Gastrointestinal Infections

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[edit] Gastrointestinal Infections

Subhas Banerjee

J. Thomas Lamont

Infections of the gastrointestinal tract are seen in about 10% of patients examined in medical practice. Worldwide, infectious diarrheas are second only to cardiovascular disease as a cause of death. The primary care physician can evaluate and treat these common disorders in the office; only a minority require specialist consultation.

[edit] OFFICE DIAGNOSIS OF INFECTIOUS DIARRHEA

The cornerstone in diagnosing intestinal infection is a meticulous history of the present illness, especially duration of the illness and exposure to possible sources of infective pathogens (Table 111-1). Viral gastroenteritis and toxin-mediated food poisoning are brief illnesses with short incubation periods, as is traveler's diarrhea. Bacterial dysenteries are generally longer in duration, more severe, and accompanied by more serious signs and symptoms of colitis, including bloody diarrhea, fever, prostration, and weight loss. Familiarity with the basic patterns of these dysenteries allows a tentative diagnosis to be made at the initial visit.

Table 111-1 Clinical Features of Common Infectious Diarrheas

A simple algorithm can be used to categorize the usual infectious diarrheas encountered in office practice (Fig. 111-1). Acute diarrhea lasting less than 1 week indicates infectious diarrhea. The physician should ask about antibiotic exposure, recent travel, exposure to infected persons, and homosexual contacts. Patients with bloody diarrhea, fever, chills, and dehydration are likely to have bacterial or amebic dysentery, whereas watery diarrhea with only mild cramps suggests viral infection.

Figure 111-1 Diagnostic algorithm for infectious diarrhea.

Infectious diarrhea can be categorized according to the agent involved (viral, bacterial, parasitic), the mode of acquisition (food poisoning, traveler's diarrhea), and the pathophysiologic mechanism (ingestion of preformed toxin, epithelial invasion) (Table 111-2). A brief physical examination of the abdomen may provide additional diagnostic information. Tenderness in both lower quadrants suggests infectious colitis (Shigella, Campylobacter, Entamoeba histolytica), whereas middle or upper abdominal tenderness suggests Salmonella or Campylobacter infection or viral gastroenteritis. In some elderly patients, Clostridium difficile infection may cause an ileus with only minimal diarrhea, abdominal distention, and reduced bowel sounds. Rectal examination provides the opportunity to examine the stool for blood or mucus and to test for occult blood. Significant abdominal tenderness, rebound, and rigidity indicate severe disease and the need for hospital admission and prompt surgical consultation.

Table 111-2 Classification of Infectious Diarrheas

After a careful history the physician should obtain a fresh stool specimen for bacterial culture, parasite examination, and testing for leukocytes (Box 111-1). Invasive pathogens such as Shigella, Campylobacter, and enteropathogenic or enteroinvasive strains of Escherichia coli produce a leukocyte-containing diarrhea, whereas viral gastroenteritis and some toxin-mediated diarrheas are rarely accompanied by fecal leukocytes. However, stool leukocytes are absent in 40% to 50% of stool specimens from patients with proven bacterial enteritis. Stool leukocytes are also present in idiopathic inflammatory bowel disease and ischemic colitis, but these conditions can generally be excluded by a careful history. Flexible sigmoidoscopy or colonoscopy can provide useful diagnostic information in selected patients with acute infectious diarrhea, particularly those with pseudomembranous colitis, amebic dysentery, or sexually transmitted anorectal disease. However, these invasive tests are generally reserved for evaluation of severe or chronic diarrhea that has not been diagnosed by simpler tests.

In office practice, a specific etiologic agent is not identified for most patients. Even in prospective studies using a sophisticated battery of stool culture techniques, more than half of outpatient acute diarrheas cannot be ascribed to aspecific pathogen. In a typical office setting, 25% or fewer patients with acute, presumably infectious diarrhea will have a positive stool culture. Patients with negative tests may be infected with fastidious organisms or may have noninfectious causes of acute diarrhea (e.g., food intolerance, stress).

[edit] VIRAL GASTROENTERITIS

The major viral agents causing gastroenteritis are Rotavirus and Norwalk virus, which account for approximately 30% to 40% of gastrointestinal infections worldwide.

[edit] Rotavirus

Rotavirus is the most important etiologic agent in severe dehydrating diarrheal illness of children aged 6 to 24 months.^[1] Older family members may develop a mild or asymptomatic infection. The annual epidemic starts in southwestern states in the late fall and spreads across the United States during winter, reaching the northeastern states by spring. Transmission is fecal-oral, and asymptomatic shedding of the virus before and after clinical diarrhea aids its spread, particularly in day-care centers. After an incubation period of 1 to 2 days, the child develops a 5-to 6-day illness, with vomiting followed by watery diarrhea. Fecal leukocytes are absent, and the stool may be acidic and test positive for reducing substances, indicating carbohydrate malabsorption from lactase and sucrase deficiency as a result of villous damage from the infection. The diagnosis can be confirmed by detection of rotavirus antigen in stool. Treatment is supportive, with fluid and electrolyte replacement using oral rehydration or intravenous (IV) solutions in severe cases. Infection is followed by antibody-mediated protection from reinfection in more than 90% of patients. Rotavirus vaccines tested in field trials provide 50% overall protection against all rotavirus diarrheas and 70% protection against severe diarrhea.

[edit] Norwalk Virus

Norwalk virus predominantly affects older children and adults, and the resulting gastroenteritis is one of the most common causes of work absenteeism in U.S. society.^[2] Transmission is fecal-oral with a high attack rate, and outbreaks have occurred in hospitals, in nursing homes, and on cruise ships resulting from food handlers contaminating food and drink; family outbreaks are also common. Oysters and shellfish have been responsible for several outbreaks. The incubation period is approximately 1 to 2 days. Symptoms of gastroenteritis are mild and brief, usually lasting 24 to 48 hours. The disease tends to be self-limited in most patients and rarely requires special treatment. Occasionally it can be quite debilitating with vomiting, frequent loose watery stools, diffuse myalgias, chills, and fever. As with other viral gastroenteritides, fecal leukocytes are absent. Specific culture or serologic tests are not currently available. The diagnosis can be established by viral antigen detection in the stool, but given the mild nature of the illness, this is rarely necessary except for epidemiologic studies. Transient disaccharidase deficiency due to small bowel villous damage may result in diarrhea persisting for 1 to 2 weeks after the initial attack. The antibody response does not appear to protect against reinfection.

[edit] BACTERIAL DIARRHEAS

Bacterial enteropathogens can cause diarrhea by several well-defined mechanisms: (1) secretion of a preformed exotoxin during storage of food, (2) colonization of the intestinal tract without mucosal invasion but with release of enterotoxin, and (3) invasion of the intestinal epithelium with or without enterotoxin production (see Table 111-2). ``Food poisoning refers to infectious diarrhea of various etiologies acquired by eating contaminated food.^[3] Outbreaks of food poisoning are typically more common in warm weather, when food is stored at higher room temperatures, which allows bacterial multiplication and release of protein exotoxins. These organisms or their toxins are then ingested and cause an acute illness within a few hours.

[edit] Staphylococcus aureus

Food poisoning caused by Staphylococcus aureus is now the second most common cause of reported outbreaks of food-borne illness, after Salmonella. The illness is caused by ingestion of one of five preformed enterotoxins (A through E, most often A) produced by certain strains of Staphylococcus.^[4] Skin lesions on the hands of food handlers are typically responsible for introducing the bacteria into food. Improper food handling practices, including slow cooling of food and reheating before serving, allow for proliferation of the bacteria and toxin production. Previously cooked proteinaceous foods that have been reheated are most often implicated. Because the illness results from a preformed enterotoxin, its onset is swift and abrupt, occurring 4 to 8 hours after ingestion of the contaminated food. The cardinal manifestations of nausea and vomiting, followed by abdominal colic, profuse watery diarrhea, and prostration, rarely last more than 24 hours. Fever is usually absent. Most sufferers do not seek medical attention, but occasional patients may become dehydrated and require IV fluid replacement. The diagnosis of S. aureus food poisoning is suggested when several people who share the same contaminated food develop the clinical picture just described, with the characteristically short incubation period. A definitive diagnosis can be made only if the contaminated food is shown to contain large numbers of enterotoxin producing staphylococci or by enterotoxin detection in the implicated food; however, this is impractical in office or hospital practice. Antibiotic treatment is not indicated for this short-term disease, since bacterial proliferation in the host does not occur.

[edit] Clostridium perfringens

Clostridium perfringens type A is primarily responsible for food poisoning in humans.^[5]C. perfringens type C produces a severe necrotizing enteritis rarely if ever seen in the United States. C. perfringens is ubiquitous in the environment and can be routinely isolated from human and animal feces, air, water, and soil. Fortunately, only small numbers of naturally isolated C. perfringens strains carry the gene for the enterotoxin (CPE gene) responsible for the food poisoning syndrome. The usual vectors are meat and poultry, which are often contaminated with heat-resistant C. perfringens spores. The spores are able to germinate if the food is stored after cooking with slow or inadequate cooling. Reheating to an inadequate temperature then allows further bacterial proliferation, producing an inoculum capable of causing disease. Symptoms may occur simultaneously in several individuals who ate the same meal 6 to 24 hours previously. Diarrhea and cramping abdominal pain lasting 12 to 24 hours are the typical symptoms. Nausea may be present, but vomiting is distinctly rare, as is fever. Stool cultures are not helpful because C. perfringens is part of the normal fecal flora. If necessary for epidemiologic investigation of an outbreak, the diagnosis can be established by polymerase chain reaction (PCR) of the CPE gene from stool specimens or by an enzyme-linked immunosorbent assay (ELISA) for enterotoxin in stool. Antibiotic treatment is not indicated.

[edit] Bacillus cereus

Bacillus cereus, an organism increasingly implicated as a cause of food poisoning, is ubiquitous in soil and frequently present in raw, dried, and processed foods.^[6] The organism is able to produce two distinct enterotoxins, one similar to the heat-labile E. coli enterotoxin that causes watery diarrhea and one similar to the enterotoxin of S. aureus that produces emesis. B. cereus food poisoning is usually associated with rice dishes that have initially been boiled, which B. cereus spores can withstand, and then left to simmer or kept warm in steam heaters for prolonged periods, during which the pathogen multiplies and produces toxins. Outbreaks are therefore more common in countries where rice is a staple; for example, B. cereus accounts for up to 28% of food poisoning in Taiwan. Diarrhea and abdominal cramping are the most common symptoms, followed by nausea and less often vomiting. The illness is short-lived, and recovery usually occurs within 48 hours. Two cases of fulminant hepatic failure have been reported in association with B. cereus food poisoning in youngsters.^[7]

[edit] Shigella Species

Shigellosis, an acute self-limited enteric infection, is a common cause of bacillary dysentery^[8] and accounts for up to 20% of all cases of infectious diarrhea worldwide, particularly in areas of poor hygiene and overcrowding. The four major groups are S. dysenteriae, S. flexneri, S. boydii, and S. sonnei. The most important isolates in the United States are S. sonnei, which accounts for three fourths of isolates, and S. flexneri, which accounts for most of the remaining cases. U.S. outbreaks tend to be sporadic, but minor epidemics from a single food source or in custodial institutions or day-care centers have been described. The mode of spread is predominantly fecal-oral, with infected food handlers posing the major health hazard. A distinguishing feature of this pathogen is the small number of organisms required for an infective dose, thus explaining its rapid spread within closed groups.

Shigella causes disease primarily by invasion of and multiplication within the colonic epithelium, which induces an acute colitis. Certain strains release an enterotoxin that causes a profuse watery diarrhea in early stages, before colonic inflammation and dysentery. After an incubation period of 24 to 48 hours, the onset of diarrhea is heralded by abdominal pain, tenderness, and cramping. Fever may occur, but bacteremia is rare. The diarrhea is liquid and greenish with strands of mucus, blood, and leukocytes. The entire colon may be involved, and 20% to 30% of patients may pass gross blood (hematochezia). In general, Shigella dysentery is a self-limited disease; fever abates within approximately 4 days, and diarrhea and abdominal cramping subside in a week. Bacteremia, leukemoid reactions, thrombocytopenia, seizures, colonic perforation, and the hemolytic uremic syndrome have been reported in severe childhood shigellosis. Reactive arthritis may subsequently occur in patients with the histocompatibility antigen HLA-B27.

Sigmoidoscopic appearances in severe cases may mimic ulcerative colitis, with mucosal hyperemia, friability, and ulceration. The diagnosis is made by isolation of the organism from stool cultures or rectal swabs. Stool cultures typically remain positive for several days or weeks after clinical illness has subsided. Antibiotic therapy is indicated (see Treatment).

[edit] Salmonella Species

Salmonella is one of the major diarrheal pathogens of the world, with more than 40,000 cases reported annually in the United States. Since most diarrheal infectious diseases are underreported, the actual figure is likely much higher. Salmonella is divided into three species:S. typhi, the causative agent of classic typhoid fever;S. choleraesuis; and S. enteritidis, which is divided into many serotypes. Salmonella species, particularly S. enteritidis and S. choleraesuis, can be cultured from a variety of nonhuman hosts, including poultry, rats, reptiles, wild birds, and flies. The main animal reservoirs for human disease are poultry and livestock. Supermarket chicken and eggs are often contaminated with Salmonella species, which are present in the intestinal tracts of commercially raised poultry and animals. An estimated 85% of community-acquired salmonellosis in the United States is related to ingestion of contaminated food, whereas 15% arises from person-to-person spread. In contrast to Shigella species, where small inocula can cause disease, infection with Salmonella requires ingestion of 10,000 to 100 million organisms, although smaller numbers will cause infection in patients with hypochlorhydria. Salmonella infection produces two forms of illness. The gastroenteritis is similar to other bacterial diarrheas, and typhoid (enteric) fever comprises a profound systemic illness lasting 4 to 6 weeks if left untreated. Diarrhea does not usually occur until the later weeks of the illness.

[edit] Salmonella Gastroenteritis.

Caused primarily by serotypes of S. enteritidis, including S. typhimurium, S. heidelberg, S. newport, and S. agona, this disease shows seasonal variation, with the highest incidence reported during July through November. It is usually associated with infection from poultry products and eggs.^[9] Poultry from avian carriers becomes contaminated during evisceration and packing. Thus adequate cooking of poultry and poultry products is important in disease prevention. The high incidence of Salmonella in raw poultry and eggs makes food handlers particularly susceptible to infection. Onset of clinical symptoms occurs 8 to 48 hours after ingestion of organisms, reflecting the time required for multiplication and invasion of the small bowel epithelium. Nausea and vomiting are prominent initially, followed by colicky abdominal pain and diarrhea, which is frequently mixed with mucus and blood. Fever and bacteremia may occur. The course of the disease is 2 to 5 days, followed by a gradual reduction of symptoms. Reactive arthritis or Reiter's syndrome may develop in patients with HLA-B27. The carrier state occurs much less often after gastroenteritis than enteric fever. In previously healthy hosts the illness is usually mild, and antimicrobial therapy may not improve the course of gastroenteritis and prolongs the carrier state (Fig. 111-2). Patients with immunosuppression, diabetes, hypochlorhydria or achlorhydria, sickle cell disease, and other chronic debilitating conditions may develop bacteremia and sepsis with osteomyelitis and metastatic abscess formation after a bout of Salmonella gastroenteritis. These patients require antibiotic therapy.

Figure 111-2 Effect of antibiotic therapy in prolonging carrier state in acute Salmonella gastroenteritis. (From Wistrom J et al:Ann Intern Med 17:207, 1992.)

[edit] Typhoid (Enteric) Fever.

Classic enteric fever is caused by S. typhi, although other species of Salmonella, including S. paratyphi, produce a similar illness with a shorter and milder course. About 70% of U.S. cases occur in patients with a history of recent travel abroad, with the highest risk in Mexico, the Indian subcontinent, and the Phillipines.^[10] In this form of salmonellosis the organism multiplies in the small intestine and invades the epithelium but produces minimal inflammation and cell destruction. S. typhi appears to use the cystic fibrosis transmembrane regulator (CFTR) for entry into intestinal epithelial cells. The organisms then gain access to the bloodstream through intestinal lymphatics, and a short-lived primary bacteremia ensues 24 to 72 hours after inoculation. This primary bacteremia is transient and terminated by phagocytosis of the organisms by the cells of the reticuloendothelial system. The organisms survive intracellularly and continue to multiply, giving rise to a second, more prolonged bacteremia accompanied by high fever with a relative bradycardia, headaches, abdominal pain in right lower quadrant, and myalgias that can last days to weeks. During this phase of continuous bacteremia, all organs are exposed to viable organisms, and metastatic infection may lead to complications (e.g., pneumonia, meningitis, myocarditis, septic arthritis, osteomyelitis). Delirium, diarrhea, and small bowel ulceration with perforation or bleeding may occur later. Patients with sickle cell disease, aortic aneurysms, cancer, hemolytic anemia, and valvular heart disease are more prone to developing prolonged bacteremia and tissue abscesses. For unknown reasons the gallbladder is almost universally infected during this period, and organisms multiply to a higher titer in bile, usually without the production of cholecystitis.

Diagnosis is made by blood cultures early in the disease. Stool cultures become positive secondary to the shedding of a large number of organisms into the bile during the third to fourth week of disease. At this time the serologic test (Widal's test) also becomes positive. Antibiotic therapy considerably shortens the course of this otherwise prolonged illness (see Treatment). Chronic carriage of Salmonella, resulting from chronic infection of the gallbladder after enteric fever, provides a human reservoir for this organism. Approximately 50% of patients continue to shed organisms in the stool at 6 weeks, and 5% to 10% continue to excrete up to the third month. The chronic carrier state occurs in 1% or fewer patients and is defined as positive stool cultures 1 year after initial infection.

[edit] Escherichia coli

Diarrhea-producing strains of E. coli can be classified into five groups based on the mechanisms of diarrhea: enterotoxigenic, enteropathogenic, enteroadherent, enteroinvasive, and enterohemorrhagic. These groups produce different clinical syndromes that vary in clinical features, geographic incidence, and host susceptibility (Table 111-3). Specific strains are diagnosed by serotyping the flagellar and somatic antigens, which is useful in the study of E. coli epidemics. In clinical practice the results of specific typing on stool samples are not available for at least several days, by which time patients have often recovered.

Table 111-3 Mechanisms of Diarrhea in Escherichia coli Infection

Enterotoxigenic E. coli (ETEC) organisms adhere to the small bowel mucosa and produce diarrhea by release of several toxins. LT, or heat-labile toxin, resembles cholera toxin and produces a watery diarrhea by triggering fluid secretion in the intestine. ST, or heat-stable toxin, is a peptide that stimulates intestinal guanylate cyclase, causing fluid secretion. ETEC is a major cause of diarrhea in travelers from industrialized societies who are visiting developing or third-world countries (traveler's diarrhea) and in infants and children in these countries. The usual mode of transmission is contaminated food or water. ETEC produces a mild illness lasting 2 to 4 days and characterized by abdominal cramps, low-grade fever, and diarrhea with the passage of watery stools. Anorexia and vomiting may occur early in the illness.

Enteropathogenic E. coli (EPEC) organisms are an occasional cause of profuse watery diarrhea in infants in the United States and Europe. These strains possess a virulence factor, with the ability to adhere to intestinal epithelial cells, a property lacking in nonpathogenic E. coli. As with ETEC, diarrhea associated with EPEC is usually self-limited, except in infants, in whom massive dehydration may occur.

Enteroadherent strains of E. coli (EAEC) are seldom encountered in clinical practice, and the mechanism for diarrhea is still not clear. These strains adhere to liver cells in culture, a feature that distinguishes them from other pathogenic strains. Infected individuals develop a mild, nonbloody diarrhea.

The enteroinvasive and enterohemorrhagic forms of E. coli involve the colon primarily and produce a clinical picture of acute dysentery. Enteroinvasive E. coli (EIEC) may cause traveler's diarrhea or rarely food-borne outbreaks of dysentery with bloody diarrhea, especially in children in developing countries. The main pathogenic feature is invasion of and proliferation within enterocytes, a feature that also characterizes Shigella species. Patients infected with EIEC complain of fever, malaise, anorexia, cramps, watery diarrhea, or the passage of mucus or blood. The diarrhea is short-lived, with spontaneous recovery within 2 to 4 days of onset, and complications are rare except in malnourished infants. Although not well studied, antibiotics may reduce the duration of illness, as in shigellosis (Box 111-2).

The most serious form of E. coli diarrhea is caused by infection with enterohemorrhagic E. coli (EHEC). EHEC accounts for up to a third of all cases of hemorrhagic colitis in the United States. The 0157:H7 strain of E. coli was first identified as the cause of hemorrhagic colitis after the ingestion of contaminated hamburger. Outbreaks are now reported with increasing frequency, particularly from the Pacific Northwest region of the United States, but sporadic cases are diagnosed in all areas. Although undercooked ground beef remains the major source of infection, outbreaks have also been reported after consumption of unpasteurized milk and apple juice and after swimming in contaminated lakes. E. coli 0157:H7 produces two Shigella-like toxins that inhibit protein synthesis within intestinal cells, but their role in hemorrhagic colitis is obscure. As with all types of dysentery, a wide range of symptoms follows infection with EHEC.^[11] In a typical case 12 to 24 hours of abdominal cramps and watery diarrhea are followed by fever and bloody stools. Severe cases of EHEC infection are often accompanied by white blood cell counts in excess of 20,000/mm³, dehydration, and azotemia. Severe infection, particularly in children and the elderly, may be complicated by the hemolytic uremic syndrome (HUS), which carries a fatality rate of 25%. E. coli 0157:H7 may be the major etiologic factor in HUS in children, with 77% of patients of HUS showing recent infection with the organism.^[12] Antibiotic treatment does not decrease the duration of symptoms or the risk of progressing to HUS. Preventive measures include adequate cooking of ground beef, pasteurization of milk and cider, and strict hygienic measures at food-processing centers and by food handlers.

[edit] Campylobacter Species

Campylobacter jejuni, C. coli, and C. fetus are the most common causes of bacterial diarrheal illness in the United States, with isolation rates exceeding those of Salmonella and Shigella. Campylobacter species are also a major cause of traveler's diarrhea in winter months in subtropical areas.Campylobacter resembles Salmonella in its mode of transmission to humans from eggs and poultry. In addition, sick pets and other domestic animals may harbor Campylobacter as a pathogen and may serve as reservoirs of human disease. The pathogenesis of Campylobacter colitis involves invasion of the mucosa and toxin production, as in Shigellosis.

Typically, C. jejuni and C. coli produce moderate to severe diarrhea that may be watery or bloody, fever, constitutional symptoms, and abdominal pain. Pain may be so severe that it mimics an acute surgical condition (e.g., appendicitis, diverticulitis). Rarely, toxic megacolon with perforation can occur. The illness usually lasts less than a week. One study showed that 26% of patients with Guillain-Barré syndrome had Campylobacter infection in the preceding month, compared with only 1% to 2% of controls.^[13] Cross-reacting serum antibodies to C. jejuni antigens and brain gangliosides have been implicated in this association. HUS has also been associated with Campylobacter infections, and reactive arthritis may develop in patients with HLA-B27. Fecal leukocytes are usually present, and the diagnosis can be established by stool cultures and occasionally by blood cultures in febrile patients. Sigmoidoscopy may reveal evidence of an acute proctocolitis resembling inflammatory bowel disease. Antibiotic treatment is indicated if the clinical presentation suggests bacteremia or if severe acute dysentery is present.

[edit] Clostridium difficile

Clostridium difficile, the pathogen responsible for antibiotic-associated colitis and diarrhea, is a common cause of nosocomial infections.^[14] The organism is a gram-positive anaerobe whose spores are widely distributed in hospital rooms and soil. Colonization of the large bowel occurs only when the normal colonic microflora is altered by antibiotics or cancer chemotherapy drugs. Once it has colonized, C. difficile releases two potent toxins, A and B, which are implicated in pathogenesis.

Diarrhea occurs in up to 25% of patients receiving antibiotics. In most patients this is not related to C. difficile infection, particularly in outpatients, in whom this infection is uncommon. The cause of noninfectious antibiotic diarrhea is related to antibiotics interfering with the ability of the colonic microflora to metabolize dietary carbohydrates to short-chain fatty acids and other end products. During antibiotic therapy the bowel flora cannot digest this carbohydrate, allowing it to remain in the lumen, where it attracts water and causes diarrhea.

C. difficile infections primarily are hospital acquired; outpatient cases account for less than 1% of total cases. Patients in the hospital are often exposed to the two conditions necessary to develop disease: antibiotic therapy and C. difficile spores. These spores persist for months or even years on commodes, toilets, soiled bed linen, bed rails, call buttons, and floors. Hospital personnel, although not infected or colonized, often carry C. difficile on their hands, rings, or stethoscopes and thus can spread the infection within the hospital. Risk factors associated with C. difficile infection include recent exposure to antibiotics in the hospital, occupying a hospital room with an infected roommate, exposure to rectal thermometers, sigmoidoscopy or enema, and treatment in an intensive care unit. Approximately one patient in five acquires C. difficile infection after admission, and a third of these develop clinical illness with diarrhea or colitis. Most culture-positive patients remain asymptomatic and probably serve as a reservoir for infection of other patients. At discharge, some patients are still culture positive for C. difficile and presumably carry the organism home or to long-term care facilities.

C. difficile causes a wide spectrum of disease, ranging from the asymptomatic carrier state to life-threatening colitis with toxic megacolon and perforation. In a typical case, diarrhea starts during the administration of antibiotics or within a few days of stopping antibiotics. The most frequently implicated antibiotics are ampicillin, amoxicillin, cephalosporins, and clindamycin, but almost all antibiotics (including metronidazole) have been implicated. Diarrhea is usually watery or mushy and may be blood tinged, but frank rectal bleeding is rare and should suggest another diagnosis. Lower abdominal cramps, distention, and low-grade fever may occur. Persistent or worsening fever, abdominal pain, and distention may indicate severe disease with impending megacolon or perforation. Elevation of the white blood cell count above 20,000/mm³, hypoalbuminemia, ascites, and metabolic acidosis indicate severe colitis.

Diagnosis of C. difficile infection is based on demonstration of the cytotoxin in stools with either the cytotoxin assay or an immunoassay for toxins A and B. Culture of the organism is considered too sensitive for routine clinical use, since up to 20% of inpatients treated with antibiotics become transient carriers without diarrhea or other symptoms and do not require treatment. Diagnosis can be easily confirmed by bedside sigmoidoscopy without bowel preparation; pseudomembranes are visible as yellow or white raised plaques studding the rectal mucosa (Fig. 111-3).

Figure 111-3 Proctoscopic appearance of pseudomembranes in rectum. White raised plaques scattered over mucosa are typical of acute pseudomembranous colitis secondary to C. difficile infection. (From Triadafilopoulos G, LaMont JT: In Walker WA et al, editors:Pediatric gastrointestinal disease, vol 1, Philadelphia, 1991, Decker.)

[edit] Treatment

Oral rehydration with clear liquids or Gatorade is the mainstay of therapy for patients with mild viral or bacterial diarrhea. IV hydration may be required in the patient with severe diarrhea or abdominal pain. Most authorities caution against the use of antidiarrheal agents (e.g., diphenoxylate, codeine, paregoric) because these drugs interfere with the flushing effect of diarrhea that eliminates organisms and their toxins. However, bismuth subsalicylate suspensions (Pepto-Bismol), 2 tablespoons four times daily, or kaopectate in the same dose is useful in controlling diarrhea, nausea, and other symptoms in mild infectious enteritis.

The effectiveness of antibiotics for bacterial dysentery is controversial. Confusion arises because some bacterial infections of the bowel respond to antibiotic therapy. Also, the specific diagnosis of the offending organism is usually not available for 3 or 4 days or longer after stool samples are submitted to the laboratory, by which time the patient is usually better. Antibiotic therapy clearly benefits patients with Salmonella enteric fever, shigellosis, C. difficile infection, and traveler's diarrhea (Table 111-4). Campylobacter septicemia responds to antibiotics, but their benefit in uncomplicated Campylobacter enteritis is unproved. Antibiotic treatment is not indicated for most patients with uncomplicated Salmonella gastroenteritis and may even increase the incidence and fecal shedding of the organism (see Fig. 111-2).

Table 111-4 Treatment of Viral and Bacterial Diarrheas

Another problem in the antibiotic treatment of enteric infections is the rapid acquisition of antibiotic resistance by Shigella, Salmonella, and Campylobacter species. Recent studies indicate that many strains of Shigella isolates in developing countries are resistant to ampicillin (28% to 90%), tetracycline (56% to 100%), and trimethoprim-sulfamethoxazole (TMP-SMX, 56% to 92%).^[8] Fortunately, the quinolone antibiotics are still effective against most strains of Shigella. The quinolone antibiotics also remain effective against Salmonella typhi and nontyphoid Salmonella, although resistance is starting to emerge, with 4% to 7% low-level resistance and less than 1% high-level resistance. Up to 6% of E. coli isolates in the United Kingdom are now resistant to ciprofloxacin, as are a startling 41% to 88% of Campylobacter strains in Europe and Asia.

A practical approach is to avoid antibiotics in patients with mild gastroenteritis or acute food poisoning (predominantly vomiting). For patients with moderate or severe diarrhea with fever, tachycardia, chills, rectal bleeding, or abdominal pain, empiric broad-spectrum antibiotic coverage can be instituted with ciprofloxacin (500 mg) or norfloxacin (300 mg) twice daily. Antibiotics can be stopped or changed once stool culture and antibiotic sensitivity results are available. The duration of treatment is 3 to 5 days for traveler's diarrhea and 5 days for most other uncomplicated bacterial dysenteries other than Salmonella typhi, which is usually treated for 2 weeks. The asymptomatic carrier state, with fecal shedding of enteric pathogens, often occurs after clinical recovery from most forms of bacterial dysentery, but this does not necessarily indicate relapse and usually does not require therapy.

C. difficile can be treated with metronidazole (250 mg four times a day for 10 days) or vancomycin (125 mg). The response to therapy is rapid, with symptoms often disappearing in 3 to 5 days; 125 mg of vancomycin is just as effective as 500 mg (Fig. 111-4). Because of its lower cost, metronidazole is the drug of choice. Relapse of C. difficile colitis occurs in 15% to 20% of patients after successful initial therapy and should be treated with a second course of metronidazole or vancomycin. Multiple relapses occur in some patients and may respond to tapering doses of either agent for 1 to 2 months.

Figure 111-4 Response to treatment of pseudomembranous colitis with 125 vs. 500 mg of vancomycin. (From Fekety R et al:Am J Med 86:15, 1989.)

[edit] TRAVELER'S DIARRHEA

[edit] Epidemiology

Traveler's diarrhea disrupts the vacations of millions of travelers, primarily those visiting developing countries, where sewage disposal systems tend to be inadequate. The incidence of traveler's diarrhea varies considerably with the destination, and attack rates in developing countries approach 50% (Box 111-3). Longer journeys are associated with an increased risk of developing a diarrheal illness. Younger tourists are more likely than older adults to develop diarrhea because they may eat in lower quality restaurants or from street vendors. Patients with immunodeficiency, hypochlorhydric patients, and those with a history of prior gastrointestinal disease (e.g., inflammatory bowel disease) are at increased risk for acquiring traveler's diarrhea. Older travelers, those with extensive travel experience, and those undertaking organized travel through a tour company are at a lower risk.

Traveler's diarrhea is acquired through consumption of contaminated food and drink. Even intelligent travelers fail to heed common sense dietary advice; traveler's diarrhea was reported in 50% of gastroenterologists attending a conference in Mexico City. Common sources of acquisition include tap water, ice cubes, unpasteurized milk products, uncooked vegetables and salads, unpeeled fruit, and raw or undercooked shellfish, seafood, and meat.

[edit] Microbiology

The pathogens isolated from patients with traveler's diarrhea vary with the country visited and the timing and techniques of stool culture.^[15] Most pathogens are bacterial, and E. coli species account for the majority of infections, especially ETEC (up to 70%) and EAEC (up to 15%). Campylobacter and Shigella species are the other two important bacterial offenders, each accounting for approximately 10% to 15% of infections. Other rare bacterial pathogens include Salmonella, Aeromonas, and Vibrio. In high-risk areas such as Thailand, up to one third of diarrheal illnesses may be caused by polymicrobial infection, with two to four pathogens isolated on stool culture. Such parasites as Entamoeba, Giardia, Cryptosporidium, and Cyclospora are isolated rarely (1% to 2%). Viral infections are found in less than 1% of returning travelers with diarrhea. No pathogen has been isolated in up to 40% of cases in series worldwide.

[edit] Clinical Presentation

The clinical features of traveler's diarrhea depend on the pathogen involved, but the vast majority of cases are relatively mild. ETEC accounts for most cases and produces a mild 2-to 4-day illness with acute watery diarrhea (usually less than five bowel movements a day), abdominal cramps, and mild nausea without vomiting. Usually the patient is confined to bed for a day or two, but a change in itinerary is not required. Up to 10% of patients traveling to high-risk areas may develop a more serious illness with fever and bloody stools, often related to infection with Shigella or Campylobacter species. Less than 1% of patients require hospital admission with fever, severe dysentery, and dehydration. Dehydration often occurs in patients with associated vomiting, which limits maintenance of oral hydration. Importantly, no deaths have been reported from traveler's diarrhea.

About 2% of patients may experience protracted diarrhea after returning home, and parasitic infection should be considered, particularly Cryptosporidium and Cyclospora species. Protracted diarrhea may also result from secondary disaccharidase deficiency; this usually resolves in 6 to 8 weeks. Postinfectious irritable bowel syndrome occurs in 1% to 4% of patients after acute infectious gastroenteritis and may persist for months or years. This condition is indistinguishable from idiopathic irritable bowel syndrome (see Chapter 110 ).

[edit] Prevention and Prophylaxis

Avoidance of tap water, raw foods, and foods from street vendors decreases the risk of traveler's diarrhea. Washed citrus fruits, carbonated drinks, and dried foods are usually safe. Pretravel consultation and education allow travelers to cope better with their illness; despite a higher attack rate with travel to high-risk areas, they are less likely to require medical help or seek posttravel consultation. Routine antibiotic prophylaxis should be discouraged because of the risks of side effects and possible development of resistant strains of bacterial pathogens in the community. Prophylaxis is appropriate for high-risk patients, however, including those with other significant illness (e.g., diabetes mellitus, severe heart disease), for whom diarrhea would be especially deleterious. Prophylaxis can also be considered for some business travelers. In most travelers, however, short-term treatment of illness once it develops is preferable to antibiotic prophylaxis.

Bismuth subsalicylate has the advantages of protection, no effect on bacterial resistance, and low cost; the protection rate is about 66%. Two tablespoons (15 ml each) or two well-chewed tablets (262 mg each) should be taken four times a day with meals. The dosing frequency often makes compliance difficult. TMP-SMX offers satisfactory prophylaxis for travelers to Mexico, with protection rates up to 95%. It is taken in a dose of one tablet (160 mg TMP, 800 mg SMX) once a day. It is less useful in Africa, Asia, and South America, where resistance to TMP-SMX is high. The major adverse reaction is photodermatitis, a particularly undesirable risk for vacationers to beach resorts. Ciprofloxacin or norfloxacin provides protection rates of up to 95% in most parts of the world. A once-daily dose is taken for prophylaxis, 500 mg for ciprofloxacin or 300 mg for norfloxacin. These drugs are safer than TMP-SMX, with fewer reported adverse effects. Their use in children is not recommended because of possible effects on joint cartilage.

[edit] Treatment

Travelers should be advised about oral rehydration with mineral water, bottled drinks, and high-salt foods (e.g., crackers, chips, soup).^[15] Healthy travelers should be given two medicines to carry on their journey: loperamide or a similar antidiarrheal agent, and a broad-spectrum antibiotic effective against enteric organisms (e.g., quinolone, TMP-SMX). The patient with mild diarrhea should avoid milk, alcohol, and spicy food; take loperamide only; and increase intake of fluids and salt. Moderate diarrhea (more than 10 watery stools a day, abdominal cramps) can be treated with loperamide with the addition of ciprofloxacin (500 mg) or norfloxacin (200 mg) twice daily for 3 to 5 days. In severe diarrhea with fever greater than 100.4° F (38° C) or bloody stools, loperamide should not be used, and the patient should be treated only with antibiotics. If dysentery symptoms persist for more than 3 to 4 days, medical consultation is recommended to exclude parasites or other conditions and to ensure adequate rehydration.

[edit] PARASITIC INFESTATIONS CAUSING DIARRHEA

The diagnosis of parasitic infestation requires proper stool examination by an experienced parasitologist. In this age of international travel, many parasitic infections are acquired abroad and become symptomatic after the patient returns home. A careful travel history and a high index of suspicion are critical to the diagnosis of parasitic disease.

[edit] Giardia duodenalis

The organism is distributed worldwide, with the vast majority of infestations being asymptomatic.^[16]Giardia is a common cause of diarrhea among travelers, with certain areas posing exceptionally high risks, such as St. Petersburg, Russia, where attack rates of up to 30% have been reported in travelers. In the United States, Giardia infestations are acquired mainly from contaminated water supplies, many of which are located in frequently visited, remote wilderness settings. Patients with hypogammaglobulinemia, particularly selective immunoglobulin A deficiency, are at highest risk. Hypochlorhydric or achlorhydric patients, including those with a prior gastrectomy, are also more susceptible.

The major symptom of giardiasis is diarrhea, which may be acute, intermittent, or chronic and is often accompanied by dull cramping pain above the umbilicus, anorexia, nausea, bloating, and flatulence. A less common but important presentation is steatorrhea and progressive weight loss. Diagnosis of giardiasis can be made in 50% of patients by stool examination, but the remainder require examination of a duodenal aspirate for the characteristic organisms. The duodenal aspirate is best obtained at endoscopy, which also allows duodenal mucosal biopsies to be examined for the organisms. Patients with giardiasis and underlying immunoglobulin deficiency syndromes frequently have flat or clublike villi on duodenal biopsy as well as diminished plasma cells in the lamina propria, in contrast to celiac disease, where villous flattening is accompanied by an intense plasma cell infiltrate.

Metronidazole, 250 mg three times a day for 7 days, is highly effective therapy. For patients with immunoglobulin deficiency, long-term metronidazole can restore the normal villous architecture and reverse the malabsorption syndrome.

[edit] Entamoeba histolytica

Of the seven species of amebae known to parasitize the human intestinal tract, only Entamoeba histolytica is pathogenic.^[17] Infection with this organism occurs worldwide but is much higher in tropical areas where poor sanitary conditions prevail. Clinical symptoms of amebiasis occur more often in endemic areas, in military personnel returning from the Far East, and in migrant laborers from Mexico, but the disease also occurs in individuals who have not traveled outside the United States. Humans are the principal host and reservoir for E. histolytica, and infection occurs through ingestion of cysts from contaminated water or food sources. Spread is predominantly fecal-oral, although venereal transmission is a significant hazard among homosexuals.

Most isolates of E. histolytica are nonvirulent, and the trophozoites lack the ability to invade tissue. Thus the most frequently encountered clinical variant of this disease is the asymptomatic cyst passer. In these asymptomatic patients, E. histolytica exists as a commensal in the large intestine. Once the ameba is encysted and passed into the environment, it is relatively resistant and can survive up to 10 days. The invasive motile trophozoite of E. histolytica cannot survive in the environment and plays no role in fecal-oral spread of the disease. Occasionally an asymptomatic cyst passer develops acute invasive amebiasis, and current recommendations are that all symptomatic cyst passers (except in highly endemic areas) be treated, since they are the reservoir of disease and pose an infective risk to others.

Symptomatic disease produces a variety of presentations. Some patients have chronic disease characterized by bouts of diarrhea, abdominal pain, and weight loss. The diarrhea usually contains blood and mucus, and tender hepatomegaly and pain over the cecum and ascending colon may be present. Occasionally a mass lesion called an ameboma, comprising a fibrous and granulomatous reaction to the infection, may develop in the large bowel, causing confusion with colon carcinoma. Other individuals have an acute dysenteric illness with fever, abdominal pain, tenesmus, and bloody diarrhea. Massive colonic bleeding, toxic megacolon, and perforation are potential complications. Extraintestinal invasion mostoften affects the liver, where hepatic abscesses form. A critical concern is to distinguish amebiasis from ulcerative or Crohn's colitis, since mistaken treatment with corticosteroids can accelerate amebic colitis and foster systemic invasion.

Diagnosis can be established by examining fresh stool specimens, which may show cysts in asymptomatic carriers and characteristic trophozoites containing ingested red blood cells in patients with dysentery. Sigmoidoscopy may reveal discrete yellow-based rectosigmoid ulcers with undermined edges and characteristically normal intervening mucosa. The disease may be predominantly right sided, however, resulting in a normal sigmoidoscopic appearance. Serologic tests are sensitive in detecting invasive amebic disease, including hepatic abscess and colonic mucosal invasion, but remain positive for an extended period after treatment of the disease. Metronidazole, 750 mg three times a day for 10 days (active against trophozoites), followed by diloxanide furoate, 500 mg three times a day for 10 days (to eliminate cysts), is effective therapy for active intestinal infection with E. histolytica.

[edit] SEXUALLY TRANSMITTED GASTROINTESTINAL INFECTIONS

Two forms of sexually transmitted gastrointestinal infections are described: a diarrheal syndrome and acute proctitis.^[18] Venereal transmission of enteric pathogens such as Shigella, Salmonella, E. histolytica, G. duodenalis, and C. jejuni occurs through oral-anal contact and may produce a picture of acute diarrhea or dysentery.

Acute proctitis occurs in men who have sex with men and in women who participate in anoreceptive sexual intercourse. The classic sexually transmitted pathogens, such as Neisseria gonorrhoeae, Treponema pallidum, Chlamydia trachomatis, Haemophilus ducreyi, herpes simplex virus, and human papillomavirus, have all been identified in anorectal lesions in acute proctitis (Table 111-5). The clinical features of acute proctitis are nonspecific and mimic idiopathic inflammatory bowel disease. The most common presenting symptoms include discharge, rectal pain, tenesmus, hematochezia, and diarrhea. Likewise, the sigmoidoscopic appearance of the rectal mucosa is nonspecific and includes mucosal erythema, granularity, friability, and ulceration. A specific infectious agent usually cannot be identified on the basis of clinical symptoms or sigmoidoscopic appearance. Before the institution of therapy, cultures must be obtained for the variety of organisms expected in this setting. Rectal swabs should be cultured for N. gonorrhoeae and C. trachomatis, and viral cultures should be sent to a reference laboratory for herpes simplex isolation. Routine bacterial stool cultures and stool examination for E. histolytica are also obtained. After identification of specific pathogens, therapy is directed toward each of the organisms identified; broad-spectrum empiric therapy is avoided.

Table 111-5 Sexually Transmitted Anorectal Infections

[edit] EVIDENCE-BASED MEDICINE

The primary source for this chapter was MEDLINE. Electronic searches dating back to 1994 were conducted in April 1999.

[edit] REFERENCES