Diarrheagenic Escherichia coli

Pathogenic subtypes of Escherichia coli that cause diarrhea are called diarrheagenic E. coli and include enterohemorrhagic E. coli (EHEC), enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), enteroinvasive E. coli (EIEC), and enteroaggregative E. coli (EAEC). Transmission is typically through contaminated food or water. Clinical manifestations include watery diarrhea, dysentery, abdominal pain, dehydration, and/or fever; clinical presentation varies by subtype. Diagnostic studies (e.g., stool culture and/or gastrointestinal pathogen panel for diarrhea) are typically reserved for patients with red flags in diarrhea. Outpatient management with oral rehydration therapy is usually sufficient. Hospitalization and antibiotic therapy are considered for patients with red flags in diarrhea, although antibiotic therapy is not used for those with EHEC.

EHEC produces Shiga toxin and can cause severe colitis and hemolytic uremic syndrome (HUS). Diagnosis of EHEC is confirmed with identification of colorless O157:H7 colonies on sorbital MacConkey agar and/or the presence of Shiga toxin. Management is supportive. Antibiotics are strongly contraindicated in EHEC because they do not improve the disease course and may increase the risk of HUS.

Pathogen

• Escherichia coli (E. coli): gram-negative, rod-shaped, indole-positive, and flagellated bacterium ^[1]
• Diarrheagenic strains of E. coli include:^[1]
  • EHEC
  • ETEC
  • EPEC
  • EIEC
• Some strains are an essential component of the bacterial gut flora and even have a protective effect against enteropathogens. ^[2]

Transmission

• For EHEC, cattle intestines are the primary reservoir; all other diarrheagenic strains are mainly found in humans. ^[3]
• Fecal-oral transmission, e.g., from: ^[1][4]
  • Contaminated food (e.g., raw or undercooked meat products, vegetables, fruits)
  • Contaminated water (e.g., drinking water, swimming)
  • Person-to-person

General principles

• Consider diarrheagenic E. coli in patients with clinical features of infectious gastroenteritis and typical patient history (e.g., recent exposure).
• Obtain laboratory studies for patients with red flags in diarrhea (e.g., bloody stools, severe dehydration). ^[5]
• Stool studies can be used to confirm the diagnosis.
• All stool samples obtained for community-acquired diarrhea should be tested for EHEC. ^[6][7]
• Definitive diagnosis of non-EHEC diarrheagenic E. coli subtypes is usually only required in regional outbreaks. ^[6][8]
• Blood tests are not routinely required, but may be used to evaluate for complications. ^[9]

Laboratory studies

Stool studies ^[9][10]

The following studies are used to confirm the diagnosis.

• Stool culture: confirms the diagnosis and identifies the E. coli subtype
• Gastrointestinal pathogen panel: identifies the E. coli subtype
• Shiga toxin study (e.g., enzyme immunoassay): evaluates for EHEC

Many US clinical laboratories only perform diagnostic studies for EHEC, not other types of diarrheagenic E. coli. ^[8]

Blood tests ^[9]

Blood tests are not routinely required, but they may show supportive findings and/or indicate complications if performed for workup of infectious gastroenteritis.

• CBC
  • ↑ WBC
  • Features of HUS (i.e., anemia, thrombocytopenia)
• CMP: laboratory findings in dehydration and hypovolemia (e.g, ↑ BUN/creatinine ratio, ↓ GFR, electrolyte abnormalities) ^[11][12]
• Inflammatory markers: ↑ CRP
• Blood cultures: E. coli in peripheral blood

• Food poisoning
• Other causes of bacterial gastroenteritis
• Norovirus infection
• Rotavirus infection
• See also "Pathogens causing diarrhea."

The differential diagnoses listed here are not exhaustive.

General principles ^[9][10]

• Outpatient management is sufficient for most patients.
• Provide supportive care for diarrhea as needed.
  • Provide rehydration and electrolyte replenishment.
  • Return patients to a normal diet as soon as tolerated, starting with clear liquids and foods that are easy to digest.
• Antibiotic therapy is not routinely recommended but may be considered for certain patients.
• Refer patients with features of severe gastroenteritis for inpatient care and monitoring.

Antibiotic therapy ^[9]

• Not recommended for most patients
• Strongly contraindicated in patients with EHEC
• If EHEC is not suspected, antibiotic therapy may be considered for certain patients with bloody diarrhea, e.g.:
  • Infants aged < 3 months
  • Patients after recent international travel and high fever or signs of sepsis
  • Patients with immunocompromise and severe disease
• Empiric antibiotic therapy for diarrheagenic E. coli ^[10][13]
  • Most adults: fluoroquinolones (e.g., ciprofloxacin ) ^[10][13]
  • Children and pregnant individuals: azithromycin (off-label) ^[13]
  • Infants aged < 3 months: third-generation cephalosporin ^[9]

Do not use antibiotics if EHEC is suspected. Obtain diagnostic studies and monitor for signs of HUS. ^[9]

Etiology

Pathogen ^[1][14]

• EHEC (a subtype of Shiga toxin-producing E.coli) ^[3]
  • Produces Shiga toxin (verotoxin)
  • Can cause bloody diarrhea and HUS
• E. coli O157:H7; is the most frequently isolated strain of EHEC and the strain most commonly associated with HUS worldwide.

EHEC leads to HUS.

Transmission

• Fecal-oral route ^[9]
• Contaminated food (associated with industrial food production in high-income countries)
  • Raw milk
  • Raw or undercooked beef or vegetables ^[5]
• Contact with contaminated stool

EHEC is a subtype of STEC. Undercooked STEAK is a common source of EHEC infection.

Pathophysiology ^[15]

• EHEC bacteria are infected by bacteriophages that integrate their genes into the bacteria's genome; these genes then code for toxins (verotoxin/Shiga toxin 1 and 2).
• Adhesion to receptors of gut cells; → Shiga toxin secretion → cleavage of adenine from the rRNA → inactivation of the 60S subunit → protein synthesis inhibition → cell death → necrosis and inflammation of the GI mucosa → watery-bloody diarrhea with mucus (otherwise known as dysentery)

Clinical features ^[16][17]

The incubation period is typically 3 days; clinical features usually last 1 week. ^[16]

• Watery diarrhea or bloody diarrhea
• Abdominal ; cramping and tenderness
• Dehydration
• Possibly, fever
• Vomiting
• Some patients develop features of HUS, e.g.: ^[16]
  • Abnormal bleeding, petechiae
  • Pallor, jaundice
  • Oliguria
  • See also “Hemolytic uremic syndrome."

Shiga toxin-related HUS occurs in around 4% of patients with E. coli O157:H7 and is more common in children < 5 years of age and older adults (especially ≥ 65 years of age). ^[17]

Diagnosis ^[17]

Approach

• Evaluate for EHEC in patients with community-acquired diarrhea with red flags in diarrhea and/or suspected HUS. ^[8][16]
• Obtain stool studies to confirm the diagnosis.
• Obtain blood tests to evaluate for complications (see "Diagnostic approach to diarrheagenic E. coli").

Thrombocytopenia, hemolytic anemia, and acute kidney injury are the typical triad for HUS.

Stool studies

• Stool culture: Sorbitol MacConkey agar detects EHEC based on sorbitol-fermenting properties and differentiates between strains.
  • O157:H7 EHEC: colorless colonies
  • Non-O157:H7 EHEC: pink colonies
• Gastrointestinal pathogen panel
  • Confirms EHEC by identifying Shiga toxin-encoding genes ^[18]
  • Detects O157:H7 EHEC directly
• Shiga toxin studies (e.g., Shiga toxin enzyme immunoassay): confirms EHEC by detecting Shiga toxin

EHEC is a nationally notifiable disease in the US; report all cases to the local health department. ^[19]

Management ^[9][17][19]

• Refer patients with high-risk features (e.g., hypovolemia, dysentery) for inpatient care and monitoring.
• Antibiotic therapy is contraindicated.
• Provide symptomatic management and supportive care for diarrhea.
  • Rehydrate and replace electrolytes (e.g., oral rehydration therapy, IV fluid).
  • Avoid antiperistaltic agents (e.g., diphenoxylate/atropine), which increase the risk of systemic complications.
• Monitor for HUS (e.g., daily CBC and BMP for inpatients). ^[9]
• Perform contact precautions to avoid further transmission of EHEC.

Effective supportive management in patients with EHEC reduces the risk of developing HUS. ^[16]

Antibiotic therapy is contraindicated in EHEC because it does not improve the disease course and may increase the risk of developing HUS. ^[19]

Epidemiology ^[20]

• Enterotoxigenic E. coli (ETEC) is the most common causative pathogen of traveler's diarrhea. ^[5]
• A major cause of diarrhea among children in resource-limited countries
• Common in low-income countries ^[3]

ETEC causes Traveler's diarrhea.

Pathophysiology ^[21]

• ETEC produces two types of enterotoxins:
  • Heat-labile enterotoxin (AB toxin; two-component protein, similar to cholera toxin): activation of adenylate cyclase → ↑ cAMP levels → ↑ chloride secretion → water efflux into the intestinal lumen → secretory diarrhea
  • Heat-stable enterotoxin: activation of guanylate cyclase → ↑ cGMP levels → ↓ NaCl reabsorption → water efflux into the intestinal lumen → secretory diarrhea
• No invasion of the intestinal mucosa and no inflammation

Clinical features ^[16][20]

The incubation period ranges from 5 hours to 2 days. Symptoms typically last 3–5 days and include the following: ^[16]

• Watery diarrhea (mild to severe)
• Abdominal cramping
• Nausea; , possibly vomiting
• Fever
• Decreased appetite

Diagnosis ^[8][9]

• Traveler's diarrhea is usually diagnosed clinically.
• Diagnostic testing for ETEC is not usually required.
• ETEC can be identified on gastrointestinal pathogen panel or stool culture.

Treatment ^[16][20][22]

• ETEC is typically self-limiting.
• Provide supportive care for diarrhea (e.g., oral rehydration therapy).
• Antidiarrheal agents (e.g., bismuth subsalicylate compounds) may be considered to decrease the frequency of bowel movements.
• Antibiotics may shorten the duration of symptoms but are not routinely recommended.
  • Consider antibiotics for traveler's diarrhea in patients with severe illness (e.g., red flags in diarrhea).
  • Options include azithromycin, ciprofloxacin, and rifaximin.

Prevention ^[20][22]

• Recommend food and water precautions.
• Consider pharmacological prophylaxis for traveler's diarrhea (e.g., bismuth subsalicylate).
• Prophylactic antibiotics are not routinely recommended but may be considered for individuals at increased risk for serious complications (e.g., immunocompromised patients).

Epidemiology ^[16]

• Enteropathogenic E. coli (EPEC) leads to infantile diarrhea and is a common cause of diarrhea in children aged < 2 years.
• Adults are less susceptible to EPEC infection.
• More common in low-income countries
• One of the leading causes of death in children in low-income countries.

EPEC causes Pediatric diarrhea.

Pathophysiology ^[23]

• EPEC blocks absorption by attaching to the apical surfaces of the intestinal epithelium, causing the villi to flatten.
• No toxin production is involved.

Clinical features ^[14][16]

The incubation period is short (hours to days) and clinical features typically last under 2 weeks.

• Watery diarrhea (e.g., frequent watery bowel movements 10–20 per day) ^[24]
• Vomiting
• Low-grade fever
• Clinical features of dehydration ^[16]

Management ^[8][16]

• EPEC can be diagnosed clinically; diagnostic confirmation is not routinely required.
• Typically self-limiting
• Provide supportive care for diarrhea as needed (e.g., oral rehydration therapy).
• Consider empiric antibiotic therapy for E. coli in certain patients, e.g.:
  • Infants who appear severely unwell ^[9]
  • Patients with persistent symptoms ^[16]

The pathomechanism and clinical presentation of enteroinvasive E. coli (EIEC) are very similar to Shigellosis. ^[25]

Pathophysiology ^[16]

• Enteroinvasive E. coli (EIEC) invades the colonic epithelium.
• Invasion of gut epithelium → inflammation and necrosis

EIEC Invades the Intestinal mucosa.

Clinical features ^[16][25]

• Typically mild watery diarrhea
• May cause symptoms similar to shigellosis, e.g.:
  • Bloody diarrhea, possibly with mucus (dysentery)
  • Fever
  • Malaise, fatigue
  • Abdominal cramps

Management ^[16]

• Diagnostic confirmation is not routinely required but may be considered in patients with severe symptoms.
• Typically self-limiting
• Provide supportive care for diarrhea as needed (e.g., oral rehydration therapy).
• Consider empiric antibiotic therapy for diarrheagenic E. coli in patients with severe or persistent symptoms. ^[16]

Epidemiology ^[16]

• Enteroaggregative E. coli (EAEC) is most common in children, individuals with HIV, and travelers to low-income countries. ^[9]
• Also occurs in medium and high-income countries, and in adults

Clinical features ^[16]

• Watery diarrhea, possibly with mucus
• Possibly dysentery
• Low-grade fever
• Nausea
• Abdominal pain

Management ^[16]

• Diagnostic confirmation is not routinely required but may be considered in patients with severe symptoms.
• Provide supportive care for diarrhea as needed (e.g., oral rehydration therapy).
• For severe illness, antibiotic therapy may be considered.
• See empiric antibiotic therapy for diarrheagenic E. coli or antibiotics for traveler's diarrhea, depending on the clinical presentation.