The Clinical and Prognostic Importance of Positive Blood Cultures in Adults

Article Outline

• Abstract
• Methods
  • Study Design
  • Study Cohort
  • Data Collection
  • Study Definitions
  • Primary Outcome
  • Statistical Analysis
• Results
  • Patient Characteristics
  • Microbiology
  • Source of Infection
  • Health Care Acquisition
  • Case-fatality Ratio (CFR), Bivariable, and Multivariable Analysis
• Discussion
• Acknowledgments
• References
• Copyright

Abstract 

Background

Bloodstream infections are a major cause of morbidity and mortality in adults. Bloodstream infections should be reassessed periodically because of increased antibiotic resistance, more patients receiving immunomodulatory therapy, improved antiretroviral therapy, and acquisition of infection in health care settings other than hospitals.

Methods

We conducted retrospective assessment by infectious disease physicians of hospitalized adults with positive blood cultures at 3 academic medical centers.

Results

Two thousand two hundred seventy positive blood culture episodes occurred in 1706 patients. Of 2669 isolates, 51% represented true infection, 41% contamination, and 8% unknown clinical significance. Although coagulase-negative staphylococci were most common, only 10% were clinically significant. Among 1225 true bloodstream infections, the most frequent isolates were Staphylococcus aureus, Escherichia coli, Enterococcus spp., Klebsiella pneumoniae, coagulase-negative staphylococci, Pseudomonas aeruginosa, Candida albicans, Enterobacter cloacae, and Serratia marcescens. Intravenous catheters were the most common primary source of bloodstream infection (23% of episodes). Most (81%) bloodstream infections were acquired in the hospital or other health care settings. Crude and attributable in-hospital case-fatality ratios were 20% and 12%, respectively, lower than in previous studies. Increasing age, hypotension, absence of fever, hospital acquisition, extreme white blood cell count values, and the presence of the acquired immunodeficiency syndrome, malignancy, or renal disease were significantly associated with an increased risk of in-hospital attributable death in multivariable analysis.

Conclusions

The proportion of bloodstream infections due to intravenous catheters is continuing to increase. Most episodes were acquired in the hospital or other health care setting. In-hospital case-fatality ratios have decreased compared with previous studies. Several previously identified factors associated with an increased mortality remain statistically significant.

Keywords: Bacteremia, Bloodstream infection, Fungemia

The clinical significance of positive blood cultures has been studied in detail over the past 3 decades.¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹ These studies have helped describe the most common etiologic microorganisms, sources of infection, and underlying conditions associated with death in true bloodstream infections. Sequential studies have documented the increasing importance of intravenous access devices as sources of bloodstream infection and reductions in case-fatality ratio (CFR) in the early 1990s compared with the mid-1970s.¹, ², ³ Since the early 1990s, more drug-resistant microorganisms have emerged, more effective human immunodeficiency virus (HIV) therapies have been developed, and an increasing number of patients are receiving immunomodulatory treatments, including those following organ transplantation. Furthermore, a new category of acquisition has been proposed that distinguishes other health care settings from community- and hospital-acquired settings.¹⁰ Because these developments might have a substantial impact on the distribution, characteristics, and outcomes of adult bloodstream infections, the current study was undertaken to update our understanding of contemporary bacteremia and fungemia and compare the findings with 2 previous similarly designed studies.¹, ², ³

Back to Article Outline

Methods 

Study Design 

A multicenter retrospective study was performed on an open cohort of adults who had at least one positive blood culture at 3 academic hospitals (Robert Wood Johnson University Hospital, Duke University Medical Center, and the Durham Veterans Affairs Medical Center) from January 1 through December 31, 2004. Institutional review board approval was obtained at all 3 institutions.

Study Cohort 

Patients who had blood culture isolates obtained from standard bacterial, fungal, or mycobacterial blood culture automated detection systems (BACTEC, BD Biosciences, Sparks, MD and BacT/ALERT, bioMérieux, Durham, NC) were identified by the clinical microbiology laboratory database at each institution. Bacterial and fungal isolates that were referred from outside medical institutions were excluded from the study. All potential subjects were screened by reviewing the hospital medical record. Eligible subjects were aged ≥18 years and were hospitalized at one of the study institutions where access to in-depth information about the clinical management and outcome was available.

Data Collection 

The medical chart of each subject was reviewed by an infectious disease physician, and data were abstracted onto a standardized worksheet to assess the presence of 25 types of variables at the time the positive blood culture was collected. These included the medical institution, age, sex, service specialty, place of acquisition, microorganism, clinical significance, source of infection, presence of endocarditis, white blood cell count, blood pressure, body temperature, and underlying comorbidities. The preexisting medical conditions of interest included diabetes mellitus, renal insufficiency (serum creatinine ≥2), corticosteroid use (prednisone ≥20 mg/day for 2 weeks), malignancy, HIV infection, hematopoietic stem cell transplantation, solid organ transplantation, cirrhosis, trauma, and recent surgery (within 2 weeks). The appropriateness of antimicrobial therapy was assessed at 3 different time points: before the blood culture flagged positive, after the Gram stain result, and when the final identification or susceptibility result was available. Use of adjunctive therapy (eg, drainage, catheter removal, or activated protein C infusion) and outcome (discharged alive, attributable death, and nonattributable death) also were recorded. Deaths were considered attributable to a true bloodstream infection if it was felt by the physician reviewer that the episode caused or significantly contributed to death during hospitalization.

Study Definitions 

An episode of bacteremia, fungemia, or mycobacteremia was defined by a positive blood culture, which must have occurred >2 days after any previous positive result unless it was clear to the investigator that the new positive was part of the same episode.³ Polymicrobial episodes were defined as having >1 clinically significant blood culture isolate occurring within 2 days of each other. Clinical significance was categorized as either true bloodstream infection, contamination, or unknown significance. These assessments were made based on the number of positive cultures, presence of a plausible source, and clinical manifestations. Acquisition was categorized as community-acquired, hospital-acquired (hospitalized ≥48 hours at the time the blood culture was drawn), or other health care-associated (eg, previous hospitalization within 90 days, attending a hemodialysis or intravenous [IV] chemotherapy clinic within 30 days, home IV therapy or specialized nursing care within 30 days, or resident of long-term care facility).¹⁰ The presence of infective endocarditis was determined by modified Duke criteria.¹¹ Hypotension was defined as having a systolic blood pressure ≤90 mm Hg at the time the blood culture was drawn; subsequent vasopressor therapy or having urine output <80 mL over a 4-hour period also were accepted. The appropriateness of antimicrobial therapy was assessed based on the final antimicrobial susceptibility results by Clinical Laboratory Standards Institute criteria, published consensus treatment recommendations, and pharmacologic properties.¹², ¹³, ¹⁴

Primary Outcome 

The primary outcome of the study was in-hospital death attributable to a true bloodstream infection. Because subjects varied greatly in the duration of their subsequent hospital stay, and post-discharge follow-up was not feasible for the vast majority of survivors, only in-hospital CFR was measured. The CFR was calculated as the number of subjects with a true bloodstream infection that died during hospitalization divided by the total number of true bloodstream infections.

Statistical Analysis 

For categorical variables and CFR, differences between proportions were tested using the χ² test; P-values ≤.05 were used as the threshold for significance and no adjustments were made for multiple comparisons. Bivariable analyses were conducted to identify associated risk factors for attributable CFR using logistic regression (Stata 9.2, StataCorp, College Station, Tex). Both 95% confidence intervals of the odds ratio estimate and P-values were presented. A multivariable logistic regression model was constructed (SAS 9.1, SAS Institute Inc., Cary, NC) with the same variables used in the multivariable analysis of the 1992 study,³ that is, increasing age, hospital acquisition, fungi or non-E. coli Enterobacteriaceae pathogens, polymicrobial infection, source (respiratory, bowel, peritoneal, or unknown), predisposing factors (malignancy, acquired immunodeficiency syndrome, or renal failure), hypotension, extremes of leukocyte count (<4000 or >20,000/mm³), neutropenia (absolute neutrophil count <1000/mm³), absence of fever (temperature <38.0°C), and inappropriate antimicrobial therapy at ≥2 time points. Bootstrapped modeling was used to find variables that were found to have a reproducible statistically significant association in at least 60% of models. Stepwise multivariable regression was subsequently performed using the selected variables. Measures of associations were reported as adjusted odds ratios with 95% confidence intervals and P-values.

Back to Article Outline

Results 

Patient Characteristics 

A total of 2669 blood culture isolates from 2270 positive blood culture episodes in 1706 patients were reviewed. There were 1225 patients who developed a true bloodstream infection and had a median age of 60 years (interquartile range 50-72 years). Approximately 60% of adult patients with a true bloodstream infection were male, 59% were white, and 80% had at least one predisposing comorbid illness. The patients from the Durham Veterans Affairs Medical Center were older, with a higher proportion of diabetes mellitus compared with Duke University Medical Center and the Robert Wood Johnson University Hospital (Table 1).

Table 1. Characteristics of a Cohort of Adult Bloodstream Infection Episodes at Duke University Medical Center, the Durham VA Medical Center, and Robert Wood Johnson University Hospital During 2004

	All Patients	%	DUMC	%	DVAMC	%	RWJUH	%
Age, median	60 years		57 years		67 years		65 years
Sex
Male	731	60	374	50	223	99	134	53
Female	494	40	372	50	1	1	121	47
Race
White	709	59	417	56	131	58	161	69
Nonwhite	499	41	329	44	93	42	77	31
Place of acquisition
Community	228	19	133	18	46	21	49	20
Hospital	568	46	312	42	115	51	141	55
Other health care setting	429	35	301	40	63	28	65	25
Predisposing conditions (n)
0	249	20	146	20	39	17	64	25
1	510	42	309	41	92	41	109	42
2	370	30	231	31	73	33	66	26
3	84	7	55	7	17	8	12	5
4	12	1	5	1	3	1	4	2
Comorbid condition
Diabetes mellitus	403	33	236	32	117	52	50	20
HIV/AIDS	45	4	20	3	17	8	8	3
Organ transplantation	94	8	72	10	4	2	18	7
Malignancy	373	30	228	31	54	24	91	36
Neutropenia	118	10	85	11	6	3	27	11
Corticosteroid use	83	7	41	6	8	4	34	13
Serum creatinine ≥2	316	26	194	26	64	29	58	23
Cirrhosis	32	3	28	4	4	2	0	0
Trauma	19	2	17	2	0	0	2	1
Recent surgery	184	15	120	16	32	13	32	14

DUMC=Duke University Medical Center; DVAMC=Durham Veteran Affairs Medical Center; RWJUH=Robert Wood Johnson University Hospital; HIV=human immunodeficiency virus; AIDS=acquired immunodeficiency syndrome.

Microbiology 

Of 2669 total blood culture isolates, 1364 (51%) represented true infection, 1101 (41%) contamination, and 204 (8%) unknown clinical significance (Table 2). The most frequently isolated microorganisms causing episodes of true bloodstream infection were Staphylococcus aureus (23%), Escherichia coli (12%), Enterococcus spp. (9%), Klebsiella pneumoniae (9%), coagulase-negative staphylococci (CoNS; 8%), Pseudomonas aeruginosa (4%), Candida albicans (3%), Enterobacter cloacae (3%), Serratia marcescens (3%), and Bacteroides spp. (2%). Consistent with previous studies, >90% of positive blood culture episodes due to S. aureus, E. coli and other Enterobacteriaceae, Streptococcus pneumoniae, β-hemolytic streptococci, P. aeruginosa, obligate anaerobic Gram-negative bacteria, Candida spp., and Mycobacterium spp. were judged to represent true bloodstream infection. Although CoNS grew from 38% of all positive blood cultures, only 10% of CoNS represented true bloodstream infection. Similarly, only 30% of viridans streptococci and very few Corynebacterium spp., Bacillus spp., Micrococcus spp., Lactobacillus spp., and Propionibacterium spp. represented true infection (Table 2). Over 15% of episodes due to Enterococcus spp., non-glucose fermenting Gram-negative bacilli (eg, Acinetobacter spp., Stenotrophomonas maltophilia, and Pseudomonas non-aeruginosa spp.), and viridans streptococci were of uncertain clinical significance. Among the 1225 true bloodstream infection episodes, 115 (9%) were polymicrobial, which was less than the 1975 study (18%; P <.001)¹ but similar to the 1992 study (9%).³

Table 2. Microorganisms Isolated from Positive Adult Blood Cultures at DUMC, DVAMC, and RWJUH, 2004

DUMC=Duke University Medical Center; DVAMC=Durham Veteran Affairs Medical Center; RWJUH=Robert Wood Johnson University Hospital.

Source of Infection 

Approximately 71% of all true bloodstream infection episodes had an identifiable source, including 32% that were culture-proven and another 25% that were confirmed by localized clinical findings (Table 3). The source remained unknown in 29% of true bloodstream infections, which is similar to previous reports. IV catheters were the leading identifiable source of bloodstream infections, representing 23% of episodes. This is higher compared with 3% (14/500, P <.001) in the 1975 study¹ and 19% (161/843, P=.05) in the 1992 study.³ The genitourinary (12%) and respiratory (8%) tracts were the next leading identifiable sources.

Table 3. Sources of Bacteremia and Fungemia

Gram-positive pathogens including S. aureus (30%), CoNS (16%), and Enterococcus spp. (11%), in addition to Candida spp. (15%) and K. pneumoniae (7%), were the most frequent cause of IV catheter bloodstream infections. In contrast, Enterobacteriaceae, including E. coli (44%) and K. pneumoniae (8%), in addition to Enterococcus spp. (8%) and P. aeruginosa (6%), were the most frequently isolated pathogens from genitourinary tract episodes. S. aureus (26%), S. pneumoniae (22%), and K. pneumoniae (7%) were recovered most frequently from respiratory tract episodes. Bloodstream infections from intra-abdominal foci were most frequently caused by E. coli (21%), K. pneumoniae (18%), Enterococcus spp. (13%), and obligate anaerobic Gram-negative bacilli (12%). S. aureus (86%) caused most bone- and joint-associated bloodstream infections.

Health Care Acquisition 

Using the revised definition of health care acquisition setting,¹⁰ only 19% of bloodstream infections were community acquired, compared with 53% if the older definition had been used (Table 4). Hospital acquisition and acquisition in other health care settings represented 46% and 35% of episodes, respectively. Consistent with previous studies,¹, ³ S. pneumoniae remained mostly community acquired, whereas very few episodes due to Candida spp., CoNS, and P. aeruginosa were truly community acquired.¹, ², ³ Approximately 45% of S. aureus bacteremias were associated with exposure at other health care settings, predominantly recent hospitalization and attendance of an outpatient hemodialysis or intravenous therapy treatment center. Of the 13% of S. aureus bacteremias that were community acquired, 31% (13/42) were methicillin-resistant, compared with 55% (145/263) of S. aureus bacteremias acquired in hospital or other health care settings (P=.004).

Table 4. Place of Acquisition of Microorganisms Causing Bacteremia and Fungemia

IV=intravenous.

Case-fatality Ratio (CFR), Bivariable, and Multivariable Analysis 

The overall crude and attributable in-hospital CFRs were 20% and 12%, respectively (Table 5). The microorganisms associated with highest attributable CFR were β-hemolytic streptococci (22%), Enterococcus spp. (19%), P. aeruginosa (17%), Enterobacteriaceae other than E. coli (14%), obligate anaerobic bacteria (14%), and Candida spp. (14%). In the bivariable analysis, the factors associated with attributable CFR were increasing age, hypotension, absence of fever, hospital acquisition, increasing number of predisposing comorbid conditions, cirrhosis, renal failure, corticosteroid use, extremes of white blood cell count, source (respiratory, bowel, or peritoneum), Enterococcus spp., organ transplantation service, and nonsusceptible antimicrobial therapy at ≥2 decision points (Table 6). IV catheters, genitourinary source, CoNS, community acquisition, and use of adjunctive therapy were associated with lower unadjusted odds ratio for attributable death. About 11% of all bloodstream infections were associated with inappropriate or nonsusceptible antimicrobial therapy at ≥2 decision points; such episodes were associated with a significantly increased attributable CFR in the bivariable analysis (Table 6). In the multivariable logistic regression model, the statistically significant factors associated with in-hospital death attributable to a bloodstream infection were increasing age, hypotension, absence of fever, hospital acquisition, extremes of white blood cell count, and having either malignancy, HIV, or renal disease.

Table 5. Sources and Case-fatality Ratio (CFR) for Episodes of Unimicrobial Bacteremia and Fungemia, According to Microorganism

IV=intravenous.

Table 6. Bivariable and Multivariable Analysis of Factors Associated with Attributable Death Due to Episodes of Adult Bloodstream Infection During 2004

	Unadjusted Odds Ratio	95% CI	P Value	Adjusted Odds Ratio	95% CI	P Value
Demographic and clinical features
Increasing age (per 1 year)	1.02	1.01-1.03	.002	1.03	1.02-1.05	<.001
Increasing age (per 10 years)				1.41	1.26-1.58	<.001
Male	1.07	0.75-1.52	.7
Nonwhite race	0.91	0.64-1.29	.6
Hypotension	5.69	3.98-8.16	<.001	4.46	3.14-6.32	<.001
Absence of fever	2.65	1.87-3.75	<.001	3.38	2.46-4.65	<.001
Community acquisition	0.38	0.21-0.69	.001
Hospital acquisition	1.68	1.19-2.38	.003	3.50	2.50-4.89	<.001
Other health care acquisition	0.93	0.65-1.33	.7
White blood cell count <4000 or >20,000/mm3	2.03	1.43-2.88	<.001	1.59	1.13-2.22	.007
Absolute neutrophil count <1000/mm3	1.41	0.85-2.33	.2
Nonsusceptible ABX therapy at ≥2 time points	1.88	1.17-3.03	.009
Adjunctive therapy	0.58	0.41-0.58	.002
Infective endocarditis	2.14	1.04-4.42	.04
Comorbid conditions
Increasing number of conditions	1.43	1.18-1.73	<.001
Diabetes mellitus	1.31	0.92-1.86	.1
HIV infection, non-AIDS	1.61	0.54-3.77	.5
AIDS	1.25	0.48-3.29	.6
Any HIV infection	1.35	0.59-3.07	.5
Hematopoietic stem cell transplantation	1.62	0.54-4.86	.4
Solid organ transplantation	1.33	0.68-2.58	.4
Any organ transplantation	1.41	0.79-2.52	.2
Acute leukemia or lymphoma	0.80	0.46-1.39	.4
Solid malignancy	0.87	0.55-1.39	.6
Any malignancy	0.82	0.56-1.20	.3
Cirrhosis	6.97	3.40-14.29	<.001
Serum creatinine >2 mg/dL	2.02	1.41-2.89	<.001
Trauma	0.40	0.05-3.00	.4
Recent surgery	0.75	0.45-1.27	.3
Corticosteroid use	1.81	1.02-3.22	.04
Malignancy, AIDS, or serum creatinine >2 mg/dL	1.42	1.00-2.02	.05	1.74	1.25-2.40	<.001
Microorganism
Staphylococcus aureus	0.91	0.61-1.36	.6
Methicillin-resistant S. aureus	1.17	0.58-2.35	.7
Coagulase-negative staphylococci	0.15	0.04-0.63	.01
Enterococcus spp.	1.77	1.04-3.01	.03
Streptococcus pneumoniae	0.60	0.14-2.55	.5
Viridans streptococci	0.34	0.04-2.54	.3
β-hemolytic streptococci	2.11	0.84-5.31	.1
E. coli	0.71	0.04-1.25	.2
Non-E. coli Enterobacteriaceae	1.28	0.85-1.91	.2
P. aeruginosa	1.55	0.71-3.39	.3
Other nonfermentative gram-negative bacilli
Obligate anaerobic bacteria	1.21	0.56-2.62	.6
Candida spp.	1.19	0.64-2.20	.6
Mycobacterium spp.	1.20	0.14-10.08	.9
Fungi or non-E. coli Enterobacteriaceae	1.36	0.94-1.95	.1
Unimicrobial bloodstream infection	0.84	0.48-1.47	.5
Polymicrobial bloodstream infection	1.19	0.68-2.07	.5
Source
Intravascular catheter	0.61	0.38-0.96	.03
Respiratory	2.16	1.29-3.62	.004
Genitourinary	0.24	0.09-0.59	.002
Surgical wound infection	2.05	0.92-4.57	.08
Bowel or peritoneum	2.93	1.51-5.69	.002
Intra-abdominal abscess	0.28	0.07-1.18	.08
Biliary	0.79	0.31-2.04	.6
Bone or joint	0.96	0.41-2.29	.9
Skin	1.58	0.75-3.32	.2
Other	0.99	0.44-2.22	1.0
Unknown source	1.22	0.84-1.75	.3
Respiratory, bowel, peritoneum, or unknown	1.97	1.40-2.77	<.001
Hospital service
General medicine	1.14	0.77-1.70	.5
General surgery	0.65	0.36-1.18	.2
Cardiothoracic surgery	1.53	0.51-4.57	.4
Other surgery	0.35	0.11-1.14	.08
Obstetrics and gynecology	0.31	0.04-2.31	.2
Solid organ transplant	1.91	0.90-4.06	.09
Hematopoietic stem cell transplant	1.74	0.65-4.70	.3
Any transplant	1.89	1.02-3.48	.04

CI=confidence interval; ABX=antibiotic; HIV=human immunodeficiency virus; AIDS=acquired immunodeficiency syndrome.

A steadily increasing trend between age and increased risk of attributable death was observed after examining the relationship between the 2 variables (Figure 1). A similar relationship also was seen between increasing number of predisposing comorbid conditions and attributable mortality (Figure 2).

• 
  • View Large Image
  • Download to PowerPoint

• Figure 1. 

  Relationship between age and risk of attributable death due to an adult bloodstream infection.

• 
  • View Large Image
  • Download to PowerPoint

• Figure 2. 

  Relationship between the number of comorbid conditions and risk of attributable death due to an adult bloodstream infection.

Back to Article Outline

Discussion 

Studies over the past 4 decades have documented both recurrent findings and evolving changes in the microbiology, epidemiology, and outcomes of adult bloodstream infections.¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹ Compared with the 2 similarly designed studies that were performed by members of our group, S. aureus and E. coli remain the most frequently isolated bloodstream pathogens.¹, ², ³ Approximately 40% of all positive blood culture episodes represent contamination, mostly due to coagulase-negative staphylococci. Since the 1990s, IV catheters have become the most common identifiable source of bloodstream infection, and the relative proportion appears to be increasing. As a consequence of medical progress and extensive health care exposure, the relative frequency of Enterobacteriaceae other than E. coli and Candida spp. bloodstream infections have been increasing, whereas bacteremias due to S. pneumoniae and viridans group streptococci appear to be decreasing at our institutions. Episodes of obligate anaerobic bacteremia represent about 5% of episodes, compared with 16% and 4% in the 1975 and 1992 studies, respectively.¹, ³ M. avium complex bacteremia also has decreased, likely due to the availability of highly active antiretroviral therapy for HIV infection and efficacy of prophylaxis for patients with CD4 counts below 100/mm³.¹⁵

Using a recently revised definition,¹⁰ only 19% of bloodstream infections were community acquired, and these were associated with a lower unadjusted odds ratio of attributable death. Although molecular strain typing was not performed, nearly one third of community-associated S. aureus bacteremias were methicillin resistant, thus confirming the growing overlap of methicillin resistance between community and health care S. aureus isolates.¹⁶, ¹⁷, ¹⁸ This observation also highlights the importance of empiric methicillin-resistant S. aureus coverage if S. aureus bacteremia is suspected, whether acquisition occurs in the community or health care setting. This is further underscored by the continued observation that inappropriate antimicrobial therapy at ≥2 decision points remained significantly associated with attributable mortality in the bivariable analysis.

In the present study, the overall crude in-hospital CFR was lower compared with the 1975 study (42% [212/500]; P <.001),² but similar to the 1992 study (22% [190/843]; P=.2).³ The overall attributable in-hospital CFR was 12%, which also was lower than 19% (97/500; P<.001) in the 1975² and 17% (148/843; P <.001) in the 1992 study.³ The improvement in outcome may be explained by earlier clinical recognition and initiation of appropriate antimicrobial therapy, improved ability of modern blood culture systems to detect low-grade bacteremia, or other improvements in the quality of medical care. A large US sepsis study based on National Hospital Discharge Survey between 1979 and 2000 also found that crude in-hospital mortality consistently fell from 28% to 18%, but that the population-adjusted annual incidence of sepsis increased from 83 to 240 per 100,000, and deaths due to sepsis increased from 22 to 44 per 100,000.¹⁹ This could signify a growing patient population with significant comorbid conditions that require more frequent hospitalization and, consequently, develop more frequent health care-related complications, including bloodstream infection.

In the current study and in previous studies of bacteremia and fungemia done by our group¹, ² as well as by others,⁴ the absence of fever was associated with increased mortality. The explanation for this intriguing observation is not known. It might be that lack of fever leads to delayed diagnosis because blood cultures are not obtained until later in the course of illness, resulting in delayed therapeutic intervention. However, an equally, if not more, plausible explanation is the effect of temperature on host defenses. Indeed, studies of infection using a variety of vertebrate and mammalian models have demonstrated that infected animals either adjust body temperature upward (endotherms), seek higher ambient temperature (poikilotherms), or have higher survival rates at higher ambient temperatures (poikilotherms held at specific temperatures).¹⁹ Other studies demonstrate that neutrophil migration, T-cell proliferation, and production of interferon and other cytokines are enhanced in the presence of fever.¹⁹ Taken together, the data suggest that fever is an indicator of intact host defenses and that elevated temperatures have had adaptive value for survival in an evolutionary sense.

Contrary to some previous reports, we could not find a significant association between attributable mortality from bloodstream infection and nonwhite race.²⁰, ²¹ We also did not detect any significant increased odds of attributable death with male sex, S. aureus, or P. aeruginosa, as in our earlier studies.², ³ The bivariable analysis, however, did show associated odds ratios of attributable death with organ transplantation, high-dose corticosteroid use, infective endocarditis, and increasing number of predisposing factors that were not found in previous studies.

In the multivariable analysis, increasing age was significantly associated with increased odds ratio for attributable in-hospital death and confirms a large observational longitudinal study using hospital discharge data in the US.²² The presence of hypotension, absence of fever, hospital acquisition, extreme values of white blood cell count, and the presence of malignancy, the acquired immunodeficiency syndrome, or elevated serum creatinine ≥2 also were associated with significant adjusted odds ratio for attributable CFR and were consistent with results from the 1992 study.³ Health care acquisition also has been statistically significantly associated with CFR in other studies.¹⁰, ²³, ²⁴

This study of more than 1100 adult patients with bacteremia and fungemia used methodology similar to 2 previous studies performed by our group and provides insight into the contemporary microbiology, epidemiology, and outcomes of adult bloodstream infections as well as comparisons over 3 decades. Although subjective assessments were made to determine whether a positive blood culture patient isolate represented true bloodstream infection and whether death was attributable to the episode, these studies avoided reliance on hospital discharge diagnosis coding and crude mortality. Moreover, the clinical definitions and variables studied were consistent over the 3 decades of comparative studies. Hospital discharge coding may be biased toward increased diagnosis of sepsis and bloodstream infection in order to improve reimbursement.¹⁹ This study lacked a validated comorbidity index, which might have confounded our results. However, we collected data on eight of the 19 conditions of the modified Charlson score that might help account for a substantial proportion of any confounding.²⁵

In summary, our findings not only delineate the current reality of adult bloodstream infections but also call attention to new challenges. For example, traditional infection control practices aimed at decreasing hospital-acquired infections need to be extended to all health care facilities because health care-associated infections including bacteremia and fungemia occur in diverse settings and not only during inpatient stays. Also, the importance of early diagnosis and intervention with effective antimicrobial therapy will likely be crucial to achieve further decreases in mortality associated with bloodstream infection.

Back to Article Outline

Acknowledgments 

We thank Lauren Lindblad and Shein Chung-Chow of the Duke Clinical Research Institute for their assistance with the multivariable logistic regression model. We appreciate all the efforts of the Duke University Medical Center, Robert Wood Johnson University Hospital, and Durham Veteran's Affairs Medical Center Clinical Microbiology Laboratory staff.

Back to Article Outline

References 

1. Weinstein MP, Reller LB, Murphy JR, Lichtenstein KA. The clinical significance of positive blood cultures: a comprehensive analysis of 500 episodes of bacteremia and fungemia in adults. I. Laboratory and epidemiologic observations. Rev Infect Dis. 1983;5:35–53
   • View In Article
   • MEDLINE
2. Weinstein MP, Murphy JR, Reller LB, Lichtenstein KA. The clinical significance of positive blood cultures: a comprehensive analysis of 500 episodes of bacteremia and fungemia in adults (II. Clinical observations, with special reference to factors influencing prognosis). Rev Infect Dis. 1983;5:54–70
   • View In Article
   • MEDLINE
3. Weinstein MP, Towns ML, Quartey SM, et al. The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults. Clin Infect Dis. 1997;24:584–602
   • View In Article
   • MEDLINE
   • CrossRef
4. Diekema DJ, Beekmann SE, Chapin KC, et al. Epidemiology and outcome of nosocomial and community-onset bloodstream infection. J Clin Microbiol. 2003;41:3655–3660
   • View In Article
   • MEDLINE
   • CrossRef
5. Lark RL, Chenoweth C, Saint S, et al. Four year prospective evaluation of nosocomial bacteremia: epidemiology, microbiology, and patient outcome. Diagn Microbiol Infect Dis. 2000;38:131–140
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (798 KB)
   • CrossRef
6. Lark RL, Saint S, Chenoweth C, et al. Four-year prospective evaluation of community-acquired bacteremia: epidemiology, microbiology, and patient outcome. Diagn Microbiol Infect Dis. 2001;41(1-2):15–22
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (287 KB)
   • CrossRef
7. Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39:309–317
   • View In Article
   • CrossRef
8. Edmond MB, Wallace SE, McClish DK, et al. Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis. 1999;29:239–244
   • View In Article
   • MEDLINE
9. Cockerill FR, Wilson JW, Vetter EA, et al. Optimal testing parameters for blood cultures. Clin Infect Dis. 2004;38:1724–1730
   • View In Article
   • CrossRef
10. Friedman ND, Kaye KS, Stout JE, et al. Health care-associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med. 2002;137:791–797
    • View In Article
11. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633–638
    • View In Article
    • MEDLINE
    • CrossRef
12. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing, 14th informational supplement (M100-S14). Wayne, PA: National Committee for Clinical Laboratory Standards; 2004;
    • View In Article
13. Gilbert DN, Moellering RC, Eliopoulos GM, et al. The Sanford Guide to Antimicrobial Therapy. 34th edition. Sperryville, VA: Antimicrobial Therapy, Inc; 2004;
    • View In Article
14. Mandell GL, Bennett JE, Dolin R. Principles and Practice of Infectious Diseases. 5th edition. Philadelphia: Elsevier; 2000;
    • View In Article
15. Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1–207quiz CE1-4
    • View In Article
16. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med. 2006;355:666–674
    • View In Article
    • CrossRef
17. King MD, Humphrey BJ, Wang YF, et al. Emergence of community-acquired methicillin-resistant Staphylococcus aureus USA 300 clone as the predominant cause of skin and soft-tissue infections. Ann Intern Med. 2006;144:309–317
    • View In Article
18. Seybold U, Kourbatova EV, Johnson JG, et al. Emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections. Clin Infect Dis. 2006;42:647–656
    • View In Article
    • CrossRef
19. Kluger MJ, Kozak W, Conn CA, et al. The adaptive value of fever. In:  Mackowiak P editors. Fever: Basic Mechanisms and Management. Philadelphia: Lippincott-Raven Publishers; 1997;p. 255–266
    • View In Article
20. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348:1546–1554
    • View In Article
    • CrossRef
21. Esper AM, Moss M, Lewis CA, et al. The role of infection and comorbidity: Factors that influence disparities in sepsis. Crit Care Med. 2006;34:2576–2582
    • View In Article
    • MEDLINE
    • CrossRef
22. Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med. 2006;34:15–21
    • View In Article
    • MEDLINE
    • CrossRef
23. Shorr AF, Tabak YP, Killian AD, et al. Healthcare-associated bloodstream infection: a distinct entity? (Insights from a large U.S. database). Crit Care Med. 2006;34:2588–2595
    • View In Article
    • MEDLINE
    • CrossRef
24. Crane SJ, Uslan DZ, Baddour LM. Bloodstream infections in a geriatric cohort: a population-based study. Am J Med. 2007;120:1078–1083
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (104 KB)
    • CrossRef
25. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–383
    • View In Article
    • MEDLINE
    • CrossRef