Abstract

To assess changes since the mid-1970s, we reviewed 843 episodes of positive blood cultures in 707 patients with septicemia. The five most common pathogens were Staphylococcus aureus, Escherichia coli, coagulase-negative staphylococci (CNS), Klebsiella pneumoniae, and Enterococcus species. Although CNS were isolated most often, only 12.4% were clinically significant. Half of all episodes were nosocomial, and a quarter had no recognized source. Leading identifiable sources included intravenous catheters, the respiratory and genitourinary tracts, and intraabdominal foci. Septicemia-associated mortality was 17.5%. Patients who received appropriate antimicrobial therapy throughout the course of infection had the lowest mortality (13.3%). Multivariate analysis showed that age (relative risk [RR], 1.80), microorganism (RR, 2.27), source of infection (RR, 2.86), predisposing factors (RR, 1.98), blood pressure (RR, 2.29), body temperature (RR, 2.04), and therapy (RR, 2.72) independently influenced outcome. Bloodstream infections in the 1990s are notable for the increased importance of CNS as both contaminants and pathogens, the proportionate increase in fungi and decrease in anaerobes as pathogens, the emergence of Mycobacterium avium complex as an important cause of bacteremia in patients with advanced human immunodeficiency virus infection, and the reduction in mortality associated with infection.

The presence of living microorganisms in blood has substantial clinical importance. From the diagnostic standpoint, a positive blood culture yielding a clinically important microorganism represents either failure of host defenses to contain an infection at its primary focus or failure of the physician to effectively eradicate, drain, excise, or otherwise remove that focus of infection. The presence of bacteremia or fungemia also is an indicator of disseminated infection and, as such, generally indicates a poorer prognosis than that associated with localized disease. A positive blood culture, however, is not always clinically significant, since contamination may occur or the positive result might represent the transient and self-limited presence of microorganisms in the blood [1].

Our current understanding of the clinical significance of positive blood cultures has been enhanced by studies reported over several decades [2–21]. In recent years there have been many changes in medical practice, influenced in part by technologic advances and in part by the increased incidence of diseases not recognized previously. Just a few examples include the more frequent use of invasive or prosthetic devices; the increase in solid-organ and bone marrow transplantation as well as improvements in posttransplantation medical management; the introduction of HIV infection and AIDS as a scourge on late 20th century society; and therapeutic advances in the form of improved imaging techniques, less invasive methods of draining pus from closed spaces, and availability of broader spectrum antiinfective therapy.

We therefore undertook a comprehensive analysis of positive blood cultures in the 1990s. As a template for this project, we used an earlier review of bacteremia and fungemia [10, 11] authored by two of the current investigators (M.P.W. and L.B.R.). Although the earlier work has been widely recognized, the aforementioned changes in medicine and its practice argued for the need to reevaluate the clinical and prognostic importance of positive blood cultures. The primary goal of this study, therefore, was to determine the current microbiology, epidemiology, and prognostic importance of positive blood cultures, with special reference to similarities with and differences from the earlier reports from our group [10, 11, 22, 23].

Materials and Methods

For a 12-month period, February 1992 through January 1993, all inpatients ≥18 years of age with culture-positive blood were evaluated at Duke University Medical Center (DUMC), in Durham, NC; Robert Wood Johnson University Hospital (RWJUH), in New Brunswick, NJ; and the Salt Lake City Veterans Administration Medical Center (SLCVAMC), in Salt Lake City. Each patient was observed prospectively from the time the blood culture became positive, unless the patient had been discharged or had died before review of the hospital records by one of the investigators, in which case the review of the medical record was retrospective. Charts were evaluated according to the method of Feinstein et al. [24, 25], such that if the presence or absence of a particular finding was not clearly indicated, that case was excluded from analysis for that finding.

During the study period, 20 mL or more of blood was obtained for each culture and inoculated into media for processing on the BACTEC NR660 (Becton Dickinson Diagnostic Instrument Systems, Sparks, MD) or BacT/Alert (Organon Teknika, Durham, NC) blood culture system or both systems at all three centers. Blood was obtained at the bedside by house officers, medical students, or other trained health care personnel (nurses, phlebotomists, etc.) using 70% isopropyl alcohol and then 10% povidone-iodine. Although most of the blood culture specimens were obtained by peripheral venipuncture, it was not possible to determine specifically which ones were obtained in this manner and which were obtained through access devices.

Bottles were transported to the laboratory and incubated until flagged as positive or for 7 days in either BACTEC nonradiometric instruments (NR6 and NR7 bottles) or BacT/Alert continuous-monitoring instruments (BacT/Alert aerobic and anaerobic bottles). Broth from positive bottles was gram-stained and subcultured with use of standard techniques [26]. Susceptibility testing of isolates was done according to guidelines established by the National Committee on Clinical Laboratory Standards [27, 28].

All information obtained from patients' records was recorded on data worksheets and then transferred to a database software program for analysis.

Definitions

Definitions for this study for the most part were identical to those of Weinstein et al. [10, 11]. Only a few will be detailed here. New or modified definitions also will be detailed.

True septicemia vs. contamination. Each positive blood culture was assessed critically by one of the investigators, each an infectious disease physician. All isolates were categorized as true-positives, contaminants, or of unknown clinical significance. The categorical decision was made after the following factors were taken into account: the patient's clinical history, physical findings, body temperature at the time of the blood culture, leukocyte count and differential cell counts, number of positive blood cultures out of the total number performed, results of cultures of specimens from other sites, imaging results, histopathologic findings, and clinical course and response to therapy. If the clinical significance of the positive culture was not clear on the basis of the available information, the isolate was categorized as being of unknown significance.

Episode. An episode of bacteremia, fungemia, or mycobacteremia was defined by the first positive blood culture in a series or by any new positive blood culture result that occurred >48 hours after the previous positive result, unless it was clear to the investigator that the new positive culture was part of the same episode. For example, a positive blood culture for Staphylococcus aureus on the fifth day of antibiotic therapy for S. aureus endocarditis was considered part of the original bacteremic episode.

Community- vs. hospital-acquired septicemia. Each episode was classified as either community- or hospital-acquired septicemia, according to guidelines of the Centers for Disease Control and Prevention [29]. Septicemia in nursing home patients with positive blood cultures was always classified as hospital-acquired, whereas that in patients transferred from other outside facilities was classified according to their total period of hospitalization at both institutions.

Antimicrobial Therapy

Data on antimicrobial therapy were obtained at four chronologic points for each episode. These points were as follows: (1) at the time the first positive blood culture specimen was obtained, (2) after the blood culture was performed but before positive culture results were reported (i.e., empirical therapy), (3) after the blood culture was reported to be positive and gram-stained smear results were made known to the primary physician(s) but before organism identification and susceptibility test results were available, and (4) after organism identification and susceptibility test results were reported to the physicians.

Therapy was assessed critically at each time point on the basis of the clinical information available (time points 1–3) or the identification of the isolate and susceptibility test results (time point 4).

Treatment was judged to be the first choice if it was in accordance with the recommendations of a standard reference for antimicrobial therapy [30] and an alternative choice if the etiologic microorganism(s) was (were) susceptible to the agent administered but that agent was not considered the first choice. For purposes of judging the adequacy of therapy, both first-choice and alternative-choice agents were considered appropriate. Therapy was designated as the wrong choice if the causative microorganism was resistant to the antibiotic given. Superfluous therapy was defined as either the administration of unnecessary antibiotics in addition to a first- or alternative-choice agent or the administration of antibiotics for contaminant isolates. Ineffective or superfluous agents given for infections elsewhere in the body were recorded separately.

If a patient died before susceptibility results became available, that fact was recorded. When no therapy was given after the report of a positive blood culture to the physician, one of three assessments was made: (1) appropriate, if the isolate was a contaminant; (2) appropriate, if the episode was judged to represent true but transient bacteremia or fungemia that resolved spontaneously without adversely affecting the patient; or (3) inappropriate, if the culture represented true sepsis and the patient's status deteriorated because of the infection.

Outcome

The outcome of each episode was categorized as follows. The patient was (1) discharged alive, (2) alive but still hospitalized 30 days or longer after the onset of bacteremia or fungemia, (3) dead from causes attributable to the septicemic episode, or (4) dead from causes unrelated to septicemia. For the purposes of this study, mortality is termed associated or nonassociated in the subsequent text and tables.

Statistical Methods

For univariate analyses, statistical significance was calculated with the χ2 test as described by O'Brien and Shampo [31]. The multivariate analysis and the resulting significance calculations were based on the logistic regression model [32], as implemented by the function “glm” in the statistical package S+ [33].

Results

During the study period, 1,585 blood culture-positive episodes occurred in 1,267 patients and yielded 1,844 microorganisms. Nine hundred forty-four microorganisms were isolated from 707 patients who had 843 episodes of true bacteremia or fungemia. There were 658 contaminant episodes and 84 episodes of unknown clinical significance.

Microbiological Features

The microorganisms isolated from positive blood cultures and the frequency with which they caused true bacteremia or fungemia are shown in table 1. The most common isolates from blood were coagulase-negative staphylococci. S. aureus was the microorganism most frequently causing true bacteremia; 87.2% of isolates were judged clinically significant. In contrast, only 12.4% of the coagulase-negative staphylococci were clinically significant, but they ranked as the third most frequent cause of bacteremia by virtue of their high prevalence.

Table 1.

Microorganisms isolated from blood of patients at Duke University Medical Center, Robert Wood Johnson University Hospital, and the Salt Lake City VA Medical Center, February 1992 through January 1993.

Table 1.

Microorganisms isolated from blood of patients at Duke University Medical Center, Robert Wood Johnson University Hospital, and the Salt Lake City VA Medical Center, February 1992 through January 1993.

Given the frequency with which coagulase-negative staphylococci were isolated from blood and the difficulty in determining their clinical significance, we analyzed Staphylococcus epidermidis isolates on the basis of the number of culture sets positive vs. the number of sets performed for each episode. The results are shown in table 2. When only a single culture set yielded S. epidermidis, the culture result almost always was judged to be of indeterminate significance or to represent contamination. When all of two or three culture sets yielded S. epidermidis, the isolates usually were judged clinically significant, but a substantial minority were of unknown (i.e., indeterminate) significance.

Table 2.

Clinical significance of Staphylococcus epidermidis isolates (unimicrobial episodes only).

Table 2.

Clinical significance of Staphylococcus epidermidis isolates (unimicrobial episodes only).

Whereas pneumococci always represented real infection, enterococcal isolates did so only 70% of the time, and viridans streptococci more often were contaminants (49%) than clinically significant isolates (38%) (table 1). Among the gram-negative aerobic and facultative bacteria, Escherichia coli was the most common isolate, and this microorganism was second only to S. aureus as a cause of septicemia. Overall, the Enterobacteriaceae and Pseudomonas aeruginosa represented true bacteremia >95% of the time when isolated.

Anaerobic bacteria were not common blood pathogens, accounting for only 3.9% of clinically important isolates. The isolation of a member of the Bacteroides fragilis group, however, almost always indicated true bacteremia (89%). Clostridium perfringens usually represented contamination when isolated from the blood, whereas the isolation of other Clostridium species usually represented true bacteremia.

Yeasts were relatively common isolates from blood cultures and almost always represented true fungemia when detected (91.7%). These organisms were present as clinically important pathogens almost twice as often as anaerobic bacteria, and Candida albicans ranked among the top 10 microorganisms causing septicemia. All mycobacteria and all but one Cryptococcus neoformans isolate were isolated from HIV-infected patients.

Of the 843 episodes of bacteremia and fungemia, 764 (90.6%) were unimicrobial and 79 (9.4%) were polymicrobial. Two microorganisms were isolated in 57 (72.2%) of the poly-microbial episodes, and >3 microorganisms were isolated in 22 episodes (27.8%).

Epidemiological Features

Age and sex. Patients ranged in age from 17 to 103 years (mean, 56.2 years). Patients with HIV infection were younger (mean age, 36.9 years). Four hundred ninety of the episodes (58.1%) occurred in men. Ninety-nine percent of the episodes at the SLCVAMC, vs. 54% at both DUMC and RWJUH, were in men.

Community- vs. hospital-acquired infection. Of the 843 episodes, 404 (47.9%) were of community-acquired infection and 439 (52.1%) were of nosocomial infection. The microorganisms isolated in these episodes, categorized according to place of acquisition, are shown in table 3. Microorganisms more often associated with nosocomial acquisition were coagulasenegative staphylococci, enterococci, Enterobacteriaceae other than E. coli,P. aeruginosa,Clostridium species, Bacteroides species, and yeasts other than C. neoformans. A somewhat surprising finding was that nearly 40% of P. aeruginosa bacteremias were community-acquired.

Table 3.

Community-acquired and hospital-acquired microorganisms and major microorganism groups involved in episodes of bacteremia and fungemia.

Table 3.

Community-acquired and hospital-acquired microorganisms and major microorganism groups involved in episodes of bacteremia and fungemia.

Hospital service. Six hundred twenty of the 843 bacteremic and fungemic episodes (73.5%) occurred in patients hospitalized on the medical services of our institutions. Patients hospitalized on the nontransplantation surgical services accounted for 21.3% of total episodes, with the remaining 5.2% of episodes distributed among the transplantation surgery, obstetric and gynecologic services, and emergency and outpatient departments. Pneumococcal bacteremia, not surprisingly, was seen almost exclusively in patients on the medical service.

Proportionately, enterococcal and pseudomonas bacteremias were twofold more common on the general and transplantation surgical services than on the medical service. Indeed, P. aeruginosa accounted for only 4.4% of septicemias on the medical service. Fungemia was proportionately most common on the transplantation surgical service, accounting for nearly 25% of septicemic episodes. Anaerobic bacteremia, which was uncommon in general, was seen most frequently in patients on the general surgery service (6.6% of episodes) and obstetric and gynecologic service (11.1% of episodes).

Sources of infection. The sources of bacteremia and fungemia were identifiable in 627 (74.4%) of episodes and are listed in table 4. Intravenous catheters were the most common primary foci for septicemia. Despite the availability of increasingly sophisticated imaging techniques, the sources for nearly one-fourth of episodes could not be determined.

Table 4.

Sources of bacteremia and fungemia.

Table 4.

Sources of bacteremia and fungemia.

The relationship between microorganism and sources of unimicrobial bacteremia and fungemia are presented in table 5, which also delineates those episodes confirmed by cultures of specimens other than blood or by clinical evidence. The majority of S. aureus and coagulase-negative staphylococcal bacteremias were associated with intravascular devices. Not surprisingly, pneumococcal bacteremia was most often associated with pneumonia, but in 7 of 34 episodes (20.6%) a primary source could not be determined. Among the Enterobacteriaceae, primary foci of infection below the diaphragm predominated (table 5), as would be expected given the normal habitat of these bacteria. In contrast, the most common focus for bacteremia due to P. aeruginosa was the respiratory tract, which was the focus more than twice as frequently as the next most common focus, the genitourinary tract.

Table 5.

Sources and confirmatory evidence for episodes of unimicrobial bacteremia and fungemia, according to microorganism.

Table 5.

Sources and confirmatory evidence for episodes of unimicrobial bacteremia and fungemia, according to microorganism.

Several microorganisms or microorganism groups were associated at a particularly high frequency with bacteremia or fungemia in which a primary focus for infection could not be determined. These included the viridans streptococci (44.4%), Enterobacter cloacae (58.3%),Klebsiella pneumoniae (33.3%), Candida species (37.5%), Torulopsis glabrata (41.7%), and Mycobacterium avium complex (100%). All of the E. cloacae bacteremias and many of the fungemias and K. pneumoniae bacteremias with unknown sources occurred in patients with underlying malignancies.

Clinical Observations

In order to determine whether certain indicators might assist in assessing the clinical significance of positive blood cultures, we examined the relationship between positive cultures and the peripheral leukocyte count, absolute neutrophil count, blood pressure, and body temperature at the time the first positive blood culture specimen was obtained for a given episode. We also examined the relationship between each of these variables and the microorganisms isolated from true positive cultures. In addition, we critically assessed the antimicrobial therapy as described in the Materials and Methods section.

Leukocyte count and absolute neutrophil count. Patients with culture-positive blood and a peripheral leukocyte count of <4,000/µL or ≥20,000/µL were significantly more likely (P < .001) to have true bacteremia or fungemia episodes (62.5% and 60.3%, respectively) than contaminant episodes when compared with patients who had peripheral leukocyte counts between 4,000 and 19,999/µL (proportion of true bacteremias, 49.2%). Similarly, patients with absolute neutropenia were significantly more likely (P < .001) than nonneutropenic patients to have a positive blood culture represent true bacteremia or fungemia (70.2% vs. 51.4% of positive cultures, respectively).

The distribution of microorganisms causing septicemia in neutropenic and nonneutropenic patients is shown in table 6. Neutropenic patients were significantly less likely to have bacteremia due to S. aureus (P < .0001; RR, 0.33) but were significantly more likely to have fungemia (P < .01; RR, 1.81) and polymicrobial bacteremia (P < .0001; RR, 2.63) than were nonneutropenic individuals.

Table 6.

Microorganisms recovered from and types of episodes in patients with bacteremia and fungemia, according to absolute neutrophil count.

Table 6.

Microorganisms recovered from and types of episodes in patients with bacteremia and fungemia, according to absolute neutrophil count.

Blood pressure. Approximately 14% of patients were hypotensive at the time the first positive blood culture specimen was obtained. The positive blood cultures of these patients were more likely to represent true bacteremia than were positive blood cultures of patients with normal blood pressure at the time cultures were performed (72.7% vs. 51.1% of positive cultures, respectively; P < .0001). The distribution of microorganisms causing bacteremia and fungemia in these patients is shown in table 7. There were no statistically significant differences in microorganisms or microorganism groups in hypotensive vs. normotensive patients. However, polymicrobial episodes occurred significantly more often in hypotensive patients than in patients whose blood pressure was normal at the time of blood culture (P < .05; RR, 1.58).

Table 7.

Microorganisms recovered from and types of episodes in hypotensive and normotensive patients with bacteremia and fungemia.

Table 7.

Microorganisms recovered from and types of episodes in hypotensive and normotensive patients with bacteremia and fungemia.

Temperature. Cultures of patients who were hypothermic (temperature, <36°C) or who had marked fever (temperature, ≥40°C) were more likely to be true-positives (67.7% and 69.6% of positive cultures, respectively) than were those of patients whose temperatures were normal (39.2% of positive cultures) or moderately elevated (55.9% of positive cultures) at the time the positive blood culture specimen was obtained.

Endocarditis. Of 31 episodes (in 31 patients) of endocarditis, 11 were due to S. aureus, 10 to viridans streptococci, and 3 to enterococci. All episodes were unimicrobial; 30 of the 31 were due to gram-positive bacteria, and one was caused by K. pneumoniae. Twenty-one patients presented following <1 week of symptoms, 8 following 1–3 weeks of symptoms, and 2 following >3 weeks of symptoms. Seven of 11 patients with endocarditis due to S. aureus and 7 of 10 patients with endocarditis caused by viridans streptococci presented following <1 week of symptoms.

Antibiotic therapy. Of the 1,585 episodes of positive blood cultures, 454 (28.6%) involved patients receiving antimicrobial agents at the time the first positive blood culture specimen was obtained. The proportion of patients who were receiving antibiotics was the same regardless of whether growth repreented true bacteremia or contamination. Of the 843 episodes of true bacteremia or fungemia, 71 (8.4%) occurred in patients who were receiving therapy that was effective against the microorganism(s) that grew in the blood culture. This proportion was the same at all three hospitals (range, 8.0%–9.1%).

Appropriate antimicrobial therapy was administered to a substantial majority of patients at all of the time points assessed. Excluding the 48 patients who died prior to the availability of susceptibility test results, 620 of 795 patients (78%) received appropriate therapy at all time points. In addition, 111 patients (14%) were given appropriate therapy after susceptibility test results were available, regardless of whether they had received inappropriate empirical therapy at an earlier time point.

Patients with unimicrobial septicemia were more likely than those with polymicrobial septicemia to be treated with appropriate therapy, especially after susceptibility test results were available (92.7% vs. 83.6%, respectively). At all time points assessed, medical patients were somewhat more likely than surgical patients to receive appropriate therapy. Among medical patients, the proportion who received appropriate therapy at the different time points ranged from 89.4% to 91.0%, versus a range of 83.0% to 87.1% among surgical patients.

After susceptibility test results were available, approximately one-quarter of all patients were receiving antimicrobial agents judged to be superfluous for the infecting microorganism(s) and clinical setting. Twenty-six patients (3.3%) were receiving agents to which their infecting organisms were resistant in vitro, and nine patients (1.1%) received no antimicrobials despite a clinical setting that should have mandated therapeutic intervention.

Outcome and Factors Influencing Prognosis

One hundred forty-eight patients (17.5%) died of causes directly or indirectly attributable to an episode of septicemia (associated mortality). Five hundred thirty-five patients (63.5%) were discharged alive, 118 (14.0%) were alive but remained hospitalized 30 days after onset of the septicemic episode, and 42 (5.0%) died from causes that were judged by the investigators not to be associated with the bacteremia or fungemia. There were no significant differences in mortality at the three collaborating hospitals.

Univariate Analyses

Age and sex. The effect of age on outcome of bacteremia and fungemia was assessed according to the decade of life of the infected patients. As shown in figure 1, septicemia-associated mortality gradually increased with age and was especially notable after the age of 70 years. The infection-associated mortality for septicemic patients over 70 years of age was 24.2%, compared with 15.2% for patients 70 years of age or less. In comparison with other patients, the relative risks of death from bacteremia and fungemia for patients between 71 and 80 years of age and >80 years of age were 2.58 and 3.4, respectively. There were no significant differences in infection-associated mortality between septicemic men and women.

Figure 1.

Outcome of bacteremia or fungemia, according to age group of patients (graphic = alive at discharge; ■ = death, associated with septicemia).

Figure 1.

Outcome of bacteremia or fungemia, according to age group of patients (graphic = alive at discharge; ■ = death, associated with septicemia).

Hospital service. The septicemia-associated mortality rates ranged from zero among obstetric and gynecologic patients to 19% and 23% among medical and cardiovascular surgery patients, respectively. However, none of the differences in mortality, when sorted according to hospital service, were statistically significant.

Place of acquisition of bacteremia and fungemia. Patients who developed bacteremia or fungemia during the course of hospitalization had an infection-associated mortality rate of 20.3%, vs. 14.6% for patients with community-acquired disease. The relative risk of death associated with nosocomial septicemia was 1.39 (P < .05).

Microorganism. The microorganism isolated and type of bacteremia or fungemia (Le., unimicrobial or polymicrobial) influenced outcome (table 8). Among the common etiologic agents of bacteremia and fungemia, the lowest associated mortality occurred with coagulase-negative staphylococci (5.5%) and the highest with yeasts and fungi (35.8%). Infection-associated mortality was lower with gram-positive unimicrobial bacteremia (11.1%) than with gram-negative bacteremia (17.6%), anaerobic bacteremia (18.2%), or fungemia (35.8%).

Table 8.

Associated mortality in episodes of bacteremia and fungemia and relative risk of death, as related to etiologic microorganisms in unimicrobial episodes and to the type of episode.

Table 8.

Associated mortality in episodes of bacteremia and fungemia and relative risk of death, as related to etiologic microorganisms in unimicrobial episodes and to the type of episode.

The mortality associated with pneumococcal bacteremia was greater than that associated with enterococcal or S. aureus bacteremia (table 8). Also noteworthy was the mortality rate with P. aeruginosa bacteremia, which was less than that with bacteremia due to enteric gram-negative rods other than E. coli (table 8). The mortality associated with polymicrobial bacteremia was more than twice that associated with unimicrobial episodes.

Source of infection. The outcome of bacteremia and fungemia was affected by the primary source of infection (table 9). For risk factor analysis, we assigned a risk of 1.0 to septicemia associated with iv catheters in order to maintain consistency with our earlier work [11]. Significantly increased septicemia-associated mortality and relative risk of death occurred with respiratory tract sources (P < .05), with bowel and peritoneal sources (P < .01), and when a primary focus of infection could not be found (P < .05).

Table 9.

Associated mortality in episodes of bacteremia and fungemia, according to source of infection.

Table 9.

Associated mortality in episodes of bacteremia and fungemia, according to source of infection.

Body temperature. The mortality associated with bacteremia and fungemia was inversely related to the body temperature of patients at the time the first positive blood culture specimen was obtained (figure 2). Risk factor analysis showed significantly increased mortality (P < .05) among the patients who were hypothermic at the onset of septicemia.

Figure 2.

Septicemia-associated mortality as related to temperature of patients at the time the first positive blood culture specimen was obtained.

Figure 2.

Septicemia-associated mortality as related to temperature of patients at the time the first positive blood culture specimen was obtained.

Blood pressure. Septic shock, as evidenced by the presence of hypotension at the time the first positive blood culture specimen was obtained, was associated with increased mortality. Table 10 reveals that this relationship was a virtually uniform finding, regardless of the etiologic microorganism or the type of septic episode.

Table 10.

Associated mortality in episodes of bacteremia and fungemia, as related to etiologic microorganism in unimicrobial episodes, type of episode, and blood pressure status at the time of onset of septicemia.

Table 10.

Associated mortality in episodes of bacteremia and fungemia, as related to etiologic microorganism in unimicrobial episodes, type of episode, and blood pressure status at the time of onset of septicemia.

Leukocyte count and absolute neutrophil count. The relationship between septicemia-associated mortality and total leukocyte count or absolute neutrophil count is shown in table 11. Patients who had leukocyte counts of <4,000/µL or ≥20,000/µL had a twofold increase in relative risk of death from septicemia. Patients with absolute neutropenia had a significantly increased relative risk of death in comparison with that for nonneutropenic patients.

Table 11.

Associated mortality in episodes of bacteremia and fungemia, as related to leukocyte count and absolute neutrophil count.

Table 11.

Associated mortality in episodes of bacteremia and fungemia, as related to leukocyte count and absolute neutrophil count.

Predisposing factors. The influence of predisposing factors on the outcome of septicemia was analyzed both when individual factors were present alone and when multiple factors were present (table 12). Nearly one-quarter of the patients had no predisposing factors, and these patients had the lowest septicemia-associated mortality (8.2%; RR, 1.0). The greatest mortality was associated with moderate renal failure (61.5%; RR, 7.54).

Table 12.

Influence of predisposing factors on associated mortality in episodes of bacteremia and fungemia.

Table 12.

Influence of predisposing factors on associated mortality in episodes of bacteremia and fungemia.

Although the relative risk of death was high in the presence of severe renal failure and biopsy-proven cirrhosis, statistical significance was not achieved because of the relative infrequency of each of these predisposing factors as the sole underlying problem. Not surprisingly, there was a direct relationship between septicemia-associated mortality and the number of predisposing factors present. Thus, mortality was greater among the patients with multiple predisposing factors than among patients with only a single factor.

Antibiotic and other therapy. The mortality associated with bacteremia and fungemia clearly was affected by the type of antimicrobial therapy administered (table 13). The great majority (78%) of patients received appropriate therapy at all three time points at which assessments were made, and this group of patients had the lowest septicemia-associated mortality. Patients who received inappropriate empirical therapy but whose physicians administered appropriate therapy once the blood culture was reported to be positive also had low mortality. By contrast, among the small group of patients who received inappropriate therapy at all three time points, three of nine (33%) died of causes attributable to sepsis.

Table 13.

Associated mortality in episodes of bacteremia and fungemia, as related to appropriateness of antimicrobial therapy at different time points during septicemia.

Table 13.

Associated mortality in episodes of bacteremia and fungemia, as related to appropriateness of antimicrobial therapy at different time points during septicemia.

Indeed, the data shown in table 13 clearly indicate that septicemia-associated mortality increased in proportion to the duration of inappropriate antimicrobial therapy. Since our definition of appropriate empirical therapy allowed for the possibility that the organism(s) grown in blood culture might not be susceptible to the agents given, we also assessed outcome in terms of whether the infecting organisms were susceptible to therapy being administered at each time point. The results of this analysis were very similar; that is, associated mortality was lowest (9.8%) when the organism was susceptible at all three time points and also was low (12.6%) when patients received effective antimicrobial therapy after blood cultures were reported to be positive.

When mortality following the availability of susceptibility test results was analyzed alone, the mortality rates when first-choice or alternative-choice agents were given were identical (8.3%), but the rate was 24% when superfluous therapy was given. Since superfluous therapy included at least one agent with in vitro activity against the infecting microorganism, other factors that may have influenced outcome were assessed. Patients receiving superfluous therapy were twofold to threefold more likely to have absolute granulocytopenia, fungemia, or polymicrobial episodes than were patients who received first-choice or alternative-choice agents.

The removal, excision, or drainage of a primary focus of infection, if feasible, often has a salutary effect on the outcome of septicemia. Therefore, we assessed outcome when such therapeutic maneuvers were undertaken. The results confirmed the beneficial effect of these interventions. Among patients who survived until susceptibility test results were available, associated mortality was 6.2% (14 of 224) when an infected focus was excised, drained, or removed, vs. 15.6% (87 of 557) when no additional interventions were (or could be) undertaken (P < .001). Among patients with catheter-associated bacteremia or fungemia, removal of the catheter was associated with death due to septicemia in only 3.9%.

Multivariate Analysis

Based on the results of univariate analysis, high- and low-risk categories were established for each variable assessed. When there was more than one high-risk component for a variable (e.g., microorganism, source, or predisposing factor), these components were grouped and assigned a univariate relative risk for the purpose of multivariate analysis. Then, with use of logistic regression, the relative risk of death was determined for each variable in the presence of all others.

The results of this analysis are shown in table 14. Those variables associated with a significantly increased risk of death in multivariate analysis were advanced age (>70 years); isolation of fungi or Enterobacteriaceae other than E. coli; a primary source of infection in the respiratory tract, bowel, or peritoneum or that was unknown; underlying malignancy, AIDS, or renal failure; shock, as manifested by hypotension; inability to mount a febrile response to sepsis; and inappropriate antibiotic therapy at two or more of the time points assessed.

Table 14.

Comparison of univariate and multivariate analysis of factors affecting risk of death in patients with bacteremia and fungemia.

Table 14.

Comparison of univariate and multivariate analysis of factors affecting risk of death in patients with bacteremia and fungemia.

Discussion

It was our hypothesis that the many changes in medicine since the mid-1970s, when two of us and other investigators [10, 11] comprehensively reviewed a large series of patients with bacteremia and fungemia, would lead to substantive changes in the microbiology, epidemiology, and clinical and prognostic significance of positive blood cultures in the 1990s. Indeed, the more aggressive and widespread use of prosthetic materials and intravascular devices, the occurrence of syndromes such as AIDS not known 2 decades ago, and therapeutic advances in imaging, interventional radiology, and antimicrobial therapy virtually ensured the presence of important differences and underscored the need for this update.

In order to best compare the differences and similarities of bacteremia and fungemia in the 1990s versus the mid-1970s, we used definitions, including clinical and diagnostic criteria, that were similar to those in our earlier work [10, 11]. However, we performed this study prospectively, gathering data concurrently on patients with culture-positive blood, to better assess the ways in which physicians used laboratory results for therapeutic decisions.

Laboratory Observations

True septicemia vs. contamination. The observations from this study suggest that contaminants in blood cultures are more frequent in the 1990s than they were 2 decades ago. Of 1,585 positive blood culture episodes in the current study, 658 (41.5%) were judged to represent contamination and another 84 (5.3%) were of indeterminate significance. Thus, only about half of all positive blood cultures represented true bloodstream infection. These findings contrast markedly with the observations in our earlier study, in which approximately one-third of all positive blood cultures represented contamination [10].

There are several possible explanations for these findings. One is the increasing use of central, long-term intravascular catheters (e.g., Hickman and Broviac) and the utilization of these access devices for the purpose of obtaining blood for culture. Access ports from intravascular devices may be more difficult to sterilize than skin at venipuncture sites, thereby resulting in increased contamination rates; at least one study has documented increased contamination rates when blood culture specimens are obtained from central lines [34].

Although physicians may believe they are benefiting their patients by obtaining blood culture specimens from catheters (i.e., saving patients from needlesticks), they actually may be doing a disservice, since culture contaminants (false-positive cultures) have been shown to result in longer hospitalizations and increased costs to patients and institutions [35].

A second possible reason for the increased incidence of contaminants is blood culture technique. Although several recent studies have indicated that the current single-needle technique for obtaining blood and inoculating cultures is not associated with increased rates of contamination [14, 36, 37], Spitalnic et al. [38], in a meta-analysis, have suggested otherwise. Alternatively, it may be that in institutions such as ours, in which house officers and medical students obtain the majority of blood culture specimens, failure to apply antiseptic solutions (usually iodophors and alcohol) properly and to let them exert their antimicrobial effect over 1–2 minutes as recommended results in increased contamination.

Possible remedies include use of blood culture teams from the laboratory's phlebotomy service, which seems unlikely in the managed care era, or the development and use of potentially more effective antiseptic skin preparation materials (e.g., 2% iodine tincture) before blood sampling. A final possible explanation for increased rates of contamination of blood cultures could be that newer blood culture systems and media are more sensitive and capable of detecting the few viable skin bacteria that might remain after appropriate antiseptic preparation.

Of the 843 septicemias, a source was confirmed by culture in 294 (34.9%) and by clinical evidence in 282 (33.4%). Of the remaining 267 episodes, at least two blood cultures were positive for the same microorganism in 181 (67.8%; 21.5% of total septicemias). Thus, there was objective evidence of true infection in 757 of the 843 episodes (89.8%), an observation that is remarkably similar to that in our earlier study [10]. This finding is important clinically, since it suggests that, despite increased rates of contamination of blood cultures, in the great majority of instances physicians should be able to determine with some confidence whether a positive blood culture represents significant infection.

Nevertheless, positive blood cultures yielding coagulasenegative staphylococci may present great interpretative difficulties, even when more than one culture set is positive. For example, Zaidi et al. [39] have found that coagulase-negative staphylococci with identical species designations, serotypes, and antibiograms recovered from the blood of infants sometimes represented different strains when the isolates were analyzed by molecular typing techniques. Similarly, even when both of two blood cultures yielded S. epidermidis of the same biotype in the current study, we were frequently not certain of the isolates' clinical significance (table 2).

Patterns of positive blood cultures. In our earlier study [10], we noted different patterns of blood culture positivity in patients with endocarditis, those with true septicemia that was not due to endocarditis, and those with contaminant isolates. Similar observations were made in this study. Thus, in patients with endocarditis, a disease characterized by continuous seeding of blood from the infected heart valve, all blood cultures obtained in a series were positive.

By contrast, for patients with septicemia not due to endocarditis, most but not all blood cultures obtained in a series were positive, a finding consistent with the understanding that bloodstream infection in such patients may be short-lived or intermittent (abscesses). For patients whose blood cultures were contaminated, an initial positive culture in a series virtually always was followed by negative cultures. When a subsequent culture was positive, it usually was positive with a different microorganism (e.g., S. epidermidis followed by a diphtheroid).

The proportion of patients with polymicrobial septicemia in this study (79 of 843; 9.4%) is consistent with findings in earlier studies, in which frequencies of polymicrobial bacteremia ranged from 6% to 18% [10, 17, 40–43].

Epidemiological Observations

Place of acquisition of septicemia. At our institutions the proportions of episodes that were of community-acquired septicemia and hospital-acquired septicemia were nearly equal (48% vs. 52%). This observation contrasts with the results of our earlier study at the University of Colorado hospitals, in which nearly two-thirds of episodes were nosocomial [10]. The difference may relate not only to patient-population variability [44, 45] but also to changes in health care, particularly shorter lengths of stay in the 1990s than those of 2 decades ago, as well as outpatient surgery and chemotherapy.

In contrast to the relative equivalence of community- and hospital-acquired septicemic episodes overall, there were important differences with regard to individual microorganisms. For example, 91% of pneumococcal bacteremias and all mycobacteremias and cryptococcemias were community-acquired. These observations are consistent with prior reports (on pneumococci) and with our understanding of the epidemiology of infections due to these microorganisms [10, 44, 46]. However, nosocomial pneumococcal bacteremia can occur and may be relatively common in institutions with longer patient stays [47, 48].

Fungemia, enterococcal bacteremia, and coagulase-negative staphylococcal bacteremia disproportionately were nosocomial in origin (table 3). The observations for fungi and enterococci were virtually identical to those in our earlier studies of bacteremia [10] and probably relate to the fact that infection with these microorganisms tend to occur in more debilitated patients. The predominance of hospital-acquired coagulase-negative staphylococcal bacteremia is explained by the current use of long-term indwelling central and peripheral catheters as well as other prosthetic devices, the ubiquity of these bacteria as normal skin flora, and the ability of these relatively avirulent microorganisms to adhere to the surfaces of biomaterials.

P. aeruginosa bacteremia usually occurs as a nosocomial infection. In the current study, P. aeruginosa bacteremia was community-acquired in 39.6% of episodes, compared with 17% in our earlier study. The explanation for this difference in the epidemiology of P. aeruginosa bacteremia may be related in part to the prevalence of HIV infection. In bacteremic patients known to be infected with HIV, P. aeruginosa was the third most frequently isolated pathogen, and in seven of 11 episodes in these patients, bacteremia was community-acquired. Several recent reports have documented similar findings in patients with HIV infections [49–51].

Hospital service. The overwhelming majority of bloodstream infections in this series occurred in patients hospitalized on either the medical services (73.6%) or nontransplantation surgical services (21.3%), an observation similar to that in our previous report [10] in which 54.6% of episodes occurred in medical patients and 27.2% of episodes occurred in surgical patients.

The current study also confirmed the rarity of P. aeruginosa bacteremia in medical patients (4.4% of episodes), the absence of enterococcal bacteremias in obstetrical and gynecologic patients, the high proportion of fungemias in transplantation patients (23.1% of episodes), and the proportionately increased frequency of anaerobic bacteremia in patients hospitalized on the surgical and gynecologic services (6.6% and 11.1% of episodes, respectively).

Sources of septicemia. One of the striking findings in the current series in comparison with our earlier work [10] was the ascendancy of intravascular catheters as an important source of bloodstream infections. Whereas only 3% of episodes were catheter-related in the previous study, iv catheters were the source of 19% of the episodes in the current series. The increasing importance of intravascular catheters also was noted by Mylotte et al. [47], who examined nosocomial bacteremia between 1979 and 1987; in that study, the proportion of episodes associated with intravascular devices increased from 6% (1979) to 19% (1987). During a similar time period, the proportion of bloodstream infections due to intravascular devices at a university hospital in Berlin was consistently ∼16% [19].

The inability to determine the focus of bacteremia and fungemia remains a vexing problem. Despite substantial advances in diagnostic imaging over the past 2 decades, 26% of the septicemic episodes in this series, compared with 31% in our earlier study [10], had no discernible focus. Leibovici and colleagues [20] noted similar results; 23% of episodes during 1988 and 1989 at their university hospital in Israel were of unknown origin.

Since episodes with unknown foci are associated with increased mortality ([11, 20] and present study), improved methods for determining the primary site of infection in septicemic patients clearly are needed. Microorganisms from unknown foci commonly are assumed to have a gut mucosal source. The organisms associated highly with an unknown source in this study (e.g., E. cloacae, K. pneumoniae, Candida species, T. glabrata, viridans streptococci, and M. avium complex) support this hypothesis.

When we examined the sources of septicemia according to each microorganism or microorganism group (table 5), there were several noteworthy observations. For example, in the years since our previous study, the proportion of S. aureus bacteremias associated with intravascular catheters has nearly doubled, from 20% to 35%. Respiratory and skin sources remained important primary foci for staphylococcal bacteremia. The recent report by Roberts and colleagues [18] confirmed the importance of intravascular and pulmonary foci for staphylococcal bacteremia. In addition, in the current study and in the report by Roberts et al. [18], respiratory foci for klebsiella bacteremia were considerably less prominent than we observed previously [10]; intraabdominal and genitourinary sources now predominate. In contrast to the findings of Roberts et al., who found enterococcal bacteremia most commonly to have wound sources [18], our patients most often had genitourinary tract foci.

Epidemiology of septicemia in neutropenic patients. The differences in the microbiology of bacteremia and fungemia in neutropenic patients compared with nonneutropenic patients (table 6) stand in contrast with the observations in our earlier report [10]. In the present series bacteremia due to S. aureus was significantly less common and fungemia significantly more common in neutropenic than nonneutropenic patients, whereas there were no such differences noted in the previous study. However, in both series, polymicrobial episodes were more frequent in granulocytopenic patients.

A study of bacteremia and fungemia in granulocytopenic patients during 1985 and 1986 at the University of Colorado Health Sciences Center [52], which was the site of our earlier study, showed both similarities to and differences from the distributions of microorganisms in the 1975–1977 review [10] and the current one. For example, in the study by Ehni et al. [52], fungemias were proportionately less common (2%, vs. 11% [10] and 12% [current study]) and P. aeruginosa bacteremias were more common (27%, vs. 9% [10] and 7% [current study]). However, the proportionate frequency of bacteremias due to Enterobacteriaceae was similar in all three studies.

In the study by Ehni and colleagues [52] and the present report, bacteremia due to S. aureus accounted for -5% of episodes in neutropenic patients, whereas in the 1975–1977 review [10], 13% of episodes in neutropenic patients were caused by S. aureus. Finally, the increasing importance of bacteremia due to coagulase-negative staphylococci in neutropenic patients was evident in the study of Ehni et al. [52] and in the current one (14% and 8% of episodes in neutropenic patients, respectively). In our earlier review, coagulase-negative staphylococcal bacteremia was sufficiently uncommon in granulocytopenic patients that it did not merit mention [10].

A possible explanation for the higher rates of fungemia currently includes the extensive use of more effective antipseudomonal β-lactam drugs such as piperacillin, ceftazidime, and imipenem. Although their early and empirical use may decrease mortality owing to P. aeruginosa infection, their prolonged pressure on normal gut flora is associated with overgrowth of yeasts and increased risk of subsequent fungemia [53]. The relative importance of coagulase-negative staphylococci presently probably relates to the common and prolonged use of central iv catheters and the resistance of this group of organisms to commonly used antimicrobial agents.

Epidemiology of septicemia in hypotensive patients. Septic shock most frequently has been associated with gram-negative bacteremia. Indeed, in our earlier review [10], aerobic or facultative gram-negative rods accounted for 53% of the isolates from hypotensive patients. In the current series, however, whereas we observed that aerobic or facultative gram-negative rods continued to be common etiologic agents of septic shock, they were isolated less frequently than in the past (43% of isolates). S. aureus was detected twice as frequently in hypotensive patients in the current series (16%, vs. 7% in the earlier series), and anaerobic bacteria were detected substantially less often in hypotensive patients (4%, vs. 11% in the earlier series). In both series, hypotensive patients were twice as likely as nomiotensive patients to have polymicrobial bacteremia ([10] and table 7).

Clinical and Prognostic Observations

Our observations suggest that the mortality associated with bacteremia and fungemia appears to have decreased during the past 2 decades. However, this conclusion may not be applicable widely and should be interpreted with caution. Indeed, the differences in patient population as well as the prospective nature of the current study vs. our retrospective earlier review [11] limited the ability to make direct comparisons with the previous work. Nonetheless, mortality attributable to septicemia in this study was markedly less than in the 1975–1977 study (17.5% vs. 31%, respectively). Moreover, Geerdes et al. [19] recently reported that between 1979 and 1989, mortality from septicemia at a university hospital in Berlin decreased from 34% to 21%.

Crude mortality has varied substantially in recent reports of bacteremic patients, ranging from 16% at a Swedish university hospital from 1973 to 1980 [54] to >40% among patients with nosocomial bacteremia from 1981 to 1983 at a university hospital in the United States [55] and with gram-negative bacteremia at a Turkish university hospital from 1983–1989 [21]. By comparison, crude mortality among septicemic patients at the University of Colorado during 1975–1977 was 42% [11], vs. 22.5% in this study (patients were followed for a maximum of 30 days after detection of bacteremia). Most comparable to our data are the observations of Roberts and colleagues, who recently reported a 30-day mortality of 27% among bacteremic patients studied during 1984–1987 in western Canada [18].

Age and sex. Numerous reports have emphasized the importance of advanced age as an unfavorable prognostic factor in septicemic patients [11, 15, 18, 21, 54, 55]. In contrast to our earlier data, which showed a statistically significant increase in mortality due to septicemia after age 40 years [11], in this series significantly increased mortality occurred after age 70 years. No differences in mortality according to sex were evident in this study or in a recent report from a Swedish university hospital [54].

Place of acquisition of bacteremia and fungemia. Nosocomial septicemias historically have been associated with substantially higher mortality than community-acquired septicemias [9, 11, 44]. In the current series and in another recent report [21], however, the evidence suggests that the increase in mortality associated with hospital-acquired bacteremia and fungemia may be less dramatic than reported in the past. Uzun et al. [21] noted crude mortality of 46% in episodes of nosocomial bacteremia vs. 37% in those of community-acquired bacteremia. In this series, associated mortality due to nosocomial septicemia was 20.3%, vs. 14.6% due to community-acquired septicemia.

Microorganisms. Many studies have looked at the mortality rates with bloodstream infections due to individual microorganisms; some have focused only on certain patient populations. Unfortunately, definitions of mortality in the various reports have not been uniform: some have evaluated total (or crude) mortality, others have evaluated only septic deaths (those judged to be directly related to septicemia), and still others have addressed mortality judged directly or indirectly attributable to septicemia. Furthermore, not all studies have indicated clearly whether mortality rates have been calculated on the basis of unimicrobial episodes, thereby excluding the confounding variable of concomitant bacteremia with other microorganisms. These differences make direct comparisons of mortality in other reports problematic, and the comments that follow should be interpreted accordingly.

The lower mortality overall from bacteremia in this series compared with that noted in our earlier work [11] was reflected in the mortality rates associated with individual microorganisms or groups thereof (table 8). Several comparisons and contrasts with regard to etiologic microorganisms deserve emphasis. Fungemia, which was associated with more than a sixfold increased risk of death in the earlier series [11], also carried a sixfold increased relative risk of death in the present study (table 8). Overall mortality associated with fungemia, however, was lower in the current series than in our earlier report [11], and the associated mortality in this series was somewhat less (36%) than that due to candida and torulopsis fungemias (44%) in Detroit in the mid-1980s [56].

Among episodes of polymicrobial septicemia, for which the directly related mortality was 35% in the earlier series [11], the associated mortality in this series was 34% and the risk of death was significantly increased compared with that in unimicrobial episodes. The mortality associated with poly-microbial bacteremia in the recent report by Cooper et al. [17] was remarkably similar to the observations in our earlier and current series.

In our earlier review, the mortality directly related to pneumococcal bacteremia was 15% (crude mortality, 22%), vs. 17.6% associated mortality in this series. Data from other recent reports are consistent with these findings [57, 58]. These data provide impressive evidence that there has been little change in the outcome of Streptococcus pneumoniae bacteremia since the classic studies of Austrian and Gold >3 decades ago [59].

By contrast, the dramatically increased risk of death from bacteremia due to P. aeruginosa in our earlier report (RR, 6.84) was moderated in this study (RR, 3.04). The mortality associated with pseudomonas bacteremia was 16.7%, compared with 36% for deaths directly due to bacteremia in the earlier review [11]. Two studies examining pseudomonas bacteremia during the early 1980s revealed case fatality rates attributable to sepsis of 41% and 48% [60, 61]. Thus, our data suggest the possibility that the outcome of bacteremia due to P. aeruginosa may have improved over the past decade.

Mortality from bacteremia due to gram-positive organisms also was lower in the current study than in the prior review [11]. In the case of S. aureus, septicemia-associated mortality in the current series was 11.9%, compared with crude mortality of 33% and directly related mortality of 9% in the earlier series. By comparison, in the recent report from Lautenschlager et al. [62] encompassing the years 1980–1986 in Basel, Switzerland, total mortality was 34% and directly related mortality was 20%.

Coagulase-negative staphylococcal bacteremia had the lowest attributable mortality of all microorganism groups in the current study (5.5%); case-fatality rates were somewhat higher during the mid-1980s: 13.6% at the University of Iowa Hospital [63] and 18% at a large hospital in Spain [64]. The mortality associated with enterococcal bacteremia was 13% in this series, considerably lower than the crude or directly related mortality (45% and 27%, respectively) in our earlier series [11], despite the presence of vancomycin-resistant enterococci at both RWJUH and DUMC during the current study period. By comparison, reports based on data from the 1980s have described case fatality rates associated with enterococcal bacteremia varying from 12% to 51% [65–67].

Several studies have recently provided data on the outcome of bacteremia due to members of the family Enterobacteriaceae. Mortality due to E. coli bacteremia appears to be lower now than 2 decades ago. In our earlier report [11], 41% of patients died of causes directly related to bacteremia, compared with an associated mortality of 10.3% in this study.

Grandsen et al. [68] prospectively evaluated E. coli bacteremia in London from 1969 through 1987 and noted a case-fatality rate of 20.7%; approximately half the deaths were judged to be directly related to sepsis. Similarly, the recent review by Roberts and colleagues [18] noted that the 30-day mortality due to E. coli bacteremia was 21.5%. Mortality associated with K. pneumoniae bacteremia has ranged from 14.6% in the current study to 37% (crude mortality) in another recent report [69]. Korvick et al. [70] reported 19% mortality at 14 days in a recent multicenter study of 230 patients with klebsiella bacteremia.

Mortality associated with serratia bacteremia was 30% among our patients; by contrast, Saito and colleagues [71] reported a mortality rate of 23% in cancer patients between 1982 and 1987. In the present series, associated mortality among 12 patients with E. cloacae bacteremia was 8.3%, compared with crude mortality of 24% in a recent multicenter study of 129 patients with enterobacter (all species) bacteremia [72]. The attributable mortality between 1980 and 1992 among patients with Proteus mirabilis bacteremia was 25.6% in a recent report [73], remarkably similar to the bacteremia-associated mortality of 23.1% in this series.

Source of infection. As in our earlier study [11], the mortality associated with bacteremia was increased when the primary focus of infection was either unknown or at a site that was difficult to treat, such as the respiratory tract or the bowel and peritoneum. Similarly, when the primary focus of infection could be removed or drained easily (e.g., the genitourinary tract), the mortality was reduced (table 9). The higher mortality in septicemia with an unknown primary focus of infection also has been noted by others [19–21].

Body temperature. The current study confirmed the observations made in our earlier report [11], namely, that the inability of a patient to mount a febrile response to septicemia is a poor prognostic sign (figure 2). This relationship has been noted by others [9, 74, 75] but could not be confirmed in a study designed to examine independent predictors of mortality associated with bloodstream infections [55]. Kluger [76] and Roberts [77] have each recently presented information to support the premise that the presence of physiologically elevated body temperature is beneficial.

Blood pressure. The well-known association between hypotension as a marker for septic shock and poor outcome was again confirmed during this study. This association was noted not only in prior studies [9, 11, 74] but also in more recent reports [18–21]. Compared with data in our earlier review [11], the incremental risk of death when hypotension was present was greater in the current series than was noted previously (RR, 2.8 vs. 2.0).

Total leukocyte count and absolute neutrophil count. Infection-associated mortality and relative risk of death from bacteremia were increased among patients with leukopenia and absolute granulocytopenia, as in our earlier study [11]. In addition, in this study mortality was increased also among patients with total leukocyte counts ≥20,000/µL. Recent studies in varied patient groups have provided similar observations [17, 60].

Predisposing factors. For consistency and to enable accurate comparisons of risk associated with various underlying conditions that may affect mortality among patients with bacteremia and fungemia, we used the same criteria and definitions as in our earlier review [11] and included HIV infection and AIDS, neither of which were known at the time the earlier study was undertaken. Moreover, the risk associated with each factor was judged when that condition was the only one present (table 12).

As in the earlier study [11], increased risk of death in bacteremia was associated with the presence of malignancies and biopsy-proven hepatic cirrhosis. In contrast with our earlier observations, the presence of moderate renal failure (serum creatinine level, 2.0–5.0 mg/dL) but not severe renal failure (serum creatinine level, >5 mg/dL) was associated with increased mortality among bacteremic patients.

Although this observation may seem paradoxical, we interpret the results to suggest that patients with chronic renal failure probably were undergoing dialysis and therefore had stable albeit poor renal function, whereas those with moderate renal failure were more likely to have acute deterioration of function and greater metabolic instability which, in turn, was associated with a greater likelihood of a poor outcome. Finally, the presence of AIDS was associated with an increased risk of death associated with bacteremia or fungemia.

Antibiotic and other therapy. Intuitively, one would expect that administration of antimicrobial agents active in vitro against the infecting microorganism(s) would be associated with improved prognosis. Our prior study and others [11, 78, 79] have supported this assumption, and the current study again confirmed the principle (table 13). By assessing therapy at several different time points, we hoped to determine that degree to which appropriate treatment affected outcome at each stage.

One might have expected, for example, that appropriate therapy given early (empirical therapy time point) would be associated with lower attributable mortality than would appropriate therapy delayed until after susceptibility test results were available to the physician. Indeed, this was the case. As is evident in table 13, the lowest attributable mortality occurred among those patients who received appropriate therapy throughout the course of their septicemic episodes (10.4%). Prompt initiation of appropriate therapy by physicians after notification of a positive blood culture also was associated with low mortality (13.3%). If appropriate therapy was not initiated until after susceptibility test results were available, mortality was 25.8%.

Why 60 (7.6%) of 791 septicemic patients received inappropriate therapy even after the identification and antibiotic susceptibilities of infecting microorganisms were reported is uncertain (table 13). Antibiotic misuse has been studied by others. In one report [80], the most common form of misuse in bacteremic patients was the administration of superfluous agents, a finding that corroborates our observations. In another study [81], multivariate analysis showed that four clinical variables (i.e., nosocomial bacteremia, recent prior antibiotic therapy, nursing home residence, and central iv catheters) and four microorganisms (i.e., Candida,Acinetobacter,Enterococcus, and Pseudomonas species) were independently associated with inappropriate antimicrobial therapy. Our data also showed that the use of inappropriate therapy was more likely to occur on the surgical services.

A fundamental principle in the management of bloodstream infections has always been that eradication of the primary source of infection is a necessary component of the therapeutic regimen. Thus, removal, drainage, or excision of an infected focus, when possible, should result in an improved prognosis.

Both the current study and our prior report [11] provide support for this principle. Indeed, in the current study, infection-associated mortality among patients who had a primary focus that was excised, drained, or removed was less than one-third that among patients who did not have these interventions (6.2% vs. 22.0%, respectively).

Multivariate Analysis of Factors Influencing Prognosis

As in the earlier review by our group [11], we subjected each of the variables that were associated with an increased risk of death in univariate analyses to multivariate analysis (table 14). In the earlier report, seven variables were independently associated with an increased risk of death; all but one were confirmed in the current study. These included advanced age, microorganism, source of infection, predisposing factors, hypotension, and absence of fever. Nosocomial acquisition of bacteremia was not an independent predictor of death in the current study, in contrast to the observations in the earlier report.

In our earlier report we were unable to include antimicrobial therapy in the multivariate analysis. Inclusion of therapy was possible in this study and confirmed the importance of administering appropriate antimicrobial agents.

Although advanced age again was an independent predictor of poor prognosis, the increased risk statistically was greatest after age 70 years in the current study, compared with age >40 years in the earlier series. Septicemia caused by a high-risk microorganism also was again an independent risk factor in multivariate analysis, but there were some changes in the individual microorganisms associated with a high risk of death. In the earlier report there was increased risk with gram-negative rods generally, whereas in the current study increased risk was observed only with Enterobacteriaceae other than E. coli.

The reasons for this difference are not readily apparent. Speculation might focus on greater resistance to antimicrobial agents among these strains than among E. coli. In contrast to the results of the earlier series, enterococcal bacteremia was not associated with increased risk in the current study. However, fungemia was confirmed to be associated with poor prognosis, in concordance with our earlier observations.

Primary foci of infection in the respiratory tract, bowel, or peritoneum and septicemia from an unknown source again were shown to be independent predictors of poor prognosis. However, primary foci in abscesses, skin, and surgical wounds, each of which was associated with an increased risk of death in the earlier series, were not associated independently with increased risk in the present study.

As in the earlier study, the presence of underlying diseases associated with high risk in univariate analysis was an independent predictor of increased mortality in the multivariate analysis. The underlying diseases associated with high risk were somewhat different from those in the earlier report and included AIDS, a syndrome that was unknown at the time of the earlier review; renal failure, which was not a high-risk factor in the prior study; and malignancies, which were high-risk factors in the earlier study.

Comparative Features of Bacteremia and Fungemia in the 1970s and 1990s

During the past 20 years, numerous changes have occurred in medicine and health care. Nevertheless, several fundamental aspects of bloodstream infections have remained constant. Major examples include the continued frequency with which S. aureus and E. coli are causative agents of bacteremia; the importance of the respiratory tract, genitourinary tract, and bowel as primary foci; the association between gram-negative or polymicrobial bacteremia and septic shock; and the importance of advanced age, difficult-to-eradicate or unknown sources, malignancies and renal failure, hypotension, and absence of fever as independent predictors of a poor outcome (table 15).

Table 15.

Major similarities and differences in positive blood cultures, 1975–1977 [10, 11] and 1992–1993.

Table 15.

Major similarities and differences in positive blood cultures, 1975–1977 [10, 11] and 1992–1993.

The differences noted in the 1990s provide cause for concern but perhaps also for optimism (table 15). The increased proportion of blood isolates representing contamination is of concern, especially in an environment that mandates cost-effective care. The frequency of coagulase-negative staphylococcal isolation particularly is problematic, since it often is difficult for clinicians to determine the clinical significance of these bacteria. The decrease in anaerobic bacteremia and proportionate increase in fungemia have prompted some authorities to recommend changes in routine blood culture techniques [82].

The most frequent source of bloodstream infections has become the intravenous catheter, and it may be expected that prosthetic materials and devices will continue to be important sources of infection. HIV infection and AIDS have allowed M. avium complex to become a bloodstream pathogen, and the increased frequency of community-acquired P. aeruginosa bacteremia also seems to be associated with HIV-infected patients [49–51].

The most optimistic finding with regard to bacteremia and fungemia in the 1990s is that mortality associated with these serious infections has decreased. The reasons for this improved outcome are not fully explained but could be related to earlier detection with use of modern blood culture systems; more sophisticated imaging methods that better elucidate primary foci of infection; the frequency of infections emanating from easily removed (iv catheters) or drained (genitourinary tract) foci; and improved antimicrobial agents and use thereof by clinicians.

Although we have shown that mortality is lower than it was 2 decades ago, bacteremia and fungemia remain serious syndromes with substantial risk. Moreover, the combination of an aging population, improved survival among immunocompromised patients and those with organ transplants, and the emergence of β-lactam-drug-resistant gram-positive and gram-negative bacteria as well as vancomycin-resistant enterococci (and possibly staphylococci in the future) [83], will continue to challenge all who care for patients with bloodstream infections.

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