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most common primary site of infection to be the respiratory tract (34%) followed by
abdomen (25%), blood (17%), urinary tract (8%) and skin and soft tissue (7%) [10].
Although less common, CNS and endocardial infections are notable for their high
morbidity and mortality. An international point prevalence study of infections in
ICU patients found similar proportions although in contrast to the septic shock
group respiratory tract infections accounted for 64% of infections [11]. In the latter
study, microbiological culture results were positive in 70% of infected patients;
62% of the positive isolates were gram-negative organisms, 47% were grampositive, and 19% were fungi. Patients who had longer ICU stays prior to the study
day had higher rates of infection, especially infections due to resistant Staphylococcus,
Acinetobacter, Pseudomonas and Candida species.
Antimicrobial resistance patterns vary enormously around the world and even
between neighbouring institutions. Organisms resistant to practically all commonly
used antimicrobials have now been described and empiric antibiotic regimes need to
reect this unfortunate trend.
B. Reddi
17.4 Pathogenesis
17.4.1 Innate Immunity inSepsis
The rst response to an invading pathogen is mediated by the innate immune system.
Pattern recognition receptors (such as Toll-like receptors (TLRs) and C-type lectin
receptors) on the surface of macrophages, neutrophils, dendritic cells and natural
killer cells recognise structurally conserved molecules that are broadly shared by
pathogens such as lipoteichoic acid, peptidoglycan, lipopolysaccharide, agellin,
viral RNA and mannan (a fungal cell wall carbohydrate). Intracellular pattern recognition receptors (such as NOD-like receptors) which recognise conserved bacterial
and viral molecular patterns have also been identied. As well as these pathogen
associated molecular patterns (PAMPs), receptors also bind endogenous ligands,
termed damage associated molecular patterns (DAMPs), that enter the microenvironment when host cells undergo non-apoptotic death. These molecules, which
include fragments of nuclear and mitochondrial DNA, cytosolic heat shock proteins
and chromatin associated high mobility group box 1 (HMGB1) instigate the inammation associated with trauma, burns and pancreatitis. Pattern recognition receptor
signalling activates transcription factors such as NFκB which induce inammatory
cytokine expression and promote immune cell maturation and proliferation [12].
Humoral elements of the immune system such as complement and the contact system of the coagulation cascade also bind to conserved elements of the microbial
surface and contribute to innate immunity and the inammatory milieu [13].
Cytokines and complement fragments attract and activate local and circulating
immune cells which amplify the inammatory cascade and exert direct microbicidal
activity by liberating substances such as lysozyme and reactive oxygen species
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(ROS). As well as direct antimicrobial activity, many cells of the innate immune
system (for example macrophages and dendritic cells) act as antigen presenting
cells, displaying antigen bound to major histocompatibility complex (MHC) to
T-cells of the adaptive immune system. T-helper cells co-ordinate both the ongoing
innate immune response and a more antigen specic T- and B-lymphocyte response.
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17.4.2 Immunosuppression inSepsis
Most patents who die of sepsis in the ICU have unresolved foci of infection at postmortem. Furthermore, patients admitted to hospital with sepsis frequently develop
secondary nosocomial infections often with minimally virulent or opportunistic
pathogens such as Stenotrophomonas, Acinetobacter, Candida or reactivated
Cytomegalovirus. It has been suggested that following an initial pro-inammatory
phase, sepsis manifests a subsequent anti-inammatory phase [14]. In support of
this hypothesis it has been shown that inammatory cells extracted from patients
with sepsis produce less tumour necrosis factor α (TNFα), interleukin-1 (IL-1) and
IL-6 in response to lipopolysaccharide than controls. Furthermore, levels of the
anti-inammatory cytokine IL-10 are elevated in patients with sepsis and the IL-10/
TNFα ratio correlates with mortality. Delayed type hypersensitivity reactions are
impaired in sepsis and patients dying of sepsis exhibit profound apoptosis-induced
loss of CD4 and CD8 T-lymphocytes, B-lymphocytes and dendritic cells with a shift
towards immunoregulatory T-lymphocyte phenotype. Notably, therapies which suppress inammatory cytokine activity such as TLR-4 and TNFα antagonists have
failed to improve outcomes. These ndings suggest that sepsis and septic shock
does not always reect a maladaptive hyper-inammatory response to infection but,
at least in some cases, may identify a group of patients generating an inappropriate
immune suppressive, anergic phenotype. Indeed preliminary data indicate that
T-lymphocyte stimulating and anti-apoptotic agents (such as IL-7 and programmed
death ligand-1 antagonism, respectively) might be more effective [14].
17.4.3 Microvascular Alterations inSepsis
TLRs are also expressed on endothelial cells where they promote leucocyte trafcking, tissue factor pathway activation and endothelial permeability. Endothelial permeability is also increased by leucocyte and platelet derived arachidonic acid
derivatives, platelet activating factor (PAF), complement products and glycocalyx
shedding. Tissue oedema not only leads to hypovolaemia and increased blood viscosity but impairs oxygen and metabolite diffusion, changes tissue architecture,
blocks capillary blood ow and lymphatic drainage, and is associated with renal,
cerebral and cardiac dysfunction [15]. Glycocalyx shedding as a consequence of
bacterial toxin and leucocyte mediated damage further exacerbates tissue oedema
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and has been particularly noted in the kidney, liver and lung. Glycocalyx shedding
also interferes with endothelial shear stress ow monitoring and vasomotor
regulation.
Microvascular perfusion is further compromised by a shift to a local prothrombotic prole: IL-6, ROS and bacterial toxins reduce ADAMTS-13 (a disintegrin and
metalloproteinase with thrombospondin motifs) activity resulting in highly thrombotic von Willebrand Factor multimers. TNFα promotes tissue factor expression on
macrophages and endothelial cells. Tissue factor pathway inhibitor, thrombomodulin and protein C activity are reduced, whilst plasminogen activator inhibitor is
increased. Meanwhile endothelial cell damage and apoptosis leaves pro-thrombotic
extracellular matrix exposed and inammatory cells secrete PAF. The net consequence is a tendency for thrombus formation and microvascular occlusion [16]
although reduced platelet function has also been documented [17]. Cross-talk
between the coagulation and immune systems promoting amplication and dissemination of local coagulopathy can lead to the systemic consumptive coagulopathy
characteristic of disseminated intravascular coagulation.
Microvascular occlusion can also arise from the release of neutrophil extracellular traps (NETs), webs of chromatin barbed with antimicrobial proteins which
trap and kill microorganisms. Whilst benecial in containing and clearing infection,
NETs have been observed to occlude capillaries and exacerbate tissue damage [18].
In addition, regional vasomotor regulation (including metabolic and myogenic regulation) is impaired by glycocalyx damage, endothelial damage, downregulation of
endothelial nitric oxide synthase (eNOS) and secretion of local vasoconstrictors
such as endothelin and thromboxane A2. NETs, clots, reduced erythrocyte deformability, leucocyte aggregates, extrinsic compression from tissue oedema and vasomotor dysregulation lead to a decrease in the number of functional capillaries and
heterogeneity in microvascular perfusion with blood shunted past islands of ischaemic, hypoxic tissue through areas of relatively luxuriant ow. Patchy ischemia of
this nature can be directly visualised in myocardium, renal cortex, gut and other
vascular beds [19].
B. Reddi
17.4.4 Mitochondrial Dysfunction inSepsis
Mitochondria are responsible for oxidative phosphorylation and ATP synthesis,
regulation of ROS and control of apoptosis. Activity of complex I, II and IV of the
mitochondrial electron transport chain is signicantly reduced in critically ill
patients with a corresponding decrease in ATP levels, possibly under the inuence
of ROS, NO, TNFα and IL-1. Whether this is an adaptive response to limit oxygen
consumption, ROS-mediated damage, or to promote aerobic glycolysis, or a consequence of cell injury which contributes to multiorgan dysfunction in sepsis, remains
uncertain [20].
Microvascular shunting and mitochondrial dysfunction underlie the observation
that an oxygen extraction decit and multi-organ dysfunction (MOD) can persist
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despite resolution of macrovascular haemodynamic variables. Evidence of tissue
hypoxia frequently co-exists with globally supranormal oxygen delivery and elevated mixed venous oxygen saturation.
17.4.5 Pathological Vasodilation inSeptic Shock
Septic shock is characterised by systemic hypotension and tissue hypoperfusion.
Uncontrolled arterial vasodilation dissipates the head of pressure required to appropriately distribute blood ow, whilst reduced venomotor tone (coupled with uid
loss through leaky endothelium) reduces stressed venous volume, ventricular preload and cardiac output.
Pathological vasodilation is a manifestation of both increased baseline vessel
calibre and reduced sensitivity to endogenous and administered vasoconstrictors.
Inammatory cytokines promote the production of NO from the cationic amino acid
L-arginine by activating inducible NOS (iNOS) in neutrophils and vascular smooth
muscle cells. Compared to eNOS, iNOS produces far greater amounts of NO (nanomolar rather than picomolar) and lacks feedback control. iNOS inhibitors improve
vascular tone and blood pressure in patients with septic shock but not their outcome
[21], perhaps reecting the complexity of trying to interrupt an endogenous pathway which exerts both useful and toxic effects. Endothelium derived prostacyclin,
the anaphylotoxins C3a and C5a (products of the complement cascade), PAF, adrenomedullin and other endogenous vasodilators all contribute to pathological vasodilation. Septic shock is associated with initial spikes in plasma corticosteroid and
vasopressin levels followed by relative deciencies in both [22, 23], whilst ROS
oxidise and deactivate circulating noradrenaline. Moreover, even invitro, sensitivity
to α1-receptor agonists is reduced in arterioles from animals with septic shock
potentially as a consequence of receptor downregulation, increased myosin phosphatase activity and increased ATP sensitive K
+
channel conductance [24, 25].
17.4.6 Sepsis Induced Cardiac Dysfunction
In early sepsis, cardiac output may be impaired despite normal contractility because
of reduced preload secondary to venodilation, capillary uid leak and inadequate
diastolic lling time. This may be partly overcome with uid loading and judicious
vasopressor use. Sepsis is also associated with elevation in pulmonary vascular
resistance, a possible consequence of endothelial injury; elevated right ventricular
afterload contributes to impaired RV contractility and RV dilation (which may, in
turn, compromise LV lling). In up to 50% of cases of sepsis, however, intrinsic
myocardial systolic and diastolic function are depressed as part of the MOD syndrome complicating sepsis. Postulated mechanisms of myocardial dysfunction in
sepsis and septic shock are listed in Table 17.2 [26, 29]. Signicantly,
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Table 17.2 Mechanisms of myocardial dysfunction in sepsis [26, 27]
Pathophysiological mechanism Causative factors
Downregulated β
downstream pathway activity
Dysregulated Ca
sarcoplasmic reticulum
Direct cardiomyocyte injury Bacterial toxins, ROS, leucocyte
Suppressed mitochondrial activity, reduced
oxygen utilisation and loss of redox homeostasis
Mechanically compromised contraction and
relaxation
-adrenergic receptors and
1
2+
transients, Ca2+ leak from
NO, TNFα, IL-1, other ‘myocardial
depressant factors (MDF)
NO, ROS, MDF
DAMPs, PAMPs binding to TLR
Leucocyte binding to cardiomyocyte
adhesion molecules [
degranulation, NETs, microvascular
dysfunction, MDF
DAMPs, PAMPs binding to TLR
ROS, NO, cytokines, MDF
Myocardial oedema
28]
B. Reddi
cardiomyocyte death is a rare event in sepsis and does not explain the degree of
functional depression observed. A fundamental question is the extent to which
observed alterations are protective versus maladaptive. For instance, NO reduces
myocardial oxygen consumption, acts as a free radical scavenger, promotes coronary blood ow and improves ventricular compliance [29]. Interestingly survivors
tend to have lower ejection fraction and larger LV end diastolic volume (EDV) than
non- survivors suggesting that operating with higher ventricular preload is somehow
protective in sepsis despite being energetically less favourable in health [27].
17.4.7 Other Sepsis Induced Organ Dysfunction
Sepsis is a multisystem disorder which can cause dysfunction in any organ system.
Examples include encephalopathy, acute respiratory distress syndrome (ARDS),
acute kidney injury (AKI), acute liver injury, loss of gut integrity, polyneuropathy
and myopathy.
Up to 65% of patients with septic shock will develop AKI.Once thought to be
primarily driven by microcirculatory insufciency, it is now recognised that AKI
often develops in the context of normal or high renal blood ow. Although microvascular dysfunction and local inammation can drive tubular injury the surprisingly bland histopathology and often rapid recovery suggest that some of the tubular
dysfunction observed is functional and perhaps adaptive; cytokines, PAMPs and
DAMPs induce cell cycle arrest and downregulate metabolism [28]. Encephalopathy
frequently accompanies sepsis and is mediated by cerebral endothelial changes with
increased blood:brain barrier permeability, ischaemic lesions, microabscesses and
microglial activation [30]. Common themes in the multi-organ dysfunction (MOD)
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syndrome are a causative role for inammatory cytokines and PAMPs/DAMPs,
microvascular and endothelial dysregulation, suppressed mitochondrial activity and
often functional impairment rather than necrosis, the latter suggesting that some
elements of MOD reect adaptive changes to reduce cellular stress. Genetic evaluation is a promising future research direction, as certain polymorphisms in genes
coding for cytokines are associated with more severe MOD.
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17.5 Clinical Manifestations
Taking a rational history of symptoms, risk factors and exposures, accompanied by
systematic clinical examination, often identies the presence and source of infection. Patients progressing to sepsis typically present with dysregulated temperature,
tachycardia, tachypnoea and leucocytosis/leucopaenia with organ dysfunction manifest as altered mental status (restlessness, delirium, obtundation), respiratory failure, oliguria, ileus, jaundice or bleeding diathesis. Although a classical transition
from a hyperdynamic circulation with bounding pulses and warm peripheries to a
low cardiac output state, with cold, mottled skin, lactic acidosis and narrow pulse
pressure is recognised, patients can present, and die, at any point along this spectrum. Hypotension must be considered in the context of pre-morbid blood pressure
and the inuence of chronic illness and concurrent medication use recognised. For
instance, a patient with coronary artery disease will be less tolerant of diastolic
hypotension, and beta-blocker therapy may mask tachycardia.
17.6 Investigation
Investigation should focus on the anatomic source of infection, the causative
organism and complications of the primary infection. Laboratory signs of sepsis
per se are often non-specic and arise from the underlying cause of sepsis or consequent hypoperfusion and/or organ dysfunction. Common ndings are listed in
Box 17.2. Both C-reactive protein and procalcitonin (PCT) have similar sensitivity
(0.77 vs. 0.78), specicity (0.79) and area under the receiver operating curve (0.85
vs. 0.86) for identifying sepsis [31]. Serum PCT is elevated in response to bacterial
infection and falls during recovery. Furthermore, levels are prognostic. A recent
randomised controlled trial and subsequent meta-analysis of over 4000 patients
concluded that overall mortality from sepsis was reduced when antimicrobial initiation, de- escalation or cessation was guided by algorithms incorporating PCT
measurement [32, 33].
Sterilisation of blood cultures can occur within minutes of administering antibiotics and it is recommended that, provided substantial delay to antimicrobial administration is not incurred, blood, cerebrospinal uid, sputum, urine or wound cultures
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Box 17.2
Laboratory ndings consistent with the presence of sepsis
• Leukocytosis or leukopenia
• Normal white cell count with >10% immature forms
• Thrombocytopaenia
• Elevated prothrombin and activated partial thromboplastin time, low
brinogen, elevated brin degradation products
• Hyperglycaemia
• Elevated urea and creatinine
• Hyperbilirubinaemia, hypoalbuminaemia, deranged liver enzymes
• Elevated troponin
• Adrenal insufciency (hyponatraemia, hyperkalaemia, normal anion gap
acidosis)
• Euthyroid sick syndrome
• Elevated C-reactive protein
• Elevated pro-calcitonin (see text)
• Elevated lactate (tissue hypoperfusion, catecholamine driven aerobic glycolysis, reduced pyruvate dehydrogenase activity, mitochondrial
dysfunction)
B. Reddi
be taken before antibiotics are given when sepsis is suspected. Identifying the
organism permits de-escalation of antibiotic therapy reducing antibiotic resistance,
side effects, costs and potentially mortality [34]. It is recommended that two or
more sets (aerobic and aerobic) of blood cultures be taken. Blood cultures may be
drawn together, and yield has not been shown to be improved if timed to temperature spikes [35]. Diagnostic methods such as polymerase chain reaction assays and
microarrays are being translated into clinical practice and will hopefully better
inform antibiotic prescribing [36].
Other investigations that may be valuable include plain X-ray, CT or MR imaging, echocardiographic examination of heart valves, bronchoalveolar lavage or aspiration of body uids (e.g. joints).
17.7 Treatment
Sepsis and septic shock are medical emergencies. Resuscitation and treatment
should take place immediately and concurrently. The concept of ‘Early Goal
Directed Therapy’ (EGDT) was applied to management of septic shock following a
seminal study published over a decade ago suggesting that protocolised uid administration, vasopressor therapy, inotrope use and blood transfusion to achieve target
mean arterial pressure, central venous pressure and central venous oxygen
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saturation was associated with improved survival [37]. Although the benets of
‘protocolised care’ in this single centre study were not replicated in subsequent
larger, multi-centre trials this may reect in part an improvement in the ‘usual care’
afforded to patients with sepsis and septic shock [38]. The EGDT concept served to
establish sepsis as a clinical entity demanding timely, multifaceted treatment and
triggered an effective research program which has culminated in the development of
the evidence based Surviving Sepsis Campaign (SSC) Guidelines [39] and a progressive reduction in sepsis mortality. Unless otherwise specied the management
approach described in this chapter reects the recommendations of these evidence
based guidelines.
17.7.1 Initial Resuscitation
As with any acutely unwell patient the airway should be immediately assessed and
secured if necessary. Adequate arterial oxygenation should be achieved using supplementary oxygen or assisted ventilation as appropriate. Severe sepsis is the most
common cause of ARDS.A lung protective ventilation strategy [40] should be used
with consideration of prone positioning, neuromuscular blockade and judicious
titration of positive end-expiratory pressure.
Circulatory management is a critical and challenging aspect of sepsis and septic
shock management. In patients with septic shock an initial uid bolus of 30mLs/
kg administered within the rst 3h appears safe and is recommended, albeit on
limited evidence. More rapid infusion may be warranted in some patients.
Crystalloids and colloids appear similarly efcacious [41] although hydroxyethyl
starch (HES) is no longer recommended since HES 130/0.42 administration has
been associated with poorer outcomes [42]. Balanced crystalloid solutions are a
rational option [43, 44]. Where patients have already received substantial volumes
of crystalloid there may be a case for continuing uid resuscitation with albumin
solution [39]. Following initial uid resuscitation, blood pressure, heart rate, tissue
perfusion (including brain, kidney, gut, skin), plasma lactate and mixed venous
oxygen saturation (SvO
ciency persists and to guide the decision between further uid therapy, vasopressor
use or inotropy.
The potential benet of volume expansion, related to an increase in cardiac output and oxygen delivery, must be balanced by the risk of aggravating lung and tissue
oedema. Fluid therapy should be carefully titrated, prescribing limited volumes
with regular re-evaluation are preferable to large volumes with infrequent monitoring. Using static measures of uid status such as central venous pressure to guide
uid administration in sepsis has been shown to be physiologically awed and clinically unreliable [45–47]. Instead, dynamic assessment predicts more accurately
which patients are likely to respond to a uid bolus with an increase in stroke volume. This can be achieved by passive leg raise, assessment of cardiopulmonary
interactions or directly measuring the change in cardiac output following uid
) are re-evaluated to identify whether circulatory insuf-
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B. Reddi
administration [48, 49]. Latterly, recognising the association between positive uid
balance and mortality in sepsis [50], a concept of ‘de-resuscitation‘ has gained currency, emphasising the need to limit uid administration in patients who are no
longer shocked or uid responsive, and to instigate diuresis once vasopressors
are weaned.
In shocked patients with an inadequate or detrimental response to uid therapy,
vasopressor support may be warranted. Below a critical mean arterial pressure
(MAP) threshold autoregulation is exhausted and vital organ perfusion is limited by
MAP. Multiple studies have evaluated the benets of different MAP targets in
patients with septic shock treated with vasopressors, ranging from 65 to 85mmHg.
Higher pressures have been associated with greater cardiac output, varying effects
of tissue perfusion indices and higher rates of arrhythmia [51–53]. The only study
powered to identify mortality difference found no benet in targeting 65 rather than
85 mmHg, but a reduction in the need for renal replacement therapy amongst
patients with chronic hypertension in the higher target pressure group [54]. Although
an initial blood pressure target of 65mmHg is reasonable for most patients, higher
targets might be considered in patients with a history of chronic hypertension in
whom the effective autoregulation range is shifted towards higher pressures.
However, blood pressure is not an ends in itself. Once a pressure target is attained,
the patient should be re-evaluated for adequacy of tissue perfusion using the clinical
indices described above (end-organ function, lactate etc.) and the target reconsidered accordingly. Lactate clearance in particular appears to be associated with outcome and resuscitation paradigms centred on promoting resolution of lactic acidosis
have shown promise [55]. Once euvolaemia is established, noradrenaline is recommended as a rst line vasopressor augmenting both vasomotor tone and cardiac
output (through an increase in cardiac preload and contractility) [56]. Vasopressin is
noradrenaline-sparing but has an unclear effect on patient-centred outcomes.
Vasopressin is an option for cases of refractory vasodilatory shock but its use can be
complicated by splanchnic, myocardial and digital ischaemia [57, 58]. Exogenous
angiotensin II has also shown promise as a therapeutic option in vasodilatory shock
[
59]. Because vasopressor sensitivity is variable throughout the circulation, and
some regions are already relatively ischaemic, administering high doses of exogenous vasopressors risks critically impairing vital organ perfusion especially if hypovolaemia and reduced cardiac output are not addressed.
Although septic shock may be associated with augmented or ‘hyperdynamic’
circulation because of reduced systemic vascular resistance and tachycardia, some
patients have either pre-existing or sepsis-related ventricular dysfunction.
Echocardiography is an important early adjunct to clinical examination. Findings
should be interpreted in the context of the prevailing loading conditions, which
greatly inuence stoke volume and ejection fraction and may be profoundly
deranged in sepsis. Systolic dysfunction may respond better to inotropic support
and strategies to augment cardiac output [60] rather than further uid or vasopressor
administration. Dobutamine is a rapidly effective, titratable inotrope which improves
indices of tissue perfusion, although it’s use can be complicated by tachyarrhythmia
and excessive vasodilation. Dosage should be titrated by monitoring indices of
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tissue perfusion in response to manipulation of cardiac output. As noted above,
normal/high SvO2 can be misleading in the presence of impaired oxygen extraction
and may not reliably identify impaired cardiac output. Conversely, low SvO2 (<65%)
suggests low cardiac output. Levosimendan promotes contractility, relaxation and
reduces pulmonary artery pressure whilst circumventing the β-receptor and exhibiting a favourable oxygen consumption prole. However, it is costly, difcult to titrate
and associated with arguably worse outcomes than standard care [61].
Preliminary human studies indicate that selective β1-adrenergic receptor blockade (titrated to keep heart rate< 95 bpm) may improve cardiac function, lactate
clearance, microvascular blood ow and even survival [62]. Putative mechanisms
include augmented diastolic lling and improved myocardial efciency, inhibition
of inammatory and pro-apoptotic pathways, and mitigating myocardial catecholamine toxicity and cytosolic Ca2+ overload.
The use of vasoactive and inotropic agents usually requires continuous invasive
arterial pressure monitoring and frequently central venous access. Pulse contour
analysis devices or echocardiographic monitoring may be helpful. Because of the
need for frequent re-evaluation and advanced physiologic monitoring, patients with
severe sepsis and septic shock are generally best managed in an intensive care
environment.
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17.7.2 Antimicrobial Therapy
The benets of early initiation of antimicrobial therapy in patients with septic shock
are widely recognised. Each hour delay in delivery of antibiotic is associated with a
mortality cost [63] and administration within 1h is recommended as a minimum
target. Furthermore, indices of organ dysfunction and length of stay are adversely
affected by delayed antibiotic therapy [39]. The data relating timing of antibiotics
and outcome in patients with less severe sepsis is less clear. Sepsis is often overdiagnosed [64] and in light of data suggesting that overtreatment may increase mortality [65] it is arguable that when a patient is not shocked and has a lower probability
of infection, spending time gathering more data to conrm the diagnosis and obtain
appropriate microbiology samples is justiable [66].
Initial antibiotic cover should have broad activity against the likely causative
pathogens. Inappropriate empiric therapy is associated with up to ve-fold increase in
mortality [67]. The choice will be determined by factors such as the patient’s clinical
presentation, immune status, recent healthcare facility admission and antibiotic use,
and local microbial ecology. Patients who are considered vulnerable to infection with
multidrug-resistant gram-negative pathogens such as Pseudomonas, Acinetobacter or
Klebsiella should receive a supplementary gram-negative agent in addition to the
empiric regime to increase the probability that they receive at least one active agent.
Similarly, vancomycin, teicoplanin, or another anti-MRSA agent can be used when
risk factors for MRSA exist. Broadening cover in this way, to ensure potential organisms are covered by one of the administered agents, is distinct from the concept of
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