Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

97. Severe Sepsis and Septic Shock

S. Lena Kang-Birken


 Images The spectrum of microorganisms associated with sepsis has changed from predominantly gram-negative bacteria in the late 1970s and 1980s to gram-positive bacteria as the major pathogens since the late 1980s.

 Images Candidemia is a major cause of morbidity and mortality. Candida albicans remains the most common pathogen (45.6%); however, non–albicans Candida species collectively is more frequently isolated (54.4%).

 Images Sepsis presents a complex pathophysiology, characterized by the activation of multiple overlapping and interacting cascades leading to systemic inflammation, a procoagulant state, and decreased fibrinolysis.

 Images Mortality rates with sepsis are higher for older patients with preexisting disease, intensive care unit care, and multiple organ failure.

 Images Prompt initiation of broad-spectrum, parenteral antibiotic therapy is required due to the high incidence of complications and mortality with sepsis.

 Images A significant volume of fluid leaks from the vasculature occurs with sepsis, and initial fluid resuscitation with large volumes of fluid is required. There is no difference in clinical outcomes between colloid and crystalloid fluid resuscitation.

 Images Norepinephrine is generally preferred over dopamine as the vasopressor to correct hypotension in septic shock.

 Images Early goal-directed therapy during the first 6 hours, consisting of hemodynamic monitoring with a central venous catheter, volume resuscitation, inotropic therapy, and red blood cell transfusions, demonstrated a significant clinical outcome benefit with a 16% absolute reduction in 28-day mortality.

 Images A blood glucose level less than 150 mg/dL (8.3 mmol/L) is recommended for the majority of critically ill patients to reduce morbidity and mortality without the detrimental effects associated with hypoglycemia.

 Images IV hydrocortisone is recommended for adult patients with septic shock whose blood pressure is unresponsive to fluids and vasopressors.

Sepsis and severe sepsis continue to pose major healthcare burden. The incidence of sepsis in the United States increased from 82.7 cases per 100,000 population in 1979 to 240.4 cases per 100,000 population in 2000, for an annualized increase of 8.7 percent.1 Severe sepsis increased from 200 cases per 100,000 in 2003 to 300 cases per 100,000 in 2007, a 50% increase.2 Despite aggressive medical care and advances, overall in-hospital deaths increased from 75 per 100,000 in 2003 to 87 per 100,000 in 2007, a 16% increase.2 With increasing total hospital costs to $24.3 billion, there is a vital need for clinicians to comprehend the pathophysiology and to appreciate the management options for acutely ill patients with severe sepsis or septic shock.2


In 1992, a joint committee of the American College of Chest Physicians and the Society of Critical Care Medicine standardized the terminology related to sepsis for several reasons: (a) widespread confusion with the use of these terms, (b) the need to provide a flexible classification scheme for patient identification, (c) identification of an earlier therapeutic intervention, and (d) standardization of research protocols.3

The criteria for the new terms provide specific physiologic variables that can be used to categorize a patient as having bacteremia, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, or multiple-organ dysfunction syndrome (MODS), suggesting an important continuum of progressive physiologic decline (Table 97–1). The classification of sepsis was modified to include severe sepsis, septic shock, and refractory septic shock (Fig. 97–1).4 Severe sepsis refers to patients with an acute organ dysfunction, such as acute renal failure or respiratory failure. Septic shock refers to sepsis patients with arterial hypotension that is refractory to adequate fluid resuscitation, thus requiring vasopressor administration. It is important to note that progression from sepsis to MODS can occur in the absence of an intervening period of septic shock. Finally, refractory septic shock exists if dopamine IV infusion greater than 15 mcg/kg/min or norepinephrine greater than 0.25 mcg/kg/min is required to maintain a mean blood pressure greater than 60 mm Hg.

TABLE 97-1 Definitions Related to Sepsis



FIGURE 97-1 Relationship of infection, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock. (ARDS, acute respiratory distress syndrome; CI, cardiac index; DIC, disseminated intravascular coagulation; MODS, multiple-organ dysfunction syndrome.)


Predisposing factors of septic shock include age, male gender, nonwhite ethnic origin in North Americans, comorbid diseases, malignancy, immunodeficiency or immunocompromised state, chronic organ failure, alcohol dependence, genetic factors, and seasonal variation.1,58

The leading primary sites of microbiologically documented infections that lead to sepsis are the respiratory tract (39% to 50%), intraabdominal space (8% to 16%), and urinary tract (5% to 37%).2,9 Although almost any microorganism can be associated with sepsis and septic shock, the most common etiologic pathogens are gram-positive bacteria (52% of patients), followed by gram-negative bacteria (37.6%), polymicrobial infections (4.7%), anaerobes (1.0%), and fungi (4.6%).1,10

Gram-Positive Bacterial Sepsis

Images Since 1987, gram-positive organisms have been the predominant pathogens in sepsis and septic shock, accounting for 52.1% of all cases.1 They are commonly caused by Staphylococcus aureus, Streptococcus pneumoniae, coagulase-negative staphylococci, and Enterococcus species.912

S. aureus bacteremia is associated with an overall mortality rate ranging between 10% and 30%.13 Factors related to a higher mortality include older age, shock, preexisting renal failure, and the presence of a rapidly fatal underlying disease. Staphylococcus epidermidis is most often related to infected intravascular devices, such artificial heart valves and stents, and the use of IV and intraarterial catheters. Enterococci are isolated most commonly in blood cultures following a prolonged hospitalization and treatment with broad-spectrum cephalosporins.

Gram-Negative Bacterial Sepsis

While the overall percentage of gram-negative sepsis has decreased, the number of cases remains substantial.1,10 Escherichia coli (8% to 30%), Klebsiella species (8% to 23%), and Pseudomonas aeruginosa(7% to 18%) are the most commonly isolated gram-negative microorganisms in sepsis.912,14 Other common gram-negative pathogens include Serratia species, Enterobacter species, and Proteus species. P. aeruginosa and Acinetobacter species are more likely to be associated with prior antibiotic exposure.14

A greater proportion of patients with gram-negative bacteremia develop clinical sepsis, and also more likely to produce septic shock in comparison to gram-positive organisms, 50% versus 25%, respectively.9,10,12 Specifically, P. aeruginosa sepsis has been associated in a higher mortality rate.10,14 The major factor associated with the outcome of gram-negative sepsis appears to be the severity of any underlying conditions. Patients with rapidly fatal conditions, such as acute leukemia, aplastic anemia, and burn injury to >70% of the body’s surface, have a significantly worse prognosis than those patients with nonfatal underlying conditions such as diabetes mellitus and chronic renal insufficiency.1,2

Anaerobic and Miscellaneous Bacterial Sepsis

Anaerobic bacteria such as Bacteroides fragilis and Clostridium species are usually considered low-risk organisms for the development of sepsis. If present, anaerobes are often found together with other pathogenic bacteria that are commonly found in sepsis. Polymicrobial infections accounted for 5% to 39% of sepsis.1,1012,14 Mortality rates associated with polymicrobial infections are similar to sepsis caused by a single organism. Although some clinicians believe the particular combination of organisms present in polymicrobial sepsis can provide clues to the source of infection, no clear source for the infection can be identified in up to 25% of cases.

Fungal Sepsis

Images Candidemia is among the most common fungal etiologic agents of bloodstream infections. Although Candida albicans was the most commonly isolated fungus from blood cultures (45.6%), collectively, non-albicans Candidaspecies were more frequently isolated (54.4%).1012,15,16 Non-albicans Candida species include C. glabrata (26%), C. parapsilosis (15.7%), C. tropicalis (8.1%), and C. krusei (2.5%). Other fungi identified as causes of sepsis are CryptococcusCoccidioidesFusarium, and Aspergillus.11 Risk factors for fungal infection include abdominal surgery, poorly controlled diabetes mellitus, prolonged granulocytopenia, broad-spectrum antibiotic treatment, corticosteroid treatment, prolonged hospitalization, central venous catheter, total parenteral nutrition, hematologic malignancy, and chronic indwelling bladder (Foley) catheter. Recent exposure to azoles is an important risk factor for infection with fluconazole-resistant Candida spp.17 Furthermore, a prospective nationwide surveillance study of candidemia suggested a close correlation between antibacterial drug exposure and bloodstream infection with C. glabrata and fluconazole-resistant Candida isolates.17

In a prospective analysis of the Antifungal Therapy Alliance database, the overall crude 12-week mortality rate for sepsis due to candidemia was 35.2%.15 A higher in-hospital mortality was reported (61%) among healthcare-associated candidemia.16 The highest mortality rate of 52.9% was observed in patients with C. krusei candidemia; C. parapsilosis candidemia was associated with the lowest 12-week mortality rate (23.7%). Hematologic diseases, neutropenia, and a higher number of positive blood cultures were associated with poor outcome irrespective of the patient’s gender, age, or days of antifungal drug treatment.


Sepsis is the result of complex interactions among the invading pathogen, the host immune system, and the inflammatory responses. The inflammatory response leads to damage to host tissue, and the antiinflammatory response causes leukocytes to activate. Once the balance to control the local inflammatory process to eradicate the invading pathogens is lost, systemic inflammatory response occurs, converting the infection to sepsis, severe sepsis, or septic shock.

Cellular Components for Initiating the Inflammatory Process

The pathophysiologic focus of gram-negative sepsis has been on the lipopolysaccharide component of the gram-negative bacterial cell wall. Commonly referred to as endotoxin, this substance is unique to the outer membrane of the gram-negative cell wall and is generally released with bacterial lysis. Lipid A, the innermost region of the lipopolysaccharide, is highly immunoreactive and is considered responsible for most of the toxic effects. Although lipid A can affect tissues directly, its predominant effect is to activate macrophages and trigger inflammatory cascades critical in the progression to sepsis and septic shock.18 Endotoxin forms a complex with an endogenous protein called a lipopolysaccharide-binding protein, which then engages the CD14 receptor on the surface of a macrophage. Subsequently, cytokine mediators are activated and released by the macrophages.

In gram-positive sepsis, the exotoxin peptidoglycan on the cell wall surface appears to exhibit proinflammatory activity. Although it competes with lipid A for similar binding sites on CD14, the potency of peptidoglycan is less than that of endotoxin.18 However, an important feature of gram-positive bacteria such as S. aureus and S. pyogenes is the production of potent exotoxins, some of which have been associated with septic shock.

Pro- and Antiinflammatory Mediators

Sepsis involves activation of inflammatory pathways, and a complex interaction between proinflammatory and antiinflammatory mediators plays a major role in the pathogenesis of sepsis. The key proinflammatory mediators are tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), which are released by activated macrophages.1820 Other mediators that may be important for the pathogenesis of sepsis are interleukin-8 (IL-8), platelet-activating factor (PAF), leukotrienes, and thromboxane A2.

The TNF-α levels in plasma can be increased in patients with a variety of diseases and in many healthy people. However, there is a correlation of plasma TNF-α levels with the severity of sepsis. It is highly elevated early in the inflammatory response in most patients with sepsis.1921 The TNF-α release leads to activation of other cytokines (IL-1 and IL-6) associated with cellular damage. In addition, TNF-αstimulates the release of cyclooxygenase-derived arachidonic acid metabolites (thromboxane A2 and prostaglandins) that contribute to vascular endothelial damage. Higher levels of IL-6 and IL-8 have been reported in patients with septic shock than those with SIRS.8

The significant antiinflammatory mediators include interleukin-1 receptor antagonist (IL-1RA), interleukin-4 (IL-4), and interleukin-10 (IL-10).18,19 These antiinflammatory cytokines inhibit the production of the proinflammatory cytokines and down regulate some inflammatory cells. Levels of IL-10 and IL-1RA are higher in septic shock than in sepsis, and higher levels are found among nonsurviving patients than in survivors.19,20

The activation and secretion of pro- and antiinflammatory mediators in septic shock occur as a simultaneous immune response as early as the first 24 hours of diagnosis.14 As Fig. 97–2 illustrates, the balance between pro- and antiinflammatory mechanisms determines the degree of inflammation, ranging from local antibacterial activity to systemic tissue toxicity, organ failure, or death.1921


FIGURE 97-2 The balance between pro- and antiinflammatory mediators. (CARS, compensatory antiinflammatory response syndrome; IL, interleukin; IL-1RA, interleukin-1 receptor antagonist; SIRS, systemic inflammatory response syndrome; TNF, tumor necrosis factor.)

Cascade of Sepsis

Images The cascade leading to development of sepsis is complex and multifactorial, involving various mediators and cell lines. Endothelial cells produce a variety of cytokines that mediate a primary mechanism of injury in sepsis. When injured, endothelial cells allow circulating cells such as granulocytes and plasma constituents to enter inflamed tissues, which can result in organ damage.

The microcirculation is affected by sepsis-induced inflammation. The arterioles become less responsive to either vasoconstrictors or vasodilators. The capillaries are less perfused even at the early phases of septic shock, and there is neutrophil infiltration and protein leakage into the venules.22

The inflammatory process in sepsis is also directly linked to the coagulation system. Proinflammatory mechanisms that promote sepsis are also procoagulant and antifibrinolytic, whereas fibrinolytic mechanisms can be antiinflammatory.23 A key endogenous substance involved in inflammation of sepsis is activated protein C, which enhances fibrinolysis and inhibits inflammation. Levels of protein C are reduced in patients with sepsis.23


Septic shock is the most ominous complication associated with sepsis, and it may lead to several complications including disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and multiple organ failure. The organs that failed most frequently are lungs (18%) and kidneys (15%).1 The less frequent are cardiovascular failure (7%), hematologic failure (6%), metabolic failure (4%), and neurologic failure (2%).1 Mortality occurs in approximately half of the patients with septic shock.

Disseminated Intravascular Coagulation

DIC is the inappropriate activation of the clotting cascade that causes formation of microthrombi, resulting in consumption of coagulation factors, organ dysfunction, and bleeding. Sepsis remains the most common cause of DIC, and the incidence of DIC increases as the severity of sepsis increases. In sepsis alone, the incidence was 16% in comparison to 38% in septic shock.24,25 DIC occurs in up to 50% of patients with gram-negative sepsis, but it is also common in patients with gram-positive sepsis.

DIC begins with the activation and production of the proinflammatory cytokines, such as TNF, IL-1, and IL-6, which appear to be the principal mediators, along with endotoxin. The combination of excessive fibrin formation, inhibited fibrin removal from a depressed fibrinolytic system, and endothelial injury result in microvascular thrombosis and DIC.

Complications of DIC vary and depend on the target organ affected and the severity of the coagulopathy. DIC can produce acute renal failure, hemorrhagic necrosis of the GI mucosa, liver failure, acute pancreatitis, ARDS, and pulmonary failure. Furthermore, as the procoagulant state appears to be the key in the pathogenesis of MODS, coagulation dysfunction and MODS often coexist in sepsis.

Acute Respiratory Distress Syndrome

Pulmonary dysfunction, the most common organ dysfunction in sepsis, usually precedes other organs, and it can even initiate the development of SIRS with resultant MODS. Activated neutrophils and platelets adhere to the pulmonary capillary endothelium, initiating multiple inflammatory cascades with a release of a variety of toxic substances. There is diffuse pulmonary endothelial cell injury, increased capillary permeability, and alveolar epithelial cell injury. Consequently, interstitial pulmonary edema occurs that gradually progresses to alveolar flooding and collapse. The end result is loss of functional alveolar volume, impaired pulmonary compliance, and profound hypoxemia.

Coagulation is locally upregulated in the injured lung, whereas fibrinolytic activity is depressed. These abnormalities occur concurrently and favor alveolar fibrin deposition. Anticoagulant interventions that block the extrinsic coagulation pathway can protect against the development of pulmonary fibrin deposition as well as lung dysfunction and acute inflammation.25 Overall, fibrin deposition in the injured lung and abnormalities of coagulation and fibrinolysis are integral to the pathogenesis of ARDS.

Hemodynamic Effects

The hallmark of the hemodynamic effect of sepsis is the hyperdynamic state characterized by high cardiac output and an abnormally low systemic vascular resistance (SVR).22,26 TNF-α and endotoxin directly depress cardiovascular function. Endotoxin depresses left ventricular (LV) function independent of changes in LV volume or vascular resistance. Myocardial dysfunction is common in severe sepsis and septic shock, affecting 64% of patients, and involves LV in more than half of the patients.26

Persistent hypotension raises concern for the balance of oxygen delivery (DO2) to the tissues and oxygen consumption (VO2) by the tissues. Sepsis results in a distributive shock characterized by inappropriately increased blood flow to particular tissues at the expense of other tissues, which is independent of specific tissue oxygen needs. This perfusion defect is accentuated by an increased precapillary atrioventricular shunt. If perfusion decreases, oxygen extraction increases, and the arteriovenous oxygen gradient widens. Cellular DO2 is decreased, but VO2 remains unaffected. When increased oxygen demand occurs without increased blood flow, the increased VO2 is compensated by increased oxygen extraction. If perfusion decreases sufficiently in the face of high metabolic demands, then the reserve DO2can be exceeded, and tissue ischemia results. Significant tissue ischemia leads to organ dysfunction and failure. Therefore, systemic DO2 relative to VO2 should be optimized by increasing oxygen delivery or decreasing oxygen consumption in a hypermetabolic patient.

Acute Renal Failure

Early acute kidney injury occurs in 42% to 64% of adult patients with sepsis and septic shock.27,28 Without normal urine output, fluid overload in extravascular space including the lungs develops, leading to impairment of pulmonary gas exchange and severe hypoxemia. Consequently, compromised oxygen delivery exacerbates peripheral ischemia and organ damage. Adequate renal perfusion and a trial of loop diuretics should be initiated promptly in oliguric or anuric patients with MODS along with dialysis to facilitate volume and electrolytes.


Table 97–2 lists some of the common clinical features of sepsis, although several of these findings are not limited to infectious processes. The initial clinical presentation can be referred to as signs and symptoms of early sepsis, defined as the first 6 hours. They are typically fever, chills, and change in mental status. Hypothermia can occur with a systemic infection, and this is often associated with a poor prognosis.29 In patients with sepsis caused by gram-negative bacilli, hyperventilation can occur even before fever and chills, and it can lead to respiratory alkalosis as the earliest metabolic change.

TABLE 97-2 Signs and Symptoms Associated


Progression of uncontrolled sepsis leads to clinical evidence of organ system dysfunction as represented by the signs and symptoms attributed to late sepsis. With the exception of rapidly progressing cases as in meningococcemia, P. aeruginosa, or Aeromonas infection, the onset of shock is slow and usually follows a period of several hours of hemodynamic instability. Oliguria often follows hypotension. Increased glycolysis with impaired clearance of the resulting lactate by the liver and kidneys and tissue hypoxia because of hypoperfusion result in elevated lactate levels, contributing to metabolic acidosis. Altered glucose metabolism, including impaired gluconeogenesis and excessive insulin release, is evidenced by either hyperglycemia or hypoglycemia.


Images As the patient progresses from SIRS to sepsis to severe sepsis to septic shock, mortality increases in a stepwise fashion. Mortality rates are higher for patients with advanced age, preexisting disease, including chronic obstructive pulmonary disease, neoplasm, and human immunodeficiency virus disease, intensive care unit (ICU) care, more failed organs, positive blood cultures, and Pseudomonas species infection.10,13 In one analysis of cases, mortality increased with age from 10% in children to 38.4% in those 85 years or older.1 ICU admission was required in 51.1% of patients with severe sepsis; of those patients, mortality was reported in 34.1%.1 Mortality from severe sepsis and MODS is most closely related to the number of dysfunctioning organs. As the number of failing organs increased from two to five, mortality increased from 54% to 100% (Fig. 97–3).30 Duration of organ dysfunction can also affect the overall mortality rate.


FIGURE 97-3 Mortality related to the number of failing organs.

An elevated lactate concentration of >4 mmol/L in the presence of SIRS significantly increases ICU admission rates, and persistent elevations in lactate for more than 24 hours are associated with a mortality rate as high as 89%.31 Inversely, patients with higher lactate clearance after 6 hours of emergency department intervention have improved outcome compared with those with lower lactate clearance. There was an ~11% decrease in the likelihood of mortality for each 10% increase in lactate clearance.31

Diagnosis and Identification of Pathogen

The presence of clinical features suggesting sepsis should prompt further evaluation of the patient. In addition to obtaining a careful history of any underlying conditions and recent travel, injury, animal exposure, infection, or use of antibiotics, a complete physical examination should be performed to determine the source of the infection.

A collection of specimens should be sent for culture prior to initiating any antimicrobial therapy. In critically ill septic patients, two or three sets of blood cultures should be collected without temporal separation between the sets.32,33 With suspected catheter-related infection, a pair of blood cultures should be drawn through every lumen of each vascular access device.33 In severe community-acquired pneumonia, blood cultures and respiratory secretions must be obtained. Urinary antigen detection of Legionella sero group 1 is recommended during outbreaks. To document a soft tissue infection, a Gram stain and bacterial culture of any obvious wound exudates should be performed. A needle aspiration of a closed infection such as cellulitis or abscess may be needed for stain and bacterial culture. In abdominal infections, fluid collections identified by imaging studies should be aspirated for Gram stains and aerobic and anaerobic cultures. Recent development of accurate and rapid identification tests has demonstrated positive impact on prescribing appropriate therapy in bloodstream infections such as methicillin-resistant Staphylococcus aureus (MRSA) and Candida spp.34,35

A lumbar puncture is indicated in the case of mental alteration, severe headache, or a seizure, assuming that there are no focal cranial lesions identified by computed tomography scan. Further tests may be indicated to assess any systemic organ dysfunction caused by severe sepsis. The laboratory tests should include hemoglobin, white blood cell (WBC) count with differential, platelet count, complete chemistry profile, coagulation parameters, serum lactate, procalcitonin (PCT), and arterial blood gases.


In 2008, a “surviving sepsis” campaign guideline for management of severe sepsis and septic shock was published as an international effort to increase awareness and improve outcome in severe sepsis.32 The primary goals of therapy for patients with sepsis are (a) timely diagnosis and identification of the pathogen, (b) rapid elimination of the source of infection medically and/or surgically, (c) early initiation of aggressive antimicrobial therapy, (d) interruption of pathogenic sequence leading to septic shock, and (e) avoidance of organ failure. Supportive care such as stress ulcer prophylaxis and nutritional support is important to prevent complications during the stay in the ICU. Table 97–3describes the summary of the surviving sepsis campaign treatment recommendations.

TABLE 97-3 Evidence-based Treatment Recommendations for Sepsis and Septic Shock


Elimination of the Source of Infection

After the source of infection is identified, prompt efforts to eradicate that source should be made.32 With an infected intravascular catheter, the catheter should be removed and cultured. Urinary tract catheters should be removed if association with sepsis is suspected. Suspicion of soft tissue (cellulitis or wound infection) or bone involvement should lead to aggressive debridement of the affected area. Evidence of an abscess or sepsis associated with any intraabdominal pathology should prompt surgical intervention.

Antimicrobial Therapy

Images The most recent guidelines from the Surviving Sepsis Campaign recommended starting IV antibiotic therapy as early as possible because early administration of broad-spectrum antibiotics is critical in decreasing the risk of mortality.32 Early administration (within 1 hour vs. 6 hours of diagnosis) of broad-spectrum antibiotics was independently associated with lower hospital mortality in patients with severe sepsis.36,37

Delays in the initiation of effective antimicrobial therapy after the onset of hypotension were significant predictors of mortality.38 In a large retrospective study, inappropriate initial antimicrobial therapy occurred in about 20% of patients with septic shock, and was associated with a fivefold reduction in survival in comparison to those who received appropriate therapy (52.0% vs. 10.3%, respectively).12Therefore, early administration of appropriate antimicrobial therapy is critical in the treatment of severe sepsis and septic shock.

Pharmacokinetics of Antimicrobial Agents in Critically Ill Patients

Pathophysiologic changes have been reported in sepsis that can affect drug distribution, and adjusted dosing regimens are required in critically ill patients with sepsis.39 Initially high creatinine clearance can be seen in patients with normal serum creatinine because of increased renal preload. Volume of distribution can increase because of fluid accumulation from leaky capillaries and/or altered protein binding. Consequently, some antimicrobial agents, especially for hydrophilic antimicrobials including aminoglycosides, β-lactams, carbapenems, and vancomycin can result in lower peak serum concentrations with usual doses.40 However, as sepsis progresses, organ perfusion decreases because of significant myocardial depression and leads to multiple organ dysfunction. Consequently, clearance of antimicrobial agents is decreased, prolonging the elimination half-life and accumulation of metabolites. Hence, in addition to selecting the most appropriate antimicrobial agents, a clinician must ensure effective antibiotic usage, such as proper dosing, interval of administration, optimal duration of treatment, monitoring of drug levels when appropriate, and avoidance of unwanted drug interactions. The lack of adherence to these requirements can lead to suboptimal or excessive tissue concentrations that can promote antibiotic resistance, toxicity, and inadequate efficacy despite appropriate antibiotic selection.

Selection of Antimicrobial Agents

The selection of an empiric regimen should be based on the suspected site of infection, the most likely pathogens, acquisition of the organism from the community or hospital, the patient’s immune status, and the antibiotic susceptibility and resistance profile for the institution. All patients should be treated initially with parenteral antibiotics for optimal drug concentrations within the first hour of recognition of severe sepsis after appropriate cultures have been taken.32 Empiric therapy for an immunocompromised patient should be broad enough to cover likely pathogens and penetrate adequately into the presumed infection site. Once the pathogen and its susceptibility pattern are known, the antimicrobial regimen should be modified accordingly.

Table 97–4 lists antimicrobial regimens that can be used empirically based on the possible source of infection. In the nonneutropenic patient with a urinary tract infection, ceftriaxone and fluoroquinolones are generally recommended. When there is increased risk of P. aeruginosa in sepsis or hospital-acquired infections, an antipseudomonal antibiotic, such as ceftazidime, is recommended.41

TABLE 97-4 Empiric Antimicrobial Regimens in Sepsis


S. pneumoniae is the most common cause of community-acquired pneumonia, and it accounts for ~60% of all deaths. The rising incidence of penicillin-resistant S. pneumoniae requires empiric use of newer “respiratory” fluoroquinolones. Levofloxacin or moxifloxacin can be used as monotherapy, as they offer excellent coverage against penicillin-resistant pneumococci and aerobic gram-negative bacteria, as well as atypical pathogens, including Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae.42 Addition of a macrolide to a β-lactam empirical therapy improves outcome in severe pneumonia, and clarithromycin and azithromycin are effective against atypical pathogens and better tolerated than erythromycin.43

In nosocomial pneumonia, enteric gram-negative bacteria such as Enterobacter and Klebsiella species and P. aeruginosa are the major pathogens in addition to S. aureus. If P. aeruginosa infection is suspected, β-lactam antipseudomonal agents (ceftazidime or cefepime), antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin), or an aminoglycoside should be included in the regimen.44 When S. aureus is likely to be methicillin-resistant, linezolid may be preferred to vancomycin because of the poor penetration of vancomycin into the lungs, as well as the worldwide emergence of glycopeptide intermediately resistant S. aureus.45,46

Secondary peritonitis as a consequence of perforation of the GI tract is usually polymicrobial involving enteric aerobes and anaerobes, and as many as five organisms are isolated per patient. In general, if resistance for a given antibiotic is greater than 10% to 20% for a common intraabdominal pathogen in the community, that agent should be avoided. Because of widespread resistance of Escherichia coli to ampicillin/sulbactam, it is no longer recommended.47,48 Emerging fluoroquinolone-resistant E. coli and the local prevalence of extended-spectrum β-lactamase-producing strains of Klebsiella species and E. coli should be considered in choosing empiric therapy.47Bacteroides fragilis, the major pathogen, has shown uniform susceptibility to metronidazole, carbapenems, and β-lactam/β-lactamase inhibitors.49 High resistance rates were observed for clindamycin and moxifloxacin (as high as 60% for clindamycin and >80% for moxifloxacin), with relatively stable low resistance (5.4%) for tigecycline.

In addition to surgical intervention, broad-spectrum antibiotics, such as β-lactamase inhibitor combination agent (piperacillin/tazobactam) and tigecycline are appropriate in treating intraabdominal infections.48 Carbapenems such as imipenem, meropenem, and doripenem are indicated in the treatment of resistant pathogens, including Enterobacteriaceae and P. aeruginosa, in critically ill patients.48

Skin and soft tissue infections (SSTIs) range from cellulitis to rapidly progressive necrotizing fasciitis, which may be associated with septic shock and toxic shock syndrome. Staphylococci and streptococci long have been the leading causes of SSTIs, but severe SSTIs can be caused also by indigenous aerobes and anaerobes such as Clostridium species.50 Early initiation of appropriate empiric broad-spectrum antimicrobial therapy is essential and should include coverage against MRSA due to the high prevalence of community-associated MRSA strains.45,50 Vancomycin, daptomycin, and linezolid have comparable clinical efficacy and safety data for complicated skin and skin-structure infections caused by MRSA.45,51,52 A multicenter study of MRSA, vancomycin-resistant Enterococcus (VRE) faecium and coagulase-negative staphylococci bacteremic patients with sepsis suggested 70% success rate with daptomycin.53

Combination therapy does not appear to be more effective than monotherapy in reducing organ failure or mortality.11 However, the greatest benefit of combination therapy appeared to be in patients with Pseudomonas or multidrug-resistant gram-negative bacteremia and in neutropenic patients with severe sepsis or septic shock.32,54,55

The antimicrobial regimen should be reassessed after 48 to 72 hours based on the microbiological and clinical data. Once the culture results and antimicrobial susceptibility data return, therapy should be directed toward the isolated pathogen as part of good antibiotic stewardship to prevent drug toxicities and the development of nosocomial superinfections with Candida species, Clostridium difficile, or VRE.56Furthermore, improved patient care outcomes have been demonstrated with such de-escalation of antibiotic therapy.57

Antifungal Therapy

Candida species are most frequently associated with fungal infections, and the resulting candidemia is frequently associated with sepsis syndrome and a high mortality rate.15,58 Septic shock caused by C. albicans demonstrated 24.6% survival with initial appropriate therapy but only 4.6% survival without (ninefold decrease).12 Of the patients with candidemia, delayed appropriate antifungal treatment and failure to achieve timely source control were independently associated with a greater risk of hospital mortality.59,60 Accurate and rapid identification of candida would prompt timely initiation of appropriate therapy.35

Treatment of invasive candidiasis involves amphotericin B-based preparations, azole antifungal agents, and echinocandin antifungal agents, or combinations. The choice depends on the clinical status of the patient, the fungal species and its susceptibility, relative drug toxicity, presence of organ dysfunction that would affect drug clearance, and the patient’s prior exposure to antifungal agents.

Empirical fluconazole therapy for suspected nosocomial bloodstream infections can be appropriate for hospitalized patients at high risk for fungal infections, including those receiving total parenteral nutrition, with bowel perforation, Candida colonization, malignancy, emergency surgery, or with persistent or new signs and symptoms of infections despite receiving broad-spectrum antibacterial therapy.61,62However, recent exposure to antibiotics and fluconazole have been associated with fluconazole-resistant Candida species.17,63 A global survey evaluating the Candida bloodstream infections reported a low overall fluconazole resistance (5% of ICU isolates and 4.4% of non-ICU isolates).64 Only C. glabrata was the only species to exhibit resistance to both azoles and echinocandins. Further investigation of in vitro susceptibilities of 1,669 bloodstream infection isolates of C. glabrata reported 9.7% resistance to fluconazole, of which 8% to 9.3% were resistant to enchinocandins.65

Caspofungin, the first echinocandin antifungal agent, appears to be potent against all Candida species, including C. glabrata, C. krusei, and Candida lusitaniae, as well as Aspergillus species. IV caspofungin was equally effective but better tolerated than amphotericin B deoxycholate for invasive candidiasis.66 In an international, randomized, double-blind trial, the micafungin 100-mg group was noninferior to caspofungin for the treatment of candidemia and other forms of invasive candidiasis demonstrated (76.4% vs. 72.3%).67 Anidulafungin, the latest echinocandin to be approved, achieved a success rate of 73.2% against invasive candidiasis in comparison to the 61.1% treatment success rate of fluconazole.68 The difference was not statistically significant.

In general, suspected systemic mycotic infection leading to sepsis in nonneutropenic patients should be treated empirically with parenteral fluconazole, caspofungin, anidulafungin, or micafungin.62 An echinocandin is preferred for a patient with recent azole exposure or if the patient is clinically unstable because of its greater activity against fluconazole-resistant Candida species and non-albicans species, including C. glabrata and C. krusei.62 In neutropenic patients, a lipid formulation of amphotericin, caspofungin, or voriconazole is recommended. Azoles should be avoided for empiric therapy in patients who have received an azole for prophylaxis.62

Duration of Therapy

The average duration of antimicrobial therapy in the normal host with sepsis is 7 to 10 days, and fungal infections can require 10 to 14 days.32,44,62 However, the duration can be longer in patients with a slow clinical response, undrainable focus of infection, or neutropenia. In a neutropenic patient, therapy is usually continued until the patient is no longer neutropenic and has been afebrile for at least 72 hours. After the patient is hemodynamically stable, afebrile for 48 to 72 hours, has a normalizing WBC count, and is able to take oral medications, then a “step-down” from parenteral to oral antibiotics can be considered for the remaining duration of therapy.

PCT is a biomarker that increases in response to endotoxins and inflammatory cytokines that are released during systemic bacterial infections. Hence, the PCT level may also be used to guide the length of antibiotic therapy. PCT has been studied as a marker to initiate and discontinue antibiotics in patients with severe sepsis or septic shock and surgical intensive care patients.69 However, the survival benefit has not been clearly defined.

Clinical Controversy…

The biomarker PCT rises early in severe sepsis by pneumonia and bloodstream infections, and a growing body of evidence supports the use of PCT to differentiate bacterial from vial respiratory diagnoses, to help risk stratify patients, and to guide antibiotic therapy decisions in terms of initiating and optimizing duration of therapy.69,70,71 Randomized controlled trials further suggested that clinical algorithms based on PCT levels resulted in reduced antibiotic use.70 However, a systematic review of randomized controlled trials investigating PCT algorithms for antibiotic decisions in adult patients with respiratory tract infections and sepsis found no significant difference in mortality between PCT-treated and control patients overall (odds ratio (OR), 0.91; 95% confidence interval (CI), 0.73 to 1.14).72 There was a consistent reduction in antibiotic prescriptions and duration of therapy. The Procalcitonin and Survival Study Group in Demark compared the standard of care arm and the PCT arm using a strategy of escalation of broad-spectrum antimicrobials and intensified diagnostics based on daily PCT measurements in the multidisciplinary ICU.73 No significant difference in mortality between the PCT arm and the standard of care arm (31.5% vs. 32.0%; absolute risk reduction 0.6%) was reported. PCT-guided antimicrobial escalation leads to increased use of broad-spectrum antimicrobials, organ-related harm, and prolonged admission to the ICU. Further trials are needed to determine the safety and efficacy of antibiotic sparing PCT strategies in critically ill patients.

Hemodynamic Support

A high cardiac output and a low SVR characterize septic shock. Patients can have hypotension as a result of low SVR and abnormal distribution of blood flow in the microcirculation, resulting in compromised tissue perfusion. Because approximately half of patients with septic shock die of multiple organ system failure, they should be monitored carefully, and aggressive hemodynamic support should be initiated.

Hemodynamics change rapidly in sepsis, and noninvasive evaluation can give inaccurate assessment of filling pressures and cardiac output, requiring a right-sided heart catheter in the ICU setting.32Hemodynamic support can be divided into three main categories: fluid therapy, vasopressor therapy, and inotropic therapy.

Fluid Therapy

Images Septic patients have enormous fluid requirements as a result of peripheral vasodilation and capillary leakage. In ~50% of septic patients who initially present with hypotension, fluids alone will reverse hypotension and restore hemodynamic stability. Rapid fluid resuscitation improves the 28-day survival rate in patients with sepsis-induced hypoperfusion.32 The goal of fluid therapy is to maximize cardiac output by increasing the LV preload, which will ultimately restore tissue perfusion. Fluid administration should be titrated to clinical end points such as heart rate, urine output, blood pressure, and mental status. Increased serum lactate, a by-product of cellular anaerobic metabolism, should normalize as tissue perfusion improves.

Isotonic crystalloids, such as 0.9% sodium chloride (normal saline) and lactated Ringer solution, are commonly used for fluid resuscitation. A patient in septic shock typically requires up to 10 L of crystalloid solution during the first 24-hour period. These solutions distribute into the extracellular compartment. Approximately 25% of the infused volume of crystalloid remains in the intravascular space, whereas the balance distributes to extravascular spaces. Although this could impair diffusion of oxygen to tissues, clinical impact is unproven.

The most commonly used colloids are 5% albumin, a naturally occurring plasma protein, and 6% hetastarch, a synthetic colloid formulation. These solutions offer more rapid restoration of intravascular volume because they produce greater intravascular volume expansion per quantity of volume infused. Colloids produce less peripheral edema than crystalloid, but there is no significant clinical impact. However, synthetic colloids cause dose-related renal impairment and increased bleeding.74 The use of colloid solutions and blood products can be particularly important if there is significant blood loss associated with sepsis or if the patient had severe preexisting anemia.

The Saline versus Albumin Fluid Evaluation (SAFE) trial found no difference in the 28-day mortality rate in critically ill patients (21.1% with saline vs. 20.9% with albumin).75 Although crystalloid solutions require two to four times more volume than colloids, they are generally recommended for fluid resuscitation because of the lower cost. However, colloids can be preferred, especially when the serum albumin is less than 2 g/dL (20 g/L).

Central venous pressure (CVP) is used to monitor fluid status in patients with septic shock. Initial fluid resuscitation should target a CVP between 8 and 12 mm Hg within the first 6 hours of presentation.32Fluid challenges should continue until hemodynamic stability is reached as long as CVP is at goal. The rate of fluid administration should be reduced if hemodynamic measures do not improve despite adequate or increasing cardiac filling pressures. Resuscitation typically includes IV normal saline 500 mL every 15 minutes until the target CVP is reached.

Patients receiving fluid challenges require close monitoring of volume status to avoid pulmonary and systemic edema. Aggressive volume expansion can cause an increase in pulmonary capillary pressure, leading to an increase in lung water and associated hypoxemia.76 There is no significant difference in the incidence of pulmonary edema between the crystalloid and colloid solutions.

Vasopressor and Inotropic Therapy

When fluid resuscitation alone provides inadequate arterial pressure and organ perfusion, vasopressors and inotropic agents should be initiated. Inotropic agents such as dopamine and dobutamine have been effective in improving cardiac output by increasing cardiac contractility. Vasopressors such as norepinephrine should be considered when a systolic blood pressure is less than 90 mm Hg or mean arterial pressure (MAP) is <65 mm Hg after adequate LV preload and inotrope therapy. Although inotropes and vasopressors are effective in life-threatening hypotension and in improving cardiac index (CI), there are significant complications such as tachycardia and myocardial ischemia and infarction as a result of the change in myocardial oxygen consumption in patients with coexisting coronary disease. Thus, a catecholamine infusion should be titrated gradually to restore MAP without impairing stroke volume.

Images Agents commonly considered for vasopressor or inotropic support include dopamine, dobutamine, norepinephrine, phenylephrine, and epinephrine (Table 97–5).77 Norepinephrine should generally be considered to be the first-choice vasopressor in septic shock after failure to restore adequate blood pressure and organ perfusion with appropriate fluid resuscitation. Norepinephrine is a potent α-adrenergic agent with less pronounced β-adrenergic activity. It increases MAP and SVR because of its vasoconstrictive effects on peripheral vascular beds. Doses of 0.01 to 3 mcg/kg/min can reliably increase blood pressure with little changes in heart rate or CI. Despite the earlier concern of decreased renal blood flow associated with norepinephrine, data in humans and animals demonstrate a norepinephrine-induced renal blood flow as well as urine and cardiac output.77 Norepinephrine is a more potent agent than dopamine in refractory septic shock. Norepinephrine resulted in greater increases in arterial blood pressure in comparison to patients with septic shock who were treated with dopamine (93% with norepinephrine vs. 31% with dopamine).77 In a meta-analysis evaluation the randomized trials comparing norepinephrine and dopamine, dopamine was associated with a higher risk of death and more frequently associated with arrythmias.78

TABLE 97-5 Receptor Activity of Cardiovascular Agents Commonly Used in Septic Shock


Dopamine is a natural precursor of norepinephrine and epinephrine, and it exhibits dose-dependent pharmacologic effects. It is an α- and β-adrenergic agent with dopaminergic activity. Doses >5 mcg/kg/min increase MAP and cardiac output, primarily because of the increase in heart rate and cardiac contractility through stimulation of β-adrenergic receptors. At higher doses, α-adrenergic effects predominate, resulting in arterial vasoconstriction. Because of combined vasopressor and inotropic effects, dopamine is more useful in patients with hypotension and compromised systolic function. However, it is also more arrhythmogenic and can cause more tachycardia.32,77,79 It should be used with caution in patients who have underlying heart disease.

Phenylephrine, a selective α1-agonist, has rapid onset, short duration, and primary vascular effects, and it is least likely to produce tachycardia. Limited data suggest it can increase blood pressure modestly in fluid-resuscitated patients, and it does not appear to impair cardiac or renal function. Phenylephrine appears useful when tachycardia limits the usage of other vasopressors.77

Epinephrine is a nonspecific α- and β-adrenergic agonist. Ranging from 0.1 to 0.5 mcg/kg/min, cardiac output is increased at lower doses, and vasoconstriction occurs predominantly at higher doses. Epinephrine should be reserved for patients who fail to respond to traditional therapies for increasing or maintaining blood pressure, as it impairs blood flow to the splanchnic system, increases the lactate level, and causes dysrhythmia more frequently than other vasoactive agents.77

During hypotension, endogenous vasopressin levels increase and maintain arterial blood pressure, as vasopressin is a direct vasoconstrictor without inotropic or chronotropic effects. However, there is a vasopressin deficiency in septic shock most likely caused by inadequate production. Low doses of vasopressin (0.01 to 0.04 units/min) produce a significant increase in MAP in septic shock, and it may be beneficial to add vasopressin in severe sepsis and septic shock that is refractory to other vasopressors.77 Vasopressin should not be used as a single agent for refractory hypotension. Although it can be used to reduce norepinephrine requirements, this has not been shown to improve mortality rates.80

Dobutamine is a β-adrenergic inotropic agent that many clinicians consider to be the preferred drug for improvement of cardiac output and oxygen delivery, particularly in early sepsis before significant peripheral vasodilation has occurred. Doses of 2 to 20 mcg/kg/min increase the CI, ranging from 20% to 66%. However, heart rate often increases significantly.77 Dobutamine should be considered in severely septic patients with low CI but adequate filling pressures and blood pressure. A vasopressor such as norepinephrine and an inotrope such as dobutamine can be used to maintain both MAP and cardiac output.

In summary, for the septic patient with clinical signs of shock and significant hypotension unresponsive to aggressive fluid therapy, norepinephrine is the preferred agent for increasing MAP. Epinephrine should be considered for refractory hypotension. Dopamine and epinephrine are more likely to induce or exacerbate tachycardia than norepinephrine and phenylephrine. In a septic patient with low CI after adequate fluid therapy and adequate MAP, dobutamine is the first-line agent. Alternatively, dopamine in moderate doses (5 to 10 mcg/kg/min) can also be used as an initial agent because of its selective effect on increasing cardiac output with its minimal effect on SVR.

Early Goal-Directed Therapy

Images Initial resuscitation of a patient in severe sepsis or sepsis-induced tissue hypoperfusion should begin as soon as the syndrome is recognized. A randomized, controlled trial evaluated the timing of the goal-directed therapy involving adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with demand prior to admission to the ICU.81 The goals during the first 6 hours included CVP of 8 to 12 mm Hg, MAP ≥65 mm Hg, urine output ≥0.5 mL/kg/h, and a central venous or mixed venous oxygen saturation ≥70% (≥0.70). During the first 6 hours of resuscitation, the early goal-directed therapy group had a central venous catheter placed and received more fluid than with traditional therapy (5 vs. 3.5 L), dobutamine therapy to a maximum of 20 mcg/kg/min, and red blood cell transfusions. The 28-day mortality rate was 30% in the early goal-directed therapy group, in comparison to 46.5% in the traditional therapy group consisting of fluid resuscitation, followed by vasopressor therapy if required. Increased oxygen delivery from the red blood cell transfusions to achieve a hematocrit of ≥30% (≥0.30) in the early goal-directed therapy group appeared to be the primary difference between the two groups.

Compliance with the goals of early goal-directed group was closely correlated with the overall mortality rate. At 18 hours after diagnosis of severe sepsis and septic shock patients meeting goals had a greater reduction in mortality than those who did not (26.8% vs. 9.4%, P < 0.01).82 A decade later, over 50 publications involving 18,000 adult patients have shown early goal-directed therapy to decrease in progression of organ failure, reduction in mortality, and decrease in overall healthcare cost by 20%, primarily due to shorter length of hospital stay.83,84

Adjunctive Therapies

ARDS and hypoxia are common in septic patients, even in those without pulmonary infection. Oxygen therapy is indicated to maintain oxygen saturation greater than 90% (0.90), and with progressive pulmonary insufficiency, the patient can require assisted ventilation.

Images Hyperglycemia and insulin resistance are frequently associated with sepsis regardless of the presence of diabetes prior to sepsis, and more severe hyperglycemia is associated with higher morbidity and mortality.32 However, intensive insulin therapy is no longer the standard of care in critically ill patients. Results from a randomized control trial showed that more patients receiving intensive insulin therapy (target serum glucose of 81 to 108 mg/dL [4.5 to 6 mmol/L]) had a higher incidence of severe hypoglycemia and increased mortality at 90 days compared with patients receiving conventional insulin therapy (target ≤180 mg/dL [≤10.0 mmol/L]).85 Further analysis of patients with moderate (41 to 70 mg/dL [2.3 to 3.9 mmol/L]) and severe hypoglycemia (≤40 mg/dL [≤2.2 mmol/L]) reported death rate of 23.5% with moderate hypoglycemia and 35.4% with severe hypoglycemia.86 Severe hypoglycemia in the absence of insulin therapy was also associated with a higher risk of death. A glucose range of less than 150 mg/dL (8.3 mmol/L) is recommended for the majority of critically ill patients to improve the outcome while reducing the risk of hypoglycemia.32

Images Cortisol levels vary widely in patients with septic shock, and some studies have suggested increased mortality associated with both low and high serum cortisol levels. An adrenocorticotropic hormone (ACTH) stimulation test has been used to identify those patients who have a relative adrenal insufficiency who should then receive supplemental steroid.32 Corticosteroids have been studied as adjunctive therapy in patients with severe sepsis and septic shock to decrease the duration of shock and to decrease mortality.

A multicenter, randomized, controlled trial demonstrated significant shock reversal and decrease in mortality (absolute reduction 10%) in patients with severe septic shock who were given low-dose corticosteroids within 8 hours after the onset of shock.87 Fludrocortisone 50 mcg orally and hydrocortisone 200 to 300 mg/day for 7 days in three or four divided doses or by continuous infusion were used in patients with adrenal insufficiency, requiring high-dose or increasing vasopressor therapy within the first 8 hours of septic shock.87 A subsequent meta-analysis of 12 randomized trials reported decreased mortality compared to placebo (38% vs. 44%; relative risk 0.84).88 There was no benefit for those patients without adrenal insufficiency. However, in the large multicenter trial, the Corticosteroid Therapy of Septic Shock (CORTICUS), no significant benefit was noted in patients regardless of ACTH stimulation test outcome.89

Clinical Controversy…

A systematic review reported a significant reduction in 28-day all-cause mortality and hospital mortality in patients receiving prolonged courses (>5 days) of low-dose corticosteroid therapy (≤300 mg hydrocortisone or equivalent/day).88 The CORTICUS trial found no survival benefit among patients who received prolonged courses of hydrocortisone, but reported a trend in shock reversal for patients who received hydrocortisone.89 Based on the current Surviving Sepsis guidelines, corticosteroids should be reserved for patients who continue to be hypotensive despite adequate fluids and vasopressor therapy, are maintained on an outpatient corticosteroid regimen, or may be initiated at physician discretion.

Corticosteroids should be weaned once the patient is off vasopressors, although comparative clinical trials comparing whether steroids should be abruptly discontinued or tapered are lacking.

Deep vein thrombosis prophylaxis with either low-dose unfractionated heparin or low-molecular-weight heparin should be initiated in general ICU patients, including those with severe sepsis and septic shock.32 Similarly, stress ulcer prophylaxis should be initiated in all patients with severe sepsis and septic shock.32 Proton pump inhibitors and H2 receptor antagonists are equivalent in their ability to increase gastric pH.

HMG-CoA reductase inhibitors (statins) have diverse pharmacologic effects ranging from decreasing low-density lipoproteins to antiinflammatory and antithrombotic properties. As severe sepsis is characterized by a dysregulation of inflammation and coagulation, statins have been evaluated for their role in the treatment or prevention of severe sepsis. Most studies suggested a clinical benefit for stains, and yet, others have shown no benefit but possible harm.

Clinical Controversy…

A variety of observational studies reported mixed results in the role of statins in treatment of sepsis.9094 Meta-analysis for various infection-related outcomes revealed ORs in favor of statin use versus no statin (0.61; 95% CI 0.48 to 0.73) for 30 day mortality and 0.40 (95% CI, 0.23-0.57) for sepsis-related mortality.90 A multicenter cohort study evaluated 1,895 patients hospitalized with pneumonia and sepsis for benefits of prior use of statin and continuation of statin in hospital.92 No protective effect for statin on clinical outcomes was observed. After adjusting for patient characteristics, there was no mortality benefit for prior use (OR, 0.90 (0.63 to 1.29); P = 0.57) or continued statin use (OR, 0.73 (0.47 to 1.13); P = 0.15). More prospective trials are needed to clearly define the role of prior statins in severe sepsis and septic shock as well as to develop strategies to continue or discontinue statin once admitted in the ICU for sepsis.


Despite the initial enthusiasm for immunotherapeutic interventions for sepsis, overall results have been generally disappointing including drotrecogin alfa (recombinant human activated protein C, rhAPC), an endogenous anticoagulant with antiinflammatory properties. During severe sepsis, the activation of protein C is inhibited by inflammatory cytokines.

Drotrecogin, the first antiinflammatory agent to be approved for sepsis, promotes fibrinolysis and the inhibition of coagulation and inflammation. The Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial showed all-cause mortality at 28 days reduced significantly from 30.8% with placebo to 24.7% in those receiving drotrecogin.95 However, serious bleeding, including intracranial hemorrhage and a life-threatening bleeding episode, occurred in 3.5% of patients who received drotrecogin in comparison to 2% of patients in the placebo group. Since the approval, ongoing debate on the study’s methodology and outcomes has questioned the effectiveness, safety, and place in therapy of drotrecogin alfa. Consequently, the PROWESS-SHOCK study, a randomized, multinational, placebo-controlled, double-blind clinical trial, was initiated in March 2008 to help refine appropriate patient identification for treatment with drotrecogin alfa and to confirm the benefit-risk profile.96 Planned enrollment was 1,700 patients with severe sepsis and persistent shock, and data collection ended in September 2011. Study design details and the outcomes have not been reported. However, a preliminary analysis submitted to the FDA suggested that the PROWESS-SHOCK study did not meet the primary endpoint of a significant reduction in 28-day all-cause mortality in patients with septic shock treated with drotrecogin alfa compared with placebo. Among 1,680 patients who completed the study, the all-cause mortality rates were 26.4% (223 of 846) in patients treated with drotrecogin alfa and 24.2% (202 of 834) in the placebo group, for a relative risk of 1.09 (95% CI, 0.92 to 1.28; P = 0.31). Severe bleeding events occurred in 1.2% and 1% of the drotrecogin alfa and place groups, respectively, suggesting no increased harm. The study failed to demonstrate overall improvement in survival, and without clear demonstration of benefits outweighing the risks, the product was withdrawn from the market worldwide.96


Patients presenting with severe sepsis and septic shock are critically ill and their management in an intensive care setting can be overwhelming. While it is critical to manage the complications involving multiple organ systems to ultimately sustain life during the initial hours, infection source identification is imperative as severe sepsis and subsequent multiorgan dysfunction arise from an uncontrolled infection. Clinical presentation of each patient should be considered carefully and should prompt further evaluation of any underlying conditions, recent travel, injury, animal exposure, infection or use of antibiotics along with a complete physical examination to determine the possible source of infection. Based on the individual patients’ findings and the most likely source of infection, the empiric regimen may be completely different from one patient to another. A patient presenting with sepsis secondary to a community-acquired pneumonia may receive ceftriaxone and azithromycin where another patient presenting with secondary peritonitis as a consequence of perforation of the GI tract may require a broad-spectrum regimen such as ertapenem or piperacillin/tazobactam.42,43,48 Catheter-related sepsis may require a removal of the line as well as initiating vancomycin. There is abundant evidence in the literature demonstrating a correlation between the prompt and appropriate antibiotics and the overall survival rate.36,37Severe sepsis and complications such as shock, ARDS, and DIC result from an acute infection. As such, prompt identification of the source of infection in an individual patient and customizing the empiric antibiotic regimen may be the key to controlling the multiorgan dysfunctions and overall mortality rate.




    1. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546–1554.

    2. Lagu T, Rothberg MB, Shieh MS, et al. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med 2012;40:754–761.

    3. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864–874.

    4. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250–1256.

    5. Tiruvoipati R, Ong K, Gangopadhyay H, et al. Hypothermia predicts mortality in critically ill elderly patients with sepsis. MCB Geriatr 2010;10:70–78.

    6. Danai PA, Moss M, Mannino DM, et al. The epidemiology of sepsis in patients with malignancy. Chest 2006;129: 1432–1440.

    7. Netea MG, van der Meer JWM. Immunodeficiency and genetic defects of pattern-recognition receptors. N Engl J Med 2011;364:60–70.

    8. Danai PA, Sinha S, Moss M, et al. Seasonal variation in the epidemiology of sepsis. Crit Care Med 2007;35:410–415.

    9. Zahar JR, Timsit JF, Garrouste-Orgeas M, et al. Outcomes in severe sepsis and patients with septic shock: Pathogen species and infection sites are not associated with mortality. Crit Care Med 2011;39:1886–1895.

   10. Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: Results of the SOAP study. Crit Care Med 2006;34:344–353.

   11. Brunkhorst FM, Oppert M, Marx G, et al. Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis. JAMA 2012;307:2390–2399.

   12. Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009;136: 1237–1248.

   13. van Hal SJ, Jensen SO, Vaska VL, et al. Predictors of mortality in Staphylococcus aureus bacteremia. Clin Microbiol Rev 2012;25:362–386.

   14. Johnson MT, Reichley R, Hoppe-Bauer J, et al. Impact of previous antibiotic therapy on outcome of gram-negative severe sepsis. Crit Care Med 2011;39:1859–1865.

   15. Horn DL, Neofytos D, Anaissie EJ, et al. Epidemiology and outcomes of candidemia in 2019 patients: Data from the prospective antifungal therapy alliance registry. Clin Infect Dis 2009;48:1695–1703.

   16. Diekema D, Arbefeville S, Boyken L, et al. The changing epidemiology of healthcare-associated candidemia over three decades. Diagn Microb Infect Dis 2012;73:45–48.

   17. Ben-Ami R, Olshtain-Pops K, Krieger M, et al. Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection. Antimicrob Agents Chemother 2012;56:2518–2523.

   18. Tamayo E, Fernandez A, Almansa R, et al. Pro- and anti-inflammatory responses are regulated simultaneously from the first moments of septic shock. Eur Cytokine Network 2011;22:82–87.

   19. Andaluz-Ojeda D, Bobillo E, Iglesias V, et al. A combined score of pro- and anti-inflammatory interleukins improves mortality prediction in severe sepsis. Cytokine 2012;57: 332–336.

   20. De Pablo R, Monserrat J, Reyes E, et al. Mortality in patients with septic shock correlates with anti-inflammatory but not proinflammatory immunomodulatory molecules. J Intensive Care Med 2011;26:125–132.

   21. Heper Y, Akalin EH, Mistik R, et al. Evaluation of serum C-reactive protein, procalcitonin, tumor necrosis factor alpha, and interleukin-10 levels as diagnostic and prognostic parameters in patients with community-acquired sepsis, severe sepsis, and septic shock. Eur J Clin Microbiol Infect Dis 2006;25:481–491.

   22. Kanoore Edul VS, Enrico C, Laviolle B, et al. Quantitative assessment of the microcirculation in healthy volunteers and in patients with septic shock. Crit Care Med 2012;40: 1443–1448.

   23. Fourrier F. Severe sepsis, coagulation, and fibrinolysis: Dead end or one way? Crit Care Med 2012;40:2704–2708.

   24. Semeraro N, Ammollo CT, Semeraro F, et al. Sepsis-associated disseminated intravascular coagulation and thromboembolic disease. Mediter J Hematol Infect Dis 2010;2:e2010024.

   25. Levi M, Toh CH, Thachil J, et al. Guidelines for the diagnosis and management of disseminated intravascular coagulation. Br J Haematol 2009;145:24–33.

   26. Pulido JN, Afessa B, Masaki M, et al. Clinical spectrum, frequency, and significance of myocardial dysfunction in severe sepsis and septic shock. Mayo Clin Proc 2010;87:620–628.

   27. Bagshaw SM, George C, Bellomo R. Early acute kidney injury and sepsis: A multicentre evaluation. Crit Care 2008;12:R47.

   28. Bagshaw SM, Lapinsky S, Dial S, et al. Acute kidney injury in septic shock: Clinical outcomes and impact of duration of hypotension prior to initiation of antimicrobial therapy. Intensive Care Med 2009;35:871–881.

   29. Cunha BA. With sepsis: If fever is good, then hypothermia is bad! Crit Care Med 2012;40:2926–2927.

   30. Awad SS. State-of-the-art therapy for severe sepsis and multisystem organ failure. Am J Surg 2003;186: 23S–30S.

   31. Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004;32:1637–1642.

   32. Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36: 296–327.

   33. Coelho FR, Martins JO. Diagnostic methods in sepsis: The need of speed. Rev Assoc Med Bras 2012;58:498–504.

   34. Davies J, Gordon CL, Tong SY, et al. Impact of results of a rapid Staphylococcus aureus diagnostic test on prescribing of antibiotics for patients with clustered gram-positive cocci in blood cultures. J Clin Microbiol 2012;50:2056–2058.

   35. Aittakorpi A, Kuusela P, Koukila-Kahkola P, et al. Accurate and rapid identification of Candida spp. frequently associated with fungemia by using PCR and the microarray-based Prove-it sepsis assay. J Clin Microbiol 2012:50: 3635–3640.

   36. Ferrer R, Artigas A, Suarez D, et al. Effectiveness of treatments for severe sepsis: A prospective, multicenter, observational study. Am J Respir Crit Care Med 2009;180:861–866.

   37. Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010;38:1045–1053.

   38. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589–1596.

   39. Pea F. Plasma pharmacokinetics of antimicrobial agents in critically ill patients. Curr Clin Pharmacol 2013;8:5–12 [Epub ahead of print].

   40. Baptista JP, Sousa E, Martins PJ, et al. Augmented renal clearance in septic patients and implications for vancomycin optimisation. Int J Antimicrob Agents 2012;39:420–423.

   41. Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International clinical practice guidelines from the Infectious Diseases Society of America. Clin Infect Dis 2010;50:625–663.

   42. Mandell LA, Wunderinnk RG, Anzueto A, et al. Infectious Disease Society of America/American Thoracic Society consensus guidelines on management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44: S27–S72.

   43. Pereira JM, Paiva JA, Rello J. Severe sepsis in community-acquired pneumonia—Early recognition and treatment. Eur J Intern Med 2012;23:412–419.

   44. American Thoracic Society Documents. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388–416.

   45. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52: 1–38.

   46. Mullins CD, Kuznik A, Shaya FT, et al. Cost-effectiveness analysis of linezolid compared with vancomycin for the treatment of nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Ther 2006;28: 1184–1198.

   47. Baquero F, Hsueh PR, Paterson DL, et al. In vitro susceptibilities of aerobic and facultatively anaerobic gram-negative bacilli isolated from patients with intra-abdominal infections worldwide: 2005 results from Study for Monitoring Antimicrobial Resistance Trends (SMART). Surg Infect 2009;10:99–104.

   48. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 2010;50:133–164.

   49. Snydman DR, Jacobus NV, McDermott LA, et al. Update on resistance of Bacteroides fragilis group and related species with special attention to carbapenems 2006–2009. Anaerobe 2011;17:147–151.

   50. Lipsky BA, Moran GJ, Napolitano LM, et al. A prospective, multicenter, observational study of complicated skin and soft tissue infections in hospitalized patients: Clinical characteristics, medical treatment, and outcomes. BMC Infect Dis 2012;12:227.

   51. Bliziotis IA, Plessa E, Peppas G, et al. Daptomycin versus other antimicrobial agents for the treatment of skin and soft tissue infections: A meta-analysis. Ann Pharmacother 2010;44:97–106.

   52. Bounthavong M, Hsu DI. Efficacy and safety of linezolid in methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infection (cSSTI): A meta-analysis. Curr Med Res Opin 2010;26: 407–421.

   53. Brown JE, Fominaya C, Christensen KJ, et al. Daptomycin experience in critical care patients: Results from a registry. Ann Pharmacother 2012;46:495–502.

   54. Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev 2012;25:450–470.

   55. Qureshi ZA, Paterson DL, Potoski BA, et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: Superiority of combination antimicrobial regimens. Antimicrob Agents Chemother 2012;56: 2108–2113.

   56. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Disease Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007;44:159–177.

   57. Heenen S, Jacobs F, Vincent JL. Antibiotic strategies in severe nosocomial sepsis: Why do we not de-escalate more often? Crit Care Med 2012;40:1404–1409.

   58. Shorr AF, Gupta V, Sun X, et al. Burden of early-onset candidemia: Analysis of culture-positive bloodstream infections from a large U.S. database. Crit Care Med 2009;37:2519–2526.

   59. Grim SA, Berger K, Teng C, et al. Timing of susceptibility-based antifungal drug administration in patients with Candida bloodstream infection: Correlation with outcomes. J Antimicrob Chemother 2012;67:707–714.

   60. Kollef M, Micek S, Hampton N, et al. Septic shock attributed to Candida infection: Importance of empiric therapy and source control. Clin Infect Dis 2012;54:1739–1746.

   61. Azoulay E, Dupont H, Tabah A, et al. Systemic antifungal therapy in critically ill patients without invasive fungal infection. Crit Care Med 2012;40:813–822.

   62. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;48:503–535.

   63. Shah DN, Yau R, Lasco TM, et al. Impact of prior inappropriate fluconazole dosing on isolation of fluconazole-nonsusceptible Candida species in hospitalized patients with candidemia. Antimicrob Agents Chemother 2012;56: 3239–3243.

   64. Pfaller MA, Messer SA, Moet GJ, et al. Candida bloodstream infections: Comparison of species distribution and resistance to echinocandin and azole antifungal agents in Intensive Care Unit (ICU) and non-ICU settings in the SENTRY Antimicrobial Surveillance Program (2008–2009). Int J Antimicrob Agents 2011;38:65–69.

   65. Pfaller MA, Castanheira M, Lockhart SR, et al. Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata. J Clin Microbiol 2012;50:1199–1203.

   66. Mora-Duarte J, Betts R, Rotstein R, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002;347:2020–2029.

   67. Pappas PG, Rotstein CMF, Betts RF, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 2007;45:883–893.

   68. Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007;356:2472–2482.

   69. Schroeder S, Hochreiter M, Koehler T, et al. Procalcitonin-guided algorithm reduces length of antibiotic treatment in surgical intensive care patients with severe sepsis: Results of a prospective randomized study. Langenbecks Arch Surg 2009;394:221–226.

   70. Schuetz P, Amin DN, Greenwald JL. Role of procalcitonin in managing adult patients with respiratory tract infections. Chest 2012;141:1063–1073.

   71. Layios N, Lambermont B, Canivet JL, et al. Procalcitonin usefulness for the initiation of antibiotic treatment in intensive care unit patients. Crit Care Med 2012;40:2304–2309.

   72. Schuetz P, Chiappa V, Briel M, et al. Procalcitonin algorithms for antibiotic therapy decisions. Arch Intern Med 2011;171:1322–1331.

   73. Jensen JU, Hein L, Lundgren B, et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: A randomized trial. Crit Care Med 2011;39:2048–2058.

   74. Bayer O, Reinhart K, Kohl M, et al. Effects of fluid resuscitation with synthetic colloids or crystalloids alone on shock reversal, fluid balance, and patient outcomes in patients with severe sepsis: A prospective sequential analysis. Crit Care Med 2012;40:2543–2551.

   75. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247–2256.

   76. Durairaj L, Schmidt GA. Fluid therapy in resuscitated sepsis: Less is more. Chest 2008;133:252–263.

   77. Hollenberg SM. Inotrope and vasopressor therapy of septic shock. Crit Care Nurs Clin North Am 2011;23:127–148.

   78. Backer DD, Aldecoa C, Njimi H, et al. Dopamine versus norepinephrine in the treatment of septic shock: A meta-analysis. Crit Care Med 2012;40:725–730.

   79. Sakr Y, Reinhart K, Vincent JL, et al. Dose dopamine administration in shock influence outcome? Results of the sepsis occurrence in acutely ill patients (SOAP) study. Crit Care Med 2006;34:589–597.

   80. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877–887.

   81. Rivers E, Nguyen B, Havstad S, et al. Early goal–directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368–1377.

   82. Coba V, Whitmill M, Mooney R, et al. Resuscitation bundle compliance in severe sepsis and septic shock: Improves survival, is better late than never. J Intensive Care Med 2011;26:304–313.

   83. Rivers EP, Katranji M, Jaehne KA, et al. Early interventions in severe sepsis and septic shock: A review of the evidence one decade later. Minerva Anestesiol 2012;78:712–724.

   84. Shorr AF, Micek ST, Jackson WL, et al. Economic implications of an evidence-based sepsis protocol: Can we improve outcomes and lower costs? Crit Care Med 2007;35:1257–1262.

   85. The NICE-SUGAR Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283–1297.

   86. The NICE-SUGAR Investigators. Hypoglycemia and risk of death in critically ill patients. N Engl J Med 2012;367:1108–1118.

   87. Annane D, Sebille V, Charpentier C, et al. Effects of treatment with low-dose hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862–871.

   88. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: A systematic review. JAMA 2009;301:2362–2375.

   89. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358: 111–124.

   90. Janda S, Young A, Fitzgerald JM, et al. The effect of statins on mortality from severe infections and sepsis: A systematic review and meta-analysis. J Crit Care 2010;25:656.e7–22.

   91. Al Harbi SA, Tamim HA, Arabi YM. Association between statin therapy and outcomes in critically ill patients: A nested cohort study. BMC Clin Pharmacol 2011;11:12.

   92. Yende S, Milbrandt EB, Kellum JA, et al. Understanding the potential role of statins in pneumonia and sepsis. Crit Care Med 2011;39:1871–1878.

   93. Kruger PS, Harward ML, Jones MA, et al. Continuation of statin therapy in patients with presumed infection: A randomized controlled trial. Am J Respir Crit Care Med 2011;183:774–781.

   94. Goodin J, Manrique C, Dulohery M, et al. Effect of statins on the clinical outcomes of patients with sepsis. Anaesth Intensive Care 2011;39:1051–1055.

   95. Bernard GR, Vincert JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709.

   96. FDA Drug Safety Communication: Voluntary market withdrawal of Xigris (drotrecogin alfa, activated) due to failure to show a survival benefit.