This study was presented with preliminary data in 26 ^th International Symposium on Intensive Care and Emergency Medicine, Brussels, 2006.

Introduction

Fungal infections had increasing importance among the ICU infections, and Candida species had risen to the 4 ^th frequently seen ICU infections (₁). Among Candida species, Candida albicans is the most frequently seen cause of fungal infections. Although, since the beginning of the 90s the emerging trend has stopped (₂, ₃), the incidence of fungal infections is continuing to increase, both in Europe and in the USA. More patients are becoming immune-suppressed (due to AIDS, aggressive chemotherapy, and the larger number of bone marrow and organ transplants now taking place), while medical advances such as mechanical ventilation have succeeded in allowing more critically ill patients to be treated by stabilizing their condition. Furthermore, excessive antibiotic use and resistance provides a fertile breeding ground for the incidence of fungal infections.

Intensive Care Unit is a place for the treatment of the most severe, often immune-deficient patients. On the other hand, their treatment often requires invasive procedures, support of vital organs and constant monitoring. All of these are predisposing factors for the development of fungal infections. The risk factors of patients with Candida infections include the effect of treatment with multiple antimicrobials for extended periods; the presence of central venous catheters; administered total parenteral nutrition (TPN); colonization by Candida species; abdominal surgery; compromised immune status; mechanical ventilation and prolonged stay in the ICU (₄). Prolonged stay in ICU is an independent risk factor along. Fungal infections can prolong hospitalization time (₅, ₆) and increase medical cost (₇). For these reasons, fungal infections developing in ICU should be fought effectively.

It is often hard to differentiate colonization from infection and many critically ill patients are heavily colonized with Candida species, especially when receiving broad-spectrum antibacterial (₃). With the exception of candidemia, in most Candida isolates, it is nearly impossible to distinguish colonization from infection (₃). Moreover, sepsis caused by the Candida species is clinically indistinguishable from bacterial infections. It is very hard to diagnose fungal infections. In these patients, bacterial infections are thought to be the cause at the beginning. These bacterial diseases are attempted to obliterate and for this reason antibiotics are used intensively. Diagnosis of the clinical status is almost impossible. Sometimes only the presence of risk factors may cause fungal infections to be suspect. Besides, Candida species are the cause of almost all urinary fungal infections. The most serious clinical problem is to decide whether candiduria is a sign of urinary infection or just a temporary colonization or contamination (₈).

In addition, the prognosis of patients developing Candida infections is already very poor and the mortality rates of them are expected to be high (₉).

The aim of this study was to compare the fungal infections' mortality rates with other our ICU patients having fungal infections' risk factors and prolonged stay.

Methods

The ICU of the Ataturk Training and Research Hospital in Izmir, Turkey, is a general medical and surgical reanimation unit with 10 beds and about 400 admissions per year. This study was performed by retrospective chart review. Intensive care medical records of 2373 patients who were admitted to ICU between 2002 and 2008 were analyzed retrospectively.

A hundred twenty-five patients who had risk factors for the development of fungal infection were included in the study. Sixty-three of them had Candida infection which was represented by candidemia.

In all patients with clinical evidence of SIRS criteria and infection, culture samples (venous blood, tips of removed intravascular catheters, endotracheal aspirates, operation site and urine) had been obtained. Patients who developed clinically and microbiologically documented Candida infection were identified through a microbiological laboratory survey and data were recorded in intensive care medical records. The review of patients' chart was performed in order to identify clinically relevant episodes. Candida species were isolated from culture samples. Patients with at least one culture result positive for Candida species were assigned to the Candida group.

Controls were admitted to ICU between 2002 and 2008 patients who were mechanically ventilated in the ICU for at least 2 weeks, treatment with multiple antimicrobials (>2) for extended periods (over one weeks) and had central venous catheters.

Exclusion criteria were neutropenic and immune-suppressed patients, having fungal infection (at the hospital admission) patients and DNR (do not resuscitate) patients.

Candidemia group and control patients were compared for age, gender, disease severity as measured by Acute Physiology and Chronic Health Evaluation (APACHE) II score at the admission and Sequential Organ Failure Assessment (SOFA) score (the worst score prior to the onset of the Candida infection or corresponding day in the control patient), length of mechanical ventilation support (total days) (LOMV), length of ICU stay (on the total ICU day) (LOICUS), the ratio of TPN application, numbers of antibiotics, length of antibiotic day and length of catheter day. In addition, the risk factors and mortality rate of Candida infections were assessed and the patients with Candida infection were compared with controls for risk factors and mortality.

Besides, we subdivided Candida infections into two groups as candidemia and candiduria. The patients having the positive blood culture for Candida species were assigned to the candidemia group; the patients having the positive urine culture (at least 10 ⁵ CFU/ml) (₁₀) were assigned to the candiduria group. The risk factors, mortality and morbidity of candiduria and candidemia infections were assessed. We also compared candidemia and candiduria cases exclusively with the control group in terms of the same risk factors, mortality and morbidity.

Statistical methods: All statistical analysis was performed using Statistical Programmer for Social Sciences (SPSS) 11.0 for Windows. The Chi-square-test was used to compare categorical variables. Data for continuous variables are presented as mean (SD) and were compared with the independent samples t test. P values < 0.05 were considered significant.

Results

Intensive care medical records of 2373 patients who were admitted to our ICU between 2002 and 2008 were analyzed retrospectively. We found 63 ICU patients with candidemia and 62 controls. Mortality ratio was found to be 50.79 % in Candida infections.

The LOMV (days), age and gender of Candida infection group and control group were similar (p=0.214, 0.222 and 0.858, respectively). With regard to the number of antibiotics used which is known to be risk factors of fungal infection development, there was no significant differences established between the two groups (p=0.515). However, the length of ICU stay, the length of antibiotic day, and the length of catheter day were established to be more prolonged in the control group (p=0.026, 0.000, and 0.000, respectively). In severe critical diseases, the risk of fungal infection development is high. There was no statistically significant difference between the Candida and control groups for SOFA score (p=0.122) but APACHE II score was significantly higher in candida group than controls (p=0.38). Also, when we compared the mortalities of the Candida infection group to the control group having the same risk factors of fungal infection, no statistically significant difference was established (50.79 % and % 48.38 respectively, p=0.859) (Table-1).

Figure 1

Table 1: The characteristics and the survival rate of 28 patients with Candida infection and 62 controls.

F: female, M: male, LOMV: length of mechanical ventilator, LOICUS: lenght of ICU stay (*) p<0.05

Candida infections were composed of patients with candidemia and candiduria, 33 of the cases were candidemia and 30 were candiduria. When we compare the two groups to each other for risk factors which are length of mechanical support (p=0.523), ICU stay (p=0.742), length of invasive catheter day (p=0.937), APACHE II (p=0.611) and SOFA scores (p=0.614), there were no statistically significant differences. In only candidemia group, the TPN application (p=0.04), the number of antibiotics used (p=0.036), and the length of antibiotic days (p=0.000) were significantly high. However, the rate of mortality in candiduria and candidemia groups were similar (p=0.617) (Table-2).

Figure 2

Table 2: The characteristics and the survival rate of the candidemia and candiduria groups.

When the Candida infection group divided into candidemia and candiduria, both groups were compared each other for age, sex, the risk factors and the mortality rate. (*) p<0.05

When we compared only the candidemia group to the control group for age, gender, LOMV, LOICUS and the numbers of antibiotics used, there were no statistically significant differences established. Besides, APACHE II and SOFA scores values were found to be similar between the candidemia and control groups (p=0.137 and p=0.328, respectively). In addition, TPN application in candidemia group was high were than controls (p=0.003). In the control group, length of antibiotic day and length of invasive catheter day were found to be more prolonged than the candidemia group (p=0.11 and p=0.000). But, there was no statistically difference between them for mortality rate (54.55% for candidemia, 48.38% for controls, p=0.668) (Table-3).

Figure 3

Table 3: The characteristics and the survival rate of the candidemia and the controls groups.

The Candidemia group was compared the controls for age, sex, the risk factors and the mortality rate. (*) p<0.05

The candiduria group had lower length of antibiotic day (9.37 ± 5 versus 45 32.61, p=0.000) and length of catheter day (21.42 ± 16 versus 49.05 ± 30.53, p=0.000) than the controls. Although candiduria group had higher APACHE II score (p=0.047), there was no statistically significant difference between the candiduria group and controls for mortality rate (46.66% versus 48.38%, p=1) (Table-4).

Figure 4

Table 4: The characteristics and the survival rate of the candiduria and control groups.

The Candiduria group was compared the controls for age, sex, the risk factors and the mortality rate. (*) p<0.05

Discussion

We found that there was a high mortality and morbidity rate in patients with Candida infections. In Candida patients, there were high APACHE II and SOFA scores, long ICU staying time, long period of mechanic ventilation, more prolonged and multiple antibiotic usages, TPN application and an increase of invasive catheter days. Risk factors associated with Candida infections include treatment with multiple antimicrobials for extended periods (₄), presence of central venous catheter and total parenteral nutrition (₄, ₁₁, ₁₂), high APACHE II and SOFA scores (₁₃), long ICU staying time (₄, ₉, ₁₄, ₁₅) and long period of mechanical ventilation (₁₃, ₁₅). Besides, in several publications it is notified that in Candida infections increases mortality rate (₅, ₆, ₉, ₁₆, ₁₇, ₁₈, ₁₉).

When we formed the control group including the same risk factors and compare the mortalities of two groups while considering all risk factors, we found that Candida infection did not increase mortality rate (% 50.79 versus % 48.38, p=0.859) (Table-1).

In other studies researching the effects of Candida infections on mortality, contradictory results were reported. In the study researching risk factors from the point of view of mortality in candidemia developing in ICU patients, mortality of patients with candidemia was found to be 58% and no relationship was found between mortality and intravenous catheterization or wide spectrum antibiotic usage (₁₆). In a multi-center, matched-cohort retrospective study, candidemia patients were reported to have an increased mortality rate when compared to the control group carrying relative risk factors (₅). In another retrospective cohort study, it was reported that nosocomial candidemia patients stay in mechanical ventilation and ICU longer when compared to the control group, but on the other hand, there was no difference between these two groups in terms of mortalities (₁₅). The study further claimed that mortality is related to age, severity of the primary disease and acute disease. In a study done in patients with malignant (65%) and severe but non-malignant disease (35%), Ellis et al found that crude mortality is 50% and mortality attributable to candidemia is 30% (₁₇). They reported that mortality rate increased due to the length of stay at ICU and being in septic shock. In another retrospective, observational, comparative study, it was reported that when all risk factors are included, only malnutrition is a predictor in terms of mortality, but others are not (₂₀). In a Meta analysis of a systematic review of matched cohort and case-control studies done by Falagas et al, it was concluded that candidemia seriously increases mortality (₉).

In general, the mortality rate in Candida infections is high. The mortality ratio is reported to be 55%-65% (₁₆, ₁₈). Our study found the mortality ratio of Candida infections to be 50.79%. However, differing from other studies, when we compared the Candida group with a control group including the same risk factors for Candida infection development, we observed no difference in the mortality (p=0.859). Nevertheless, in all previous mortality studies, only candidemia was considered instead of the Candida infections. In our study, there was no difference in terms of mortality rate when compared to the control group (in candidemia: 54.55 %, in control group: 48.38 %, P=0.617) (Table-3).

When we subdivided Candida infection group into two groups as candidemia and pure candiduria, in the candidemia group the number of antibiotics used and antibiotic day which are the risk factors of fungal infections were found to be higher than in the candiduria. However, we observed no difference in terms of mortality rate (Table-2) (54.55 % in the candidemia group, 46.66 % in the candiduria group. P=0.617). In a prospective cohort observational and multicenter study, mortality ratio in candiduria was found to be 48.8 % (₂₁). Candiduria is generally missed by clinicians. Ayeni et al also attracted attention to this issue and proposed that clinicians do not follow the guidelines in management of candiduria according to the findings in their study (₂₂). The usual response to candiduria is to replace the urinary catheter. However, in a prospective study done by Akalin et al, it was reported that 56% of candiduria infections continued when the urinary catheter was replaced (₈). It is thought that in the ICU's Candiduria infections are more readily observed than expected. In a prospective study done by Passos et al, they determined candiduria in 44.4% of ICU patients and they proposed that staying in ICU is the most important risk factor for Candida infections (₂₃). Although there was no difference between candiduria and candidemia in terms of results, non-aggressive management of candiduria cases (₂₂) and increasing amount of Candida infections in ICU (₂₄) showed that we have to be careful in ICU. In addition, the inability of Clinical differentiating sepsis development from Candida than that form bacterial infections is the other difficult factor of this issue. In addition, it was found that 80% of candiduric patients developed candidemia with the same species in multicenter, prospective study (₂₅).

Our study has a limitation in that was not multicenter study and has limitation data. However, we found that candiduria, candidemia and control cases whom having same risk factors for fungal infection had similar high mortality rate.

Conclusion

Despite the fact that there is no difference between the results of patients carrying the same risk factors with Candida infections, Candida infections should be managed like severe infections or critical illness and its proper management should be paramount. Severity of blood infections developed by Candida is obvious. However, candiduria should be treated more aggressively. Otherwise, the nosocomial infections brought about through urinary tract will be of greater threat to the patients' life more severely.

Acknowledgements

Correspondence to

TAYFUN ADANIR Address: P. B: 12 Hatay 35370 IZMIR TURKEY E-mail: tadanir@tnn.net Phone: 00902322444444-2380 FAX: 00902322434848