Diarrheagenic Escherichia coli

[Snowy Owl]

Diarrheagenic Escherichia coli

Last updated September 22, 2006
http://www.cidrap.umn.edu/cidrap/con...colioview.html


Agent

Classification

• Escherichia coli is a member of the genus Escherichia within the family Enterobacteriaceae.
• Members of this family are widely distributed in the environment, and selected strains can cause a variety of infections in hospital and community settings (see References: Donnenberg 2005).
• The genus Escherichia contains several species:
  • E coli (the type species; usually isolated from the human bowel but causes a range infections)
  • E hermannii (rare in humans; most often found in wound infections)
  • E albertii, a new species designation that is biochemically similar to Hafnia alvei (rare in humans; causes diarrheal illness) (see References: Huys 2003)
  • E blattae (generally not recovered from human specimens; commensal organism of cockroaches)
  • E fergusonii (rare in humans; may be identified in human feces and has been isolated from blood)
  • E vulneris (rare in humans; recovered from wound infections)
• E coli is the most common species of facultative anaerobe found in the human gastrointestinal tract and the most commonly encountered pathogen in the Enterobacteriaceae family (see References: Donneberg 2005).
• E coli can cause diarrheal illness as well as numerous other types of infections (including urinary tract infections, meningitis [particularly in neonates and immunocompromised patients], sepsis, wound infections, nosocomial pneumonia, cellulitis, osteomyelitis, septic arthritis, and others).
• The genome consists of a single circular chromosome of about 4 to 5 million base pairs (bp) depending on the strain, and may include multiple plasmids of various sizes (4 kilobases [kb] to several hundred kb) that are dispersed within the cytoplasm. Additional genes can be contained on bacteriophages (viruses that infect the bacteria) or within transposons (small sequences of DNA that can move between the chromosome and the plasmids). Bacteriophages and transposons may contain genes that encode for various virulence factors.
• The DNA of several strains has been sequenced and the differences between these have helped explain some aspects of virulence and pathogenicity (see References: Kaper 2004).
• E coli can be characterized by shared liposaccharide (O) and flagellar (H) antigens that define serogroups (O antigen only) or serotypes (O and H antigens).
• Serotyping is important for E coli associated with diarrheal disease because a strain causing an outbreak can be differentiated from normal stool flora by its unique O:H antigenic character. Most pathogenic E coli belong to specific serotypes, which can facilitate identification even in isolated cases (see References: Bopp 2003, Donnenberg 2005, Evans 1996, Kaper 2004).

Key Microbiologic Characteristics

• E coli organisms have the following characteristics:
  • Gram-negative, rod-shaped bacilli
  • 1 to 3 microns long and 0.5 microns in diameter
  • Non?spore-forming, facultative anaerobes
  • Most strains are motile, and movement is by peritrichous flagellae
  • Attach to cell surfaces by fimbriae
  • Ferment glucose and other sugars
  • Reduce nitrate to nitrite
  • Produce catalase but not oxidase
  • Can be distinguished from other members of Enterobacteriaceae by the ability of most strains to ferment lactose and produce indole from tryptophan
• More than 175 O antigens and 53 H antigens have been recognized, but only a few serotype combinations are associated with diarrheal disease (see References: Bopp 2003, Kaper 2004).

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Pathogenesis

• E coli can cause diarrhea by at least six different mechanisms and each type is associated with a different pathotype and different virulence determinants (see Major Mechanisms of Pathogenesis below) (see References: Donnenberg 2005).
• The six recognized pathotypes for diarrheagenic E coli are as follows:
  • Enteropathogenic E coli (EPEC)
  • Enterohemorrhagic E coli (EHEC, also known as Shiga toxin?producing E coli [STEC] and formerly referred to as verotoxin-producing E coli [VTEC])
  • Enterotoxigenic E coli (ETEC)
  • Enteroaggregative E coli (EAEC)
  • Enteroinvasive E coli (EIEC)
  • Diffusely adherent E coli (DAEC)

Mechanism of Pathogenesis

• Most strains of E coli live harmlessly in the colon and are poorly adapted to causing disease in healthy persons, but several pathogenic strains can cause specific illness in healthy and immunocompromised individuals (see References: Qadri 2005).
• General steps in the pathogenic process include:
  • Ingestion
  • Bacterial attachment via pili, fimbriae, or fibrillae
  • Colonization of the ileal mucosa
  • Expression of bacterial mechanisms to allow evasion of host defenses
  • Multiplication of bacteria
  • Host damage (for selected strains) (see References: Donnenberg 2005, Kaper 2004)
• Some pathogenic E coli strains produce cytotonic enterotoxins (encoded on plasmid or bacteriophage DNA) that induce watery diarrhea without causing substantial tissue damage.
• Other strains harbor plasmid-encoded invasion factors that allow invasion of the mucosa or plasmid- or bacteriophage-encoded cytotoxic enterotoxins that can cause tissue damage. Either of these factors can induce a host inflammatory reaction and lead to dysentery (see References: Evans 1996, Mokady 2005).

Virulence Factors

Several highly adapted strains have acquired virulence factors that allow them to cause disease. In addition to structural properties that allow survival in the gastrointestinal tract (see References: Foster 2004), virulence factors include:

• Adhesin/colonization factors (specific adherence factors that allow colonization of atypical sites for E coli):
  • Fimbriae (pili) or fibrillae aid cell surface binding
  • Outer membrane surface structures can trigger signal transduction pathways or cytoskeletal rearrangements that can lead to illness
  • Proteins that bind to cell surface receptors can trigger cytokine cascades (eg, lipopolysaccharide, flagellin)
• Toxins (secreted toxins and other effector proteins):
  • Heat-labile enterotoxin (LT) activates adenylate cyclase which eventually leads to chloride secretion and diarrhea. LT-producing strains induce watery diarrhea among adults in Asia, travelers to Central America, and children in several regions (see References: Guerrant 1980, Guerrant 2005).
  • Heat-stable enterotoxin a (STa) activates guanylate cyclase that provokes ion secretion, which leads to diarrhea.
  • Heat-stable enterotoxin b (STb) activates intracellular calcium that stimulates ion secretion, which leads to diarrhea.
  • Cytotoxins (Shiga-like toxin [SLT]-1, SLT-2) cause hemorrhagic colitis or hemolytic uremic syndrome (HUS). SLT-1 is virtually identical to Shiga toxin, which is produced by Shigella dysenteriae type 1 and SLT-2 also is very similar to the Shiga toxin molecule. SLT 1 or 2 are encoded on a lambda-like bacteriophage; the ability to produce SLT was a key step in the evolution of EHEC from EPEC (see References: Reid 2000, Strockbine 1986).
• Type 2 secretion systems (T2SSs):
  • T2SSs are comprised of about 12 proteins that form a piston-like structure for exporting proteins and toxins across the outer membrane.
  • These systems are encoded on pathogenicity islands (segments of chromosomal DNA that are flanked by insertion or repeat elements) or on plasmids (see References: Clarke 2003, Lathem 2002).
• Type 3 secretion systems (T3SSs):
  • T3SSs contain genes encoding proteins that form a "molecular syringe" for injection of bacterial proteins or toxins.
  • As with T2SSs, these systems can be encoded on pathogenicity islands or on plasmids (see References: Donneberg 2005, Galan 1999).
• Plasmids:
  • Plasmids are genetic elements that can be transmitted between bacteria.
  • Plasmids are not virulence factors per se, but they can encode genes for a variety of factors that contribute to pathogenesis, including antibiotic resistance, fimbriae, toxins, secretion systems, and invasion factors.
  • Transmission of plasmids plays a large role in the growing problem of antibiotic resistance (see References: Prats 2003).

Major Mechanisms of Pathogenesis

The principal mechanisms of pathogenesis and the major serogroups for diarrheagenic strains are shown in the table below and are briefly described in the discussion following the table. Mechanisms are not completely understood for some types.

<table class="table1" align="left" border="0" cellpadding="0" cellspacing="0"> <tbody><tr> <td colspan="4" class="tableheader1" valign="top"> Mechanisms of Pathogenesis and E coli Serotypes
</td> </tr> <tr> <td class="colhead" valign="top"> Pathogen/Type
</td> <td class="colhead" valign="top"> Mechanism
</td> <td class="colhead" valign="top"> Genetic Element Responsible
</td> <td class="colhead" valign="top"> Major Serogroups
</td> </tr> <tr> <td class="tablecell" valign="top"> ETEC
</td> <td class="tablecell" valign="top">
</td> <td class="tablecell" valign="top">
</td> <td class="tablecell" valign="top">
</td> </tr> <tr> <td class="tablecell" valign="top"> LT
</td> <td class="tablecell" valign="top"> ?Adherence via CFA-1 through CFA-4
?Produce LT (cholera-like toxin) which activates adenylate cyclase
</td> <td class="tablecell" valign="top"> LT-1 plasmid, LT-2 chromosome
</td> <td class="tablecell" valign="top"> LT+ST: O groups 11,15,20,25,27, 60, 63, 75, 80, 85, 88, 89, 99, 101, 109, 114, 139, 153
</td> </tr> <tr> <td class="tablecell" valign="top"> STa
</td> <td class="tablecell" valign="top"> Produce STa which activates guanylate cyclase
</td> <td class="tablecell" valign="top"> Plasmid
</td> <td class="tablecell" valign="top"> ST: O groups 12, 78, 115, 148, 149, 153, 159, 166, 167
</td> </tr> <tr> <td class="tablecell" valign="top"> STb
</td> <td class="tablecell" valign="top"> Produce STb which activates intracellular calcium; cyclic nucleotide independent bicarbonate secretion
</td> <td class="tablecell" valign="top"> Plasmid
</td> <td class="tablecell" valign="top"> ST: O groups 12, 78, 115, 148, 149, 153, 159, 166, 167
</td> </tr> <tr> <td class="tablecell" valign="top"> EHEC/STEC
</td> <td class="tablecell" valign="top"> ?Attaching, effacing
?Produce Shiga-like toxin (SLT) 1 or 2 which inhibits protein synthesis
</td> <td class="tablecell" valign="top"> Chromosome (pathogenicity island); phage
</td> <td class="tablecell" valign="top"> Mainly O157:H7;O26:H11; O103:H2; O111:H21+ and about 50 others
</td> </tr> <tr> <td class="tablecell" valign="top"> EIEC
</td> <td class="tablecell" valign="top"> Local mucosal invasion
</td> <td class="tablecell" valign="top"> Plasmid (type 3 secretion system); chromosome
</td> <td class="tablecell" valign="top"> O groups 11, 28ac, 29, 115, 124, 136, 143, 144, 147, 152, 164, 167, 173
</td> </tr> <tr> <td class="tablecell" valign="top"> EPEC
Locally adherent attaching and effacing E coli
</td> <td class="tablecell" valign="top"> ?Adhere focally via bundle-forming pili
?Attach to and efface brush border epithelium by injection and phosphorylation of Tir and subsequent intimin binding
</td> <td class="tablecell" valign="top"> ?Plasmid (60 MDa, pMAR2, with EAF and bfpA)
?Chromosomal locus of enterocyte effacement (LEE)
</td> <td class="tablecell" valign="top"> O18:H-,7,14; O26:H-; Oh44:H118, 44; O55:H-, 6, 7; O86:H34; O88; O111:H-, 27; O127:H-; O128ab:H2,7; O142:H6; O145:H8;O158:H23
</td> </tr> <tr> <td class="tablecell" valign="top"> EAEC
</td> <td class="tablecell" valign="top"> Aggregative adherence to HEp-2 cells
</td> <td class="tablecell" valign="top"> Plasmid
</td> <td class="tablecell" valign="top"> O3:H2; O44; O78:H33;O15:H11; O77:H18; O51:H11; O77:H18; O51:H11
</td> </tr> <tr> <td class="tablecell" valign="top"> Enteroaggregative
STa-like toxin-1
(EAST-1)
</td> <td class="tablecell" valign="top"> Activate guanylate cyclase
</td> <td class="tablecell" valign="top"> Plasmid
</td> <td class="tablecell" valign="top"> O?:H10, among others (O78, 86, 91, 92)
</td> </tr> <tr> <td class="tablecell" valign="top"> Plasmid-encoded toxin
(PET)
</td> <td class="tablecell" valign="top"> Secretion, cytotoxicity
</td> <td class="tablecell" valign="top"> Plasmid
</td> <td class="tablecell" valign="top">
</td> </tr> <tr> <td class="tablecell" valign="top"> DAEC
</td> <td class="tablecell" valign="top"> Diffuse adherence
</td> <td class="tablecell" valign="top"> Chromosomal
</td> <td class="tablecell" valign="top"> Strain F1845, 189, 57-1
</td> </tr> <tr> <td colspan="4" class="tablefooter" valign="top"> Abbreviations: CFA, colonization factor antigen; CNF, colony necrotizing factor; LT, heat-labile; ST, heat-stable.
Adapted from Guerrant 2005, Nguyen 2006 (see References).
</td> </tr> </tbody></table>

EHEC/STEC: Adhere to colon epithelial cells and induce the attaching and effacing lesions. Bacteria produce one or more Shiga toxins (also known as verocytotoxins) whose systemic absorption leads to potentially life-threatening complications (see References: Robinson 2006).

• Illness presents as mild nonbloody diarrhea or severe bloody diarrhea (hemorrhagic colitis).
• Hemolytic uremic syndrome (HUS; a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure) develops in some patients, most commonly children.
• O157 STEC is thought to cause at least 80% of cases of HUS in North America (see References: Lynn 2005).

EPEC: Adhere to small bowel enterocytes but destroy the normal microvillar architecture provoking characteristic attaching and effacing lesions.

• After initial adhesion, protein translocation by type 3 secretion systems induce "pedestal" cytoskeletal rearrangement that cups the bacteria.
• Cytoskeletal derangements are accompanied by an inflammatory response and diarrhea.
• Atypical strains have been associated with prolonged diarrhea in children (see References: Nguyen 2006).

ETEC: Cause watery diarrhea that can range from a mild, self-limiting illness to a severe purging disease similar to cholera.

• Bacteria are associated with childhood diarrhea in the developing world and travelers' diarrhea among those visiting developing countries (see References: Bopp 2003, Nataro 1998, Qadri 2005).

• These bacteria do not produce Shiga toxins and are not invasive.
• ETEC adhere to small bowel enterocytes and elaborate enterotoxins that provoke intestinal secretion and diarrhea.
• Colonization is mediated by one or more proteinaceous fimbrial or fibrillar colonization factors (CFs) that are designated by colonization factor antigen (CFA), CS (coli surface antigen), or putative colonization factor (PFA).
• ETEC strains produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and strains may express either or both (see References: Qadri 2005).
• LTs are related to cholera enterotoxin and provoke diarrhea by activating the main chloride channel and by simulating prostaglandin synthesis and the enteric nervous system, both of which can stimulate secretion and inhibit absorption.
• ST is a small peptide that resembles a mammalian peptide hormone (guanylin) and binds to the guanylin receptor. This results in elevation of cyclic AMP which, through a series of steps, leads to secretion of chloride.

EIEC: Biochemically, genetically, and pathogenetically closely related to Shigella species.

• EIEC invade colonic epithelial cells, lyse the phagosome, multiply intracellularly, and move through the cell via nucleating actin microfilaments, move laterally through the epithelium via direct cell-to-cell spread, or exit and re-enter the basolateral plasma membrane (see References: Kaper 2004).
• Bacteria induce a mostly watery diarrhea (occasionally bloody) via a pathogenic mechanism similar to that of Shigella and also induce apoptosis in infected macrophages (see References: Zychinsky 1992).
• Genes for the complicated pathogenic mechanism are present on a 213 kb virulence plasmid that is found in EIEC and Shigella, and includes a mosaic of genetic elements that code for a T3SS secretion system, a 120 kilodalton (kD) outer membrane protein (IcsA), and insertion elements (see References: Buchreiser 2000).
• Additional virulence factors include a plasmid-encoded serine protease (SepA), chromosomally encoded aerobactin iron-acquisition system and other secreted proteases encoded by genes located on pathogenicity islands of the chromosome (see References: Kaper 2004).

EAEC: Increasingly recognized as a cause of persistent diarrhea in children and adults in developing countries (see References: Russo 2006) and also play a role in chronic diarrhea among patients who are infected with HIV.

• EAEC organisms do not secrete LT or ST, and in testing, adhere to HEp-2 cells in an autoaggregative fashion ("stacked brick" configuration).
• Adhere to small and large bowel epithelial cell in a thick biofilm and express secretory enterotoxins and cytotoxins.
• Induce mild but significant mucosal damage (see References: Hicks 1996). This effect is more severe in the colon, and animal studies indicate that some EAEC strains may be capable of limited invasion of the mucosal surface (see References: Abe 2001).
• Toxins include Shigella enterotoxin 1 (ShET1) that may contribute to diarrhea and enteroaggregative E coli ST (EAST1), a 38-amino acid homolog of the ETEC STa toxin.
• Many strains secrete an autotransporter toxin (called PET) encoded by a large virulence plasmid that also contains the aggregative adherence fimbriae (AAF).
• A novel EAEC flagellin protein induces interleukin-8 (IL-8) release that stimulates neutrophil transmigration across the epithelium, a phenomenon that can itself lead to tissue disruption and fluid secretion.
• Although no single virulence factor has been unequivocally associated with EAEC virulence, epidemiologic studies implicate a group of plasmid and chromosomal virulence factors, similar to that of other enteric pathogens (see References: Kaper 2004, Russo 2006).

DAEC: Organisms elicit a characteristic diffuse aggregative pattern of adherence to HEp-2 cells.

• Strains induce a cytopathic signal transduction effect in the small bowel enterocytes that is characterized by the growth of long finger-like cellular projections that wrap around the adherent bacteria.

• About 75% of DAEC strains produce a fimbrial adhesin (designated F1845) or a related adhesin (see References: Kaper 2004).
• The adhesin mechanism requires the binding and clustering of the decay-accelerating factor (DAF) receptor by Dr fimbriae.
• Binding of Dr adhesins activates signal transduction cascades, and some evidence indicates the presence of other virulence factors.

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Epidemiology

A variety of different serotypes of E coli have been shown to cause diarrheal illness. The most common serotypes identified are shown in the table below.

<table class="table1" align="left" border="1" cellpadding="0" cellspacing="0"> <tbody><tr> <td colspan="5" class="tableheader1" valign="top"> Frequently Encountered Serotypes of Diarrheagenic E coli
</td> </tr> <tr> <td class="colhead" valign="top"> ETEC
</td> <td class="colhead" valign="top"> EPEC
</td> <td class="colhead" valign="top"> EIEC
</td> <td colspan="2" class="colhead" valign="top"> STEC
</td> </tr> <tr> <td class="tablecell" valign="top"> O6:NM*
O6:H16*
O15:H11*
O20:NM
O25:NM*
O25:H42
O27:NM*
O27:H7*
O27:H20*
O49:NM*
O63:H12*
O78:H11
O78:H12*
O128:H7*
O128:H28*
O153:H45*
O159:NM*
O159:H4
O159:H20*
O167:H5
O169:H41*
</td> <td class="tablecell" valign="top"> O55:NM*
O55:H7*
O55:H7
O86:NM
O86:H34
O111:NM*
O111:H2*
O111:H12
O111:H21
O114:NM*
O114:H2*
O119:H6*
O125:H21*
O126:NM
O126:H27
O127:NM*
O127:H6*
O127:H9
O127:H21
O128:H2*
O128:H12
O142:H6*
O157:H45*
</td> <td class="tablecell" valign="top"> O28:NM
O29:NM
O112:NM
O124:NM
O124:H7
O124:H30*
O136:NM
O143:NM*
O144:NM
O152:NM
O164:NM*
O167:NM
ONT:NM*
</td> <td class="tablecell" valign="top"> O1:NM
O2:H6
O2:H7
O5:NM
O9:NM
O14:NM
O22:H5
O26:NM
O26:H11*
O45:H2
O48:H21
O50:H7
O55:H7
O79:H7
O83:H1
O91:NM
O91:H10
O91:H21
O103:H2
O104:NM
O104:H21*
O111:NM*
O111:H2*
</td> <td class="tablecell" valign="top"> O111:H8*
O113:H21*
O118:H2*
O118:H12
O118:H16
O121:H19*
O128:NM
O128:H2
O128:H45
O137:H41
O145:NM*
O153:H2
O153:H25
O157:NM*
O157:H7*
O163:H19
O165:NM
O165:H25
O172:NM
Orough:H9
ONT:NM
</td> </tr> <tr> <td colspan="5" class="tablefooter" valign="top"> Abbreviations: NM, nonmotile; NT, nontypeable; Orough, O antigen rough and serotype not determined.
*Outbreak-associated serotype.
Adapted from Bopp 2003: Escherichia, Shigella, and Salmonella (see References).
</td> </tr> </tbody></table> United States

EHEC/STEC

• EHEC/STEC strains are the most frequently identified diarrheagenic E coli serotypes in North America and Europe (see References: Frenzen 2005).
• The EHEC/STEC pathotype was first recognized in 1982 in the United States following an outbreak of serotype E coli O157:H7, which was associated with consumption of undercooked hamburgers from a national fast-food restaurant chain (see References: Riley 1983).
• Since that time, numerous outbreaks of E coli O157:H7 have been recognized in the United States and it is still the most common STEC serotype in this country.
• CDC estimates that O157 STEC infections cause 73,000 illnesses annually, resulting in more than 2,000 hospitalizations and 60 deaths. The annual estimated cost of illness from O157 STEC was $404 million (in 2003 dollars), including $370 million for premature deaths, $30 million for medical care, and $5 million in lost productivity (see References: Frenzen 2005).
• Preliminary 2005 data from the Foodborne Diseases Active Surveillance Network (FoodNet) of CDC's Emerging Infections Program revealed 16,614 laboratory-confirmed cases of foodborne infections, and among these were 473 E coli O157 infections and 146 non-O157 STEC infections (see References: CDC 2006: Preliminary FoodNet data, 2005). The FoodNet system collects data from 10 sites across the country through active, population-based surveillance for laboratory-diagnosed illness. Although the system provides the best available estimate on the incidence of various enteric pathogens transmitted commonly through food, there are a number of limitations to the system and the data do not necessarily reflect the true incidence of infection (since many illnesses do not come to clinical detection and are not laboratory-confirmed). Given these caveats, the 2005 FoodNet data demonstrate the following findings.
  • The overall incidence per 100,000 population was 1.06 for E coli O157 (range among surveillance sites, 0.39-2.35) and 0.33 for non-O157 STEC (range, 0.03-0.80), but considerable variation existed in incidence among the different sites.
  • Among 145 non-O157 isolates that were tested for O antigens, 117 (81%) had an identifiable antigen (see References: CDC 2006: Preliminary FoodNet data, 2005):
    • O26: 37 (32%)
    • O103: 36 (31%)
    • O111: 23 (20%)
    • Nontypeable isolates made up the rest
  • Comparing estimated annual incidence figures from the period 1996-1998 to that of 2005 revealed that the incidences of several infections declined. E coli O157 incidence decreased significantly (29%; Confidence Interval [CI], 12%-42%). Most of this decline occurred during 2003 and 2004 (see References: CDC 2005: Preliminary FoodNet data, 2004).
  • This finding continues a trend seen in the 2004 data which show that the incidence declined below the 2010 national target of 1.0 case per 100,000 in the overall FoodNet dataset and in 7 of 10 surveillance sites (see References: CDC 2005: Preliminary FoodNet data, 2004).
  • Researchers attribute the decrease in incidence to the new regulatory testing program for E coli O157:H7 in raw ground beef (see References: Naugle 2005, Naugle 2006).
  • Similarly, the estimated incidence of postdiarrheal HUS in children 5 years old or younger decreased 45% in 2004 compared with 2000-2001, which supports a decrease in STEC incidence. The limited time span of observation, however, does not provide enough data to determine if this trend is significant (see References: CDC 2005: Preliminary FoodNet data, 2004).
• From 1998 to 2002, officials in 49 states reported 350 outbreaks representing 8,598 cases of E coli O157:H7, 1,493 hospitalizations (17%), 354 cases of HUS (4%), and 40 deaths (0.5%) (see References: Rangel 2005).
• Most cases of HUS are attributed to O157 STEC infection.

Other E coli Pathotypes

Other E coli pathotypes (ETEC, EPEC, EAEC, and DAEC) are infrequently identified in the United States. While lack of available laboratory testing may play a role, incidence of infection caused by these organisms appears to be low (see References: Clarke 2003, Russo 2006).

• Despite the overall low incidence, outbreaks of ETEC are being increasingly recognized in the United States. Between 1996 and 2003, 16 ETEC outbreaks were identified; three occurred on cruise ships and the rest occurred in the United States (see References: Beatty 2004).
• ETEC is a major cause of travelers' diarrhea worldwide and may be seen in travelers returning to the United States from developing countries.

Global

EHEC/STEC

Among developed countries outside the United States, STEC is the most common cause of E coli-associated diarrhea.. In Europe, E coli O157:H7 has been reported in the United Kingdom, Ireland, Belgium, Germany, and the Czech Republic, but non-O157 serotypes are isolated more often than O157 strains; O111:NM, O26:H11, O103:H2 are most commonly identified (see References: Beatty 2004, Bopp 2003: Escherichia, Shigella, and Salmonella, Ethelberg 2004, Lynn 2005).

STEC incidence varies depending on the country. Rates range from 1.4 per 100,000 population in Ireland to 2.6 per 100,000 in Australia. In Japan, the incidence was 2.74 per 100,000 population, a rate higher than that of the United States (1.06 per 100,000 population). The rates among different prefectures in Japan varied; in some urban areas incidence rates were about the same as (eg, Ibaraki 1.1/100,000) or lower than (eg, Niigata, 0.9/100,000) those in the United States. Factors implicated in Japanese areas with higher rates included higher percentage of elderly, higher number of people in households, and higher percentage of children (see References: Sakuma 2006).

Other E coli pathotypes

Acute infectious diarrhea is the second most common cause of death in children living in the developing countries, accounting for about 20% of the cases.

• ETEC is the most frequently isolated enteropathogen in community-based studies in the developing world of children 5 years old or younger (see References: Girard 2006).
• ETEC strains account for about 280 million diarrhea episodes and about 400,000 deaths annually (see References: Qadri 2005).
• ETEC also is a major cause of travelers' diarrhea (see References: Donnenberg 2005).
• EPEC was originally recognized in the 1940s as a cause of nosocomial diarrhea in infants. Today, these organisms are still a leading cause of severe diarrhea in infants and young children (<6 months of age) in the developing world (see References: Donnenberg 2005). A recent report found that atypical EPEC strains appear to be a cause of prolonged diarrhea in children in Australia (see References: Nguyen 2006).
• EIEC is less common than ETEC or EPEC in the developing world and is associated with only a few characteristic serotypes (see References: Nataro 1998).
• EAEC strains were first recognized in 1987 and are most often associated with illness in developing countries. EAEC strains have been shown to cause acute and chronic diarrhea the developing world (mostly in young children) and chronic diarrhea in HIV-infected persons (see References: Donnenberg 2005). Asymptomatic infection can cause subclinical inflammatory enteritis and growth disturbances (see References: AAP 2003).
• DAEC infections have not been well studied but have been recognized as a cause of diarrhea in the developing world, particularly among children.

Reservoirs

EHEC/STEC: The principal reservoir is the intestinal tract of cattle and other large herbivorous animals, but other animals also may serve as reservoirs. Free-living bird populations such as Canada geese have been found to harbor E coli strains, some of which are resistance to antibiotics and are believed to be responsible for water contamination (see References: Cole 2006).

Bacteria can survive for long periods in the environment, even at very low pH and can proliferate in vegetables and other foods. Manure from cattle or other animals that is used as fertilizer can contaminate produce (eg, potatoes, lettuce, sprouts, fallen apples) and water (see References: AAP 2003).

• A wide variety of food items have been associated with the disease:
  • Undercooked ground beef
  • Roast beef, sausages
  • Unpasteurized milk
  • Unchlorinated water
  • Lettuce (see References: Hilborn 1999)
  • Spinach (see References: CDC 2006: Advice to consumers; CDC 2005: Escherichia coli O157:H7)
  • Cantaloupe
  • Unpasteruized apple juice
  • Cheese
  • Mushrooms
  • Sprouts (alfalfa and radish) (see References: Samadpour 2006)

EPEC: People

ETEC: Contaminated food or water (primarily a disease arising from failure of sanitation)

EIEC: Contaminated food, possibly people

EAEC: Contaminated food, people

DAEC: Contaminated food, people, modes of transmission

• Transmission of most diarrheagenic E coli strains occurs from consumption of food or water contaminated with human or animal feces (see References: CDC 2005: Preliminary FoodNet data, 2004, Kaper 2004, Kassenborg 2004). For some pathotypes, fewer than1,000 colony forming units can cause disease; therefore, person-to-person transmission from infected symptomatic people or asymptomatic carriers can be an important mechanism for secondary spread (see References: Belongia 1993, Russo 2006).

EHEC/STEC: Major modes of transmission include consumption of contaminated foods (especially undercooked ground beef), exposure to contaminated recreational or drinking water, or contact with farm and petting zoo animals (see References: CDC 2002, CDC 2005: Compendium of measures; CDC 2006: Preliminary FoodNet data, 2005, Cho 2006, Frenzen 2005, Kassenborg 2004).

• Among 350 outbreaks of E coli O157:H7 reported in the United States from 1982-2002, the major identified transmission routes were (see References: Rangel 2005):
  • Foodborne: 183 outbreaks (52%)
  • Unknown: 74 outbreaks (21%)
  • Person-to-person: 31 outbreaks (9%)
  • Animal contact (farms, county fairs, petting zoos): 11 outbreaks (3%)
  • Laboratory-related: 1 outbreak involving two cases (0.3%)
• Person-to-person transmission most often occurs in schools, long-term care institutions, families, and day-care centers (see References: Belongia 1993, Bopp 2003: Detection, isolation).
• A recent report suggested that E coli O157:H7 contaminated surfaces in a building via dispersion through the air (perhaps through stirring up contaminated sawdust from the floor). Individuals who then touched contaminated surfaces became infected when they subsequently ate or drank without adequately washing their hands. This led to an outbreak associated with exposure to the building (see References: Varma 2003).

EPEC: The major mode of transmission is person-to-person contact.

• Although outbreaks among infants in industrialized countries have largely disappeared, atypical EPEC have caused large outbreaks of diarrheal disease among children and adults in industrialized countries (see References: Nguyen 2006).
• Nosocomial outbreaks have been reported and have been associated with person-to-person transmission as well as transmission via fomites and contaminated formula or weaning foods (see References: Nataro 1998).

ETEC: Transmission is primarily via consumption of fecally contaminated food or water (see References: Qadri 2005).

EIEC: Several foodborne outbreaks have been identified, including in the United States (see References: Gordillo 1992). Person-to-person spread also can occur.

• EAEC: Several nosocomial outbreaks have been identified but the mechanisms of transmission were not clear. Foodborne transmission has been suggested (see References: Nataro 1998).

DAEC: Modes of transmission have not been clarified. Risk factors for infection include:

• Consumption of contaminated food, especially undercooked ground beef, but increasingly contaminated produce (see References: Frenzen 2005, Kassenborg 2004)
• Drinking or swimming in contaminated water (see References: BGOSHU 2000)
• Contact with livestock and other animals (see References: CDC 2005: Compendium of measures; Cho 2006; Keen 2006)
• Travel to developing countries
• Immunocompromised status
• Age: Young children less than age 5 and the elderly are more likely to have serious complications.

Examples of Key Foodborne/Waterborne Outbreaks

Large outbreaks of EHEC/STEC from contaminated beef and other food products have occurred in the United States and other countries and have served as the impetus for implementation of food-monitoring techniques. Examples of outbreaks include the following

• Japan, 1996: More than 6,300 cases of E coli O157:H7 occurred among schoolchildren in 1996 who ate sprouts contaminated at four large growers (see References: Besser 2003, Watanabe 1999).
• United States, 1992-1993: A total of 501 cases, including 151 hospitalizations were caused by ground beef contaminated with E coli O157:H7. Hamburgers from a fast food chain caused the outbreak that lasted from December 1992 through Feb 1993 (see References: Bell 1994).
• Colorado, 2002: Contaminated ground beef was linked to 28 E coli O157:H7 infections in Colorado and six other states. The manufacturer recalled 18.6 million lbs of ground beef products that was produced at the processing plant identified as the source (see References: CDC 2002). An earlier outbreak of E coli O157:H7 infections in Colorado had been associated with commercially prepared hamburger patties (see References: CDC 1997).
• New York, 1999: E coli O157:H7 was cultured from 128 of 775 patients with suspected infections in upstate New York. Patients had attended a county fair in August 1999. Epidemiologic analysis identified a contaminated water distribution system as the possible source and laboratory testing supported this finding (see References: Bopp 2003).
• Canada, 2000: A large outbreak of E coli O157:H7occurred in Walkerton, Ontario, Canada, in 2000 with 1,436 cases, 27 cases of HUS, and 6 deaths. The source was found to be contaminated ground water (see References: BGOSHU 2000, Clark 2003). The overall estimated number of cases associated with the outbreak was more than 2,300 (see References: McQuigge 2000).
• Alpine, Wyoming, 1998: E coli O157:H7 was responsible for illness affecting 157 persons. The organism was traced to an unchlorinated water system (see References: Olsen 2002).
• North Carolina, 2005: A total of 108 patients were affected, 82 of whom reported visiting a petting zoo at the North Carolina state fair. Of 41 laboratory-confirmed cases of STEC, 38 yielded E coli O157:H7 isolates that were indistinguishable by pulsed-field gel electrophoresis (PFGE) (see References: CDC 2005).
• Florida, 2005: A cluster of 22 E coli O157:H7 infections, including seven cases of HUS, were related to attendance at Florida Fairs and Festivals during Feb 10-21, 2005, and Mar 3-13, 2005. Investigators found no common food or water exposures, but cases had common animal exposures (through a petting zoo). Subsequent surveillance identified 63 patients who had symptoms of E coli O157:H7 infection within 10 days or HUS within 21 days after visiting the implicated fairs. Seventeen patients were hospitalized (see References: CDC 2005).
• United States, 2006: Well over 150 people in more than 20 states have been infected with E coli O157:H7 in an ongoing outbreak. Nearly 30 cases of HUS with one fatality have occurred (see References: CDC: Update on multi-state outbreak of E. coli O157:H7 infections from fresh spinach). The cases have been traced to raw spinach, and farms in three counties in California are being investigated as the possible source. On Sep 14, the FDA issued a warning for consumers to avoid eating bagged fresh spinach, and on the 17th the agency expanded the warning to include all raw, fresh spinach. The California food company that has been named as a possible source, Natural Selections Foods, has recalled more than 30 brands of bagged spinach (see References: FDA 2006).

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Clinical Features

<table class="table1" align="left" border="0" cellpadding="0" cellspacing="0"> <tbody><tr> <td colspan="4" class="tableheader1" valign="top"> Clinical and Diagnostic Features of Diarrheagenic E coli Infections
</td> </tr> <tr> <td class="colhead" valign="top"> Organism
</td> <td class="colhead" valign="top"> Incubation Period
</td> <td class="colhead" valign="top"> Clinical Features
</td> <td class="colhead" valign="top"> Diagnostic Features
</td> </tr> <tr> <td class="tablecell" valign="top"> EHEC/STEC (O157:H7 and other serotypes)
</td> <td class="tablecell" valign="top"> 1-8 days
</td> <td class="tablecell" valign="top"> ?Diarrhea is often grossly bloody, but diarrhea without blood may occur
?Abdominal pain and vomiting may occur
?Fever is usually absent
?About 8% develop HUS (more common in children)
?Thrombocytopenic purpura (TTP);(more common in adults) may also occur
</td> <td class="tablecell" valign="top"> ?Stool culture requires special media
?Testing of stool must be requested
</td> </tr> <tr> <td class="tablecell" valign="top"> ETEC
</td> <td class="tablecell" valign="top"> 1-3 days
</td> <td class="tablecell" valign="top"> ?Watery diarrhea
?Diarrhea lasts 3-7 days, but can be protracted (months with relapses)
?Stool does not contain leukocytes, mucus, or blood
?Fever usually absent
?Abdominal cramps, sometimes with nausea and headache
</td> <td class="tablecell" valign="top"> ?Detection of toxin-producing E coli in stool
?Requires special techniques that must be requested (most laboratories do not perform testing)
?Testing performed by reference or research laboratories
</td> </tr> <tr> <td class="tablecell" valign="top"> EPEC
</td> <td class="tablecell" valign="top"> Variable
</td> <td class="tablecell" valign="top"> ?Severe acute diarrhea
?Low grade fever
?Vomiting
?May be persistent and protracted, resulting in weight loss, malnutrition, and death
</td> <td class="tablecell" valign="top"> ?Detection of organism by PCR or DNA probes for bfp or eae genes or tissue culture assay for local adherence (typical strains only)
?Testing performed by reference or research laboratories
</td> </tr> <tr> <td class="tablecell" valign="top"> EIEC
</td> <td class="tablecell" valign="top"> Variable
</td> <td class="tablecell" valign="top"> ?Usually presents as watery diarrhea?Dysentery with bloody diarrhea occurs in <10% of patients
?Fever
?Abdominal cramps
? Illness is similar to Shigella infection

</td> <td class="tablecell" valign="top"> ?Isolation of same serotype from stool of 2 or more ill persons
?PCR or DNA probes for inv genes
?Testing performed by reference or research laboratories
</td> </tr> <tr> <td class="tablecell" valign="top"> EAEC
</td> <td class="tablecell" valign="top"> Variable
</td> <td class="tablecell" valign="top"> ?An emerging infection
?Limited clinical descriptions, but may be associated with intestinal colic, bloody stool, and mucus
?Correlated with interleukin-8 production
?Associated with chronic diarrhea in developed countries and acute diarrhea in developing countries
</td> <td class="tablecell" valign="top"> ?Diagnosis is difficult
?Confirmation is by tissue culture adhesion assays (performed in reference laboratories)
?DNA and PCR tests lack sufficient sensitivity and specificity
</td> </tr> <tr> <td class="tablecell" valign="top"> DAEC
</td> <td class="tablecell" valign="top"> Variable
</td> <td class="tablecell" valign="top"> Poorly described
</td> <td class="tablecell" valign="top"> ?Tissue culture assay for diffuse adherence
?Testing performed by reference or research laboratories
</td> </tr> <tr> <td colspan="4" class="tablefooter" valign="top"> Abbreviations: HUS, hemolytic uremic syndrome; PCR, polymerase chain reaction.
Adapted from CDC: Guide to confirming a diagnosis in foodborne disease; CDC 2003, CDC: Diagnosis and management of foodborne illnesses; CDC 2004, Donnenberg 2005 (see References).
</td> </tr> </tbody></table>

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Differential Diagnosis

Infections to consider in the differential diagnosis of STEC/EHEC (main symptom bloody diarrhea):

• Campylobacter species
• Entamoeba histolytica
• Salmonella
• Shigella species
• Yersinia enterocolitica

Infections to consider in the differential diagnosis of ETEC and other types of E coli (main symptom watery diarrhea) (see References: CDC 2003: Guide to confirming a diagnosis; CDC 2004: Diagnosis and management of foodborne illnesses):

• Campylobacter species
• Clostridium perfringens
• Cryptosporidium parvum
• Cyclospora cayetanensis
• Giardia lamblia
• Isospora belli
• Plesiomonas shigelloides
• Salmonella
• Shigella species
• Vibrio cholerae
• Vibrio parahemolyticus
• Yersinia enterocolitica

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Laboratory Diagnosis

E coli is diagnosed by typing the serotype from stool samples, enzyme immunoassay, or by other methods (eg, polymerase chain reaction [PCR], see References: Lopez-Saucedo 2003).

Specimen Collection

• Stool submitted for culture of bacterial enteric pathogens should also be examined forSTEC (see References: Besser 2003, Bopp 2003).
• Stool samples (10 mL of liquid or 1 marble-sized whole stool) should be collected into a sterile, leak-proof, wide-mouth container.
• Rectal swabs are used for patients for whom obtaining stool samples is difficult (eg, infants, patients who cannot defecate) and during outbreaks when specimens are collected from many patients. Swabs should be placed in an appropriate transport media (eg, Cary-Blair, Stuart, buffered glycerol-saline) and placed in tubes containing medium sufficient to cover the cotton tips (see References: CDC 2003: Guide to specimen collection;Thompson 2003).

Transport

• Samples should be refrigerated at 4?C if testing is to be done within 48 hours, otherwise samples should be frozen at ?70?C.
• Whole stool should be refrigerated and processed within 2 hours of collection.
• A portion of each stool sample should be stored frozen below -15? C for antigen or PCR testing if needed (see References: Besser 2003;CDC 2003: Guide to specimen collection).

Diagnostic Testing

Diagnosis of diarrheagenic E coli is difficult for most clinical laboratories, because of the difficulty in differentiating illness-causing organisms from the usual E coli strains present in stool (see References: AAP 2003, Voetsch 2004).

STEC/EHEC

• Because E coli O157:H7 does not ferment sorbitol, plating stool on sorbitol-MacConkey agar can be used as a screening tool. Any odorless, nonfermenting colonies can then be tested with O157 antiserum or latex reagent to identify the pathogen (see References: Bopp 2003).
• Biochemical identification of STEC O157 isolates is needed because other species may cross react with O157 antiserum or latex reagents.
• Commercially available H7 antisera can be used to identify O157:H7
• Since an increasing proportion of STEC infections are not being caused by E coli O157, an alternative approach is to screen for Shiga toxin in the stool using an enzyme immunoassay (EIA). If the stool is positive for Shiga toxin, then the laboratory can go back and attempt to identify the serotype. This method allows identification of non-O157 STEC infections that may be missed by routine screening on sorbitol-MacConkey media.
• Nearly all O157 STEC and 60% to 80% of nonO157 STEC produce a characteristic E coli hemolysin, enterohemolysin. Washed sheep blood agar supplemented with calcium is used as a differential medium for the detection of enterohemolysin.
• Enterohemolysin-producing colonies can be differentiated from alpha hemolysin colonies of other E coli strains because alpha hemolysin colonies are visible after 3 to 4 hr of incubation.
• Pulsed-field gel electrophoresis (PFGE) can be used to identify specific strains and to compare isolates. This can be useful for determining outbreak-related infections (see References: Bender 1997).
• Isolation and serotyping non-O157 STEC from fecal specimens that are positive by EIA should be attempted when feasible because identifying the serotype can be used to detect outbreaks and to monitor trends in STEC infections nationwide

ETEC, EPEC, EIEC, and EAEC

These pathotypes are identified by detection of their respective virulence-associated factors (toxins, adherence, or invasiveness). Techniques for testing include bioassays (eg, cell culture), immunologic assays (eg, immunoblotting or EIA), and DNA assays (eg, PCR, colony blots).

• Methods for identification of ETEC, EPEC, EIEC, and EAEC generally are available only in reference laboratories or research settings.
• Most methods involve screening of isolated colonies, or in the case of PCR, a sweep of confluent growth from a MacConkey plate. In contrast to O157 STEC, about 80% of other E coli strains ferment sorbitol rapidly.
• Fecal specimens should be plated on a differential medium of low selectivity (eg, MacConkey) and 15 to 20 colonies of both lactose fermenting and nonfermenting colonies should be inoculated onto an agar slant and subsequently screened for virulence factors.
• Cefixime-tellurite sorbitol MacConkey agar is mostly used for culture of animal and food specimens because of its specificity, but it can also be used for culture of human specimens.
• Many EIEC strains are nonmotile and fail to decarboxylate lysine, although some are motile or lysine positive.

Material adapted from Bopp 2003 and Thompson 2003 (see References).

Serologic Testing

• Serologic classification of E coli is usually based on somatic (O) and flagellar (H) antigens. Although more than 175 O antigens and 53 H antigens are currently recognized, the number of serotype combinations responsible for diarrheal disease is small (see Epidemiology above).
• Commercial antisera for tube agglutination tests are available, but testing is not usually performed routinely. Serotyping and virulence testing for well characterized outbreaks are usually done through arrangement with state health departments and the CDC.

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Antimicrobial Susceptibility

Antimicrobial resistance in E coli has been reported in the United States (see References: Hannah 2005, Manges 2001, Roe 2003) and worldwide (see References: Bartoloni 2006, Branger 2005, Estrada-Garcia 2005, Kuntaman 2005, Oteo 2005), but pathogen occurrence and susceptibility profiles vary region to region (see References: von Baum 2005).

United States

Recent examples of resistant E coli carriage or infections in the United States include:

• Stool carriage of fluoroquinolone-resistant E coli was detected among residents in a long-term care facility in Philadelphia (see References: Maslow 2005). On multivariable analysis, only prior fluoroquinolone use was identified as an independent risk factor for fluoroquinolone-resistant E coli colonization: however, person-to-person clonal spread of fluoroquinolone-resistant E coli was common and occurred in the absence of fluoroquinolone exposure.
• Stool carriage of drug-resistant E coli also was identified among a sample of household residents in rural Idaho (see References: Hannah 2005). Most carriers of drug-resistant E coli lacked conventional risk factors. Resistance was clustered in households and consistent with either spread of organisms between persons in close contact or common source acquisition (eg, shared contaminated food). Prevalence of intestinal carriage of E coli resistant to nalidixic acid was 3%, to trimethoprim-sulfamethoxazole was 11%, and to extended spectrum cephalosporins was 1%. Nalidixic acid resistance was associated with recent use of antimicrobials in the household.
• Cephalosporin-resistant E coli was detected among more than 100 campers affected by gastroenteritis at a summer camp (see References: Prats 2003). Nine of the 22 symptomatic campers had cephalosporin-resistant E coli and related resistant E coli were detected in two asymptomatic food handlers. The mode of dissemination suggested food or water as the vehicle.

Global

• In developing countries resistance levels are usually high for broad-spectrum penicillins and trimethoprim and low for third-generation cephalosporins and nitrofurantoin (see References: von Baum 2005).
• The emerging resistance to fluoroquinolones (see References: Kuntaman 2005) and the production of extended-spectrum beta-lactamases by multidrug resistant E coli strains (see References: Oteo 2005) has prompted much concern in the developing world, and has implications for developed nations (see References: Paton 2006)
• Although antibiotics can be useful when used appropriately, multidrug resistance among hospitalized patients and healthy children underscore the need for judicious use of antibiotics.
• A study of Latin American children revealed that among 430 children younger than age 5 hospitalized for diarrhea in Mexico, 62 had diarrheagenic E coli and 73% (45) had strains that were resistant to common antimicrobial drugs (62% multidrug resistant; >70% resistant to trimethoprim-sulfamethoxazole and ampicilin) (see References: Estrada-Garcia 2005).
• In a study of 3,174 healthy children in Bolivia and Peru, examination of fecal carriage of drug-resistant E coli was high. Resistance rates were as follows: for ampicilin, 95%; trimethoprim-sulfamethoxazole, 94%; tetracycline, 93%; streptomycin, 82%; and chloramphenical, 70%. Lower resistance rates were observed for nalidixic acid (35%), kanamycin (28%), gentamicin (21%), and ciprofloxacin (18%) (see References: Bartoloni 2006).

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Treatment

• Treatment is usually supportive; antibiotics are not usually required (see References: CDC 2004: Diagnosis and management of foodborne illnesses; Russo 2006).
• Patients who are dehydrated should receive oral administration of solutions with electrolytes (see References: AAP 2003).
• Children who have inflammatory or bloody diarrhea should not be given antimotility agents.
• Patients who have no laboratory evidence of hemolysis, thrombocytopenia, or nephropathy 3 days after diarrhea resolves have a low risk of HUS.
• Those who have hemorrhagic colitis should have careful follow-up (complete blood cell count with smear, blood urea nitrogen concentration and creatinine levels) to detect changes that suggest HUS.

Antibiotic Therapy

• Some studies have suggested that children who have hemorrhagic colitis from STEC are at greater risk of HUS if they are treated with antibiotics (see References: Wong 2000). For this reason, most clinicians do not recommend antibiotics for treatment of STEC infections.
• Persons with travelers' diarrhea who develop three or more loose stools in an 8-hour period (especially if associated with nausea, vomiting, abdominal cramps, fever, or blood in stools) may benefit from antimicrobial therapy (see References: CDC 2005: Travelers' diarrhea).

• • Antibiotics usually are given for 3-5 days.
  • Currently, fluoroquinolones are the drugs of choice. Commonly prescribed regimens are 500 mg of ciprofloxacin twice a day or 400 mg of norfloxacin twice a day for 3-5 days.
  • Trimethoprim-sulfamethoxazole and doxycycline are no longer recommended because of the high level of resistance to these agents.
  • Bismuth subsalicylate also may be used as treatment: 1 fluid ounce or two 262 mg tablets every 30 minutes for up to eight doses in a 24-hour period, which can be repeated on a second day.

• Patients suspected of having systemic infection should receive parenteral antimicrobial therapy (see References: AAP 2003).
• CDC does not recommend antimicrobial drugs to prevent travelers' diarrhea because routine antimicrobial prophylaxis increases the traveler's risk for adverse reactions and for infections with resistant organisms.

• • Bismuth subsalicylate (taken as either two tablets four times daily or two fluid ounces four times daily) appears to reduce the incidence of travelers' diarrhea.
  • Use of bismuth subsalicylate should be avoided by persons who are allergic to aspirin, during pregnancy, and by persons taking certain other medications (eg, anticoagulants, probenecid, or methotrexate). In addition, persons should be informed about potential side effects, in particular about temporary blackening of the tongue and stool, and rarely ringing in the ears. Because of potential adverse side effects, prophylactic bismuth subsalicylate should not be used for more than 3 weeks.

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Vaccines

• No vaccines have been approved, but some vaccine candidates have advanced to clinical trials and other experimental treatments are being developed.
• An E coli O157:H7 vaccine produced at the National Institutes of Health has been tested in a phase 2 clinical trial (see References: Ahmed 2006).
  • The vaccine tested consisted of an E coli O157:H7 O-specific polysaccharide covalently linked to recombinant exoprotein A of Pseudomonas aeruginosa.
  • The trial demonstrated that children who received 1 or 2 doses had increased titers of serum IgG LPS antibodies.
  • Patients had a greater than 4-fold increase in serum IgG LPS antibodies after 1 week and an 8-fold increase at 6 weeks.
  • A second dose did not elicit a booster response.
  • At 26 weeks after the first dose, the geometric mean titer of the serum IgG LPS antibodies was about 20-fold higher than the prevaccination titer.
  • Serum samples had high titers of bactericidal activity that correlated roughly with serum IgG LPS antibody titers.
  • Patients had no serious adverse reactions after either dose.
  • A phase 3 trial concurrent with routine infant immunization is planned.
• Human serum amyloid P component has been shown to protect against E coli O157:H7 Shiga toxin 2 in a mouse model. Mice that received 50 mg/kg doses of human SAP twice a day were completely protected against twice the LD50 of Shiga toxin 2. Administration of exogenous SAP to patients who have EHEC and HUS may offer potential benefit, but efficacy in humans must be tested in clinical trials (see References: Armstrong 2006).

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Travel Implications

Diarrhea from STEC is rare in travelers, but ETEC is a major cause of travelers' diarrhea worldwide and other E coli pathotypes (EAEC, EIEC) also have been shown to cause diarrhea in travelers. These infections are usually acquired by ingesting contaminated food or water (see References: AAP 2003). Travelers to developing countries should consider the following precautions (see References: CDC 2005: Travelers' diarrhea):

• Eat only thoroughly cooked foods prepared in facilities that practice safe food handling techniques.
• Consume pasteurized milk and milk products.
• Drink bottled beverages or beverages made with water that has been boiled 5 minutes or local municipal water that has been adequately treated with chlorine or other appropriate disinfectant.
• Avoid eating raw or undercooked meat and seafood.
• Avoid eating raw fruits (eg, oranges, bananas, avocados) and vegetables unless the traveler peels them.
• Avoid eating foods or drinking beverages purchased from street vendors or other establishments where unhygienic conditions are present.
• Avoid drinking water (including ice in beverages) from sources where there is any question about the quality of the water supply, including tap water. Safe beverages include bottled carbonated beverages, hot tea or coffee, beer, wine, and water boiled or appropriately treated with iodine or chlorine.
• To reduce the spread of infection, ensure that infected persons especially children, wash their hands carefully and frequently with soap and do not prepare or handle food items.

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Infection Control Recommendations

• Patients with E coli infections should be managed with Standard Precautions (see References: CDC/HICPAC 1996).
• According to CDC and the Hospital Infection Control Practices Advisory Committee (HICPAC), Contact Precautions should be added when caring for diapered or incontinent children younger than age 6 for the duration of illness (see References: CDC/HICPAC 1996):
  • Place the patient in a private room or if a private room is not available, place in a room with a patient who has an active infection with the same pathogen. When a patient is not available and cohorting is not possible, at least 3 feet of spatial separation should be maintained between the infected patient and other patients and visitors.
  • Gloves should be worn when entering the room and removed before leaving the room; hands should be washed with an antimicrobial agent or waterless handwashing agent immediately after removing gloves, and clean hands should not touch potentially contaminated items or environmental surfaces.
  • Gowns should be worn when entering the room if clothing will have substantial contact with the patient, environmental surfaces, or items in the room; the gown should be removed before leaving the patient's environment.
  • Patient transport should be limited to essential purposes only; if the patient is transported out of the room, precautions should be maintained.
  • Noncritical patient-care equipment should be dedicated whenever possible. If equipment cannot be dedicated, then it should be adequately cleaned and disinfected between uses.
• According to the American Academy of Pediatrics (AAP), Contact Precautions are indicated for all patients with E coli diarrhea for the duration of illness (see References: AAP 2003). AAP also recommends the following:
  • For patients who have HUS or hemorrhagic colitis attributable to STEC, Contact Precautions should be continued until diarrhea resolves and the results of 2 consecutive stool cultures are negative for E coli O157:H7.
  • During outbreaks of EPEC, Contact Precautions for infants with EPEC diarrhea should be maintained until cultures of stool taken after cessation of antimicrobial therapy are negative for the infecting strain.

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Public Health Measures

Control of foodborne E coli in the United States has been addressed by implementing barriers to contamination of food sources as outlined below in the section, Information for Businesses. In addition, public health agencies have advocated education of consumers and food service establishments to assure adequate cooking of hamburger and avoidance of cross-contamination in the kitchen (see section below: Information for Consumers). Finally, public health agencies at the state and local levels conduct surveillance for E coli O157:H7 to enhance early detection of outbreaks. Several national surveillance systems monitor trends in disease occurrence to identify new information about the epidemiology of this pathogen (see References:CDC:Escherichia coli O157:H7: surveillance).

Physicians should maintain a high index of suspicion for diarrheal illness:

• Order the appropriate laboratory tests if indicated.
• Report positive culture results to local public health officials.

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Information For Businesses

Hundreds of strains of the bacterium E coli exist in the intestines of healthy humans and animals, but E coli O157:H7 is the strain often associated with foodborne illness in the United States. Most of the infections have come from eating undercooked ground beef. Consequently, the US government has taken steps to address this problem (see References: Becker 2005).

Ground Beef

• The Food Safety and Inspection Service (FSIS) of the US Department of Agriculture (USDA) implemented a testing program for E coli 0157:H7 in 1994, and revised it in 2002 and 2004. The FSIS revisions (see References: FSIS 2004: Microbiological testing program; FSIS 2004: Microbiological testing program, revision 1) required manufacturers of raw ground beef products to reassess their HACCP (hazard analysis and critical control point) plans to incorporate new scientific data about epidemiology of the pathogen in cattle and subsequent contamination of beef carcasses (see References: FSIS 2004: Microbiological testing program).
• Pathogen-specific performance standards for raw products allow direct measures of progress in controlling and reducing pathogens (see References: FSIS 2001, FSIS 2002).
• FSIS has prepared several guidance documents to help industry reduce the occurrence of E coli O157:H7 (see References: FSIS 2005: Fact Sheets), and HACCP plans for plants and managers have also been published in the US (see References: CFSAN 2006: A manual for voluntary use, CFSAN 2006: A regulator's manual) and Europe (see References: Van Schothorst 2004).
• The US testing program and the revisions appear to have contributed to the documented reduction in E coli O157:H7 in raw ground beef samples (see References: CDC 2006: Preliminary FoodNet data, 2005, Naugle 2006,) and for voluntary recalls of contaminated meat, such as the recent recall of 156,235 pounds of ground beef products on May 5, 2006 (see References: FSIS 2006: Oklahoma firm recall).
• In the period from 1996 to 2004, the incidence of E coli infections has been reduced by 42%, a level that has reached the national goal in the Healthy People 2010 report (see References: FSIS 2005: Foodborne illnesses decline).

Produce

In 2004, the Food and Drug Administration's Center for Food Safety and Nutrition (CFSAN), in cooperation with CDC and USDA, implemented an action plan designed to target microbial food safety hazards in or on produce consumed in the US (domestic or foreign produce products) (see References: CFSAN 2004).

• Prevent contamination of fresh produce with pathogens
• Minimize the public health impact when contamination of fresh produce occurs.
• Improve communication with producers, packers, processors, transporters, distributors, preparers, consumers, and other governmental entities about fresh produce.
• Facilitate and support research relevant to the contamination of fresh produce.

The FDA has developed the Lettuce Safety Initiative as a response to the recurring outbreaks of E coli O157:H7 associated with fresh and fresh-cut lettuce. The initiative is intended to reduce public health risks by focusing on the product, agents, and areas of greatest concern (see References: CFSAN 2006: Lettuce safety initiative).

New treatment methods may impact produce contamination, but will require federal regulatory approval before methodology can be implemented by companies. Recent research shows that treating alfalfa seeds for 3 minutes with a fatty acid-based sanitizer can reduce levels of E coli O157:H7, Salmonella typhimurium, and Listeria monocytogenes by 5 to 7 log and may provide a viable alternative to the recommended 20,000 ppm of chlorine normally employed for sanitization. The solution contains naturally occurring fatty acids that disrupt bacterial respiration and do not reduce the sprout germination rate (see References: Pierre 2006).

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Information for Consumers

Consumption of undercooked hamburger (ground beef) is the single most common cause of human illness in the United States from E coli O157:H7 (see References: CFSAN 2004), although other products, such as unpasteurized milk or juice and contaminated produce (spinach and lettuce) have been responsible for large outbreaks (See Examples of Key Foodborne/Waterborne Outbreaks).

Because E coli strains are widely distributed in the environment, consumers should also take care when engaging in other activities, such as working with farm animals, petting domestic animals, and handling sick pets.

Basic Food Safety Measures

• Safe food storage, handling, and cooking methods are important for preventing E coli infections. Consumers should maintain proper sanitation measures and also avoid cross contaminating food by following appropriate procedures in the kitchen to prevent foodborne illnesses (see References: FSIS 2002; PFSE 2006: Fight Bac!; PFSE 2006: Safe food handling).
• Basic food safety suggestions include :
  • Clean: Wash hands often
  • Separate: Don?t cross contaminate. Separate raw, cooked, and ready to eat foods while shopping, preparing, or storing. Never place cooked food on a plate that previously held raw meat, poultry, or seafood.
  • Cook: Cook food to proper temperature. Use a food thermometer to be sure (see References: FSIS 2006: Is it done yet?; FSIS 2006: Thermy).
  • Chill: Refrigerate promptly. Refrigerate or freeze perishables, prepared foods, and leftovers within 2 hours. Never store uncooked foods on the shelf above prepared foods because the juice may drip into and contaminate the cooked food.
• Additional measures for safe food handling and food safety for consumers are available from US government sources and from the World Health Organization (see References: PFSE 2006: Safe food handling, WHO 2006). Additional measures for food safety after natural disasters have also been prepared (see References: WHO 2004, WHO 2005).

Beef Product Safety Measures

• Fact sheets are available and provide information about beef, including storing, handling, preparing, and cooking beef and beef products (see References: FSIS 2005: Escherichia coli; FSIS 2006: Is it done yet?; FSIS 2003: Meat preparation). Important points to remember:
  • Cook hamburgers and ground beef to 160? F as measured by a meat thermometer.
  • Cooked ground beef should have no pink color, and the juices should run clear.
  • Whole muscle meats such as steaks and roasts may be cooked to 145? F (medium rare), 160? F (medium), or 170? F (well done).
  • Cooking charts are also available for different types of meat (see References: FSIS 2003: Meat preparation).

Produce Safety Measures

The CDC recommends that consumers wash fruits and vegetables thoroughly, especially those that will not be cooked (see References: CDC 2005: Escherichia coli O157:H7). Important points include:

• Bagged salad greens should be washed; however, washing cannot remove all bacteria from produce contaminated before bagging.
• Some products should be avoided by consumers at risk: Children less than age 5 years, immunocompromised persons, and the elderly should avoid eating alfalfa sprouts until their safety can be assured. Decontamination methods for alfalfa seeds and sprouts are currently being investigated (see References: CDC 2005: Escherichia coli O157:H7).
• Consumers should not drink unpasteurized juice or milk.
• Safety measures for fruits and vegetables are available in food safety procedures (see References: PFSE 2006: Fight Bac!. PFSE 2006: Safe food handling).

In light of the ongoing E coli O157:H7 outbreak from spinach, CDC recommends the following:

• Consumers should not eat any fresh spinach or salad blends containing fresh spinach that will be consumed raw.
• E coli O157:H7 in spinach can be killed by cooking at 160?F for 15 seconds (Water boils at 212?F). If spinach is cooked in a frying pan and all parts do not reach 160?F, then all bacteria may not be killed. If consumers choose to cook the spinach, they should not allow raw spinach to contaminate other foods and food contact surfaces, and they should wash hands, utensils, and surfaces with hot, soapy water before and after handling the spinach.
• Persons who experience diarrhea after consuming fresh spinach or salad blends containing fresh spinach are urged to visit their health care provider and ask that their stool specimen be tested for E coli O157:H7.
• Persons who ate fresh spinach or salad blends and feel well do not need to see a health care provider. (see References: CDC 2006: Advice for consumers).

Animal Contact

Contact with animals can present a risk for E coli infection, and CDC also has issued recommendations to prevent disease associated with animals in public settings, such as petting zoos (see References: CDC 2005: Compendium of measures). The importance of washing hands thoroughly after handling or petting animals cannot be overemphasized.

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Information for Food Service Establishments

The FDA's report (see References: FDA 2000) on foodborne illness in selected retail establishments suggested that these businesses establish active managerial control of foodborne risk factors. Steps include:

• Develop and implement written standard operating procedures (SOPs) that address foodborne illness risk factors.
• Provide the necessary resources, equipment, and supplies to implement SOPs.
• Assess SOPs to ensure control over all risk factors.
• Establish monitoring procedures that focus on critical processes and practices.
• Identify methods to routinely assess the effectiveness of the SOPs.

A subsequent FDA report (see References: FDA 2004) on risk factors for foodborne illness noted that although improvement occurred in some areas, institutional food service, restaurants, and retail food store facilities still remained out of compliance for some areas:

• Improper hold/time and temperature (improper cold holding of potentially hazardous foods and inadequate date marking of refrigerated ready-to-eat potentially hazardous foods)
• Poor personal hygiene of employees (rates ranged from 34% for hospital food services to 74% for full-service restaurants)
• Contaminated equipment/prevention of contamination (rates ranged from 25% in elementary schools to 58% in deli departments)

The findings of relatively high out-of-compliance areas suggested that industry efforts to achieve active managerial control over these risk factors and to train employees in appropriate techniques still needed improvement (see References: FDA 2004). A new study of this type is planned for 2008 and will review progress in these establishments.

Voluntary regulatory program standards for retail establishments can be accessed (see References: CFSAN 2001).The FDA has also prepared guidance documents to help professionals with regulatory food service and retail food inspections and help them develop methods to implement their own plans (see References: CFSAN 2006: Regulators guide; CFSAN 2006: Manual of voluntary HACCP).

If a food service worker has a documented STEC infection, he or she should not be allowed to return to work or to be employed to handle food until two successive fecal specimens (stool or rectal swab) collected at least 24 hours apart (and not sooner than 48 hours after the last dose of any antibiotic) are negative for STEC organisms (see References: APHA 2000).

Additional information about retail food protection, including food handling, food code, storage, labeling, HACCP, hand hygiene, and other areas relevant to foodborne illnesses is available and can be downloaded (see References: CFSAN 2005: Retail food protection; CFSAN 2003: Hand hygiene in retail and food service establishments).

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