Bacterial Sepsis

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 A closely derived term of septicemia was used for bacterial infection in the blood, which has been replaced by the term bacteremia.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 2 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.[11]

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 for more detail.

The etiology of sepsis is diverse, and clinical clues to various organ systems aid in appropriate workup and diagnosis. It is 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, pericarditis, 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 signs4; 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 been reported after prostatic biopsy ^[12]
• 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 epidemiologic exposures, and associated rashes or other symptoms

There are numerous noninfectious causes of fever and organ dysfunction that can mimic sepsis[13] :

• 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 ^[14] (Open Table in a new window)

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

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 cause systemic infection. The gastrointestinal tract also can 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 serve as entry points, including the conjunctiva, the upper respiratory tract, and the genitourinary tract. External disease-transmitting vectors, such as arthropods, also can cause infection.[6, 15]

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.[15, 16, 17, 18] Impaired pulmonary, hepatic, or renal function may result from excessive cytokine release during the septic process.

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.[19]

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.[20] In addition, survivors consistently demonstrate impaired quality of life.[21]

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 are associated with worsened outcome.[22]

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.[23, 24, 25, 26]

Infection site

Sepsis due to urinary tract infection has the lowest mortality rate, whereas mortality rates are higher with unknown sources of infection, gastrointestinal sources (highest in ischemic bowel), and pulmonary sources.[27, 28, 29]

Infection type

Sepsis due to nosocomial pathogens has a higher mortality rate than sepsis caused by 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.[30, 31, 32, 33]

Restoration of perfusion

Failure to attempt aggressive restoration of perfusion early may 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.

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.[19]

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).

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

According to Surviving Sepsis Campaign Guidelines 2021, new changes have been made to the guidelines.[1]

 

Nonspecific signs and symptoms

The history and physical examination findings are nonspecific but may suggest the likely source of the septic process and thereby help determine the appropriate antimicrobial therapy and other interventions. General signs and symptoms of sepsis may include the following:

• Fever, with or without shaking chills (temperature >38.3ºC or < 36ºC)
• Impaired mental status (in the setting of fever or hypoperfusion)
• Increased breathing rate (>20 breaths/min) resulting in respiratory alkalosis
• Warm or cold skin, depending on the adequacy of organ perfusion and dilation of the superficial skin vessels
• Hypotension requiring pressor agents to maintain systolic blood pressure above 65 mm Hg

Systemic signs and symptoms

The clinical features depicted below may provide important diagnostic clues.

Respiratory infection

Cough, chest pain, and dyspnea may suggest pneumonia or empyema but also may be observed in patients with pulmonary embolism or pleural effusion.

Gastrointestinal (GI) or genitourinary (GU) infection

The patient may have a history of antecedent conditions predisposing to perforation or abscess. In many cases, the history is critical for diagnosis. Abdominal findings on physical examination may be absent or unimpressive.

• 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, or cholecystitis).
• Diffuse abdominal pain may suggest pancreatitis or generalized peritonitis, whereas right upper abdominal quadrant (RUQ) tenderness may suggest a biliary tract etiology (eg, cholecystitis, cholangitis), and tenderness in the right lower abdominal quadrant (RLQ) suggests appendicitis or Crohn disease. Discrete tenderness over the left lower abdominal quadrant suggests diverticulitis, particularly in elderly patients.
• A rectal examination may reveal exquisite tenderness caused by a prostatic abscess or, more commonly, an enlarged noninflamed prostate suggestive of prostatitis.
• A urinary tract source is suggested by an antecedent history of pyelonephritis, stone disease, congenital abnormal collecting system, prostatic hypertrophy, or previous operations or procedures involving the prostate or kidneys. ^{[34, 35]} Costovertebral angle tenderness with a fever suggests acute pyelonephritis. Subacute or chronic pyelonephritis may manifest as only mild tenderness.

Intravenous line infection

Evidence of infection at a central IV line site suggests the probable etiology.[36] However, it is important to note that many patients with central IV line infections do not have superficial evidence of infection at the insertion site. Always suspect IV line infections, especially when other sources of sepsis are eliminated.[37, 38] Central IV lines are the lines most commonly associated with bacteremia or sepsis.

Peripheral venous lines and arterial lines are rarely associated with bacteremia. Thrombophlebitis may be noted at the peripheral IV line site.

Surgical wound infection

Pain, purulent exudate, or crepitus in a surgical wound may suggest wound infection, cellulitis, or abscess.

Signs of end-organ hypoperfusion

These signs include the following:

• Warm, flushed skin may be present in the early phases of sepsis. The skin may become cool and clammy with progression to shock due to redirection of blood flow to core organs. Decreased capillary refill, purpura cyanosis, or mottling may be seen.
• Altered mental status, obtundation, restlessness
• Oliguria or anuria due to hypoperfusion
• Ileus or absent bowel sounds

Special considerations

Elderly patients may present with peritonitis and may not experience rebound tenderness of the abdomen.[39]

Elderly individuals, persons with diabetes, and patients on beta-blockers may not exhibit an appropriate tachycardia as blood pressure falls.

Younger patients develop a severe and prolonged tachycardia without hypotension until acute decompensation occurs.

Patients with chronic hypertension may develop critical hypoperfusion at a blood pressure that is higher than in healthy patients (ie, relative hypotension).

An acute surgical abdomen in a pregnant patient may be difficult to diagnose.[40] The most common cause of sepsis in pregnancy is urosepsis.[40]

The physical examination may vary according to the organ system involved and the infectious versus noninfectious etiology of sepsis. 

The most dire complication of sepsis is the high rate of morbidity and mortality associated with it especially if it is not identified in a timely manner and resuscitative measures including IV fluids, pressors, IV antibiotics, or specific therapies are not initiated urgently or emergently.

Multiple clinical, laboratory, radiologic, and microbiologic data are required for the diagnosis of sepsis and septic shock. Sepsis should never be diagnosed based on a single abnormality. However, the diagnosis is often made empirically at the bedside upon presentation or retrospectively when follow-up data return (eg, positive blood culture result) or a response to antibiotics is evident. Importantly, the identification of a pathogenic organism, although preferred, is not always feasible since the responsible organism may be unidentified in many patients.

In general, the workup for sepsis may include the following:

• Blood culture and urine analysis and culture
• Chemistry studies that can suggest organ dysfunction, such as liver or kidney function tests
• Serum lactate levels obtained urgently and serially.
• Chest radiology
• Diagnostic imaging of the chest and abdomen/pelvis
• Cardiac studies such as ECG and troponins, as indicated
• Interventions such as paracentesis, thoracentesis, lumbar puncture, or aspiration of an abscess, as clinically indicated
• Measurement of biomarkers of sepsis such as procalcitonin levels

Complete blood cell count

A complete blood cell (CBC) count is usually not specific. Leukocytosis with a left shift is also a nonspecific diagnostic finding and can be seen in noninfectious conditions. Leukopenia, anemia, and thrombocytopenia may be observed in sepsis.

Complete metabolic profile

A complete metabolic profile identifies changes in organ function, especially the liver and kidneys.

Bacterial cultures

Obtain blood cultures in all patients upon admission. Negative blood culture results are also necessary to include pseudosepsis in the differential diagnosis.[44] 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.

If central intravenous (IV) line sepsis is suspected, remove the line and send the tip for semiquantitative bacterial culture. If culture of the catheter tip yields positive results and demonstrates 15 or more colonies and if the isolate from the tip matches the isolate from the blood culture, an infection associated with the central IV line is diagnosed.

ICU patients are at a greater risk for colonization by MRSA, vancomycin-resistant enterococci (VRE), and carbapenem-resistant Enterobacteriaceae (CRE). It is critical to deescalate or change the empiric antibiotic regimen once the organism susceptibilities are available.

Gram staining

Buffy coat analysis of CBC may be useful in identifying certain infectious agents, although the yield is low.[45]

Urinalysis with reflex to culture

If urosepsis is suspected, obtain a urine Gram stain, urinalysis, and urine culture. A systematic review found that in adult ICU patients, catheter-associated urinary tract infection was associated with significantly higher mortality and a longer stay.[46]

Microbiology

Organism identification via culture in a patient who fulfills the definition of sepsis is highly supportive of a sepsis diagnosis but is unnecessary. The rationale behind its lack of inclusion in the diagnostic criteria for sepsis is that a culprit organism goes unidentified in up to half of patients who present with sepsis, and a positive culture result is not required to make a decision regarding treatment with empiric antibiotics.

Unique laboratory findings

Laboratory and clinical features that may suggest an underlying etiology of sepsis are as follows:

• Leukocytosis (WBC count >12,000/µL) or leukopenia (WBC count < 4000/µL)
• Normal WBC count with greater than 10% immature forms (left shift with bandemia)
• Hyperglycemia (plasma glucose level >140 mg/dL or 7.7 mmol/L) in the absence of diabetes ^[25]
• Plasma C-reactive protein level of more than 2 standard deviations above the reference value
• Arterial hypoxemia (PaO ₂/FiO ₂ ratio < 300 mm Hg)
• Acute oliguria (urine output < 0.5 mL/kg/hour for at least 2 hours despite adequate fluid resuscitation)
• Creatinine increase >0.5 mg/dL or 44.2 mmol/L
• Coagulation abnormalities (INR >1.5 or PTT >60 seconds)
• Thrombocytopenia (platelet count < 100,000/µL) ^[24]
• Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 mmol/L)
• Adrenal insufficiency (eg, hyponatremia, hyperkalemia) and euthyroid sick syndrome can also be found in sepsis.
• Hyperlactatemia (serum lactate >2 mmol/L) can result from organ hypoperfusion in the presence or absence of hypotension and indicates a poor prognosis. A serum lactate level of 4 mmol/L or more (especially arterial lactate) indicates septic shock.
• Plasma procalcitonin and presepsin elevation is associated with bacterial infection and sepsis. ^{[7, 8, 9, 10]}

Procalcitonin levels

Procalcitonin (PCT) is an acute-phase reactant that is elevated in severe bacterial infections. In most clinical assays, the reference range of PCT is below detectable. Measurement of PCT and C-reactive protein (CRP) at onset and on the fourth day of treatment can predict survival of patients with ventilator-associated pneumonia. A decrease in either one of these marker values predicts survival.[9]

A study from van Nieuwkoop et al examined the use of PCT levels in predicting bacteremia in a group of 581 patients, 136 of whom had bacteremia; PCT levels successfully identified 94-99% of the patients with bacteremia.[7]

Heyland et al, in a systematic review of the economic value of PCT-guided reduction in antibiotic use in intensive care, found that with hospital mortality and length of stay unchanged, PCT testing to reduce antibiotic treatment broke even when daily antibiotics cost about $150 in Canadian dollars.[8]

Chest Radiography

No radiologic signs are specific to the identification of sepsis, but chest radiography can aid in identifying a specific infection site. Chest radiography is important to rule out pneumonia and diagnose other causes of pulmonary infiltrates, such as the following:

• Pulmonary drug reactions
• Pulmonary embolism
• Pulmonary hemorrhage
• Primary or metastatic pulmonary neoplasms
• Lymphangitic spread of malignancies
• Large pleural effusions
• Pneumothorax
• Hydrothorax
• Fluid overload
• Congestive heart failure (CHF)
• Acute myocardial infarction (MI)
• Acute respiratory distress syndrome

Chest CT Scanning

Chest CT scanning is a very sensitive modality for diagnosing the lung pathology listed above.

Perform abdominal ultrasonography if biliary tract obstruction is suspected based on the clinical presentation. However, abdominal ultrasonography is suboptimal for the detection of abscesses or perforated hollow organs. Ultrasonograms in patients with cholecystitis may show a thickened gallbladder wall or biliary calculi but no dilatation of the common bile duct (CBD). Stones in the biliary tract may or may not be visible in patients with cholangitis, but the CBD typically is dilated.[47]

Use computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen if a nonbiliary intra-abdominal source of infection is suspected on the basis of the history or physical examination findings. Abdominal CT or MRI is also helpful in delineating intrarenal and extrarenal pathology. Gallium or indium scanning has no place in the initial workup of sepsis; patients with sepsis are acutely ill by definition, and rapid diagnostic tests (eg, CT or MRI of the abdomen and ultrasonography of the right upper quadrant) are time-critical, life-saving tools. However, MRI is more time consuming than CT scanning, and the latter is preferred in emergent situations.[47]

If acute MI is likely, perform electrocardiography (ECG) and obtain cardiac enzyme levels. Remember that certain patients may present with a silent, asymptomatic MI, which should be included in the differential diagnosis of otherwise unexplained fever, leukocytosis, and hypotension. Silent MIs are common in elderly patients and in those who have recently undergone abdominal or pelvic surgical procedures. They are also common in individuals with alcoholism, diabetes, and uremic conditions.

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
• Cardiac enzyme levels
• Echocardiography to evaluate for structural heart disease

Invasive diagnostic procedures that may be considered are discussed below.

Thoracentesis/paracentesis

Perform thoracentesis for diagnostic purposes in patients with substantial pleural effusion. Perform paracentesis in patients with gross ascites.

Surgical incision and drainage

Drainage of fluid collections/abscesses is crucial in establishing good source control and in facilitating a good clinical response to subsequent antibiotic therapy.

Bronchoscopy

Bronchoscopy with washing, lavage, or other invasive sampling is performed in patients with suspected pneumonia and in patients with suspected invasive fungal infections of the lung.

Swan-Ganz catheterization

In highly selected cases, a Swan-Ganz catheter may be useful in managing the fluid status of the patient and in assessing left ventricular dysfunction; however, routine use is not recommended.

Site-specific soft tissue imaging includes ultrasonography, CT scanning, or MRI to assess for possible abscess, fluid collection, or necrotizing skin infection. These are essential for diagnostic purposes and for monitoring the response to therapy.

Contrast-enhanced CT scanning or MRI of the brain/neck is performed to assess for possible masses, abscess, fluid collection, or necrotizing infection.

Early aggressive medical therapy is indicated in patients with suspected sepsis.[30, 31, 48, 49, 50, 51, 52, 53, 54, 55]

Sepsis Treatment

Patients with sepsis are generally ill and require inpatient hospitalization or admission to the intensive care unit (ICU) for monitoring and treatment. Admission to an ICU depends on the severity of the septic process and the degree of organ dysfunction. In July 2018, the US Centers for Medicare and Medicaid Services (CMS) began public reporting of a national sepsis bundle quality measure, commonly referred to as SEP-1. Early data demonstrated that only half of sepsis patients nationally received the full CMS-recommended bundle for emergency and hospital care. The treatment guidelines have been revised by IDSA/ Emergency Medicine Collaborative Task Force[56]  and Surviving Sepsis Campaign Guidelines 2021.[1]

Determine the likely source of the infection, and administer intravenous (IV) empiric antimicrobial agents until culture results become available, at which point more narrow-spectrum agents can be used (see below). In addition, offer supportive therapy aimed at maintaining organ perfusion, and provide respiratory support when necessary.[50, 57, 58]

A recent prospective study of 5787 adult patients with severe sepsis revealed the importance of goal-directed treatment. Patients triaged and managed according to 4 clinical goals (blood cultures before antibiotics, lactate before 90 minutes, IV antibiotics before 180 minutes, and 30 mL/kg of IV fluids before 180 minutes) were significantly less likely to die in the hospital than were those for whom all 4 of these goals were not met (22.6% vs 26.5%, respectively).[59]

In a multivariate regression analysis adjusted for age, admission to the intensive care unit (ICU), vasopressor initiation, central venous catheter insertion, and monitoring of central venous pressure and central venous oxygen saturation, complete compliance with the clinical goals was associated with a survival odds ratio of 1.194 (1.04-1.37).[59]

Early evaluation in patients with presumed intra-abdominal or pelvic sepsis is essential, and surgical consultation should be obtained in appropriate patients.

Obtain a consultation with a surgeon for patients with presumed intra-abdominal or pelvic sepsis. Obtain a consultation with an infectious disease specialist, as indicated, in patients with presumed or proven sepsis.[30]

Appropriate antimicrobial therapy depends on adequate coverage of the bacteria associated with the specific organ or organ system associated with the infection.[30, 31, 32, 48, 49]  Agents suitable for empiric monotherapy regimens (depending on the source and underlying microbiology of the sepsis because the agent must be able to cover all of the likely pathogens) may include the following:

• Imipenem
• Meropenem
• Tigecycline
• Piperacillin-tazobactam
• Ampicillin-sulbactam
• Moxifloxacin

Combination therapeutic regimens include metronidazole plus either levofloxacin, aztreonam, a third- or fourth-generation cephalosporin, or an aminoglycoside.

Many advocate also using antistaphylococcal coverage (eg, vancomycin) empirically.

Although no drug regimen may be superior to another, time to first dose administration is very important. Mortality data suggest that early administration of appropriate antibiotics is correlated with better survival. Alternative agents may be used alone or in combination, with a good adverse-effect profile.[30, 31, 48, 49]

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, although duration may vary according to the source, site, and severity of the infection. As soon as patients are able to tolerate medications orally, they may be switched to an equivalent oral antibiotic regimen in an IV-to-oral conversion program.

Empiric therapy for IV line infections

A detailed discussion of catheter-associated infections is available in the IDSA catheter-associated line-related infections (CRBSI) guidelines.[60] IV line infections most often are due to Staphylococcus aureus (methicillin-sensitive S aureus [MSSA] or methicillin-resistant S aureus [MRSA]), but gram-negative bacilli can be involved. The preferred empiric therapy for these infections is meropenem or cefepime (for Pseudomonas) plus additional coverage for staphylococci.[37, 38] If MRSA is prevalent in the institution, add linezolid, vancomycin, or daptomycin. Otherwise, nafcillin, oxacillin, or cefazolin provide adequate coverage for MSSA.

Unless coagulase-negative, methicillin-sensitive staphylococci are recovered from the blood, with high-level bacteremia (3 or 4 positive blood cultures out of 4), avoid vancomycin for empiric therapy if possible; these are low-virulence organisms and may represent contaminants. If treatment is advised, the duration of therapy depends on the severity and site of infection.[60]

Treatment of staphylococcal central line infection and fungal or gram-negative organisms typically requires removal of the line.

Minimize the use of vancomycin in order to prevent the emergence of vancomycin-resistant enterococci (VRE).[37]

Empiric therapy for biliary tract infections

IDSA guidelines for complicated intra-abdominal infections such as biliary tract infections are available.[61] The main biliary tract pathogens include Escherichia coli, Klebsiella species, and Enterococcus faecalis. Coverage for staphylococci is not needed in the biliary tract. Anaerobes can also be important, especially in patients with diabetes or immunosuppression.

Preferred monotherapy regimens for biliary tract infections include imipenem, meropenem, ampicillin-sulbactam, or piperacillin-tazobactam. Cephalosporins or quinolones in combination with metronidazole are alternate first-line agents for the treatment of biliary tract infections.

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 do not require special coverage unless the patient has recurrent infection or enterococci have been specifically and repeatedly isolated. 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 regimens for intra-abdominal and pelvic infections include imipenem, meropenem, piperacillin-tazobactam, ampicillin-sulbactam, or tigecycline. Alternate combination therapy for intra-abdominal and pelvic infections consists of clindamycin or metronidazole plus a third- or fourth-generation cephalosporin, aztreonam, levofloxacin, or an aminoglycoside. Some authors raise concerns about the use of tigecycline.

Empiric therapy for urosepsis

The primary uropathogens include gram-negative aerobic bacilli, such as coliforms or enterococci. Pseudomonas aeruginosa, Enterobacter species, and Serratia species are rare uropathogens and are associated with urologic instrumentation.

Monotherapy for urosepsis due to aerobic gram-negative bacilli may include aztreonam, levofloxacin, a third- or fourth-generation cephalosporin, or an aminoglycoside. However, preferred monotherapy for enterococcal urosepsis involves ampicillin or vancomycin. For VRE urosepsis, linezolid or daptomycin may be used.

Empiric therapy for community-acquired urosepsis consists of levofloxacin, aztreonam, or an aminoglycoside plus ampicillin. For nosocomial urosepsis, a fourth-generation cephalosporin, piperacillin-tazobactam, imipenem, or meropenem, with or without an aminoglycoside, is preferred.

Empiric therapy for staphylococcal, pneumococcal, and meningococcal sepsis

S aureus sepsis is usually associated with infection caused by devices or bacterial endocarditis. Empiric therapy may be with an anti-staphylococcal penicillin (nafcillin or oxacillin), vancomycin, a cephalosporin, daptomycin, or linezolid, depending on the concern for MRSA.

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 (CSF) and should be given in meningeal doses. Consider the regional prevalence of drug-resistant pneumococci when selecting an antibiotic.

Empiric therapy for sepsis of unknown origin

The usual sources of sepsis are the distal gastrointestinal (GI) tract, the pelvis, and the genitourinary (GU) tract. Organisms that should be covered from these areas 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 tigecycline.

Empiric combination therapy includes metronidazole plus levofloxacin, aztreonam, or a third- or fourth-generation cephalosporin.

Outpatient management

If orally administered antibiotics are continued at home, advise the patient about possible adverse effects. 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 specific clinical scenarios, which may require prolonged courses of oral antibiotics for cure or complete clinical resolution.

The initial sepsis guidelines were published in 2004 and then revised in 2008 and 2012. The 2016 clinical practice guidelines are a revision of the 2012 Surviving Sepsis Campaign (SSC) guidelines for the management of severe sepsis and septic shock. The latest guidelines were 2021 Surviving Sepsis Campaign Guidelines that were revised by IDSA/ Emergency Medicine Collaborative Task Force [56] and Surviving Sepsis Campaign Guidelines 2021.[1]

Major New Recommendations in the 2012 Update

Emphasis was directed to (1) first-hour fluid resuscitation and inotrope therapy directed to goals of threshold heart rates, normal blood pressure, and capillary refill of 2 seconds or less with specific evaluation after each bolus for signs of fluid overload, as well as first-hour antibiotic administration and (2) subsequent ICU hemodynamic support directed to goals of ScVO2 greater than 70% and cardiac index (CI) 3.3-6 L/min/m2 with appropriate antibiotic coverage and source control.[62]

Another major new recommendation in the 2012 update was that hemodynamic support of septic shock should be addressed at the institutional level rather than only at the practitioner level, with well-planned coordination between the family, community, prehospital, emergency department, hospital, and ICU settings. The 2012 guidelines recommend that each institution implement their own adopted or home-grown bundles that include the following:

• Recognition bundle containing a trigger tool for rapid identification of patients with suspected septic shock at that institution
• Resuscitation and stabilization bundle to drive adherence to consensus best practice at that institution
• Performance bundle to monitor, improve, and sustain adherence to that best practice

The 2016 Surviving Sepsis Campaign Guidelines

The 2016 guidelines[63, 64] give a detailed overview of initial resuscitation, screening, and diagnosis of sepsis. The management decisions concerning antibiotic therapy, fluid administration, source control, administration of pressors and steroids, blood products, anticoagulants, immunoglobulins, mechanical ventilation, sedation, analgesia, glucose control, blood purification, renal replacement therapy, bicarbonate, venous thromboembolism and stress ulcer prophylaxis, nutrition, and setting goals of care are addressed. The main differences between the 2012 and 2016 guidelines are discussed in detail in the cited reference.[65]

Unfortunately, a consensus could not be reached between some of the sponsoring organizations. A position paper issued by the IDSA does not endorse the Society of Critical Care Medicine/European Society of Intensive Care Medicine (SCCM/ESICM) 2016 Surviving Sepsis Campaign guidelines for the management of sepsis and septic shock, despite the IDSA's participation in the development of the guidelines. In particular, while the IDSA agrees that the SCCM/ESICM recommendations are life-saving for patients with septic shock, they may lead to overtreatment in those with milder variants of sepsis and sepsis syndromes. The IDSA does not endorse routine initiation of antibiotic therapy within one hour of suspecting sepsis nor administration of combination antibiotic therapy and a 7- to 10-day course of antibiotic therapy for all patients, regardless of presentation factors. The IDSA also notes unclear recommendations for removal of catheters when considered as the source of sepsis and for the role of procalcitonin when monitoring therapeutic response.[66]

As more research related to timing of therapy is completed, further guideline refinement is expected, and perhaps a consensus regarding the treatment approach can be achieved.

The 2021 Surviving Sepsis Campaign Guidelines

In 2021 after the Covid pandemic the guidelines for Sepsis have been changed significantly in terms of sepsis screening, diagnosis with qSOFA vs NEWS, MEWS or SIRS criteria, use of antibiotics, resuscitation including pressor support, IV fluids and use of steroids and blood purification techniques. Following is a tabulated list of changes from prior guidelines for a quick reference. 

Table 1. Table of Current Recommendations and Changes From Previous 2016 Recommendations ^[1] (Open Table in a new window)

The goals of pharmacotherapy are to eradicate the infection, reduce morbidity, and prevent complications.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Imipenem/cilastatin (Primaxin IV)

Imipenem-cilastatin is a carbapenem with activity against most gram-positive organisms (except MRSA), gram-negative organisms, and anaerobes. It is used for treatment of multiple-organism infections in which other agents do not have wide-spectrum coverage or are contraindicated owing to their potential for toxicity.

Meropenem (Merrem)

Meropenem is a carbapenem with slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared with imipenem. It is less likely to cause seizures and has superior penetration of the blood-brain barrier compared with imipenem.

Piperacillin and tazobactam (Zosyn)

Piperacillin-tazobactam inhibits the biosynthesis of cell wall mucopeptide and is effective during the stage of active multiplication. It has antipseudomonal activity.

Ampicillin and sulbactam (Unasyn)

Ampicillin and sulbactam is a drug combination of a beta-lactamase inhibitor with ampicillin. It interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. It is an alternative to amoxicillin if the patient is unable to take medications orally. It covers skin, enteric flora, and anaerobes and is not ideal for nosocomial pathogens.

Clindamycin (Cleocin)

Clindamycin is primarily used for its activity against anaerobes. It has some activity against Streptococcus species and methicillin-sensitive S aureus (MSSA).

Metronidazole (Flagyl, Metro)

Metronidazole is an imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. It is usually combined with other antimicrobial agents, except when used for Clostridium difficile enterocolitis, in which monotherapy is appropriate.

Cefepime (Maxipime)

Cefepime is a fourth-generation cephalosporin. It has gram-negative coverage comparable to ceftazidime but has better gram-positive coverage (comparable to ceftriaxone). Cefepime is active against Pseudomonas species. It has increased effectiveness against extended-spectrum beta-lactamase (ESBL)–producing organisms. Its poor capacity to cross blood-brain barrier precludes its use for treatment of meningitis.

Levofloxacin (Levaquin)

Levofloxacin is a fluoroquinolone with excellent gram-positive and gram-negative coverage. It is an excellent agent for pneumonia and has excellent abdominal coverage as well. High urine concentration necessitates reduced dosing in urinary tract infection.

Vancomycin

Vancomycin provides gram-positive coverage and good hospital-acquired MRSA coverage. It is now used more frequently because of the high incidence of MRSA. Vancomycin should be given to all septic patients with indwelling catheters or devices. It is advisable for skin and soft-tissue infections.

Trimethoprim/sulfamethoxazole (Bactrim DS, Septra DS)

The broad spectrum and action of trimethoprim and sulfamethoxazole (TMP-SMZ) against organisms found in patients with cystic fibrosis and the convenience of oral administration make this combination useful for treatment of milder infections in an outpatient setting.

Aztreonam (Azactam)

Aztreonam is a monobactam, not a beta-lactam, antibiotic that inhibits cell wall synthesis during bacterial growth. It is active against gram-negative bacilli but has very limited gram-positive activity and is not useful for anaerobes. Aztreonam lacks cross-sensitivity with beta-lactam antibiotics. It may be used in patients who are allergic to penicillins or cephalosporins.

The duration of therapy depends on the severity of infection and is continued for at least 48 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. Doses that are smaller than indicated should not be used.

Transient or persistent renal insufficiency may prolong serum levels. After the initial loading dose of 1 or 2 g, reduce the dose by one half for an estimated CrCl of 10-30 mL/min/1.73 m2. When only the serum creatinine concentration is available, the following formula (based on sex, weight, and age) can approximate CrCl (serum creatinine should represent a steady state of renal function):

• Males: CrCl = [(weight in kg)(140 - age)] divided by (72 X serum creatinine in mg/dL)

• Females: 0.85 X above value

In patients with severe renal failure (CrCl < 10 mL/min/1.73 m2), those supported by hemodialysis, a usual dose of 500 mg, 1 g, or 2 g is given initially.

The maintenance dose is one fourth of the usual initial dose given at the usual fixed interval of 6, 8, or 12 hours. For serious or life-threatening infections, supplement maintenance doses with one eighth of the initial dose after each hemodialysis session.

Elderly persons may have diminished renal function. Renal status is a major determinant of dosage in these patients. Serum creatinine may not be an accurate determinant of renal status. Therefore, as with all antibiotics eliminated by the kidneys, obtain estimates of CrCl and make appropriate dosage modifications. Insufficient data are available regarding intramuscular (IM) administration to pediatric patients or dosing in pediatric patients with renal impairment. Aztreonam is administered intravenously only to pediatric patients with normal renal function.

Linezolid (Zyvox)

Linezolid is used as an alternative drug in patients allergic to vancomycin and for treatment of vancomycin-resistant enterococci. It is also effective against MRSA and penicillin-susceptible S pneumoniae infections.

This agent is an oxazolidinone antibiotic that prevents formation of the functional 70S initiation complex, which is essential for the bacterial translation process. Linezolid is bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci.

Ceftriaxone (Rocephin)

Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Ceftriaxone is used for increasing prevalence of penicillinase-producing microorganisms. It inhibits bacterial cell wall synthesis by binding to 1 or more penicillin-binding proteins. Cell wall autolytic enzymes lyse bacteria, while cell wall assembly is arrested.

Daptomycin (Cubicin)

Daptomycin causes membrane depolarization by binding to components of the cell membrane of susceptible organisms. It inhibits DNA, RNA, and protein synthesis intracellularly. It is a bactericidal antibiotic.

Nafcillin (Nallpen)

Nafcillin is a broad-spectrum penicillin. It is used for methicillin-sensitive S aureus and is the initial therapy for suspected penicillin G–resistant streptococcal or staphylococcal infections. In severe infections, start with parenteral therapy and change to oral therapy as the condition warrants. Because of thrombophlebitis, particularly in elderly persons, administer parenterally for only 1-2 days; change to oral therapy as indicated clinically.

Rifampin (Rifadin)

Rifampin is for use in combination with at least 1 other antituberculosis drug. It inhibits RNA synthesis in bacteria by binding to the beta subunit of DNA-dependent RNA polymerase, which, in turn, blocks RNA transcription. Cross-resistance may occur.

Daptomycin (Cubicin)

This is the first of a new antibiotic class called cyclic lipopeptides. It binds to bacterial membranes and causes rapid membrane potential depolarization, thereby inhibiting protein, DNA, and RNA synthesis, and ultimately causing cell death. It is indicated for complicated skin and skin structure infections caused by S aureus (including methicillin-resistant strains), S pyogenes, S agalactiae, S dysgalactiae, and E faecalis (vancomycin-susceptible strains only).

Tigecycline (Tygacil)

Tigecycline is a glycylcycline antibiotic that is structurally similar to tetracycline antibiotics. It inhibits bacterial protein translation by binding to the 30S ribosomal subunit, and it blocks the entry of amino-acyl tRNA molecules in ribosome A site. It is indicated for complicated skin and skin structure infections caused by E coli, E faecalis (vancomycin-susceptible isolates only), S aureus (methicillin-susceptible and -resistant isolates), S agalactiae, S anginosus group (includes S anginosus, S intermedius, and S constellatus), S pyogenes and B fragilis.