Sepsis

History

• Presentation varies, depending on causative agent and portal of entry ^r2
• Low threshold of suspicion and early recognition of sepsis are essential for successful outcomes ^r2
• Thorough and timely history focuses on symptoms, comorbidities, recent surgery, recent antibiotic use, presence of medical devices, and travel ^r2
• Common generalized symptoms of sepsis include: ^r2
  • Fever, chills; rigors may be reported ^c1c2c3
  • Confusion, anxiety ^c4c5
  • Fatigue, malaise ^c6c7
  • Myalgia ^c8
  • Dyspnea ^c9
  • Nausea and vomiting ^c10c11
  • Decreased urination ^c12
• Localizing symptoms may include: ^r2
  • Headache and stiff neck when meningitis is the cause of sepsis ^c13c14
  • Cough and pleuritic chest pain with pneumonia ^c15c16
  • Abdominal pain with gastrointestinal or genitourinary source ^c17
  • Diarrhea with gastrointestinal luminal infections, such as Clostridioides difficile or toxigenic Escherichia coli infection ^c18
  • Flank pain and dysuria with kidney infection ^c19c20
  • Bone or joint pain with osteomyelitis or septic arthritis ^c21c22
  • Skin or soft tissue pain with abscesses, wounds, or other soft tissue infections ^c23c24c25
• Older adults may have limited or nonspecific symptoms (eg, poor oral intake, inanition) ^r2c26c27

Physical examination

• Physical examination focuses on detecting generalized signs of sepsis and determining the source; a careful and thorough examination may uncover an unexpected site
• Generalized evidence of sepsis is highly variable but commonly includes:
  • Fever (above 38.5 °C) or hypothermia (below 36 °C) ^c28
    • Fever is the most common sign of sepsis
  • Hypotension (systolic blood pressure lower than 90 mm Hg and/or mean arterial pressure lower than 70 mm Hg) ^c29c30
    • Presenting sign in 40% of patients with sepsis ^r2
  • Tachycardia (heart rate greater than 90 beats per minute) ^c31
  • Tachypnea (respiratory rate greater than 20 breaths per minute) ^c32
  • Rigors may be observed ^c33
  • Altered mental status; older patients may present with irritability or agitation ^c34c35c36
  • Increased capillary refill time (longer than 3 seconds) ^c37
  • Mottled skin on inspection; petechiae may be seen with severe thrombocytopenia or meningococcemia ^c38c39
  • Diaphoresis; clammy skin ^c40c41
• Respiratory, gastrointestinal, and genitourinary systems and skin and soft tissue are the most common sites of infection leading to sepsis; signs specific to affected system include:
  • Respiratory
    • Cough; production of purulent or foul-smelling sputum may be observed by clinician or reported by patient ^c42c43
    • Hemoptysis may be observed by clinician or reported by patient with severe pneumonia, including tuberculosis ^c44
    • Dullness to percussion may indicate pleural effusion (parapneumonic effusion or empyema) or consolidation ^c45
    • Rhonchi and/or rales on auscultation ^c46
    • Egophony on auscultation indicates consolidation ^c47
  • Gastrointestinal
    • Abdominal distention on inspection ^c48
    • Decreased bowel sounds on auscultation owing to ileus ^c49
    • Abdominal pain with guarding on palpation; rigidity and rebound indicate peritonitis ^c50c51c52
      • Localization of tenderness may indicate source (eg, right upper quadrant for liver or gallbladder infection) ^c53
  • Genitourinary
    • Costovertebral tenderness and suprapubic pain on palpation ^c54c55
    • Vaginal discharge or bleeding ^c56c57
  • Skin and soft tissue
    • Wounds, ulcerations, furuncles, or carbuncles on inspection ^c58c59c60
      • Surgical incisions and IV sites on currently or recently hospitalized patients ^c61c62
    • There may be erythema and/or edema on inspection ^c63c64
    • Drainage may be evident, either spontaneous or expressed ^c65
    • Crepitus or fluctuance may be palpable; an indurated tender phlebitic cord may be noted at site of infected peripheral IV line ^c66c67
    • Lymphadenopathy may be detected proximal to infection site ^c68
  • Other less common findings may include:
    • Meningismus, Kernig sign, or Brudzinski sign in meningitis ^c69c70c71
    • Point tenderness over a vertebral body may indicate spinal osteomyelitis and/or epidural abscess ^c72
    • Warm, swollen joint may be a site of septic arthritis ^c73c74
    • New heart murmur or change in character of a murmur suggesting endocarditis ^c75

Causes

• Microbial pathogens breach skin and/or mucosal barriers to cause systemic infection ^c76
  • Wide range of microbial pathogens may be implicated, depending on site of primary infection, community patterns, and host characteristics
    • Most sepsis cases are caused by bacteria; fungi and viruses are less common causes but are significant causes of sepsis in immunocompromised patients ^c77c78
      • Gram-positive bacteria are responsible for most cases of septic shock in the acute care setting, followed by gram-negative and mixed bacterial infections
    • Candidal species are commonly implicated in patients with neutropenia and in infections associated with indwelling catheters (eg, bloodstream, urinary) and other devices ^c79
    • Influenza virus may cause sepsis directly or may predispose to secondary bacterial infection and sepsis ^c80
  • Respiratory, gastrointestinal, and genitourinary systems and skin and soft tissue are the primary sites in most infections leading to sepsis (about 80%) ^r2
    • Common sources of infections leading to sepsis include:
      • Respiratory tract infections (account for 35% of sepsis cases) ^r10c81
        • Community-acquired pneumonia ^d1
          • Streptococcus pneumoniae and Staphylococcus aureus are commonly implicated in sepsis caused by pneumonia ^c82c83
          • Either may occur de novo or after influenza
        • Hospital-acquired and ventilator-associated pneumonias ^d2
          • Commonly associated with antibiotic-resistant pathogens ^c84
      • Genitourinary tract infections (account for 25% of sepsis cases) ^r10c85d3
        • Usually gram-negative or enterococcal species ^c86c87
          • Pyelonephritis ^c88
          • Cystitis ^c89
        • Infections related to indwelling urinary catheters ^d4
          • Antibiotic-resistant organisms are often implicated in hospital and long-term care settings ^c90
          • Candidal species are common causes in patients with diabetes and patients who have received broad-spectrum antibiotics ^c91
        • Obstruction of urine flow owing to impacted kidney stones or prostatic hypertrophy increases the risk of severe infection ^c92c93
      • Gastrointestinal tract infections (account for 11% of sepsis cases): often polymicrobial, involving enteric gram-negative bacilli, streptococcal species, and anaerobes ^{r10c94c95c96c97}
        • Appendicitis, with or without perforation and abscess ^c98d5
        • Cholecystitis, cholangitis; biliary obstruction caused by gallstone impaction increases the risk of severe infection ^c99c100d6
        • Bowel infarction or perforation with peritonitis ^{c101c102c103d7}
        • Diverticulitis, with or without diverticular abscess ^c104c105d8
        • Pancreatitis may cause sepsis due to infection or may cause an inflammatory response that mimics sepsis ^c106d9
      • Skin and soft tissue infections (account for 11%^r10 of sepsis cases) ^c107c108
        • Cellulitis ^c109d10
          • Usually caused by Staphylococcus aureus or streptococci ^c110c111
            • Community-acquired MRSA infections are prevalent in many areas ^c112
            • Presentation of MRSA infection is often characterized by deep red or violaceous erythema surrounding a necrotic center, resembling a spider bite
        • Carbuncles ^c113
          • Usually caused by Staphylococcus aureus^c114
        • Wounds (traumatic or surgical) ^c115c116
          • Traumatic wounds can be infected with a variety of organisms, depending on the circumstances
            • Highly resistant Acinetobacter baumannii infections have been associated with combat wounds ^c117
          • Surgical wound infections may reflect nature of surgery (eg, colon surgery may be complicated by infection caused by enteric pathogens) or may be caused by common skin organisms ^c118
            • Antibiotic resistance is common
        • Infections related to intravascular access devices ^c119
          • May be isolated to insertion site, but secondary bacteremia is common in sepsis
          • Usually gram-positive organisms (Staphylococcus aureus, coagulase-negative staphylococci), but gram-negative bacilli and yeast are also common pathogens ^{c120c121c122c123c124}
        • Necrotizing fasciitis ^c125d11
          • Group A Streptococcus or synergistic polymicrobial infections are the most common cause of this unusual life-threatening condition ^c126c127c128
      • Less common but important sources of sepsis include:
        • Bone and joint infections
          • Osteomyelitis ^c129d12
            • Wide variety of pathogens, depending on cause (hematogenous versus contiguous focus)
          • Septic arthritis ^c130
            • Common causes vary with age; overall, Staphylococcus aureus and streptococci are the most common causes ^c131c132
        • Central nervous system infections ^c133
          • Meningitis ^c134d13
            • Typical pathogens vary by age range; Streptococcus pneumoniae and Neisseria meningitidis are the most common ^c135c136
          • Encephalitis ^c137d14
            • Usually viral; HSV and West Nile virus have been associated with sepsis ^c138c139
          • Epidural abscess ^c140
            • Uncommon; spinal epidural abscesses are usually secondary to bacteremia, with Staphylococcus aureus as the most frequent pathogen ^r11c141

Risk factors and/or associations

Primary diagnostic tools

• Diagnosis is based primarily on history and physical examination, coupled with laboratory test results providing evidence for an inflammatory process and a microbial infection ^c179
• Presence of organ dysfunction, integral to the diagnosis of sepsis, can be identified as an increase from baseline of 2 points or more in SOFA score (Sequential Organ Failure Assessment; originally the Sepsis-Related Organ Failure Assessment) ^r7
  • qSOFA score (Quick Sequential Organ Failure Assessment or Quick Sepsis-Related Organ Failure Assessment) does not require laboratory testing and is as accurate as the full tool for patients not in the ICU ^c180
  • Score is more specific than sensitive: a negative test result does not rule out sepsis and should not be considered a barrier to further testing and monitoring when diagnosis is suspected ^r22
• Initial laboratory tests for all patients include a CBC with differential; a metabolic panel; creatinine, bilirubin, and lactate levels; coagulation tests; blood gas levels; and urinalysis ^{r2r7c181c182c183c184c185c186c187c188}
  • Elements of SOFA score include platelet count, bilirubin level, creatinine level, and PaO₂ (partial pressure of oxygen) ^r7
  • Obtain results promptly; in particular, measure lactate level within 1 hour of presentation of patient with possible sepsis ^r1
• For all patients, obtain blood and a specimen from any suspected source of infection for culture. Do this before initiation of antimicrobial therapy if it can be done without significant delay (less than 45 minutes) ^r23c189
• Additional laboratory tests may provide etiologic information (eg, rapid influenza antigen testing; 1,3-β-D-glucan assay; legionella and pneumococcal antigens) ^{r2r23c190c191c192}
• Perform imaging (eg, radiography, ultrasonography, CT, MRI) to confirm suspected anatomical site of infection; specific choice of imaging mode depends on site of suspected infection ^{r24c193c194c195c196}
• Measurement of MAP (mean arterial pressure) is indicated for patients with persistent hypoperfusion after fluid challenge ^r23
  • May provide support for diagnosis of sepsis and forms a baseline to guide fluid and vasopressor treatment
• Several serum markers have been suggested as indicators of sepsis (eg, procalcitonin, C-reactive protein), but their role in both diagnosis and management remains unclear ^{r25r26c197c198}

Laboratory

• CBC ^r24c199
  • Infection is suggested by a WBC count higher than 12,000 cells/mm³ or lower than 4000 cells/mm³, or by immature WBCs constituting more than 10% of the total
  • Platelet count lower than 100,000 cells/mm³ suggests hypoperfusion and organ dysfunction; may precede disseminated intravascular coagulation
• Metabolic and chemistry panels ^r24c200c201
  • Blood glucose level higher than 140 mg/dL in a patient without diabetes suggests injury or illness (including sepsis)
  • Creatinine level increase of 0.5 mg/dL or greater suggests renal impairment and hypoperfusion; level greater than 2 mg/dL suggests sepsis
  • Elevated liver enzyme levels and/or bilirubin level greater than 2 mg/dL suggest hepatic impairment and hypoperfusion
• Lactate level ^c202
  • Elevated serum lactate level is both diagnostic and prognostic for sepsis because it suggests end-organ dysfunction
    • Obtain within 1 hour of clinical suspicion of sepsis; longer intervals are associated with delays in administration of fluids and antibiotics and with higher mortality rates ^r1
    • Monitored serially in protocols for goal-directed therapy for sepsis
  • In adults, blood lactate level greater than 2 mmol/L is a defining criterion for septic shock ^r27
    • Low lactate level (0-2.5 mmol/L) is associated with a mortality rate of 4.9% ^r8
    • Intermediate lactate level (2.5-3.9 mmol/L) is associated with a mortality rate of 9% ^r8
    • High lactate level (greater than 4 mmol/L) is associated with a mortality rate of 28.4% ^r8
  • In children, elevated blood lactate levels are also associated with increased mortality from septic shock, but the optimal threshold has not been established ^r27
• Coagulation tests ^r24c203
  • INR greater than 1.5 suggests coagulopathy associated with organ dysfunction
  • Activated partial thromboplastin time greater than 60 seconds suggests coagulopathy associated with organ dysfunction
• Urinalysis and urine output ^c204c205
  • Provides assessment of renal function and fluid balance
  • Pyuria suggests urinary tract infection as the source of sepsis
  • Urine output less than 0.5 mL/kg/hour for more than 2 hours despite fluid resuscitation suggests hypoperfusion and/or renal dysfunction ^r24
• Cultures to determine pathogen and susceptibility to antibiotics
  • Blood cultures ^c206
    • Obtain specimens before starting broad-spectrum antimicrobial therapy, provided that obtaining them does not cause a significant delay in administration of antimicrobials (ie, 45 minutes) ^r23r27
      • Sensitivity of blood cultures is significantly reduced if done even shortly after initiation of empiric antimicrobial therapy ^r28
    • Draw 2 sets of blood specimens for culture, each for both aerobic and anaerobic incubation, from separate sites ^r23
    • If vascular access devices are present and have been in place for 48 hours or more, draw blood for culture from each device if possible and from at least 1 peripheral site ^r23
      • If the specimen from the peripheral site and the specimen from the vascular access device develop the same pathogen on culture, the vascular access device is likely the source of sepsis
        • Culture positivity more than 2 hours earlier in blood drawn from the device compared with blood drawn simultaneously from another site has been suggested as evidence of device infection, but data are not conclusive
      • If the vascular access device was placed within 48 hours, culture from that site is not necessary
    • Blood culture results may be negative for 50% to 65% of patients with sepsis ^r2
  • Urine cultures ^c207
    • Performed in conjunction with urinalysis for patients with suspected sepsis if urinary tract is a possible source ^r24
  • Stool culture ^c208
    • May be performed for patients with diarrhea who have been in the hospital for less than 72 hours; patients who have been in the hospital for more than 72 hours are not likely to have diarrhea caused by enteric pathogens
    • In addition, consider tests for Clostridium difficile toxin in patients with diarrhea and recent antibiotic use
  • Sputum culture ^c209
    • Performed in conjunction with Gram stain for suspected respiratory source of sepsis ^r24
    • Mechanical ventilator use is associated with pneumonia and may be the source of sepsis
      • Quantitative cultures may help to discriminate between infection and colonization
  • Skin and soft tissue culture ^c210
    • Performed in conjunction with Gram stain on drainage from abscesses or surgical sites ^r24
    • Culture of intact skin (eg, in cellulitis) is of little value and should not be done
  • Cerebrospinal fluid cultures ^c211
    • Done in conjunction with cell count and differential, chemistry, Gram stain, and other special tests as indicated
• Rapid influenza molecular testing on nasopharyngeal secretions is recommended for suspected influenza during periods of high influenza activity ^r29c212
• Urine testing for legionella and pneumococcal antigens is advisable for patients with severe community-acquired pneumonia ^r29c213c214
• Serum 1,3-β-D-glucan assay and mannan and anti-mannan antibody assays are recommended when fungal sepsis is suspected ^r23c215

Imaging

• Radiography
  • Chest radiography is used to confirm the presence of pneumonia ^c216
  • Abdominal radiography identifies bowel perforation by the presence of free air; it may also provide preliminary imaging clues for other causes of sepsis by showing the presence of gallstones, kidney stones, or other abnormalities that can be further explored with other tests ^c217
  • Plain radiographs may also be of value in showing the presence of air in soft tissues (eg, necrotizing infections) or osteomyelitis ^c218
• Ultrasonography
  • Abdominal ultrasonography is used to identify abdominal infections (eg, appendicitis, cholecystitis, pancreatitis) ^r30c219
  • Renal ultrasonography is used to identify renal obstruction or pyelonephritis ^c220
  • Echocardiography is used to identify endocarditis in patients with a cardiac murmur or suspected IV drug use ^c221
• CT
  • CT of chest is used to confirm pneumonia as the source infection if chest radiography is not diagnostic ^c222
  • CT of abdomen and pelvis is used to identify abdominal or pelvic abscesses (eg, pancreatic abscess, renal abscess) or ischemic bowel ^c223
  • CT may also be used to determine depth and extent of some serious soft tissue infections (eg, necrotizing fasciitis) ^c224
• MRI
  • MRI of brain and/or spine is used in evaluation of meningitis, encephalitis, and epidural abscess ^c225c226

Functional testing

• SOFA score ^r7c227
  • Either the standard score or the quick version (qSOFA) is recommended for all patients to identify organ dysfunction, a defining feature of sepsis ^r4
  • Do not use qSOFA as a single screening tool for sepsis or septic shock ^r4
  • In the standard version (0-4 points), an increase from baseline of 2 points or more indicates presence of organ failure; if baseline is unknown, assume it to be 0. Assign 0 to 4 points for each of the following parameters:
    • PaO₂/FiO₂ ratio (partial pressure of oxygen to fraction of inspired oxygen)
      • 0 points: 400 or higher
      • 1 point: less than 400
      • 2 points: less than 300
      • 3 points: less than 200 with respiratory support
      • 4 points: less than 100 with respiratory support
    • Platelet count (×10³ cells/mm³)
      • 0 points: 150 or higher
      • 1 point: less than 150
      • 2 points: less than 100
      • 3 points: less than 50
      • 4 points: less than 20
    • Bilirubin level (mg/dL)
      • 0 points: less than 1.2
      • 1 point: 1.2 to 1.9
      • 2 points: 2 to 5.9
      • 3 points: 6 to 11.9
      • 4 points: 12 or higher
    • MAP/vasopressor requirement (given over at least 1 hour)
      • 0 points: 70 mm Hg or higher
      • 1 point: lower than 70 mm Hg
      • 2 points: dopamine dosage less than 5 mcg/kg/minute or any dose of dobutamine
      • 3 points: dopamine dosage 5.1 to 15 mcg/kg/minute or any dose of epinephrine
      • 4 points: dopamine dosage higher than 15 mcg/kg/minute or epinephrine dosage higher than 0.1 mcg/kg/minute or norepinephrine dosage higher than 0.1 mcg/kg/minute
    • Glasgow Coma Scale score
      • 0 points: 15
      • 1 point: 13 to 14
      • 2 points: 10 to 12
      • 3 points: 6 to 9
      • 4 points: less than 6
    • Creatinine level (mg/dL)
      • 0 points: lower than 1.2
      • 1 point: 1.2 to 1.9
      • 2 points: 2 to 3.4
      • 3 points: 3.5 to 4.9
      • 4 points: 5 or higher
    • Urine output (mL/day)
      • 3 points: less than 500
      • 4 points: less than 200
  • qSOFA score
    • Consists of 3 parameters. Presence of any 2 of the following is indicative of organ dysfunction and possible sepsis:
      • Respiratory rate of 22 breaths per minute or faster
      • Altered mentation
      • Systolic blood pressure of 100 mm Hg or lower
• Measurement and monitoring central vein hemodynamic parameters is appropriate for patients with evidence of hypoperfusion (eg, hypotension that persists after fluid challenge) ^r23c228
  • MAP
    • Calculation of average pressure in 1 cardiac cycle and a measure of organ perfusion
    • MAP of less than 60 mm Hg suggests that tissue oxygen and nutrient needs are not being met

Most common ^r2

• Hypovolemic or hemorrhagic shock ^c229c230
  • Rapid fluid loss resulting in inadequate circulating volume and hypoperfusion; most often caused by burns, trauma, gastrointestinal bleeding, or ruptured abdominal aortic aneurysm
  • Similar features: tachypnea, tachycardia, malaise, hypotension, hypoxia, decreased capillary refill, mottled skin, oliguria, pallor, and altered mental status
  • Differentiating features: absence of fever; abnormalities in WBC count are usually absent or minimal
  • Diagnosed by history, physical examination, and imaging that indicate source of hemorrhage or other volume loss
• Pulmonary embolism ^r31c231d15
  • Sudden occlusion of a pulmonary artery, most often caused by a dislodged thrombus
  • Similar features: dyspnea, tachypnea, hypoxia
  • Differentiating features: onset of symptoms is abrupt; pleuritic chest pain is common
  • Diagnosed by multidetector-row CT angiography or CT pulmonary angiography, which detects pulmonary emboli; D-dimer levels are usually elevated
• Myocardial infarction ^c232d16
  • Myocardial necrosis resulting from occlusion of a coronary artery
  • Similar features: dyspnea, fatigue
  • Differentiating features: retrosternal chest pain and/or pressure radiating to neck, jaw, shoulder, and/or arm
  • Diagnosed by ST elevation, ST depression, or T-wave inversion on ECG; cardiac troponin level is elevated
• Acute pancreatitis ^r32c233d9
  • Sudden onset of parenchymal and pancreatic fat necrosis with inflammation of pancreas
  • Similar features: fever, diaphoresis, nausea, vomiting
  • Differentiating features: sudden onset of constant epigastric or left upper quadrant pain that may radiate to the back, chest, or flanks
  • Diagnosed by serum amylase and lipase levels more than 3 times the upper reference limit, with confirmatory findings from abdominal imaging
• Diabetic ketoacidosis ^r33c234d17
  • Decompensated state of diabetes that presents with the biochemical triad of hyperglycemia, ketonemia, and metabolic acidosis
  • Similar features: tachycardia, hypotension, weakness, nausea, vomiting
  • Differentiating features: polyuria, polydipsia, polyphagia, absence of fever, Kussmaul respirations, acetone breath
  • Diagnosed by hyperglycemia, positive urine and serum ketones, decreased arterial pH, elevated anion gap, and decreased serum bicarbonate level
• Adrenal insufficiency ^r34c235d18
  • Cortisol and mineralocorticoid deficiency in primary adrenal insufficiency, or suppression of hypothalamic-pituitary axis in secondary adrenal insufficiency
  • Similar features: tachycardia, weakness, vomiting, hypotension, altered mental status
  • Differentiating features: increased skin pigmentation, salt craving, weight loss, more gradual progression of symptoms
  • Diagnosed by decreased serum cortisol level and elevated adrenocorticotropic hormone level
• Transfusion reaction ^r35c236
  • Adverse reaction to blood or blood product transfusion
  • Similar features: fever, rigors, dyspnea
  • Differentiating features: pruritus, urticaria, angioedema, evidence of hemolysis
  • Diagnosed by history of blood transfusion and analysis of pretransfusion and posttransfusion blood samples

Admission criteria

Sepsis requires inpatient acute care for monitoring, IV antimicrobial therapy, and supportive care

Recommendations for specialist referral

• Refer to an infectious disease specialist to identify cause and direct appropriate antimicrobial therapy
• Consult a clinical pharmacologist to optimize dosing regimen
• Refer to critical care specialists to guide resuscitative efforts in septic shock
• Additional specialist referral depends on cause of sepsis and/or organ dysfunction resulting from sepsis; may include cardiologist, pulmonologist, nephrologist, or gastroenterologist
• Surgical referral may be required for source control of abdominal or necrotizing infections

Drug therapy

• Antimicrobial agents ^r2c237
  • Broad-spectrum penicillins ^c238
    • Ampicillin-sulbactam ^c239
      • Ampicillin Sodium, Sulbactam Sodium Solution for injection; Infants, Children, and Adolescents: 100 to 200 mg/kg/day ampicillin component (150 to 300 mg/kg/day ampicillin; sulbactam) IV divided every 6 hours (Max: 8 g/day ampicillin [12 g/day ampicillin; sulbactam]); doses up to 400 mg/kg/day ampicillin component (600 mg/kg/day ampicillin; sulbactam) have been reported for serious infections.
      • Ampicillin Sodium, Sulbactam Sodium Solution for injection; Adults: 3 g (2 g ampicillin and 1 g sulbactam) IV every 6 hours.
    • Piperacillin-tazobactam ^r23c240
      • Piperacillin Sodium, Tazobactam Sodium Solution for injection; Infants, Children, and Adolescents: 80 mg/kg/dose piperacillin component (90 mg/kg/dose piperacillin; tazobactam) IV every 6 hours (Max: 4 g/dose piperacillin [4.5 g/dose piperacillin; tazobactam]).
      • Piperacillin Sodium, Tazobactam Sodium Solution for injection; Adults: 4.5 g (4 g piperacillin and 0.5 g tazobactam) IV every 6 hours.
  • Cephalosporins ^c241
    • Third generation ^r23c242
      • Ceftriaxone ^c243
        • Ceftriaxone Sodium Solution for injection; Infants, Children, and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) IV every 12 hours.
        • Ceftriaxone Sodium Solution for injection; Adults: 1 to 2 g IV every 12 to 24 hours.
      • Ceftazidime ^c244
        • Antipseudomonal cephalosporin
        • Ceftazidime Sodium Solution for injection; Infants and Children: 90 to 150 mg/kg/day (Max: 6 g/day) IV divided every 8 hours; 200 to 300 mg/kg/day (Max: 6 g/day) IV divided every 8 hours for serious P. aeruginosa infections.
        • Ceftazidime Sodium Solution for injection; Adolescents: 2 g IV every 8 hours.
        • Ceftazidime Sodium Solution for injection; Adults: 2 g IV every 8 hours.
    • Fourth generation ^r23c245
      • Cefepime ^c246
        • Cefepime Hydrochloride Solution for injection; Infants, Children, and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 hours.
        • Cefepime Hydrochloride Solution for injection; Adults: 2 g IV every 8 hours.
  • Carbapenems ^r23c247
    • Imipenem-cilastatin ^c248
      • Imipenem, Cilastatin Sodium Solution for injection; Infants 1 to 2 months: 25 mg/kg/dose IV every 6 hours.
      • Imipenem, Cilastatin Sodium Solution for injection; Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose IV every 6 hours (Max: 2 g/day).
      • Imipenem, Cilastatin Sodium Solution for injection; Adults: 500 mg IV every 6 hours or 1 g IV every 8 hours.
    • Meropenem ^c249
      • Meropenem Solution for injection; Infants, Children, and Adolescents: 20 to 40 mg/kg/dose (Max: 2 g/dose) IV every 8 hours.
      • Meropenem Solution for injection; Adults: 2 g IV every 8 hours.
  • Levofloxacin ^r23c250
    • Provides coverage of respiratory pathogens and gram-negative aerobic bacteria, including Pseudomonas aeruginosa
    • Levofloxacin, Dextrose Solution for injection; Adults: 750 mg IV every 24 hours.
  • Azithromycin ^c251
    • Azithromycin Solution for injection; Infants, Children, and Adolescents 4 months to 15 years†: 10 mg/kg/dose (Max: 500 mg/dose) IV once daily for 2 days, followed by oral therapy to complete a 5-day treatment course.
    • Azithromycin Solution for injection; Adolescents 16 to 17 years: 500 mg IV once daily for at least 2 days, followed by oral therapy to complete a 5-day treatment course.
    • Azithromycin Solution for injection; Adults: 500 mg IV once daily for at least 5 days.
  • Aminoglycosides ^c252
    • Amikacin (extended-interval dosing) ^c253
      • Enhanced antipseudomonal activity
      • Amikacin Sulfate Solution for injection; Infants, Children, and Adolescents: 15 to 22.5 mg/kg/dose IV/IM every 24 hours.
      • Amikacin Sulfate Solution for injection; Adults: 15 to 20 mg/kg/dose IV/IM every 24 hours.
    • Gentamicin (extended-interval dosing) ^r23c254
      • Gentamicin Sulfate Solution for injection; Infants, Children, and Adolescents: 5 to 7.5 mg/kg/dose IV/IM every 24 hours.
      • Gentamicin Sulfate Solution for injection; Adults: 5 to 7 mg/kg/dose IV/IM every 24 hours.
  • Vancomycin ^c255
    • Oral
      • For Clostridioides difficile infection
        • For initial episode
          • Vancomycin Hydrochloride Oral solution; Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 125 mg/dose) PO 4 times daily for 10 days.
          • Vancomycin Hydrochloride Oral capsule; Adults: 125 mg PO 4 times daily for 10 days.
        • For fulminant infection
          • Vancomycin Hydrochloride Oral solution; Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO 4 times daily for 10 days; consider adding metronidazole IV.
          • Vancomycin Hydrochloride Oral capsule; Adults: 500 mg PO or via nasogastric tube 4 times daily with IV metronidazole. If clinical improvement after 48 to 72 hours, consider decreasing the dose to 125 mg PO every 6 hours for 10 days. If an ileus is present, consider adding vancomycin as a retention enema.
    • IV
      • Vancomycin Hydrochloride Solution for injection; Infants 1 to 2 months: 45 to 60 mg/kg/day IV divided every 6 to 8 hours; adjust dose based on target PK/PD parameter. Consider loading dose of 20 to 35 mg/kg IV.
      • Vancomycin Hydrochloride Solution for injection; Infants and Children 3 months to 11 years: 60 to 80 mg/kg/day IV divided every 6 hours (Usual Max: 3,000 mg/day; may require up to 3,600 mg/day); adjust dose based on target PK/PD parameter. Consider loading dose of 20 to 35 mg/kg IV.
      • Vancomycin Hydrochloride Solution for injection; Obese Infants and Children 3 months to 11 years: 20 mg/kg/dose (Max: 3,000 mg/dose) IV loading dose, followed by 60 to 80 mg/kg/day IV divided every 6 hours (Usual Max: 3,000 mg/day; may require up to 3,600 mg/day); adjust dose based on target PK/PD parameter.
      • Vancomycin Hydrochloride Solution for injection; Children and Adolescents 12 to 17 years: 60 to 70 mg/kg/day IV divided every 6 to 8 hours (Usual Max: 3,000 mg/day; may require up to 3,600 mg/day); adjust dose based on target PK/PD parameter. Consider loading dose of 20 to 35 mg/kg (Max: 3,000 mg/dose) IV.
      • Vancomycin Hydrochloride Solution for injection; Obese Children and Adolescents 12 to 17 years: 20 mg/kg/dose (Max: 3,000 mg/dose) IV loading dose, followed by 60 to 70 mg/kg/day IV divided every 6 to 8 hours (Usual Max: 3,000 mg/day; may require up to 3,600 mg/day); adjust dose based on target PK/PD parameter.
      • Vancomycin Hydrochloride Solution for injection; Adults: 20 to 35 mg/kg/dose (Max: 3,000 mg/dose) IV loading dose, followed by 15 to 20 mg/kg/dose IV every 8 to 12 hours; adjust dose based on target PK/PD parameter.
      • Vancomycin Hydrochloride Solution for injection; Obese Adults: 20 to 25 mg/kg/dose (Max: 3,000 mg/dose) IV loading dose, followed by 15 to 20 mg/kg/dose IV every 8 to 12 hours (Usual Max: 4,500 mg/day); adjust dose based on target PK/PD parameter.
  • Fidaxomicin ^c256
    • For Clostridioides difficile infection
      • Fidaxomicin Oral suspension; Infants 6 months and older weighing 4 to 6 kg: 80 mg PO twice daily for 10 days.
      • Fidaxomicin Oral suspension; Infants and Children 6 months and older weighing 7 to 8 kg: 120 mg PO twice daily for 10 days.
      • Fidaxomicin Oral suspension; Infants and Children 6 months and older weighing 9 to 12.4 kg: 160 mg PO twice daily for 10 days.
      • Fidaxomicin Oral suspension; Children and Adolescents weighing 12.5 kg or more: 200 mg PO twice daily for 10 days.
      • Fidaxomicin Oral tablet; Adults: 200 mg PO twice daily for 10 days.
  • Metronidazole ^c257
    • Oral
      • For nonsevere initial Clostridioides difficile infection
        • Metronidazole benzoate Oral powder; Infants, Children, and Adolescents: 7.5 mg/kg/dose (Max: 500 mg/dose) PO every 6 to 8 hours for 10 days.
        • Metronidazole Oral tablet; Adults: 500 mg PO 3 times daily for 10 days.
    • IV
      • For general sepsis
        • Metronidazole Solution for injection; Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided every 8 hours.
        • Metronidazole Solution for injection; Adults: 500 mg IV every 8 to 12 hours.
      • For fulminant initial Clostridioides difficile infection
        • Metronidazole Solution for injection; Infants, Children, and Adolescents: 7.5 mg/kg/dose (Max: 500 mg/dose) IV every 6 to 8 hours for 10 days plus vancomycin.
        • Metronidazole Solution for injection; Adults: 500 mg IV every 8 hours plus vancomycin.
  • Clindamycin ^c258
    • Clindamycin Solution for injection; Infants, Children, and Adolescents 1 month to 16 years: 40 mg/kg/day (Max: 2,700 mg/day) IV divided every 6 to 8 hours.
    • Clindamycin Solution for injection; Adolescents 17 years: 600 to 900 mg IV every 8 hours; doses up to 4,800 mg/day IV have been used for life-threatening infections in adults.
    • Clindamycin Solution for injection; Adults: 600 to 900 mg IV every 8 hours; doses up to 4,800 mg/day IV have been used for life-threatening infections.
  • Antiviral agents ^c259
    • Oseltamivir ^c260
      • Oseltamivir Phosphate Oral suspension; Infants 1 to 8 months: 3 mg/kg/dose PO twice daily for 5 days.
      • Oseltamivir Phosphate Oral suspension; Infants 9 to 11 months: 3.5 mg/kg/dose PO twice daily for 5 days.
      • Oseltamivir Phosphate Oral suspension; Children weighing 15 kg or less: 30 mg PO twice daily for 5 days.
      • Oseltamivir Phosphate Oral suspension; Children weighing 16 to 23 kg: 45 mg PO twice daily for 5 days.
      • Oseltamivir Phosphate Oral suspension; Children weighing 24 to 40 kg: 60 mg PO twice daily for 5 days.
      • Oseltamivir Phosphate Oral suspension; Children and Adolescents weighing more than 40 kg: 75 mg PO twice daily for 5 days.
      • Oseltamivir Phosphate Oral capsule; Adults: 75 mg PO twice daily for 5 days.
    • Peramivir ^c261
      • Peramivir Solution for injection; Infants and Children 6 months to 12 years: 12 mg/kg/dose (Max: 600 mg/dose) IV as a single dose.
      • Peramivir Solution for injection; Adolescents: 600 mg IV as a single dose.
      • Peramivir Solution for injection; Adults: 600 mg IV as a single dose.
  • Antifungal agents ^c262
    • Caspofungin ^r23c263
      • Caspofungin Solution for injection; Infants 1 to 2 months†: Very limited data available. 25 mg/m2/dose IV once daily may provide comparable exposure to usual dose in adults. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Caspofungin Solution for injection; Infants, Children, and Adolescents 3 months to 17 years: 70 mg/m2/dose (Max: 70 mg/dose) IV loading dose on day 1, followed by 50 mg/m2/dose (Max: 70 mg/dose) IV once daily. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. May increase dose to 70 mg/m2/dose (Max: 70 mg/dose) if there is an inadequate clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Caspofungin Solution for injection; Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
• Vasopressors ^c264
  • Norepinephrine ^c265
    • First line therapy ^r4
    • Norepinephrine Bitartrate Solution for injection; Infants†, Children†, and Adolescents†: 0.1 mcg/kg/minute continuous IV infusion; titrate to clinical response (Usual Max: 2 mcg/kg/minute).
    • Norepinephrine Bitartrate Solution for injection; Adults: 0.1 mcg/kg/minute (weight-based) or 8 to 12 mcg/minute (flat-dose) continuous IV infusion, initially. Titrate by 0.02 mcg/kg/minute (or more in emergency cases) to clinical response. Usual dosage range: 0.05 to 0.4 mcg/kg/minute (weight-based) or 2 to 4 mcg/minute (flat-dose). Infusion rates up to 3.3 mcg/kg/minute have been used.
  • Epinephrine ^c266
    • May be added to norepinephrine or used as an alternative where norepinephrine is unavailable ^r4
    • Epinephrine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 1 mcg/kg/minute continuous IV infusion. Titrate to clinical response.
    • Epinephrine Hydrochloride Solution for injection; Adults: 0.01 to 2 mcg/kg/minute continuous IV infusion. Titrate by 0.05 to 0.2 mcg/kg/minute every 10 to 15 minutes to clinical response.
  • Vasopressin ^c267
    • May be added to norepinephrine or used as an alternative where norepinephrine is unavailable ^r4
    • Vasopressin Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 8 milliunits/kg/minute continuous IV infusion; reserve for catecholamine-resistant shock, dosage range not well established.
    • Vasopressin Solution for injection; Adults: 0.01 unit/minute continuous IV infusion, initially; titrate by 0.005 unit/minute every 10 to 15 minutes to clinical response. Max: 0.07 unit/minute.
  • Dopamine ^c268
    • May be added to norepinephrine or used as an alternative where norepinephrine is unavailable ^r4
    • Dopamine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 1 to 5 mcg/kg/minute continuous IV infusion, initially. Titrate by 2.5 to 5 mcg/kg/minute until desired hemodynamic response is attained. Usual Max: 15 to 20 mcg/kg/minute.
    • Dopamine Hydrochloride Solution for injection; Adults: 2 to 5 mcg/kg/minute continuous IV infusion, initially. Titrate by 5 to 10 mcg/kg/minute until desired hemodynamic and/or renal response is attained. Usual dosage: 2 to 20 mcg/kg/minute. Max: 50 mcg/kg/minute.
• Inotropes ^c269
  • Dobutamine ^c270
    • May be considered as an adjunct or alternative to vasopressor therapy in select cases ^r4
      • Elevated cardiac filling pressures and low cardiac output suggestive of myocardial dysfunction
      • Persistent clinical signs of hypoperfusion after adequate volume and MAP have been achieved
    • Dobutamine Hydrochloride Solution for injection; Infants, Children, and Adolescents: 0.5 to 1 mcg/kg/minute continuous IV/IO infusion. Titrate every few minutes to clinical response. Usual dose: 2 to 20 mcg/kg/minute.
    • Dobutamine Hydrochloride Solution for injection; Adults: 0.5 to 1 mcg/kg/minute continuous IV infusion. Titrate every few minutes to clinical response. Usual dose: 2 to 20 mcg/kg/minute. Max: 40 mcg/kg/minute.
• Corticosteroids ^c271
  • Hydrocortisone ^c272
    • Continuous IV hydrocortisone if fluid resuscitation and vasopressor therapy do not restore hemodynamic stability ^r23
    • Hydrocortisone Sodium Succinate Solution for injection; Infants and Children 1 month to 2 years: 2 mg/kg [weight-based], 25 mg [flat-dose], or 100 mg/m2 [BSA-based] IV bolus, followed by 1 to 2 mg/kg/day [weight-based] or 50 to 100 mg/m2/day [BSA-based] IV in divided doses at 6-hour intervals or as a continuous IV infusion.
    • Hydrocortisone Sodium Succinate Solution for injection; Children 3 to 12 years: 2 mg/kg (Max: 100 mg) [weight-based], 50 mg [flat-dose], or 100 mg/m2 [BSA-based] IV bolus, followed by 1 to 2 mg/kg/day [weight-based] or 50 to 100 mg/m2/day [BSA-based] IV in divided doses at 6-hour intervals or as a continuous IV infusion.
    • Hydrocortisone Sodium Succinate Solution for injection; Adolescents: 2 mg/kg (Max: 100 mg) [weight-based], 100 mg [flat-dose], or 100 mg/m2 [BSA-based] IV bolus, followed by 1 to 2 mg/kg/day [weight-based] or 50 to 100 mg/m2/day [BSA-based] IV in divided doses at 6-hour intervals or as a continuous IV infusion.
    • Hydrocortisone Sodium Succinate Solution for injection; Adults: 50 mg IV every 6 hours or 200 mg/day continuous IV infusion.

Nondrug and supportive care

Comorbidities

• Common comorbidities include conditions that cause immunosuppression: ^c295
  • HIV infection ^r3r16c296
  • Hematologic malignancies ^r3c297
  • Splenic deficiency ^r3c298
  • Chronic conditions requiring high-dose corticosteroids or other immunosuppressant therapy ^r3
  • Chronic kidney failure ^r16c299
  • Diabetes mellitus ^r16c300
  • Excessive alcohol use ^r16c301

Special populations

• Older adult patients ^r6
  • More likely to have repeated antimicrobial exposure owing to chronic illness and medical intervention, resulting in multidrug-resistant microbial flora; very-broad-spectrum empirical antimicrobial therapy is required
  • Age-related renal and hepatic impairment put older adult patients at higher risk for adverse events related to drug therapy; careful drug monitoring is required, and dose adjustment may be necessary
  • Increased capacitance of vasculature in older adult patients creates a narrower therapeutic range of fluid resuscitation; there is a risk for either underresuscitation or fluid overload
• Pediatric patients ^r24r83r84
  • Assessment parameters are altered for pediatric patients
    • Vital signs and WBC counts are age dependent (tables are available^r83)
    • Target MAP is generally between the 5th and 50th percentiles or higher than the 50th percentile for age ^r27
    • Pediatric patients who are in septic shock often have a lactate level within normal range; do not exclude sepsis based on lactate levels within normal range ^r24
    • May use trends in lactate level to guide resuscitation ^r27
  • Young children are at greater risk for respiratory collapse than older children and adults ^r83
    • Begin high-flow oxygen within the first few minutes
    • Avoid mechanical ventilation if less invasive means of respiratory support are adequate owing to associated increased intrathoracic pressure, which can reduce venous return and worsen shock ^r24
      • If mechanical ventilation is necessary, institute lung-protective strategies (eg, high-frequency oscillatory ventilation)
    • Extracorporeal membrane oxygenation is suggested for pediatric patients with refractory respiratory failure related to septic shock and/or refractory septic shock ^r24r27r84
  • Vascular access is more difficult in pediatric patients but may be aided by use of ultrasonography
    • Intraosseous route is an option for fluid resuscitation and delivery of antibiotics and other medications ^r84
      • Avoid prolonged attempts to obtain IV access if difficult and quickly move to intraosseous route, except in children weighing less than 3 kg for whom intraosseous access is contraindicated ^r85
      • All emergency medications can be administered via interosseous route ^r85
    • As soon as access is obtained, administer isotonic crystalloids (preferred) or albumin ^r84
      • Balanced/buffered crystalloids (eg, lactated Ringer solution) are preferred over 0.9% saline unless there is a specific indication for an alternative type of fluid ^r27
      • Give bolus of 10 to 20 mL/kg over 5 to 10 minutes and repeat as needed, to a total of 40 to 60 mL/kg, aiming to restore age-appropriate blood pressure and heart rate, capillary refill (2 seconds or less), strong peripheral pulses, urine output (more than 1 mL/kg/hour), and mentation ^r27
      • A pump may be required to deliver such volume at the necessary rate
  • Vasopressors and inotropic agents may be required earlier in pediatric patients owing to limited ability to increase heart rate beyond higher baseline rates typical in children ^r84
    • Either epinephrine or norepinephrine is the first line agent given when hemodynamic parameters do not improve with fluids (40 to 60 mL/kg) or when signs of fluid overload preclude further fluid resuscitation
  • May consider adjunctive hydrocortisone for children with septic shock refractory to fluid and vasoactive-inotropic therapy ^r27
  • Give stress doses of hydrocortisone to children with acute or chronic corticosteroid exposure, hypothalamic-pituitary-adrenal axis disorders, congenital adrenal hyperplasia, or recent treatment with ketoconazole or etomidate ^r27
  • Hypoglycemia and hypocalcemia are common in children with sepsis; the former may be an indicator of adrenal insufficiency ^r84
  • Pediatric patients are at increased risk for toxic shock; clindamycin (in addition to primary antistaphylococcal or antistreptococcal therapy) and antitoxin therapy (eg, IV immunoglobulin) are recommended for toxic shock syndrome with refractory hypotension ^r24
  • Up to 50% of children with sepsis do not have an obvious source of infection ^r85