Chapter 5. Acute Diarrheal Disorders

• High fever, frequent bloody stools, severe abdominal pain, dehydration, and no improvement after 3–4 days of initial supportive treatment are worrisome features.
• Sigmoidoscopy and biopsy are indicated in patients with bloody dysenteric stools and tenesmus lasting more than 3–4 days.
• Upper endoscopy and biopsy are indicated in patients with persistent diarrhea and evidence of malabsorption.
• Routine stool cultures aid in identifying Salmonella, Shigella, and Campylobacter but rarely provide useful information if diarrhea develops 2–3 days after hospitalization.
• Clinical features of shigellosis, salmonellosis, and Campylobacter colitis (diarrhea, tenesmus, fever, abdominal cramps) often overlap.
• Consider Clostridium difficile infection after both recent and remote (within 3 months) use of antibiotics and if diarrhea develops during hospitalization.
• Risk factors for severe C difficile infection include age >65, renal failure, immunosuppression, and white blood cell count >20,000/μL.
• Consider enterohemorrhagic Escherichia coli (E coli O157:H7) in patients with bloody diarrhea, abdominal pain, leukocytosis, and little or no fever, especially if uremia or microangiopathic anemia develops; if suspected, avoid antibiotics.
• Giardiasis is best diagnosed using stool enzyme-linked immunosorbent assay (ELISA) directed against Giardia antigens as an adjunct to microscopic stool exam.
• Up to 10% of patients who have had infectious diarrhea may develop a postinfectious irritable bowel syndrome.

General Considerations

Acute diarrheal diseases remain a major global public health problem, responsible for an estimated two million or more deaths annually. Most deaths occur in developing countries and many occur in infants and young children. The majority of acute diarrheal episodes reflect gastrointestinal infections, but medications, food intolerances, or the abrupt onset of chronic disease may be causative (Table 5–1). In the United States, acute diarrheal diseases are a major health and economic problem resulting in between 200 million and 400 million total episodes, 900,000 hospitalizations, and approximately 6000 deaths per year.

Acute diarrheal diseases are second only to respiratory infections as a cause of time lost from work in the United States. As a symptom, diarrhea can be defined as an increase in frequency, volume, and often urgency of the passage of stool and as a decrease in stool consistency. More objectively as a sign, diarrhea is an increase in stool mass to greater than 200 g/24 h, the upper limit of normal stool weight. Acute diarrheal disease is generally defined as having begun within 2 weeks of presentation; diarrhea that persists for more than 3 weeks is considered subacute or chronic.

Pathogenesis

Normal Absorption and Secretion

Under normal circumstances, adults ingest approximately 2 L of fluid per day. An additional 7 L of endogenous secretions from salivary, gastric, pancreatic, biliary, and enteric sources enter the intestine for an approximate 24-hour load of 9 L. Ingested nutrients are dissolved or suspended in this 9-L fluid load. The healthy small intestine will absorb about 7.5 L, largely in the duodenum and jejunum. Of the 1.5 L that traverse the ileocecal valve, the colon absorbs approximately 1.3 L, resulting in a stool mass of no more than 200 g/24 h. The maximum absorptive capacity of the small intestine is about 12 L and that of the colon, 4–6 L, for a total of 18 L; roughly double the normal daily fluid load.

Major Mechanisms of Diarrhea (Table 5–2)

An increased fluid load sufficient to overwhelm the intestinal and colonic absorptive capacity of about 12 L usually results in diarrhea. Excessive endogenous fluid secretion is the usual culprit, but excessive fluid intake may contribute. Examples of diseases that cause diarrhea by excessive secretion include cholera, toxigenic E coli infection, or, rarely, a vasoactive intestinal peptide-secreting tumor.

Epithelial cell absorptive and digestive function in the small and large intestine is impaired and permeability of the epithelial barrier is increased by the mucosal damage caused by a variety of gastrointestinal viral, bacterial, and protozoal infections and protozoal infestations. In addition, the available absorptive surface may be reduced as in, for example, rotavirus and norovirus enteritis and in giardiasis. Increased intraluminal osmolality is a cause of acute diarrhea. Ingestion of poorly absorbed or nonabsorbable laxatives such as magnesium citrate or magnesium hydroxide or polyethylene glycol 3350 are the classic examples, but impaired nutrient absorption in some intestinal infections contributes to diarrhea by increasing intraluminal osmolality. All of the mechanisms detailed above may be causative in acute diarrheal diseases in which there is substantial mucosal inflammation as occurs in most invasive and some toxigenic bacterial enterocolitides. If mucosal inflammation is mild or absent, as in cholera, enhanced fluid secretion, altered permeability, enhanced motility, or, in the case of laxative ingestion, increased intraluminal osmolality are the major mechanisms.

Clinical Findings

Symptoms and Signs

A careful history and physical examination are crucial in the evaluation of patients presenting with acute diarrhea and should provide information as to the possible nature, underlying cause, and severity of the diarrhea. Historical points that should be explored include (1) any recent travels; (2) the nature of recent food ingestion, including type, preparation (fully cooked, rare, or raw), and location (home, restaurant, or street vendor); (3) occurrence of a similar illness among recent contacts; (4) medication history, especially new medications or past or current use of antibiotics; (5) sexual history; and (6) predisposing conditions, such as compromised immune status.

The character of the diarrhea also provides clues as to the site of involvement by the process causing the diarrhea. A large stool volume with little urgency, no tenesmus, and only a moderate increase in stool number suggests involvement primarily of the small intestine and more proximal colon, whereas frequent, low-volume dysenteric stools containing blood and mucus associated with urgency and tenesmus suggest disease involving the rectum and distal colon. Although a patient's subjective description of the nature of the diarrhea is helpful, examination of the stool by the clinician is most useful.

On physical examination, the presence or absence of fever should be determined. Hypotension, orthostasis, tachycardia, poor skin turgor, and dry mucous membranes indicate dehydration, a major cause of morbidity and mortality in acute diarrheal diseases, especially in the young and the elderly. A careful abdominal examination is essential to assess for evidence of localized abdominal infections (eg, appendicitis or diverticulitis) that may be associated with diarrhea. The abdomen should also be assessed for distention, which might suggest megacolon, and for the presence of peritoneal signs.

Laboratory Findings

The majority of patients with acute diarrhea in developed countries have relatively mild, self-limited illness, which resolves in a day or two and requires no specific diagnostic studies. A major goal of the initial assessment, including the history and physical examination, is to identify patients who have more serious disease meriting prompt and specific diagnostic studies and aggressive treatment (Figure 5–1). Worrisome features include high fever, dehydration, frequent bloody stools with tenesmus (dysentery), severe abdominal pain, an immunosuppressed host, and no improvement in or progression of symptoms after 3–4 days of supportive treatment (see Figure 5–1). Useful tests for further evaluation include assessment of stool for fecal leukocytes, stool culture, blood culture, stool examination for ova and parasites, stool testing for C difficile toxin, endoscopy and mucosal biopsy, and, in selected cases, abdominal imaging studies.

Fecal Leukocytes and Stool Lactoferrin

Examination of stool suspensions stained with methylene blue for the presence of fecal leukocytes is a time-honored test for evaluation of patients with acute diarrhea. Neutrophils are usually present in patients with dysenteric stools (containing blood and mucus) caused by infection with invasive bacteria (Table 5–3) and colitides unassociated with infection, as can occur in acute onset or during acute exacerbations of inflammatory bowel disease (IBD). In other words, the presence of neutrophils indicates the presence of an inflammatory colitis or enterocolitis but not its cause. Thus, the test lacks specificity for infectious colitis, and its reported sensitivities for invasive bacterial infections are only in the range of 60–70%, in part because the presence of neutrophils in stools is variable in patients with diarrhea caused by Salmonella or Yersinia infection. Fecal leukocytes are usually absent from the watery stools caused by viral infections and toxin-producing bacteria with exceptions being C difficile- and cytomegalovirus-induced enterocolitis, in which fecal neutrophils may be present (see Table 5–3).

Despite its limitations, fecal leukocyte testing remains worthwhile and, if positive, helps select patients who merit more extensive diagnostic evaluation and possibly empiric antibiotic therapy. Fecal lactoferrin, a surrogate marker for fecal neutrophils, can be measured using a latex agglutination assay. The test has been used most widely in assessing patients with IBD. It appears to be more sensitive, less observer dependent, but more costly than the conventional fecal leukocyte assay. Falsely positive results may occur in breast-fed infants.

Stool Culture

The indications for and cost-effectiveness of obtaining stool cultures from patients with acute diarrhea are still being debated. However, there is general consensus that too many are obtained. Most surveys report an incidence of positive stool cultures in only 1.5–3% of submitted stools with an estimated cost of more than $1000 per positive culture. As indicated earlier, most episodes of acute diarrhea are self-limited and resolve within 48–72 hours, often before the results of a stool culture are available. Stool cultures are rarely informative in nonimmunosuppressed patients who develop diarrhea 3 or more days after hospitalization.

Stool cultures should be obtained from patients with severe dehydration, fever exceeding 102°F (38.9°C), dysenteric stools, and stools that contain neutrophils, and from those in whom the culture may ultimately guide therapy. Stool cultures should also be obtained from all immunosuppressed patients who develop diarrhea or patients with other severe comorbidities, including idiopathic IBD. Stool cultures should be obtained for epidemiologic purposes if an outbreak of diarrheal disease is suspected.

Once obtained, the stool specimen should be sent to the laboratory as soon as possible to minimize false-negative results. The clinician should also be cognizant of which organisms are identified by the particular laboratory performing the culture. In some laboratories, only Salmonella, Shigella, and Campylobacter are identified during routine processing. Hence, the clinician should specify other organisms if suspected, such as Yersinia, enterohemorrhagic E coli (EHEC), Aeromonas, or noncholera Vibrio, so that proper media and culture conditions are used.

Blood Culture

Blood cultures should be obtained from patients with high fever, those with shaking chills, and those who are immunosuppressed.

Stool Examination for Ova and Parasites

The yield of positive examinations for ova and parasites is low among patients with acute diarrhea as most parasitic infestations that cause diarrhea cause symptoms lasting several weeks or more. Indications for assessment include diarrhea that persists for more than 2 weeks, a history of travel to areas endemic for parasitic disease, exposure to children in day care centers or summer camps, a concomitant history of immunosuppression (HIV, chemotherapy, immunosuppressive drugs), known idiopathic IBD, homosexuals, and unexplained peripheral eosinophilia. As ova and parasites can be passed intermittently, optimal testing requires prompt examination of each of three specimens collected on separate days. If giardiasis or cryptosporidiosis is suspected, enzyme-linked immunosorbent assays (ELISAs) or immunochromatographic assays that detect Giardia and/or Cryptosporidium antigens are useful adjuncts to microscopic examination of the stool, with sensitivities of 80–90%.

Clostridium Difficile Toxin

The recently reported rising incidence and increased morbidity and mortality of C difficile colitis (see later discussion) underscores the importance of C difficile toxin testing of the stool for timely diagnosis and implementation of therapy for this important disease. Groups at risk and, hence, indications for the test include patients who have received recent or even distant antibiotic therapy, patients who develop diarrhea in a hospital or other institutional setting, immunosuppressed patients, and patients with idiopathic IBD. Community-acquired cases in the absence of known recent antibiotic use are being increasingly recognized.

The cytotoxicity assay using cultured fibroblasts has been the gold standard for testing for C difficile toxin, with sensitivity of approximately 70–90% and almost absolute specificity. However, the test is costly and requires 2–3 days for completion. Also available are several less expensive ELISAs for stool C difficile toxin, which are somewhat less sensitive but provide a result within 1 day. A new commercial quantitative polymerase chain reaction (PCR) test that provides results in hours has recently been approved for use in the United States. Sensitivity and specificity documented with this PCR are comparable to or greater than those of the time-consuming cytotoxicity assay.

Endoscopy and Biopsy

Sigmoidoscopy and biopsy can be very useful in selected patients with acute diarrhea. Sigmoidoscopy is indicated in patients with bloody, dysenteric stools and tenesmus lasting more than 3–4 days. The endoscopic appearance of the mucosa is often indistinguishable in patients with acute infectious diarrhea caused by invasive organisms compared with patients with idiopathic IBD, but in such patients, it provides some information as to extent and severity of disease. Additionally, rectosigmoid biopsies may help distinguish acute infectious diarrhea from diarrhea caused by an acute flare of IBD (Plates 1 and 2). Sigmoidoscopy can also help to exclude ischemic colitis, which may present with abdominal pain and bloody diarrhea. Sigmoidoscopy can provide a rapid, tentative diagnosis of C difficile colitis if the characteristic pseudomembranous lesions are present. Additionally, sigmoidoscopy can provide rapid diagnosis of amoebiasis if secretions from the edge of ulcers are examined microscopically and the organism is seen. Mucosal biopsy from immunosuppressed patients may detect cytomegalovirus or herpetic proctocolitis. Upper endoscopy is indicated in patients with persistent diarrhea and malabsorption and, through examination of duodenal aspirates and mucosal biopsies, may detect parasitic infections including giardiasis, cryptosporidiosis, Isospora infection, and occasionally strongyloidiasis.

Imaging Studies

Imaging studies are usually not required in patients with uncomplicated acute diarrhea. An abdominal flat and upright film may be useful if there is worrisome abdominal distention in order to screen for toxic megacolon, which can occur in C difficile colitis and colonic amoebiasis. On occasion, computed tomography (CT) or ultrasound scan of the abdomen and pelvis may be indicated, if there is associated severe abdominal pain, tenderness, or evidence of peritoneal irritation, to exclude a focal intra-abdominal or pelvic process.

Treatment

General Principles

Some general principles of treatment of acute diarrhea are summarized next. When specific therapy of a defined cause of acute diarrhea is indicated as, for example, for C difficile colitis, such treatment is described later, in the section entitled "Acute Diarrheal Disease Caused by Specific Infections."

Treatment of Dehydration

Oral rehydration therapy will suffice in most patients who develop acute diarrhea. In milder cases, juices, broth, and water along with salted crackers usually suffice. If dehydration is more severe, oral rehydration fluids should be utilized. The World Health Organization (WHO) recommends the following formula per liter of water:

• 2.6 g sodium chloride
• 2.5 g sodium bicarbonate or 2.9 g trisodium citrate
• 1.5 g potassium chloride
• 13.5 g glucose or 27 g sucrose

Several oral rehydration solutions in addition to that recommended by the WHO are commercially available. Rehydrate closely mimics WHO oral rehydration solutions, whereas others (Pedialyte, Enfalyte) contain less sodium and may require intake of a larger volume. Maintaining a 1:1 molar ratio of sodium to carbohydrate facilitates sodium transport in diarrheal diseases in which the enteric sodium–glucose co-transport mechanism remains intact as, for example, in cholera or enterotoxigenic E coli (ETEC) infection. Some clinicians favor preparations formulated with complex carbohydrates such as rice-based solutions (CeraLyte). The WHO recommends zinc supplementation of oral rehydration solutions for children (10 mg/day for infants <6 months old; 20 mg/day for children >6 months old), but there are no recommendations for adults due to lack of data.

Intravenous hydration is often overutilized in developed countries such as the United States. However, if diarrhea is massive and dehydration severe, especially in infants and young children, the elderly, and patients unable to rehydrate orally due to nausea, vomiting, or other comorbidities, intravenous rehydration is indicated. Serum electrolyte levels should be closely monitored and imbalances corrected.

Antidiarrheal Drugs

The antimotility agent loperamide can be used with caution to provide symptomatic relief in patients without high fever, colonic distention, or dysenteric stools. The usual dose is 4 mg initially followed by 2 mg every 4–6 hours, as required for persistent diarrhea, not to exceed 10 mg/24 h. Absorption may be increased by prolonging contact time of luminal contents with mucosa, although oral fluid intake should be continued. Fluid may pool in the gut lumen as antimotility agents do not decrease intestinal secretion. Diphenoxylate has also been used but is less desirable as it crosses the blood-brain barrier and has central opiate actions. Antimotility drugs should generally be avoided in patients with dysentery, and no antimotility drug should ever be used if the possibility of toxic megacolon is a concern. Moreover, there is some evidence that suggests that the use of antimotility agents, while reducing the number of stools, may prolong the course of some enteric infections, including those caused by Shigella and ETEC, perhaps by prolonging the time required for clearance of causative organisms and toxins from the gut. Bismuth subsalicylate reduces stool number, but there is no evidence that fecal fluid losses are decreased significantly.

Empiric Antibiotic Therapy

Although a controversial topic, antibiotics are overutilized in acute infectious diarrhea. Most episodes are self-limited and clear within 2–4 days or less without specific therapy; hence, most patients would derive little or no benefit and risk potential harm if antibiotics were indiscriminately prescribed. Their use predisposes to the development of resistant organisms. They provide no benefit in viral diarrhea caused by rotaviruses or noroviruses and may be harmful in EHEC infections, prolong fecal excretion of nontyphoidal Salmonella, and precipitate C difficile colitis. Their benefit in Yersinia, Campylobacter, and Aeromonas infections is controversial.

Generally accepted indications for the use of an empiric antibiotic (at this writing usually a quinolone) include fever greater than 102°F (38.9°C) and chills, severe dysentery, traveler's diarrhea that is severe or affects an individual in whom a shortened duration of illness is critical, individuals with severe dehydration and prolonged, severe diarrhea (1 week or more), and the immunocompromised host.

Antibiotics should be avoided in patients with bloody stools, abdominal pain, but little or no fever until EHEC has been excluded from consideration.

Specific Antibiotic Therapy

Recommendations regarding antibiotic therapy for specific pathogens that cause acute infections are discussed in the next section.

As indicated previously, most acute diarrheal disease is caused by transmissible infectious viruses, bacteria, or parasites. Infectious organisms cause disease by a number of mechanisms (Table 5–4). Some actually invade and proliferate in the intestinal epithelium, underlying mucosa, and lymphoid follicles. Others produce tissue-damaging cytotoxins while in the lumen and in contact with the epithelium. Still others elaborate enterotoxins that produce profound functional alterations but no detectable histologic lesion. Some adhere to the epithelial surface and induce epithelial damage and mucosal inflammation without invasion. Finally, still others produce toxins in vitro that, when ingested, induce symptomatic gastrointestinal illness.

The human host has defenses that resist enteric infections. Gastric acid secretion reduces bacterial colonization of the proximal small intestine, and there is evidence that individuals who have had acid-reducing gastric surgery are more susceptible to nontyphoidal salmonellosis and selected other enteric infections. Normal gastric motility is a defense factor; stasis predisposes to intestinal intraluminal bacterial proliferation, and there is evidence that the use of antimotility agents prolongs diarrhea caused by some enteric pathogens. The normal intestinal flora itself is protective. Its alteration by antibiotic therapy predisposes to C difficile colitis and reduces the number of organisms required to produce nontyphoidal salmonellosis. Antibodies secreted into the intestinal lumen by the intestine and via the biliary tract appear to play a protective role in reducing colonization of pathogens in the gut.

Viral Infections

Noroviruses

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.

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.

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.

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.

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.

Rotaviruses

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.

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.

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.

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.

The overall prognosis is excellent, with the vast majority of patients recovering completely within 7–10 days, except as noted earlier.

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.

Other Viruses

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.

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.

Bacterial Infections

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.

Shigelloses

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.

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.

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.

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.

Nontyphoidal Salmonellosis

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.

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.

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.

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.

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.

Campylobacter

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.

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.

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.

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.

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.

Yersinia

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.

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.

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.

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.

Listeriosis

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.

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.

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.

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.

Noncholera Vibrio

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.

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%.

Isolation from stool samples requires use of selective media; hence, the laboratory should be alerted that infection with noncholera Vibrio is suspected.

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.

Vibrio Cholerae

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.

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.

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.

Aeromonas

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.

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.

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.

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.

Plesiomonas

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.

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.

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.

Enterotoxigenic E Coli (ETEC)

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.

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.

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.

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.

Enteropathogenic E Coli (EPEC)

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.

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.

Enteroaggregative E Coli (EAEC)

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.

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.

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.

Enteroinvasive E Coli (EIEC)

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.

Enterohemorrhagic E Coli (EHEC)

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.

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.

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.

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.

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.

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.

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.

Staphylococcus Aureus

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.

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.

Bacillus Cereus

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.

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.

Clostridium Perfringens

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.

Clostridium Difficile

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

Klebsiella Oxytoca

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.

Protozoal Infections

Giardia Lamblia

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.

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.

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).

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.

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.

Cryptosporidiosis

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.

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.

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.

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.

Cyclospora Cayetanensis

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.

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.

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.

Isospora Belli

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.

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.

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.

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.

Entamoeba Histolytica

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.

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.

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.

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.

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.

Fungal Infections: Microsporidia

Previously considered to be protozoa, microsporidia are now classified as fungi. Numerous species infect many life forms, and over 10 species are known to cause disease in humans, with Enterocytozoon bieneusi the most common. Involvement of many organs in addition to the intestine has been reported and will not be described here. The majority of clinically significant infections occur in AIDS and other immunosuppressed patients, although infections in travelers and otherwise healthy individuals have been documented.

Ingestion of spores via person-to-person, animal-to-person, foodborne, or waterborne routes has been incriminated as sources of transmission. Microsporidia spores have been isolated from the stools of asymptomatic, healthy, immunocompetent individuals raising questions as to whether the organisms are always the cause of gastrointestinal symptoms ascribed to them. Nevertheless, both self-limited diarrhea and occasionally chronic diarrhea have been reported, especially in travelers and in the elderly.

In immunosuppressed AIDS patients and some immunosuppressed transplant patients, dehydration and malabsorption clinically indistinguishable from that associated with coccidial infections such as cryptosporidiosis have been noted in association with microsporidial organisms invading intestinal mucosa and with identification of E bieneusi or Enterocytozoon intestinalis in stool specimens. As in cryptosporidiosis, biliary tract involvement can occur.

Diagnosis is established by stool examination, which is facilitated by using special stains such as a modified trichrome stain or identification of the organism in tissue samples such as intestinal mucosal biopsies by light or electron microscopy.

Albendazole (400 mg twice daily for 2–4 weeks) is the treatment of choice for microsporidiosis but is of limited efficacy in the treatment of E bieneusi infections, the most common form associated with diarrheal disease. Hence, restoration of immunocompetence with HAART in AIDS patients and reduced immunosuppression in transplant patients is desirable if possible. Numerous other antibiotic, antiparasitic, and antifungal agents have been tried without much benefit in immunosuppressed patients with chronic diarrhea who harbor these organisms. Treatment with the antibiotic fumagillin at 60 mg daily for 2 weeks showed promising results in one small placebo-controlled trial and in several uncontrolled reports, although worrisome bone marrow depression was noted in some drug recipients.

Traveler's Diarrhea

With increasing economic globalization and the increased popularity of tourism to developing nations, traveler's diarrhea affects literally millions of travelers each year. A generally accepted definition for traveler's diarrhea is the passage of three or more loose to diarrheal stools in 24 hours often but not invariably associated with other symptoms, including abdominal discomfort, nausea, vomiting, hematochezia, and fever, depending on the cause. Symptoms most often develop 2–10 days after arrival of the traveler but may occur at any time during foreign exposure.

The incidence of traveler's diarrhea varies greatly with geographic region and correlates with the level of sanitation at the travelers' destination. Incidence rates as high as 50% have been noted for selected Asian, Central African, and Latin American countries, whereas estimated rates are 10–20% in Southern European countries, the Caribbean Islands, and Northern African countries. Estimated rates among travelers to and in Northern Europe, the United States and Canada, Australia, and New Zealand are well under 10%. Risk factors for the individual traveler other than destination are conditions that interfere with host defenses against enteric infections, as discussed earlier in this chapter. In particular, immunosuppressed patients and patients with hypochlorhydria caused by pharmacologic agents or gastric surgery may be especially vulnerable to developing traveler's diarrhea.

Virtually any of the specific organisms discussed individually in this chapter may be the causative agent for any given case of traveler's diarrhea. Pathogenic bacteria have been estimated to cause up to 90% of traveler's diarrhea in some studies in which an etiologic agent was identified. ETEC and EAEC appear as the most common causes, but invasive bacteria including Campylobacter, Salmonella, Shigella species, and invasive E coli predominate among those with dysentery. Both rotaviruses and noroviruses are established causes, the latter being increasingly recognized in outbreaks among cruise passengers. Protozoa such as Giardia and cryptosporidia, while less common, have been isolated from a substantial number of travelers with more protracted diarrhea, especially among those who develop malabsorption.

The clinical features will not be belabored here, and the reader is referred to the descriptions of specific infections earlier in the chapter. By far the most common presentation is that associated with ETEC or EAEC infection, with abrupt onset of watery diarrhea lasting a few hours to as long as 5 days. However, the entire spectrum of the clinical features of gastrointestinal infections may be seen, ranging from a few loose stools to severe dysentery with fever or protracted diarrhea with malabsorption, depending on the cause of the infection and the host's immune response capacity.

Because a specific diagnosis is rarely established during travels, treatment is largely empiric. If diarrhea is severe, rehydration is crucial, preferably using an oral rehydration solution with a formula similar to that recommended by the WHO or, if necessary, intravenous hydration. Loperamide (2 mg up to four times daily) can provide symptomatic relief but should not be used in patients with dysentery of unknown cause and should be avoided in patients with possible C difficile (those taking prophylactic antibiotics) given the risk of development of toxic megacolon. There is also some evidence, though not conclusive, that antimotility agents can prolong the duration of some enteric infections such as shigellosis. Effective antibiotic therapy reduces the duration of ETEC and EAEC, the most common causes of traveler's diarrhea. Development of antibiotic resistance is a major problem and has reduced the efficacy of trimethoprim–sulfamethoxazole, aminopenicillins, and tetracyclines. Instead, ciprofloxacin or azithromycin are now recommended. The nonabsorbed antibiotic rifaximin is effective against ETEC and, although expensive, may ultimately become the empiric antibiotic treatment of choice for nondysenteric traveler's diarrhea.

Prevention is the most effective approach to reducing the burden of traveler's diarrhea. Patient education is a crucial component of this strategy. Travelers should be instructed not to consume water that has not been thoroughly boiled, filtered with iodine-containing filters, or chemically treated with bleach or tincture of iodine. Drinks, especially those with ice, should be avoided. Teeth should be brushed with bottled or treated water, and ingestion of water while showering should be avoided. Only thoroughly cooked vegetables, fish, shellfish, and meat should be eaten. Sauces and dips such as guacamole are a frequent source of infection. Fruits, unless freshly peeled, should not be eaten. Fruit-, vegetable-, and meat-containing salads should be avoided.

Bismuth subsalicylate (two tablets or 30 mL of the liquid preparation four times daily) can be taken as prophylaxis. However, compliance is generally poor due to the inconvenience, and salicylate toxicity is a small risk especially if intake is prolonged. Antibiotic prophylaxis for the casual, healthy tourist, although often used, is not generally recommended in view of cost and the risk of inducing antibiotic resistance among pathogens. Rather, providing a prescription for ciprofloxacin or azithromycin for use should the traveler develop diarrhea is more appropriate. Undesirable side effects of antibiotic prophylaxis may include allergic reactions, antibiotic-induced diarrhea, C difficile colitis, and yeast infections. Antibiotic prophylaxis can be justified for individuals who are immunocompromised, who have IBD or other significant comorbidities, or for those travelers whose responsibilities and schedule are such that severe traveler's diarrhea would be more than an inconvenience and would potentially negate the purpose of their journey. Quinolones such as ciprofloxacin (500 mg daily) are most widely used, although resistance to these agents is increasing. Rifaximin (200 mg twice daily) is promising, reducing diarrhea more than threefold among travelers to Mexico in one study with little apparent alteration of the colonic flora. The orally administered whole cell vaccine with the nontoxic cholera toxin B subunit (Dukoral) is effective against ETEC. It is FDA approved in the United States for prophylaxis of traveler's diarrhea, but as recommended by the Infectious Diseases Society of America, casual use must be weighed against cost, potential side effects, and the fact that only some of the episodes of traveler's diarrhea caused by ETEC will be prevented by the vaccine.

Medication-Related Diarrhea

Literally hundreds of medications can produce diarrhea. One only has to peruse the adverse reaction sections related to individual medications in the current Physician's Desk Reference to appreciate the scope of the problem. Only a few of the major causes are listed in Table 5–1. To that list could be added antiarrhythmics, cholinergic agents, prokinetics, prostaglandins, and many more. A careful history of all medications, both prescription and nonprescription, as well as herbal remedies and nutritional supplements—including when they were begun—must be obtained if unnecessary and costly evaluation seeking the cause of the diarrhea is to be avoided. In the vast majority of cases, though not all, medication-related diarrhea begins within a few days of the initiation of treatment with or a change in dosage of the offending agent.