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Escherichia coli
Escherichia coli
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137 Escherichia coli Edwin J. Asturias
Escherichia coli is a genetically diverse species comprising nonpathogenic gut commensals and strains responsible for intestinal and extraintestinal infections in humans.1 Commensal E. coli is the predominant facultative anaerobe of the human gut microbiota, and it colonizes the gastrointestinal tract within hours after birth. E. coli is a gram-negative bacillus and oxidase-negative organism of the family Enterobacteriaceae. It grows
well aerobically and anaerobically, preferably at 37°C. Approximately 90% of strains ferment lactose and produce indole and cadaverine by means of lysine decarboxylase. Classic and molecular serotyping is based on the Kauffman classification scheme using the O (somatic) polysaccharides and H (flagellar) surface antigens. Currently, 174 E. coli somatic and 53 flagellar antigens
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are recognized, but only a small subgroup produce disease in humans.2,3 Pathogenic E. coli have evolved various pathotypes (i.e., group of strains of the same species causing a common disease), and multilocus sequence typing (MLST) is a common method for strain typing and establishing relatedness. Before 2011, only few reports of Shiga toxin–producing enteroaggregative E. coli (EAEC) causing bloody diarrhea and hemolytic uremic syndrome (HUS) existed, but the outbreak of E. coli O104:H4 in Germany proved the plasticity of EAEC and enterohemorrhagic E. coli (EHEC) to form a hybrid (EAHEC). Pathogenic E. coli virulence factors usually are encoded by large plasmids or chromosomal pathogenicity islands. E. coli lacking specific virulence factors also can be opportunistic pathogens of compromised hosts.
PATHOGENESIS Enteric Infections Based on the types of virulence factors and host clinical symptoms, E. coli strains are classified as seven major pathotypes for enteric infections: enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), enterohemorrhagic E. coli (EHEC), enteroinvasive E. coli (EIEC, including Shigella sp), enteroaggregative E. coli (EAEC), and diffusely adherent E. coli (DAEC). ETEC adheres to the small bowel mucosa using one of the fimbrial colonization factor antigens (CFAs), of which more than 25 have been identified, but seven (i.e., CFA/I and CS1–CS6) are considered important. After colonization, ETEC produces one or both of two enterotoxins: heat-labile enterotoxin (LT) and heat-stable enterotoxin (ST).4–6 Most ETEC express LT alone (27%) or in combination with ST (33%), with variations across regions and populations. LT, a strong immunogen in humans, possesses one A subunit and five identical B subunits. It belongs to the family of AB5 enterotoxins, and they act as adenylate cyclase inducers. ST shares structural similarity with heat-stable toxins from V. cholerae O1/non-O1 and Yersinia enterocolitica, and it acts by binding the agedependent surface membrane receptor guanylyl cyclase type C (GC-C). GC-C stimulation is followed by an increase in intracellular cGMP concentrations, activation of protein kinase A (PKA) or cGMP-dependent protein kinase type II (cGKII) and increased chloride secretion through apical cystic fibrosis transmembrane conductance regulator (CFTR) channels, leading to diarrhea. ST also can induce bicarbonate secretion in a non–cGMP-, non–GC-C-, and non–CFTR-dependent manner. The phenotypic hallmark of EPEC is its ability to produce attaching and effacing (AE) lesions (Fig. 137.1).7–9 AE lesions are characterized by
actin remodeling of the host cell cytoskeleton and development of a bundle-forming pilus, allowing EPEC to inject intimin (i.e., virulence factor) into the cytosol of enterocytes, causing extensive effacement of the microvilli. Like EPEC, EHEC also adheres to luminal enterocytes and produces AE lesions.10,11 EHEC contains a pathogenicity island called the locus of enterocyte effacement (LEE), which is crucial for development of AE lesions. After colonic colonization, EHEC releases one or more toxins related to the Shiga toxin of Shigella dysenteriae (i.e., Shiga-like toxin [Stx]) that are cytotoxic to vascular endothelium. Similar to EHEC, EIEC can invade colonic enterocytes and spread laterally through the mucosa and lamina propria. EIEC produces secretogenic enterotoxins responsible for the watery diarrhea manifested in most cases. EAEC adheres tenaciously to the intestinal mucosa in a characteristic biofilm. Adherence is mediated by fimbrial organelles called aggregative adherence fimbriae (AAFs). After colonization is achieved, EAEC secretes a series of cytotoxic, secretogenic, and proinflammatory proteins.12
Extraintestinal and Disseminated Infections Extraintestinal infections are primarily urinary tract infections (UTIs) caused by uropathogenic E. coli (UPEC) and sepsis or meningitis caused by neonatal meningitis E. coli (NMEC).
Uropathogenic E. coli Colonization and adherence are key preceding events in UTI pathogenesis.13 A typical UTI begins with periurethral contamination by intestinal E. coli, followed by urethral colonization and migration to the bladder, which requires appendages such as flagella and pili. UPEC survives by invading the bladder epithelium, producing toxins and proteases to release nutrients from the host cells, and synthesizing siderophores to obtain iron. UPEC binds to uroplakins, the major protein that forms a crystalline array of umbrella cell apical plasma membranes, which protects the bladder. Expressed at the surface of uroepithelial cells, α3β1 integrins also can serve as receptors for UPEC. E. coli can then ascend to the kidneys, attaching by adhesins or pili to colonize the renal epithelium and produce tissue-damaging toxins. The pathogenesis of renal damage by E. coli is not fully understood, but direct cellular damage by UPEC hemolysin or direct invasion may be important. By crossing the tubular epithelial barrier, UPEC can access the bloodstream, resulting in bacteremia. UPEC also can form intracellular biofilms called pods, which may promote persistence and relative antibiotic resistance.
Neonatal Meningitis E. coli A distinct extraintestinal pathotype known as NMEC has the ability to survive in blood and invade the meninges of infants.14 Typical NMEC strains carry the K1 capsular polysaccharide and sitA genes with at least two of three other genes: vat, neuC, and iucC. NMEC strains that carry more virulence genes are more invasive to cerebral microvascular endothelial cells. NMEC strains also have a greater ability to produce biofilms.
EPIDEMIOLOGY
FIGURE 137.1 Electron photomicrograph of the attaching and effacing lesion induced in the gnotobiotic piglet ileum after oral administration of a human enteropathogenic E. coli (EPEC) strain. Bacteria are seen intimately attached to the epithelial cells, which respond by forming cup-like pedestals composed of cytoskeletal protein. An identical lesion can be induced by human EHEC strains. (From Baldini MM, Kaper JB, Levine MM, et al. Plasmid-mediated adhesion in enteropathogenic Escherichia coli. J Pediatr Gastroenterol Nutr 1983;2:543.)
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Children are especially susceptible to intestinal infection due to E. coli. ETEC causes an estimated 280 million cases of diarrhea each year in children younger than 5 years of age and approximately 380,000 deaths mainly due to dehydration. ETEC infection also accounts for 50% to 60% of traveler’s diarrhea cases or approximately 60 million cases per year.15 For many years, EPEC was considered only second to rotavirus as the most common cause of diarrhea in hospitalized children and responsible for 8% to 10% of outpatient cases of acute gastroenteritis, with important regional and temporal variations. The recent demonstration that EPEC can colonize children asymptomatically, especially those who are breastfeeding, suggests that EPEC requires the interplay of multiple factors to cause diarrhea. Shiga toxin–producing E. coli (STEC) is a foodborne zoonotic agent associated with outbreaks worldwide since it was first identified in 1982. STEC causes hemorrhagic colitis through ingestion of contaminated food or water, including contaminated ground beef, steak, salami, dairy
Escherichia coli
products (e.g., raw milk, cheese, butter, cookie dough), and vegetables (e.g., spinach, lettuce, sprouts). A low infectious dose (i.e., 50–100 colony-forming units) is sufficient to cause disease in humans. The incidence of STEC infections in the United States in 2012 reported by the Foodborne Diseases Active Surveillance Network (FoodNet) was 0.92 cases per 100,000 people for O157:H7 and 1.43 cases per 100,000 people for non-O157 STEC. In 2013, 87 cases of postdiarrheal HUS were reported among children younger than 18 years of age (0.79 cases/100,000), with half occurring in children younger than 5 years of age (1.55 cases/100,000). The incidence of STEC in other high-income countries varies from 0.4 cases per 100,000 people in Australia to 5.33 cases per 100,000 people in Ireland. Much higher incidences are reported in other middle- and low-income countries such as Argentina and India. Each year, UTIs affect 150 million people worldwide. In the United States, the cumulative incidence data for UTIs indicate that 3% to 7% of girls and 1% to 2% of boys are diagnosed with a UTI by 6 years of age. UPEC is the most common causative agent for uncomplicated (75%) and complicated (65%) UTIs.16,17 NMEC is the main cause of bacterial meningitis in preterm infants and is second to group B streptococci in term neonates. NMEC is sevenfold more frequent among preterm than term infants. Two peaks of infection are recognized: 0 to 3 days, mostly in preterm neonates, and 11 to 15 days in term neonates. Infection rates increase with decreasing birth weight. Most infants with NMEC infections are preterm, and the mortality rate is as high as 33%. A significant increase in multidrug-resistant NMEC strains has been observed recently.18
CLINICAL MANIFESTATIONS E. coli remains one of the most common bacterial infections in children. It can manifest as acute gastroenteritis, UTI, bloodstream infection (BSI), and meningitis.
Acute Gastroenteritis Clinical manifestations of acute gastroenteritis depend on the E. coli pathotype. ETEC causes profuse, watery diarrhea and abdominal cramping. Fever, nausea with or without vomiting, chills, loss of appetite, headache, and muscle aches also can occur. The incubation period is 1 to 3 days after exposure and lasts for 3 or 4 days up to 1 week. The severity of ETEC infection usually is less than that of cholera. ETEC is the most common cause of travelers’ diarrhea in people of all ages, with onset occurring an average of 7 to 9 days after the start of travel. EPEC and EAEC usually cause a self-limited, watery diarrhea with a short incubation period of 6 to 48 hours. Nausea, abdominal cramps, and mild fever also can occur. EPEC strains cause diarrhea primarily in nonbreastfeeding children. Persistent diarrhea (>14 days) has been reported with EPEC and especially with EAEC. EAEC is the second leading cause of travelers’ diarrhea worldwide. EIEC causes diarrhea that usually is watery, but dysentery develops in a few cases. EHEC infection characteristically causes hemorrhagic colitis without fever, and it often can be confused with intussusception, inflammatory bowel disease, or ischemic colitis. EHEC infections can evolve to HUS. DAEC causes diarrhea particularly in children. AIEC is the most recently recognized diarrheal pathotype that later was associated with Crohn disease.
Urinary Tract Infection UPEC is the most common cause of UTIs in children, and risk factors include very young age, no circumcision, constipation, urinary tract anomalies, spinal disorders, and immunodeficiency. In young children, UTI can manifest as fever alone, accompanied by irritability, poor feeding, vomiting, failure to thrive, or jaundice. A UTI should be considered in any infant or child younger than 24 months of age with fever without an apparent source of infection. In older children and adolescents, cystitis typically manifests with dysuria, urgency, and frequency or sometimes with enuresis. Pyelonephritis often is associated with more severe or systemic symptoms, including fever, back and flank pain, nausea, and vomiting. Ascending infection can result in BSI and systemic inflammatory response syndrome or septic shock (i.e., urosepsis).
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Other Extraintestinal Manifestations Extraintestinal E. coli infections can be community-acquired or healthcare-associated infections. NMEC is a major cause of gramnegative neonatal bacterial meningitis in high- and low-income countries. Many of the survivors have neurologic sequelae.
POSTDIARRHEAL MANIFESTATIONS Hemolytic Uremic Syndrome After the characteristic self-limited hemorrhagic colitis, 5% to 7% of EHEC cases develop HUS, which is characterized by the triad of hemolytic anemia, thrombocytopenia, and acute renal failure. HUS is the direct result of the release of Stx, a potent toxin that can enter the systemic circulation through absorption across the epithelium. Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2) are structurally and enzymatically similar but distinct immunologically. Stx1 mimics Stx from Shigella, whereas Stx2 shares only 55% of the amino acid sequence, is more potent than Stx1 in humans, and is more commonly associated with hemorrhagic colitis and HUS. Stx binds to the globotriaosylceramide (Gb3) receptor in endothelial cells of the microvasculature of the intestine, kidney, and brain. Formation of a biofilm by some STEC strains (e.g., highly virulent EAEC serotype O104:H4) caused 34 deaths and 908 HUS cases in Germany in 2011.19 HUS most commonly occurs in children between 1 and 5 years of age. Oliguria and hypertension are the most common signs of renal injury; seizures, coma, and hemiparesis signal neurologic complications that occur in up to one third of cases.20 HUS is a nonconsumptive coagulopathy with thrombocytopenia but minimal decrease of clotting factors. Other complications include transient hepatocellular injury in 40% and pancreatitis leading to diabetes mellitus. Management of HUS requires careful fluid and electrolyte balance and prompt recognition of acute renal failure to prevent fluid overload and lessen hypertension. Antimotility agents should not be administered to anyone with inflammatory or bloody stools or to any child with diarrhea exposed to a person with HUS or hemorrhagic colitis because these drugs are a risk factor for progression of STEC diarrhea. Antibiotics for the treatment of STEC infection are controversial due to induction of the phage lytic cycle and the potential for increased production of Stx. Although some studies have identified an increased risk of HUS with use of trimethoprim-sulfamethoxazole or β-lactam antibiotics, a metaanalysis of all available studies did not reveal a consistent association of antibiotic administration with HUS risk.21–23 HUS is a life-threatening disease with a 5% mortality rate. Among survivors, 5% to 10% develop end-stage renal disease or permanent neurologic damage. The duration of E. coli O157:H7 shedding seems to be age dependent, with children younger than 5 years carrying the organism for longer periods after the resolution of symptoms.24 A nondiarrheal form of HUS not associated with Stx of EHEC or Shigella dysenteriae type 1 has is caused by the neuraminidase produced by Streptococcus pneumoniae infections, which also causes complicated pneumonia.
Inflammatory Bowel Disease Inflammatory bowel diseases, primarily Crohn disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract due to dysfunction of the epithelial barrier with deregulation of the mucosal immune system and the gut microbiota. Some studies postulate a role for AIEC and intestinal dysbiosis in inflammatory bowel disease.25 E. coli has been recovered from 65% of chronic lesions in resected ileums of patients with Crohn disease, with strains capable of adherence to buccal cells in vitro. High E. coli antigen and antibody concentrations are found in the blood and resected intestinal specimens of Crohn disease patients. The AIEC genome, similar to that of UPEC, encodes type 1 pili. AIEC binding depends on expression of pili on the bacterial surface and on expression of carcinoembryonic antigen–related cell adhesion molecule 6 (CEACAM6) receptors on the apical surface of ileal epithelial cells. CEACAM6 receptors are increased in the ileal mucosa of Crohn disease patients. AIEC infection also induces the release of tumor necrosis factor-α by macrophages, a key cytokine in bowel inflammation and granuloma
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formation.26 In a genetically susceptible host, AIEC may result in permanent changes in the microbiota that can lead to chronic inflammation and inflammatory bowel disease.27
LABORATORY FINDINGS AND DIAGNOSIS Although the diagnosis of E. coli gastroenteritis begins with a routine stool culture, identification of strains belonging to different pathotypes requires proof of expression of one or more group-specific virulence factors. One exception is EHEC O157:H7, which can be distinguished by its inability to ferment sorbitol, yielding colorless colonies on MacConkey agar with added sorbitol. The yield of O157:H7 is substantially higher when stool culture is performed within the first 6 days of diarrheal illness. EHEC (STEC) is now routinely identified by most clinical and public health laboratories by a stx1 or stx2 gene using antigen or nucleic acid amplification. MALDI-TOF mass spectrometry can detect extracted proteins from bacterial cells from growth on primary stool culture and identify all E. coli pathotypes to the species level. The FilmArray gastrointestinal panel can simultaneously detect 22 enteric pathogens directly from stool specimens, such as EAEC, EPEC, ETEC, EIEC, and EHEC (i.e., Stx1 and Stx2), including O157:H7 strains. Although more sensitive (95% to 100%), the FilmArray panel has a specificity between 35% and 80% because many E. coli detected are associated with copathogens. UTI diagnosis requires a urinalysis demonstrating evidence of pyuria and a urine culture growing more than 50,000 colony-forming units/mL of E. coli.28,29 Transurethral bladder catheterization or a suprapubic aspirate are the preferred urine collection methods for children. Midstream clean voiding can be used in older children and adolescents.
TREATMENT Most E. coli diarrheal infections are self-limited and may not require antibiotic therapy. Support of fluid and electrolyte status is the therapeutic priority. If indicated, oral trimethoprim-sulfamethoxazole, azithromycin, or cefixime for 5 days is considered adequate therapy for ETEC, EIEC, EAEC, and EPEC infections.30–32 Fluoroquinolones are preferable in adolescents and adults. Antimicrobial therapy for ETEC disease is limited by frequent resistance to commonly used antibiotics. Multidrugresistant E. coli strains, a consequence of widespread use of antibiotics in animal and food products, result primarily from β-lactamase production (3% to 36%) and have complicated the therapy of these infections. Extended-spectrum β-lactamases are reported in 15% of cases, and strains can also exhibit chromosomal or plasmid-encoded fluoroquinolone resistance (8% to 40%). Treatment of UTI should be initiated only when the diagnosis is confirmed. For the febrile young child, empiric therapy may be indicated before urine culture results are final. The goals of treatment of acute UTI are to eliminate the acute infection, to prevent complications, and to reduce the likelihood of renal damage. Oral antibiotic therapy is effective in most children with UTIs. A narrow-spectrum cephalosporin, amoxicillin−clavulanic acid, or trimethoprim-sulfamethoxazole is an appropriate choice, depending on local resistance patterns. Nitrofurantoin, which is excreted in the urine but has a low therapeutic concentration in the bloodstream, should not be used to treat febrile infants with UTI because it may be insufficient to treat pyelonephritis or urosepsis. Data on short 1- to 3-day courses for febrile UTIs show inferiority to courses of 7 to 14 days; the minimal duration of therapy therefore should be 7 days. UTIs can lead to renal scarring and kidney failure. Since 2011, the American Academy of Pediatrics guidelines for management of a first UTI in children between 2 and 24 months of age recommend performance of a voiding cystourethrogram (VCUG) only for patients with an abnormal renal or bladder ultrasound result.28,29 Definitive therapy for septicemia or meningitis due to E. coli should be based on in vitro susceptibility tests and the use of bactericidal agents with penetration into the central nervous system. Repeat lumbar
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puncture is recommended to document eradication of the infecting pathogen. Duration of therapy is based on response and usually is 10 to 14 days for neonates with uncomplicated septicemia and a minimum of 21 days (and at least 14 days after sterilization of cerebrospinal fluid) for meningitis.
SPECIAL CONSIDERATIONS E. coli is on the Centers for Disease Control and Prevention (CDC) list of biologic agents potentially threatening to public health and safety. The E. coli O157:H7 strain is recognized as a category B agent because of its food safety hazard and ease of production.
PREVENTION Strategies for the prevention and control of the spread of E. coli include access to safe water, handwashing and hygiene, decreasing the risk of food contamination, sanitation measures, public education, and vaccination. Exclusive breastfeeding exerts a protective effect against acute gastroenteritis in the first 4 to 6 months of life. Travelers should consume only cooked food and boiled or bottled beverages when visiting developing areas. Prevention of EPEC and EIEC in indigenous populations is best accomplished by improvements in sanitation, food storage, and personal hygiene. Prevention of EHEC infection has centered on protection of the food supply, especially beef products. Animal carriage of STEC can be diminished by vaccination and improved farm practices. All commercially prepared hamburgers are required to reach an internal temperature of 68°C (155°F), which kills E. coli. Hamburgers should be cooked until no pink remains and until juices are clear. Treatment of STEC with antibiotics or toxin-binding agents does not prevent HUS. Vaccination may be an important primary prevention strategy for humans against the most harmful strains, such as ETEC, UPEC, and NMEC. Despite being a global priority, no effective vaccine is available for the prevention of these infections.33,34 A patch LT antigen vaccine tested in adult travelers did not fully protect them against ETEC diarrhea in Mexico and Guatemala due to a mismatch in prevalent strains.35 A vaccine intended to target 80% of ETEC strains globally would require seven or eight colonization factors (i.e., CFA/I, CS1–3, CS4–6, and CS21), assuming the use of an LT toxin component, and it must ensure high levels of mucosal and systemic protection. Vaccines against the K1 capsule on the surface of UPEC and NMEC have not been protective, and the capsular antigen match to host sialic acid has raised concerns about autoimmune reactions similar to previous meningococcal B vaccine candidates. All references are available online at www.expertconsult.com.
KEY REFERENCES 7. Croxen MA, Law RJ, Scholz R, et al. Recent advances in understanding enteric pathogenic Escherichia coli. Clin Microbiol Rev 2013;26:822–880. 9. Ochoa TJ, Contreras CA. Enteropathogenic Escherichia coli infection in children. Curr Opin Infect Dis 2011;24:478–483. 17. Montini G, Tullus K, Hewitt I. Febrile urinary tract infections in children. N Engl J Med 2011;365:239–250. 19. Loos S, Ahlenstiel T, Kranz B, et al. An outbreak of Shiga toxin-producing Escherichia coli O104:H4 hemolytic uremic syndrome in Germany: presentation and short-term outcome in children. Clin Infect Dis 2012;55:753–759. 24. Thomas DE, Elliott EJ. Interventions for prevention of diarrhea-associated hemolytic uremic syndrome: systematic review. BMC Public Health 2013;13:799. 28. Roberts KB, Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595–610. 31. Guarino A, Ashkenazi S, Gendrel D, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014. J Pediatr Gastroenterol Nutr 2014;59:132–152.
Escherichia coli
REFERENCES 1. Nataro JP, Kaper JB. Diarrheagenic Escherichia coli. Clin Microbiol Rev 1998;11:142. 2. Wang L, Rothemund D, Curd H, Reeves PR. Species-wide variation in the Escherichia coli flagellin (H-antigen) gene. J Bacteriol 2003;185:2936–2943. 3. DebRoy C, Roberts E, Fratamico PM. Detection of O antigens in Escherichia coli. Anim Health Res Rev 2011;12:169–185. 4. Sahl JW, Sistrunk JR, Fraser CM, et al. Examination of the enterotoxigenic Escherichia coli population structure during human infection. MBio 2015;6(3):e00501. 5. Qadri F, Svennerholm AM, Faruque AS, Sack RB. Enterotoxigenic Escherichia coli in developing countries: epidemiology, microbiology, clinical features, treatment, and prevention. Clin Microbiol Rev 2005;18:465–483. 6. Kopic S, Geibel JP. Toxin mediated diarrhea in the 21 century: the pathophysiology of intestinal ion transport in the course of ETEC, V. cholerae and rotavirus infection. Toxins (Basel) 2010;2:2132–2157. 7. Croxen MA, Law RJ, Scholz R, et al. Recent advances in understanding enteric pathogenic Escherichia coli. Clin Microbiol Rev 2013;26:822–880. 8. Clements A, Young J, Constantinou K, Frankel G. Infection strategies of enteric pathogenic Escherichia coli. Gut Microbes 2012;3:71–87. 9. Ochoa TJ, Contreras CA. Enteropathogenic Escherichia coli infection in children. Curr Opin Infect Dis 2011;24:478–483. 10. Spears KJ, Roe AJ, Gally DL. A comparison of enteropathogenic and enterohaemorrhagic Escherichia coli pathogenesis. FEMS Microbiol Lett 2006;255:187–202. 11. Pacheco AR, Sperandio V. Shiga toxin in enterohemorrhagic E.coli: regulation and novel anti-virulence strategies. Front Cell Infect Microbiol 2012;2:1–12. 12. Hebbelstrup Jensen B, Olsen KE, Struve C, et al. Epidemiology and clinical manifestations of enteroaggregative Escherichia coli. Clin Microbiol Rev 2014;27:614–630. 13. Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infection: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol 2015;13:269. 14. Wijetunge DS, Gongati S, DebRoy C, et al. Characterizing the pathotype of neonatal meningitis causing Escherichia coli (NMEC). BMC Microbiol 2015;15:211. 15. Wenneras C, Erling V. Prevalence of enterotoxigenic Escherichia coli-associated diarrhea and carrier state in the developing world. J Health Popul Nutr 2004;22:370–382. 16. Becknell B, Schober M, Korbel L, Spencer JD. The diagnosis, evaluation and treatment of acute and recurrent pediatric urinary tract infections. Expert Rev Anti Infect Ther 2015;13:81–90. 17. Montini G, Tullus K, Hewitt I. Febrile urinary tract infections in children. N Engl J Med 2011;365:239–250. 18. Basmaci R, Bonacorsi S, Bidet P, et al. Escherichia coli meningitis features in 325 children from 2001 to 2013 in France. Clin Infect Dis 2015;61:779–786. 19. Loos S, Ahlenstiel T, Kranz B, et al. An outbreak of Shiga toxin-producing Escherichia coli O104:H4 hemolytic uremic syndrome in Germany: presentation and short-term outcome in children. Clin Infect Dis 2012;55:753–759.
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20. Trachtman H, Austin C, Lewinski M, Stahl RA. Renal and neurological involvement in typical shiga toxin-associated HUS. Nat Rev Nephrol 2012;8:658. 21. Wong CS, Jelacic S, Habeeb RL, et al. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000;342:1930. 22. Safdar N, Said A, Gangnon RE, et al. Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: s meta-analysis. JAMA 2002;288:996. 23. Tzipori S, Sheoran A, Akiyoshi D, et al. Antibody therapy in the management of Shiga toxin-induced hemolytic uremic syndrome. Clin Microbiol Rev 2004;17:926. 24. Thomas DE, Elliott EJ. Interventions for prevention of diarrhea-associated hemolytic uremic syndrome: systematic review. BMC Public Health 2013;13:799. 25. Petersen AM, Halkjær SI, Gluud LL. Intestinal colonization with phylogenetic group B2 Escherichia coli related to inflammatory bowel disease: a systematic review and meta-analysis. Scand J Gastroenterol 2015;50:1199–1207. 26. Conte MP, Longhi C, Marazzato M, et al. Adherent-invasive Escherichia coli (AIEC) in pediatric Crohn’s disease patients: phenotypic and genetic pathogenic features. BMC Res Notes 2014;7:748. 27. Chassaing B, Koren O, Carvalho FA, et al. AIEC pathobiont instigates chronic colitis in susceptible hosts by altering microbiota composition. Gut 2014;63:1069–1080. 28. Roberts KB, Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595–610. 29. Mori R, Lakhanpaul M, Verrier-Jones K. Diagnosis and management of urinary tract infection in children: summary of NICE guidance. BMJ 2007;335:395–397. 30. Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001;32:331. 31. Guarino A, Ashkenazi S, Gendrel D, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014. J Pediatr Gastroenterol Nutr 2014;59:132–152. 32. Garaiova I, Muchová J, Nagyová Z, et al. Probiotics and vitamin C for the prevention of respiratory tract infections in children attending preschool: a randomised controlled pilot study. Eur J Clin Nutr 2015;69:373–379. 33. Zhang W, Sack DA. Current progress in developing subunit vaccines against enterotoxigenic Escherichia coli-associated diarrhea. Clin Vaccine Immunol 2015;22:983–991. 34. Fleckenstein J, Sheikh A, Qadri F. Novel antigens for enterotoxigenic Escherichia coli vaccines. Expert Rev Vaccines 2014;13:631–639. 35. Behrens RH, Cramer JP, Jelinek T, et al. Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala. Lancet Infect Dis 2014;14:197–204.
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137 Escherichia coli Edwin J. Asturias
Escherichia coli is a genetically diverse species comprising nonpathogenic gut commensals and strains responsible for intestinal and extraintestinal infections in humans.1 Commensal E. coli is the predominant facultative anaerobe of the human gut microbiota, and it colonizes the gastrointestinal tract within hours after birth. E. coli is a gram-negative bacillus and oxidase-negative organism of the family Enterobacteriaceae. It grows
well aerobically and anaerobically, preferably at 37°C. Approximately 90% of strains ferment lactose and produce indole and cadaverine by means of lysine decarboxylase. Classic and molecular serotyping is based on the Kauffman classification scheme using the O (somatic) polysaccharides and H (flagellar) surface antigens. Currently, 174 E. coli somatic and 53 flagellar antigens
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are recognized, but only a small subgroup produce disease in humans.2,3 Pathogenic E. coli have evolved various pathotypes (i.e., group of strains of the same species causing a common disease), and multilocus sequence typing (MLST) is a common method for strain typing and establishing relatedness. Before 2011, only few reports of Shiga toxin–producing enteroaggregative E. coli (EAEC) causing bloody diarrhea and hemolytic uremic syndrome (HUS) existed, but the outbreak of E. coli O104:H4 in Germany proved the plasticity of EAEC and enterohemorrhagic E. coli (EHEC) to form a hybrid (EAHEC). Pathogenic E. coli virulence factors usually are encoded by large plasmids or chromosomal pathogenicity islands. E. coli lacking specific virulence factors also can be opportunistic pathogens of compromised hosts.
PATHOGENESIS Enteric Infections Based on the types of virulence factors and host clinical symptoms, E. coli strains are classified as seven major pathotypes for enteric infections: enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), enterohemorrhagic E. coli (EHEC), enteroinvasive E. coli (EIEC, including Shigella sp), enteroaggregative E. coli (EAEC), and diffusely adherent E. coli (DAEC). ETEC adheres to the small bowel mucosa using one of the fimbrial colonization factor antigens (CFAs), of which more than 25 have been identified, but seven (i.e., CFA/I and CS1–CS6) are considered important. After colonization, ETEC produces one or both of two enterotoxins: heat-labile enterotoxin (LT) and heat-stable enterotoxin (ST).4–6 Most ETEC express LT alone (27%) or in combination with ST (33%), with variations across regions and populations. LT, a strong immunogen in humans, possesses one A subunit and five identical B subunits. It belongs to the family of AB5 enterotoxins, and they act as adenylate cyclase inducers. ST shares structural similarity with heat-stable toxins from V. cholerae O1/non-O1 and Yersinia enterocolitica, and it acts by binding the agedependent surface membrane receptor guanylyl cyclase type C (GC-C). GC-C stimulation is followed by an increase in intracellular cGMP concentrations, activation of protein kinase A (PKA) or cGMP-dependent protein kinase type II (cGKII) and increased chloride secretion through apical cystic fibrosis transmembrane conductance regulator (CFTR) channels, leading to diarrhea. ST also can induce bicarbonate secretion in a non–cGMP-, non–GC-C-, and non–CFTR-dependent manner. The phenotypic hallmark of EPEC is its ability to produce attaching and effacing (AE) lesions (Fig. 137.1).7–9 AE lesions are characterized by
actin remodeling of the host cell cytoskeleton and development of a bundle-forming pilus, allowing EPEC to inject intimin (i.e., virulence factor) into the cytosol of enterocytes, causing extensive effacement of the microvilli. Like EPEC, EHEC also adheres to luminal enterocytes and produces AE lesions.10,11 EHEC contains a pathogenicity island called the locus of enterocyte effacement (LEE), which is crucial for development of AE lesions. After colonic colonization, EHEC releases one or more toxins related to the Shiga toxin of Shigella dysenteriae (i.e., Shiga-like toxin [Stx]) that are cytotoxic to vascular endothelium. Similar to EHEC, EIEC can invade colonic enterocytes and spread laterally through the mucosa and lamina propria. EIEC produces secretogenic enterotoxins responsible for the watery diarrhea manifested in most cases. EAEC adheres tenaciously to the intestinal mucosa in a characteristic biofilm. Adherence is mediated by fimbrial organelles called aggregative adherence fimbriae (AAFs). After colonization is achieved, EAEC secretes a series of cytotoxic, secretogenic, and proinflammatory proteins.12
Extraintestinal and Disseminated Infections Extraintestinal infections are primarily urinary tract infections (UTIs) caused by uropathogenic E. coli (UPEC) and sepsis or meningitis caused by neonatal meningitis E. coli (NMEC).
Uropathogenic E. coli Colonization and adherence are key preceding events in UTI pathogenesis.13 A typical UTI begins with periurethral contamination by intestinal E. coli, followed by urethral colonization and migration to the bladder, which requires appendages such as flagella and pili. UPEC survives by invading the bladder epithelium, producing toxins and proteases to release nutrients from the host cells, and synthesizing siderophores to obtain iron. UPEC binds to uroplakins, the major protein that forms a crystalline array of umbrella cell apical plasma membranes, which protects the bladder. Expressed at the surface of uroepithelial cells, α3β1 integrins also can serve as receptors for UPEC. E. coli can then ascend to the kidneys, attaching by adhesins or pili to colonize the renal epithelium and produce tissue-damaging toxins. The pathogenesis of renal damage by E. coli is not fully understood, but direct cellular damage by UPEC hemolysin or direct invasion may be important. By crossing the tubular epithelial barrier, UPEC can access the bloodstream, resulting in bacteremia. UPEC also can form intracellular biofilms called pods, which may promote persistence and relative antibiotic resistance.
Neonatal Meningitis E. coli A distinct extraintestinal pathotype known as NMEC has the ability to survive in blood and invade the meninges of infants.14 Typical NMEC strains carry the K1 capsular polysaccharide and sitA genes with at least two of three other genes: vat, neuC, and iucC. NMEC strains that carry more virulence genes are more invasive to cerebral microvascular endothelial cells. NMEC strains also have a greater ability to produce biofilms.
EPIDEMIOLOGY
FIGURE 137.1 Electron photomicrograph of the attaching and effacing lesion induced in the gnotobiotic piglet ileum after oral administration of a human enteropathogenic E. coli (EPEC) strain. Bacteria are seen intimately attached to the epithelial cells, which respond by forming cup-like pedestals composed of cytoskeletal protein. An identical lesion can be induced by human EHEC strains. (From Baldini MM, Kaper JB, Levine MM, et al. Plasmid-mediated adhesion in enteropathogenic Escherichia coli. J Pediatr Gastroenterol Nutr 1983;2:543.)
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Children are especially susceptible to intestinal infection due to E. coli. ETEC causes an estimated 280 million cases of diarrhea each year in children younger than 5 years of age and approximately 380,000 deaths mainly due to dehydration. ETEC infection also accounts for 50% to 60% of traveler’s diarrhea cases or approximately 60 million cases per year.15 For many years, EPEC was considered only second to rotavirus as the most common cause of diarrhea in hospitalized children and responsible for 8% to 10% of outpatient cases of acute gastroenteritis, with important regional and temporal variations. The recent demonstration that EPEC can colonize children asymptomatically, especially those who are breastfeeding, suggests that EPEC requires the interplay of multiple factors to cause diarrhea. Shiga toxin–producing E. coli (STEC) is a foodborne zoonotic agent associated with outbreaks worldwide since it was first identified in 1982. STEC causes hemorrhagic colitis through ingestion of contaminated food or water, including contaminated ground beef, steak, salami, dairy
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products (e.g., raw milk, cheese, butter, cookie dough), and vegetables (e.g., spinach, lettuce, sprouts). A low infectious dose (i.e., 50–100 colony-forming units) is sufficient to cause disease in humans. The incidence of STEC infections in the United States in 2012 reported by the Foodborne Diseases Active Surveillance Network (FoodNet) was 0.92 cases per 100,000 people for O157:H7 and 1.43 cases per 100,000 people for non-O157 STEC. In 2013, 87 cases of postdiarrheal HUS were reported among children younger than 18 years of age (0.79 cases/100,000), with half occurring in children younger than 5 years of age (1.55 cases/100,000). The incidence of STEC in other high-income countries varies from 0.4 cases per 100,000 people in Australia to 5.33 cases per 100,000 people in Ireland. Much higher incidences are reported in other middle- and low-income countries such as Argentina and India. Each year, UTIs affect 150 million people worldwide. In the United States, the cumulative incidence data for UTIs indicate that 3% to 7% of girls and 1% to 2% of boys are diagnosed with a UTI by 6 years of age. UPEC is the most common causative agent for uncomplicated (75%) and complicated (65%) UTIs.16,17 NMEC is the main cause of bacterial meningitis in preterm infants and is second to group B streptococci in term neonates. NMEC is sevenfold more frequent among preterm than term infants. Two peaks of infection are recognized: 0 to 3 days, mostly in preterm neonates, and 11 to 15 days in term neonates. Infection rates increase with decreasing birth weight. Most infants with NMEC infections are preterm, and the mortality rate is as high as 33%. A significant increase in multidrug-resistant NMEC strains has been observed recently.18
CLINICAL MANIFESTATIONS E. coli remains one of the most common bacterial infections in children. It can manifest as acute gastroenteritis, UTI, bloodstream infection (BSI), and meningitis.
Acute Gastroenteritis Clinical manifestations of acute gastroenteritis depend on the E. coli pathotype. ETEC causes profuse, watery diarrhea and abdominal cramping. Fever, nausea with or without vomiting, chills, loss of appetite, headache, and muscle aches also can occur. The incubation period is 1 to 3 days after exposure and lasts for 3 or 4 days up to 1 week. The severity of ETEC infection usually is less than that of cholera. ETEC is the most common cause of travelers’ diarrhea in people of all ages, with onset occurring an average of 7 to 9 days after the start of travel. EPEC and EAEC usually cause a self-limited, watery diarrhea with a short incubation period of 6 to 48 hours. Nausea, abdominal cramps, and mild fever also can occur. EPEC strains cause diarrhea primarily in nonbreastfeeding children. Persistent diarrhea (>14 days) has been reported with EPEC and especially with EAEC. EAEC is the second leading cause of travelers’ diarrhea worldwide. EIEC causes diarrhea that usually is watery, but dysentery develops in a few cases. EHEC infection characteristically causes hemorrhagic colitis without fever, and it often can be confused with intussusception, inflammatory bowel disease, or ischemic colitis. EHEC infections can evolve to HUS. DAEC causes diarrhea particularly in children. AIEC is the most recently recognized diarrheal pathotype that later was associated with Crohn disease.
Urinary Tract Infection UPEC is the most common cause of UTIs in children, and risk factors include very young age, no circumcision, constipation, urinary tract anomalies, spinal disorders, and immunodeficiency. In young children, UTI can manifest as fever alone, accompanied by irritability, poor feeding, vomiting, failure to thrive, or jaundice. A UTI should be considered in any infant or child younger than 24 months of age with fever without an apparent source of infection. In older children and adolescents, cystitis typically manifests with dysuria, urgency, and frequency or sometimes with enuresis. Pyelonephritis often is associated with more severe or systemic symptoms, including fever, back and flank pain, nausea, and vomiting. Ascending infection can result in BSI and systemic inflammatory response syndrome or septic shock (i.e., urosepsis).
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Other Extraintestinal Manifestations Extraintestinal E. coli infections can be community-acquired or healthcare-associated infections. NMEC is a major cause of gramnegative neonatal bacterial meningitis in high- and low-income countries. Many of the survivors have neurologic sequelae.
POSTDIARRHEAL MANIFESTATIONS Hemolytic Uremic Syndrome After the characteristic self-limited hemorrhagic colitis, 5% to 7% of EHEC cases develop HUS, which is characterized by the triad of hemolytic anemia, thrombocytopenia, and acute renal failure. HUS is the direct result of the release of Stx, a potent toxin that can enter the systemic circulation through absorption across the epithelium. Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2) are structurally and enzymatically similar but distinct immunologically. Stx1 mimics Stx from Shigella, whereas Stx2 shares only 55% of the amino acid sequence, is more potent than Stx1 in humans, and is more commonly associated with hemorrhagic colitis and HUS. Stx binds to the globotriaosylceramide (Gb3) receptor in endothelial cells of the microvasculature of the intestine, kidney, and brain. Formation of a biofilm by some STEC strains (e.g., highly virulent EAEC serotype O104:H4) caused 34 deaths and 908 HUS cases in Germany in 2011.19 HUS most commonly occurs in children between 1 and 5 years of age. Oliguria and hypertension are the most common signs of renal injury; seizures, coma, and hemiparesis signal neurologic complications that occur in up to one third of cases.20 HUS is a nonconsumptive coagulopathy with thrombocytopenia but minimal decrease of clotting factors. Other complications include transient hepatocellular injury in 40% and pancreatitis leading to diabetes mellitus. Management of HUS requires careful fluid and electrolyte balance and prompt recognition of acute renal failure to prevent fluid overload and lessen hypertension. Antimotility agents should not be administered to anyone with inflammatory or bloody stools or to any child with diarrhea exposed to a person with HUS or hemorrhagic colitis because these drugs are a risk factor for progression of STEC diarrhea. Antibiotics for the treatment of STEC infection are controversial due to induction of the phage lytic cycle and the potential for increased production of Stx. Although some studies have identified an increased risk of HUS with use of trimethoprim-sulfamethoxazole or β-lactam antibiotics, a metaanalysis of all available studies did not reveal a consistent association of antibiotic administration with HUS risk.21–23 HUS is a life-threatening disease with a 5% mortality rate. Among survivors, 5% to 10% develop end-stage renal disease or permanent neurologic damage. The duration of E. coli O157:H7 shedding seems to be age dependent, with children younger than 5 years carrying the organism for longer periods after the resolution of symptoms.24 A nondiarrheal form of HUS not associated with Stx of EHEC or Shigella dysenteriae type 1 has is caused by the neuraminidase produced by Streptococcus pneumoniae infections, which also causes complicated pneumonia.
Inflammatory Bowel Disease Inflammatory bowel diseases, primarily Crohn disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract due to dysfunction of the epithelial barrier with deregulation of the mucosal immune system and the gut microbiota. Some studies postulate a role for AIEC and intestinal dysbiosis in inflammatory bowel disease.25 E. coli has been recovered from 65% of chronic lesions in resected ileums of patients with Crohn disease, with strains capable of adherence to buccal cells in vitro. High E. coli antigen and antibody concentrations are found in the blood and resected intestinal specimens of Crohn disease patients. The AIEC genome, similar to that of UPEC, encodes type 1 pili. AIEC binding depends on expression of pili on the bacterial surface and on expression of carcinoembryonic antigen–related cell adhesion molecule 6 (CEACAM6) receptors on the apical surface of ileal epithelial cells. CEACAM6 receptors are increased in the ileal mucosa of Crohn disease patients. AIEC infection also induces the release of tumor necrosis factor-α by macrophages, a key cytokine in bowel inflammation and granuloma
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PART III Etiologic Agents of Infectious Diseases SECTION A Bacteria
formation.26 In a genetically susceptible host, AIEC may result in permanent changes in the microbiota that can lead to chronic inflammation and inflammatory bowel disease.27
LABORATORY FINDINGS AND DIAGNOSIS Although the diagnosis of E. coli gastroenteritis begins with a routine stool culture, identification of strains belonging to different pathotypes requires proof of expression of one or more group-specific virulence factors. One exception is EHEC O157:H7, which can be distinguished by its inability to ferment sorbitol, yielding colorless colonies on MacConkey agar with added sorbitol. The yield of O157:H7 is substantially higher when stool culture is performed within the first 6 days of diarrheal illness. EHEC (STEC) is now routinely identified by most clinical and public health laboratories by a stx1 or stx2 gene using antigen or nucleic acid amplification. MALDI-TOF mass spectrometry can detect extracted proteins from bacterial cells from growth on primary stool culture and identify all E. coli pathotypes to the species level. The FilmArray gastrointestinal panel can simultaneously detect 22 enteric pathogens directly from stool specimens, such as EAEC, EPEC, ETEC, EIEC, and EHEC (i.e., Stx1 and Stx2), including O157:H7 strains. Although more sensitive (95% to 100%), the FilmArray panel has a specificity between 35% and 80% because many E. coli detected are associated with copathogens. UTI diagnosis requires a urinalysis demonstrating evidence of pyuria and a urine culture growing more than 50,000 colony-forming units/mL of E. coli.28,29 Transurethral bladder catheterization or a suprapubic aspirate are the preferred urine collection methods for children. Midstream clean voiding can be used in older children and adolescents.
TREATMENT Most E. coli diarrheal infections are self-limited and may not require antibiotic therapy. Support of fluid and electrolyte status is the therapeutic priority. If indicated, oral trimethoprim-sulfamethoxazole, azithromycin, or cefixime for 5 days is considered adequate therapy for ETEC, EIEC, EAEC, and EPEC infections.30–32 Fluoroquinolones are preferable in adolescents and adults. Antimicrobial therapy for ETEC disease is limited by frequent resistance to commonly used antibiotics. Multidrugresistant E. coli strains, a consequence of widespread use of antibiotics in animal and food products, result primarily from β-lactamase production (3% to 36%) and have complicated the therapy of these infections. Extended-spectrum β-lactamases are reported in 15% of cases, and strains can also exhibit chromosomal or plasmid-encoded fluoroquinolone resistance (8% to 40%). Treatment of UTI should be initiated only when the diagnosis is confirmed. For the febrile young child, empiric therapy may be indicated before urine culture results are final. The goals of treatment of acute UTI are to eliminate the acute infection, to prevent complications, and to reduce the likelihood of renal damage. Oral antibiotic therapy is effective in most children with UTIs. A narrow-spectrum cephalosporin, amoxicillin−clavulanic acid, or trimethoprim-sulfamethoxazole is an appropriate choice, depending on local resistance patterns. Nitrofurantoin, which is excreted in the urine but has a low therapeutic concentration in the bloodstream, should not be used to treat febrile infants with UTI because it may be insufficient to treat pyelonephritis or urosepsis. Data on short 1- to 3-day courses for febrile UTIs show inferiority to courses of 7 to 14 days; the minimal duration of therapy therefore should be 7 days. UTIs can lead to renal scarring and kidney failure. Since 2011, the American Academy of Pediatrics guidelines for management of a first UTI in children between 2 and 24 months of age recommend performance of a voiding cystourethrogram (VCUG) only for patients with an abnormal renal or bladder ultrasound result.28,29 Definitive therapy for septicemia or meningitis due to E. coli should be based on in vitro susceptibility tests and the use of bactericidal agents with penetration into the central nervous system. Repeat lumbar
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puncture is recommended to document eradication of the infecting pathogen. Duration of therapy is based on response and usually is 10 to 14 days for neonates with uncomplicated septicemia and a minimum of 21 days (and at least 14 days after sterilization of cerebrospinal fluid) for meningitis.
SPECIAL CONSIDERATIONS E. coli is on the Centers for Disease Control and Prevention (CDC) list of biologic agents potentially threatening to public health and safety. The E. coli O157:H7 strain is recognized as a category B agent because of its food safety hazard and ease of production.
PREVENTION Strategies for the prevention and control of the spread of E. coli include access to safe water, handwashing and hygiene, decreasing the risk of food contamination, sanitation measures, public education, and vaccination. Exclusive breastfeeding exerts a protective effect against acute gastroenteritis in the first 4 to 6 months of life. Travelers should consume only cooked food and boiled or bottled beverages when visiting developing areas. Prevention of EPEC and EIEC in indigenous populations is best accomplished by improvements in sanitation, food storage, and personal hygiene. Prevention of EHEC infection has centered on protection of the food supply, especially beef products. Animal carriage of STEC can be diminished by vaccination and improved farm practices. All commercially prepared hamburgers are required to reach an internal temperature of 68°C (155°F), which kills E. coli. Hamburgers should be cooked until no pink remains and until juices are clear. Treatment of STEC with antibiotics or toxin-binding agents does not prevent HUS. Vaccination may be an important primary prevention strategy for humans against the most harmful strains, such as ETEC, UPEC, and NMEC. Despite being a global priority, no effective vaccine is available for the prevention of these infections.33,34 A patch LT antigen vaccine tested in adult travelers did not fully protect them against ETEC diarrhea in Mexico and Guatemala due to a mismatch in prevalent strains.35 A vaccine intended to target 80% of ETEC strains globally would require seven or eight colonization factors (i.e., CFA/I, CS1–3, CS4–6, and CS21), assuming the use of an LT toxin component, and it must ensure high levels of mucosal and systemic protection. Vaccines against the K1 capsule on the surface of UPEC and NMEC have not been protective, and the capsular antigen match to host sialic acid has raised concerns about autoimmune reactions similar to previous meningococcal B vaccine candidates. All references are available online at www.expertconsult.com.
KEY REFERENCES 7. Croxen MA, Law RJ, Scholz R, et al. Recent advances in understanding enteric pathogenic Escherichia coli. Clin Microbiol Rev 2013;26:822–880. 9. Ochoa TJ, Contreras CA. Enteropathogenic Escherichia coli infection in children. Curr Opin Infect Dis 2011;24:478–483. 17. Montini G, Tullus K, Hewitt I. Febrile urinary tract infections in children. N Engl J Med 2011;365:239–250. 19. Loos S, Ahlenstiel T, Kranz B, et al. An outbreak of Shiga toxin-producing Escherichia coli O104:H4 hemolytic uremic syndrome in Germany: presentation and short-term outcome in children. Clin Infect Dis 2012;55:753–759. 24. Thomas DE, Elliott EJ. Interventions for prevention of diarrhea-associated hemolytic uremic syndrome: systematic review. BMC Public Health 2013;13:799. 28. Roberts KB, Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595–610. 31. Guarino A, Ashkenazi S, Gendrel D, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014. J Pediatr Gastroenterol Nutr 2014;59:132–152.
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20. Trachtman H, Austin C, Lewinski M, Stahl RA. Renal and neurological involvement in typical shiga toxin-associated HUS. Nat Rev Nephrol 2012;8:658. 21. Wong CS, Jelacic S, Habeeb RL, et al. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000;342:1930. 22. Safdar N, Said A, Gangnon RE, et al. Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: s meta-analysis. JAMA 2002;288:996. 23. Tzipori S, Sheoran A, Akiyoshi D, et al. Antibody therapy in the management of Shiga toxin-induced hemolytic uremic syndrome. Clin Microbiol Rev 2004;17:926. 24. Thomas DE, Elliott EJ. Interventions for prevention of diarrhea-associated hemolytic uremic syndrome: systematic review. BMC Public Health 2013;13:799. 25. Petersen AM, Halkjær SI, Gluud LL. Intestinal colonization with phylogenetic group B2 Escherichia coli related to inflammatory bowel disease: a systematic review and meta-analysis. Scand J Gastroenterol 2015;50:1199–1207. 26. Conte MP, Longhi C, Marazzato M, et al. Adherent-invasive Escherichia coli (AIEC) in pediatric Crohn’s disease patients: phenotypic and genetic pathogenic features. BMC Res Notes 2014;7:748. 27. Chassaing B, Koren O, Carvalho FA, et al. AIEC pathobiont instigates chronic colitis in susceptible hosts by altering microbiota composition. Gut 2014;63:1069–1080. 28. Roberts KB, Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595–610. 29. Mori R, Lakhanpaul M, Verrier-Jones K. Diagnosis and management of urinary tract infection in children: summary of NICE guidance. BMJ 2007;335:395–397. 30. Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001;32:331. 31. Guarino A, Ashkenazi S, Gendrel D, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014. J Pediatr Gastroenterol Nutr 2014;59:132–152. 32. Garaiova I, Muchová J, Nagyová Z, et al. Probiotics and vitamin C for the prevention of respiratory tract infections in children attending preschool: a randomised controlled pilot study. Eur J Clin Nutr 2015;69:373–379. 33. Zhang W, Sack DA. Current progress in developing subunit vaccines against enterotoxigenic Escherichia coli-associated diarrhea. Clin Vaccine Immunol 2015;22:983–991. 34. Fleckenstein J, Sheikh A, Qadri F. Novel antigens for enterotoxigenic Escherichia coli vaccines. Expert Rev Vaccines 2014;13:631–639. 35. Behrens RH, Cramer JP, Jelinek T, et al. Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala. Lancet Infect Dis 2014;14:197–204.
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