Abstract
We studied a cohort of 2201 patients hospitalized in 15 French intensive care units (ICUs) for ⩾ 48 h during a 4-mo period to assess the incidence and outcomes of primary and definite catheter-related bloodstream (CRB) or secondary nosocomial bloodstream infection (NBSI). Variables associated with ICU death and duration of stay were determined by logistic regression, and attributable mortality and length of stay (LOS) from a nested matched case–control (96 pairs) study, stratified on the source of bacteremia. Bacteremia occurred in 5% (95% CI 4.1–6%) of patients with ⩾ 48 h ICU stay. Primary, CRB, and secondary NBSI accounted for 29%, 26%, and 45% of the 111 episodes, respectively. NBSI was associated with a markedly increased risk of death (OR = 4.6; 95% CI 2.9–7.1) and an attributable mortality of 35% (95% CI, 28%–47%). In the case–control study, the excess mortality was 20% (p = 0.03) in patients with primary bacteremia and CRB, and 55% (p < 0.001) for secondary bacteremia; in patients with CRB only, the excess mortality was 11.5%. The median excess ICU LOS in survivors of NBSI was 9.5 d, and was similar, irrespective of its source. The risk of mortality associated with primary and catheter-related bacteremia appears much lower than that of secondary bacteremia, but is sizable, and the excess LOS incurred by the various categories of bacteremia is comparable. Differentiating catheter-related bacteremia from both primary and other secondary bacteremia appears warranted in studies conducted in critically ill patients.
Nosocomial bloodstream infection (NBSI) is a leading cause of death in critically ill patients (1, 2). The overall incidence of nosocomial bacteremia has been increasing recently (3-5). At one institution, a 3-fold increase in NBSI rates has been noted over the past decade, from 6.7/1000 to 18.4/1000 discharges (4). Much of this increase appears to be due to primary bacteremia (3), which accounts for 20% to 30% of all nosocomial bacteremias (3, 6). Changes in the distribution of organisms have also been noted, with increasing rates of coagulase-negative staphylococci, Staphylococcus aureus, Enterococci, and Candida sp. (3, 7). Most of these changes appear related to intravascular device-associated infection, likely reflecting the increasing proportion of intensive care beds in hospitals and associated increased illness severity of patients, and possibly increased awareness of coagulase-negative staphylococci as a significant pathogen (3, 8). Intravascular device-associated infections are therefore of major concern to both infection control professionals and health care providers, especially in the intensive care unit (ICU) setting.
Several studies using various approaches have examined the impact of NBSI on outcome of patients (1, 6, 9). In surgical ICU patients, Pittet and coworkers found a 35% higher mortality in bacteremic patients compared with matched controls (1). In a large European prevalence study of nosocomial infection (EPIC), bacteremia or sepsis was associated with a 1.7 odds ratio for death, using multiple regression techniques (10). Using a similar analytic strategy, Fagon and coworkers found that NBSI was associated with a 2.5 odds ratio of mortality in a cohort of 1978 patients from one medical ICU (11). However, the respective impact of the different categories of bacteremia, whether primary bacteremia, bacteremia secondary to catheter infection, or secondary to other sources, remains unclear. In hospital-wide and multiinstitutional surveillance systems of nosocomial bacteremia, it is difficult to differentiate catheter-related bacteremia from true primary bacteremia (3, 4, 12). Thus, estimates of the overall consequences of NBSI may not apply to catheter-related bacteremia. Two recent case–control studies have suggested that primary or central venous catheter-related bacteremia occurring in critically ill patients was not associated with a significantly higher mortality than in matched control patients (13, 14); both these studies used matching on variables reflecting severity of illness recorded just before the occurrence of bacteremia to adjust for severity of patients. However, this approach may result in underestimating the impact of infection on outcome of patients.
Determining the impact of nosocomial infections on outcome of patients is important to design future studies, and to assess the impact of preventive measures. We therefore conducted this study to determine the incidence of nosocomial bacteremia in ICU patients, and the relative proportion of secondary, primary, or definite catheter-related bacteremia; and to estimate the influence of the source of NBSI on mortality and ICU length of stay. For these purposes, we examined a cohort of patients from 15 ICUs in France, assessed factors associated with mortality and length of stay in the cohort, and used both logistic regression and a nested case–control study of bacteremic cases to estimate attributable mortality and length of stay of bacteremia, comparing catheter-related and primary bacteremia with secondary bacteremia.
This prospective cohort study was conducted between February 15 and June 15, 1998 in 15 adult ICUs of university and university-affiliated hospitals in the Paris area. There were 11 medical and 4 surgical-trauma ICUs, for a total of 222 beds. Participating ICUs had an ongoing continuous monitoring of nosocomial infections, including routine culture of all central venous catheters using a quantitative culture technique (15). No antimicrobial-coated catheters were used during the study period.
Patients newly admitted to the participating ICUs were included in the cohort if they were aged ⩾ 16 yr and stayed in the ICU for ⩾ 48 h; readmissions were excluded.
A “case” was defined as any new patient in whom ICU-acquired bacteremia was diagnosed, as identified by one or more positive blood cultures obtained > 48 h following ICU admission, and unrelated to an infection present on ICU admission. Bacteremia related to an infection acquired outside the ICU was excluded. Only the first episode of bacteremia in a given patient was included in the analysis. Bacteremia occurring after a “do not resuscitate” order had been issued was excluded from analysis.
Nosocomial (ICU-acquired) bacteremia was defined as either one or more positive blood culture of a known pathogen; at least two blood cultures positive with the same microorganism taken from blood samples obtained at least 2 h apart within a 48-h period were required for the following microorganisms: coagulase-negative staphylococci, Corynebacterium sp., Micrococcus sp., Bacillus sp., Propionibacterium sp., or strictly aerobic gram-negative organisms other than Pseudomonas aeruginosa and Acinetobacter baumannii. Polymicrobial bacteremia was identified when at least two different microorganisms were recovered from blood within a 48-h period (16), and at least two of these microorganisms fulfilled the above criteria for ICU- acquired bacteremia.
Episodes of ICU-acquired bacteremia were classified as secondary to an identified source when both blood and a clinically identified source grew the same microorganism (i.e., identical species, phenotype, and antimicrobial resistance profile). Bacteremia was defined as definitely catheter related in the presence of catheter exit site inflammation with or without signs of systemic inflammatory response, and recovery of at least 103 colony-forming units of the same organism from blood and the intravascular tip of a central venous or arterial catheter (15, 17). Bacteremia was classified as primary in the absence of an identified source of infection growing the same organism(s) as recovered from blood. For purpose of analysis, definite catheter-related bacteremias and primary bacteremias were grouped together as “catheter-related and primary bacteremia” and compared with “secondary” bacteremias, unless otherwise stated. Antimicrobial therapy was deemed appropriate when at least one antibiotic active in vitro on all organisms causing ICU-acquired bacteremia was administered in appropriate dosage within the first 48 h of occurrence of bacteremia (16).
One of us (B.R.) prospectively collected surveillance data in each ICU. The following sources of information were used: nosocomial surveillance data from each unit, medical and nursing records, computerized admission and diagnostic coding of all patients admitted in each ICU, and listings of all positive blood and catheter cultures recorded in each hospital's clinical microbiology laboratory. For bacteremic patients, the entire medical record was reviewed, using daily and summary charts for review of relevant clinical events and antibiotics administered, and interview with the physicians in charge of the patient and with the microbiologist when appropriate. Original microbiological results, results from other laboratories, and all data needed for scoring calculations were checked.
For all patients included in the cohort, we prospectively collected information on patients' age, sex, and underlying diseases as described by Kreger and coworkers (stratified as rapidly or ultimately fatal, or nonfatal) (18), admission category (classified as medical, scheduled or unscheduled surgery, or trauma), and location prior to ICU admission (stratified in three classes: direct admission, when the patient was admitted to the ICU from home or the emergency room; intrahospital transfer, when the patient was transferred from another unit of the same hospital; or interhospital transfer, when the patient was transferred from another hospital). In addition, we recorded the Simplified Acute Physiology Score II (SAPS II) in the 24 h following ICU admission (19), and the main reason for ICU admission and secondary diagnoses. For patients having ICU-acquired bacteremia, we recorded the date of occurrence of the first episode of bacteremia and its source, the microorganisms involved and their antimicrobial resistance pattern, and the appropriateness of antimicrobial therapy administered within the first 48 h of occurrence of bacteremia.
Data were analyzed using the Stata (Stata Corp., College Station, TX) software program. Proportions were compared using the chi-square test of homogeneity or the Fisher exact test; continuous variables were compared using the t test when normally distributed, and the Kruskal–Wallis test otherwise. Paired analysis was conducted using the McNemar's test for qualitative variables, and the Wilcoxon signed rank test for continuous data.
Stepwise logistic regression analyses of variables associated with ICU mortality and length of stay were performed according to Hosmer and Lemeshow (20), using the forward procedure. A p value ⩽ 0.10 by univariate analysis was selected for entering variables tested in the model. Quantitative variables such as age and SAPS II were introduced as continuous variables, and qualitative variables were categorized. For the latter variables, those that had only two classes were coded as binary variables (0, 1); variables represented by more than two classes were transformed into dummy variables and arbitrarily coded, using the clinically least severe as the reference category, which was ascribed a score of 1. Testing for significant interaction between variables was introduced into the model at the last step of the regression analysis. The time to occurrence of bacteremia was forced into the model (as a continuous variable) in an attempt to adjust for risk factors appearing during ICU stay. Multivariate analysis of mortality was first performed in the whole population and then in patients with bacteremia. Because of some missing values, 1989 patients (90.3% of all patients in the cohort) were included in these analyses.
Because the distribution of length of ICU stay was skewed and bacteremia occurred after a median of 10 d, we first determined the median ICU length of stay in the whole cohort, and then used a stepwise multiple logistic regression to determine variables associated with a longer than median length of ICU stay. Thereafter, we performed a pairwise case–control (1:1) analysis, first in the whole population and then in surviving pairs only, using factors previously found associated with a longer than median ICU length of stay as matching variables to select appropriate controls for bacteremic cases. In addition, controls were selected as having a duration of ICU stay at least as long as that of the case up to the occurrence of bacteremia. The case–control study was conducted on the whole population of patients having ICU-acquired bacteremia, and in the subgroups of patients having secondary, or primary and catheter-related bacteremia.
Between February 15 and June 15, 1998, 3281 patients were admitted to the 15 participating ICUs. Medical ICUs accounted for 82.4% of admissions, and surgical/trauma ICUs for 17.6%. Of these, 891 (27.2%) ICU admissions were excluded because they were of < 48 h duration, and 90 (2.7%) patients were excluded due to readmission. The proportion of missing values for all variables recorded did not exceed 10%, except in one ICU, where 31% of the patients had missing values; the 99 patients from this ICU (5 of whom had ICU-acquired bacteremia) were therefore excluded from further analysis, and 2201 patients remained in the cohort. Table 1 shows the clinical characteristics of these patients and of those having ICU-acquired bacteremia.
| Variables | Whole Cohort (n = 2201) | NBSI (n = 111) | p Value† | |||
|---|---|---|---|---|---|---|
| Number of Cases (%) or Mean (SD)* | Number of Cases (%) or Mean (SD)* | |||||
| Age, yr | 58.9 (19.0) | 61.2 (17.0) | 0.16 | |||
| Sex ratio, male/female | 1.47 | 2.3 | 0.07 | |||
| Patient origin | 0.32 | |||||
| Direct admission | 1162 (52.8) | 54 (48.6) | ||||
| Intrahospital transfer | 807 (36.7) | 41 (36.9) | ||||
| Other hospital | 227 (10.3) | 16 (14.4) | ||||
| Admission category | < 0.001 | |||||
| Medical | 1560 (76.1) | 65 (58.6) | ||||
| Unscheduled surgery | 223 (10.9) | 19 (17.1) | ||||
| Scheduled surgery | 149 (7.3) | 8 (7.2) | ||||
| Multiple trauma | 118 (5.8) | 18 (16.2) | ||||
| Leading diagnostic | 0.047 | |||||
| Medical | 1923 (87.4) | 78 (70.3) | ||||
| Cardiac failure | 354 (16.8) | 11 (9.9) | ||||
| Respiratory failure | 723 (34.3) | 36 (32.4) | ||||
| Digestive tract | 116 (5.5) | 5 (4.5) | ||||
| Central nervous system | 180 (8.5) | 9 (8.1) | ||||
| Metabolic disorders | 101 (4.8) | 6 (5.4) | ||||
| Renal failure | 35 (1.7) | 1 (0.9) | ||||
| Drug intoxication | 143 (6.8) | 1 (0.9) | ||||
| Obstetrical | 12 (0.6) | 0 (0.0) | ||||
| Other medical | 165 (7.8) | 9 (8.1) | ||||
| Surgical | 278 (12.6) | 33 (29.7) | ||||
| Abdominal | 76 (3.6) | 8 (7.2) | ||||
| Cardiac | 15 (0.7) | 2 (1.8) | ||||
| Vascular | 11 (0.5) | 3 (2.7) | ||||
| Other surgery | 58 (2.8) | 2 (1.8) | ||||
| COPD | 227 (10.5) | 3 (2.7) | 0.007 | |||
| Immunodepression | 389 (19.3) | 29 (26.4) | 0.055 | |||
| Underlyling disease | ||||||
| Nonfatal | 1194 (61.3) | 62 (55.9) | ||||
| Ultimately fatal | 492 (25.3) | 32 (28.8) | ||||
| Rapidly fatal | 262 (13.4) | 17 (15.3) | ||||
| Admission SAPS II score | 35.1 (17.9) | 45.9 (17.9) | < 0.001 | |||
| ICU length of stay, d | 11.1 (16.6) | 34.3 (28.4) | < 0.001 | |||
| ICU deaths | 407 (18.5) | 60 (54.0) | < 0.001 |
Nosocomial bacteremia occurred in 111 (3.5%; 95% confidence interval [CI] 2.9%–4.2%) of all ICU admissions, after a median of 10 d following admission (interquartile range [IQR], 6 to 18 d). In the 2201 patients staying for ⩾ 48 h, the incidence of NBSI was 5% (95% CI [4.1%–6.0%]) or 4.5/1000 patient-ICU days, and varied between 4.3% (95% CI [3.4%–5.2%]) and 9.5% (95% CI [6.2%–12.8%]), respectively, in medical and surgical ICUs (p < 0.001). Patients admitted following trauma had the highest incidence (16.2%) of bacteremia (Table 1).
Of the 111 episodes analyzed, 61 (55%) were primary bacteremia and catheter related, and 50 (45.0%) were secondary to other sources (a single source in 46 patients and several likely sources in 4 patients); 29 (26% of all episodes) were classified as definite intravascular catheter-related infection. Thirty-three patients (30%) had several positive blood cultures with the same organism. Forty-four (39.6%) episodes involved gram-positive cocci only; almost half (45.5%) of these episodes were caused by Staphylococcus aureus, 34.1% by coagulase negative staphylococci, and 18.2% by enterococci (Table 2). Gram-negative bacilli were recovered in only 44 (39.6%) episodes; Enterobacteriaceae accounted for two-thirds of these episodes, and one-third of these episodes was caused by strict aerobic gram-negative bacilli (mostly Pseudomonas aeruginosa). Gram-negative anaerobes were recovered in only three cases (2.7%), and in eight cases (7.2%) blood cultures grew Candida sp. Bacteremia was polymicrobial in 12 cases (10.8%), of which 58% were catheter-related bacteremia. A larger proportion of Enterobacteriaceae was recovered from episodes of secondary bacteremia (Table 2). Appropriate antimicrobial therapy was administered to 66 (59.5%) patients within 48 h of the first positive blood culture.
| Source of Bacteremia | All Episodes (n = 111) | |||||||
|---|---|---|---|---|---|---|---|---|
| Primary (n = 32) | Catheter Related (n = 29) | Other Secondary (n = 50) | ||||||
| Gram-positive cocci | 15 | 12 | 17 | 44 | ||||
| S. aureus | 4 | 4 | 11 | 20 | ||||
| Coagulase-negative | ||||||||
| staphylococci | 7 | 7 | 1 | 15 | ||||
| Enterococci | 4 | 0 | 4 | 8 | ||||
| Streptococci | 0 | 0 | 1 | 1 | ||||
| Gram-negative bacilli | 10 | 8 | 26 | 44 | ||||
| Enterobacteriaceae | 4 | 5 | 19 | 28 | ||||
| Aerobic gram-negative | 6 | 3 | 7 | 16 | ||||
| Anaerobes | 1 | 0 | 2 | 3 | ||||
| Candida | 4 | 2 | 2 | 8 | ||||
| Polymicrobial | 2 | 7 | 3 | 12 | ||||
| Total organisms | 34 | 36 | 53 | 123 | ||||
The crude ICU mortality rate was 18.5% among patients in the whole cohort, and 54% in patients with ICU-acquired bacteremia (Table 1). In the logistic regression analysis, bacteremia was an independent risk factor for mortality (OR = 4.6 [95% CI 2.9–7.1]; p < 0.0001), as well as age (p < 0.0001), the admission SAPS II (p < 0.0001), and being transferred from another hospital (p < 0.0001) or from a ward (p = 0.03). The time elapsed from ICU admission to occurrence of NBSI was not associated with mortality.
Variables associated by univariate analysis with death in bacteremic patients were (Table 3) age, the patient's location prior to ICU, the admission category, the prognosis of underlying disease, the admission SAPS II, and the source of bacteremia. After multiple logistic regression, the independent variables associated with ICU death in bacteremic patients (Table 3) were a rapidly or ultimately fatal underlying disease (OR = 3.1, p = 0.01), the admission SAPS II (p = 0.04), and age (p = 0.045). Secondary bacteremia was associated with a poorer prognosis (OR = 2.2; 95% CI 0.92–5.15, p = 0.08) than primary and catheter-related bacteremia. Of the 60 deaths recorded among bacteremic patients, 24 (40%) occurred early (< 72 h) after bacteremia, and 36 (60%) deaths occurred among the 87 patients who survived > 72 h after bacteremia. The independent risk factors for early (< 72 h) mortality were an inappropriate initial antibiotic therapy (OR = 2.9 [1.1–7.9], p = 0.031) and a rapidly or ultimately fatal underlying disease (OR = 3.5 [1.3–9.4], p = 0.016).
| Number of Cases | Number of Deaths (%) | p Value* | Adjusted Odds Ratio [95% CI] | p Value* | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Age | 61.2 (17) | 0.006 | 1.026 [1.0–1.05] | 0.045 | ||||||
| Sex | 0.8 | |||||||||
| Male | 77 | 41 (53) | — | |||||||
| Female | 34 | 19 (56) | — | |||||||
| Patient location prior to ICU | 0.017 | 0.19 | ||||||||
| Direct admission | 54 | 22 (41) | 1 | |||||||
| Intrahospital transfer | 41 | 26 (63) | 1.7 [0.6–4.3] | |||||||
| Other hospital | 16 | 12 (75) | 2.2 [0.5–9.2] | |||||||
| Admission category | 0.001 | 0.49 | ||||||||
| Medical | 63 | 38 (60) | 1 | |||||||
| Unscheduled surgery | 22 | 15 (68) | 1.9 [0.6–6.1] | |||||||
| Scheduled surgery | 8 | 5 (62) | 0.8 [0.2–4.3] | |||||||
| Trauma | 18 | 2 (11) | 0.5 [0.1–3.1] | |||||||
| Immunodepression | 0.34 | — | ||||||||
| Yes | 81 | 42 (52) | — | |||||||
| No | 29 | 18 (62) | — | |||||||
| Underlying disease | ||||||||||
| Absent/nonfatal | 62 | 25 (40) | 1 | |||||||
| Ultimately/rapidly fatal | 49 | 35 (71) | 0.001 | 3.1 [1.3–7.3] | 0.010 | |||||
| SAPS II on admission | 45.9 (17.9) | 0.005 | 1.3 [1.0–1.06] | 0.041 | ||||||
| Microbiological category | 0.54 | — | ||||||||
| CoNS | 15 | 7 (47) | — | |||||||
| Other | 96 | 53 (55) | — | |||||||
| Source of bacteremia | 0.008 | |||||||||
| Primary and catheter-related | 61 | 26 (43) | 1 | |||||||
| Secondary | 50 | 34 (68) | 2.2 [0.92–5.15] | 0.08 | ||||||
| Appropriate antimicrobial therapy† | 0.85 | — | ||||||||
| Yes | 66 | 37 (56) | ||||||||
| No | 43 | 23 (53) | — | |||||||
The median ICU length of stay was 5 (IQR, 3 to 12) d for the entire cohort and 27 (IQR, 14 to 46) d for bacteremic cases. The independent variables associated with a longer than median length of stay in the whole cohort, as identified by logistic regression analysis, were age, the patient location prior to ICU admission, the admission category, the SAPS II score, a rapidly or ultimately fatal underlying disease, and ICU-acquired bacteremia (Table 4).
| Number of Patients | Number of LOS ⩾ 5 d (%) | p Value | Adjusted Odds Ratio [95% CI] | p Value | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Age* | 2199 | — | < 0.001 | 1.0 [1.0–1.01] | 0.026 | |||||
| Sex | ||||||||||
| Male | 1312 | 749 (57.1) | 0.08 | 0.6 | ||||||
| Female | 887 | 473 (53.3) | ||||||||
| Patient origin | < 0.001 | |||||||||
| Direct admission | 1163 | 574 (40.4) | 1 | |||||||
| Intrahospital transfer | 809 | 487 (60.2) | 1.4 [1.3–177] | 0.002 | ||||||
| Other hospital | 227 | 161 (70.9) | 2.4 [1.7–3.4] | < 0.0001 | ||||||
| Admission category | < 0.001 | |||||||||
| Medical | 1562 | 823 (52.7) | 1 | |||||||
| Unscheduled surgery | 224 | 161 (71.9) | 2.0 [1.4–2.9] | < 0.0001 | ||||||
| Scheduled surgery | 149 | 83 (55.7) | 0.95 [0.6–1.4] | 0.8 | ||||||
| Trauma | 118 | 73 (61.9) | 1.8 [1.15–2.85] | 0.01 | ||||||
| Immunodepression | ||||||||||
| Yes | 390 | 237 (60.8) | 0.03 | 0.40 | ||||||
| No | 1627 | 890 (54.7) | ||||||||
| Underlying disease | ||||||||||
| Absent/nonfatal | 1195 | 595 (49.8) | 1 | |||||||
| Ultimately/rapidly fatal | 756 | 489 (64.7) | < 0.001 | 1.5 [1.2–1.8] | < 0.0001 | |||||
| SAPS II* | 2047 | — | < 0.001 | 1.02 [1.01–1.02] | < 0.0001 | |||||
| ICU-acquired bacteremia | ||||||||||
| Yes | 111 | 60 (54.0) | < 0.001 | 21.7 [6.8–69.3] | < 0.0001 | |||||
| No | 2086 | 347 (16.6) |
To determine the excess mortality and length of stay attributable to bacteremia, we used a pairwise (1:1) case–control study, selecting controls matched to bacteremic cases on the variables identified above. Control patients had to fulfill all the following six criteria: the same admission category, location prior to ICU admission, age (± 5 yr), severity of underlying disease as compared with the corresponding case, and a similar (± 5 points) SAPS II score; in addition, controls had to have an ICU length of stay at least as long as that of the corresponding case up to the occurrence of bacteremia. When several control patients were available, the patient having the highest and closest admission SAPS II to the case patient was selected. Adequately matched controls were available for 96 of 111 (86.5%) bacteremic patients.
The characteristics of cases and controls did not differ in terms of variables used for matching and of major diagnostic categories (Table 5). There were 50 (52.1%) deaths among cases and 16 (16.7%) among their matched control patients. Thus, the excess overall mortality of ICU-acquired bacteremia was 35.4%. The 42 cases having secondary (non-catheter-related) bacteremia had an excess ICU mortality of 55%, whereas in the 54 patients with primary or catheter-related bacteremia, the mortality attributable to bacteremia was 20.4% (95% CI [3.7%– 37%]; p = 0.03). In the subgroup of 28 patients with definite catheter-related bacteremia, the attributable mortality was estimated at 11.5% (95% CI [−14%–37%]; p = 0.3) (Table 6).
| Number (%) or Mean (SD) for Cases | Number (%) or Mean (SD) for Controls | p Value | ||||
|---|---|---|---|---|---|---|
| Age | 60.3 (19.2) | 62.9 (18.2) | 0.23 | |||
| Sex, male | 65 (67.7) | 60 (62.5) | 0.45 | |||
| Patient location prior or ICU | 0.99 | |||||
| Direct admission | 46 (48.0) | 47 (43.5) | ||||
| Other wards | 37 (38.5) | 36 (37.5) | ||||
| Other hospital | 13 (13.5) | 13 (13.5) | ||||
| Admission category | 0.99 | |||||
| Medical | 59 (61.5) | 58 (60.4) | ||||
| Unscheduled surgery | 15 (15.6) | 15 (15.6) | ||||
| Scheduled surgery | 5 (5.2) | 6 (6.2) | ||||
| Trauma | 17 (17.7) | 17 (17.7) | ||||
| Admission diagnosis | 0.39 | |||||
| Medical | 67 (69.8) | 65 (67.7) | ||||
| Cardiac failure | 8 (8.3) | 9 (9.4) | ||||
| Respiratory failure | 32 (33.3) | 24 (25.0) | ||||
| Digestive tract | 3 (3.1) | 6 (6.3) | ||||
| Central nervous system | 8 (8.3) | 10 (10.4) | ||||
| Metabolic disorders | 7 (7.3) | 2 (2.1) | ||||
| Renal failure | 2 (2.1) | 2 (2.1) | ||||
| Other medical | 7 (7.3) | 12 (12.5) | ||||
| Surgical | 29 (30.2) | 31 (32.3) | ||||
| Abdominal | 4 (4.2) | 5 (5.2) | ||||
| Cardiac | 3 (3.1) | 3 (3.1) | ||||
| Vascular | 3 (3.1) | 0 (0.0) | ||||
| Other surgery | 2 (2.1) | 6 (6.3) | ||||
| Immunodepression | 25 (26.0) | 25 (26.0) | 1 | |||
| McCabe score | 1 | |||||
| Nonfatal | 55 (57.3) | 55 (57.3) | ||||
| Ultimately or rapidly fatal | 45 (46.7) | 45 (46.7) | ||||
| SAPS II on admission | 45.1 (17.3) | 46.2 (17.2) | 0.60 | |||
| ICU length of stay | 32.2 (27.4) | 26.6 (21.5) | 0.023 | |||
| ICU deaths | 50 (52.1) | 16 (16.7) | 0.001 |
| Catheter-related Bacteremia | Primary Bacteremia | Secondary Bacteremia | All Bacteremias | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | |||||||||
| Mortality, n (%) | 10/26 (38.5) | 7/26 (26.9) | 14/28 (50) | 6/28 (21.4) | 26/42 (61.9) | 3/42 (7.1) | 50/96 (52.1) | 16/96 (16.7) | ||||||||
| Attributable, % [95 CI] | 11.5 [−14.5, 37.5] | 28.6 [5.6, 51.6] | 54.8 [35.9, 73.6] | 35.4 [23, 48] | ||||||||||||
| p Value | 0.095 | 0.11 | 0.006 | 0.0002 | ||||||||||||
| LOS, d | ||||||||||||||||
| All pairs, median | 32.5 | 17.5 | 21.5 | 20 | 24 | 21 | 24.5 | 19 | ||||||||
| Surviving pairs, [IQR] | 33 [21–58] | 19 [11–40] | 29 [24–50] | 21 [11–32] | 29 [24–54] | 22 [13–52] | 31 [23.5–56] | 21.5 [13–36] | ||||||||
| p Value | 0.23 | 0.016 | 0.13 | 0.01 | ||||||||||||
Case patients with ICU-acquired bacteremia stayed in the ICU a median of 5.5 d longer than control patients (Table 6). In surviving pairs only (n = 41), the median ICU length of stay was 9.5 d longer in bacteremic cases than in matched controls (31 [IQR 23.5–56] versus 21.5 [13–36] d, p = 0.01). In patients with primary or catheter-related bacteremia, the median attributable ICU LOS was 9.5 d (28 [IQR 14–44] d versus 18.5 [IQR 13–39] d; p = 0.34); and in surviving pairs only (n = 26), the median ICU length of stay was 12.5 d longer in bacteremic cases (31.5 [IQR 21–52] d) than in matched controls (19 [IQR 11–32] d, p = 0.025).
Because the impact of primary and catheter-related bacteremia on outcome of patients is still debated, we designed this multicenter study to assess the morbidity and mortality associated with ICU-acquired bacteremia, and contrast primary and catheter-related bacteremia to secondary bacteremia. Our study confirms others demonstrating that nosocomial bacteremia is an independent risk factor for mortality of ICU patients (OR = 4.6), with an attributable mortality of about 35%. In the case– control study, primary and catheter-related bacteremia had a significant, but more than 2-fold lower attributable mortality than secondary bacteremia (20.5% versus 55%); definite catheter-related bacteremia was associated with an approximately 2-fold lower excess mortality (estimated at 11.5%) than primary bacteremia. The median excess length of ICU stay of patients surviving the bacteremic episode was 9.5 d overall, and was similar in patients with primary or catheter-related bacteremia (12.5 d) and those with secondary bacteremia (7 d).
We estimated the mean attack rate of ICU-acquired BSI at 5 per 100 admissions (or 4.5/1000 patient-days) in ICU patients admitted for > 48 h. In recent studies, the incidence of ICU-acquired bacteremia ranged from 2.7 to 7.4 per 100 admissions (1, 9, 11, 21, 22). In a prior multicenter study from 24 hospitals in France (6), we found an overall incidence of NBSI in ICU patients of 4.1 (95% CI 3.3–5.0) per 100 ICU admissions, a figure about 10-fold higher than in the general hospital population (0.44 bacteremia per 100 hospital admissions). However, ICUs participating in the present survey all belonged to large university or university-affiliated hospitals, which may account for the relatively high bacteremia rate (3, 6).
As noted above, much of the increase in incidence of nosocomial bacteremia in hospitalized patients (3, 4) appears to be due to ICU-acquired cases, particularly to intravascular catheter-associated infections. Overall, primary and definite catheter-related bacteremia accounted for 55% of all episodes recorded in this study, with primary bacteremia accounting for 29% and definite catheter-related bacteremia for 26%. In a recent Spanish multicenter study, catheter-related and primary bacteremia accounted, respectively, for 37% and 28% of all ICU-acquired bacteremia (9). In another study from the United States (4), 20% of all episodes of NBSI were associated with catheter infection and 22% were considered primary (non-catheter-related infection). In our study, the incidence of definite catheter-associated bacteremia was 0.88 per 100 ICU admissions, comparable to the 0.75 rate reported from hospitals participating to the National Nosocomial Infections Surveillance System (23). Although we did not use molecular subtyping of organisms to confirm the source of bacteremia, we used strict definitions for catheter-related infections, and it is unlikely that we overestimated the incidence rate of bacteremia. Accordingly, the incidence rate and distribution of nosocomial and catheter-related bacteremia in our study are comparable with those recorded in several recent studies.
In the series focusing on ICU patients, the crude mortality of bacteremia ranged between 25% and 62% (4, 6, 24). However, most prior studies were conducted at a single institution, and few have specifically addressed the epidemiology and prognosis of nosocomial bacteremia in ICU patients or examined the influence of primary and catheter-related bacteremia on the outcome of patients (1, 6, 25). To further examine the specific outcomes of primary and catheter-related bacteremia, we included 2201 consecutive patients from 15 ICUs of large university-affiliated hospitals. We found in both our cohort analysis and case–control study a 35% overall mortality attributable to ICU-acquired bacteremia. This figure is remarkably similar to the 35% overall mortality attributable to nosocomial bacteremia reported by Pittet and coworkers in surgical ICU patients (1). In one study, the risk of death was 5-fold higher in bacteremic patients compared with nonbacteremic patients (22), comparable to our estimate of a 4-fold higher risk of death. Secondary bacteremia was associated with a 2.7-fold higher risk of death than primary or catheter-related bacteremia. In one study, secondary bacteremia had a 1.6-fold higher risk of mortality than primary bacteremia (12); this study, however, was not restricted to ICU patients. Our results are consistent with those of several previous studies showing a higher mortality associated with secondary bacteremia (e.g., from an abdominal or pulmonary source) than with primary bacteremia (5, 6, 12, 16, 21, 26).
Two recent studies have addressed the specific question of the outcome of patients with primary and/or catheter-related bacteremia (13, 14). DiGiovine and coworkers studied 68 patients with primary (including catheter-related) bacteremia matched to 68 control patients on diagnosis and severity of illness using variables recorded on the day prior to the occurrence of bacteremia (13); they found no excess mortality attributable to bacteremia (35.3% versus 30.9%, p = 0.51). Similarly, in a case– control study of 38 patients with catheter-related bacteremia, matched to 75 control patients on variables recorded on ICU admission, Soufir and coworkers found that bacteremia was associated with a 2-fold higher risk of mortality; however, the relative risk of death was of only 1.3 (95% CI 0.69–2.46) after controlling for the severity of patients assessed 3 d before the occurrence of bacteremia (14). Therefore, although their conclusions were slightly different, both studies found a nonsignificant impact of primary or catheter-related bacteremia on survival of patients. However, the methods used in these two studies (i.e., matching cases and controls on the severity of illness just before the occurrence of bacteremia) may result in overfitting, and actually underestimate the true influence of bacteremia on outcome of patients.
We used both logistic regression and a nested case–control study to assess the impact of the various categories of bacteremia on the outcome of patients. Our findings suggest that primary and catheter-related bacteremia do have a sizable attributable mortality. In our case–control analysis, primary and catheter-related bacteremia were associated with an attributable mortality of 20% (95% CI 3.7%–37%). When differentiating definite catheter-related from primary bacteremia, we estimated the mortality associated with the former at 11.5%. This figure is substantially (although not significantly) lower than that of non-catheter-related primary bacteremia (29%), itself having an almost 2-fold lower attributable mortality than that of secondary bacteremia (55%). Our estimate for catheter-related NBSI is very close to the 13% attributable mortality reported in a prior case–control study focusing on bacteremia caused by coagulase-negative staphylococci (8), the major pathogen currently involved in catheter-associated bacteremia. However, there was a wide confidence interval around our estimate (95% CI [−14%–37%]; p = 0.3), and a larger sample of catheter-associated bacteremia would have been necessary to estimate more accurately the mortality associated with this infection. Although we used a different approach and did not adjust on severity variables recorded just before the infection, our findings appear consistent with those of Soufir and coworkers, who estimated the attributable mortality associated with catheter-related bacteremia at 10% to 20% (14).
In surveillance programs of nosocomial bacteremia, it is often difficult to differentiate catheter-related bacteremia from true primary bacteremia (3, 4, 12), in the absence of a systematic policy for diagnosing catheter-associated bacteremia including routine culture of all central venous catheters suspected of infection. In many reports, primary bacteremia is therefore pooled with bacteremia identified as secondary to an intravascular catheter, on the premise that most cases are in fact associated with an intravascular line infection. This pragmatic approach to surveillance may be suboptimal in the ICU, where the incidence of both primary and secondary NBSI is highest, and the diagnosis of catheter-related infection may be easier to confirm. Our analysis of outcomes of bacteremia, contrasting its various sources, would justify routinely differentiating true catheter-associated bacteremia from primary bacteremia in epidemiological and outcome studies in ICU patients.
After controlling for variables associated with a longer than median (> 5 d) ICU stay in the whole cohort (the patient origin, admission category, age, SAPS II, and McCabe score), we estimated the excess ICU length of stay incurred by bacteremia at 5.5 d overall and 9.5 d in surviving patients. The estimated excess length of ICU stay in survivors (9 to 12 d) was comparable for all sources of bacteremia. In a previous study of bacteremic patients from one surgical ICU, the excess length of ICU stay of bacteremic patients was 8 d, both in the whole cohort studied and in surviving pairs (1). Our findings are also similar to those recently reported by DiGiovine and coworkers, who found a mean excess length of ICU stay of about 10 d in survivors of primary bacteremia (13).
Understanding the risk factors and evaluating the impact of nosocomial infection are important to allocate resources devoted to infection control and for the design of clinical trials evaluating therapeutic or preventive strategies. As intravascular device-associated infections are increasingly prevalent in ICU patients, and new preventive strategies are emerging (27), it is necessary to assess more accurately their impact on patients' outcomes. Primary bacteremia—about half of which appears in fact secondary to definite catheter-related infection—accounts for 25% to 50% of all nosocomial bacteremia in ICUs. Compared with other sources of bacteremia, such infections have a more modest, but significant impact on mortality of ICU patients, and a comparable influence on the length of ICU stay. Our results further suggest that differentiating definite catheter-related bacteremia from bacteremia with no identified source may be useful in studies conducted in critically ill patients.
Hôpital de Bicêtre: C. Richard, A. Mercat, K. Samii, O. Mimoz, P. Gillard, K. Amal, S. Leotard, and P. Nordmann; Hôpital Bichat-Caude Bernard: C. Paugam, J. M. Desmonts, M. Thuong, B. Régnier, C. Gibert, J. L. Trouillet, A. Scanvic, and A. Andremont; Hôpital Broussais: A. Novara, J. Y. Fagon, L. Gutmann, and A. Buu Hoı̈; Hôpital Cochin: Y. Ozier, F. Baudin, F. Bellenfant, J. F. Dhainaut, H. Blanchard, and A. Philippon; Hôpital Henri Mondor: G. Dhonneur, A. Boyer, E. Girou, C. Brun-Buisson, P. Legrand, and C. Soussy; Hôpital de la Pitié-Salpétrière: P. Derennes, T. Similowsky, J. Robert, J. Nguyen, and V. Jarlier; Hôpital Rotschild: W. Rosenbaum and J. C. Nicolas; Hôpital Saint-Antoine: E. Maury, G. Offenstadt, D. Lesage, and J. C. Petit; Hôpital Saint-Louis: J. R. Legall, G. Leleu, and P. Lagrange; Hôpital Saint-Joseph: J. Carlet, B. Misset, M. Ben Ali, and J. Acar; Hôpital Tenon: C. Mayaud, M. Denis, A. Parrot, and G. Arlet.
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Members of the ICU–Bacteremia study group are provided in the Appendix.
