Escherichia coli Infection

Etiology

E. coli is part of commensal intestinal flora and is also found on the floors of hospitals and long-term care facilities. E. coli is the most common gram-negative bacteria in the human gastrointestinal tract and lacks virulence in this setting. However, when found outside of the intestinal tract, E. coli can cause urinary tract infections (UTI), pneumonia, bacteremia, and peritonitis, among others.[2][3][4] 

E. coli is a major cause of nosocomial infections, including catheter-associated UTIs and ventilator-associated pneumonia (VAP).[5] E. coli can also be found in soil, on vegetables, and in water, as well as in undercooked meats. Pathogenic strains cause intestinal illness in humans when ingested.

Epidemiology

Escherichia coli results in intestinal illness as well as infection outside of the intestine. Intestinal illness caused by E. coli is caused by one of five subtypes, and they are identified according to their O and H antigens. The O antigen is determined by a repeating polysaccharide chain present in the lipopolysaccharide (LPS) outer membrane, and the flagellum determines the H antigen.[1]

• ETEC causes watery diarrhea in resource-limited settings and is commonly found in food and water in areas without adequate sanitation. Approximately 100,000,000 organisms must be ingested to cause illness in a healthy person. It is the single most important organism causing traveler’s diarrhea. ETEC is also a significant contributor to dehydrating diarrheal illness in infants and children in resource-limited settings.[6]
• EPEC was the first E. coli pathotype identified as a causative agent of watery diarrhea primarily in infants and young children in resource-limited settings and is responsible for sporadic and epidemic outbreaks.[7] Diarrheal illness caused by EPEC is most commonly contracted through ingestion but can also be spread person-to-person.[8]
• EAEC is a causative organism of acute and chronic watery diarrhea in resource-limited and resource-rich regions and recently has been increasingly identified as a cause of traveler’s diarrhea.[9][10]
• EHEC/STEC produces Shiga-toxin and includes serotypes O157:H7, as well as others.[11][12][13] EHEC/STEC has been responsible for large diarrheal outbreaks after ingesting contaminated produce (e.g., spinach, sprouts, lettuce, fruit) and undercooked beef. EHEC/STEC is linked to the consumption of raw dairy products. EHEC/STEC is commonly found in ground beef, which can be contaminated during processing. Vegetables are contaminated when crops are fertilized with manure containing EHEC/STEC, and water runoff from these crops leads to EHEC/STEC found in water systems. Relatively low inoculums (102 CFU) result in illness, facilitating the ease of transmission from the environment to humans and humans to humans.[14][15] The World Health Organization reports there are roughly 2.8 million cases of EHEC/STEC infections globally as of 2014.[16] According to the CDC, there were reportedly 3,127 cases in the United States in 2019.[17] While the number of reported cases of O157:H7 declined in the United States in 2019, the number of non-O157:H7 EHEC/STEC cases rose by 35% compared to the previous year. This is likely due to more readily available PCR-based assays to identify organisms that allow laboratories to distinguish E. coli O157:H7 from non-O157:H7 strains. EHEC/STEC infections are common across all age groups, but hemolytic uremic syndrome (HUS) resulting from EHEC/STEC infections is most common in children less than five years old and adults greater than 60 years old.
• EIEC-induced diarrheal illness is uncommon due in part to the relatively large inoculum required, although recent studies suggest EIEC-induced diarrhea may be underdiagnosed. EIEC is closely related to Shigella and is contracted through ingesting undercooked meats and contaminated vegetables.[18]

Extraintestinal illness caused by E. coli results from a translocation of gut bacteria into other parts of the body or the environmental spread in hospitals and long term care facilities. E. coli is the predominant gram-negative bacteria to cause extraintestinal illness in humans and can cause urinary tract infection, abdominal and pelvic infection, pneumonia, bacteremia, and meningitis, among others.

Pathophysiology

Intestinal illness caused by E. coli results from the ingestion of bacteria and the innate ability of E. coli to overcome host defenses. Gram-negative bacteria are characterized by their cell envelope, which comprises an inner cytoplasmic cell membrane, peptidoglycan cell wall, and outer membrane. The outer membrane is made of a lipid bilayer, associated proteins, and lipopolysaccharide (LPS), resulting in a toxic reaction if lysed. Pathogenic E. coli strains each has distinctive virulence factors encoded on plasmids, transposons, and bacteriophages.

• ETEC: Colonizing fimbriae expressed by ETEC enable the bacteria to attach to the intestinal wall. Once connected, ETEC expresses a heat-labile toxin (LT) and/or heat-stable toxin (ST), which are secretory toxins encoded on plasmids.[19] LT stimulates adenylate cyclase leading to increased intracellular cyclic adenosine monophosphate (cAMP) and the subsequent chloride secretion from intestinal crypt cells. This mechanism also inhibits intestinal villi from absorbing sodium chloride. This process leads to free water secretion into the intestinal lumen, thus producing watery diarrhea. ST stimulates guanylate cyclase leading to increased intracellular cyclic guanosine monophosphate (cGMP) and the subsequent chloride secretion and inhibition of sodium chloride absorption, thus producing watery diarrhea.
• EPEC: A bundle-forming pilus (BFP) is encoded by the plasmid (pEAF), enabling EPEC to form a localized attachment to enterocytes in the small intestine. Once bound, the outer membrane protein colonization factor, intimin, facilitates enhanced adherence. Intimin is an outer membrane protein colonization factor encoded on the eae gene within the locus of enterocyte effacement (LEE) chromosomal island. The LEE chromosomal island elaborates approximately 20 secretory toxins that are injected in the enterocyte by a type III injectisome.[20][21] These toxins result in a series of events, ultimately leading to the characteristic effacement of microvilli, increased permeability of tight junctions, and alterations in water and electrolyte secretion and absorption. EspF is a LEE-secreted protein that is not involved with attaching and effacing. It appears to disrupt the intestinal barrier function by increasing monolayer permeability via alteration of electrical resistance. EspF has several protein-protein interaction domains that may function by interacting with endocytic regulation. Two other secreted proteins, EspG and EspG2, inhibit luminal membrane chloride absorption by decreasing surface expression of the Cl-/OH-exchanger via disruption of microtubules.
• EAEC: EAEC exhibits a stacked brick pattern of adherence to epithelial cells. The virulence plasmid encodes the transcriptional activator AggR which activates several virulence factors, although scientific understanding of this process is not complete.[22] AggR likely induces aggregative adherence fimbriae (AAF/I-III), adhesin, surface protein dispersin, and the enterotoxins Pet, EAST-1, ShET1, and ShET2. Dispersin likely promotes AAF-mediated colonization.[23]
• EHEC/STEC: EHEC/STEC produces bloody diarrhea due to its ability to express Shiga toxin 1 (Stx1) and or Shiga toxin 2 (Stx2).[24][25] Stx1 and Stx2 are closely related to Shiga toxin (Stx) produced by Shigella dysenteriae. EHEC/STEC, which expresses Stx2, results in bloody diarrhea and may also express Stx1, while bacteria that do not express Stx2 do not induce bloody diarrhea. The Stxs are a group of bacterial AB protein toxins composed of one A subunit and five identical B subunits capable of inhibiting protein synthesis through their ability to target eukaryotic ribosomes. The A subunit is responsible for inhibiting protein synthesis while the B pentamer binds glycosphingolipid Gb3, a cellular receptor on endothelial cells. The inhibition of protein synthesis results in enterocyte cell death and subsequent inflammatory colitis. The EHEC/STEC genome also encodes intimin, which is its primary adhesin, and EHEC/STEC possesses a plasmid (pO157) that expresses a pore-forming toxin termed EHEC-hemolysin.[26][27] Once EHEC/STEC attach and produce localized intestinal damage, the Stx toxins enter the host and travel to target organ epithelial cells. Glomerular epithelial cells undergo similar damage as enterocytes, and as a result of cell death, detach from the glomerular membrane. This inflammatory state results in thrombosis and activation of the coagulation cascade yielding subsequent thrombocytopenia, anemia, and renal damage, the HUS triad. EHEC/STEC is also known for its ability to induce hemolytic uremic syndrome (HUS). HUS is characterized by the triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and renal insufficiency.
• EIEC: Like EHEC, enterotoxins induce secretory diarrhea. Subsequent colonization and invasion of colonic mucosa, replication, cell-to-cell spread result in inflammatory colitis.[18]

Extraintestinal infections caused by E. coli are generally the result of the translocation of commensal E. coli outside of the intestine. The urinary tract is the most common extraintestinal site of infection caused by E. coli. UTIs are a significant reason for ambulatory care visits in the US and is the second most common cause of hospitalization after pneumonia.[28][29] Urinary tract infections from E. coli result from bacteria ascending the urethra and are more common in women than men, given the proximity of the urethra. Community-acquired pneumonia (CAP) caused by E. coli is common, but ventilator-associated pneumonia (VAP) is more common.[30] Hospitalized patients, particularly those on mechanical ventilation, are at an increased risk of aspirating gastric contents. E. coli bacteremia is often the result of a primary E. coli infection at another site. Community-acquired E. coli bacteremia is most frequently the result of urinary tract infections in older adults, while hospitalized patients likely develop bacteremia as a result of lower respiratory tract infection.

History and Physical

An in-depth history and physical exam are important in establishing the diagnosis of E. coli infection. Symptom onset, duration, and severity, as well as any alleviating and aggravating factors, including any over-the-counter medications trialed, may help distinguish it from other intestinal illnesses. It is especially important to distinguish between watery and bloody diarrhea and to ask about recent travel and diet history, which may provide clues to suggest E. coli as the etiology of illness. ETEC is the most common bacterial cause of traveler's diarrhea, and management relies on high clinical suspicion. Symptoms usually start more than 16 hours after the ingestion of contaminated food, whereas diarrheal illness caused by organisms other than E. coli may have onset much more rapidly. If a patient presents with an extraintestinal manifestation of E. coli, it's essential to ask about prior infections and assess for the risk of drug-resistant organisms. When a patient presents with symptoms consistent with cystitis, it's also important to know about indwelling instrumentation, such as ureteral stents or Foley catheters. 

The physical exam allows health practitioners to assess the severity of illness. Patients presenting with vital signs suggestive of systemic disease should be cared for in an appropriate setting, such as a hospital-based emergency department or in-patient ward where comprehensive care can be provided. All patients should be assessed for clinical signs of dehydration by evaluating mucous membranes and skin turgor. Clinicians should auscultate the heart and lungs in all patients suspected of disease caused by E. coli. Finally, a focused exam should support the patient-provided history that may yield additional findings to guide patient care. Patients presenting with intestinal and genitourinary symptoms should have a thorough abdominal exam performed, whereas patients suspected of having sepsis caused by E. coli should undergo a comprehensive physical exam.

Evaluation

Routine laboratory evaluation is not generally required in well-appearing patients with diarrheal illness as the disease is often self-limiting. However, they may support clinical suspicion and guide treatment in patients with concerning signs or symptoms suggesting systemic illness. Patients with suspected EHEC/STEC infection should have a baseline complete blood count (CBC) and a basic metabolic panel (BMP) obtained. Obtain stool cultures in patients with prolonged diarrheal illness, in patients with systemic signs or symptoms, and those with dysentery.[31] Pathogenic E. coli are not distinguishable from one another based solely on appearance; therefore, further biochemical tests are necessary.

E. coli are non-spore-forming, flagellated, and facultatively anaerobic. They have the inherent ability to ferment lactose and produce indole, and before PCR-based assays, E. coli were identified via selective culture media.[1] E. coli are classically grown on MacConkey agar, culture media containing lactose. E. coli also produces indole during metabolism, and bacterial growth on MacConkey agar with indole production is diagnostic for E. coli. EHEC/STEC can also ferment sorbitol. Therefore, to further distinguish EHEC/STEC from other E. coli strains, bacteria are grown on sorbitol-containing media. Interestingly, non-O157:H7 EHEC strains that do not ferment sorbitol have recently been identified by PCR. As PCR-based assays become more readily available, these strains will continue to be more frequently identified. All patients with inflammatory diarrhea acquired outside of the United States should have stool cultured for E. coli, as well as Salmonella, Shigella, and Campylobacter.

While molecular diagnosis is not required in mild illness, specific pathogens can be identified via PCR-based assays. ETEC is distinguished by the identification of LT and ST genes. EPEC is identified by the detection of the pEAF plasmid or its encoded BFP factor. EAEC is identified through the detection of the AggR regulon. EHEC/STEC is identified through the nucleic acid amplification test (NAAT) of Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2).[32] EIEC can be detected via NAAT. Many EIEC strains are identified by the presence of the lacY gene, which encodes lactose permease.

Summary

• E. coli
  • Gram-negative bacilli, non-spore-forming, flagellated, facultatively anaerobic
  • Ferments lactose (grows on MacConkey agar)
  • Catalase positive
  • Oxidase negative
•  ETEC
  • Culture: MacConkey agar, indole producing
  • Molecular diagnosis: LT or ST genes
• EHEC/STEC
  • Culture
    • O157:H7: Sorbitol-MacConkey agar, indole producing
    • Non-0157:H7: MacConkey agar
  • Molecular diagnosis: NAAT of Stx1 and Stx2
• EIEC
  • Culture: MacConkey agar (glucose and xylose), indole producing
  • Molecular: NAAT of lacY
• EPEC
  • Culture: MacConkey agar, indole producing
  • Molecular diagnosis: pEAF plasmid or BFP factor
• EAEC
  • Culture: MacConkey agar, indole producing
  • Molecular diagnosis: AggR regulon

For patients with extraintestinal illness, culturing blood, urine, or sputum will identify E. coli. Many gram-negative bacilli have developed antibiotic resistance genes, and E. coli is no exception. Extended-spectrum beta-lactamase (ESBL) -producing E. coli confer resistance to most beta-lactamase antibiotics (e.g., cephalosporins, monobactams, etc.). In contrast, carbapenemase-producing E. coli strains possess genes conferring resistance to carbapenems (e.g., imipenem, ertapenem, and meropenem).

Treatment / Management

Treatment is dependent on the strain, as well as the illness. Care of the patient with an intestinal disease caused by E. coli begins with symptomatic management.[31][33] Diarrheal illness can be extremely distressing for patients. Experts recommend rehydration and antidiarrheals as the mainstays of treatment for mild disease. Oral rehydration is recommended first-line therapy for all patients with diarrheal illness when tolerated and is equally efficacious as compared to intravenous hydration (IV). IV hydration is recommended when patients cannot tolerate oral intake. Distressing symptoms are treated with antimotility agents such as bismuth-subsalicylate and loperamide. (A1)

Antibiotics are not recommended as first-line treatment for diarrheal illness caused by E. coli for most patients due to the harmful side effects and association with antibiotic resistance. For patients with severe disease (e.g., more than six stools per day, fever, dehydration necessitating hospitalization, diarrhea lasting more than seven days, or bloody diarrhea), antibiotics may be reasonable. Rifaximin, azithromycin, and ciprofloxacin are currently recommended by the Infectious Diseases Society of America (IDSA) and the International Society of Travel Medicine (ISTM) to treat E. coli diarrheal illness. For patients suspected of having EHEC/STEC, antibiotics are not recommended, especially in children and older adults, due to the increased risk of hemolytic uremic syndrome.

Summary of Treatment

Watery Diarrhea

• Rehydration
  • Oral fluids, if tolerated
  • IV fluids if oral fluids not tolerated
• Antimotility agents
  • Bismuth salicylate
    • Adults: 524 mg every 30 min for up to 8 doses
    • Children
      • 12-18 years: 524 mg every 30 min up to 8 doses
      • <12 years: limited data available
  • Loperamide:
    • 4 mg, then 2 mg following each unformed stool.
    • Max dose 16 mg per day (prescription), 8 mg (OTC).
    • Duration: no more than two days
    • Children: Not recommended for infectious diarrhea
• Antibiotics
  • May be prescribed when >2 unformed stools per day
  • Adults
    • Fluoroquinolones
      • Ciprofloxacin: 750 mg once; or 500 mg BID for three days
      • Levofloxacin: 500 mg once; or 500 mg daily for three days
    • Azithromycin: 1,000 mg once; or 500 mg daily for three days
    • Rifaximin: 400 mg BID or 200 mg TID for three days
  • Children
    • Azithromycin: 10 mg/kg on day 1, 5 mg/kg on days 2 and 3

Bloody Diarrhea

• Rehydration
  • Oral fluids, if tolerated
  • IV fluids if oral fluids not tolerated or clinically indicated 
• Antimotility agents
  • Not recommended for patients with dysentery as these may prolong illness
• Antibiotics
  • Not recommended for patients with presumed EHEC/STEC
  • Adults
    • Fluoroquinolones
      • Ciprofloxacin: 750 mg once; or 500 mg BID for three days
      • Levofloxacin: 500 mg once; or 500 mg daily for three days
    • Azithromycin: 1,000 mg once; or 500 mg daily for three days
    • Rifaximin: 400 mg BID or 200 mg TID for three days
  • Children
    • Azithromycin: 10 mg/kg on day 1, 5 mg/kg on days 2 and 3

EHEC/STEC

Patients identified as having EHEC/STEC, particularly children less than 12 years of age, should be hospitalized. Hospitalization reduces the risk of community spread and allows for aggressive therapy and close monitoring.[34] Hospitalized patients should receive intravenous hydration with isotonic fluids (0.9% NaCl or Lactated Ringer's).[35] Antibiotics, as previously mentioned, are not routinely recommended for patients with confirmed EHEC/STEC infections due to the increased risk of HUS.[36] Unlike other diarrheal illnesses, antimotility agents may increase the risk of HUS in patients with EHEC/STEC infections and should not be recommended. It is also essential to avoid other medications that could worsen renal function, including nonsteroidal anti-inflammatory drugs (NSAIDs). Patients with EHEC/STEC-induced HUS commonly develop hemolytic anemia and thrombocytopenia and may require transfusion. These patients experience ongoing hemolysis and should not receive blood transfusions early in illness unless they are hemodynamically unstable. Platelet transfusion should also be avoided unless severe thrombocytopenia or bleeding due to the increased risk of thrombosis associated with HUS.(A1)

Extraintestinal Illness

Antimicrobial therapy directed against E. coli should be based on local antibiograms demonstrating susceptibility and resistance patterns. Choosing between oral and intravenous formulations is disease-specific and should be guided by clinical presentation. In general, extraintestinal infections caused by E. coli are susceptible to a variety of antibiotics, as listed below. E. coli can harbor genes for antibiotic resistance, and antibiotic therapy targeting these organisms must be tailored.

• Antibiotics suitable for E. coli infections
  • Beta-lactam antibiotics
    • Cephalosporins
    • Carbapenems
    • Monobactams
  • Nitrofurantoin
  • Trimethoprim-sulfamethoxazole
  • Fosfomycin
  • Fluoroquinolones
• ESBL-producing E. coli (Antibiotic choice is dependent on local resistance patterns)
  • Cefepime
  • Ceftazidime
  • Imipenem
  • Ertapenem
  • Meropenem
• Carbapenemase-producing E. coli
  • Ceftazidime-avibactam
  • Colistin
  • Polymyxin B

Differential Diagnosis

Intestinal illness can be caused by a variety of organisms. Watery diarrheal illness is most commonly caused by viruses, including norovirus and rotavirus, but can also be caused by bacteria, including Staphylococcus aureus, Bacillus cereus, and Vibrio cholerae, among others. For patients presenting with inflammatory or bloody diarrhea, it’s important to consider etiologies including Shigella spp, Salmonella spp, Campylobacter jejuni, and Yersinia enterocolitica, among others. Extraintestinal infections previously discussed can be caused by a variety of viruses and bacteria and are dependent on the specific illness.

Prognosis

Most diarrheal illnesses have a favorable prognosis, and those caused by E. coli are no different. E. coli infections resulting in watery diarrhea are generally self-limited, but even when antibiotics are required, the illness is treatable, and patients make a full recovery. Children who develop HUS due to EHEC/STEC are at the most significant risk for morbidity and mortality. Approximately four percent of children who develop EHEC/STEC-induced HUS will die, and another five percent will develop significant long-term sequelae, including end-stage renal disease and stroke.[37][38] Another 20 to 30 percent will develop other sequelae; those who do not suffer the harmful effects often make a full recovery within two weeks.[39][40][41]

The prognosis of patients who develop extraintestinal infections caused by E. coli is dependent on comorbid conditions. E. coli itself is not an indicator of poor prognosis. However, patients with extraintestinal infections caused by E. coli (except cystitis) are generally sicker at baseline. For example, E. coli is a common cause of spontaneous bacterial peritonitis (SBP) in patients with ascites, and even when treated, SBP is associated with up to a four percent mortality risk.[42]

Complications

Patients who develop diarrheal illness are at an increased risk for dehydration, but this can often be prevented through adequate hydration and early symptomatic intervention. Long-term complications include chronic diarrhea and irritable bowel syndrome, but these occur in a small number of patients. Patients with EHEC/STEC diarrheal illness are at risk for developing hemolytic uremic syndrome, which is more common in children less than five years old and adults older than 60.

The risk of developing HUS is dependent on a number of factors, including Stx gene expression, and in infections caused by Stx2-expressing EHEC/STEC, the risk of HUS may be as high as 24%. Children who develop EHEC/STEC induced HUS are the greatest risk for long-term sequelae. As previously mentioned, approximately five percent will develop end-stage renal disease or stroke, and another 20 to 30 percent will develop sequelae, including hypertension, proteinuria, and subclinical decline in glomerular filtration rate (GFR). Complications associated with extraintestinal E. coli infections are disease-specific and out of the scope of this review.