Current Diagnosis & Treatment in Infectious Diseases

Section II - Clinical Syndromes

17. Sepsis Syndrome

Andrew D. Badley MD

James M. Steckelberg MD

Essentials of Diagnosis

  • Sepsis should be suspected in patients who present with any combination of fevers, hypotension, altered mental status, or evidence of tissue hypoperfusion.
  • The diagnosis requires Systemic Inflammatory Response Syndrome (SIRS), documented infection as the presumed cause of SIRS, and absence of alternative causes of SIRS.
  • In a patient who is critically ill with SIRS, the etiology is often not immediately apparent; therefore a careful history and physical exam are required to determine the most likely specific cause.

General Considerations

The Greek origins of the term sepsis refer to the process of putrefaction and decay. Historically, it has come to mean the presence of pathogenic microorganisms or their biologically active products in the host. It is the presence of biologically active products that causes the inflammatory response leading to such clinical sequelae as fever and hypotension. If the inflammatory response proceeds unchecked, it may ultimately lead to organ dysfunction, multiorgan failure, and death.

Recently, the term Systemic Inflammatory Response Syndrome (SIRS) has been introduced. This term refers to a specific host systemic response that may be elicited by a variety of clinical events, including infection, burns, pancreatitis, ischemia, trauma, hemorrhage, immune-mediated tissue injury, and exogenous stimuli. SIRS resulting from infection is called sepsis. Furthermore, sepsis that leads to altered tissue perfusion of vital organs (resulting in one or more of oliguria, hypoxemia, elevated lactate, or altered mentation) is called sepsis syndrome. Sepsis and sepsis syndrome are distinguished from infection, which is inflammation in response to invasion of a normally sterile site by microorganisms, and bacteremia, which is the presence of bacteria in the blood (Figure 17-1). When faced with a patient with SIRS, the objective is to define, if possible, its etiology, and, if SIRS is caused by infection, to administer appropriate antibiotics and supportive care guided by the patient's history and physical examination (Table 17-1).

  1. Epidemiology.Data from the Centers for Disease Control indicate that the incidence of sepsis increased from 73.6 cases/100,000 person years in 1979 to 175.9 cases/100,000 person years in 1987, when sepsis became the 13th leading cause of death. Several factors may contribute to the increasing incidence of sepsis: (1) increased incidence and survival of persons predisposed to sepsis, such as persons infected with HIV, patients with cancer, the elderly, and those who have had organ transplants; (2) increased use of medical prostheses such as intravascular catheters and indwelling urinary catheters; and (3) widespread (and, at times, inappropriate) use of antimicrobial agents that predispose toward the selection of virulent or multiply resistant pathogens.
  2. Pathogenesis.The leading microbial cause of sepsis and septic shock is infections with gram-negative bacteria that initiate a cascade of events leading to SIRS. Bacteria may be in the bloodstream only transiently; therefore, sepsis and septic shock are not always associated with bacteremia. An integral component of the gram-negative–bacterial cell wall, lipopolysaccharide (LPS), is responsible for initiating a cascade that results in cytokine release and the early physiologic changes associated with septic shock (Figure 17-2). LPS within the circulatory system may form a complex with either bactericidal permeability-increasing protein or with LPS-binding protein. Complexes of bactericidal permeability-increasing protein–LPS are fated for destruction, whereas LPS-binding protein–LPS complexes bind with their receptor, CD14. Once bound by LPS-binding protein–LPS complex, CD14 initiates an intracytoplasmic signaling cascade that ultimately results in the translocation of nuclear factor kappa B (NF-κB) into the nucleus. NF-κB is a transcription factor that, once present in the nucleus, initiates the transcription of numerous cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-2, IL-6, IL-8, platelet activating factor, and interferon-γ. These and other potential mediators including nitrous oxide, intracellular adhesion molecules, prostaglandins, and leukotrienes have been directly or indirectly implicated in the pathogenesis of septic shock (Box 17-1).

The sepsis syndrome may also occur after infections with gram-positive bacteria, viruses, protozoa, rickettsia, and helminths (none of which contain LPS). In these situations, alternate pathways of cytokine induction are invoked. Components of gram-positive bacteria including peptidoglycan and teichoic acids can directly activate the alternate pathway of the complement cascade. Once activated, the complement cascade induces lymphocyte proliferation and activation, as well as phagocyte activation, which generates the production of inflammatory cytokines. Gram-positive–bacterial components can also directly induce cytokine production; both peptidoglycan and lipoteichoic acid can induce IL-1 release from monocytes and macrophages, and lipoteichoic acid can additionally induce TNF-α and IL-6 release. Other bacterial proteins are also capable of causing cytokine production. Gram-positive enterotoxins and exotoxins can directly cause the release of IL-1, IL-6, and TNF-α. Furthermore, staphylococcal toxic shock syndrome toxin-1 is a more potent stimulus of IL-1 release than is LPS.


Figure 17-1. Interrelationship between infection, sepsis, and the systemic inflammatory response syndrome (Reproduced with permission, from JAMA 1995;273:155).

Regardless of the organism responsible for inducing sepsis, a common final pathway characterized by the release of proinflammatory mediators is activated, resulting in fever, hypotension, decreased organ perfusion, and other potential complications (see below).

Clinical Findings

The clinical findings associated with sepsis syndrome may be related either to the pathophysiology of SIRS or to the infection that is the underlying cause of sepsis syndrome. The clinical findings associated with SIRS are similar regardless of the mechanism responsible for inducing the inflammatory cascade. Infections that are commonly associated with sepsis syndrome in a normal host include pneumonia, meningitis, upper urinary tract infections, cellulitis, and intra-abdominal catastrophes (perforated viscus, diverticular abscess, etc). A careful history may identify an infection(s) for which a patient is at increased risk.

Table 17-1. Clues to the diagnosis of sepsis.


· Any patient may develop sepsis.

· Patients with impaired immune systems are at higher risk.

· Alterations in local defenses (such as breaks in the skin, burns) place patients at risk.


· Signs and symptoms of infection

· Impaired hemodynamics and tissue perfusion consistent with the Systemic Inflammatory Response Syndrome (SIRS):

· Hyperthermia (>38°C) or hypothermia (< 36°C)

· Tachypnea (respiratory rate > 20 breaths/min)

· Hypotension (systolic blood pressure < 90 mmHg, or drop of > 40 mmHg from baseline)


· Leukocytosis (> 12 × 109 cells/L) or leukopenia (< 4 × 109 cells/L)

· Left shift in leukocyte differential (> 10% band forms)

· Changes that reflect decreased tissue perfusion: elevated lactate dehydrogenase, evidence of organ hypoperfusion (elevated creatinine, rising transaminases, thrombocytopenia, hypoxemia)

· Changes associated with the site of underlying infection (decreased pO2 in a patient with pneumonia, etc.)

  1. Signs and Symptoms.The signs and symptoms of sepsis syndrome are varied and may reflect in part the underlying infection that is the cause of the inflammatory response. A patient with sepsis may have few complaints or may complain of fevers, chills, pain, rash, or dyspnea. The focus of the physical examination should be to identify the source and severity of the underlying infection, as well as any associated complications. Essentials of the physical examination of a patient with suspected sepsis syndrome include the following:
  • Vital signs should include temperature, respiratory rate, and blood pressure.
  • Medical appliances such as intravenous lines and urinary catheters should be examined to determine whether these sites represent a potential portal of entry for infectious agents.
  • The head and neck should be examined, looking for nuchal rigidity, conjunctival petechiae, and Roth spots.
  • The oropharynx should be examined, looking for thrush (suggesting an underlying immunosuppressive state including chronic illness, HIV infection, malignancy, or chronic steroid use), quinsy, periodontal abscess, or evidence of herpes simplex infection.
  • Examination of the skin may provide important diagnostic clues such as rashes of disseminated meningococcemia or ecthyma gangrenosum (seen with disseminated Pseudomonas infection) are important diagnostic clues. In addition, petechiae associated with disseminated intravascular coagulation may be present, as well as Janeway lesions and Osler's nodes. Last, signs of cellulitis or necrotizing fasciitis are an obvious clue to the cause of sepsis syndrome.

Figure 17-2. Physiologic changes in the bloodstream associated with septic shock.

  • The pulmonary system should be examined, focusing on signs of pneumonitis: impaired oxygenation, pulmonary consolidation, and empyema. Because patients with sepsis syndrome often develop adult respiratory distress syndrome (ARDS), it may be difficult to differentiate the pulmonary findings of pneumonia form those of ARDS.
  • The cardiac examination will frequently be abnormal, owing to the compensatory changes associated with sepsis. Although uncommon, infective endocarditis may uncommonly lead to sepsis syndrome; therefore the finding of a new or changing murmur (especially a regurgitant one) is important. In addition, patients with sepsis syndrome will frequently be hypotensive; therefore a careful cardiac examination is needed to differentiate cardiogenic shock (with elevated jugular venous pressure, gallop rhythms, and evidence of right and/or left-sided congestive failure) from noncardiogenic shock caused by sepsis, which is initially a hyperdynamic, high-cardiac-output state.
  • Examination of the abdomen focuses on tenderness, guarding, or absence of bowel sounds, suggestive of an intra-abdominal event such as perforation of a hollow viscus. In addition, it should be noted whether a patient has had a prior splenectomy, which is associated with an increased risk for certain infections.
  • Examination of kidneys seeks flank tenderness or increased size (by palpation, or by ballottement).
  • Thorough pelvic and rectal examinations are necessary for all septic patients, to look for evidence of rectal or perirectal abscess, pelvic inflammatory disease, and prostatitis.
  1. Laboratory Findings.Laboratory findings associated with sepsis syndrome may reflect decreased organ perfusion or may reflect the underlying infection. Frequently leukocytosis or leukopenia is present. In addition, anemia may be seen, which may be dilutional (after fluid resuscitation efforts) or associated with underlying chronic disease. Thrombocytopenia may accompany the development of disseminated intravascular coagulation, or reactive thrombocythemia may occur. Hypoxemia may be seen with pneumonitis or in response to the development of ARDS. If hypercarbia is seen in association with hypoxia, impending ventilatory failure may be present. Rising creatinine (with rising urea), elevations in lactose dehydrogenase (LDH), or rising transaminases are signs of decreased organ perfusion and are suggestive of sepsis syndrome.

For most patients with sepsis syndrome, initial laboratory screening should include the following: complete blood count, urinalysis, coagulation profile, glucose, blood urea nitrogen, creatinine, electrolytes, liver enzymes, bilirubin, lactose dehydrogenase, amylase, lipase, arterial blood gas, chest X-ray, and electrocardiogram. In addition, if meningitis is suspected, screening should also include cerebrospinal fluid testing for glucose, protein, cell count, culture, and rapid bacterial antigen testing. Microbiologic testing should be dictated by the clinical presentation, but in most patients, urine, sputum, and blood should be cultured for bacteria.

In selected patients, Swan Ganz catheters may be used to assess cardiac output, systemic vascular resistance, and pulmonary capillary wedge pressure. In early shock due to SIRS, cardiac output will be increased, systemic vascular resistance will be normal or low, pulmonary capillary wedge pressures will be normal or low, and venous oxygen saturation will be increased. These indices are of value in differentiating hypotension due to cardiogenic, hypovolemic, toxin mediated, or neurogenic causes, as well as assessing the adequacy of volume resuscitation.

  1. Imaging.There are no imaging procedures that are specific for sepsis syndrome; however, carefully selected radiographic evaluations may aid in establishing the underlying infection. Every patient should have a chest X-ray performed, and, based on the clinical presentation, CT scanning or ultrasonography of the chest or abdomen may be appropriate.

BOX 17-1 Cytokines Implicated in the Pathology of Sepsis Syndrome.



Dominant Physiologic Effects



Vasodilation, hypotension, induces fever, induces production of acute-phase reactant proteins by liver


T-helper cells, NK cells

Similar effects to TNF-α


Macrophages, endothelium

Vasodilation, induces fever


Neutrophils, endothelium

Causes microvascular leak, negative inotropic effects, causes platelet aggregation


T cells, B cells

B-cell differentiation


Endothelium, monocytes



T cells

Decreases arterial pressure, cardiac ejection fraction


T lymphocytes

Acts on hypothalamus to produce fever


Metabolite of arachidonic acid

Increases vascular permeability and vasoconstriction, decreases coronary blood flow, increases pulmonary vascular resistance

Thromboxane A2

Metabolite of arachidonic acid

Platelet aggregation, neutrophil aggregation, increased vascular permeability

Prostaglandin E2

Metabolite of arachidonic acid

Promotes catabolism, acts on hypothalamus to cause fever

Differential Diagnosis

A patient with sepsis syndrome will have characteristic findings suggestive of SIRS; however, at the time of presentation, it may not be readily apparent that the etiology of SIRS is infection. Therefore all potential etiologies for SIRS must be considered in the differential diagnosis. The presence of burns, trauma, and some exogenous stimuli may be readily apparent, although at times it may be difficult to determine whether these conditions are complicated by infection.

Clues to the potential presence of pancreatitis include an antecedent history of alcohol ingestion or of biliary colic. Not having such a history, however, does not exclude pancreatitis as a potential etiology of SIRS; therefore serum lipase and amylase determinations should be considered on all patients with SIRS. The diagnosis of ischemia (eg, ischemic bowel) as a potential precipitant of SIRS is often more difficult to establish, although signs and symptoms referable to the ischemic organ should provide clinical clues. In establishing the etiology of SIRS, the value of a careful history and physical exam cannot be overstated.

Virtually any focus of infection with virtually any organism can lead to the development of sepsis syndrome. Most commonly, the infectious agents responsible for causing sepsis syndrome in the community are bacteria, and the most common infections are community-acquired pneumonia, upper urinary tract infections, meningitis, and cellulitis. In hospitalized patients, line-associated bacteremia, aspiration pneumonia, ventilator-associated pneumonia, wound infections, and abscesses are typical causes of sepsis syndrome.


The clinical findings related to sepsis syndrome are a reflection of the pervasive nature of the inflammatory mediators of sepsis. Virtually every organ system is affected in sepsis syndrome, although the degree of involvement of each organ varies widely between patients. Just as the effects of sepsis syndrome are present in virtually every organ system so are potentialcomplications.

  1. Central Nervous System.Toxic metabolic encephalopathy is associated with sepsis syndrome and is a consequence of several factors including cerebral hypoperfusion, medications, hypoxia, the biologically active products of the infective agent, and inflammatory mediators of sepsis. Encephalopathy may progress to coma, seizures, cerebral edema, and potentially death. In addition, in patients who are critically ill for prolonged periods, a distal sensory/motor polyneuropathy of unknown etiology, called critical illness polyneuropathy, may develop. Last, cerebral hemorrhage, or infarction may occur as a result of the coagulation abnormalities associated with sepsis syndrome.
  2. Pulmonary System.The lungs may be affected in sepsis in several ways. They may be the primary site of infection giving rise to sepsis (ie, pneumonia) or may be subject to the forces of increased left-ventricular end diastolic pressure characteristic of a failing left ventricle. The development of hypoxia and hypocarbia may reflect the development of capillary leakage, leading to impaired gas exchange and consequent hyperventilation characteristic of ARDS. Abnormalities of oxygenation and ventilation can become refractory to mechanical ventilation and lead to death.
  3. Cardiovascular System.The early cardiovascular response to the release of circulating inflammatory cytokines is characterized by normal or increased cardiac output with low systemic vascular resistance and a loss of vascular responsiveness to sympathetic agents (such as epinephrine). Later, myocardial dysfunction and a decrease in the ejection fraction of the left ventricle may occur as a result of a putative myocardial depressant factor. The compensatory increase in heart rate is an attempt to maintain tissue perfusion by increasing cardiac output; failure to compensate appropriately may be indicative of a poor prognosis. Myocardial workload, in an attempt to compensate for the falling tissue perfusion, may increase markedly in sepsis syndrome; if the myocardium is unable to maintain adequate perfusion, cardiac ischemia may occur, leading to arrhythmias, myocardial infarctions, and death.
  4. Gastrointestinal System.Normal gut motility and permeability may be altered in sepsis as a result of the effects of endotoxin and cytokines, resulting in the altered absorption of oral medications and bacterial overgrowth. Gastrointestinal complications of sepsis syndrome include bacterial overgrowth, which increases risk for developing nosocomial pneumonia, and functional obstructions such as toxic megacolon caused by impaired motility.
  5. Renal and Hepatic Systems.The renal and hepatic systems commonly show evidence of dysfunction due to hypoperfusion and capillary leakage, although the use of medications including aminoglycosides, acetaminophen, and others may also contribute to organ injury. Elevations in levels of transaminases and hyperbilirubinemia are common and are associated with a poor prognosis. Rarely, liver injury may progress to ischemic hepatitis. Prerenal azotemia secondary to hypoperfusion is the most common form of renal dysfunction in sepsis syndrome, but other intrinsic renal disorders including acute glomerulonephritis and interstitial nephritis may occur.
  6. Hematologic System.The hematologic system may be altered in sepsis syndrome, notably through the development of disseminated intravascular coagulation and impaired bone marrow synthesis of cellular precursors. Anemia, leukopenia, and thrombocytopenia may be due in part to failure of production of marrow precursors. Anemia may be corrected by transfusion, but leukopenia may impair host defenses, and thrombocytopenia may lead to bleeding, thereby aggravating hypotension, anemia, and tissue hypoperfusion.
  7. Musculoskeletal System.Skeletal muscle dysfunction may be a consequence of the effects of endotoxin and hypoperfusion (also a consequence of the release of inflammatory mediators). Muscle injury may be reflected by rising creatinine kinase levels. Prolonged muscle dysfunction may lead to wasting and the development of critical illness myopathy.
  8. Endocrine System.The physiologic stresses associated with sepsis may unmask occult endocrine deficiency states or, more rarely, may induce adrenal hemorrhage resulting in Addison's disease. The euthyroid sick syndrome is characterized by impaired conversion of T4 to T3 and by abnormal production of thyroid-binding globulin. This results in abnormal measurements of T4 and T3 with normal or decreased levels of thyroid-stimulating hormone.


The aims of treatment for patients with sepsis syndrome are threefold:

  • Elimination of the infectious agent(s) responsible for inducing sepsis.
  • Supportive care based in the intensive care unit aimed at normalizing oxygenation, ventilation, blood pressure, and tissue perfusion.
  • Therapies intended to interrupt inflammatory mediators of sepsis.
  1. Elimination of Infectious Agent(s).Eliminating infectious agents often consists of administering empiric antibiotics together with appropriate surgical drainage or débridement. The complete medical history and physical examination, in addition to the clinical scenario, are used to generate a microbiologic differential diagnosis and guide selection of empiric antibiotic therapy. Host factors that may predispose patients to certain infections are shown in Box 17-2. In a critically ill patient with sepsis syndrome, several possible microbial etiologies commonly exist. Therefore broad-spectrum empiric antibiotic therapies are used until further microbiologic data are available, which might indicate that a more specific antimicrobial regimen is appropriate. Once available, culture data and sensitivity profiles should be used to narrow the spectrum of antibiotics (often to only one agent). The choice of initial antibiotics is based on the likelihood of specific microorganisms for the given clinical scenario (Box 17-3), and the choice of subsequent antibiotics is guided by the results of microbiology testing.
  2. Supportive Care.Supportive care should be based in the intensive care unit and is aimed at normalizing oxygenation, ventilation, blood pressure, and tissue perfusion. The principal means of achieving this goal is aggressive fluid resuscitation, along with possible adjunctive therapy with pressors.
  3. Experimental Therapies.Experimental therapies for sepsis are aimed at interrupting the inflammatory cascade that is common (SIRS caused by diverse stimuli). To date, no such therapies have become part of the standard practice of the medical management of the sepsis syndrome, but numerous strategies in various phases of development exist (Box 17-4).

Current knowledge concerning the pathogenesis of sepsis continues to increase. To date, > 30 mediators have been implicated; consequently, strategies aimed at blocking one mediator are not likely to be successful in reversing the process. Furthermore, clinical trials of sepsis therapies have enrolled patients with a variety of predisposing factors, in whom sepsis has been induced by a variety of agents. It is therefore possible that one therapy may be of benefit in a certain subgroup of patients (ie, cancer patients with pneumococcal sepsis), but this effect would not be detected in such trials. Future studies aimed at defined populations with similar etiologies for sepsis are underway.


The proportion of patients with sepsis who develop septic shock varies between 20% and 40%. Despite increased understanding of its pathogenesis and advances in supportive care, the crude mortality rate of septic shock remains between 50% and 80%.

Prevention & Control

Because sepsis syndrome is not one infection, there is no one thing that can be done to prevent its development. In general, early recognition of infection and appropriate therapy may help to prevent the development of the “sepsis cascade.” For individuals in the community, appropriate vaccinations, including pneumococcal vaccination for patients with chronic obstructive pulmonary disease, may help to decrease the incidence of infections and perhaps of sepsis syndrome. For hospitalized patients, several measures may decrease the incidence of sepsis syndrome: (1) appropriate use of prophylactic perioperative antibiotics, (2) restriction of the use of medical appliances (such as intravenous lines) to only those patients with definite indications, and (3) strict adherence to infection control procedures (to decrease the rate of spread of infection among other patients), including adherence to hand washing policies by hospital staff. In addition, for patients who are at special risk for the development of infections, such as transplant recipients, compliance with prophylactic antibiotics (such as trimethoprim-sulfamethoxazole) is also effective in reducing the incidence of infections and therefore the incidence of sepsis syndrome.

BOX 17-2 Common Microbial Etiologies of Sepsis.

Host Factor

Likely Pathogens

Normal host

Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Staphylococcus aureus

Interrupted integument

Staphylococcus species, Streptococcus pyogenes, Enterobacteriaceae, Pseudomonas aeruginosa

Abnormal urinary tract

Escherichia coli, Enterobacteriaceae


Klebsiella species, Streptococcus pneumoniae


Gram-negative rods; Vibrio, Yersinia, Salmonella species


Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Capnocytophagia canimorsus


Escherichia coli, Pseudomonas species, mucormycosis


Streptococcus pneumoniae, Neisseria meningiditis, Escherichia coli, Haemophilus influenzae


Staphylococcus aureus, Pseudomonas aeruginosa, nosocomial gram-negative bacteria

Cystic fibrosis

Multiresistant Pseudomonas and Burkholderia species


Pneumocystis carinii, Pseudomonas species (pneumonia), Mycobacterium avium intracellulare complex, cytomegalovirus

Solid organ translant

Gram-negative bacteria, cytomegalovirus

Intravascular devices

Staphylococcus aureus, coagulase-negative Staphylococcus species

Chronic steroid use

Streptococcus pneumoniae, Haemophilus influenzae


Group B Streptococcus, Listeria monocytogenes, Streptococcus pneumoniae, Haemophilus influenzae

Posoperative patients

Staphylococcus aureus, Enterobacteriaceae, nosocomial gram-negative bacteria


Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae, Listeria monocytogenes

BOX 17-3 Empiric Therapies for Clinical Presentations Underlying Sepsis Syndrome.

Suspected Source

Empiric Therapy

Community-acquired pneumonia

Third-generation cephalosporin1 + erythromycin2 (or clarithromycin OR azithromycin) OR doxycycline3

Nosocomial aspiration pneumonia

Third-generation cephalosporin1 +/- clindamycin4

Nosocomial pneumonia

Ceftazidime5 OR cefepime6 OR imipenem/meropenem7 OR antipseudomonal penicillin8


Cefazolin9 OR penicillinase-resistant penicillin10; vancomycin if methicillin-resistant staphylococcus aureus (MRSA) suspected

Upper urinary tract infection

Third-generation cephalosporin1 OR ampicillin11 + aminoglycoside12


Cefotaxime13 OR ceftriaxone14 PLUS Vancomycin in areas with penicillin-resistant pneumococci;
Infant < 3 mo, ampicillin1 and aminoglycoside12

Intra-abdominal sepsis (eg, perforated viscus)

Ampicillin11 OR third-generation cephalosporin1 and aminoglycoside12 and metronidazole15 OR ampicillin/sulbactam16 OR ticarcillin/clavulanate17 OR piperacillin/tazobactam18 OR imipenem/meropenem7

Fever in neutropenic host

Ceftazidime5 OR cefepime6 OR imipenem/meropenem7

Septic arthritis

Cefazolin9 OR penicillinase-resistant penicillin;10 vancomycin if MRSA possible
Infant, penicillinase-resistant penicillin10 + third-generation cephalosporin1

Diabetic foot ulcer

Third-generation cephalosporin1 and clindamycin4 OR piperacillin/ tazobactam18 OR ticarcillin/clavulanate17 OR imipenem/meropenem5

Pelvic inflammatory disease

Cefoxitin19 or cefotetan20 PLUS doxycycline3 or clindamycin4 Alternately, third-generation cephalosporin1plus metronidazole15

Biliary sepsis (eg, cholangitis)

Ampicillin11 and aminoglycoside12 and metronidazole15 OR piperacillin/tazobactam18 OR ampicillin/sulbactam16 OR ticarcillin/ clavulanate17 OR imipenem/meropenem5


Vancomycin + aminoglycoside12 + piperacillin/tazobactam8 OR imipenem/meropenem5

1Cefotaxime, 1-2 g IV every 8 h (pediatric 150 mg/kg IV divided every 8 h) or ceftriaxone 1-2 g IV every 24 h (pediatric 50 mg/kg IV once daily).
2Erythromycin, 1 g IV every 6 h (pediatric 40 mg/kg IV divided every 6 h).
3Doxycycline, 100 mg IV/PO every 12 h (pediatric 5 mg/kg PO divided every 12 h).
4Clindamycin, 600-900 mg IV every 8 h (pediatric 20 mg/kg IV divided every 8 h).
5Ceftazidime, 1-2 g IV every 8 h (pediatric 150 mg/kg IV divided every 8 h).
6Cefepime, 1-2 g IV every 12 h (pediatric 50 mg/kg IV every 8 h)
7Imipenem, 500 mg IV every 6 h (pediatric 50 mg/kg IV divided every 6 h); meropenem, 1 g IV every 8 h (pediatric 40 mg/kg IV divided every 8 h).
8Ticarcillin, 3 g IV every 6 h (pediatric 100 mg/kg IV every 8 h) or piperacillin, 3 g IV every 6 h (pediatric 300 mg/kg IV divided every 6 h).
9Cefazolin, 1 g IV every 8 h (pediatric 80 mg/kg IV divided every 8 h).
10Nafcillin, 1 g IV every 4 h (pediatric 150 mg/kg IV divided every 6 h) or oxacillin, 1 g IV every 4 h (pediatric 150 mg/kg IV divided every 6 h).
11Ampicillin, 1 g IV every 6 h (pediatric 150 mg/kg divided every 6 h).
12Gentamicin, 1.3 mg/kg IV every 8 h (pediatric 7.5 mg/kg divided every 8 h) or tobramicin, 1.3 mg/kg IV every 8 h (pediatric 5 mg/kg divided every 8 h)
13Cefotaxime, 2 g IV every 4 h (pediatric 200 mg/kg IV divided every 6 h).
14Ceftriaxone, 2 g IV every 12 h (pediatric 100 mg/kg IV divided every 12 h).
15Metronidazole, 500 mg IV every 6 h (pediatric 30 mg/kg IV divided every 12 h).
16Ampicillin/sulbactam, 3.0 g every 6 h (pediatric 150 mg/kg IV divided every 6 h, not for use below 12 years old).
17Ticarcillin/clavulanate, 3.1 g IV every 6 h (pediatric same dose, not for use below 12 years old).
18Piperacillin/tazobactam, 3.375 g IV every 6 h (pediatric dosage not established).
19Cefoxitin, 1-2 g IV every 8 h (pediatric 80 mg/kg IV divided every 6 h).
20Cefotetan, 2 g IV every 12 h (pediatric dose not established).

BOX 17-4 Potential Therapies for Interrupting the Inflammatory Mediators of Sepsis




No benefit

Antiendotoxin monoclonal antibodies

No consistent benefits, ? decreased mortality in patients with gram-negative sepsis

IL-1 receptor antagonists

No benefit

Platelet-activating factor antagonists

No benefit

Bradykinin antagonists

No benefit

Nonsteroidal anti-inflammatory agents

No benefit

Anti-TNF antibodies

No survival benefit

TNF receptor fusion proteins

No survival benefit

NOsynthetase blockade

Under investigation

Cell wall adhesion molecular blockade

Under investigation

Anti-intercellular adhesion molecule antibodies

Under investigation

Recombinant bactericidal/permeability increasing protein

No data in humans


No data in humans

Anti-LPS binding protein antibodies

No data in humans

Anti-IL-6 antibodies

No data in humans

Lipid A competitive antagonists

No data in humans

Hemofiltration/plasma exchange

No data in humans




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