AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Sepsis is a clinical term used to describe symptomatic bacteremia, with or without organ dysfunction. Sustained bacteremia, in contrast to transient bacteremia, may result in a sustained febrile response that may be associated with organ dysfunction. Septicemia refers to the active multiplication of bacteria in the bloodstream that results in an overwhelming infection.

Pathophysiology

The pathophysiology of sepsis is complex and results from the effects of circulating bacterial products, mediated by cytokine release, caused by sustained bacteremia. Cytokines, previously termed endotoxins, are responsible for the clinically observable effects of the bacteremia in the host. Impaired pulmonary, hepatic, or renal function may result from excessive cytokine release during the septic process.

Frequency

United States

Sepsis is an overused term often misapplied to patients with fever, leukocytosis, and hypotension due to other causes, including pseudosepsis. True sepsis is a common cause of hospitalization in the United States. Frequent sources of infection are listed in History.

International

Sepsis is a common cause of mortality and morbidity worldwide.

Mortality/Morbidity

The prognosis of sepsis depends on the underlying status and host defenses, prompt and adequate surgical drainage of abscesses, relief of any obstruction of the intestinal or urinary tract, and appropriate and early empiric antimicrobial therapy with the drug spectrum appropriate to the presumed septic source.

Race

Sepsis does not appear to have a racial predisposition.

Sex

Sepsis does not appear to have a sexual predisposition.

Age

Elderly men are more likely to develop urosepsis due to benign urinary tract obstruction caused by prostatic hypertrophy.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The patient’s history is essential in determining the likely source of the septic process. This, in turn, determines the appropriate antimicrobial therapy.
• Sources of infection
• • Suspect intravenous-line infections when other sources of sepsis are eliminated and the intravenous line has been in place for a prolonged period, usually more than one week. Central intravenous lines are the lines most commonly associated with bacteremia or sepsis. Peripheral venous lines are almost never involved, and arterial lines are rarely associated with bacteremia, although it can still occur.
  • Patients with an intra-abdominal or pelvic source of infection usually have a history of antecedent conditions that predispose to perforation or abscess (eg, chronic or retrocecal subacute appendicitis, diverticulitis, Crohn disease, previous abdominal surgery, cholecystitis).
  • The urinary tract source is suggested by an antecedent history of pyelonephritis, stone disease, congenital abnormal collecting system, prostate enlargement, or previous prostate or renal surgery.
• Patients with diabetes, systemic lupus erythematosus (SLE), or alcoholism or who are taking steroids are also at an increased risk for bacteremia.
• Patients with nonspecific symptoms are usually acutely ill with fever, with or without shaking chills. Mental status may be impaired in the setting of fever or hypoperfusion.

Physical

• Physical examination
• • This may be helpful in suggesting a potential source for sepsis. An infected central intravenous-line site immediately suggests the probable etiology. However, it is important to note that only 50% of patients with central intravenous-line infections have evidence of infection at the insertion site.
  • Right upper abdominal quadrant tenderness may suggest gallbladder etiology (eg, cholecystitis, cholangitis).
• Diffuse abdominal pain suggests pancreatitis (not sepsis) or generalized peritonitis.
• Discrete tenderness over the left lower abdominal quadrant suggests diverticulitis, particularly in elderly patients.
• Tenderness in the right lower abdominal quadrant in a young adult suggests appendicitis or Crohn disease.
• A rectal examination may reveal exquisite tenderness due to prostatic abscess or, more commonly, an enlarged noninflamed prostate suggestive of benign prostatic hypertrophy (BPH).
• Costovertebral angle (CVA) tenderness with a temperature of 102°F defines acute pyelonephritis. Subacute or chronic pyelonephritis may manifest as only mild tenderness.
• Patients with bacteremia from any source often display an increased breathing rate due to respiratory alkalosis.
• The skin of patients with sepsis may be warm or cold, depending on the adequacy of organ perfusion and dilatation of the superficial vessels of the skin.
• In many cases, the history is critical for diagnosis, and abdominal findings on physical examination may be unimpressive or absent.

Causes

• Sepsis or septic shock may be associated with the direct introduction of microbes into the bloodstream via intravenous infusion (eg, intravenous line, other device-associated infections).
• An intra-abdominal or pelvic structure may be perforated, compromised, or ruptured.
• Bacteremia due to bacteruria (urosepsis) may complicate cystitis in compromised hosts. Intrarenal infection (pyelonephritis), renal abscess (intrarenal or extrarenal), acute prostatitis, or prostatic abscess may cause urosepsis in immunocompetent hosts.
• Sepsis is not a random occurrence and is usually associated with the conditions discussed above.
• Sepsis may be caused by overwhelming pneumococcal infection in patients with impaired or absent splenic function.
• Meningococcemia from a respiratory source may also result in sepsis, with or without associated meningitis.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Table 1. Clinical Conditions Associated With Sepsis and Its Mimics

Adapted from: Cunha BA, Shea KW. Fever in the intensive care unit. Infect Dis Clin North Am. Mar 1996;10(1):185-209.¹

Pseudosepsis

It is important to consider other causes or conditions that mimic the clinical and hemodynamic parameters of sepsis. The causes of pseudosepsis need identification because they require supportive, rather than antimicrobial, therapy. Pseudosepsis is a common cause of misdiagnosis in hospitalized patients, particularly in the emergency department and in medical and surgical intensive care units. The most common causes of pseudosepsis include the following:

• GI hemorrhage
• Pulmonary embolism
• Acute myocardial infarction (MI)
• Acute pancreatitis (edematous or hemorrhagic)
• Diuretic induced hypovolemia
• Relative adrenal insufficiency

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Blood cultures
• • Obtain blood cultures in all patients upon admission to demonstrate the organism responsible for infection. Negative blood culture results are also necessary to include pseudosepsis in the differential diagnoses.
  • Blood culture isolates might suggest the underlying disease process. Bacteroides fragilis suggests a colonic or pelvic source, whereas Klebsiella species or enterococci suggest a gallbladder or urinary tract source more frequently than an intra-abdominal source.
  • A CBC count is usually not helpful because of the numerous conditions that mimic sepsis (eg, pseudosepsis) and that manifest as leukocytosis with variable degrees of a left shift. Leukocytosis with a left shift is a nonspecific diagnostic finding. It is as common in noninfection as in infection.
• Other
• • Obtain a urine Gram stain, urinalysis, and urine culture if urosepsis is suspected.
  • If central intravenous-line sepsis is suspected, remove the line and send the tip for semiquantitative bacterial culture. If the catheter-tip culture results are positive and demonstrate 15 or more colonies and if the catheter-tip isolate matches the blood-culture isolate, an infection associated with the central intravenous line is diagnosed.
  • Obtain a buffy coat of the white cells from peripheral blood stained by acridine orange, or use the Gram method to demonstrate bacteria responsible for the bacteremia or septic process. While the yield is low, stained buffy coat smears, if positive, are the best rapid test available to demonstrate organisms that cause bacteremia. If the stained buffy coat smear yields a positive result, it demonstrates the morphology of the bacteria that is causing the bacteremia, which provides rapid information on which to base empiric antimicrobial therapy.

Imaging Studies

• Chest radiography is important to rule out pneumonia and diagnose other causes of pulmonary infiltrates, as follows:
• • Pulmonary drug reactions
  • Pulmonary emboli
  • Pulmonary hemorrhage
  • Primary or metastatic pulmonary neoplasms
  • Lymphangitic spread of malignancies
  • Large pleural effusions
  • Pneumothorax
  • Hydrothorax
  • Fluid overload
  • Congestive heart failure
  • Acute MI
  • Acute respiratory distress syndrome should suggest an intra-abdominal source (eg, acute pancreatitis).
• Ultrasonography
• • Perform abdominal ultrasonography if biliary tract obstruction is suspected based on the clinical presentation.
  • Sonograms in patients with cholecystitis may show a thickened gallbladder wall or biliary calculi but no dilatation of the common bile duct.
  • Stones in the biliary tract are visible in patients with cholangitis, but the common bile duct is dilated.
  • Abdominal ultrasonography is suboptimal for the detection of abscesses or perforated hollow organs.
• CT scan or MRI
• • Use CT scan or MRI of the abdomen if a nonbiliary intra-abdominal source of infection is suspected based on the history or physical examination findings.
  • CT scan and MRI are superior to ultrasonography in demonstrating all lesions except those related to the biliary tract.
  • An abdominal CT or MRI scan is also helpful in delineating intrarenal and extrarenal pathology.
• Gallium or indium scan: These modalities have no place in the initial workup of sepsis, as patients with sepsis are acutely ill by definition, and rapid diagnostic tests (eg, CT scan or MRI of the abdomen, ultrasonography of the right upper quadrant) are time-critical, life-saving tools.

Other Tests

• ECG: Obtain an ECG and cardiac enzymes in patients in whom acute MI is likely. Remember that certain patients may present with a silent asymptomatic MI, which should be included in the differential diagnoses of otherwise unexplained fever, leukocytosis, and hypotension. Silent MIs are common in elderly patients and in those who have undergone recent abdominal or pelvic surgery. They are also common in individuals with alcoholism, diabetes, and uremic conditions.

Procedures

• Thoracentesis: Perform thoracentesis for diagnostic purposes in patients with substantial pleural effusion.
• Paracentesis: Perform paracentesis in patients with gross ascites.
• Swan-Ganz catheter
• • Use data obtained via Swan-Ganz catheter to manage the fluid status of the patient and to assess left ventricular dysfunction in patients with acute MI.
  • Do not use Swan-Ganz hemodynamic parameters to diagnose sepsis. While most patients with sepsis demonstrate an increased cardiac output with a low peripheral vascular resistance, the converse is not true. Most patients with Swan-Ganz readings compatible with sepsis without a definite intravenous abdominal or GU source do not have sepsis, but rather pseudosepsis, as described above (see Other Problems to Be Considered).

Histologic Findings

Sepsis does not cause diagnostic findings in various organs.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Offer supportive therapy aimed at maintaining organ perfusion.
• Provide respiratory support, when necessary.

Consultations

• Obtain a consultation with a surgeon for patients with presumed intra-abdominal or pelvic sepsis. Early surgical consultation and involvement by the surgical team is essential, since many causes of sepsis involve a perforated viscus, abscess, or obstructing process that requires surgical intervention for cure or resolution of the infection.
• Obtain a consultation with an infectious disease specialist for all patients with sepsis included in the differential diagnoses.

Diet

• Most patients are instructed to take nothing by mouth (NPO) and can tolerate a transient decrease in caloric intake over 1-2 weeks if their fluid and electrolyte balances are maintained.

Activity

• Most patients are ill and require bed rest or admission to the ICU.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Appropriate antimicrobial therapy depends on adequate coverage of the resident flora of the organ system presumed to be the source of the septic process. Empiric monotherapy regimens include imipenem, meropenem, cefoperazone, piperacillin/tazobactam, or sulbactam/ampicillin. Combination therapeutic agents include clindamycin or metronidazole plus levofloxacin, aztreonam, trimethoprim/sulfamethoxazole (TMP-SMZ), or an aminoglycoside.

No single drug/regimen is superior to another. Alternative agents may be used alone or in combination provided they have a low reactive potential and a good adverse-effect profile.

Drug Category: Antibiotics

These agents are used to treat various types of infection.

Empiric therapy for intravenous-line infections

Since intravenous-line infections are most often due to Staphylococcus aureus (MSSA or MRSA) and less commonly due to aerobic gram-negative bacilli, the preferred empiric therapy for intravenous-line infections is meropenem, cefoperazone, or cefepime plus additional coverage for staphylococci. If MRSA is prevalent in the institution, add linezolid, vancomycin, or daptomycin.

If coagulase-negative staphylococci are recovered from the blood (high-level bacteremia, ie, 3/4 or 4/4 blood cultures positive), avoid vancomycin for empiric therapy if possible, since this is a low-virulence organism.

Treatment of coagulase-negative staphylococcal central-line infection requires removal of the line. Vancomycin may be given, but central line removal is essential. If the central line cannot be removed for clinical reasons in a patient with MRSA or coagulase-negative staphylococcal infection, empiric suppressive vancomycin therapy is acceptable.

Minimize the use of vancomycin in order to prevent the emergence of Enterococcus faecium, a vancomycin-resistant species.

Empiric therapy for biliary tract infections (cholecystitis/cholangitis)

The main biliary-tract pathogens include Escherichia coli, Klebsiella species, and Enterococcus faecalis. Coverage for staphylococci and anaerobes is not needed in the biliary tract. Anaerobes are important only in patients with diabetes who have Clostridium perfringens emphysematous cholecystitis. Preferred monotherapy for biliary-tract infections is with imipenem, meropenem, piperacillin, or cefoperazone.

Empiric therapy for intra-abdominal and pelvic infections

The main pathogens in the lower abdomen and pelvis include aerobic coliform gram-negative bacilli and B fragilis. Enterococci are permissive/opportunistic pathogens and do not require special coverage. Potent anti–B fragilis and aerobic gram-negative bacillary coverage are essential, in addition to surgical intervention when drainage or repair of intra-abdominal viscera is required.

Preferred monotherapy for intra-abdominal and pelvic infections is imipenem, meropenem, piperacillin/tazobactam, or ampicillin/sulbactam.

Preferred combination therapy for intra-abdominal and pelvic infections is clindamycin or metronidazole plus aztreonam, levofloxacin, or an aminoglycoside.

Empiric therapy for urosepsis

The primary uropathogens include gram-negative aerobic bacilli, eg, coliforms or enterococci (E faecalis, not E faecium vancomycin-resistant enterococci).

Pseudomonas aeruginosa, Enterobacter species, and Serratia species are rare uropathogens and are associated with urological instrumentation.

Preferred monotherapy for urosepsis due to aerobic gram-negative bacilli is with aztreonam, levofloxacin, third- or fourth-generation cephalosporins, or an aminoglycoside.

Preferred monotherapy for urosepsis due to enterococci (E faecalis) is with ampicillin or vancomycin (penicillin-allergic).

Empiric therapy for community-acquired urosepsis is levofloxacin, aztreonam, or an aminoglycoside plus ampicillin. For nosocomial urosepsis, piperacillin, imipenem, or meropenem monotherapy is preferred. 

Empiric therapy for other causes of sepsis

S aureus sepsis is usually associated with infection caused by devices or acute bacterial endocarditis. Empiric therapy may be with nafcillin, an anti-staphylococcal, cephalosporin, a carbapenem, linezolid, or clindamycin with or without rifampin.

Pneumococcal or meningococcal sepsis may be treated with penicillin G or a beta-lactam. In patients with associated meningococcal meningitis, the antibiotic selected should penetrate the cerebrospinal fluid and should be given in meningeal doses.

Empiric therapy for sepsis of unknown origin

The usual sources of sepsis are from the distal GI tract, pelvis, or GU tract. For intravenous-line infections, see above.

Organisms that should be covered from the GI/GU tract and pelvis include aerobic gram-negative bacilli (coliforms) and B fragilis. Enterococci are important pathogens in biliary-tract sepsis and urosepsis.

Preferred empiric monotherapy includes meropenem, imipenem, piperacillin/tazobactam, or cefoperazone.

Empiric combination therapy includes (1) levofloxacin plus either clindamycin or metronidazole, (2) aztreonam, (3) cefepime plus either clindamycin or metronidazole, or (4) ceftriaxone or aminoglycoside plus metronidazole.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Antibiotics are normally continued until the septic process and surgical interventions have controlled the source of infection. Ordinarily, patients are treated for approximately 2 weeks. Admission to an ICU or surgical ICU depends on the severity of the septic process and organ dysfunction, as well as the need for surgical intervention.
• As soon as patients are able to tolerate medications orally, the patient may be switched to an equivalent regimen of antibiotics by mouth in an intravenous-to-oral switch program.

Further Outpatient Care

• Coordinate surgical follow-up with the surgeon.

In/Out Patient Meds

• If additional antimicrobial therapy is needed outside the hospital setting, it should be given orally, not intravenously. Do not allow the total course of antibiotics to exceed 3 weeks, except for the treatment of liver abscesses, which may require prolonged courses of oral antibiotics for cure or complete clinical resolution.

Transfer

• Transfer may be necessary to a facility able to perform diagnostic imaging tests or required surgical procedures if they are not available at the admitting hospital.

Complications

• Peritonitis may result in abscesses, which may subsequently need to be drained. Inadequate correction of intra-abdominal perforation or drainage procedures may result in a continuance or relapse of the patient's septic condition.

Prognosis

• The prognosis in most patients is good, except in those with intra-abdominal or pelvic abscesses due to organ perforation. The underlying physiologic condition of the host is the primary determinant of outcome.
• Early and appropriate empiric antimicrobial therapy and surgical intervention are critical in decreasing mortality and morbidity.

Patient Education

• If orally administered antibiotics are continued at home, advise the patient about possible adverse effects.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Sepsis (Blood Infection).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The most important medicolegal concerns regarding sepsis treatment include (1) ensuring that the patient indeed does have sepsis, (2) rapidly identifying its source, and (3) implementing effective treatments. The most common error is failure to consider pseudosepsis as a cause of the presenting syndrome complex. Most causes of pseudosepsis are readily treatable and reversible if recognized and treated early.

Special Concerns

• Elderly patients may present with peritonitis and may not experience rebound tenderness of the abdomen. An acute surgical abdomen in a pregnant patient may be difficult to diagnose, but, fortunately, most pregnant women are young, healthy, and physiologically strong. The most common cause of sepsis in pregnancy is urosepsis due to an obstructed urinary tract, which may be caused by the hormone effects of pregnancy on the ureters (hydroureters) and the mechanical obstructing effect of the uterus impinging on the ureters.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Aug 1, 2008