Introduction

Critically ill patients are particularly vulnerable to nosocomial infections [1]. The risk of acquiring a nosocomial infection is 2–7 times greater in the intensive care unit (ICU) [2–4], which accounts for approximately half of all hospital acquired infections [5, 6]. The most prevalent nosocomial infections in the ICU are catheter-related blood stream infections (CR-BSIs), ventilator-associated pneumonia (VAP), and catheter-associated urinary tract infections (CA-UTI). These infections are strongly linked to increases in morbidity, mortality, and health care expenses [7–10]. The severity of underlying disease, frequency of invasive diagnostic and therapeutic procedures that breach normal host defenses, contaminated life support equipment, and the prevalence of drug-resistant microorganisms are critical factors in the high rate of infections.

A multicenter surveillance study in Korea investigating nosocomial infections reported that the overall rate of nosocomial infection is 3.7 per 100 patients discharged; and urinary tract infection, pneumonias, and surgical site infection were the most common infections in order of frequency. BSIs were the fourth most common nosocomial infection [11]. Because ICU-acquired BSIs are associated with higher in-hospital mortality [12, 13], vigorous infection control, early detection, and treatment are necessary to prevent ICU-acquired BSIs and their attributable mortality. In Korean ICUs, the number of nosocomial infections has increased annually [14]; however, information regarding BSIs specifically acquired in ICUs is lacking [15–17].

The objective of this study was to investigate the incidence of ICU-acquired BSIs, to identify the causes of these infections (i.e., the site or source of infection and the isolated causative microorganisms, irrespective of the primary reason for ICU admission), and to determine the overall hospital mortality rate and factors associated with death as well as the impact of adequate antimicrobial treatment on mortality in patients with ICU-acquired BSIs at a regional tertiary hospital in Korea.

Materials and methods

Study population

Data regarding blood culture results were collected from electronic medical records of patients admitted to the ICU in Gyeongsang University Hospital, Jinju, Korea (15 medical ICU and 900 total beds) between January 2005 and December 2010.

We only retrieved data of blood culture-positive patients and retrospectively assessed whether the positive blood culture was adequate for ICU-acquired BSIs. An ICU-acquired BSI was defined as a positive blood culture result for a clinically significant bacterial or fungal pathogen obtained >72 h after admission to the ICU. We analyzed the demographic, physiologic, and laboratory data; Acute Physiology and Chronic Health Evaluation II (APACHE II) physiology score; the site or source of infection; and the isolated microorganisms and outcomes in patients with confirmed ICU-acquired BSIs.

Patients were assessed differently according to whether they had been admitted to the ICU more than two times or whether >1 microorganism was isolated from their blood cultures during a single ICU admission due to a cause other than infection with the isolated organism. For oral care in the ICU, we used daily rinsing with chlorhexidine in the morning. This study was approved by the institutional review board of Gyeongsang University Hospital.

Definitions

The cause of ICU-acquired infection was classified using the Centers for Disease Control and Prevention (CDC) definitions [18, 19]. VAP-related BSIs were defined as a positive blood culture, for which microbiological isolates from the tracheal aspirate and blood cultures were likely to represent the same infection, in the presence of clinical evidence of pneumonia (e.g., fever >38.2 °C, purulent airway secretion, leukocytosis >12,000/mm3, and new or progressive infiltrate on the chest radiograph). CR-BSIs were defined as cases of positive tip culture from an intravascular device that had been removed 2 days prior to, or after, the positive blood culture result and for which the microbiological isolates from the tip and blood cultures were likely to represent the same species or compatible mixed growth. UTI-associated BSIs were similarly defined as isolation of the same pathogen from the urine and blood cultures in the presence of clinical evidence of UTI. Surgical wound- or soft tissue infection-associated BSIs were diagnosed if cultures were obtained from the respective sites in association with a BSI. Intra-abdominal infection-associated BSIs were defined as isolation of the same pathogen from the blood and purulent material from the intra-abdominal space, obtained using an aseptic procedure, in the presence of clinical evidence of intra-abdominal infection.

ICU-acquired BSI-related death was defined as death caused by deterioration of patients’ clinical conditions due to ICU-acquired BSIs when other causes of death were excluded after a review of medical records.

Data analysis

Categorical data are presented as numbers and percentages, and continuous data, as the mean ± standard deviation. Each variable was analyzed using a Pearson’s Chi-square test or Mann–Whitney U test. Survival differences were estimated using the Pearson’s Chi-square test and Kaplan–Meier curves, using the log-rank test. We also evaluated the factors associated with death in these patients using multivariate logistic regression analysis. Differences were considered statistically significant if p < 0.05. All analyses were performed with SPSS version 18.0 for Windows (SPSS Inc., Chicago, IL, USA).

Results

Baseline characteristics of patients

Among 1,545 patients (male:female 1,015:530; mean age 65.3 ± 13.8 years) admitted to the ICU during the study period, 129 ICU-acquired BSI episodes were identified in 124 patients (male:female 73:51; mean age 65 ± 12.7 years). The estimated risk for ICU-acquired BSIs was 5.3 per 1,000 patient days. Five patients developed two episodes of ICU-acquired BSIs due to different causes. Ninety-one (73.3 %) patients had an underlying disease. For 129 episodes of BSIs, the mean number of positive blood cultures in these patients was 1.6 ± 1.2 (range 1–9). The mean duration of ICU stay was 40.6 ± 44.5 days, and the median time interval between ICU admission and the time of diagnosis of ICU-acquired BSI was 23 ± 20.9 days. The APACHE II score, body temperature, white blood cell count, and C-reactive protein levels were 22.2 ± 5.99, 37.1 ± 0.82 °C, 13,169.2 ± 8,672.5 mm3, and 113.3 ± 73.19 mg/L, respectively, at the time of diagnosis of ICU-acquired BSIs (Table 1).

Table 1 Baseline patient characteristics
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The source of infection and microorganisms isolated from patients with intensive care unit-acquired blood stream infections

The source of infection was identified in 87 of 129 episodes of ICU-acquired BSIs. CR-BSIs were identified in 38 (29.4 %) patients; VAP in 27 (20.9 %); UTI in 7 (5.4 %); wound infection or surgical- or sore-related BSI in 10 (7.7 %); intra-abdominal infection in 3 (2.3 %); and other infections in 2 (1.5 %) patients. The source of infection was not identified in 42 (32.5 %) patients. More than 1 microorganism was isolated in 6 out of 124 patients, with a total of 136 microorganisms being isolated from the study population. Among these, the most commonly isolated organisms were Staphylococcus aureus (n = 35; 25.7 %), Candida species (n = 32; 24.8 %), Enterococcus species (n = 18; 13.9 %), and Acinetobacter species (n = 17; 13.1 %) (Table 2). In the 38 patients with CR-BSIs, the most commonly isolated microorganisms were Candida species (n = 18; 47.3 %) and S. aureus (n = 12; 31.5 %). In the 27 patients with VAP-related BSIs, the most commonly isolated microorganisms were Acinetobacter species (n = 12; 44.4 %), S. aureus (n = 7; 25.9 %), and Klebsiella pneumoniae (n = 3; 11.1 %) (Table 3).

Table 2 The source of infection and isolated microorganisms of intensive care unit-acquired blood stream infections
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Table 3 Isolated microorganisms of intensive care unit-acquired catheter-related BSI and VAP
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Outcomes of intensive care unit-acquired blood stream infections

Among the 129 cases of ICU-acquired BSIs, 98 patients died (overall hospital mortality rate, 75.9 %), and 36 of these 98 deaths (36.7 %) were due to ICU-acquired BSIs. Eighty patients died in our hospital (general ward or ICU), and 18 patients were discharged to other hospitals because of irreversible organ failure, and these patients were classified as dead patients. Eight patients were discharged to other hospitals with improvement, and these patients were classified as patients who survived. Thirty-four patients were transferred to the general ward and were discharged to their homes with improvement. The duration of survival in the ICU was significantly shorter in patients who died because of ICU-acquired BSIs than in patients with ICU-acquired BSIs who died due to other causes (27.2 ± 29.4 and 68.7 ± 80.9 days, respectively; p = 0.003; Fig. 1). The hospital mortality rate in patients with CR-BSIs or VAPs was not significantly different from that in patients with any other causes of infection (68.4 and 79.1 % for CR-BSIs and other infections, respectively; 85.1 and 73.5 % for VAPs and other infections, respectively; p > 0.05). Additionally, the rate of overall hospital mortality in all patients with BSIs due to fungal infections was not different from the rate of mortality due to nonfungal infections (74.2 and 75.5 %; p > 0.05). Among patients with ICU-acquired BSI-related death, VAPs (n = 23; 63.8 %) and CR-BSIs (n = 7; 19.4 %) were the most common infections. Additionally, the most commonly isolated microorganisms were S. aureus (n = 12; 33.3 %) and Acinetobacter species (n = 12; 33.3 %) in these patients (Tables 4).

Fig. 1
figure 1

Kaplan–Meier survival curve in patients with ICU-acquired BSIs during ICU stay. The duration of survival was significantly different for patients who died due to ICU-acquired BSIs and for patients who died from other causes

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Table 4 Source of infection and isolated microorganisms in patients with intensive care unit-acquired blood stream infection-related mortality
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Among 129 cases of ICU-acquired BSIs, 30 cases (23.2 %) received adequate antimicrobial treatment, which was defined as the use of antimicrobials to which the isolated microorganism was sensitive, as determined by the drug sensitivity test. However, adequate antimicrobial treatment was not administered in 99 (76.8 %) cases. The overall mortality rate of patients who received adequate antimicrobial treatment was 70 %, compared to 76.6 % for patients who did not receive adequate antimicrobial treatment. These rates indicate that there was no significant difference between the mortality rates regardless of the adequacy of antimicrobial treatment. In the 99 ICU-acquired BSI cases in which patients did not receive adequate antimicrobial treatment, the most common causes were CR-BSI (29 cases), VAP (22 cases), wound infection (8 cases), and UTI (5 cases). The most commonly isolated pathogens in these cases were S. aureus (n = 30), Candida species (n = 26), and Acinetobacter species (n = 3) (Table 5). For patients who had received adequate antimicrobial treatment, the most common causes were CR-BSI (9 cases), VAP (5 cases), wound infection (2 cases), and UTI (2 cases).

Table 5 Source of infection and isolated microorganisms in patients with inadequate antimicrobial treatment before the onset of intensive care unit-acquired blood infection
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In the multivariate analysis to assess the factors associated with mortality in these patients, only APACHE II scores were significantly associated with death (Table 6).

Table 6 Multivariate logistic regression analysis for the factors associated mortality in patients with intensive care unit-acquired blood infections
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Discussion

This study aimed at evaluating the characteristics and outcomes of ICU-acquired BSIs in a medical ICU at a tertiary care hospital. The results indicated that CR-BSIs and VAPs were the most common causes of ICU-acquired BSIs and that they may contribute to death among critically ill patients admitted to the ICU.

During the study period, the incidence of ICU-acquired BSIs was 8.1 %, which was higher than that observed in other studies. According to a study from China that included 1980 patients and was published in 2009, the incidence of ICU-acquired BSIs was 5.9 % [20]. Additionally, in a study of 6,339 an ICU admission at 2 university-affiliated hospitals in Australia, the incidence of ICU-acquired BSIs was 5.2 % [13]. In a French study of 3,247 ICU admissions, 232 patients (6.8 %) acquired nosocomial BSIs [8]. The relatively higher incidence of ICU-acquired BSIs may be related with the longer ICU stays, over 40 days in mean, in our study population.

In our study, CR-BSIs were the most common ICU-acquired BSIs followed by VAPs (29.4 and 20.9 %), respectively. In another Korean study, respiratory infection was the most common cause of BSIs (38.2 %; 95/249 cases), whereas CR-BSIs were the cause in only 1.6 % (4/294) of cases [21]. An Australian study found that 34 cases (20.4 %) were caused by CR infections [13] and that about 30 % of ICU-acquired BSIs in the French study were associated with intravascular catheters [8]. The relatively higher proportion of CR-BSIs in our study than that in other studies might be explained by the lack of guidelines for intravascular catheterization in our hospital during the study period; further, this may have contributed to the relatively high incidence of CR-BSIs in this study.

The overall mortality was >70 % in this study population. Crude mortality rates of 25–66 % for 10 years of study have been reported in patients with ICU-acquired BSIs [13]. In our study, VAP was one of the most common types of infection, with a high mortality rate of >80 %. In addition, the APACHE II score at the time of ICU admission and diagnosis of ICU-acquired BSIs was approximately 22 in these patients, suggesting the presence of severe underlying diseases and infections that undoubtedly contributed to the high mortality rate in these cases.

The most commonly isolated microorganisms in this study were S. aureus and Candida species. These two microorganisms were the causative pathogens in 80 % of cases and may be associated with higher incidences of CR-BSIs in this study. The microorganisms isolated in cases of ICU-acquired BSIs may differ from study to study depending on the cause of BSIs. In a study of ICU-acquired BSIs in Canada, the most common isolates were S. aureus, coagulase-negative staphylococci, and Enterococcus faecalis [22].

Among the 98 patients who died in the ICU or hospital during the study period, 36 patients died due to ICU-acquired BSIs, which accounted for 37.7 % of the overall mortality rate in the study population. This strongly suggests that meticulous infection control in ICUs may reduce ICU-related mortality in critically ill patients.

The mortality rates in BSI patients differed according to the source of infection and the causative microorganism. In our study, VAPs had the highest mortality rate (85 %; 23 of 27 cases) and accounted for 63 % of ICU-acquired BSI-related mortality. In contrast, only 7 of 38 patients with CR-BSIs died (mortality rate of 18.4 %). The most common microorganisms isolated from ICU-acquired BSI-related mortality cases were S. aureus and Acinetobacter species. These microorganisms were also the major pathogens responsible for ICU-acquired VAPs in this study. A German study assessing nosocomial S. aureus infections in ICUs revealed that BSIs and pneumonia due to S. aureus may be associated with high mortality [23]. In a Chinese study, the overall mortality due to nosocomial S. aureus BSIs was 28 %. S. aureus was associated with a high proportion of inappropriate empirical antibiotics treatment [24]. Acinetobacter species were the most common causative organisms in VAP-associated with BSIs, and they were the major causative microorganisms responsible for BSI-related mortality in this study. Moreover, most Acinetobacter species isolated in the ICU were resistant to imipenem, and they may be associated with high ICU mortality, especially in cases of bacteremia [25].

The rate of inadequate empirical antimicrobial treatment was relatively high and most cases of inadequate antimicrobial treatment were associated with fungal or methicillin-resistant S. aureus (MRSA) infections. In our hospital practice, usual empirical antimicrobial treatment was not covered with fungal or MRSA infection even in patients with severe infection. This explains the high rate of inadequate antimicrobial treatment in this study.

Although inadequate antimicrobial treatment was significantly associated with mortality in patients with nosocomial infections in previous studies, the adequacy of antimicrobial treatment did not affect mortality in our study. In previous studies on the influence of inadequate antimicrobial treatment for nosocomial infections, including BSIs, in ICU patients, inadequate antimicrobial treatment significantly increased the mortality rates among critically ill patients [26, 27]. However, another study showed a significant difference in the mortality rate [28]. In particular, one study found that BSIs due to S. aureus or Pseudomonas aeruginosa were associated with an increase in hospital mortality rates even though adequate antimicrobial therapy was provided [29].

Our study has some limitations. This study was performed using a retrospective methodology; therefore, we could not determine if the duration of hospital stay was lengthened as a secondary outcome of ICU-acquired BSIs or if BSIs were caused because of the extended hospital stay. Additionally, because the study population included patients from a single facility, our findings may not be directly generalizable to different microbiological environments worldwide. Another limitation of this study is that it focused on mortality as the only outcome; other signs and symptoms of disease severity were not evaluated. Finally, due to the retrospective nature of this study, we could only assess confirmed cases of ICU-acquired BSIs; therefore, the number of ICU-acquired BSI cases may have been underestimated.

ICU-acquired BSIs may be caused by infectious agents from endogenous or exogenous sources. The most common mode of transmission is direct contact. Therefore, the best practices for preventing healthcare-associated infections include hand hygiene, standard precautions, isolation precautions, and prudent antimicrobial use [30], which may decrease ICU-acquired infections including BSIs as well as mortality among ICU patients. In addition, aseptic procedures and antimicrobial management in the ICU may reduce ICU-acquired infections and the emergence of antimicrobial-resistant strains, which will help reduce mortality rates due to ICU-acquired infections.

In conclusion, this study showed that ICU-acquired BSIs were associated with mortality among critically ill patients admitted to the ICU, which strongly indicates that appropriate infection control systems may reduce the incidence of ICU-acquired BSIs and the related mortality among ICU patients.