. which may limit the comparability with our results.

We found an association between treatment with echinocandins and survival after 28 days. By contrast, mortality after 180 days was not influenced by echinocandins for antifungal management. There remains controversy on the impact of echinocandins on mortality [22‐25]. Of note, other factors such as comorbid conditions, disease severity, and appropriate antifungal management including source control may be more relevant for survival after candidemia, which may explain the conflicting results [22]. We found a beneficial effect of echinocandins on short-term mortality after 28 days that did not sustain the 180-day follow-up. Long-term survival in critically ill patients may be determined by the underlying condition and disease severity rather than the type of initial antifungal medication.

Compared with medical patients, patients undergoing abdominal surgery had a lower risk of mortality at 28 and 180 days. Similar results have been reported from the Spanish CANDIPOP trial that found a lower mortality from candidemia in surgical wards compared with medical wards [26]. Better outcome in surgical patients might be attributable to lower disease severity, fewer immunosuppression, and organ failure [26].

Preexisting liver cirrhosis was associated with increased 28- and 180-day mortality in our study population, which confirms the results of previous studies [27]. Next to the SOFA score as an indicator of morbidity in critical care patients and the presence of septic shock, we found an association between the Candida score and reduced survival at 28 and 180 days [28]. All factors that were identified as predictors of poor outcome in our study population have been linked with increased mortality in ICU patients before [29‐31]. Thus, our results confirm the importance of disease severity and multiorgan dysfunction for the prognosis after Candida BSI.

Candida albicans was the most frequently encountered yeast isolate in our study population, followed by Candida glabrata and Candida parapsilosis. Our findings are in line with data from the multicenter EUCANDICU trial reporting similar distribution patterns. There are conflicting results on a shift in Candida spp. towards non-albicans isolates. Several Italian studies report a decrease of Candida albicans and an increase of non-albicans Candida spp. [32, 33]. By contrast, two observational studies in French and Belgian ICUs did not observe a species shift and describe patterns similar to our results with a predominance of Candida albicans [34, 35]. We found a relatively stable Candida albicans/non-albicans ratio between 2012 and 2015. Interestingly, there was a substantial shift towards Candida albicans in the years 2016 and 2017. The decrease of non-albicans species in favor of Candida albicans might be attributable to episodic fluctuations that have been observed periodically [35]. Of note, Candida auris, a multidrug-resistant pathogen, which was first described in Japan in 2009 [36], has been recently associated with outbreaks worldwide, including Europe, could not be detected in our study population [37‐40].

Our study has several limitations that need to be addressed. Results from this retrospective analysis are of exploratory nature and should be interpreted with caution. Another limitation of this study is the lack of biomarkers that have since been used to diagnose and monitor therapy [41, 42]. However, these biomarkers ((1,3) beta-D glucan and Candida-Ag) were not widely available in our retrospective cohort and have only become established in recent years.

We did not analyze total parenteral nutrition, which is one of the leading risk factors for increased mortality after Candida BSI, as a single variable, since it is included in the Candida score. Numerous parameters have been identified as risk factors for mortality after candidemia in critically ill patients. These include a history of congestive heart failure, the presence of solid tumors with metastases, red blood cell transfusions, and the duration of antifungal treatment [24, 43‐45]. For survival analysis, we selected covariates that were considered clinically relevant or factors that had been associated with 30-day mortality in a multinational observational study in 23 European ICUs [1]. Other covariates and unknown variables that were omitted from our analyses may have biased the results of this study, which has to be considered when interpreting our findings.

Source control was defined as CVC removal in our study. We did not include other management strategies such as the removal of implanted devices, drainage of infected fluid collections or surgical debridement of infected solid tissue. We chose this definition, because we aimed to analyze the impact of measures that were immediately performed by the ICU team rather than surgical procedures.

One strength of our study is the long observation period of 10 years that allows the analysis of species distribution independently from seasonal fluctuations. Importantly, we obtained microbiological results from a mixed population of critically ill patients, including surgical and medical conditions, hematologic malignancy, solid and organ stem cell transplantation.

Most previous trials that assessed outcome after candidemia report short-term mortality rates after one month [1, 46], since the 30-day outcome is traditionally used as an endpoint in critical care trials [47]. We aimed to evaluate outcome beyond this time period and assessed long-term survival 180 days after diagnosis of Candida BSI in addition to 28-day mortality.

Candida BSI is still a serious and life-threatening disease with very high morbidity and mortality in critically ill patients. Our study demonstrates that prompt antifungal treatment improves the likelihood of survival, regardless of yeast susceptibility and exact time point of administration. Patients with liver cirrhosis and high disease severity as expressed by the SAPS II and the Candida scores, and organ failure requiring extracorporeal support are at increased risk of death 28 and 180 days after culture positivity, whereas surgical patients seem to have more favorable outcome after Candida BSI. Species distribution remained relatively constant throughout a 10-year period with Candida albicans as the predominant yeast species. Our results underline the importance of rapid treatment of Candida BSI and point to the need for a uniform definition of adequate antifungal management.