Available online http://ccforum.

com/content/12/3/213

Review
Bench-to-bedside review: Sepsis, severe sepsis and septic shock –
does the nature of the infecting organism matter?
Hongmei Gao, Timothy W Evans and Simon J Finney

Adult Intensive Care Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK

Corresponding author: Timothy Evans, [email protected]

Published: 6 May 2008 Critical Care 2008, 12:213 (doi:10.1186/cc6862)

This article is online at http://ccforum.com/content/12/3/213
© 2008 BioMed Central Ltd

Abstract patients with established sepsis using the best evidence

International guidelines concerning the management of patients available currently [6].
with sepsis, septic shock and multiple organ failure make no
reference to the nature of the infecting organism. Indeed, most Louis Pasteur was the first to link micro-organisms with
clinical signs of sepsis are nonspecific. In contrast, in vitro data human disease when he identified the streptococcal aetio-
suggest that there are mechanistic differences between bacterial, logy of puerperal sepsis [7]. It is now known that sepsis also
viral and fungal sepsis, and imply that pathogenetic differences
arises after infections with a range of micro-organisms that
may exist between subclasses such as Gram-negative and Gram-
positive bacteria. These differences are reflected in different include viruses, fungi and protozoa. However, neither the
cytokine profiles and mortality rates associated with Gram-positive Surviving Sepsis Campaign nor the guidelines of the
and Gram-negative sepsis in humans. They also suggest that American College of Chest Physicians and Society of Critical
putative anti-mediator therapies may act differently according to Care Medicine [8] make any reference to whether specific
the nature of an infecting organism. Data from some clinical trials infectious agents influence the natural history or therapy of an
conducted in severe sepsis support this hypothesis. It is likely that
episode of sepsis. Similarly, standard definitions do not focus
potential new therapies targeting, for example, Toll-like receptor
pathways will require knowledge of the infecting organism. The on the site of infection. Thus, sepsis is often considered as a
advent of new technologies that accelerate the identification of single entity, with little or no reference to the causative agent
infectious agents and their antimicrobial sensitivities may allow or the anatomical focus of infection. Does this mean that the
better tailored anti-mediator therapies and administration of anti- nature of the organism has no influence?
biotics with narrow spectra and known efficacy.
Clinically, the nature of the organism is critical in that many
Introduction possess specific virulence factors that have considerable
Sepsis and its sequelae, namely severe sepsis, septic shock prognostic significance. For example, Panton-Valentine leuko-
and multiple organ failure, dominate the case load of non- cidin secreted by staphylococci contributes to the develop-
coronary intensive care units (ICUs). Despite a fall in ment of a rapidly progressive haemorrhagic necrotizing
mortality, deaths attributable to sepsis have risen in pneumonia in immunocompetent patients [9] and a particu-
developed countries as the incidence increases in an ageing larly high mortality rate [10]. It is likely that other microbial and
population [1,2]. Moreover, patients who survive suffer host factors influence the effects of Panton-Valentine
considerable morbidity and score poorly in many domains of leukocidin [11,12]. Similarly, other bacterial subgroups
health-related quality of life assessments [3,4]. Hence, sepsis secrete toxins such as superantigenic toxic shock syndrome
is the focus of many quality improvement initiatives. The US toxin 1, exfoliative toxin, botulinum toxin and tetanus toxin. All
Institute for Healthcare Improvement’s ‘5 million lives’ are associated with additional mortality above that
campaign aims to reduce the incidence of nosocomial sepsis attributable to bacterial infection per se. However, aside from
[5]. Furthermore, the Surviving Sepsis Campaign (instigated virulence factors specific to certain organisms, differences
by the European Society of Intensive Care Medicine, are also detectable in association with broader microbial
International Sepsis Forum and Society of Critical Care classifications. Most data exist for differences between Gram-
Medicine) aims to harmonize the clinical management of positive and Gram-negative infections [13].

ICU = intensive care unit; IFN = interferon; IL = interleukin; LPS = lipopolysaccharide; PCR = polymerase chain reaction; TLR = Toll-like receptor;
TNF = tumour necrosis factor.

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Critical Care Vol 12 No 3 Gao et al.

Figure 1

Simplified schematic of intracellular signalling for TLRs. AP, activator protein; CpG DNA, cytosine-guanine dinucleotides; dsRNA, double-stranded
ribonucleic acid; IRF, interferon response factor; LPS, lipopolysaccharide; LTA, lipoteichoic acid; MAL, MyD88-adaptor-like; MAPK, mitogen-
activated protein kinase; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor-κB; ssRNA, single-stranded ribonucleic acid; TLR, Toll-like
receptor; TRAM, Toll-receptor-associated molecule; TRIF, Toll-receptor-associated activator of interferon.

Differences in the host response adaptor molecules onto three transcription factors: nuclear
Infectious pathogens are detected by the innate immune factor-κB, activator protein-1, and interferon response factor-1.
system via Toll-like receptors (TLRs). Ten TLRs have been All three factors result in the upregulation of genes for pro-
identified, through which most pathogens can be detected. inflammatory cytokines such as tumour necrosis factor (TNF)-α,
Recognition does not require previous exposure to a IL-1, and the IFNs. However, this convergence of signalling
pathogen or an enormous range of genome-encoded recep- cascades is not reflected in vitro. Specific ligands for
tors, such as is associated with the T-cell receptor. TLRs receptors result in different but overlapping responses. For
respond to molecular patterns such as unmethylated CpG example, TLR4 but not TLR2 agonists prolong neutrophil
dinucleotides that are common in bacteria but uncommon in survival [19]. Additionally, cytokine release differs in human
the host. Mammalian DNA methyltransferases result in trophoblasts [20] and peripheral blood mononuclear cells
methylation of 70% to 80% of CpG cytosines [14]. Similarly, [21-23] according to bacterial component. Although whole
TLR4 and TLR2 recognize lipopolysaccharide (LPS) and bacteria may signal via several TLRs, there remains diver-
lipoteichoic acid, structural molecules that are unique to the gence in cytokine responses to whole bacteria in vitro [24].
cell walls of Gram-negative and Gram-positive bacteria, Heat-killed streptococci induce greater IFN-γ but less IL-10
respectively. Whereas bacterial components signal via a release than heat-killed Escherichia coli in a whole blood
single TLR, it is unlikely that whole bacteria signal so exclu- model [25]. Other investigators have demonstrated that heat-
sively. Indeed, cell wall extracts from Gram-positive and killed staphylococci induce less IL-6, IL-8, IL-1β and TNF-α
Gram-negative organisms contain components that can from neonatal blood than E. coli [26].
activate both receptors [15,16]. This lack of absolute
dependence on a single receptor has obvious benefits for the These in vitro observations can be extended to the results of
host. However, mice deficient in TLR2 and TLR4 are more clinical studies. Microarray data from 52 patients suggest that
prone to infections with staphylococci [17] and Salmonella different but overlapping sets of genes are upregulated and
spp. [18], respectively, which suggests that Gram-positive these sets include genes that are implicated in the inflam-
infection may have a TLR2-dominant signal, whereas Gram- matory response [21]. The patient numbers were too small to
negative infections have a TLR4-dominant signal. exclude host interactions. Nevertheless, it is possible that
patterns of gene expression in the host could be exploited
The intracellular signalling cascades of the TLRs are therapeutically or as a diagnostic tool. Gram-negative disease
illustrated in Figure 1. These converge through common has been shown to result in greater plasma levels of TNF-α

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than Gram-positive infection [25,27]. Gram-negative meningo- tional studies have demonstrated that the appropriateness of
coccal septicaemia is associated with greater plasma IL-10 such therapy has the greatest impact on outcome in sepsis
and lower IFN-γ than Gram-positive sepsis [25]. Others have [35].
identified differences in IL-6, IL-18 and procalcitonin levels
[21]. However, such differences in cytokine profiles do not Patients with Gram-positive or Gram-negative infections have
manifest overtly in either physiological or clinical differences. responded differently in some clinical trials targeting
Signs such as fever, hypotension and tachycardia, and widely mediators of the inflammatory response [36]. Unfortunately,
used biochemical markers (for example, raised C-reactive not all have reported efficacy according to the nature of the
protein) and leucocytosis are nonspecific. By contrast, there infecting organism. However, in a randomized, double-blind,
may be differences in mortality afforded by the nature of the placebo-controlled trial of a soluble fusion protein of TNF-α
infecting organism. These differences have not remained receptor, no adverse events were observed in patients with
constant over time, because it has been observed that the Gram-negative infection, whereas patients with Gram-positive
incidence of Gram-negative sepsis is falling whereas that of infection tended to have increased mortality [37]. In contrast,
Gram-positive sepsis has remained steady [1]. Moreover, a murine monoclonal antibody directed against human TNF-α
univariate analyses have suggested that Gram-positive or tended to reduce mortality in Gram-positive infection, where-
staphylococcal infections appear to be associated with as that in Gram-negative infection mortality tended to increase
greater mortality [28-30]. In another multivariate analysis [30] [38]. The platelet-activating factor receptor antagonist
only pseudomonal infections appeared to carry a sigificantly BN52021 and the bradykinin antagonist CP-0127 both
different (higher) mortality rate. resulted in reduced mortality in Gram-negative disease, with
no effect in patients with Gram-positive infection [39,40].
These findings are important because the aetiology of sepsis Finally, patients with Gram-positive disease have potentially
has changed over time. In the 1980s the most frequently been harmed in trials of IL-1 receptor antagonists [41] and
identified organisms were Gram-negative bacteria, often of anti-LPS (HA-1A) [42]. To date, drotrecogin alfa (activated) is
gastrointestinal origin. More recently Gram-positive bacteria the only therapy that has been demonstrated to be
have accounted for the greatest proportion of hospital admis- efficacious in severe sepsis by a large, randomized, double-
sions with sepsis in which an organism is identified [1,30]. It blind, placebo-controlled trial. Drotrecogin alfa appears to be
is not clear whether this is a consequence of greater use of equally effective in patient with the broader classifications of
prostheses and invasive vascular devices [31] or of increas- Gram-positive, Gram-negative, or fungal sepsis [43,44].
ing prevalence of multiresistant organisms (for example, When examined at the level of individual organisms, the data
methicillin-resistant Staphylococcus aureus) [32]. Methicillin- suggest that some differences in therapeutic response may
resistant S. aureus is associated with increased ICU length of exist. Indeed, patients with Streptococcus pneumoniae
stay, postoperative complications, treatment costs and infection may have the greatest reduction in mortality with
mortality [32]. The incidence of fungal sepsis has also drotrecogin alfa therapy [44], although this observation was
increased. In a study of 49 US hospitals, fungi accounted for not formally evaluated.
11.7% of bloodstream infections in ICUs [1,33], with an
associated mortality of 45% [33,34]. There are few data There is considerable interest in the therapeutic opportunities
describing the cytokine profiles of severe fungaemia or afforded by the discovery of TLRs. Inhibition of signalling
viraemia relative to that of bacterial sepsis. Finally, in around pathways may limit an over-exuberant and possibly damaging
40% of cases no organism is identified as the cause of host inflammatory response. Several therapies targeting the
sepsis [30], possibly because of lack of samples, previous TLR4 pathway are under development. Being directed at
antibiotic therapy, or deficiencies in microbiological tech- TLR4, these therapies may be efficacious only in bacterial
niques. It is not known how the different microbial groups are Gram-negative sepsis, and their effectiveness will thus be
represented within this important subgroup [35]. critically dependent on the nature of the infecting organism.
For example, TAK-242 is a small molecule antagonist that
In summary, the nature of an infectious pathogen influences reduces LPS-induced production of nitric oxide, IL-1β, IL-6
the mechanism of the host response. This appears teleo- and TNF-α by human blood mononuclear cells [45,46]. It is
logically intuitive, because a common strategy would not selective for TLR4 and not TLR2, TLR3 or TLR9 signalling. In
allow the host to exclude all viruses, intracellular infections, vivo, it improves survival when it is administered to mice even
extracellular infections and microbial structures. The corollary after a normally fatal LPS challenge [47]. TAK-242 is
is that the effects of any specific anti-mediator therapies may currently undergoing phase III evaluation in a multicentre,
vary according to the nature of the infection. randomized, placebo-controlled study of patients treated
within 36 hours of the onset of severe sepsis and conco-
Differences in the response to therapeutic mitant respiratory and cardiovascular failure [48]. The primary
intervention end-point of the study is 28-day all-cause mortality. An earlier
The nature of the infecting organism is critical, primarily for study of TAK-242 [49] was stopped after enrolling 277
the selection of appropriate antimicrobial agents. Observa- patients; data are yet to be reported. Alternatively, E5564, or

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Critical Care Vol 12 No 3 Gao et al.

eritoran, is a synthetic lipodisaccharide that antagonizes LPS

This article is part of a review series on
[50]. In vivo, E5564 blocks the induction of cytokines by LPS
Infection,
and reduces lethality after injection of LPS or bacteria into
edited by Steven Opal.
mice [50]. Moreover, in a double-blind, placebo-controlled
study, a single dose of E5564 caused a dose-dependent
Other articles in the series can be found online at
reduction in temperature, heart rate, clinical symptoms,
http://ccforum.com/articles/
C-reactive protein, white cell count, TNF-α, and IL-6 after LPS
theme-series.asp?series=CC_Infection
injection [51]. E5564 is being evaluated in a phase III, double
blind, placebo-controlled study conducted in patients within
12 hours of onset of severe sepsis [52]. The primary outcome
measure is 28-day survival. Finally, two other agents yet to be Conclusion
investigated are CRX-526 (a synthetic lipid A mimetic and The nature of an infecting organism is critically important.
thus TLR4 agonist) [53] and soluble decoy TLRs [54-56]. Clinically, specific virulence factors such as exotoxins
influence the manifestations, morbidity and mortality of
Determination of the infecting organism sepsis. Furthermore, the nature of the pathogens influences
Current standard microbiological techniques identify infecting the mechanism of the host response and therefore the
organisms after culture of a clinical isolate in conditions response to any therapy. From the perspective of the
suitable for replication of the infectious agent. This may be physician, early identification of an infectious agent will allow
difficult with fastidious organisms or if patients have received confirmation that infection underlies an inflammatory process,
antibiotics. Preliminary classification is usually possible within allow the use of efficacious and narrow spectrum antibiotics,
24 hours, with full species identification and antimicrobial and may open the door to new therapies targeted at
sensitivity data becoming available 48 to 72 hours after blood pathogen-specific inflammatory pathways.
sampling. The slowness of the investigation usually mandates
the use of ‘best guess’, and often broad spectrum, antibiotics Competing interests
while awaiting results. The authors declare that they have no competing interests.

Several techniques are being developed that accelerate the Authors’ contributions
identification of infecting organisms. Many detect nucleotide HG, TE, and SF planned, drafted, read, and approved the
sequences specific to pathogens in blood after standard final manuscript.
culture. Techniques include fluorescent in situ hybridization
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