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REVIEW 10.1111/1469-0691.


Update on blood cultures: how to obtain, process, report, and interpret

T. J. Kirn and M. P. Weinstein

Departments of Medicine (Infectious Diseases) and Pathology & Laboratory Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA


The detection and identification of microorganisms circulating in the bloodstream of patients is arguably one of the most important
functions of the clinical microbiology laboratory. Effective implementation of this function requires careful consideration of specimen
collection and processing, culture techniques, result reporting, and, perhaps most importantly, result interpretation by the physician. The
purpose of this review is to provide a synopsis of the current state of the art for each of these areas, with the intention of providing
adequate information to enable clinical laboratory personnel and physicians to critically evaluate and, if required, improve their current
blood culture practices.

Keywords: blood culture, clinical microbiology, interpretation, rapid methods, specimen collection
Article published online: 13 March 2013
Clin Microbiol Infect 2013; 19: 513–520

Corresponding author: M. P. Weinstein, Departments of Medicine

(Infectious Diseases) and Pathology & Laboratory Medicine, UMDNJ-
Robert Wood Johnson Medical School, 1 Robert Wood Johnson
Place, New Brunswick, NJ 08903, USA
E-mail: Weinstei@umdnj.edu

Introduction therapeutic intervention, whereas the number of BSIs appears

to be increasing, especially those occurring in populations that
were previously less affected (outpatients).
Bloodstream infections (BSIs) represent an important cause of
Because BSIs remain an important cause of morbidity and
human morbidity and mortality. The evaluation of patients
mortality, and prompt targeted therapeutic intervention may
suspected of having a BSI routinely includes blood cultures,
improve patient outcomes, there has been significant interest
which optimally yield an aetiological diagnosis and provide the
in improving the speed and accuracy of blood culture methods
opportunity to perform antimicrobial susceptibility testing to
in the clinical microbiology laboratory. Despite these efforts,
guide therapeutic intervention when necessary. The clinical
little has changed since the introduction of continuous-
significance of positive blood cultures has been extensively
monitoring blood culture systems in the 1990s, but incremen-
evaluated over the past several decades [1–6]. These studies
tal advances in more rapid identification and susceptibility
have served to define the most frequent aetiological agents
prediction have occurred, especially for some particularly
responsible for BSIs and the range of agents, and have
troublesome pathogens. Moreover, greater advances appear
improved our understanding of the risks and outcomes
to be on the horizon.
associated with such infections. As the baseline characteristics
of patients have changed with advances in medicine (e.g. more
Blood Culture Collection
immunocompromised hosts, more indwelling catheters and
other intravascular devices, and changes in therapy for human
immunodeficiency virus), the epidemiology of BSIs has also The utility of blood culture for detecting BSI is directly
evolved, with more infections occurring in patients with influenced by the collection of optimal specimens only from
intravascular devices and in outpatient settings [5]. Addition- patients with clinical findings compatible with BSI; routine
ally, there appears to be a trend towards improved outcomes ‘surveillance’ blood cultures are costly and of little clinical value
in patients with BSIs, perhaps as a consequence of earlier [7–9]. Clearly, venipuncture is the preferred method for blood

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Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases
514 Clinical Microbiology and Infection, Volume 19 Number 6, June 2013 CMI

culture collection. Arterial blood samples do not increase Once optimal blood culture specimens are collected
diagnostic yield, and blood specimens obtained from intravas- according to the principles outlined above, they should be
cular lines have demonstrated increased rates of contamina- sent to the laboratory as promptly as possible. These
tion in some studies [10]. The American College of Physicians specimens should never be refrigerated or frozen, and should
guidelines recommend that collecting blood for culture from be held at room temperature for no more than a few hours if
intravascular devices be avoided, and the CLSI recommends necessary. Although an extended delay between blood culture
that, if one must collect a blood culture from an intravenous collection and incubation in a continuous-monitoring blood
line, it should be paired with a culture that is obtained via culture instrument is not recommended, a significant diminu-
venipuncture to assist in the interpretation of positive results tion in pathogen recovery has only been experimentally
[11,12]. The timing of blood culture collection does not appear observed when blood culture bottles have been held for
to significantly affect the recovery of clinically relevant >24 h at 4°C or room temperature and for >12 h at 37°C
microorganisms, and most authorities therefore recommend [26]. Lengthy incubation of blood culture bottles prior to
collecting multiple sets simultaneously or over a short period entering them into a continuous-monitoring blood culture
of time, except when documentation of continuous bactera- instrument may delay or impede the detection of growth by
emia is required for patients with endovascular infection the instrument, and is discouraged.
[12,13]. Whenever possible, two to four sets of blood
specimens should be collected from independent venipuncture
Laboratory Techniques for Blood Culture
sites, and, for adult patients, each set should consist of 20–
40 mL of blood [12–15]. The volume of blood drawn from
infants and children is less well prescribed, but should be based In the vast majority of institutions, most blood culture
on the child’s age and not exceed 1% of the patient’s total specimens delivered to the laboratory are entered into an
blood volume [12,16]. It is clear that the total volume of blood incubation protocol on a continuously monitored blood
cultured from adult patients is directly proportional to the culture device. There are several manufacturers of such
yield of microorganisms recovered. This is a consequence of devices, and their performance characteristics are similar [27–
the fact that most adult patients with BSIs have very low 35]. These devices incubate the blood culture bottles for a
circulating concentrations of viable microorganisms. Inade- prescribed period of time (determined by the user) and signal
quate blood volume or the collection of a single blood culture audibly and/or visually if growth is detected.
set significantly reduces the sensitivity of the test, and also Each automated blood culture system has its own associ-
makes the interpretation of results far more difficult ated medium formulations that must be selected by the user.
[13,15,17,18]. Collection of multiple sets of blood cultures The blood culture bottles typically contain proprietary
from a single venipuncture or intravascular line should also be mixtures of culture medium, an anticoagulant, and, in many
avoided. For optimal recovery of diverse BSI aetiological cases, resins or charcoal mixtures to reduce the effects of
agents, each set of blood cultures should include paired antimicrobials and other toxic compounds. Generally, combi-
aerobic and anaerobic blood culture bottles, and the aerobic nations of medium formulations that are complementary to
bottle should be filled first [12,19,20]. each other are chosen to enhance the recovery of the most
Proper skin antisepsis prior to collection of blood cultures via diverse range of microorganisms. Medium combinations typ-
peripheral venipuncture is paramount, to reduce blood culture ically include aerobic and anaerobic formulations and, in select
contamination rates and facilitate result interpretation for the circumstances, a formulation containing reagents that are ideal
clinician. A variety of skin disinfectants have been clinically for recovering mycobacteria and/or yeasts may be inoculated
evaluated, and reports comparing their relative efficacy have as well. Controlled studies comparing the performance of
been published [21–25]. On the basis of these data, current media with and without the addition of antimicrobial binding
guidance documents conclude that tincture of iodine, chlorine or absorbing agents (resins and/or charcoal compounds) have
peroxide and chlorhexidine gluconate are superior to povidine- repeatedly demonstrated that the latter formulations are
iodine preparations, and that tincture of iodine and chlorhex- clearly superior for the recovery of microorganisms, especially
idine gluconate are probably equivalent for skin antisepsis prior staphylococci and yeasts [29,34–37].
to blood culture collection [12]. Although chlorhexidine Blood cultures entered into automated, continuous-moni-
gluconate is an adequate disinfectant for older infants, children, toring protocols should routinely be incubated for 5 days.
and adults, it should not be used on infants <2 months of age, Multiple studies have shown that this incubation time is
and an alternative is therefore required in centres where this adequate for the detection of the majority of pathogens,
disinfectant is otherwise routinely employed. including fastidious bacteria that belong to the Haemophilus,

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Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, 513–520
CMI Kirn and Weinstein Blood cultures review 515

Actinobacillus, Cardiobacterium, Eikinella and Kingella (HACEK) often of unclear clinical significance when they are isolated
group, and that incubation beyond 5 days increases the with these methods [51]. In cases where fungaemia caused by a
number of contaminants recovered [38–43]. Longer incuba- mould is suspected, alternative blood culture methods should
tion times may be required when dimorphic fungaemia or be employed, such as the lysis centrifugation method, in which
bacteraemia caused by Legionella, Brucella, Bartonella or Nocar- the lysed and pelleted blood specimen can be plated on
dia spp. is suspected. Blood cultures for Mycobacterium spp. medium that specifically supports the growth of moulds and
should be incubated for 4 weeks. dimorphic fungi. Some fungi require highly specialized medium
The detection of some microorganisms is enhanced by supplements, the most noteworthy example being the
employing blood culture techniques in addition to or in place requirement for lipid supplementation for Malasezzia furfur,
of standard instrumented blood culture systems. The most which is often achieved by overlaying fungal medium with olive
common example of this principle is the utilization of the oil.
Isolator blood culture system (Wampole Laboratories, Cran-
bury, NJ, USA) for the enhanced detection of dimorphic fungi Mycobacterial blood cultures
and Bartonella spp. [44–46]. This system is unique in that it is Mycobacterial BSIs occur in immunocompromised patients
non-broth-based. Instead, blood samples obtained by veni- (either as a consequence of iatrogenic immunosuppression, or
puncture are collected into a tube that contains a lysing associated with an immunosuppressive condition) and patients
solution. The tubes are then transported to the laboratory, with long-term vascular access devices. Investigation tailored
where they are centrifuged. The supernatant is discarded, and to the recovery of mycobacterial blood isolates should thus
the pellet is inoculated onto solid medium, the composition of generally be limited to patients with such characteristics.
which may be tailored to recover the organisms (bacteria, As mycobacteria are commonly located intracellularly,
fungi, and/or mycobacteria) that are most likely or highly approaches to growing them in vitro often include lysis of
suspected on the basis of clinical findings. Although there are leukocytes prior to incubation in a rich medium that contains
clear advantages to using this approach in select circumstances fatty acids. Mycobacteria may be optimally recovered, with
(suspicion of BSI caused by dimorphic fungi or Bartonella spp.), extended incubation of 4 weeks, with manual methods such as
it is not routinely employed, as it is quite labour-intensive, it lysis centrifugation or the use of commercial ‘lytic’ media in
poses a greater risk of laboratory-acquired infection to manual or instrumented systems. These blood culture formu-
technologists, and it is inferior to standard blood culture lations typically contain a proprietary mixture of fatty acids
methods for the detection of anaerobes, Haemophilus spp., and that support mycobacterial growth, along with antimicrobial
pneumococci [47–50]. agents. Limited comparisons between formulations suggest
some variability in the performance of lytic culture media, but
comprehensive comparative studies of all formulations have
Special Considerations for Select Microor-
not been performed [52–56].
Fastidious microorganisms
Fungal blood cultures Fastidious microorganisms are rarely implicated in BSI in
Fungi represent an emerging group of organisms that are clinical practice, but when they are isolated from blood
responsible for BSI with increasing frequency. The growth cultures they often represent serious infection. In some cases,
requirements for fungi often differ from those for bacteria, the observation of signal-positive Gram stain-negative blood
most notably with regard to optimal growth temperature and culture results provides a clue that a fastidious microorganism
media. For example, most yeasts grow best at 37°C, whereas might be implicated as the BSI aetiological agent. In those
filamentous fungi often grow best at lower (27–30°C) cases, collaboration between the laboratory and clinician is
temperatures. Most routine manual and automated blood essential to ensure that appropriate steps are taken to increase
culture systems are able to support the growth of yeasts such the odds of isolation of such organisms. Some organisms may
as Candida spp. However, if suspicion is high for a BSI being be small or of unusual morphology, and not readily recognized
caused by yeast, and routine blood cultures are negative, then by the technologist. In other cases, the organism may not stain
it may be reasonable to consider a request for alternative test well with standard Gram stain protocols (e.g. Mycoplasma and
methods that are optimally designed to support the growth of Campylobacter). In those cases, alternative staining techniques
most yeasts. Moulds, and especially dimorphic fungi, often may be employed, including the use of acridine orange (to stain
grow poorly in typical instrumented blood culture systems. bacterial nucleic acids) or the use of carbol fuschin as an
Furthermore, the recovery of moulds such as Aspergillus spp. is alternative to safranin as a counterstain in the Gram stain

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Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, 513–520
516 Clinical Microbiology and Infection, Volume 19 Number 6, June 2013 CMI

protocol to enhance the staining of Campylobacter, Helicobacter, organism identification and organism-specific susceptibility
and Brucella. testing should only be performed on clinically important
Perhaps the most frequently encountered fastidious bacte- isolates, and not on organisms that probably represent
ria are the members of the HACEK group as the aetiological contaminants [57,58]. Isolates that are probably associated
agents for subacute bacterial endocarditis. As noted above, in with true BSI (as per the laboratory protocol) should be saved
the vast majority of cases, these organisms are isolated with in the laboratory (by serial subculture) for several days to
standard blood culture techniques without the need for special allow additional testing if required, and may be retained for
protocols or procedures. This is also generally true for Brucella longer periods of time (in a frozen archive) to allow
spp., Campylobacter spp., and Francisella spp., but is not true for investigation of recurrent BSIs in appropriate patients.
all fastidious bacteria.
Abiotrophia and Granulicatella are usually detected with
Interpretation of Positive Blood Cultures
automated blood culture instruments, but do not grow well
on standard, unsupplemented solid media, as they require
pyridoxal or cysteine for growth. This can be accomplished by The interpretation of positive blood culture results is often
co-cultivation with staphylococci, by the use of pyridoxal- straightforward, but sometimes presents a significant dilemma
impregnated disks placed on the surface of standard blood agar for physicians and clinical microbiologists. For the latter
plates, or by the use of specially supplemented or enriched circumstance, a variety of laboratory data must be evaluated in
media. the context of the clinical picture to arrive at an accurate
The yield of standard blood culture media for the cultivation interpretation. The pattern of positivity of blood cultures is
of Bartonella spp. is typically low. Special techniques, including often useful; when the majority of or all blood culture sets
lysis centrifugation methods and/or serological investigations, obtained by independent venipuncture are positive for the same
are thus indicated for the diagnosis of BSI caused by Bartonella microorganism, the likelihood that this represents true BSI is
spp. exceedingly high, regardless of the organism’s identity [2].
Legionella spp. require buffered charcoal yeast extract Likewise, the identities of organisms isolated from positive blood
(BCYE) for optimal growth. Recovery of Legionella can be cultures also have value. Staphylococcus aureus, Streptococcus
achieved by subculturing standard blood culture medium that pneumoniae, Enterobacteriaceae, Pseudomonas aeruginosa and
has been incubated according to the standard protocol for Candida albicans are almost always predictive of true BSI.
5 days into BCYE, or by utilizing BCYE in conjunction with Conversely, Corynebacterium spp. and Propionibacterium spp.
lysis centrifugation methods. A detailed description of all of the almost always represent contamination. The recovery of
special techniques required for the culture of other rarely viridans group streptococci, coagulase-negative staphylococci
encountered fastidious organisms (e.g. Helicobacter and Lepto- (CoNS) and enterococci is more difficult to interpret, as some
spira) is beyond the scope of this review, and has been studies have demonstrated that they represent true BSI in 38%,
provided elsewhere [12]. 15% and 78% of cases, respectively [1]. Notably, CoNS
represent one of the most commonly encountered blood
culture contaminants, but also constitute an important cause of
Isolation, Identification, and Susceptibility
BSI in the ever-expanding population of patients with implanted
devices and indwelling catheters. Interpretation for these cases
may be aided by identifying CoNS to the species level when more
Once blood cultures become positive for growth, either by than one set of blood cultures becomes positive. If the same
manual subculture techniques or signalling from automated species of CoNS is isolated from multiple blood culture sets, the
systems, a Gram stain is performed. A positive Gram stain odds that it represents true bacteraemia as opposed to
result should be regarded as a critical value, and immediately contamination increase [3]. Without this additional information,
phoned to the ordering clinician or another responsible using the number of positive blood culture sets that are
member of the healthcare team providing care to the patient. generically positive for CoNS is a less reliable predictor. Finally,
Subcultures are performed at this point, and these allow some have suggested that the number of blood culture bottles
identification and, if indicated, susceptibility testing to be (as opposed to the number of sets) has predictive value, in that
performed, typically over the next 24–48 h. the more that are positive for CoNS, the more likely it is that the
Laboratories should have a comprehensive protocol in patient has bacteraemia caused by CoNS. However, systematic
place to guide the appropriate work-up of organisms isolated evaluations of this approach have proven it to be unreliable
from blood cultures. To optimally utilize resources, complete [18,59].

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Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, 513–520
CMI Kirn and Weinstein Blood cultures review 517

on newer or novel technology. Molecular methods, including

Rapid Methods for Identification and
nucleic acid amplification assays (NAATs), DNA sequencing
Susceptibility Testing of Isolates from
approaches, DNA microarrays, and probe hybridization, have
Positive Blood Cultures
emerged as useful tools for microorganism identification, and,
in some cases, the prediction of antimicrobial susceptibility
Prompt detection, identification and susceptibility testing of for select antibiotics [62–66]. Novel phenotypic approaches
the aetiological agents responsible for BSIs is critical, as it have also been shown to reduce turn-around time for the
allows clinicians to make the most informed decisions about identification and limited susceptibility testing of select
possible therapeutic interventions. Blood cultures incubated in organisms (Kirn et al., IDSA Annual Meeting, 2011). Finally,
modern instrumented systems that are ultimately positive for matrix-assisted laser desorption ionization time-of-flight mass
most bacterial pathogens typically signal positive in a median spectrometry, which has already demonstrated widespread
time of 12–36 h, whereas the time to positivity from collection utility in the routine identification of microorganisms in the
to detection is longer for some fastidious bacteria, anaerobes, clinical microbiology laboratory, appears to be a very
and fungi [28,29]. Following detection, Gram stain rapidly promising approach to the rapid identification of organisms
provides some information to the clinician that may be useful directly from signal-positive blood culture broths [67]. The
for determining the significance of the positive result and/or major drawback of this approach, like most of the others, is
determining initial antimicrobial therapy. Standard microbio- the lack of rapid susceptibility information to accompany the
logical protocols that rely on biochemical identification of organism identity. It is not yet clear when or if this capability
microorganisms plus phenotypic antimicrobial susceptibility will be possible with matrix-assisted laser desorption ioniza-
testing follow, and may take an additional 48–72 h, assuming tion time-of-flight mass spectrometry or other rapid methods,
that the results obtained are easily interpreted. It may take and the actual clinical utility of microorganism identification in
days longer to generate final results for organisms that are the absence of susceptibility information is narrow and
difficult to identify biochemically or grow slowly in vitro. Given unproven.
the usual delay of 3–5 days from the collection of blood
cultures to the time at which final identification and suscep-
tibility results are obtained, there has been keen interest in
Rapid Methods for Detection of
reducing this interval by employing a variety of rapid methods.
Microorganisms Directly in Blood Specimens
In some cases, the time to delivery of results may be reduced
by employing traditional microbiological protocols earlier in Although technological improvements have led to reductions
the work-up. For example, the coagulase test, which is in the time required for identification and (in limited cases)
traditionally used to distinguish CoNS isolates from coagu- susceptibility testing of isolates from signal-positive blood
lase-positive isolates, may be performed directly on signal- cultures, a further improvement would obviously be the ability
positive blood culture broths that show Gram-positive cocci in to rapidly and directly detect and identify microorganisms in
clusters on Gram staining [60]. This approach allows rapid blood samples from patients with a suspected BSI. Currently
distinction between CoNS and coagulase-positive staphylo- available solutions involve the use of NAATs that are designed
cocci (which are mostly S. aureus), and may influence the to detect specific microorganisms in blood samples [68].
ability of clinicians to interpret the clinical significance of a Controlled trials evaluating the performance of such solutions
positive blood culture result and their ability to begin as compared with standard blood cultures have demonstrated
appropriate antimicrobial therapy. Obviously, this is not a reasonably good performance, with the obvious limitation that
complete solution, as it does not definitively identify the NAATs will only detect a subset of possible BSI pathogens,
organism and nor does it provide susceptibility information. To and provide no susceptibility information [68,69]. As conven-
augment such an approach, some laboratories may couple tional phenotypic susceptibility testing requires isolated
direct coagulase testing with the use of chromogenic agar organisms, if the direct NAAT is positive and the correspond-
medium, which allows identification of methicillin-resistant ing culture is negative, susceptibility information may never be
S. aureus isolates within 18–24 h [61]. Clearly, this solution available. Thus, at the present time, such an approach may
represents an improvement over traditional methods, but serve only as an adjunct to standard of care protocols. As is
applies only to one specific organism and gives susceptibility the case for rapid methods for blood culture isolate identi-
results for only one drug. fication, the actual clinical impact of rapid methods for direct
More robust approaches to improving the turn-around pathogen detection in blood specimens has not been exten-
time for the laboratory diagnosis of BSIs have focused largely sively studied.

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518 Clinical Microbiology and Infection, Volume 19 Number 6, June 2013 CMI

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520 Clinical Microbiology and Infection, Volume 19 Number 6, June 2013 CMI

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