Blood Cultures Bacteremia JAMA 2012

THE RATIONAL
CLINICAL EXAMINATION
CLINICIANS CORNER
Does This Adult Patient With Suspected

Bacteremia Require Blood Cultures?
Bryan Coburn, MD, PhD
Andrew M. Morris, MD, SM
George Tomlinson, PhD
Allan S. Detsky, MD, PhD
Context Clinicians order blood cultures liberally among patients in whom bacteremia is suspected, though a small proportion of blood cultures yield true-positive results. Ordering blood cultures inappropriately may be both wasteful and harmful.
CLINICAL SCENARIOS
Data Sources and Study Selection A MEDLINE and EMBASE search (inception
to April 2012) yielded 35 studies that met inclusion criteria for evaluating the accuracy of clinical variables for bacteremia in adult immunocompetent patients, representing 4566 bacteremia and 25 946 negative blood culture episodes.
Case 1
A 62-year-old woman presents to the

emergency department with worsening cough, shortness of breath, and fever. Her temperature on presentation
is 38.4C (101.1F). She is alert, oriented, and in no acute distress. Her
blood pressure is 120/72 mm Hg; heart
rate, 86/min; respiratory rate, 16/min;
and oxygen saturation, 94% on room
air. A complete blood count demonstrates mild normocytic anemia but neither leukocytosis nor leukopenia. She
has a left-sided infiltrate on chest radiograph. Does she need blood cultures?
Case 2
A 47-year-old man with a history of hypertension feels unwell the first day after his elective knee meniscectomy, appears flushed, and is unwilling to move
because of joint pain. His heart rate is
118/min; blood pressure, 108/56
mm Hg; and temperature, 37.4C
(99.3F). He has a diffusely tender and
effused knee but has no other abnormal physical examination findings, and
the clinical suspicion is septic arthritis. The initial blood work demonstrates leukocytosis (white blood cell
[WBC] count, 19 000/L) and an elCME available online at
www.jamaarchivescme.com
and questions on p 519.
502
JAMA, August 1, 2012Vol 308, No. 5
Objective To review the accuracy of easily obtained clinical and laboratory findings
to inform the decision to obtain blood cultures in suspected bacteremia.
Data Extraction Data were extracted to determine the prevalence and likelihood
ratios (LRs) of findings for bacteremia.
Data Synthesis The pretest probability of bacteremia varies depending on the clinical context, from low (eg, cellulitis: 2%) to high (eg, septic shock: 69%). Elevated temperatures alone do not accurately predict bacteremia (for 38C [100.3F], LR, 1.9
[95% CI, 1.4-2.4]; for 38.5C [101.2F], LR, 1.4 [95% CI, 1.1-2.0]), nor does isolated leukocytosis (LR, 1.7). The severity of chills graded on an ordinal scale (shaking chills, LR, 4.7; 95% CI, 3.0-7.2) may be more useful. Both the systemic inflammatory response syndrome (SIRS) and a multivariable decision rule with major and
minor criteria are sensitive (but not specific) predictors of bacteremia (SIRS, negative
LR, 0.09 [95% CI, 0.03-0.26]; decision rule, negative LR, 0.08 [95% CI, 0.04-0.17]).
Conclusions Blood cultures should not be ordered for adult patients with isolated
fever or leukocytosis without considering the pretest probability. SIRS and the decision rule may be helpful in identifying patients who do not need blood cultures. These
conclusions do not apply to immunocompromised patients or when endocarditis is
suspected.
www.jama.com
JAMA. 2012;308(5):502-511
evated creatinine level (2.1 mg/dL [186

mol/L]). Does he need blood cultures?
WHY IS THIS QUESTION
IMPORTANT?
Approximately 200 000 episodes of bacteremia occur in the United States each
year, with an incidence of about 10 per
1000 hospital admissions.1-3 Bacterial
bloodstream infections (BSIs) are associated with mortality of 14% to
37%.3-6 Mortality is especially high in
critically ill patients admitted to intensive care units, where excess mortality
of 35% is attributable to BSI.7,8 Bloodstream infections include infective en-
docarditis, central venous catheter

associated BSI, primary bacteremia, and
those secondary to focal infections such
as pneumonia, abscesses, osteomyelitis, or urinary tract infections. InfecAuthor Affiliations: Department of Medicine (Drs Coburn, Morris, Tomlinson, and Detsky), Division of Infectious Diseases (Drs Coburn and Morris), and Institute of Health Policy Management and Evaluation (Dr
Detsky), University of Toronto, and Department of
Medicine, Mount Sinai Hospital and University Health
Network (Drs Morris, Tomlinson, and Detsky), Toronto, Ontario, Canada.
Corresponding Author: Allan S. Detsky, MD, PhD,
Mount Sinai Hospital, 600 University Ave, Ste 429,Toronto, Ontario M5G 1X5, Canada (adetsky@mtsinai
.on.ca).
The Rational Clinical Examination Section Editors: David L. Simel, MD, MHS, Durham Veterans Affairs Medical Center and Duke University Medical Center, Durham, NC; Drummond Rennie, MD, Deputy Editor.
2012 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Albert Einstein College of Medicine User on 11/28/2012
BLOOD CULTURES FOR BACTEREMIA
tive endocarditis accounts for 3% to 8%

of cases.1-3
Published guidelines do not clearly
state when blood cultures should be
drawn. Blood cultures are commonly obtained when patients have fever, chills,
leukocytosis, focal infections, indications of sepsis, or suspected endocarditis or prior to starting parenteral antibiotics in emergency or medical patients.
Because of the high mortality associated with bacteremia, the dangers of undertreating some infections, or concern
about using inappropriate antibiotics,
physicians tend to order blood cultures
liberally. As a result, only 4% to 7% of
blood cultures drawn are positive.9,10 The
sensitivities of blood cultures drawn in
tandem or triplet for bacteremia are 90%
and 98%, respectively.11 However, obtaining cultures after antibiotic administration diminishes their sensitivity and
clinical utility.11
The term bacteremia refers to any
true-positive blood culture result, which
reflects bacterial presence in the bloodstream. As many as half of the cultures that are positive represent contaminantsorganisms inoculated from
the skin into culture bottles at the time
of sample collection. Such results are
false-positive blood cultures that can
lead to unnecessary investigations and
treatments. In one analysis, falsepositive blood cultures resulted in a
50% increase in total charges and a 64%
increase in median length of stay compared with negative blood cultures.12
Molecular detection techniques such as
polymerase chain reaction for bacterial and fungal DNA are being developed and validated to lower the number of false-negative and false-positive
blood cultures but are not in widespread clinical use.13
Herein we seek to answer the following questions from the perspective of an
emergency department or hospital-based
physician evaluating an immunocompetent patient for possible infection: (1) Are
fever or leukocytosis alone indicators of
bacteremia?(2)Aretherehistorical,physical examination, and laboratory findings
available at the time blood cultures are
drawn that allow clinicians to distinguish
patients who have bacteremia from those

who do not? (3) Do these clinical findings
help inform the decision to obtain blood
cultures?
Pathophysiology
The invasion of the blood by pathogens most often occurs as the result of
seeding of the blood from a focal source
of infection but also occurs without a
clearly identifiable cause.3 Focal infections that commonly result in bacteremia include respiratory, urinary tract,
abdominal, and central venous catheterassociated infections. Bacteremia
can induce an inflammatory response
that produces the symptoms of bloodstream infection. Mortality associated
with bacteremia increases with the severity of sepsis, although it also varies
with underlying illness and the source
of initial infection.3,14 Early appropriate antibiotic administration is associated with decreased sepsis-associated
mortality, suggesting that microbial
growth and activity are linked to disease progression.15
Examination for Signs
of Bloodstream Infection
Patient History. A number of historical clues commonly prompt the suspicion of bacteremia, including fever,
chills, and a documented or suspected
infection. History taking should include an assessment of symptoms to
suggest a specific focus of infection including gastrointestinal, respiratory, abdominal, genitourinary, skin, and soft
tissue symptoms. The presence of significant preexisting comorbidity, immunosuppression (eg, malignancy,
steroid use, neutropenia), or recent invasive instrumentation, indwelling
catheters, vascular devices, or intravenous line use should be elicited.
Physical Examination. Physical examination should begin with an assessment of vital signs. Temperature, heart
rate, and respiratory rate should be measured and the presence of rigors should
be noted. Cardiovascular, pulmonary,
abdominal, skin, and mental status examinations are always indicated. All
catheters, intravenous devices, or drain-
age tubes should be visualized and the

skin around percutaneous devices
should be palpated for warmth, erythema, or purulent drainage. The presence of embolic phenomena or a new
regurgitant murmur are potential indicators of infective endocarditis.
Laboratory Evaluation. A complete
blood count is usually obtained to look
for increased or decreased WBC counts
or the presence of an elevated neutrophil count. Toxic granulation or vacuolization of leukocytes or the presence of band forms of neutrophils may
be more specific.16,17 Low platelet count
may also be an indicator of disseminated intravascular coagulation and,
therefore, severe sepsis.14,18 Base deficit and elevated serum lactate levels are
also indicators of sepsis. Evidence of
acute kidney injury may be the earliest marker of end organ dysfunction.
Additional investigations should be
guided by suspected infectious foci and
may include urinalysis (urinary tract infection), chest radiograph (pneumonia), lumbar puncture (meningitis), and
abdominal imaging (eg, appendicitis,
diverticulitis, or cholecystitis).
METHODS
Literature Search and Selection
To find studies of the accuracy of clinical findings for predicting bacteremia in

emergency department or hospitalized
adult patients, we searched EMBASE and
MEDLINE (inception to April 2012) to
identify relevant literature using the
search string (bacteremia OR bloodstream infection) AND (predict OR prediction). The references of relevant publications were reviewed for additional
studies. English-language primary articles, book chapters, abstracts, and reviews were included. Published studies
in which epidemiologic data were presented but not stratified by group (positive or negative blood cultures) were excluded from analysis. One article
contained data that allowed calculation
of sensitivity but not specificity and was
not included in the formal analysis (data
reported herein).19 Studies in which raw
data were not reported or could not be
constructed from reported data were ex-
503
cluded. One retrospective cohort study

restricted to patients with febrile neutropenia was excluded.20
To establish estimates for the pretest probability of bacteremia in specific clinical settings, we searched
EMBASE and MEDLINE (from inception to January 2012) using bacteremia OR bloodstream infection and
terms referring to the relevant clinical
condition (eg, cellulitis or pyelonephritis). We also reviewed the reference sections of relevant publications (including narrative reviews, systematic
reviews, and society guidelines). Bacteremia rates were included if they were
based on consecutive adult patients
with the defined clinical syndrome and
more than 60% of patients in the study
underwent blood cultures. The intent
was to provide examples of pretest
probabilities rather than a metaanalytic summary measure for all possible conditions that might be associated with bacteremia.
Data Analysis
and Statistical Methods
Published raw data were used to calculate likelihood ratios (LRs) for the
specific clinical variables.21 If 3 studies examined the same clinical variable, we calculated summary LRs and
95% confidence intervals (CIs) using
the DerSimonian and Laird randomeffects approach. 22 Estimated variances of LRs were computed using the
usual methods for ratios of proportions, with their reciprocals used as
study weights. In studies with a zero cell
count, the value 0.5 was added to each
cell count to permit use of this variance estimator. The I2 heterogeneity statistic was calculated for findings reported in multiple studies and a test of
heterogeneity was based on the Cochran Q statistic.23 All univariate analyses were performed using R, version
2.13.0 (R-Project).
Study quality was assessed using a
previously developed scoring system24 as follows:
Level 1: a prospective study of at
least 100 consecutive, unselected patients
504
Level 2: a study of fewer than 100

patients meeting the same criteria as
level 1
Level 3: a retrospective study
Level 4: any study of patients selected for the presence of bacteremia
RESULTS
such as focal infection, sepsis,

specific infections, and burns
(group 2)27,30-32,34,41-49,54; and studies
of any patient in whom blood cultures were drawn, leaving the decision to draw cultures to the discretion of the ordering physician
(group 3).9,25,26,29,33,50-53,57,58
Search Results for Studies of Accuracy
We retained 35 studies assessing

clinical variables to predict bacteremia (eFigure; available at http:
//www.jama.com)9,25-58 that included a
total of 4566 bacteremia and 25 946
control episodes in adult patients. All
included studies (TABLE 1) used criteria to designate cultured organisms as
a contaminant. Generally, this was defined as an organism commonly considered a contaminant, grown only in
1 culture and in the absence of other
evidence of infection with that organism. No studies counted contaminants as positive culture results.
One study of burn patients 34 reported data suitable for analysis for a
single variable only (temperature
40.0C [103.9F]). One study was
in patients with nosocomial bacteremia admitted to a hematology/
oncology service for a known malignancy or hematologic disorder.54 This
study contributed 2 clinical variables
(presence of a central venous catheter
and prior antibiotic use) to the assessment. One retrospective study of patients with febrile neutropenia was
excluded.20 In the remaining studies,
only a small minority of cases had immunocompromising conditions or
immunocompromised patients were excluded completely. There were no other
studies limited to patients with human
immunodeficiency virus (HIV), malignancy, or neutropenia or those taking
immunosuppressive medications. Very
few patients in the included studies had
infective endocarditis.
Studies used to estimate the LRs
for clinical variables were of 3 primary types: studies that predicted
bacteremia in patients with fever
(group 1) 28,35-40,55 ; studies of bacteremia in patients with other specified indications for blood culture,
Pretest Probability of Bacteremia
In 2 studies of consecutive blood cultures, the probabilities of truepositive blood cultures were 4.1% of
51 264 cultures (2.5% contamination
rate; true-positive:contamination ratio, 1.6:1)10 and 7% of 1516 cultures
(8% contamination rate; true-positive:
contamination ratio, 0.88:1).9
The probability of bacteremia in patients with specific clinical conditions
for which physicians often obtain blood
cultures fell into 3 ranges (TABLE 2).
Patients in whom the probability was
low (14%) included ambulatory outpatients, patients with cellulitis, and patients admitted to the hospital with
community-acquired pneumonia or
community-acquired fever.38,44,59,60 The
probability of bacteremia was intermediate (19%-25%) in those with pyelonephritis.49,61 A high pretest probability of bacteremia (38%-69%) was
reported in patients with severe sepsis, septic shock, or acute bacterial
meningitis.14,32,62
A prospective study of hospitalized
patients who had blood cultures for fever had a bacteremia probability of
12%40; however, patients were identified and enrolled only after blood cultures had been drawn (ie, they were not
consecutive inpatients with fever); thus,
we believe the results overestimate the
true probability of bacteremia in hospitalized febrile patients.
Accuracy of Fever and Chills
for Diagnosing Bacteremia
As a symptom, patient report of subjective fever was an inaccurate predictor of

bacteremia, with the range of the positive and negative LRs approaching 1.0 in
4 studies (TABLE 3).27,43,49,53 As a sign,
varying temperature cutoffs were evaluated in 6231 patients with 1107 epi-
sodes of bacteremia.9,25-27,29,31,34,44,45,47,49,58
Patients with measured temperatures exceeding the commonly used threshold
of 38C or higher (100.3F) had an

increased likelihood of bacteremia (LR,
1.9; 95% CI, 1.4-2.4), while those with
temperature lower than 38C decreased the likelihood (LR, 0.54; 95%
CI, 0.38-0.78).47 Only thresholds of
Table 1. Study Characteristics a

Study
No. With
Quality
Bacteremia/
Level Prospective
Total No.
Source
Group 1: studies of febrile patients
Mellors et al,35 1987
Study Population
Study Limitations
Yes
21/135
Patients with unexplained fever 37.9C
Patients with evidence of source of fever

were excluded.
Leibovici et al,28 1991
Yes
88/501 b
Consecutively admitted febrile patients

(38C oral/38.2C rectal)
Limited to patients with fever. Score

performed poorly in subsequent trials.
Van Dissel et al,36 1998
Yes
85/464
Consecutive ED patients with fever

(fever not defined in report)
ED patients only
Groeneveld et al,37 2001
Yes
57/300
Patients admitted to hospital with fever

(38C axillary/38.3C rectal)
Febrile patients only; high proportion of

patients had SIRS.
Chirouze et al,38 2002
Yes
22/165
Consecutively admitted patients with

fever 38C
Study of uncommon blood tests; minimal

reported data included
Tokuda et al, 2005
Yes
40/526
Consecutively admitted patients with

fever 38C
Yoshida et al,55 2005
No
67/306
Retrospectively identified inpatients with

fever (38.5C) in whom blood
cultures were drawn
Retrospective study; raw data were

reported for a single variable only.
Stryjewski et al,40 2009
Yes
181/1015
Patients with health careassociated

fever (38C) in whom blood
cultures were drawn
Limited to patients with health

careassociated fever, enrolled after
blood cultures ordered
Group 2: studies of patients with

specific indications for blood culture
Fontanarosa et al,27 1992
No
79/215
Infection (not otherwise specified)
Limited to patients older than 65 y; types of

infection not specified
Infection (not otherwise specified) in

general medical ward inpatients
Febrile neutropenia patients excluded;

indication for blood culture not further
delineated
General medicine inpatients with clinical

evidence of infection
Validation of scoring systems of Bates et al9

and Leibovici et al,28 with significant
deterioration of findings of earlier
studies
39
Jones and Lowes, 1996
Yes
75/334 c
Yehezkelli et al,31 1996
Yes
111/675 d
Bates et al,32 1997
Yes
436/1342 b Emergency, ward, and ICU patients

with sepsis
30
Smith et al,43 1997
No
23/64
Perl et al,44 1999
No
9/74
Crabtree et al,45 2001
Yes
101/567
Laupland et al,46 2004
Yes
Peralta et al,47 2006
No
Chen et al,48 2006
No
Murray et al,34 2007
Bahagon et al,56 2007
Limited to patients with sepsis defined by

authors, which differs from generally
used definition
Women aged 16-44 y with pyelonephritis
Small sample of patients with pyelonephritis
Adult patients with cellulitis
Small sample of patients with cellulitis
Surgical patients with infection (lung,

peritoneum, bloodstream, line,
urinary tract, and wound infections)
Surgical patients only
99/1587
ICU patients with SIRS
Prospective database review
57/308
Adult patients with cellulitis
Retrospective study
33/158
Complicated pyelonephritis
Retrospective study of patients with

pyelonephritis and functional or
structural urinary tract abnormalities
No
73/223
Burn patients
Retrospective chart review of patients

admitted to a burn unit
No
53/350
Admitted patients with urinary tract

infection
Retrospective study; decision to order

blood cultures was left to discretion of
ordering physician.
Cham et al,41 2009
Yes
89/1407
Consecutive ED patients with community- Patients with community-acquired

acquired pneumonia
pneumonia only, data for limited
variables reported
Falguera et al,42 2009
No
191/1386
All patients with community-acquired

pneumonia admitted over a 10-y
period
Admitted patients with community acquired

pneumonia only; retrospective
database review
Apostolopoulou et al,54 2010
No
17/102
Patients with nosocomial bloodstream

infection admitted to hematology/
oncology unit for 48 h prior to
onset of bacteremia
Nosocomial bacteremia only; limited to

patients with malignancy/hematologic
disease; limited data reported were
suitable for this analysis. Case definition
included the presence of fever, chills
or hypotension.
Kim et al,49 2011
No
97/494
Women with pyelonephritis defined as

(1) fever (38.0C), (2) pyuria, and
(3) flank tenderness
Inclusion criteria included fever; limited to

patients with pyelonephritis.
(continued)
505
Table 1. Study Characteristics a (continued)

Source
Group 3: studies of patients with other
indications for blood culture
Bates et al,9 1990
Study
No. With
Quality
Bacteremia/
Level Prospective
Total No.
Study Population
Study Limitations
115/1516 b 48% Suspected focal infection, 29%

fever, 5% suspected IE, 18%
other/unknown indication for blood
culture
Yes
No prespecified indication for blood

culture; score performed poorly in
subsequent trials.
Pfitzenmeyer et al,29 1995
Yes
46/558 e
Suspected bacteremia (not otherwise

specified) in older patients

culture; limited to patients of older age
(61 y for women, 64 y for men)
Jaimes et al,26 2004
Yes
89/411
Patients hospitalized 48 h on any

inpatient service, excluding
transplant patients, pregnant
patients, and those who died
24 h after culture; 64% suspected
sepsis or bacteremia, 31%
pneumonia, 5% other indication
for blood culture

culture; exclusion of patients who died;
cumbersome calculation to predict
bacteremia; contaminants excluded
only post hoc
Wyllie et al,51 2004
Yes
530/7182
Patients admitted from the community

as emergencies to general medical
or infectious diseases services
No prespecified indication for blood culture
Nakamura et al,25 2006
No
144/739
All hospitalized patients with blood

cultures drawn, not otherwise
specified
Shapiro et al,33 2008
Yes
305/3730 b ED or newly admitted patients with

focal infection (67%), fever (13%),
suspected IE (2%), or other/unknown
(18%) indication for blood culture
de Jager et al,50 2010
No
92/184
Kaye et al,52 2011
No
Wildi et al,57 2011
Su et al,58 2011
Roque et al,53 2012
Adult patients admitted to ED with

suspected bacteremia
Case-control study; no prespecified criteria

for blood culture; limited to patients
with suspected bacteremia
830/1660
Patients aged 65 y with nosocomial

bacteremia
Case-control study; case definition

required the presence of SIRS; limited
to older patients.
Yes
38/152
ED patients with hospital stays 48 h
Limited to patients discharged from the ED

or within 48 h of admission; data
missing in 8% of patients (for results
included in this analysis)
Yes
84/558
ED patients with 2 sets of blood

cultures drawn from different sites
Composite score used biochemical tests

not routinely available at the time
decision regarding need for blood
culture is made.
No
189/1124
Consecutive adult patients admitted

to hospital in whom blood
cultures were drawn
Abbreviations: ED, emergency department; ICU, intensive care unit; IE, infective endocarditis; SIRS, sudden inflammatory response syndrome.
a Group 1 studies were of patients with fever; group 2 studies were of patients with other specified indications for blood culture, such as focal infection, sepsis, specific infections, and
burns; group 3 studies were of any patients in whom blood cultures were drawn, leaving the decision to draw cultures to the discretion of the ordering physician. See Methods section
of text for description of study quality levels.
b Sum of derivation and validation cohorts.
c Sum of 270 unselected episodes and 64 bacteremic episodes.
d Sum of academic and community hospital admissions.
e Sum of community- and hospital-acquired episodes.
Table 2. Probabilities of Bacteremia in Specific Clinical Conditions From Published Reports

Patient Population
Low risk
Cellulitis
Source
No. of Patients
Perl et al,44 1999
553
Pretest Probability
0.02
Ambulatory outpatients
Laupland et al,59 2005
3102
0.02
Community-acquired pneumonia
Metersky et al,60 2004
13 043
0.07
Community-onset fever requiring hospitalization
Chirouze et al,38 2002
165
0.13
Kim et al,49 2011
735
0.19
Velasco et al,61 2003
583
0.25
Intermediate risk
Pyelonephritis
High risk
Severe sepsis
Bates et al,32 1997
1342
0.38
Acute bacterial meningitis
Proulx et al,62 2005
118
0.53
Septic shock
Rangel-Frausto et al,14 1995
194
0.69
506
38.3C or higher (100.9F) (summary LR, 1.2; 95% CI, 1.0-1.4)

or 38.5C or higher (101.2F)
(summary LR, 1.4; 95% CI, 1.1-2.0)
were assessed in more than 1 study
(Table 3).9,25,27,29,31,44,45,58
Despite heterogeneity, chills in febrile patients (Table 3) appears more
useful for identifying bacteremia (summary positive LR, 2.2 [95% CI, 1.43.3); summary negative LR, 0.56 [95%
CI, 0.41-0.76])28,36,39,40,49 compared with
the accuracy of chills evaluated independent of the presence of fever. In 1
study, characterizing the intensity of
chills on an ordinal scale improves the
diagnostic accuracy. Shaking chills, defined as feeling extremely cold with
rigor and generalized bodily shaking
even under a thick blanket has an LR
of 4.7 (95% CI, 3.0-7.2), while the complete absence of chills has an LR of 0.24
(95% CI, 0.11-0.55).39
Accuracy of Patient History, Physical
Examination, and Laboratory
Evaluation for Diagnosing Bacteremia
(Single Variables)
Patient History. Very few historical features have been evaluated in more than
1 study (eTable 3). Prior antibiotic
use has an LR of 0.63 (95% CI,
0.41-0.98),27,41,42,47,53,54 though the studies do not allow an assessment of
whether these data represent falsenegative blood culture results.
Physical Examination. The presence of tachycardia alone (heart
rate 100/min but defined as 90/
min, 110/min, or 120/min in
some studies) was not helpful
(summary positive LR, 1.4 [95% CI,
1.2-1.8]; summary negative LR, 0.67

[95% CI, 0.59-0.77]) (eTable 4).25-27,49,58
The presence of hypotension or shock
(systolic blood pressure 90-100 mm
Hg or the need for pressors to maintain blood pressure) approximately
doubled the likelihood of bacteremia
(eTable 4).9,25,27,40,46,48,49,58
Laboratory Evaluation. Of common laboratory tests associated with infection, WBC counts and the cellular
differential are the most broadly used
(eTable 5). At the cutoffs studied, WBC
thresholds of 10 000/L to 15 000/L,
no result produced an LR higher than
1.7, while the absence of an elevated
Table 3. Fever and Chills as Indicators of Bacteremia a

Likelihood Ratio (95% CI) b
Symptoms/Signs
Chills (febrile patients only) 28,36,39,40,49
I2
P value
Chills (all patients)9,26,27,31,32,42-44,47,56,58
I2
P value
Subjective fever27,43,49,53
I2
P value
Severity of chills39 c
Shaking
Moderate
Mild
None
Temperature
40.0C34
39.0C49
38.5C25,29,44,45
I2
P value
38.3C9,27,31,58
I2
P value
38.0C47
37.8C26
Positive
2.2 (1.4-3.3)
97%
.001
1.6 (1.3-1.8)
62%
.002
1.0 (0.96-1.1)
0%
.48
Negative
0.56 (0.41-0.76)
82%
.001
0.84 (0.77-0.90)
56%
.009
0.95 (0.88-1.0)
0%
.76
4.7 (3.0-7.2)
1.7 (1.0-2.8)
0.61 (0.26-1.4)
0.24 (0.11-0.55)
0.3 (0.13-1.0)
1.1 (0.79-1.6)
1.4 (1.1-2.0)
92%
.001
1.2 (1.0-1.4)
61%
.04
1.9 (1.4-2.4)
1.5 (1.2-1.9)
1.1 (1.0-1.2)
0.95 (0.83-1.1)
0.50 (0.30-0.82)
74%
.01
0.80 (0.61-1.0)
75%
.003
0.54 (0.38-0.78)
0.65 (0.50-0.86)
a See eTable 1 and eTable 2 for results of individual studies.

b Likelihood ratios from single studies represent point estimates and 95% CI; results from 3 or more studies are random-
effects summary measures.
c Chills were ordinalized based on patient descriptions and are thus categorized as a symptom. Values represent
the serial likelihood ratio for a result at each level. Categories were defined as mild chills (feeling cold with equivalent of the need for an outer jacket); moderate chills (feeling very cold with equivalent of the need for a thick
blanket); and shaking chills (feeling extremely cold with rigor and generalized bodily shaking even under a
thick blanket).
Table 4. Multivariable Scores and Their Performance in Predicting or Excluding Bacteremia

Performance (95% CI)
Index and Source
Presence of SIRS
Jones and Lowes,30 1996
Wildi et al,57 2011 a
Clinical prediction rule (Shapiro et al, 200633)
Summary statistic
Derivation set
Validation set
Sensitivity
Specificity
Positive LR
Negative LR
0.96 (0.74-1.00)
0.80 (0.64-0.90)
0.47 (0.41-0.53)
0.27 (0.19-0.37)
1.8 (1.6-2.0)
1.1 (0.89-1.4)
0.09 (0.03-0.26)
0.75 (0.35-1.6)
0.98 (0.96-0.99)
0.97 (0.94-1.00)
0.29 (0.27-0.31)
0.29 (0.27-0.31)
1.3 (1.2-1.4)
1.4 (1.3-1.4)
1.4 (1.3-1.4)
0.08 (0.04-0.17)
0.07 (0.03-0.18)
0.10 (0.03-0.32)
Abbreviations: LR, likelihood ratio; SIRS, systemic inflammatory response syndrome.

a The study quality is limited because SIRS criteria were not clearly defined and data were missing.
507
Box. Clinical Prediction Rules

for Bloodstream Infection
Jones and Lowes30
Systemic inflammatory response
syndrome (SIRS) present with at
least 2 of the following:
Temperature 36C or 38C
Heart rate 90/min
Respiratory rate 22/min OR
pCO2 32 mm Hg on arterial
blood gas
White blood cell count
4000/L or 12 000/L OR
10% immature neutrophils
(band forms)
Shapiro et al33
Blood culture indicated if 1 major
OR 2 minor of the following:
Major
Suspicion of endocarditis
Temperature 39.4C
Indwelling catheter
Minor
Temperature 38.3C-39.3C
Age 65 years
Chills
Vomiting
Systolic blood pressure 90
mm Hg
White blood cell count
18 000/L
Creatinine 2 mg/dL
( 177 mol/L)
WBC count at the varying thresholds

did not have an LR lower than
0.60. 25-27,45,50 The presence of increased immature (band) forms of neutrophils conveyed similar information
as total WBC counts.9,27,32,56-58 Three
studies reported results for thrombocytopenia: platelet counts fewer than
150 000/L increased the likelihood of
bacteremia (positive LR, 2.0-2.1) but
the negative LR was 0.68 to 0.9149,58;
platelet counts fewer than 25 000/L
had an LR of 1.6 (95% CI, 0.9-2.7),
while platelet counts of 25 000/L or
more had an LR of 0.96 (95% CI,
0.90-1.0).25
Three studies reported that lymphopenia (lymphocyte count
508
500/L or 1000/L)50,51,58 and a

neutrophil-lymphocyte ratio greater
than 10 were correlated with bacteremia.50,51 The presence of lymphopenia or a neutrophil-lymphocyte ratio
greater than 10 increased the likelihood of bacteremia (positive LRs,
1.6-2.3 for lymphocytes 1000/L or
ratio 10 and 3.7 for lymphocytes
500/L [95% CI, 2.6-5.1]). The
absence of these factors decreased
the likelihood of bacteremia (negative LRs, 0.45-0.51 for lymphocytes
1000/L and 0.36-0.76 for ratio
10) (eTable 5).50,51
Accuracy of Clinical Impression
for Diagnosing Bacteremia
Pfitzenmeyer et al 2 9 assessed the

accuracy of the clinicians impression
of the likelihood of bacteremia in a
study population with positive blood
cultures in 8.2% (46/558) of cases.
The clinicians categorized the probability of bacteremia as high (50%),
intermediate (10%-49%), or low
(10%). The overall clinical impression of high probability increased the
likelihood of bacteremia, with an LR
of 2.3 (95% CI, 1.4-3.6); intermediate probability had an LR of 0.49
(95% CI, 0.27-0.89); and low probability impression decreased the likelihood, with an LR of 0.48 (95% CI,
0.24-0.97).
Value of Multivariable Scores
for Prediction of
Bloodstream Infections
Because individual symptoms and signs

do not substantially alter the likelihood of bacteremia, we looked for data
on explicit combinations of findings
(TABLE 4). The systemic inflammatory response syndrome (SIRS), which
was initially developed to categorize patients with sepsis-like signs and symptoms, and a clinical decision rule developed by Shapiro et al33 were both
studied to help distinguish patients with
bacteremia from those without (BOX).
Jones and Lowes30 tested SIRS as a
predictor of bacteremia. Among 270
consecutive blood culture episodes
from general medical ward patients and
64 sequential cases of bacteremia, the

presence of SIRS increased the likelihood of bacteremia (positive LR, 1.8;
95% CI, 1.6-2.0), while its absence (2
criteria present) appreciably lowered
the likelihood of bacteremia, with a
negative LR of 0.09 (95% CI, 0.030.26). Two other studies reported data
suitable for calculation of the sensitivity of SIRS criteria for bacteremia. In a
prospective study of patients admitted
to intensive care units, 108 patients had
BSIs, of which 100 fulfilled at least 2
SIRS criteria (sensitivity, 0.93; 95% CI,
0.86-0.96 derived from reported data).46
In a study of patients admitted to the
hospital for febrile illness, SIRS (fever
plus 1 additional SIRS criterion) was
present in 51 of 53 cases of bacteremia
(sensitivity, 0.96; 95% CI, 0.87-0.99).19
One additional study assessed SIRS
in patients who were discharged from
the emergency department or had admissions of less than 48 hours duration,57 providing estimates of a positive LR of 1.1 (95% CI, 0.89-1.4) and
a negative LR of 0.75 (95% CI, 0.351.6). This study had significant limitations. The SIRS criteria were not explicitly defined in the study and were
not measured in 20% of the patient
population. Forty-nine percent of patients with eligible positive cultures
were excluded for lack of data, because they were transferred from or to
another hospital, or because they died
within 48 hours of admission.
Shapiro et al33 developed and validated a clinical decision rule in 3901
patients who had blood cultures drawn
in an emergency department or within
3 hours of admission to the hospital.
The decision rule was highly sensitive
(sensitivity, 0.97 [95% CI, 0.94-1.0];
negative LR, 0.08 [95% CI, 0.040.17]), implying that when no major
and fewer than 2 minor criteria are present, the risk of bacteremia is very low
(0.9% in the validation cohort). Similar to SIRS, this decision rule was not
very specific (specificity, 0.29 [95% CI,
0.26-0.31]; positive LR, 1.4 [95% CI
1.3-1.4]).
Of the remaining studies in which prediction rules were developed,25,29,32,49,58
none provided a score with superior sensitivity to SIRS or the rule developed by
Shapiro et al33 (eTable 6). All of the remaining scoring systems have significant practical limitations, such as restriction to a specific patient population such
as elderly patients or those with urinary
tract infections,29,49 the need for complex calculations or use of rare or difficult-to-obtain variables,25,58 or poor performance when reevaluated in external
studies.32 The details of these systems are
reported in eTable 6.
LIMITATIONS
There are significant limitations to the
data included in our analysis. The probabilities of bacteremia in the studies
used to estimate the predictive accuracy of clinical variables was generally
higher (6%-37%) than the truepositive probability for series of consecutive blood cultures (4.1%-7.3%),9,10
likely because patients were selected on
the basis of signs or symptoms that suggested bacteremia. This selection process possibly resulted in biased estimates of the LRs for the clinical variable
studied. The indications for blood cultures were heterogeneous and not reported in all studies. Infective endocarditis cases represented a small
proportion of the total, and many manifestations of infective endocarditis were
not assessed (eg, the presence of a new
regurgitant murmur or persistent fever in a patient with a prosthetic heart
valve). We therefore believe that these
data do not apply to patients with suspected infective endocarditis.
Notably, there were no studies of
large numbers of patients with common immunocompromising conditions such as HIV/AIDS, malignancy, or
immunosuppressive drug use. Therefore, we believe that the data reported
herein regarding the accuracy of clinical variables for predicting bacteremia
apply only to immunocompetent patients. Immunocompromised patients
are at increased risk of bacteremic infection and are less likely to manifest
signs, symptoms, and laboratory abnormalities associated with the inflammatory response to infection.
Some experts might advocate a more

global and less quantitative approach
that starts with the presence or absence of fever, then factors in a large
amount of clinical information such as
the natural history of fever patterns associated with specific infections,
whether the patient is taking antibiotics, and the presence of some of the risk
factors evaluated in this review (eg,
central lines, underlying disease states).
A quantitative evaluation of this approach would require large patient
samples for each of these specific clinical scenarios to produce valid results.
As well, this approach would lack generalizability beyond the narrow constraints of the specific patient populations. Experienced infectious diseases
physicians also form clinical impressions using this approach, especially in
patients referred after initial evaluation. However, a large number of physicians who are faced with the decision to order blood cultures are less
experienced and do so earlier in the
course of the illness.
For some findings, there was statistically significant heterogeneity between LRs. The LR summary estimates
and confidence intervals that we derived are from random-effects models
that incorporate between-study heterogeneity. The interpretation of the results is not likely affected by the heterogeneity because the majority of
individual LRs fell in the range of limited clinical usefulness.
SIRS and the Shapiro criteria are both
sensitive indicators, identifying patients unlikely to have bacteremia.30,33
Published estimates suggest that both
are better negative predictors of bacteremia than the overall clinical impression (negative LR, 0.48; 95% CI,
0.24-0.97).29,30 However, the sample
sizes in the studies of the SIRS criteria
were small, and further empirical study
is needed to corroborate this finding.
The Shapiro decision rule has been
studied in only 1 setting and therefore
also requires prospective validation. Finally, as noted above, the accuracy of
clinical impression almost certainly varies with experience and expertise.
SCENARIO RESOLUTION
Case 1
The patient in scenario 1, an emergency department patient with pneumonia, fulfills only 1 SIRS criterion
fever, in the context of a focal infection
with low probability of bacteremia
(community-acquired pneumonia,
prior probability of bacteremia approximately 7%).60 The absence of SIRS and
Shapiro criteria decreases the likelihood of bacteremia substantially (negative LRs, 0.09 and 0.08, respectively).
Her estimated probability of bacteremia is low (0.67%) and likely much
lower than the probability of a falsepositive result; therefore, blood cultures should not be ordered for this
patient.
Case 2
In case 2, the presence of tachycardia,

knee effusion and pain, and elevated
creatinine level in an otherwise healthy
person warrants further investigation,
especially for infectious postoperative
complications. Although he is not febrile, this patient fulfills 2 SIRS criteria (tachycardia and leukocytosis) and
has a suspected infection and evidence of organ dysfunction (criteria for
severe sepsis). In addition, he fulfills 2
minor Shapiro criteria (leukocytosis and
elevated creatinine level). His pretest
probability of bacteremia is approximately 38% (for severe sepsis32) and the
presence of SIRS and Shapiro criteria
increases the probability of bacteremia. Despite the absence of fever,
blood cultures should be included in his
diagnostic evaluation.
CLINICAL BOTTOM LINE
Although the probability of bacteremia is considerable in many specific
clinical settings, the overall low probability of true-positive blood cultures
in series of consecutive patients (4.1%7.3%) suggests that many blood cultures for adult patients are ordered
when the risk of bacteremia is low. This
exposes patients to the potential harms
of a false-positive result (ie, growing a
contaminant that does not reflect true
bacteremia), which include more tests
509
(additional blood cultures, echocardiograms, etc), unnecessary antibiotic administration with possible adverse reactions, missed alternative (infectious
or noninfectious) diagnoses, and increased length of stay in the hospital.
We believe the current literature supports the following conclusions for
adults:
1. The pretest probability of bacteremia varies considerably and is determined largely by the clinical context
(including the presence or absence of
an identifiable focus of infection).
2. Blood cultures should not be ordered simply because isolated fever or
leukocytosis is present in patients for
whom the pretest probability of bacteremia is low.
3. The SIRS criteria and Shapiro decision rule show promise in further defining low-risk patients but require prospective validation.
4. The existing data do not allow
generalization of these conclusions to
immunocompromised patients or those
under consideration for endocarditis.
Author Contributions: Dr Coburn had full access to
all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis.
Study concept and design: Coburn, Detsky.
Acquisition of data: Coburn.
Analysis and interpretation of data: Coburn, Morris,
Tomlinson, Detsky.
Drafting of the manuscript: Coburn.
Critical revision of the manuscript for important intellectual content: Coburn, Morris, Tomlinson, Detsky.
Statistical analysis: Tomlinson.
Obtained funding: Coburn, Morris, Tomlinson, Detsky.
Administrative, technical, or material support: Coburn,
Morris, Tomlinson, Detsky.
Study supervision: Detsky.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure
of Potential Conflict of Interest. Dr Morris reports that
he receives salary support from Mount Sinai Hospital
and University Health Network for his work in antimicrobial stewardship. No other disclosures were
reported.
Online-Only Material: eTables 1 through 6 and the
eFigure are available at http://www.jama.com.
Additional Contributions: We thank Eileen K. Maziarz, MD, Vance Fowler, MD, and Charles Gerardo, MD,
Duke University, for advice on earlier versions of the
manuscript. We thank Ishtiaq Z. Ahmed, MD, University of Toronto, for his assistance in performing the
literature searches. No financial compensation was received.
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THE RATIONAL

Does This Adult Patient With Suspected

A 62-year-old woman presents to the

JAMA, August 1, 2012Vol 308, No. 5

evated creatinine level (2.1 mg/dL [186

docarditis, central venous catheter

2012 American Medical Association. All rights reserved.

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BLOOD CULTURES FOR BACTEREMIA

tive endocarditis accounts for 3% to 8%

patients who have bacteremia from those

age tubes should be visualized and the

To find studies of the accuracy of clinical findings for predicting bacteremia in

2012 American Medical Association. All rights reserved.

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JAMA, August 1, 2012Vol 308, No. 5

BLOOD CULTURES FOR BACTEREMIA

cluded. One retrospective cohort study

JAMA, August 1, 2012Vol 308, No. 5

Level 2: a study of fewer than 100

such as focal infection, sepsis,

Search Results for Studies of Accuracy

We retained 35 studies assessing

Pretest Probability of Bacteremia

As a symptom, patient report of subjective fever was an inaccurate predictor of

2012 American Medical Association. All rights reserved.

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BLOOD CULTURES FOR BACTEREMIA

of 38C or higher (100.3F) had an

Table 1. Study Characteristics a

Patients with unexplained fever 37.9C

Patients with evidence of source of fever

Leibovici et al,28 1991

Consecutively admitted febrile patients

Limited to patients with fever. Score

Van Dissel et al,36 1998

Consecutive ED patients with fever

Groeneveld et al,37 2001

Patients admitted to hospital with fever

Febrile patients only; high proportion of

Chirouze et al,38 2002

Consecutively admitted patients with

Study of uncommon blood tests; minimal

Tokuda et al, 2005

Consecutively admitted patients with

Yoshida et al,55 2005

Retrospectively identified inpatients with

Retrospective study; raw data were

Stryjewski et al,40 2009

Patients with health careassociated

Limited to patients with health

Group 2: studies of patients with

Infection (not otherwise specified)

Limited to patients older than 65 y; types of

Infection (not otherwise specified) in

Febrile neutropenia patients excluded;

General medicine inpatients with clinical

Validation of scoring systems of Bates et al9

Jones and Lowes, 1996

Yehezkelli et al,31 1996

Bates et al,32 1997

436/1342 b Emergency, ward, and ICU patients

Smith et al,43 1997

Perl et al,44 1999