Pathogenic Escherichia coli associated with

diarrhea
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Literature review current through: Apr 2019. | This topic last updated: Mar 13, 2019.

INTRODUCTION Escherichia coli are normal inhabitants of the human gastrointestinal tract
and are among the bacterial species most frequently isolated from stool cultures. When E.
coli strains acquire certain additional genetic material, they can become pathogenic; these
pathogenic clones circulate widely and are among the most virulent enteric pathogens.
Diarrheagenic E. coli are among the most frequent bacterial causes of gastroenteritis worldwide.

The most common diarrheagenic clones can be assigned to specific pathotypes, which have
distinct pathogenic, epidemiologic, and clinical characteristics (table 1) [1]. The characteristics of
diarrheal illness caused by the following pathotypes will be reviewed here:

●Enterotoxigenic E. coli (ETEC)

●Enteropathogenic E. coli (EPEC)
●Enteroinvasive E. coli (EIEC)
●Enteroaggregative E. coli (EAEC)

Enterohemorrhagic E. coli (EHEC) is discussed briefly here and in greater detail separately.
(See "Microbiology, pathogenesis, epidemiology, and prevention of enterohemorrhagic
Escherichia coli (EHEC)" and "Clinical manifestations, diagnosis and treatment of
enterohemorrhagic Escherichia coli (EHEC) infection".)

COMMON CLINICAL CONCEPTS

Microbiology — E. coli can be cultured readily from the stool under aerobic conditions. On
selective media, such as MacConkey agar, E. coli usually appear as dark pink colonies,
indicating that the organism ferments lactose (picture 1). Additional biochemical identification
should also be performed, since up to 10 percent of E. coli do not ferment lactose or ferment
lactose relatively slowly. The most useful biochemical identification test for E. coli is the indole
test, which is positive in up to 99 percent of E. coli strains.

Pathogenic E. coli are not distinguishable from other strains or from each other by the
appearance on culture plates or by the results of the usual biochemical tests. To determine
whether the isolated strain is one of the pathogenic clones or merely a nonpathogenic
constituent of the intestinal microbiota, one must employ additional identification techniques;
such tests are increasingly available in diagnostic laboratories. (See 'Clinical diagnosis' below.)

Enterohemorrhagic E. coli (EHEC) O157:H7 is the only pathogenic strain that can be identified
readily in the clinical laboratory using nonmolecular tests [2]. Such testing can include
determining the serotype of the strain and biochemical characteristics demonstrable on agar
plates.

The virulence traits are distinct for each category of pathogenic E. coli [3]. These virulence traits
include adherence factors that allow E. coli to attach to the intestinal mucosa, and toxins that
interrupt normal intestinal cell secretion and absorption (secretory toxins) or that damage the
intestinal cell (cytotoxins). These adherence factors and toxins are encoded on accessory
genetic elements in E. coli, such as plasmids, transposons, and bacteriophages.

Clinical diagnosis — Identification of one of these pathogenic E. coli isolates through molecular
testing on stool in a patient with diarrhea is generally sufficient to make the clinical diagnosis of
an E. coli infection. However, a high degree of clinical correlation is necessary, and some
caveats are warranted.
Prior to the increasing availability of commercial molecular tests for diagnosis of diarrheal
pathogens, E. coli pathotypes (apart from EHEC O157:H7) were not readily identified in the
clinical setting as they are indistinguishable from each other and nonpathogenic E. coli on culture
and biochemical testing (see 'Microbiology' above). When culture independent tests on stool (eg,
polymerase chain reaction [PCR] testing or commercially available molecular panels) are used
clinically, these pathogens are identified relatively frequently among patients with diarrhea.
However, some pathotypes (eg, enteroaggregative E. coli [EAEC]) have also been identified with
comparable frequency among asymptomatic patients. Furthermore, these tests detect genetic
material, which does not always indicate infection with a viable organism, and identification of
more than one pathogen is relatively common [4]. Thus, the clinical context is important when
interpreting a positive molecular result for a pathogenic E. coli. A positive test in an
asymptomatic patient does not indicate infection.

Details of the diagnosis of EHEC are discussed elsewhere. (See "Clinical manifestations,
diagnosis and treatment of enterohemorrhagic Escherichia coli (EHEC) infection".)

Approach to treatment — Supportive care with fluid, electrolyte, and nutritional management is
the cornerstone of treatment of diarrheal illnesses. (See "Approach to the adult with acute
diarrhea in resource-rich settings", section on 'Management' and "Approach to the adult with
acute diarrhea in resource-limited countries", section on 'Treatment' and "Approach to the child
with acute diarrhea in resource-limited countries", section on 'Treatment'.)

For patients with diarrhea who have a pathogenic E. coli identified on stool testing, we
suggest not routinely administering antibiotic therapy. Antibiotics can be effective in reducing the
duration of diarrhea associated with pathogenic E. coli. However, most cases of diarrhea
associated with E. coli resolve spontaneously and antibiotic therapy is associated with selection
of resistant organisms and other adverse effects. Additionally, antibiotic therapy
is not recommended in cases of Shiga toxin-producing E. coli infection because of the
association with hemolytic uremic syndrome. (See "Clinical manifestations, diagnosis and
treatment of enterohemorrhagic Escherichia coli (EHEC) infection".)

Antibiotic therapy is reasonable in patients with diarrhea associated with pathogenic E.

coli infection (other than Shiga toxin-producing E. coli [STEC] such as E. coli O157:H7) that is
severe (eg, with fever, more than six stools per day, volume depletion warranting hospitalization)
or bloody. Antibiotic therapy is also reasonable in patients with prolonged (>7 days) diarrhea,
particularly if no other pathogen has been identified. A lower threshold for antibiotic therapy is
appropriate in patients who are at risk for more severe or persistent infection, such as
immunocompromised patients.

When antibiotic therapy is indicated, azithromycin or a fluoroquinolone is generally an

appropriate choice. For infectious diarrhea, azithromycin is given as a single 1 g dose (for
patients without dysentery) or as 500 mg once daily for three days. Appropriate fluoroquinolones
include ciprofloxacin (a single 750 mg dose or 500 mg twice daily for three to five days)
and levofloxacin (500 mg as a single dose or given once daily for three to five days). Studies
evaluating the efficacy of antibiotics for particular E. coli pathotypes are limited. Azithromycin and
fluoroquinolones have been effective for enterotoxigenic E. coli (ETEC) in trials of travelers'
diarrhea [5,6] (see "Travelers' diarrhea: Clinical manifestations, diagnosis, and treatment",
section on 'Selection'). Similarly, several small trials have demonstrated that diarrhea resolved
faster when enteroaggregative E. coli (EAEC) was cleared from the stool with ciprofloxacin [7,8].

Antibiotic resistance among ETEC and EAEC is common. However, since these pathotypes are
identified primarily with culture-independent techniques, having a pathogen on hand for
susceptibility testing to inform optimal antibiotic selection is unusual.

ENTEROTOXIGENIC ESCHERICHIA COLI

Epidemiology — Enterotoxigenic E. coli (ETEC) causes watery diarrhea in young humans and
other mammals in resource-limited settings, as well as in older individuals who have not
previously been exposed to the organism [9].

Approximately 108 to 1010 ETEC must be ingested to induce diarrhea in an otherwise healthy
individual [1]; exposure to this large an inoculum occurs commonly in resource-limited settings
since the pathogen thrives in food and water supplies in the absence of adequate sanitation.
ETEC is one of the most common bacterial causes of dehydrating diarrheal illness in children
under two years of age in these regions [10,11]. These strains can also cause diarrhea in
travelers to tropical regions who are exposed to contaminated food and water. In addition, ETEC
is emerging as a significant diarrheal pathogen in some resource-rich regions [12-14].
(See "Travelers' diarrhea: Microbiology, epidemiology, and prevention".)

Pathogenesis — The pathogenesis of disease due to ETEC consists of ingestion of bacteria,

intestinal colonization, and elaboration of virulence factor(s).

ETEC must express colonizing fimbriae (CFs) to permit the attachment of the bacteria to the
intestine. Antibodies to fimbrial adhesins, specifically colonization factor antigen I, have been
shown to be protective in a mouse model [15].

Upon colonization, ETEC elaborates one or both of two major classes of plasmid-encoded
secretory toxins: heat-labile toxin (LT) and heat-stable toxin (ST) [16]. Only E. coli that contain
one or both of these toxin classes are classified as ETEC [17].

●LT is a complex family of toxins related to Vibrio cholerae cholera toxin with respect to
structure, function, and mechanism. LT acts by stimulating adenylate cyclase and
increasing intracellular cyclic adenosine monophosphate (AMP), which induces secretion of
chloride from intestinal crypt cells and inhibition of absorption of sodium chloride at the villus
tips. Secretion of free water into the intestinal lumen follows, manifesting clinically as watery
diarrhea [18]. Studies suggest that LT and its secretion apparatus can cluster at one end of
the bacterial organism, which may permit ETEC to focus toxin delivery to the host intestinal
cell [19]. (See "Cholera: Microbiology and pathogenesis".)
●There are two major STs that may be present in ETEC; only one of these, STa, is
associated with human disease. STa may exist as a human allele (designated "h") or a
porcine allele ("p"). Epidemiologic data are inconclusive with regard to the relative
pathogenicity of these alleles. Both STa alleles activate enterocyte cyclic GMP, which leads
to the stimulation of chloride secretion and inhibition of sodium chloride absorption. The end
result is secretion of free water into the intestinal lumen, which manifests clinically as watery
diarrhea [18].

Clinical features — ETEC infection has a short incubation period (one to three days), and the
onset of symptoms and signs is rapid. Diarrhea is watery and may be mild or severe. Patients
may report nausea, but vomiting is relatively uncommon. The illness is self-limiting, lasting one to
five days. (See "Travelers' diarrhea: Clinical manifestations, diagnosis, and treatment", section
on 'Clinical manifestations'.)

Molecular diagnosis — The diagnosis of ETEC is made by molecular detection of the genes for
LT or ST [20,21]. Polymerase chain reaction (PCR) or molecular panels that identify ETEC are
available in many clinical laboratories.

Classically, these organisms had previously been identified by bioassays for the secretory toxins:
the rabbit ileal loop for LT and the suckling mouse assay for ST, but these research tests have
been replaced by molecular testing in many clinical laboratories.

ENTEROPATHOGENIC ESCHERICHIA COLI Enteropathogenic E. coli (EPEC) strains

are defined by the characteristic "attaching and effacing" effect they elicit upon interaction with
epithelial cells and by the fact that they do not produce Shiga toxin (figure 1).
Epidemiology — Typical and atypical EPEC strains have been distinguished based on the
presence of certain virulence factors (see 'Pathogenesis' below). Typical EPEC (tEPEC) has
been associated with severe sporadic diarrheal illness and diarrhea outbreaks, most commonly
among children less than six months of age (and almost exclusively in children <2 years of age)
in resource-limited countries [22]. Atypical EPEC (aEPEC) are less well understood; limited
epidemiologic studies suggest that aEPEC may occur at all ages and in resource-rich countries.

Pathogenesis — Typical EPEC (tEPEC) harbor a virulence plasmid (pEAF) that encodes the
bundle-forming pilus (BFP), the factor required for colonization. In addition, tEPEC carry the
Locus for Enterocyte Effacement (LEE) chromosomal island, which contains the eae gene, which
encodes an outer membrane protein colonization factor called intimin. To be designated tEPEC,
an E. coli strain must possess both pEAF and the eae gene; isolates that have only eae are
considered atypical EPEC (aEPEC).

The site of EPEC infection is thought to be the small intestine. The steps in pathogenesis of
tEPEC for initiation of diarrheal illness include [23-26]:

●Initial localized adherence of the organisms to the enterocyte via the BFP
●Induction of signal transduction in the enterocyte by protein toxin secretion
●Development of intimin-mediated intimate adherence to the enterocyte

As above, both tEPEC and aEPEC express the LEE chromosomal island, which elaborates, in
addition to intimin, a set of >20 protein toxins that are injected directly into the target epithelial
cell. Injection of protein toxins is effected by a complex nanomachine called a type III secretion
injectisome [27,28]. The type III "effector" toxins are thought to act by binding to protein elements
of the cell's signal transduction apparatus, resulting in a complex series of events that transform
a normally absorptive epithelial cell into a secretory dynamo [29]. This is accompanied by
mobilization of intracellular calcium, activation of protein kinase C and the myosin-light-chain
kinase, and induction of tyrosine phosphorylation of proteins [30]. The effectors induce
rearrangement of cytoskeletal proteins, resulting in the classic "attaching and effacing" lesion,
alterations in water and electrolyte secretion, and increased permeability of intestinal tight
junctions.

EspF is an LEE-secreted protein that is not involved with attaching and effacing; it appears to
disrupt intestinal barrier function by increasing monolayer permeability via alteration of electrical
resistance [31]. EspF has several protein-protein interaction domains that may function by
interacting with endocytic regulation [32]. 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 [33].

Clinical features — The diarrhea associated with tEPEC in children can be severe, with
concomitant vomiting and dehydration. Stools are typically watery without blood or pus. Fever
may occur in a minority of patients. Diarrhea due to aEPEC is also watery and not as severe as
that caused by tEPEC.

If diarrhea persists, malnutrition can be a devastating complication, particularly in resource-

limited settings, where resources for supportive therapy may be limited. Micronutrient
malnutrition in severe infection may also be a result of direct mechanisms, as suggested by cell
culture data demonstrating that EPEC infection inhibits intestinal absorption of thiamine [34].

Molecular diagnosis — The gold standard for identification of tEPEC is the molecular detection
by panel or polymerase chain reaction (PCR). Such tests identify either the pEAF plasmid or its
encoded BFP factor, which produce equivalent results; these are never found in strains lacking
the LEE chromosomal island (tEPEC is defined by the presence of both the pEAF/BFP and the
LEE). In contrast, tests that target the LEE (via detection of the eae gene, which encodes intimin)
can identify isolates that lack the pEAF (by definition, aEPEC). It is not known whether all strains
meeting this molecular definition of aEPEC are bona fide human pathogens.
ENTEROHEMORRHAGIC ESCHERICHIA COLI Some strains of E. coli produce Shiga
toxin. Shiga toxin-producing strains that also demonstrate an "attaching and effacing" lesion like
enteropathogenic E. coli (EPEC) (albeit in the colon, not the small intestine) are categorized as
enterohemorrhagic E. coli (EHEC). A particularly virulent subset of EHEC organisms belongs to
serotype O157:H7 [2,35]; non-O157 serotypes also account for a large proportion of EHEC
infections (figure 1).

EHEC strains, especially those belonging to serotype O157:H7, have been responsible for large
outbreaks of bloody diarrhea, some associated with hemolytic uremic syndrome (HUS), a triad of
microangiopathic anemia, renal failure, and thrombocytopenia [36,37].

EHEC infection is discussed further elsewhere. (See "Microbiology, pathogenesis, epidemiology,

and prevention of enterohemorrhagic Escherichia coli (EHEC)" and "Clinical manifestations,
diagnosis and treatment of enterohemorrhagic Escherichia coli (EHEC) infection".)

Shiga toxin-associated hemolytic uremic syndrome is discussed further separately. (See "Clinical
manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic
syndrome (HUS) in children" and "Treatment and prognosis of Shiga toxin-producing Escherichia
coli (STEC) hemolytic uremic syndrome (HUS) in children".)

ENTEROINVASIVE ESCHERICHIA COLI Enteroinvasive E. coli (EIEC) is closely related

to Shigella and causes colitis that is similar to shigellosis. Clinical EIEC infection appears to be
uncommon, although it may be underdiagnosed. Clinical disease with EIEC begins as watery
diarrhea and may or may not proceed to bloody diarrhea and frank dysentery. Infection can
result in severe disease. In a rare outbreak of EIEC infection in the United States that involved
52 individuals who had attended a potluck party, 28 (54 percent) were hospitalized and 13 (25
percent) had sepsis [38]. Among the subset interviewed about their symptoms, median onset
was 20.5 hours after exposure, 77 percent had watery diarrhea, 54 percent had mucoid diarrhea,
and 91 percent had fever.

The organisms can be detected using nucleic acid tests, including multiplex panels. EIEC
invades the intestinal cell, multiplies intracellularly, and extends into the adjacent intestinal cells.
The same genes facilitate pathogenesis of both EIEC and Shigella [39]. EIEC may be
differentiated from Shigella principally by the fact that EIEC strains ferment glucose and xylose.
(See "Shigella infection: Epidemiology, microbiology, and pathogenesis" and "Shigella infection:
Clinical manifestations and diagnosis".)

ENTEROAGGREGATIVE ESCHERICHIA COLI Enteroaggregative E. coli (EAEC) was

first described in the 1980s, when collections of E. coli from studies of patients with diarrhea in
resource-limited settings were examined in tissue culture adherence assays [40]. E. coli that had
a distinctive palisading adherence on human epithelial type 2 (HEp-2) cells were observed more
frequently in the stools of children with diarrhea than in children without diarrhea [41].

Epidemiology — EAEC appears to be a cause of acute and chronic diarrheal illness among
many different subpopulations in both resource-limited and resource-rich regions.

Surveys of E. coli from diarrhea outbreaks in Europe have demonstrated the presence of EAEC
in both outbreaks and sporadic cases of diarrhea [42,43]. In a prospective study of patients
presenting with diarrhea to two large medical centers in the United States, EAEC was observed
in 4.5 percent of cases and was identified more frequently among cases than asymptomatic
controls [44]. One meta-analysis noted a positive correlation between acute diarrheal illness and
EAEC excretion (diagnosed by aggregative adherence assay) in the following groups [45]:

●Children residing in both resource-limited and resource-rich regions

●Adults with and without HIV infection residing in resource-limited regions
●International travelers to resource-limited regions
EAEC has also been repeatedly associated with persistent diarrhea among children studied from
Chile, Brazil, Mexico, India, and Bangladesh [46-52], and has been associated with persistent
diarrhea among adults with HIV infection, particularly those with advanced immune suppression,
in the United States and Switzerland [53,54].

Not all studies have identified a link between EAEC and clinically significant diarrhea [11,55]. In a
large multi-center, case-control study among children younger than five years of age in sub-
Saharan Africa or south Asia, EAEC was extremely common among both children with diarrhea
and controls and was not epidemiologically associated with moderate-to-severe diarrhea [11].
However, a multi-center longitudinal study of children in resource-limited countries suggested
that asymptomatic carriage of EAEC could predict linear growth retardation [56]. This association
has been previously reported in individual studies [57] and suggests that the burden of EAEC
disease may more closely parallel asymptomatic carriage than watery diarrhea.

Pathogenesis — The pathogenesis of diarrhea caused by EAEC is incompletely elucidated [41].

EAEC are capable of inducing the release of interleukin (IL)-8 from polarized colonic T84 cells
[58] and inducing epithelial barrier dysfunction [59].

Most EAEC strains harbor a transcriptional activator called AggR [60]; AggR activates a large
number of genes that are likely involved in pathogenesis. EAEC strains that possess AggR and
its regulon are termed typical EAEC strains. Given that most epidemiologic studies addressing
EAEC detect the organism by virtue of AggR-dependent genes, most of what is known about
EAEC involves typical strains.

A variety of EAEC pathogenetic mechanisms have been postulated:

●Adherence fimbriae (variants AAF/1-AAF/V) are present in nearly all typical EAEC strains,
and the AAF-encoding genes are directly controlled by AggR itself [61]. AAF-encoding
genes are carried on a virulence plasmid (pAA) in typical EAEC; pAA also encodes AggR.
An AggR-activated and pAA-encoded protein called dispersin (encoded by the aap gene)
appears to promote AAF-mediated colonization [62].
●Mucosal destruction has been demonstrated in clinical specimens and in tissue culture
assays, and a protease cytotoxin has been identified in many EAEC strains [63]. Serine
family proteases are commonly found in EAEC and may be associated with diarrheagenic
strains [64].
●Some EAEC strains may invade tissue culture cells and induce IL-8 production via
mitogen-activated protein kinase [65,66].

Clinical features — As above, both acute and chronic diarrhea have been associated with
EAEC. Patients with symptomatic infection typically present with watery diarrhea without blood in
the stools. In one study that included 37 patients with EAEC-associated diarrhea, concomitant
fever, abdominal pain, and vomiting were reported in 43, 65, and 57 percent, respectively [44].

In 2011, a typical EAEC strain that had become lysogenized with a Shiga toxin-encoding phage
was associated with a large multi-country outbreak of hemorrhagic colitis and hemolytic uremic
syndrome (HUS) [67]. This outbreak, responsible for 52 deaths, was linked to contaminated
fenugreek sprouts. The implicated strain has not been isolated since the outbreak, although
other Shiga toxin-producing EAEC have been isolated. Whether these clones will emerge
epidemiologically remains to be seen.

Molecular diagnosis — The gold standard for the diagnosis of EAEC is detection of the AggR
regulon using molecular techniques. Commonly available molecular panels detect EAEC this
way. Although no single DNA target has been epidemiologically linked to pathogenicity, the
linkage of the AggR regulon with pathogenesis suggests that targeting any number of AggR-
activated genes for detection will produce similar diagnostic performance.
Other methods for identifying EAEC include detection of aggregative adherence to HEp-2 cells in
culture; EAEC has a distinctive palisading adherence pattern. While not used in clinical
laboratories, research studies have used this technique for diagnosing cases [45].