Diseases
E. coli is the most common cause of urinary tract infection and gram-negative rod sepsis. It is one of the two important causes of neonatal meningitis and is the bacterium most frequently associated with “traveler’s diarrhea,” a watery diarrhea. Some strains of E. coli, especially the O157:H7 strain, cause bloody diarrhea and hemolytic-uremic syndrome.
Important Properties
E. coli is a straight gram-negative rod (see Figure 1), in contrast to the curved gram-negative rods of the genera Vibrio, Campylobacter, and Helicobacter.
Fig1. Escherichia coli—Gram stain. Arrow points to a gram-negative rod. (Used with permission from Professor Shirley Lowe, University of California, San Francisco School of Medicine.)
E. coli is the most abundant facultative anaerobe in the colon and feces. It is, however, greatly outnumbered by the obligate anaerobes such as Bacteroides.
E. coli ferments lactose, a property that distinguishes it from the two major intestinal pathogens, Shigella and Salmonella. It has three antigens that are used to identify the organism in epidemiologic investigations: the O, or cell wall, antigen; the H, or flagellar, antigen; and the K, or capsular, antigen. Because there are more than 150 O, 50 H, and 90 K antigens, the various combinations result in more than 1000 antigenic types of E. coli. Specific serotypes are associated with certain diseases (e.g., O55 and O111 cause outbreaks of neonatal diarrhea).
Pathogenesis
The reservoir of E. coli includes both humans and animals. The source of the E. coli that causes urinary tract infections is the patient’s own colonic flora that colonizes the urogenital area. The source of the E. coli that causes neonatal meningitis is the mother’s birth canal; the infection is acquired during birth. In contrast, the E. coli that causes traveler’s diarrhea is acquired by ingestion of food or water contaminated with human feces. Note that the main reservoir of enterohemorrhagic E. coli (EHEC) O157 is cattle and the organism is acquired in undercooked beef, for example, hamburgers.
E. coli has several clearly identified components that contribute to its ability to cause disease: pili, a capsule, endotoxin, and three exotoxins (enterotoxins), two that cause watery diarrhea and one that causes bloody diarrhea and hemolytic-uremic syndrome.
Intestinal Tract Infection
The first step is the adherence of the organism to the cells of the jejunum and ileum by means of pili that protrude from the bacterial surface. Once attached, the bacteria synthesize enterotoxins (exotoxins that act in the enteric tract), which act on the cells of the jejunum and ileum to cause diarrhea. The toxins are strikingly cell-specific; the cells of the colon are not susceptible, probably because they lack receptors for the toxin. Enterotoxigenic strains of E. coli (ETEC) can produce either or both of two enterotoxins.
(1) The heat-labile toxin (LT) acts by stimulating adenylate cyclase. Both LT and cholera toxin act by catalyzing the addition of adenosine diphosphate-ribose (a process called ADP ribosylation) to the G protein that stimulates the cyclase. This irreversibly activates the cyclase. The resultant increase in intra cellular cyclic adenosine monophosphate (AMP) concentration stimulates cyclic AMP-dependent protein kinase, which phosphorylates ion transporters in the membrane. The transporters export ions, which cause an outpouring of fluid, potassium, and chloride from the enterocytes into the lumen of the gut, resulting in watery diarrhea. Note that cholera toxin has the same mode of action.
(2) The other enterotoxin is a low-molecular-weight, heat stable toxin (ST), which stimulates guanylate cyclase.
The enterotoxin-producing strains do not cause inflammation, do not invade the intestinal mucosa, and cause a watery, nonbloody diarrhea. However, certain strains of E. coli are enteropathic (enteroinvasive) and cause disease not by enterotoxin formation but by invasion of the epithelium of the large intestine, causing bloody diarrhea (dysentery) accompanied by inflammatory cells (neutrophils) in the stool.
Certain enterohemorrhagic strains of E. coli (i.e., those with the O157:H7 serotype) (Shiga toxin-producing E. coli [STEC]) also cause bloody diarrhea by producing an exotoxin called Shiga toxin, so called because it is very similar to that produced by Shigella species. Shiga toxin is a glycosidase that acts by removing an adenine from the large (28S) ribosomal RNA, thereby stopping protein synthesis. Shiga toxin is encoded by temperate (lysogenic) bacteriophages. Shiga toxin is also called verotoxin because it has a cytopathic effect on Vero (monkey) cells in culture.
These O157:H7 strains are associated with outbreaks of bloody diarrhea following ingestion of undercooked ham burger, often at fast-food restaurants. The bacteria on the sur face of the hamburger are killed by the cooking, but those in the interior, which is undercooked, survive. Also, direct contact with animals (e.g., visits to farms and petting zoos) has resulted in bloody diarrhea caused by O157:H7 strains. E. coli O157 has a low ID50 of approximately 100 organisms.
Hemolytic-Uremic Syndrome
Some patients with bloody diarrhea caused by O157:H7 strains also have a life-threatening complication called hemolytic-uremic syndrome (HUS), which occurs when Shiga toxin enters the bloodstream and binds to small blood vessels, for example, capillaries. This syndrome consists of hemolytic anemia, thrombocytopenia, and acute renal failure. The hemolytic anemia and renal failure occur because there are receptors for Shiga toxin on the surface of the endothelium of small blood vessels, especially on the surface of kidney glomeruli. Death of the endothelial cells of small blood vessels results in a microangiopathic hemolytic anemia in which the red cells passing through the damaged area become grossly distorted and then lyse. These distorted cells are called schistocytes. Thrombocytopenia occurs because platelets adhere to the damaged endothelial surface. Death of the kidney epithelial cells leads to renal failure. Treatment of diarrhea caused by O157:H7 strains with antibiotics, such as ciprofloxacin, increases the risk of developing HUS by increasing the amount of Shiga toxin released by the dying bacteria.
Urinary Tract Infections
Certain O serotypes of E. coli preferentially cause urinary tract infections. These uropathic strains are characterized by pili with adhesin proteins that bind to specific receptors on the urinary tract epithelium. The binding site on these receptors consists of dimers of galactose (Gal-Gal dimers). These pili are also called P fimbria or pyelonephritis-associated pili (PAP). The motility of E. coli may aid its ability to ascend the urethra into the bladder and ascend the ureter into the kidney.
Systemic Infection
The other two structural components, the capsule and the endotoxin, play a more prominent role in the pathogenesis of systemic, rather than intestinal tract, disease. The capsular polysaccharide interferes with phagocytosis, thereby enhancing the organism’s ability to cause infections in various organs. For example, E. coli strains that cause neonatal meningitis usually have a specific capsular type called the K1 antigen. The endo toxin of E. coli is the cell wall lipopolysaccharide, which causes several features of gram-negative sepsis such as fever, hypotension, and disseminated intravascular coagulation.
Th-17 helper T cells that produce interleukin-17 are an important host defense against sepsis caused by enteric bacteria such as E. coli and Klebsiella. Patients infected with human immunodeficiency virus (HIV) experience a loss of Th-17 cells and are predisposed to sepsis caused by E. coli and Klebsiella.
Clinical Findings
E. coli causes a variety of diseases both within and outside the intestinal tract. The main clinical findings, the major pathogenetic factors, and the main laboratory results are described in Table 1.
Table1. Clinical Aspects of Escherichia coli
(1) Clinical findings within the intestinal tract: Diarrhea caused by enterotoxigenic E. coli (ETEC) is usually watery, nonbloody, self-limited, and of short duration (1–3 days). It is frequently associated with travel (traveler’s diarrhea, or “turista”).2 Infection with EHEC, on the other hand, results in a dysentery-like syndrome characterized by bloody diarrhea, abdominal cramping, and fever similar to that caused by Shigella. The O157:H7 strains of E. coli (STEC) also cause bloody diarrhea, which can be complicated by HUS. This syndrome is characterized by kidney failure, hemolytic anemia, and thrombocytopenia. The hemolytic anemia is caused by exotoxin induced capillary damage, which results in damage to the red cells as they pass through the capillaries. These distorted, fragmented red cells called schistocytes can be seen on blood smear and are characteristic of a microangiopathic hemolytic anemia. Strains of E. coli other than O157:H7, such as O154:H4, can also cause HUS. HUS occurs particularly in children who have been treated with fluoroquinolones or other antibiotics for their diarrhea. For this reason, antibiotics should not be used to treat diarrhea caused by EHEC.
(2) Clinical findings outside of the intestinal tract: E. coli is the leading cause of urinary tract infections. These infections occur primarily in women; this finding is attributed to three features that facilitate ascending infection into the bladder, namely, a short urethra, the proximity of the urethra to the anus, and colonization of the vagina by members of the fecal flora. It is also the most frequent cause of nosocomial (hospital acquired) urinary tract infections, which occur equally frequently in both men and women and are associated with the use of indwelling urinary catheters. Urinary tract infections can be limited to the bladder or extend up the collecting system to the kidneys. If only the bladder is involved, the disease is called cystitis, whereas infection of the kidney is called pyelonephritis. The most prominent symptoms of cystitis are pain (dysuria) and frequency of urination; patients are usually afebrile. Pyelonephritis is characterized by fever, flank pain, and costovertebral angle tenderness; dysuria and frequency may or may not occur. E. coli is also a major cause, along with the group B streptococci, of meningitis and sepsis in neonates. Exposure of the newborn to E. coli and group B streptococci occurs during birth as a result of colonization of the vagina by these organisms in approximately 25% of pregnant women. E. coli is the organism isolated most frequently from patients with hospital-acquired sepsis, which arises primarily from urinary, biliary, or peritoneal infections. Peritonitis is usually a mixed infection caused by E. coli or other facultative enteric gram-negative rod plus anaerobic members of the colonic flora such as Bacteroides and Fusobacterium.
Laboratory Diagnosis
Specimens suspected of containing enteric gram-negative rods, such as E. coli, are grown initially on a blood agar plate and on a differential medium, such as EMB agar or MacConkey’s agar. E. coli, which ferments lactose, forms pink colonies, whereas lactose-negative organisms are colorless. On EMB agar, E. coli colonies have a characteristic green sheen. Some of the important features that help distinguish E. coli from other lactose fermenting gram-negative rods are as follows: (1) it produces indole from tryptophan, (2) it decarboxylates lysine, (3) it uses acetate as its only source of carbon, and (4) it is motile.
E. coli O157:H7 does not ferment sorbitol, which serves as an important criterion that distinguishes it from other strains of E. coli. The isolation of enterotoxigenic or enteropathogenic E. coli from patients with diarrhea is not a routine diagnostic procedure. The diagnosis of bloody diarrhea caused by E. coli O-157 (STEC) can be made by using an enzyme immunoassay for Shiga toxin in the stool.
Treatment
Treatment of E. coli infections depends on the site of disease and the resistance pattern of the specific isolate. For example, an uncomplicated lower urinary tract infection (cystitis) can be treated using oral trimethoprim-sulfamethoxazole or nitrofurantoin. Pyelonephritis can be treated with ciprofloxacin or ceftriaxone. However, E. coli sepsis requires treatment with parenteral antibiotics (e.g., a third-generation cephalosporin, such as cefotaxime, with or without an aminoglycoside, such as gentamicin). For the treatment of neonatal meningitis, a combi nation of ampicillin and cefotaxime is usually given.
Antibiotic therapy is usually not indicated in mild traveler’s diarrhea. Administration of loperamide (Imodium) may shorten the duration of symptoms. Rehydration is typically all that is necessary in this self-limited disease. Azithromycin is the drug of choice for moderate or severe traveler’s diarrhea.
However, diarrhea caused by E. coli O157 should not be treated with antimotility drugs as their use increases the risk of HUS. Giving antibiotics to patients with E. coli O157 diarrhea is controversial as it may increase the risk of HUS. Treatment of diarrhea caused by E. coli O157 is typically supportive.
Treatment of HUS is typically supportive but dialysis may be necessary if renal failure occurs. If severe anemia or thrombocytopenia occurs, transfusions may be necessary.
Prevention
There is no specific prevention for E. coli infections, such as active or passive immunization. However, various general measures can be taken to prevent certain infections caused by E. coli and other organisms. For example, the incidence of urinary tract infections can be lowered by the judicious use and prompt withdrawal of catheters and, in recurrent infections, by prolonged prophylaxis with urinary antiseptic drugs (e.g., nitrofurantoin or trimethoprim-sulfamethoxazole). The use of cranberry juice to prevent recurrent urinary tract infections appears to be based on the ability of flavonoids in the juice to inhibit the binding of the pili of the uropathic strains of E. coli to the bladder epithelium.
