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Noroviruses, which include Norwalk agent, Hawaii agent, and Snow Mountain agent, are caliciviruses—small, single-stranded RNA viruses that, despite extensive efforts, have not been cultured (Table 5–5). It is estimated that these viruses produce approximately 25 million episodes of illness annually worldwide and are responsible for over 90% of outbreaks of viral gastroenteritis in the United States. Epidemic outbreaks in hospitals, nursing homes, in schools from catered food, in restaurants, and on cruise ships have been widely publicized, but endemic cases also occur. Transmission is via the fecal-oral route through contaminated food and water, from virus-contaminated environmental surfaces, and direct person-to-person contact. Histologic studies of volunteers have shown that after ingestion, noroviruses induce a mild to moderate mucosal enteritis that peaks in severity approximately 48 hours after viral ingestion and resolves completely within 4–6 weeks or earlier. Lesions of the gastric mucosa were not detected after ingestion of Norwalk agent.
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The incubation period is usually 12–48 hours, and clinical symptoms may include nausea, vomiting, watery diarrhea, and abdominal cramps. Fever, if present, is usually mild (<101.5°F [38.6°C]). The duration of clinical symptoms is short, usually ranging from a few hours to 3 days. The characteristic histologic lesion has been observed in asymptomatic volunteers after norovirus ingestion, providing evidence that some infections are subclinical. Routine laboratory studies remain normal unless severe dehydration develops, in which case elevations of blood urea nitrogen and creatinine and leukocytosis may be seen.
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The diagnosis depends on the epidemiology and clinical features. A reverse transcription PCR assay and diagnostic immunoassays are available and are used largely to identify outbreaks but are not generally used to diagnose individual patients.
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Treatment is supportive and consists of oral rehydration with carbohydrate–electrolyte solutions (see earlier discussion) and, in a small minority of patients with severe dehydration, by intravenous hydration. Symptomatic treatments such as bismuth subsalicylate and loperamide can be used but are usually not needed, and there is little evidence that they significantly influence fecal fluid losses. There is no effective antiviral agent and no available vaccine.
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The prognosis is excellent for this generally self-limited disease, although deaths may occur in association with norovirus gastroenteritis, largely in debilitated, elderly patients with significant comorbidities.
Blanton LH, Adams SM, Beard RS, et al. Molecular and epidemiologic trends of caliciviruses associated with outbreaks of acute gastroenteritis in the United States, 2000–2004.
J Infect Dis. 2006; 193:413–421.
[PubMed: 16388489]
Glass RI, Parashar UD, Estes MK. Norovirus gastroenteritis.
N Engl J Med. 2009;361:1776–1185.
[PubMed: 19864676]
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Rotaviruses are a major cause of infectious diarrhea worldwide, accounting for an estimated 500,000 or more deaths each year. In the United States, prior to the widespread use of rotavirus vaccines, approximately 2.7 million children developed rotavirus gastroenteritis yearly, resulting in over 50,000 hospitalizations and an estimated 30 deaths. However, there is increasing evidence that with the introduction of effective vaccines, those numbers have decreased substantially.
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Rotaviruses are double-stranded RNA viruses (see Table 5–5) whose classification is complex. There are several groups, which, in turn, may contain subgroups and multiple serotypes. Most but not all disease in humans is caused by group A. The virus invades, proliferates in, and destroys enterocytes, resulting in the passage of abundant virions in the stool of infected individuals for 7–10 days; however, virions can be shed for up to 3–4 weeks. Significant enteritis develops, with patchy shortening or even complete loss of villi, crypt hyperplasia, and inflammation of the lamina propria.
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Symptomatic illness is more common in winter and occurs largely in infants and young children. Watery diarrhea, which can be profuse, and vomiting are the major symptoms, accompanied by fever in 50% or more of cases. Reinfections in older children and adults are usually asymptomatic or mild but can occasionally cause severe symptoms. Dehydration is a hazard—especially in infants, if diarrhea is accompanied by vomiting that precludes adequate oral fluid intake—and is the major cause of morbidity and death. The illness generally lasts from 4–7 days, but more protracted diarrhea has been reported. The diagnosis can be confirmed by demonstrating rotavirus antigen in the stool by specific ELISA, latex agglutination, or PCR assays.
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Hydration is the cornerstone of therapy and can often be achieved with oral rehydration regimens containing sugar, salt, and water or commercial oral rehydration formulations unless diarrhea is profuse and accompanied by vomiting, in which case intravenous rehydration may be lifesaving. The American Academy of Pediatrics does not recommend symptomatic therapy, including antimotility drugs, bismuth subsalicylate, and probiotics, for children younger than age 5 years.
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The overall prognosis is excellent, with the vast majority of patients recovering completely within 7–10 days, except as noted earlier.
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A pentavalent human-bovine reassortant rotavirus vaccine (RotaTeq) and a monovalent attenuated human rotavirus vaccine (Rotarix) are licensed in the United States. Vaccination is recommended for all infants who have no contraindications.
Kahn MA, Bass DM. Viral infections: new and emerging.
Curr Opin Gastroenterol. 2010;26:26–30.
[PubMed: 19907323]
Widdowson MA, Bresee JS, Gentsch JR, et al. Rotavirus disease and its prevention.
Curr Opin Gastroenterol. 2005;21:26–31.
[PubMed: 15687881]
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Enteric adenovirus causes a rotavirus-like endemic gastroenteritis primarily in children younger than 2 years of age. Its incubation period is longer than that of rotavirus, but it appears to be less contagious. Astrovirus also causes endemic gastroenteritis primarily in children but also among elderly and immunocompromised adults; occasional multicase outbreaks have been described. Clinically, gastroenteritis caused by adenovirus and astrovirus resembles that caused by rotavirus and norovirus, and the principles of therapy are the same. Diarrhea may also accompany enterovirus and coxsackievirus infections, although manifestations involving other systems often overshadow any accompanying diarrhea.
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Whereas cytomegalovirus infections of the gastrointestinal tract notoriously affect immunocompromised patients, as discussed in Chapter 10, occasional cases of cytomegalovirus colitis have been described in apparently immunocompetent adults. In one review, 15 cases over a wide age range were described. Presenting features included diarrhea, hematochezia, fever, and abdominal pain. Endoscopy generally revealed colitis with frank ulcers, and mortality (27%) was high. When diagnosed, antiviral therapy with agents such as ganciclovir or foscarnet is indicated.
Galiatsatos P, Shrier I, Lamoureux E, et al. Meta-analysis of outcome of cytomegalovirus colitis in immunocompetent hosts.
Dig Dis Sci. 2005;50:609–616.
[PubMed: 15844689]
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Although specific bacterial infections are discussed on the following pages, the presentation of patients with shigelloses, invasive E coli and EHEC, Campylobacter, and nontyphoidal Salmonella enterocolitis may be clinically indistinguishable. As a result, the decision about whether or not to begin empiric antibiotic treatment can be difficult. Although antibiotics may be of benefit in a few infections (shigelloses, invasive E coli), they may have undesirable effects in others (EHEC, uncomplicated nontyphoidal Salmonella enterocolitis) and predispose to C difficile colitis. Hence, potential benefits versus risks must be weighed carefully.
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Shigella species are a major cause of dysenteric infectious colitis, with an estimated annual incidence of 450,000 in the United States. Four pathogenic species have been identified (Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Shigella boydii). Disease is caused by ingestion of contaminated food, water, or direct person-to-person fecal-oral spread. The Shigella species are acid-resistant; hence, a very small inoculum (≤100 bacteria) can produce disease. The bacteria invade and spread through the epithelium, produce several enterotoxins, including Shiga toxin, and induce severe, acute inflammation of the mucosa (see Plates 1 and 2) probably by causing the release of proinflammatory cytokines. There is no available vaccine.
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After an average 3-day incubation period, patients usually develop watery diarrhea, which rapidly progresses to dysenteric stools with mucus and blood, tenesmus, and, usually, fever. Some patients also develop nausea and vomiting. The severity varies and ranges from watery stools without dysentery or significant fever to severe dysentery with more than 20 low-volume stools per day, abdominal cramps, tenesmus, and high fever. Sigmoidoscopy in patients with dysentery caused by shigellosis is usually grossly indistinguishable from that observed with other dysenteric infections (Campylobacter, nontyphoidal Salmonella) or a flare of idiopathic IBD. Biopsy can be useful in distinguishing infectious proctocolitis from a flare of idiopathic proctocolitis in that chronic changes such as crypt distortion and dropout are absent despite the presence of substantial inflammation, most prominently in the upper half of the mucosa (compare Plate 1 with Plate 2). Stools from the majority of patients contain neutrophils, and the diagnosis is established by stool culture.
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In previously healthy individuals who are not immunosuppressed, shigellosis is usually self-limited and clears within about 1 week without treatment. Antibiotic therapy shortens the duration of symptoms and the fecal shedding of Shigella organisms by about 50% and should be considered if fever is high and dysentery is severe or the stool cultures are positive, especially in infants and young children but also in adults. Antibiotic therapy is clearly indicated in patients with bacteremia (<10%), food handlers, elderly or malnourished patients with comorbidities, and the immunosuppressed. If possible, it should be guided by the antibiotic sensitivity of the Shigella species isolated from stool or blood culture. If antibiotic susceptibility is unknown, the current treatment of choice is a fluoroquinolone in adults, although reports of resistance to quinolones are appearing especially in Asia, and azithromycin in children younger than 18 years of age. In all patients, supportive measures such as hydration are important, but antimotility agents are not recommended as they may prolong symptoms and fecal shedding of Shigella.
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Gastrointestinal complications are uncommon, but rectal prolapse, toxic megacolon, and even intestinal perforation have been reported. The most common gastrointestinal complication of this and other intestinal bacterial infections appears to be postinfectious irritable bowel syndrome, which occurs in as many as 10% of patients (see Chapter 24). Systemic complications include a sterile reactive arthritis occurring usually 1–2 weeks after the onset of gastrointestinal symptoms and, in rare instances, the hemolytic uremic syndrome with microangiopathic anemia, thrombocytopenia, and acute renal failure. In addition, seizures associated with high fever may occur, especially in infants and young children.
Kosek M, Yori PP, Olortegui MP. Shigellosis update: advancing antibiotic resistance, investment empowered vaccine development, and green bananas.
Curr Opin Infect Dis. 2010;23: 475–480.
[PubMed: 20689423]
Sivapalasingam S, Nelson JM, Joyce K, et al. High prevalence of antimicrobial resistance among
Shigella isolates in the United States tested by the National Antimicrobial Resistance Monitoring System from 1999 to 2002.
Antimicrob Agents Chemother. 2006;50:49–54.
[PubMed: 16377666]
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Nontyphoidal Salmonellosis
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Salmonella organisms that cause disease in humans are a zoonosis widely distributed throughout the animal kingdom. Salmonellosis is the most common cause of foodborne enterocolitis in the United States. Most of the estimated one and a half to two million annual cases that occur in the United States result from ingestion of fecally contaminated, incompletely cooked food such as meat (especially poultry and ground beef), eggs, milk and other dairy products, contaminated vegetables, and even processed foods such as peanut butter. Direct person-to-person spread and spread from common and exotic pets, especially reptiles, occur. Outbreaks from contaminated water have been described.
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Salmonella typhimurium and Salmonella enteritidis are the most common causes in the United States, but other serotypes may be isolated. Unlike Shigella organisms, salmonellae are acid-sensitive; hence, a larger inoculum is required for induction of clinical illness. Reduction of gastric acid secretion through surgery, disease, or pharmacotherapy and prior antibiotic treatment that disrupts the normal intestinal flora reduce the number of organisms required to produce infection. The extremes of age, immunosuppression, and malignancy also predispose to infection. Salmonellae adhere to and invade the intestinal epithelium. They enter macrophages, in which virulent forms can survive and then may disseminate to distant sites.
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The clinical features of Salmonella gastroenteritis are not distinctive and vary from case to case. Nausea, vomiting, and fever are common early in the course followed by abdominal cramps and diarrhea, which may be voluminous. Dysentery may occur but is less common than in shigellosis or Campylobacter enterocolitis. In most healthy adults, the disease is self-limited, with fever abating within 2–3 days and diarrhea lasting no more than 10 days. Clinical features are often more severe in those with predisposing factors such as immunosuppression, in neonates and the elderly, and in those with other comorbidities. As there are no available tests for rapid diagnosis, confirmation awaits a positive stool culture, which requires 2–3 days. Blood cultures should be obtained in those with severe symptoms and those with conditions predisposing to disseminated or recurrent disease.
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There is general agreement that antibiotics are not indicated for individuals in good general health with mild to moderate illness who are not at the extremes of age. There is no convincing evidence that such treatment significantly alters the clinical course, and several studies indicate that antibiotic treatment prolongs fecal shedding of nontyphoidal Salmonellae. Thus, supportive care with rehydration forms the basis of treatment. Whether immunocompetent patients with more severe and prolonged illness should be treated is somewhat controversial. Some authorities favor a short course of antibiotics, such as 4–7 days of a fluoroquinolone in that setting. Also controversial is whether infected food handlers and health care workers should be routinely treated.
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More definite indications for antibiotic treatment include the immunosuppressed host; those with sickle cell disease or known atherosclerotic disease, in whom dissemination may cause osteomyelitis or infection of an atherosclerotic plaque; those with vascular grafts or orthopedic prostheses; and the elderly, especially those with additional comorbidities. Most authorities would recommend at least 2 weeks of treatment for these high-risk patients, with a choice of antibiotics guided by the antibiotic resistance pattern of the infecting organism and the patient's comorbidities.
Hohmann EL. Nontyphoidal salmonellosis.
Clin Infect Dis. 2001; 15:263–269.
[PubMed: 11170916]
Patrick ME, Adcock PM, Gomez TM, et al.
Salmonella enteritidis infections, United States, 1985–1999.
Emerg Infect Dis. 2004;10: 1–7.
[PubMed: 15078589]
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Like nontyphoidal Salmonella infections, Campylobacter species that infect humans, notably Campylobacter jejuni and Campylobacter coli, are carried by a wide array of domestic and wild species. Hence, human Campylobacter infections are second only to Salmonella as a cause of foodborne enterocolitis in the United States, with contaminated poultry responsible for approximately 50% of infections. However, beef, lamb, and pork, as well as contaminated water or improperly pasteurized milk, have caused major outbreaks. Like Salmonella and Shigella, Campylobacter adhere to and then invade the intestinal epithelium of the small intestine and colon, although the exact mechanisms of adhesion and invasion differ. Like Salmonella, Campylobacter species are acid-sensitive; as a result, conditions that reduce gastric acid secretion predispose to infection by reducing the number of ingested bacteria required to produce symptomatic disease. The immunosuppressed, especially AIDS patients, and the elderly with comorbid conditions are at risk of more severe Campylobacter-induced illness.
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The clinical features are not distinctive and often closely resemble those seen with shigellosis or nontyphoidal salmonellosis. After an average 3-day incubation period, a brief prodromal phase with fever and malaise in some patients is rapidly followed by crampy periumbilical abdominal pain and diarrhea. Hematochezia occurs in 30–50% of patients, and the abdominal cramps and diarrhea are often severe. Fever occurs in 70–90% of patients. The disease is usually self-limited, with recovery in 5–9 days, although a minority (~10%) of patients suffer a relapse, usually within a few days following apparent resolution. The abdominal pain in patients with Campylobacter infection may be severe and lead to consideration of other diagnoses, such as acute appendicitis, especially in children. As with Salmonella and Shigella infections, the clinical presentation and gross endoscopic appearance of the colonic mucosa in Campylobacter enterocolitis can be indistinguishable from the acute onset or an acute relapse of colitis caused by IBD, especially ulcerative colitis.
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Definitive diagnosis requires identification of Campylobacter in stool culture. A tentative diagnosis can be made more rapidly by microscopic examination of a stool suspension using phase-contrast or darkfield optics in those instances in which large numbers of Campylobacter organisms are excreted in diarrheal stool. The rapidly motile spiral-shaped organisms are characteristic.
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Antibiotics may shorten the duration of symptoms if given within 1–2 days of onset. However, as the diagnosis is rarely established that rapidly, and the disease is self-limited in otherwise healthy individuals, routine treatment is not recommended, although this may change as some data now indicate that antibiotic treatment may reduce the incidence of postinfectious irritable bowel syndrome. Supportive therapy with rehydration is recommended. Antibiotic treatment is indicated for patients with prolonged or relapsing illness, the immunosuppressed, those with serious comorbidities, and the elderly. A 3–5-day course of a macrolide such as erythromycin or azithromycin is recommended. Fluoroquinolones are an alternative, although resistance to this group of antibiotics is high, especially in parts of Asia.
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Rarely, reactive arthritis or Guillain-Barré syndrome may complicate C jejuni infection, with a range of onset of 1 week to 2 months after the presentation with gastrointestinal symptoms.
Kirkpatric BD, Tribble DR. Update on human
Campylobacter jejuni infections.
Curr Opin Gastroenterol. 2011;27:1–7.
[PubMed: 21124212]
Ternhag A, Askikainen T, Giesecke J, et al. A meta-analysis on the effects of antibiotic treatment on duration of symptoms caused by infection with
Campylobacter species.
Clin Infect Dis. 2007;44:696–700.
[PubMed: 17278062]
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Yersinia enterocolitica and Yersinia pseudotuberculosis produce enterocolitis with diarrhea in humans. Although Yersinia species are widespread throughout the animal kingdom, the strains pathogenic to humans do not produce disease in animals but may be carried by them, especially pigs. Ingestion of contaminated food—especially undercooked pork, but also vegetables grown in contaminated soil, dairy products, and contaminated water—transmits the infection to humans. Both outbreaks and sporadic infections occur in the United States and, more commonly, in Europe. Individuals with diseases that result in increased iron stores, such as hemochromatosis and thalassemia, appear to be more susceptible to infection. Yersinia organisms invade via the epithelium overlying lymphoid follicles, which are most abundant as aggregates in the ileum and cecum (Peyer patches) but are present along the length of the alimentary tract. The organisms then proliferate in the lymphoid tissues and can spread to regional mesenteric lymph nodes.
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After an incubation period of 1–10 days (median, 4 days), two major patterns of clinical symptoms develop. A typical acute enterocolitis with fever, abdominal cramps, diarrhea (which may be bloody), and, in the minority of patients, nausea and vomiting occurs. This presentation is nonspecific and indistinguishable from that observed with Salmonella, Shigella, or Campylobacter enteritis. However, the duration of symptoms among patients with Yersinia enterocolitis tends to be longer, averaging 2 weeks in several reported outbreaks. Also, in contrast to gastroenteritis caused by other invasive bacteria, pharyngitis involving the lymphoid-rich tonsils may accompany Yersinia enterocolitis. In the other pattern of illness seen most often in adolescents and young adults, diarrhea may be mild or absent, whereas severe right lower quadrant abdominal pain, fever, and leukocytosis predominate, often mimicking acute appendicitis. If such patients undergo surgery, an acute ileitis and mesenteric adenitis is usually observed.
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Diagnosis is best established by culture of Yersinia from stool, body fluids, or tissue, if surgical specimens are available. Throat culture may be positive, especially if pharyngitis is present. The laboratory should be alerted when Yersinia infection is suspected as screening for Yersinia is usually not routine. Serologic tests can be helpful; the presence of immunoglobulin M antibodies to Yersinia and a significant rise in antibody titers between acute and convalescent sera support the diagnosis of recent infections, although the latter is of little help during acute illness. In patients in whom symptoms mimic appendicitis, imaging of the right lower quadrant via CT or ultrasound is important; ileitis and mesenteric adenitis are usually present, but the appendix generally appears normal.
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Supportive therapy with hydration is the mainstay of treatment. There is no convincing evidence that antibiotic treatment alters the clinical course of uncomplicated Yersinia enterocolitis. Indications for treatment are the immunosuppressed host, complications such as invasive infections and septicemia, and, perhaps, patients with conditions associated with increased iron stores. If oral therapy suffices, in adults a fluoroquinolone and in children trimethoprim–sulfamethoxazole are recommended for 5–7 days. If intravenous administration is required, a third-generation cephalosporin is recommended for 2–3 weeks. Complications include reactive arthritis, erythema nodosum, and, rarely, other conditions with autoimmune overtones, including myocarditis, glomerulonephritis, thyroiditis, and hepatitis.
Black RE, Slome S.
Yersinia enterocolitica.
Infect Dis Clin North Am. 1988;2:625–641.
[PubMed: 3074119]
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Listeria monocytogenes is an invasive, gram-positive, rod-shaped organism resembling diphtheroids in appearance. Listeria monocytogenes is widely found in soil, many animal species, and foodstuffs, most notably cheese, sausage, and other processed delicatessen meats. L monocytogenes can proliferate in refrigerated foods. Most infections occur sporadically, but foodborne outbreaks have also been well documented.
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In otherwise healthy immunocompetent individuals, the organism invades the intestinal mucosa and causes a self-limited febrile gastroenteritis of relatively short duration, usually 2 days or less. Symptoms are nonspecific and include fever, malaise, muscle aches, nausea, vomiting, and diarrhea. Pregnant patients commonly present with a flulike illness with or without gastrointestinal symptoms. There is a predilection for invasion of placental tissue, especially during the last trimester, with spread of the organism to the fetus and fetal death or birth of an infected neonate. In immunosuppressed hosts and the elderly, there is a predilection for central nervous system invasion with resulting meningitis, meningoencephalitis, and, rarely, brain abscess.
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The diagnosis is usually made by culture of L monocytogenes from the blood and cerebrospinal fluid. The significance of isolation of the organism from the stool is unclear as it can be isolated occasionally from asymptomatic individuals. Isolation from stool requires the use of selective media not generally used for routine stool culture. Blood cultures should be obtained from pregnant and immunocompromised patients with febrile gastroenteritis.
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There is no evidence that antibiotic therapy influences the course of uncomplicated, febrile Listeria gastroenteritis in otherwise healthy patients; in many instances, the diagnosis is not established by bacterial isolation and, if it is, symptoms will have resolved. On the other hand, infection in pregnant, elderly, or immunosuppressed patients or in any individual with evidence of spread to other tissues should be treated. Ampicillin, penicillin G, and trimethoprim–sulfamethoxazole have been effective.
Ooi ST, Lorber B. Gastroenteritis due to
Listeria monocytogenes.
Clin Infect Dis. 2005;40:1327–1332.
[PubMed: 15825036]
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Several Vibrio species distinct from Vibrio cholerae, including Vibrio parahaemolyticus, can cause diarrheal disease in humans. These organisms thrive in high salt concentrations and are found in saltwater estuaries, especially in the summer and fall, although they also can contaminate fresh water. Most outbreaks and sporadic cases of diarrheal disease result from ingestion of contaminated raw or improperly cooked seafood, especially mollusks (eg, oysters, mussels, or clams) and crustaceans, including crab and shrimp. Most noncholera Vibrio species induce diarrhea by producing enterotoxins similar to the heat-labile toxin produced by V cholerae or a heat-stable toxin similar to that produced by ETEC. V parahaemolyticus produces hemolysins, which appear to correlate with virulence.
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The clinical features of noncholera Vibrio–induced gastroenteritis are nonspecific and include diarrhea, which may be grossly bloody in 25–30% of patients, abdominal cramps, fever, and, less commonly, nausea and vomiting. The duration of illness ranges from an average of 3 days for V parahaemolyticus to 6 days for the other noncholera Vibrio species. Most species may also cause wound infections and, especially in patients who are immunosuppressed or have liver disease, septicemia, the latter with mortality as high as 20%.
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Isolation from stool samples requires use of selective media; hence, the laboratory should be alerted that infection with noncholera Vibrio is suspected.
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Supportive therapy and hydration are the mainstays of treatment. Although controlled trials are lacking and diarrhea is self-limited in immunocompetent individuals, doxycycline or quinolones have been reported to reduce the duration of diarrhea and shedding of Vibrio organisms in the stool.
Daniels NA, MacKinnon L, Bishop R, et al.
Vibrio parahaemolyticus infections in the United States, 1973–1998.
J Infect Dis. 2000;981:1661–1666.
[PubMed: 10823766]
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Cholera is endemic in developing countries in Asia, Africa, and Central and South America and also causes epidemic outbreaks in these continents largely through contamination of water supplies and, less often, foodstuffs. In North America, a few sporadic cases have occurred in recent years, probably though ingestion of contaminated food, largely shellfish. There are more imported infections among travelers than sporadic indigenous infections in the United States. The recent major cholera epidemic in Haiti raises the possibility that an increase in imported infections may become evident in neighboring Caribbean islands and throughout the Western hemisphere including the United States. Vibrio cholerae is acid-sensitive; hence, a large inoculum is required to cause infection in individuals with normal gastric acid secretion. Surviving organisms colonize the small intestine by attaching to the epithelial surface via pili and subsequently elaborate toxins that induce electrolyte and water secretion and alter epithelial permeability in the absence of mucosal inflammation.
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Infections range from asymptomatic colonization to devastating, watery diarrhea with fluid losses that can approach 1 L/h. Vomiting may accompany the diarrhea, but a significant fever is uncommon. Massive fecal fluid losses, if not replaced, can rapidly lead to severe dehydration and profound electrolyte disturbances, including hypokalemia and metabolic acidosis, with associated renal failure. The epidemiologic history and clinical picture facilitate diagnosis. Vibrio can often be seen in stool examined by phase-contrast or darkfield microscopy and on Gram stain. V cholerae is cultured on selective media.
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Prompt rehydration is imperative. Oral rehydration solution (see "General Principles of Treatment," earlier) is sufficient for most infections and has saved hundreds of thousands of lives and reduced mortality from cholera to less than 1% in adults and older children. Ongoing stool fluid losses should be measured to help guide the volume of oral fluid administration. If dehydration is severe or nausea and vomiting preclude adequate oral intake, intravenous hydration is indicated. If facilities or supplies needed for intravenous hydration are unavailable, oral solutions should be administered via nasogastric tube, although aspiration is a hazard. Antibiotics (tetracycline, doxycycline, or azithromycin, depending on susceptibility) reduce fluid losses and shorten the duration of diarrhea. The rBS-WC vaccine, an oral, killed, whole cell vaccine containing the nontoxic cholera toxin B subunit, has recently been approved for use for prophylaxis of traveler's diarrhea (see later) and provides significant protection against V cholerae and ETEC infections.
Seas C, Gotuzzo E. Vibrio cholerae. In: Mandell GL, Bennett JE, Dolin R (editors). Principles and Practice of Infectious Diseases, 6th ed. Churchill Livingston, 2005:2536.
Tobin-D-Angelo M, Smith AR, Bulens SN, et al. Severe diarrhea caused by cholera toxin-producing
Vibrio cholera serogroup O75 infections acquired in the southeastern United States.
Clin Infect Dis. 2008;47:1035–1040.
[PubMed: 18781876]
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Aeromonas species, like noncholera vibrios, thrive in brackish and freshwater environments but also cause disease in fish as well as many land animals. They produce several toxins, adhesins, hemolysins, and proteases, but the exact role of these putative virulence factors in the pathogenesis of disease in humans remains uncertain.
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The role of Aeromonas species in human diarrheal disease is somewhat controversial. Although small outbreaks among travelers are described and the organisms are sporadically cultured from patients with diarrheal disease, Aeromonas have been isolated from 5–15% of asymptomatic individuals in developing countries. An effort to induce disease in normal volunteers by oral challenge was inconclusive. However, there is general consensus that some Aeromonas species can cause diarrheal disease in some individuals.
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Symptoms range from watery to dysenteric diarrhea and may be accompanied by nausea and vomiting and, in the minority of patients, fever. Although most cases are self-limited, more protracted diarrhea lasting several weeks has been observed. Aeromonas, like noncholera vibrios, can also cause wound infections. Gram-negative sepsis may occur in immunosuppressed patients or patients with liver disease. The diagnosis is made by stool culture, but the laboratory should be alerted that Aeromonas species are being sought. Although Aeromonas grows readily on conventional media, identifying these organisms is not generally routine.
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The disease is self-limited in most patients with Aeromonas-associated diarrhea. Anecdotal reports suggest that patients with protracted diarrhea merit antibiotic treatment with trimethoprim–sulfamethoxazole or a fluoroquinolone, depending on the results of susceptibility testing. Controlled trials showing the benefit of antibiotic treatment are not available.
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Plesiomonas shigelloides, like Aeromonas species, is widely distributed in aquatic environments and among a broad range of sea and land animals. Rare or undercooked shellfish, notably oysters, as well as contaminated water have been incriminated in outbreaks of human diarrheal disease. Unlike Aeromonas, the carriage rate among asymptomatic individuals is very low. However, like Aeromonas, an attempt to induce disease in volunteers was inconclusive.
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The pathogenesis of Plesiomonas-induced gastroenteritis is poorly understood, and specific disease-producing virulence factors have not been identified. The clinical features closely resemble those of Aeromonas-induced gastroenteritis and range from watery to, in the minority of patients, dysenteric diarrhea. Nausea and vomiting are common, and abdominal cramps may be present. Fever is uncommon. Although most cases are self-limited with only a few days of symptoms, prolonged diarrhea has been reported. Diagnosis is generally made by culture of P shigelloides from the stool, but again, the bacteriology laboratory should be notified that the organism is being sought.
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There are no available controlled trials defining efficacy of treatment with antibiotics. Most cases require no more than supportive treatment. Patients who are immunocompromised and those who have chronic liver disease, bacteremia, extraintestinal infections, or prolonged diarrhea should be treated. Trimethoprim–sulfamethoxazole, quinolones, and cephalosporins are usually effective, but the choice of antibiotic should be guided by sensitivity testing.
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Enterotoxigenic E Coli (ETEC)
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ETEC have been recognized for years as a major cause of diarrheal disease in infants and children younger than 2 years of age in the developing world and, in some series, as the most common cause of traveler's diarrhea at any age. In recent years, large outbreaks in the United States and Europe have also been reported. Transmission generally is via contaminated food or water, and a large inoculum is required. Important virulence factors characterizing ETEC are heat-labile toxin (LT) and a heat-stable toxin (STa). LT closely resembles cholera toxin, stimulating cyclic adenosine monophosphate production, resulting in intestinal crypt chloride and water secretion and reduced sodium chloride absorption by enterocytes. STa stimulates cyclic guanosine monophosphate production, which, much like LT, causes enhanced chloride and water secretion and impaired sodium chloride absorption by the small intestine.
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The major clinical manifestation is diarrhea, which ranges from just a few loose stools lasting less than a day to severe, watery diarrhea that may persist for several days to a week and result in significant dehydration. Fever is uncommon and, when present, low grade. Nausea and abdominal cramps may accompany the diarrhea, but vomiting is uncommon.
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As in cholera, the involved mucosa is not inflamed; hence, fecal leukocytes are absent. ETEC require research techniques (serotyping or bioassay) for identification; they cannot be differentiated from nonpathogenic E coli by routine stool culture. In the absence of research facilities, the diagnosis is a clinical one.
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Rehydration, again, is the cornerstone of therapy; short courses of antibiotics, including fluoroquinolones and rifaximin, shorten the duration of illness by a day or so. Lack of a definitive diagnosis in most instances and the self-limited nature of the illness limit their therapeutic use. Prophylaxis is discussed later in the section on traveler's diarrhea.
Beatty ME, Adcock PM, Smith SW, et al. Epidemic diarrhea due to enterotoxigenic
Escherichia coli.
Clin Infect Dis. 2006;42: 329–334.
[PubMed: 16392076]
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Enteropathogenic E Coli (EPEC)
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EPEC primarily cause disease in infants and children younger than 2 years of age. Older children and adults may harbor the causative organism, but overt illness is uncommon. Both outbreaks and sporadic episodes are most common in developing countries. EPEC attaches to the brush-border surface of enterocytes, activating signal transduction pathways. These activated pathways in turn alter cytoskeletal components, resulting in the effacement of the absorptive surface as well as increased epithelial permeability and altered epithelial barrier function. The resulting diarrhea in neonates and young children can be severe, may be associated with vomiting, and can cause severe dehydration. Most cases are self-limited.
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Some commercial laboratories offer a Hep-2 cell adherence assay, but definitive diagnosis usually requires the resources of reference or research laboratories. Rehydration therapy is critical. Antibiotics appear effective; trimethoprim–sulfamethoxazole and colistin have been used.
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Enteroaggregative E Coli (EAEC)
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EAEC are a relatively recently recognized diarrhea-causing phenotype of E coli. EAEC cause disease in all ages and have been identified in both developing and fully industrialized countries. In one recent study, EAEC was detected in 4.5% of patients presenting with diarrhea to emergency rooms of two academic centers in Baltimore and New Haven. There is evidence that transmission by contaminated food is a major source of infection. EAEC adhere to cultured Hep-2 cells in a characteristic "stacked brick" fashion; hence, the term aggregative has been included in their name. Cytotoxin and enterotoxin secretion and specific adherence factors together with still other virulence factors have been incriminated, but the pathogenesis of diarrhea caused by EAEC is incompletely understood.
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Watery diarrhea is a prominent clinical feature and may be accompanied by low-grade fever and abdominal pain. Bloody diarrhea has been reported. Although many episodes of diarrhea are self-limited, EAEC has been identified in stools of children in developing countries and in adults with AIDS in the United States and Europe with chronic diarrhea.
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Identification of EAEC in stools requires use of the Hep-2 adherence assay, which is not performed in conventional clinical laboratories. Ciprofloxacin, rifaximin, and azithromycin have been reported to be effective therapy, shortening the duration of diarrhea caused by EAEC.
Huang DB, Nataro JP, DuPont HL, et al. Enteroaggregative
Escherichia coli is a cause of acute diarrheal illness: a meta-analysis.
Clin Infect Dis. 2006;43:556–563.
[PubMed: 16886146]
Nataro JP, Mai V, Johnson J, et al. Diarrheagenic
Escherichia coli infection in Baltimore, Maryland and New Haven, Connecticut.
Clin Infect Dis. 2006;43:402–407.
[PubMed: 16838226]
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Enteroinvasive E Coli (EIEC)
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EIEC is a relatively uncommon cause of diarrhea found largely in developing nations and, occasionally, among travelers returning to industrialized nations. It shares virulence factors with Shigella strains and invades intestinal epithelial cells, causing mucosal inflammation. The clinical picture is identical to that observed in shigellosis (see earlier discussion), with watery diarrhea often progressing to dysentery accompanied by fever and, in some patients, nausea and vomiting. Diagnosis requires DNA-probe testing by reference or research laboratories. Treatment guidelines follow those for shigellosis; severe cases, especially in children or immunocompromised adults, should be treated with fluoroquinolone (adults) or azithromycin (children) along with vigorous rehydration as needed.
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Enterohemorrhagic E Coli (EHEC)
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Since its description 25 years ago, EHEC has become recognized as a major health problem. Over 50% of outbreaks are foodborne. EHEC inhabit the intestinal tract of cattle, deer, sheep, and goats, and outbreaks have been traced to undercooked meat, especially ground beef, contaminated vegetables, fruit, and fruit products. Contaminated recreational water sites and direct animal contact, especially at petting zoos, have also been incriminated in outbreaks. Person-to-person contact in venues such as day care centers or nursing homes may also cause outbreaks as only a small inoculum (<100 organisms) can induce disease.
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Following ingestion, EHEC adhere to gut epithelial cells and cause epithelial apical surface effacement by mechanisms similar to EPEC. All EHEC strains produce one or more Shiga toxins, which, on entering the systemic circulation, damage endothelial cells, producing vascular damage that may contribute to bloody diarrhea and predispose to hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and microangiopathic hemolytic anemia. E coli O157:H7 is the most common EHEC serotype isolated in the United States, but other Shiga toxin-producing serotypes are being increasingly isolated from outbreaks in the United States and other countries.
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After an average incubation period of 3–5 days, the illness often begins with watery diarrhea for 2–5 days, progressing to bloody diarrhea in up to 90% of patients. Severe cramps and abdominal pain are common, with right lower quadrant tenderness prominent in some patients. Notably, fever is absent in most patients and, when present, is low grade. Peripheral leukocytosis of 10,000–20,000/μL is common. The duration of gastrointestinal symptoms can be only a few days to as long as 2 weeks or more. In some outbreaks, E coli O157:H7 has been isolated from patients with much milder or no symptoms, further suggesting a broad range of severity of clinical manifestations.
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Endoscopy, if performed, shows a friable, edematous, erythematous colonic mucosa with superficial ulceration. Imaging studies show colonic wall thickening, thumbprinting, and, if contrast is used, mucosal hyperemia, which is often most severe in the right colon. Fecal leukocytes may or may not be present.
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The diagnosis can often be suspected from the clinical presentation (bloody stools, abdominal pain, leukocytosis, but little or no fever) and is confirmed by stool cultures using sorbitol-MacConkey agar. An ELISA that detects Shiga toxins in the stool is also available, but occasional false-positive results have been reported.
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Treatment is supportive. Rehydration is important. Antimotility agents should be avoided. There is no evidence that antibiotic treatment provides any benefit in EHEC colitis. Indeed, some series indicate that in children, antibiotic treatment increases the risk of associated hemolytic uremic syndrome. A trial of administration of a Shiga toxin-binding agent to children with diarrhea and hemolytic uremic syndrome showed no benefit when compared with placebo.
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Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and microangiopathic anemia are the dreaded complications of EHEC infection and occur most often in children younger than 10 years, although older children and adults are not always spared. Details of treatment for these conditions are beyond the scope of this chapter, but treatment is largely supportive, often requiring dialysis for renal disease and, less often, plasma exchange for thrombotic thrombocytopenic purpura.
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;342:1930–1936.
[PubMed: 10874060]
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Staphylococcus Aureus
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Staphylococcus aureus gastroenteritis is a common cause of food poisoning. The causative food is often contaminated by a food handler. Foods rich in sugar and cream, such as custards, cakes with creamy frostings, salty meat such as ham, and mayonnaise- and cream-containing salads favor Staphylococcus growth and enterotoxin production at room temperature. Within 6 hours of ingestion of foodstuffs containing sufficient toxin, patients develop nausea and vomiting, which may be severe; abdominal cramps; and subsequently, in some, diarrhea. Fever is uncommon. Duration of symptoms rarely exceeds 24 hours, and rapid recovery is the rule.
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The diagnosis can best be established by isolating S aureus or enterotoxin from the suspected food if an outbreak is suspected. Additionally, vomitus or diarrheal stool can be tested for enterotoxin, but this in not routinely done. Treatment is supportive, with hydration and correction of metabolic alkalosis, if present, due to severe vomiting.
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Bacillus cereus, a gram-positive, spore-forming bacillus, can produce two distinct types of food poisoning. Some strains produce a heat-stable toxin in vitro that induces vomiting; other strains produce a heat-labile enterotoxin that causes diarrhea.
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The organisms that produce the vomiting syndrome have largely been associated with ingestion of rice, notably fried rice. The vegetative forms are destroyed when rice is boiled, but the spores survive. If the rice is not refrigerated, the spores germinate and toxin is produced that may not be inactivated by flash frying as the fried rice is prepared. A short 2–3-hour incubation period follows toxin ingestion. Then vomiting associated with abdominal cramping develops, which may be associated with mild diarrhea. The illness is self-limited, averaging about 8 hours, and can be treated with antiemetics and, if needed, rehydration. The organisms that produce the diarrheal syndrome have been associated with contaminated meats, sauces, and dairy products. Their longer incubation following ingestion of contaminated food (6–18 hours) suggests that the enterotoxin is produced in vivo. Major symptoms include diarrhea and abdominal cramps; vomiting occurs in less than 25% of cases. Symptoms usually clear within 24 hours and should be treated supportively with rehydration, if needed.
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Clostridium Perfringens
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Clostridium perfringens is a gram-positive, anaerobic, spore-forming bacillus widely found in nature in the intestinal flora of many animals and in soil. Type A strains produce a heat-labile enterotoxin that causes intestinal fluid secretion and is also cytotoxic to intestinal epithelium. Disease is caused almost exclusively by ingested meat that is inadequately refrigerated after cooking. After a 12–24-hour incubation, patients develop watery diarrhea and abdominal crampy pain that may be severe, usually in the absence of nausea, vomiting, or fever. Symptoms generally last less than a day and treatment is supportive; oral rehydration is usually sufficient. Type C strains can produce a much more severe illness, which has been termed enteritis necroticans or pigbel. It is characterized by intestinal necrosis that may produce perforation requiring surgery. Mortality rates as high as 40% have been reported. This disease has been described largely in South Pacific islands after festive consumption of large amounts of improperly cooked pork.
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Clostridium Difficile
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Clostridium difficile, a gram-positive, spore-forming bacillus, is the major cause of hospital-acquired infectious diarrhea but can also cause community-acquired diarrhea albeit less frequently. C difficile spores are heat and alcohol resistant and can remain infectious in vitro. They may colonize up to 40% of hospitalized patients and 3% of healthy individuals.
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Alteration of the normal enterocolonic bacterial flora by prior antibiotic administration is required for the development of C difficile colitis in the large majority of those who develop the disease. Antibiotics most often associated with C difficile-induced disease include aminopenicillins, fluoroquinolones, cephalosporins, and clindamycin, but virtually all antibiotics, even metronidazole, have been incriminated. Occasionally, cancer chemotherapy or preexisting IBD, especially with colonic involvement, appears to trigger C difficile colitis. Increasingly, the disease appears to develop in the absence of antecedent antibiotic administration even in otherwise healthy individuals. Other risk factors for development of C difficile infection include prolonged exposure in any health care facility, debilitating comorbidities, gastrointestinal surgery, and old age. Although still controversial, there is increasing evidence that chronic acid suppression with proton pump inhibitors and, to a lesser degree, H2-receptor antagonists increase the risk for developing C difficile colitis or its recurrence after seemingly effective treatment.
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Upon colonizing the intestine, most virulent C difficile strains produce toxin A and toxin B. These induce colonic epithelial cytoskeletal damage, mucosal inflammation, and mucosal fluid secretion, resulting in the clinical features described below. The toxin-induced mucosal lesion is characterized by damaged epithelium, mucosal inflammation, and the exudative pseudomembrane, which consists of necrotic debris, inflammatory cells, and mucus adherent to the mucosal surface. Strains that produce only toxin B have been isolated from patients with clinically manifest C difficile colitis.
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Recently, the highly virulent strain of C difficile (BI/NAP1/027 or PCR ribotype 027) has been identified in North American and European outbreaks. This toxinotype III strain has been shown to produce up to 16- and 23-fold greater amounts of toxin A and B, respectively. This has been ascribed to a partial deletion of the tcdC gene that normally downregulates toxin A and toxin B production. This highly virulent strain has emerged in concert with the wide use of fluoroquinolones, is frequently resistant to fluoroquinolones, and has been implicated in the increasing frequency and morbidity of C difficile enterocolitis in North America and in Europe. Another high toxin-producing hypervirulent strain (PCR ribotype 078, toxinotype V) has been isolated more recently with increasing frequency in Europe and North America.
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The clinical features of C difficile colonization may range, at the one extreme, from total lack of symptoms in carriers to, at the other extreme, fulminant diarrhea and toxic megacolon requiring emergency surgery. Symptoms usually begin a few days to 2 weeks after initiation of antibiotic treatment, although the latency period may be as long as several months. Malaise, watery diarrhea, lower abdominal pain and tenderness, and low-grade fever are characteristic features. Frank hematochezia is rare, although occult blood loss is common. Mild peripheral leukocytosis is common, and fecal leukocytes are often present, especially in patients with more than mild colitis.
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It should be stressed that many of the milder episodes of diarrhea that occur in concert with antibiotic treatment are not infectious in nature. Rather, alterations in the balance of the colonic flora impair salvage carbohydrate digestion and absorption. As a result, the amount of unabsorbed carbohydrates in the colonic lumen is increased, resulting in an osmotic diarrhea.
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Demonstration of C difficile diarrhea cytotoxin in stool samples is the gold standard for establishing the diagnosis of C difficile colitis. This test is performed by culturing fibroblasts in the presence of stool supernate. If toxin is present, the fibroblasts show evidence of cytotoxicity. Sensitivity and specificity of this test range from 95–99%, but the assay requires 2–3 days. Available enzyme immunoassays (EIAs) are more rapid and less costly, but less sensitive, and may miss 10–20% or more of stool samples that are positive when tested using the cytotoxicity assay. Some laboratories employ a two-step algorithm, initially utilizing an EIA for glutamate dehydrogenase (GDH), an enzyme produced by C difficile whether or not it is a toxigenic strain, followed by an EIA for toxin in GDH-positive stools. A recently approved rapid direct stool PCR assay is a promising diagnostic tool with reported high sensitivity and specificity.
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In some patients, an immediate, albeit only provisional, diagnosis can be made at anoscopy or sigmoidoscopy if the characteristic pseudomembrane is observed. However, the absence of the pseudomembrane does not exclude C difficile colitis as the disease may be confined to the more proximal colon and the rectum and distal colon may be spared. Moreover, not all patients with C difficile colitis develop the characteristic pseudomembrane. Imaging studies including abdominal flat films or abdominal CT are nonspecific and may show colonic wall thickening and mucosal contrast enhancement. In patients with fulminant colitis, ileus or toxic megacolon may be evident.
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Worrisome signs suggesting fulminant, potentially life-threatening colitis include florid diarrhea in excess of 10 stools per day; abrupt reduction of diarrhea in the absence of other signs of clinical improvement, which may signal the development of toxic megacolon; increasing abdominal pain and distention; high fever; hypotension, especially if pressors are required; hypoalbuminemia; a rising serum creatinine; and colonic dilation on imaging. Patients showing such symptoms and signs must be monitored closely in conjunction with a surgeon and may require vigorous therapeutic intervention (see below).
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Treatment recommendations depend on the severity of clinical illness and host of risk factors. Hospitalized patients should be isolated, and in all cases, caregivers should wash their hands with soap and water after patient contact. Purell and other alcohol-based hand cleaners do not destroy C difficile spores.
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Recently, treatment guidelines have been published by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Whenever possible, causative antibiotics should be discontinued and antimotility agents should be avoided. For patients with mild to moderate disease, metronidazole (500 mg three times daily for 10–14 days) should be begun as the initial treatment. In patients with severe disease, oral vancomycin (125 mg every 6 hours for 10–14 days) should be started. A limitation of these guidelines is that clear-cut definitions or firm consensus on what constitutes mild, moderate, and severe disease are lacking in the literature. Clearly, diarrhea in excess of 8–10 stools/24 h, leukocytosis >15,000/μL, fever >101°F, hypoalbuminemia, and a rising creatinine point to severe disease. For patients with disease characterized by fulminant diarrhea (>10 stools/24 h), fever greater than 102°F, leukocytosis >25,000/μL, marked abdominal pain or tenesmus, colonic dilation, or hemodynamic instability, both vancomycin orally or via nasogastric tube (500 mg every 6 hours) and intravenous metronidazole (500 mg every 8 hours) should be begun. In addition, if ileus is present, intracolonic administration of vancomycin (500 mg four to six times daily) should be considered. These very ill patients should be closely monitored with frequent abdominal examinations and daily abdominal flat films to assess for developing megacolon along with serial surgical assessment for the possible need for colectomy. Metronidazole or vancomycin, or both, should be continued for at least 14 days or for 10 days after symptoms have disappeared. Emergency colectomy may be lifesaving in those few patients who develop progressive fulminant diarrhea, severe ileus, and megacolon with impending perforation or generalized sepsis.
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Management of patients with C difficile infection complicating IBD can be challenging as the clinical presentations of C difficile colitis and a flare of IBD can be quite similar. If such a patient fails to improve promptly with treatment for C difficile colitis, appropriate concurrent treatment of the coexistent IBD should be implemented.
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Relapses after apparent complete resolution occur in approximately 10–25% of treated patients, most likely caused by reinfection or germination of residual spores remaining in the colon. Retreatment should follow the guidelines outlined above for initial therapy as there is no evidence that antibiotic resistance plays a role. If there are multiple relapses, tapering doses of vancomycin can be tried, starting with 125 mg four times daily and then reducing the dose frequency by 50% every week until 125 mg of vancomycin every 3 days has been administered for 2 weeks. If that fails, other antibiotics, including nitazoxanide, bacitracin, rifampin, or rifaximin, can be tried. The role, if any, of probiotics in the prevention or treatment of C difficile colitis remains unclear. As a last resort, intravenous immunoglobulin G can be tried, as some responses of refractory C difficile colitis to this treatment have been reported. In a recently published promising study, neutralizing human monoclonal antibodies against C difficile toxins A and B were administered intravenously to patients simultaneously being treated for C difficile colitis with metronidazole or vancomycin. The incidence of recurrent C difficile colitis was reduced approximately fourfold in recipients of the antibodies compared to randomized placebo recipients. Recently the macrocyclic antibiotic, fidaxomicin, which appears to have therapeutic equivalence to vancomycin with a lower incidence of post-treatment recurrence has been approved for treatment of C. difficile colitis.
Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for
Clostridium difficile infection in adults: 2010 update by the Society for Healthcare and Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).
Infect Control Hosp Epidemiol. 2010;31:431–455.
[PubMed: 20307191]
McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant strain of
Clostridium difficile. N Engl J Med. 2005;353:2433–2441.
[PubMed: 16322603]
O'Connor JR, Johnson S, Gerding DN.
Clostridium difficile infection caused by epidemic BI/NAP1/027 strain.
Gastroenterology. 2009;136:1913–1924.
[PubMed: 19457419]
O'Donoghue C, Kyne L. Update on
Clostridium difficile infection.
Curr Opin Gastroenterology. 2011;27:38–47.
[PubMed: 21099432]
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Klebsiella oxytoca causes a relatively uncommon but distinctive antibiotic-associated hemorrhagic colitis. K oxytoca has been shown to produce a cytotoxin that has been implicated in the pathogenesis of colitis. Colitis generally occurs during the first week after the introduction of antibiotic therapy, usually with a penicillin, although cases that occurred in concert with administration of other antibiotics, including cephalosporins and quinolones have been described. Most reported patients have been relatively young to middle aged. Bloody diarrhea (uncommon in C difficile colitis), abdominal cramps, low-grade fever, and mild to moderate leukocytosis are clinical features. The rectum is often spared, and a patchy hemorrhagic colitis with superficial ulcers but without a pseudomembrane is observed in colonic segments. Mucosal biopsies show an ulcerated mucosa that resembles the lesion observed in patients with EHEC with both inflammatory and ischemic features. The condition is generally self-limited, resolving promptly after the discontinuation of the causative antibiotic and requires only supportive treatment.
Högenauer C, Langner C, Beubler E, et al.
Klebsiella oxytoca as a causative organism of antibiotic-associated hemorrhagic colitis.
N Engl J Med. 2006;355:2418–2426.
[PubMed: 17151365]
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Giardia lamblia is the most common protozoal infestation in the United States, where it occurs both endemically and in epidemic outbreaks. It is a common cause of illness worldwide, especially in the developing world where sanitation is suboptimal and, hence, is a common cause of traveler's diarrhea. G lamblia infects other mammals, including beavers, dogs, and cattle. The cyst form of Giardia can survive for prolonged periods in most environments. Once cysts are ingested, the distinctive trophozoites are released in the upper small intestine where they multiply by binary fission and colonize the host. The trophozoites attach to the intestinal epithelium but do not invade the mucosa; however, they can produce significant enteritis with mucosal inflammation and architectural changes. Hence, biopsy specimens can range from those revealing normal mucosal structure to an almost flat mucosa architecturally reminiscent of a lesion of severe celiac sprue.
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Several factors increase the risk of contracting G lamblia infection. These include travel to areas where the water supply may be contaminated, drinking mountain and forest stream or lake water that has not been filtered or boiled, attendance at day care or preschool, and swimming in pools with improperly treated water or in contaminated lakes. The risk of developing giardiasis is higher in patients with immunoglobulin deficiencies and in homosexuals, although, interestingly, HIV infection by itself is not a risk factor.
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Approximately 50% of individuals infested with G lamblia have no symptoms and can be asymptomatic carriers of the parasite for many months. Those that develop symptoms commonly experience diarrhea, flatulence, abdominal cramps, and epigastric pain and nausea. Approximately one third of symptomatic patients experience vomiting. Significant malabsorption with steatorrhea and weight loss may develop. If left untreated, most symptomatic patients recover spontaneously and eliminate the parasite within 3–4 weeks. However, up to a quarter develop chronic infection if untreated, which may result in significant signs and symptoms of intestinal malabsorption (see Chapter 20).
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Stool examination for ova and parasites has been used for years to establish the diagnosis, but a single specimen has a yield of only approximately 50%, whereas examination of three separate stool samples increases the yield of positive examinations to 80–90%. The cysts and trophozoites may be seen in diarrheal stools, but only cysts are usually observed in formed stools. Several stool immunoassays, including an ELISA with reported sensitivities and specificities approaching 100%, are now being widely used by clinical laboratories. Though rarely needed now, sensitivity and specificity of examining duodenal aspirates and mucosal biopsies for trophozoites also approach 100%. It is wise to exclude the diagnosis among household members of symptomatic patients.
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Metronidazole (250 mg three times daily for 5–7 days) is the most commonly used treatment. Although the drug is not approved by the U.S. Food and Drug Administration (FDA) for treatment of giardiasis, reported efficacy rates from a single course of therapy are in the 85–95% range. A single 2-g dose of tinidazole has been reported to be 90% effective. The effectiveness of albendazole is similar to that of nitroimidazoles. Nitazoxanide (500 mg twice daily for 3 days) is 85% effective and also treats other protozoa such as Entamoeba and Cryptosporidium. Paromomycin is recommended for the treatment of pregnant patients.
Rossingnol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by
Giardia intestinalis and
Entamoeba histolytica or
E. dispar: a randomized, double-blind, placebo-controlled study of
nitazoxanide.
J Infect Dis. 2001;184:381–384.
[PubMed: 11443569]
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Cryptosporidia are widely found in the animal kingdom. Two coccidial species, Cryptosporidium hominis and Cryptosporidium parvum, are responsible for most human infections. Cryptosporidiosis is transmitted via contaminated food or water, human-to-human contact, and, occasionally, animal-to-human contact. Major waterborne outbreaks have been well documented. Ingestion of a small number of oocysts can produce colonization and disease. The oocysts release sporozoites, which attach to and invade endodermal epithelia. Ultimately, newly formed oocysts are excreted in large numbers in stools of infected individuals. Both cellular and humoral immune defects predispose to symptomatic disease; indeed, many of the earlier recognized cases of cryptosporidial infection coincided with the recognition of HIV infection.
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Although Cryptosporidium can cause biliary tract, pancreatic, and respiratory tract disease (see Chapter 10), intestinal infection is the most common manifestation. Infected persons may remain asymptomatic or develop an enteritis characterized by watery diarrhea, abdominal cramps, nausea, and malaise, which usually resolves spontaneously in 2–3 weeks in immunocompetent hosts. The diarrhea can be voluminous, especially in immunosuppressed patients in whom chronic infections with debilitating secretory diarrhea and weight loss may develop.
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The diagnosis rests upon identification of cryptosporidia organisms in stool, bile, or tissue samples. A modified acid-fast stain of stool has high specificity but mediocre sensitivity and requires the examination of at least three stool specimens if initial specimens are negative. Fluorescent ELISA tests for stool examination have high specificity and sensitivity, as does a PCR-ELISA assay that is now commercially available. Intestinal mucosal biopsy samples often reveal cryptosporidia within the extreme apical cytoplasm of the enterocytes.
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If treatment is required for immunocompetent patients, nitazoxanide is the drug of choice, although spontaneous resolution of symptoms is the rule. Immunosuppressed patients can also be treated with nitazoxanide, although only some respond. An attempt to restore immunologic competence with highly active antiretroviral therapy (HAART) in HIV-infected patients is crucial. Other agents that have been tried, with generally disappointing results, include paromomycin, metronidazole, clarithromycin, and other antibiotics. Supportive treatment with hydration and antidiarrheal agents is important in the immunosuppressed, and parenteral nutrition may be required. Octreotide has been tried, but few patients respond.
Smith HV, Corcoran, GD. New drugs for the treatment for cryptosporidiosis. Curr Opin Infest Dis. 2004;17:557–564.
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Cyclospora Cayetanensis
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Cyclospora cayetanensis, like Cryptosporidium and Isospora, is a coccidian that is widely distributed geographically and, hence, a cause of traveler's diarrhea. In immunosuppressed patients, it is a cause of protracted diarrheal illness. The major recognized vectors for human infection in the United States have been contaminated fruits and vegetables, although contaminated water is also likely in developing countries.
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After a relatively prolonged 1-week incubation period, patients develop watery diarrhea, flatulence, abdominal cramps, and malaise. The illness even in immunocompetent hosts may range from minimal to no symptoms to prolonged illness lasting several weeks and even months if left untreated. In immunosuppressed hosts, especially AIDS patients, prolonged, debilitating illness virtually identical to that caused by other coccidia (Cryptosporidium or Isospora) may develop. Diagnosis is established by demonstrating oocysts in the stool. The oocysts are autofluorescent; hence, fluorescence microscopy is useful. Alternatively, modified acid-fast staining is used. Biopsies of the intestinal mucosa reveal mucosal inflammation and protozoal epithelial invasion.
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Trimethoprim–sulfamethoxazole (160 mg/800 mg twice daily for 1 week) is effective treatment for otherwise healthy hosts; larger doses and more prolonged treatment are indicated for immunosuppressed patients. Ciprofloxacin or nitazoxanide can be used for patients intolerant of trimethoprim–sulfamethoxazole.
Herwaldt BL.
Cyclospora cayetanensis: a review, focusing on the outbreaks of cyclosporiasis in the 1990s.
Clin Infect Dis. 2000;31:1040–1057.
[PubMed: 11049789]
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Isospora belli, like the other coccidial pathogens, is widely distributed geographically. Ingestion of contaminated food or water and person-to-person contact are probably important in transmission. Travelers and immunosuppressed patients are most likely to be infected, but sporadic illness in otherwise healthy hosts occurs in the United States and other developed countries.
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Clinical features are not specific and include diarrhea, abdominal discomfort, steatorrhea, weight loss, nausea, vomiting, and malaise. Symptoms are generally self-limited in immunocompetent patients but may wax and wane for months without specific treatment. Among AIDS and other severely immunosuppressed patients, protracted illness with severe diarrhea, malabsorption, and weight loss is the rule without specific therapy.
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The diagnosis is established by identifying oocysts in the stool using autofluorescence or modified acid-fast staining. Oocysts can also be identified in duodenal aspirates, and examination of mucosal biopsy specimens reveals invasive protozoal forms in the epithelium as well as mild to severe enteritis with mild to marked architectural changes and a mixed inflammatory infiltrate containing many eosinophils. Peripheral eosinophilia may also be present.
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Treatment with trimethoprim–sulfamethoxazole for 3–4 weeks is effective in most patients, but more prolonged and even indefinite treatment may be required in AIDS and other immunosuppressed patients to prevent frequent relapses. Quinolones have been used successfully in those intolerant of trimethoprim–sulfamethoxazole. Where possible, immune reconstitution with HAART treatment is important for AIDS patients.
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Entamoeba Histolytica
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Entamoeba histolytica infection occurs throughout the world, but the highest prevalence rates are found in developing countries in Asia, Africa, and Central and South America, where sanitation is suboptimal. Simply finding amoeba by microscopic examination in stool in the course of epidemiologic studies and clinical evaluation is compromised by the fact that only 10% of E histolytica infections are symptomatic and that two noninvasive, nonpathogenic species, Entamoeba dispar and Entamoeba moshkovskii, colonize humans with far greater frequency than does E histolytica.
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E histolytica cysts are ingested by consuming contaminated food or water or via fecal-oral contact, often during sexual activity; hence, there is a higher prevalence among homosexuals. Following excystation, trophozoites bind to the colonic epithelial glycocalyx sugars via a trophozoite surface lectin and subsequently invade the colonic mucosa, causing inflammation and ulceration. Systemic dissemination may occur, most often to the liver, resulting in abscess formation.
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Clinically, colonic colonization by E histolytica produces a wide spectrum of symptoms ranging from no symptoms in the majority of patients to devastating pancolitis with toxic megacolon, requiring emergency colectomy and carrying a mortality rate as high as 50%. In most symptomatic individuals, mild initial diarrhea progresses to dysentery with blood and mucus in the stool and crampy abdominal pain, often with tenesmus. Low-grade fever may be present in the minority of amoebic colitis patients. Anemia and hypoalbuminemia may be present depending on the severity and duration of the colitis. The clinical features can closely mimic ulcerative colitis or Crohn colitis. Indeed, it is crucial to exclude amoebiasis before administering corticosteroids or other immunosuppressive drugs to presumed ulcerative colitis patients to avoid precipitating fulminant amoebic colitis with toxic megacolon or perforation. Localized infections may produce mass lesions (amoebomas), mimicking colonic malignancy.
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Testing for E histolytica-specific antigen in the stool is now available and has the advantage of selective identification of E histolytica and not morphologically identical nonpathogenic strains. Sensitivities and specificities in the range of 90% have been reported. Stool microscopy is less sensitive and less specific. Using stool concentration techniques and special stains, examination of three specimens results in a sensitivity of approximately 85%. Sigmoidoscopy with collection of mucus from ulcers for microscopy and biopsy samples from the edge of ulcers may supplement antigen testing and stool microscopy. Blood serologic testing is also useful in that absence of antibodies in someone with 7–10 days of symptoms makes the diagnosis less likely. Because antibody levels may persist for prolonged periods after exposure, a positive serologic test does not necessarily indicate acute amoebiasis.
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Patients with E histolytica colonization should be treated whether symptomatic or not with metronidazole (750 mg three times daily for 10 days) or, alternatively, with tinidazole (2 g daily for 3 days), which has fewer side effects. To eliminate residual cysts, treatment with a nitroimidazole should be followed by an intraluminally active drug such as iodoquinol (650 mg three times daily for 20 days) or paromomycin (10 mg three times daily for 7 days). Patients with severe colitis must be observed very closely for the development of surgically emergent toxic megacolon or perforation until a response to metronidazole treatment is evident.
Gonzales ML, Dans LF, Martinez EG. Antiamoebic drugs for treating amoebic colitis.
Cochrane Database Syst Rev. 2009; 15:CD006085.
[PubMed: 19370624]
Haque R, Huston CD, Hughes M, et al. Amebiasis.
N Engl J Med. 2003;348:1565–1573.
[PubMed: 12700377]