Bacterial Sepsis

Updated: Feb 05, 2019
  • Author: Amber Mahmood Bokhari, MBBS; Chief Editor: Michael Stuart Bronze, MD  more...
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Overview

Practice Essentials

Definitions

Sepsis  is a life-threatening syndrome usually caused by bacterial infection. Sepsis is a response of the body's immune system that results in organ dysfunction or failure. The systemic inflammatory response syndrome (SIRS) criteria were recently replaced by the quick Sequential Organ Failure Assessment (qSOFA) in 2016, allowing for quick bedside analysis of organ dysfunction in patients with suspected or documented infection. The qSOFA score includes a respiratory rate of 22 breaths/minute or more, systolic blood pressure of 100 mm Hg or less, and altered level of consciousness. [1, 2] For completeness, severe sepsis is defined as sepsis complicated by organ dysfunction.

Multiple organ dysfunction syndrome (MODS)  is characterized by progressive organ dysfunction in a severely ill patient, with failure to maintain homeostasis without intervention. It is the end stage in infectious conditions (sepsis, septic shock) and noninfectious conditions (eg, SIRS due to pancreatitis). The greater the number of organ failures, the higher the mortality risk, with the greatest risk associated with respiratory failure requiring mechanical ventilation. MODS can be classified as primary or secondary. [3]

Primary MODS is the direct result of identifiable injury or insult with early organ dysfunction (eg, renal failure due to a nephrotoxic agent or liver failure due to a hepatotoxic agent).

Secondary MODS is organ failure that has no attributable cause and is a consequence of the host's response (eg, acute respiratory distress syndrome [ARDS] in individuals with pancreatitis).

The following parameters are used to assess individual organ dysfunction:

  • Respiratory system: Partial pressure of arterial oxygen (PaO 2)/fraction of inspired oxygen (FiO 2) ratio
  • Hematology: Platelet count, coagulation panel (prothrombin time and partial thromboplastin time)
  • Liver: Serum bilirubin
  • Renal: Serum creatinine (or urine output)
  • Brain: Glasgow coma score
  • Cardiovascular: Hypotension and vasopressor requirement

Septic shock  is defined as sepsis with hypotension requiring vasopressor therapy to maintain a mean blood pressure of more than 65 mm Hg and a serum lactate level exceeding 2 mmol/L (18 mg/dL) after adequate fluid resuscitation. [1] This has a greater risk of mortality and long-term morbidity.

Pseudosepsis is defined as fever, leukocytosis, and hypotension due to causes other than sepsis. Examples might include the clinical picture seen with salicylate intoxication, methamphetamine overdose, or bilateral adrenal hemorrhage.

Etiology

Sepsis can be caused by an obvious injury or infection or a more complicated etiology such as perforation, compromise, or rupture of an intra-abdominal or pelvic structure. [4] Other etiologies can include meningitis, head and neck infections, deep neck space infections, pyelonephritis, renal abscess (intrarenal or extrarenal), acute prostatitis/prostatic abscess, severe skin or skin structure infections (eg, necrotizing fasciitis), postsurgical infections, or systemic infections such as rickettsial infection. A more detailed discussion of sepsis etiology in various organ systems is provided in Etiology.

Clinical Presentation

Individuals with sepsis may present with localizing symptoms related to a specific site or source of infection or may present with nonspecific symptoms. Individuals with nonspecific symptoms are usually acutely ill with fever and may present with or without shaking chills. Mental status may be impaired in the setting of fever or hypotension. Patients with bacteremia from any source often display an increased breathing rate resulting in respiratory alkalosis. The skin of patients with sepsis may be warm or cold, depending on the adequacy of organ and skin perfusion. A detailed history and physical examination is essential in determining the likely source of the septic process (See History and Physical Examination). This helps the clinician to determine the appropriate treatment and antimicrobial therapy (see Treatment for further detail).

See Clinical Presentation for more detail.

Diagnosis

A diagnosis of sepsis is based on a detailed history, physical examination, laboratory and microbiology testing, and imaging studies.

Laboratory studies that may be considered include the following:

  • Complete blood (CBC) count - May show elevated or low white blood cell count, anemia, and/or thrombocytopenia
  • Chemistry studies, such as markers of liver or kidney injury - May suggest organ dysfunction
  • Bacterial cultures - Blood cultures and site-specific cultures based on clinical suspicion (eg, wound culture, sputum culture, or urine culture)
  • Stained buffy coat smears or Gram staining of peripheral blood - May be helpful in certain infections
  • Urine studies (urinalysis, microscopy, urine culture)
  • Certain biomarkers, such as procalcitonin [5, 6, 7] and presepsin [8] - May be useful in diagnosing early sepsis and in determining prognosis

Imaging modalities should be focused on areas of clinical concern, based on the history and physical examination, and may include the following:

  • Chest radiography (to rule out pneumonia and diagnose other causes of pulmonary infiltrates)
  • Chest CT scanning (to further evaluate for pneumonia or other lung pathology)
  • Abdominal ultrasonography (for suspected biliary tract obstruction)
  • Abdominal CT scanning or MRI (for assessing a suspected non-biliary intra-abdominal source of infection or delineating intrarenal and extrarenal pathology)
  • Site-specific soft tissue imaging, including ultrasonography, CT scanning, or MRI (to assess for possible abscess, fluid collection, or necrotizing skin infection)
  • Contrast-enhanced CT scanning or MRI of the brain/neck (to assess for possible masses, abscess, fluid collection, or necrotizing infection)

The following cardiac studies may be useful if cardiac involvement or disease is suspected as a cause or complication of infection:

  • Electrocardiography (ECG) to evaluate for conduction abnormalities or delays or arrhythmias; pericarditis may be a cause of “pseudosepsis”
  • Cardiac enzyme levels
  • Echocardiography to evaluate for structural heart disease

Invasive diagnostic procedures that may be considered include the following:

  • Thoracentesis (in patients with pleural effusion)
  • Paracentesis (in patients with ascites)
  • Drainage of fluid collections/abscesses
  • Bronchoscopy with washing, lavage, or other invasive sampling (in patients with suspected pneumonia)

See Workup for more detail.

Management

Initial management may include the following:

  • Inpatient admission or ICU admission for monitoring and treatment
  • Initiation of empiric antibiotic therapy, to be followed by focused treatment based on culture, laboratory, and imaging data
  • Supportive therapy as necessary to maintain organ perfusion and respiration; timely intervention with infection source control, hemodynamic stabilization, and ventilatory support
  • Transfer if requisite facilities are not available at the admitting hospital

Appropriate empiric antimicrobial therapy depends on adequate coverage of the presumed pathogen(s) responsible for the septic process, potential antimicrobial resistance patterns, and patient-specific issues such as drug allergies or chronic medical conditions. Tying sites of infection to specific pathogens should occur, as follows:

  • Intravenous line infections: Consider broad-spectrum coverage for gram-positive organisms, especially methicillin-resistant Staphylococcus aureus (MRSA) (linezolid, vancomycin, or daptomycin) and gram-negative nosocomial pathogens (especially Pseudomonas species and other Enterobacteriaceae [piperacillin-tazobactam, carbapenems, or cefepime]), and line removal. Some of these may be Candida infections.
  • Biliary tract infections: Typical bacterial agents include Enterobacteriaceae, gut-associated anaerobes, and Enterococcus. Consider carbapenems, piperacillin-tazobactam, cephalosporins, or quinolones in combination with an anaerobic agent such as metronidazole.
  • Intra-abdominal and pelvic infections: Typically Enterobacteriaceae, gut-associated anaerobes, or Enterococcus (carbapenems, piperacillin-tazobactam, or cephalosporins or quinolones in combination with an anaerobic agent such as metronidazole)
  • Urosepsis: Typically Enterobacteriaceae or Enterococcus (carbapenems, piperacillin-tazobactam, cephalosporins, quinolones, or aminoglycosides)
  • Pneumococcal sepsis: Third-generation cephalosporins, respiratory quinolone (levofloxacin or moxifloxacin), carbapenem, or vancomycin if resistance is suspected
  • Sepsis of unknown origin: Meropenem, imipenem, piperacillin-tazobactam, or tigecycline; metronidazole plus levofloxacin, cefepime, or ceftriaxone may be alternatives

Early surgical evaluation for presumed intra-abdominal or pelvic sepsis is essential. Procedures that may be warranted depend on the source of the infection, the severity of sepsis, and the patient’s clinical status, among other factors.

Once an etiologic pathogen is identified, typically via culture, narrowed antibiotic therapy against the identified pathogen is appropriate (eg, penicillin for penicillin-susceptible Streptococcus pneumoniae).

See Treatment and Medication for more detail.

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Background

Hippocrates, in the fourth century BCE, used the term sepsis denoting decomposition. Avicenna, in the eleventh century, called diseases causing purulence as blood rot. In the nineteenth century, the term sepsis was widely used to describe severe systemic toxicity. A closely derived term of septicemia was used for bacterial infection in the blood, which has been replaced by the term bacteremia. In the last two centuries, the processes underlying infections have been better studied and elucidated. The role of microorganisms in causing infections and the intricate mechanisms of various intrinsic and extrinsic toxins in damaging body tissues that result in fever and shock has been discovered with painstaking research. At the beginning of the twentieth century, the term endotoxin was devised by Pfeiffer to explain the causative agent in infection with cholera. It was later linked to other gram-negative bacterial pathogenicity. [9]

The initial sepsis guidelines were published in 2004 and revised in 2008 and 2012. The current clinical practice guidelines are a revision of the 2012 Surviving Sepsis Campaign (SSC) guidelines for the management of severe sepsis and septic shock. (See Guidelines.)

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Etiology

The etiology of sepsis is diverse, and clinical clues to various organ systems aid in appropriate workup and diagnosis. It is also pertinent to be able to distinguish between the infectious and noninfectious causes of fever in a septic patient. The following are organ system–specific etiologies of possible sepsis:

  • Skin/soft tissue: Necrotizing fasciitis, cellulitis, myonecrosis, or gas gangrene, among others, with erythema, edema, lymphangitis and positive skin biopsy result
  • Wound infection: Inflammation, edema, erythema, discharge of pus, with positive Gram stain and culture results from incision and drainage or deep cultures
  • Upper respiratory tract: Pharyngitis, tonsillitis, or sinusitis, among others, with inflammation, exudate with or without swelling, and lymphadenopathy or positive throat swab culture or rapid test result
  • Lower respiratory tract: Pneumonia, empyema, or lung abscess, among others, with productive cough, pleuritic chest pain, consolidation on auscultation, positive sputum culture result, positive blood culture result, rapid viral testing, urinary antigen testing (eg, Pneumococcus, Legionella), quantitative culture of protected brush, or bronchoalveolar lavage
  • Central nervous system: Meningitis, brain abscess, or infected hematoma, among others, with signs of meningeal irritation, elevated CSF cell count and protein level, reduced CSF glucose level, positive Gram stain and culture results
  • Cerebrovascular system: Myocardial infarction, acute valvular dysfunction, myocarditis, pericardialis, ruptured aortic aneurysm, aortitis, or septic emboli, among others, with elevated levels of cardiac enzymes, and imaging (ultrasonography, CT scanning, or MRI) of the chest, abdomen, and/or pelvis showing vascular involvement
  • Vascular catheters (arterial, venous): Redness or drainage at insertion site, positive blood culture result (from the catheter and a peripheral site), and catheter tip culture after sterile removal
  • Gastrointestinal: Colitis, infectious diarrhea, ischemic bowel, or appendicitis, among others, with abdominal pain, distension, diarrhea, and vomiting; positive stool culture result and testing for toxigenic Escherichia coli, Salmonella, Shigella, Campylobacter, or Clostridium difficile
  • Intra-abdominal: Renal abscess, pyelonephritis, pancreatitis, cholecystitis, liver abscess, intra-abdominal abscesses, or perforation, compromise, or rupture of an intra-abdominal or pelvic structure, among others, with specific symptoms and signs; [4] aerobic and anaerobic culture of drained abdominal fluid collections; peritoneal dialysis (PD) catheter infection with cloudy PD fluid, abdominal pain, deranged cell count, and positive PD fluid culture result
  • Urinary tract: Cystitis, pyelonephritis, urethritis, or renal abscess, among others, with urgency, dysuria, pelvic, suprapubic, or back pain; urine microscopy showing pyuria or a positive urine culture result; urosepsis has also been reported after prostatic biopsy [10]
  • Female genital tract: Pelvic inflammatory disease, cervicitis, or salpingitis, among others, with lower abdominal pain, vaginal discharge, positive results on endocervical and high vaginal swabs
  • Male genital tract: Orchitis, epididymitis, acute prostatitis, balanitis, or prostatic abscess, among others, with dysuria, frequency, urgency, urge incontinence, cloudy urine, prostatic tenderness, and positive urine Gram stain and culture results
  • Bone: Osteomyelitis presenting with pain, warmth, swelling, decreased range of motion, positive blood and/or bone culture results, and MRI changes
  • Joint: Septic arthritis presenting with pain, warmth, swelling, decreased range of motion, positive arthrocentesis with cell counts, and positive Gram stain and culture results
  • Nonspecific systemic febrile syndromes: Babesiosis, rickettsial diseases, lyme disease, typhus, or typhoid fever, among others, with multiorgan involvement, specific travel and epidemiological exposures, and associated rashes or other symptoms

There are numerous noninfectious causes of fever and organ dysfunction that can mimic sepsis: [11]

  • Alcohol/drug withdrawal
  • Postoperative fever (48 hours postoperatively)
  • Transfusion reaction
  • Drug fever
  • Allergic reaction
  • Cerebral infarction/hemorrhage
  • Adrenal insufficiency/adrenal hemorrhage
  • Myocardial infarction
  • Pancreatitis
  • Acalculous cholecystitis
  • Ischemic bowel
  • Aspiration pneumonitis
  • ARDS (both acute and late fibroproliferative phase)
  • Subarachnoid hemorrhage
  • Fat emboli
  • Transplant rejection
  • Deep venous thrombosis
  • Pulmonary emboli
  • Gout/pseudogout
  • Hematoma
  • Cirrhosis (without primary peritonitis)
  • Gastrointestinal hemorrhage
  • Phlebitis/thrombophlebitis
  • IV contrast reaction
  • Neoplastic fevers
  • Decubitus ulcers

Table 1. Infectious and Noninfectious Causes of Fever [12] (Open Table in a new window)

System

Infectious Causes

Noninfectious Causes

Central nervous

Meningitis, encephalitis

Posterior fossa syndrome, central fever, seizures, cerebral infraction, hemorrhage, cerebrovascular accident

Cardiovascular

Central line, infected pacemaker, endocarditis, sternal osteomyelitis, viral pericarditis, myocardial/perivalvular abscess

Myocardial infarction, balloon pump syndrome, Dressler syndrome

Pulmonary

Ventilator-associated pneumonia, mediastinitis, tracheobronchitis, empyema

Pulmonary emboli, ARDS, atelectasis (without pneumonia), cryptogenic organizing pneumonia, bronchogenic carcinoma without postobstructive pneumonia, systemic lupus erythematosus, pneumonitis, vasculitis

Gastrointestinal

Intra-abdominal abscess, cholangitis, cholecystitis, viral hepatitis, peritonitis, diarrhea (Clostridium difficile)

Pancreatitis, acalculous cholecystitis, ischemia of the bowel/colon, bleeding, cirrhosis, irritable bowel syndrome

Urinary tract

Catheter-associated bacteremia, urosepsis, pyelonephritis, cystitis

Allergic interstitial nephritis

Skin/soft tissue

Decubitus ulcers, cellulitis, wound infection

Vascular ulcers

Bone/joint

Chronic osteomyelitis, septic arthritis

Acute gout

Other

Transient bacteremia, sinusitis

Adrenal insufficiency, phlebitis/thrombophlebitis, neoplastic fever, alcohol/drug withdrawal, delirium tremens, drug fever, fat emboli, deep venous thrombosis, postoperative fever (48 h), fever after transfusion

An abdominal wall abscess is depicted on the CT scan below.

A right lower quadrant abdominal wall abscess and A right lower quadrant abdominal wall abscess and enteric fistula are observed and confirmed by the presence of enteral contrast in the abdominal wall.

Organisms can be introduced via various mechanisms, including direct inoculation of microbes into the body or body site, such as in skin or soft tissue infections or bloodstream infections associated with indwelling venous catheters. Inhalational acquisition is a mode of infection in the setting of respiratory infection, as is aspiration of oral/gastric content. Ascending urinary tract infection can also cause systemic infection. The gastrointestinal tract can also be a source of infection if contents macroscopically rupture or seed the intra-abdominal compartment or if organisms translocate through the mucosal barrier. Other mucosal surfaces can also serve as entry points, including the conjunctiva, the upper respiratory tract, and the genitourinary tract. External disease-transmitting vectors, such as arthropods, can also cause infection. [4, 13]

The pathophysiology of sepsis is complex and results from the effects of circulating bacterial products, mediated by cytokine release, caused by sustained bacteremia. Cytokines are responsible for the clinically observable effects of bacteremia in the host. [13, 14, 15, 16] Impaired pulmonary, hepatic, or renal function may result from excessive cytokine release during the septic process.

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Prognosis

Sepsis is a common cause of mortality and morbidity worldwide. The prognosis depends on underlying health 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. [17]

The prognosis of sepsis treated in a timely manner and with appropriate therapy is usually good, except in those with intra-abdominal or pelvic abscesses due to organ perforation. When timely and appropriate therapy has been delivered, the underlying physiologic condition of the patient determines outcome.

A systematic review by Winters et al suggested that beyond the standard 28-day in-hospital mortality endpoint, ongoing mortality in patients with sepsis remains elevated up to 2 years and beyond. [18] In addition, survivors consistently demonstrate impaired quality of life. [19]

Clinical characteristics that affect the severity of sepsis and, therefore, the outcome include the host's response to infection, the site and type of infection, and the timing and type of antimicrobial therapy.

Host-related

Abnormal host immune responses may increase susceptibility to severe disease and mortality. For example, extremes of temperature and the presence of leukopenia and/or thrombocytopenia, advanced age, presence of co-morbid conditions, hyperglycemia, bleeding diatheses, and failure of procalcitonin levels to fall have all been associated with worsened outcome. [20]

Important risk factors for mortality include the patient's comorbidities, functional health status, newly onset atrial fibrillation, hypercoagulability state, hyperglycemia on admission, AIDS, liver disease, cancer, alcohol dependence, and immune suppression.

Age older than 40 years is associated with comorbid illnesses, impaired immunologic responses, malnutrition, increased exposure to potentially resistant pathogens in nursing homes, and increased use of medical devices, such as indwelling catheters and central venous lines. [21, 22, 23, 24]

Infection site

Sepsis due to urinary tract infection has the lowest mortality rate, while mortality rates are higher with unknown sources of infection, gastrointestinal sources (highest in ischemic bowel), and pulmonary sources. [25, 26, 27]

Infection type

Sepsis due to nosocomial pathogens has a higher mortality rate than sepsis due to community-acquired pathogens. Increased mortality is associated with bloodstream infections due to Staphylococcus aureus, fungi, and Pseudomonas, as well as polymicrobial infections. When bloodstream infections become severe (ie, septic shock), the outcome may be similar regardless of whether the pathogenic bacteria are gram-negative or gram-positive.

Antimicrobial therapy

Studies have shown that the early administration of appropriate antibiotic therapy (ie, antibiotics to which the pathogen is sensitive) is beneficial in septic patients demonstrating bacteremia. Previous antibiotic therapy (ie, antibiotics within the prior 90 days) may be associated with increased mortality risk, at least among patients with gram-negative sepsis. Patients who have received prior antibiotic therapy are more likely to have higher rates of antibiotic resistance, reducing the likelihood that appropriate antibiotic therapy will be chosen empirically. [28, 29, 30, 31]

Restoration of perfusion

Failure to attempt aggressive restoration of perfusion early may also be associated with an increased mortality risk. A severely elevated lactate level (>4 mmol/L) is associated with a poor prognosis in patients with sepsis.

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Epidemiology

Incidence

The incidence of sepsis and the number of sepsis-related deaths are increasing because of an increased use of immunosuppressive medications. The incidence varies by race and sex. The highest incidence is among black males. The incidence also shows seasonal variation, with the highest number of cases in winter, probably because of the increased prevalence of respiratory infections during this season. Older patients (≥65 years) account for most (60%-85%) sepsis cases, attributable to multiple comorbidities and frequent hospitalizations. [17]

Pathogens

The predominant infectious organisms that cause sepsis have changed over the years. Gram-positive bacteria are the most common etiologic pathogens, although the incidence of gram-negative sepsis remains substantial. The incidence of fungal sepsis has been rising with more patients on immunosuppressive therapies and more cases of HIV infection. In approximately half of sepsis cases, the organism is not identified (culture-negative sepsis).

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Risk Factors

Risk factors for sepsis and septic shock include the following:

  • ICU admission with subsequent nosocomial infection
  • Bacteremia
  • Advanced age (≥65 years)
  • Immunosuppression - Conditions that impair host defenses such as seen with neoplasms, renal failure, hepatic failure, AIDS, asplenism, diabetes, autoimmune diseases, organ transplant, alcoholism, and the use of immunosuppressant medications and immunomodulators
  • Community-acquired pneumonia
  • Previous hospitalization and antibiotic therapy in the preceding 90 days
  • Genetic factors - Defects of cellular and humoral immunity (low or absent antibody production, T cells, phagocytes, natural killer cells, complement)
  • Urosepsis due to benign prostatic hypertrophy (BPH) in older males or complicated UTI
  • Major trauma and burn injuries
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