- Email: [email protected]
Gastroenteritis and antibiotic-associated diarrhea
Prim Care Clin Office Pract 30 (2003) 63–80
Gastroenteritis and antibiotic-associated diarrhea Abdul Jabbar, MD*, Richard A. Wright, MD Division of Gastroenterology/Hepatology, Department of Medicine, University of Louisville, 530 South Jackson Street, Digestive Health Center, Louisville, KY 40292, USA
Acute gastroenteritis consists of mucosal inflammation of the stomach and the intestine and is characterized by a syndrome of acute anorexia, nausea, vomiting, abdominal cramps, bloating, and diarrhea. More profound gastroenteritis may present with severe dehydration, orthostatic hypotension, or neurologic deficits. Acute gastroenteritis frequently is labeled as food poisoning. The actual causes of this syndrome are numerous and include viral or bacterial infection, food allergies (eosinophilic), food poisoning, and organic or inorganic chemical agents. Ingestion can occur by way of person-to-person contact, airborne transmission (especially with virus), or more commonly, contaminated food or water. Symptoms of gastroenteritis usually begin abruptly, with the patient typically documenting the hour of onset. With few exceptions, gastroenteritis is self-limited, and patients recover within 1 to 5 days. There have been multiple outbreaks of gastroenteritis due to different infectious agents. The incidence varies from year to year. The true incidence is never known because most cases are not reported. Of 2423 reported outbreaks investigated by the Centers for Disease Control from 1988 to 1992, the cause was established for only 41% [1], which shows the current limitation in diagnostic capabilities, particularly for identifying presumptive viral pathogens. Gangarosa et al [2] analyzed hospitalizations in the McDonnell-Douglas Health information database from 1985. Gastroenteritis, as one of the top three diagnoses, was recorded as the discharge diagnosis in 98,185 hospitalizations and resulted in 1130 deaths. Analysis showed that age was the most important risk factor for death during hospitalization involving gastroenteritis. Individuals 80 years of age or older have a 3% fatality rate compared with 0.05% for children younger than * Corresponding author. E-mail address: [email protected] (R.A. Wright). 0095-4543/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0095-4543(02)00060-X
64
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
5 years. The authors of this study concluded that gastroenteritis is a large, underemphasized public health problem among the elderly. Higher mortality in gastroenteritis in elderly patients is due to concomitant myocardial, renal, cerebrovascular, and intestinal ischemia.
Etiologic agents Multiple agents have been implicated for gastroenteritis and can be classified as bacterial, viral, food intolerance (eosinophilic), and others. Bacterial infections Bacterial infection is caused by the fecal-oral route and direct contact, particularly in areas where people are housed together with poor hygiene, such as day care centers or nursing homes. The ingestion of water and food contaminated with pathogenic microorganisms is a significant source of disease transmission and can cause large outbreaks of disease. A massive salmonella outbreak was reported in Illinois in 1987 as a result of milk contamination at one plant site during the pasteurization process. More than 16,000 culture-confirmed cases were documented [3]. Cryptosporidiosis contamination of the Milwaukee water supply resulted in a large waterborne outbreak [4]. In 1993, 500 cases were identified from the western United States related to contaminated hamburger with Escherichia coli O157-H7 [5]. In developing regions of the world, acute diarrhea is epidemic, whereas in developed countries, comprehensive standards for food, water, and sewage make endemic outbreaks uncommon. A seasonal distribution is definitely seen with gastroenteritis due to bacterial and viral causes. The highest incidence for hospital admissions owing to bacterial causes is in August and September.
Pathogenesis In most intestinal infections, a pathogen enters and colonizes the intestine. There are some exceptions when colonization is not required, such as with ingestion of preformed toxins, which results in activation of cyclic adenosine monophosphate or adenylate cyclase enzymes causing secretory diarrhea. A pivotal step in colonization is adherence of the pathogen to intestinal epithelium with bacterial pilli–containing adhesions, a lectin-like molecule that interacts with sugar moieties on the microvillous membrane of intestinal mucosa, allowing attachment [6]. Pathogens produce diarrhea by three different mechanisms. (1) Some pathogens do not disrupt the mucosa but lead to diarrhea secondary to release of enterotoxins, which promote intestinal secretion (Staphylococcus aureus, Bacillus cereus, Clostridium botulinum). (2) Some bacteria disrupt
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
65
mucosal integrity through cytotoxic mediators, which may or may not invade the tissue. (3) Some pathogens have the capacity to express invasins, which trigger the host cell to initiate an energy-dependent endocytotic process that uses the host cell microfilament system. This process leads to tissue invasion by the organism and destruction of the mucosa. In general, the mechanism of the diarrhea is due to increased intestinal secretion as a result of enterotoxins, cytotoxic mediators, or decreased intestinal absorption secondary to intestinal damage or inflammation. Infection in different regions of the gastrointestinal tract can influence the character of diarrhea. Noninflammatory diarrhea is caused by impaired electrolyte and fluid absorption of the small intestine. Noninflammatory diarrhea is self-limited and requires supportive therapy only. Alternatively, antibiotics may benefit inflammatory diarrhea.
Foodborne bacterial pathogens Foodborne illness is a significant and growing global problem, with 200 different diseases currently known to be transmitted by food. Worldwide, an estimated 1 billion episodes of diarrhea are caused by foodborne pathogens annually, accounting for 70% of all human diseases [7]. Escherichia coli O157-H7 E. coli O157:H7 is so named because it possesses the one hundred fiftyseventh described somatic or O antigen and the seventh flagellar or H antigen. The organism is believed to have acquired its pathogenicity recently, when it acquired two shiga-like toxins [8]. It was first recognized as a cause of hemorrhagic colitis when it was associated with the consumption of undercooked hamburger at fast-food restaurants in 1982 [9]. In 1983, hemolytic uremic syndrome (HUS) manifested by thrombocytopenia, microangiopathic hemolytic anemia, and renal failure was first reported in children as a complication of E. coli O157:H7. Currently, E. coli O157:H7 is estimated to be responsible for 73,000 cases of diarrheal disease, resulting in 2100 hospitalizations and 60 deaths annually in the United States [7]. Hemolytic uremic syndrome is now the leading cause for dialysis in children and 50% of thrombotic thrombocytopenic purpura cases in adults in the United States. E. coli is a part of normal flora in cattle. Fifty percent of all feedlot cattle are colonized with E. coli O157:H7. Up to 90% of hamburger is contaminated. Most cases of gastroenteritis are due to contamination of beef products, fruits, or cross-contaminated infected beef products during food preparation. This organism requires a low dose of colony-forming units (10–100), similar to that of shigella. This low infectious dose has resulted in significant secondary spread in nursing home and day care centers [10].
66
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
The pathogenicity of E. coli O157:H7 is attributable to production of shiga toxins. These toxins also are termed verocytotoxins because Vero cells have been used most frequently in vitro assays of toxin detection. E. coli O157:H7 produces two types of toxins: shiga toxin 1 and shiga toxin 2, or both. E. coli O157:H7 also has the ability to attach to the intestinal mucosa surface. These toxins inhibit protein synthesis and destroy epithelial cells with resultant necrosis and edema. They bind to globotrioasosylceramide, a membrane surface receptor. These receptors are expressed highly in the cortex of human kidney, which may explain the predilection for renal involvement. These toxins also have a direct effect on vascular epithelium, creating intravascular thrombi with platelet and fibrin deposition leading to ischemic changes in the colonic microvasculature and resultant hemorrhagic colitis [11]. The incubation period averages 3 to 4 days after consumption of contaminated food. Initially, the patient has watery diarrhea for 1 to 2 days, followed by severe abdominal cramping and bloody diarrhea. Fever is low grade or absent. The absence of fever with marked abdominal pain and bloody diarrhea can be confused with ischemic colitis, intussusception, or inflammatory bowel disease. An estimated 5% of cases progress to HUS or thrombotic thrombocytopenic purpura, with a propensity for children and the elderly. The onset of HUS is usually within 1 week of the onset of diarrhea. Patients have pallor, oliguria or anuria, and edema. In elderly patients, thrombotic thrombocytopenic purpura may present with neurologic manifestations, including lethargy, agitation, seizures, or coma. Most patients have bloody diarrhea. The diagnosis is made by stool culture on sorbitol MacConkey agar (SMAC agar). The yield is 90% with acute bloody diarrhea. Another sensitive test is the EHEC assay (Meridian Diagnostic, Cincinnati, OH), which identifies the toxins in the stool. It has a sensitivity of 100% and a specificity of 99.7%, whereas culture on SMAC agar has a sensitivity of 60% and a specificity of 100% [12]. Stool examination shows abundant blood, but fecal leukocytes are either absent or rare. Plain abdominal films show predominantly right-sided findings with dilated ascending and transverse colon with ileus in 60% to 100% of cases. Colonoscopy reveals patchy erythema, edema, and superficial ulceration. Histopathology shows a mixture of ischemic and infectious changes. The treatment of E. coli O157:H7 is supportive. An accumulating body of data suggests that antibiotics are not only ineffective in ameliorating illness but also increase the risk of HUS [13]. This risk is greatest in children. In a southwestern Ontario nursing home outbreak with E. coli O157:H7, adults who received antibiotics for diarrhea were at a statistically increased risk for HUS. Physicians should not use antibiotics to treat other pathogens unless it is confirmed that E. coli O157:H7 is not present. The use of antitoxins is currently under investigation. Antimotility agents and opioids should be avoided.
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
67
Because there is no effective treatment for E. coli O157:H7, prevention becomes a matter of paramount importance. Hamburger should be cooked to an internal temperature of 155F. Irradiation of meat is now Food and Drug Administration–approved, effectively eliminating E. coli O157:H7. Contact isolation is effective in preventing spread in day care centers. Children should have two negative stool culture results before returning to day care centers.
Diarrheogenic Escherichia coli The diarrheogenic E. coli strains cause diarrhea as result of enterotoxin production, adherence, or invasion. They are divided into the following. Enterotoxigenic-producing Escherichia coli Enterotoxigenic-producing E. coli (ETEC) is the most common cause of traveler’s diarrhea. Enterotoxigenic-producing E. coli carries a virulencerelated plasmid. These strains elaborate either heat-sensitive or heat-labile toxin. Enterotoxigenic-producing E. coli adheres to and colonizes the mucosa with the help of surface fimbriae called colonization factors. Toxins are delivered through the colonization factor, leading to activation of cyclic adenosine monophosphate and subsequently leading to active water and electrolyte secretion and diarrhea. The development of vaccines against colonization factors could lead to cost-effective management of this highly prevalent public health problem. Fecal contamination of water and food is the primary reason for the high prevalence of ETEC in developing parts of the world. Enterohemorrhagic Escherichia coli Enterohemorrhagic E. coli is a relatively less common cause of diarrhea. It usually presents as self-limited watery diarrhea. Occasionally, bloody diarrhea associated with HUS can present a management problem. Enteroaggregative Escherichia coli Enteroaggregative E. coli is an unrecognized cause of traveler’s diarrhea. In one study, enteroaggregative E. coli was isolated in 29 of 64 travelers to Jamaica and Mexico. Ciprofloxacin is beneficial in this group. The presentation resembles that of enterohemorrhagic E. coli. Campylobacter In the United States and developed countries, Campylobacter is the most commonly identified bacterial organism in infectious diarrhea, with more
68
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
than 2.4 million cases occurring annually in the United States [14]. Campylobacter jejuni is responsible for 99% of these cases. Campylobacter-related gastroenteritis is most commonly due to consumption of poultry. Recent surveys have shown that 88% of chickens in the retail market are culture positive for Campylobacter, with the highest colony counts in the skin and giblets. The peak incidence occurs in infants. A second peak occurs between 15 and 30 years of age. Infections are seasonal, with peak incidence from May to August. Campylobacter invades the small and large intestine and can produce neurotoxins. It is clinically indistinguishable from salmonella and shigella infections. The most common symptoms are fever, abdominal pain, diarrhea, vomiting, systemic motor paralysis, and cranial nerve and respiratory muscle paralysis. Symptoms usually resolve in 1 week without antibiotic therapy, but symptoms may persist for 1 to 3 weeks in 20% of sick patients. Complications include cholecystitis, pancreatitis, and peritonitis. Immunologic sequelae include reactive arthritis and Guillain-Barre´ syndrome [14]. Diagnosis is by culture of Campylobacter in the stool, blood, or toxins in the stool. Occult or gross blood is present in most cases, with fecal leukocytes present in 75% of patients. Massive gastrointestinal bleeding is rare. Colonoscopy findings range from segmental colonic ulceration to diffuse colitis. The small intestine also can be affected, but to a much lesser extent. Antibiotics are beneficial in those patients with symptoms prolonged more than 1 week or with worsening fever and bloody diarrhea. Patients with human immunodeficiency virus or other immunocompromised conditions also should receive antibiotics [14]. Antibiotics can reduce the duration of Campylobacter excretion in the stool but may not shorten the uncomplicated enteritis course [14]. Erythromycin is the treatment of choice because resistance is rare. Ciprofloxacin is effective and has been shown to reduce the duration of clinical symptoms and to eradicate Campylobacter from stool, but resistance is common. Avoidance of raw chicken can prevent infection.
Salmonella Salmonella causes an estimated 3.7 million cases of gastroenteritis infections in the United States annually. Multiple outbreaks have been reported. Sporadic infections are common. The most common types in the United States are Salmonella enteritidis followed by S. typhimurium, S. newport, and S. hadar. S. enteritidis accounts for 2.4 million infections in the United States. The greatest prevalence is in children less than 1 year of age. There is significant risk of mortality and morbidity in the elderly. Almost 50% of the cases are caused by contaminated poultry, meats, eggs,
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
69
and dairy products. Gastrointestinal endoscopy is rarely implicated in the spread of this infection [15]. The pathogenicity is secondary to invasion of mucosa in the small and large intestine. Histologic findings include edema of the lamina propria and diffuse or focal acute inflammatory infiltrations with disruption of the mucosa changes with microabscesses. Predisposing conditions are sickle cell, neoplasm, corticosteroids, chemotherapy, and immunodeficient states. Gastric acid is the most important host defense. With normal acidity, greater than 99.9% of gram-negative bacteria are destroyed. Patients usually present with symptoms of nausea, vomiting, abdominal pain, and bloody diarrhea. Symptoms last 2 to 4 days with gastroenteritis and 2 to 3 weeks for hemorrhagic colitis. Toxic megacolon rarely has been reported. A carrier state of greater than 1 year has been reported, with the organism harbored in the gallbladder. This carrier state has an incidence of less than 1% [15]. Salmonella cholecystitis is rare. Diagnosis can be made by stool culture. The median duration of organism excretion is 5 weeks. Sensitivity of stool culture in adults ranges from 36% to 58%. Treatment is not recommended in uncomplicated salmonella gastroenteritis. Treating with antibiotics, particularly ciprofloxacin, may prolong fecal excretion of Salmonella. There are no prospective trials evaluating antibiotic therapy in S. colitis. Antibiotics should be given to patients with lymphoproliferative disorder, malignancy, immunosuppression, post-transplant status, and sickle cell disease; and to those who are pregnant, in early childhood, or elderly [16]. Antibiotics can be used if the patient has severe symptoms or persistent disease. Preferred antibiotics include ampicillin and trimethoprim-sulfamethoxazole. In patients with extra-intestinal manifestations (ie, osteomyelitis, pneumonia, arteritis, or meningitis), therapy with ampicillin, amoxicillin, or third-generation cephalosporins is indicated. In the carrier state, antibiotic treatment is controversial. Quinolone antibiotics are the agents of choice, although they may prolong the carrier state after acute salmonella gastroenteritis. Cholecystectomy offers the definite cure. Shigella Shigella is a gram-negative bacillus with four species: S. dysenteriae, S. flexneri, S. boydi, and S. sonnei. The dysenteri species produce a potent protein synthesis–inhibiting cytotoxin called shiga toxin. It has been associated with food and water outbreaks, but in most cases, transmissions are by way of person-to-person contact. Shigella has an estimated 0.22 cases per 1000 children per year in the United States [17]. Incidence is much higher in American Indians. Small inocula of organisms are necessary to cause the disease: 10 to 100 organisms of S. dysenteri type 1 in otherwise healthy adults. This small dose could be secondary to acid resistance [18]. Children in day care centers
70
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
and homosexual men are the two populations in developed countries that are at higher risk; S. flexneri is the most common species in male homosexuals. Symptoms begin with fever, fatigue, malaise, and anorexia. Later, watery or bloody diarrhea develops. The stool frequency ranges from 8 to 10 bowel movements per day, and the volume is high, with subsequent dehydration. Clinical dysentery is most common with S. dysenteri as compared with other species. Toxic megacolon occurs more frequently with S. dysenteriae type 1 infection. Hemolytic uremic syndrome has been reported with S. dysenteriae. Neurologic manifestations, such as seizures, rarely occur. Reiter’s syndrome has been reported as a sequelae. The diagnosis is made by stool cultures. The stool is loaded with polymorphonuclear leukocytes. Colonoscopy shows findings of erythema, edema, loss of vascular pattern, focal hemorrhages, mild friability, and adherent white mucopurulent layers, with predominant involvement of the distal colon (rectum and sigmoid). Antibiotics lower the mortality rate and shorten the illness. Suggested antibiotics are trimethoprim-sulfamethoxazole and ciprofloxacin [19]. Antidiarrheal agents predispose to toxic dilation of the colon. Prophylaxis is the most important factor in shigella infection. Handwashing with bactericidal soap can prevent transmission. Shigella can be transmitted by insects to food. Pesticides in areas of endemicity reduce incidence. Vaccines do not afford significant protection.
Vibrio cholerae and Vibrio parahaemolyticus Vibrio cholerae is a major cause of epidemic diarrhea in Asia, Africa, and Latin America. Only serogroups 01 and 0139 are associated with cholera. V. cholerae primarily infects the small intestine by production of enterotoxins that produce watery diarrhea, nausea, vomiting, circulatory collapse, and shock. If the condition is not treated, the patient can become hypotensive within 1 hour and die within 2 to 3 hours. Rapid diagnosis can be made by stool specimens, which show large numbers of bacilli with ‘‘shooting-star’’ motility and immobilize motile vibrios with Inaba antisera. Diagnosis is accomplished best by culturing the stool or rectal swab on thiosulfate citrate bile salts sucrose–selective agar. With advances in molecular biology, rapid diagnosis of cholera can be made by using AP-labeled, cytotoxin-specific oligonucleotide to identify V. cholerae from the stool specimen [20]. Cholera is a self-limited, noninvasive disease, but its capacity to cause voluminous diarrhea and its efficient fecal-oral transmission make it one of the most persistent scourges of humankind. Primary treatment is rehydration. Initial assessment should include calculation of fluid requirement and replacement of electrolytes. Antibiotics such as tetracycline or single-dose
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
71
doxycycline can reduce stool frequency, duration of illness, and fecal shedding of V. cholerae by 50% [21]. Trimethoprim-sulfamethoxazole, erythromycin, and ampicillin are alternatives. Single-dose quinolones are extremely effective in cholera therapy, and quinolone-resistant cholera are extremely rare at present. Vibrio parahaemolyticus and Vibrio mimicus outbreaks usually are associated with consumption of oysters. V. parahaemolyticus has been recognized as the major cause of acute diarrheal disease in Japan. It is reported to infect 16% of travelers to Southeast Asia. Approximately 30 to 40 cases of V. parahaemolyticus are seen in the Gulf Coast states of Alabama, Florida, Louisiana, and Texas. Sudden and profuse diarrhea and abdominal pain are the earliest and almost universal symptoms. Nausea, vomiting, headache, chills, fever, and blood and mucous in the stool are seen commonly. In rare instances, hypotension and shock have been reported [22]. The disease is self-limited and lasts only a few days. There is no controlled trial treating noncholera vibrio gastroenteritis with antibiotics. For the rare patient with prolonged diarrhea, a course of doxycycline or quinolone is reasonable. Other noncholera vibrios, such as Vibrio hollisae, V. fluvialis, and V. furnissi, are rarely if ever associated with gastroenteritis. Listeria monocytogenes There are at least 2500 cases of severe Listeria monocytogenes infections, with 500 deaths in the United States annually. More recently, L. monocytogenes has been increasingly implicated as a cause of febrile gastroenteritis in immunocompetent patients. Severe invasive infections occur predominantly in newborns, pregnant women, those who are immunocompromised, and in those older than 65 years of age. Its outbreak has been associated with hot dogs. L. monocytogenes grow well at refrigerator temperatures, making infection a special concern for foods with a longer shelf-life kept at such temperatures. Diarrhea and fever are the predominant symptoms. No effective treatment is available. The Food and Drug Administration has released a consumer advisory to reduce the incidence. Hot dogs and luncheon meats should be well reheated and steaming hot; soft cheeses and refrigerated pates should be avoided. Clostridium perfringens Clostridium is a ubiquitous organism found in human and animal feces and in soil. Meats are the most frequently contaminated food. Transmission of enough organisms to produce illness occurs typically with inadequately heated or reheated meats. Spores may survive at normal temperatures. The spores may germinate and multiply at warm temperatures
72
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
that do not inhibit bacterial growth. The incubation period is 8 to 16 hours. C. perfringens is a common contaminant of meat-related food. It produces toxins in food and feces. Enterotoxins are released during the sporulation in the large intestine. Symptoms start abruptly and include profuse diarrhea, occasional vomiting, and abdominal cramps. Culture of the suspected food is diagnostic. The clinical picture is self-limited, lasting 1 to 4 days. No treatment is necessary. Only symptomatic treatment is warranted. Staphylococcus aureus Staphylococcus aureus is a common contaminant of custard-filled pastries and processed meats. Contaminated foods contain enterotoxins. Individuals with skin or nasal mucosa colonization are the source of S. aureus [23]. Staphylococcal food poisoning occurs when contaminated food is allowed to stand long enough for the organism to multiply and produce enterotoxin. It mainly involves meats (ham, pork, beef, and poultry). The incubation period is short, ranging from 1 to 8 hours. The patient presents with vomiting, abdominal cramps, and diarrhea but no fever. In the first 24 hours, the patient has intense vomiting, with diarrhea later. Only symptomatic treatment is necessary. Bacillus cereus Bacillus cereus enterotoxin is produced in food or in the intestine. The most commonly contaminated foods are rice and bean sprouts. The incubation period is 2 to 4 hours. If pre-existing toxins are in the food, vomiting is the predominant symptom. If the toxins are formed by bacterial production in the intestine, diarrhea is the main symptom. Rhabdomyolysis and liver failure have been reported. Vomiting and diarrhea are self-limited, lasting less than 24 hours. Yersinia enterocolitica Yersinia enterocolitica is found more frequently in northern Europe than in the United States. It is found in streams, lakes, and animals. Cows, chickens, horses, cats, and dogs have been implicated. The most common clinical symptoms are abdominal pain and diarrhea. Other symptoms are nausea, vomiting, fever, and arthralgias. Approximately 40% of patients present with symptoms suggestive of appendicitis. Yersinia infection is more common in the winter. The diagnosis is made by stool culture or serology. Patients occasionally have leukocytosis, an elevated erythrocyte sedimentation rate (ESR), or occult blood in the stool. Antibiotics have not been shown to alter the disease process. Current recommendations include the use of
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
73
trimethoprim-sulfamethoxazole, tetracycline, and ciprofloxacin for treatment of severe yersinia enteritis or complications such as mesenteric adenitis, erythema nodosum, and arthritis. Viral gastroenteritis Viral gastroenteritis usually presents with diarrhea accompanied by prominently upper gastrointestinal symptoms for 1 to 4 days. It is easily confused with bacterial enteritis because symptoms are identical. Viral enteritis is most likely present when vomiting is prominent. The incubation period is longer than 14 hours, and duration of symptoms is more than 72 hours. Viral pathogens are likely when there are no warning signs of bacterial infection (ie, high fever, bloody diarrhea, abdominal pain, more than six stools per 24 hours) and there are no epidemiologic clues from the history, including sexual contact or antibiotic use [24]. In acute viral gastroenteritis, an etiologic diagnosis is suspected from clinical features and knowledge of the epidemiology. Following are the most common viruses responsible for gastroenteritis: acute sporadic and endemic childhood and adult diarrhea (rotavirus, calicivirus, Astrovirus, adenovirus, Torovirus); epidemic diarrhea (calicivirus, Astrovirus, adenovirus, diarrhea in immunocompromised hosts); cytomegalovirus; Epstein-Barr virus; adenovirus; Astrovirus; and picornavirus. The pathogenesis of diarrhea in rotavirus infection is understood poorly. The virus attaches and enters mature enterocytes at the tips of the small intestinal villi. It may lead to structural changes to the mucosa, leading to villus shortening and mononuclear infiltrates in the lamina propria. Viral attachment and entry into the cells can lead to diarrhea. Studies have suggested that one of the nonstructural viral proteins (NSP4) may act as an enterotoxin, promoting active chloride secretion mediated through increases in intracellular calcium concentration. In adults, the most important cause of viral gastroenteritis is calicivirus, also referred to as the Norwalk-like virus or small, round, structured virus. There are more than 100 different strains of Norwalk-like viruses, certain strains being predominant in any given time period or regions. When acute gastroenteritis sweeps through a semiclosed community (ie, family, school, residential home, or hospital), affecting adults and children with high attack rate, the illness is most likely due to calicivirus. According to the Centers for Disease Control, 9.2 million cases of food-related illnesses are caused by these viruses each year in the United States. Transmission of these viruses varies from contaminated food, person-to-person contact, raw oysters, and contaminated water. The frequency of rotavirus as a cause of sporadic adult gastroenteritis is not known. Adult infection usually occurs as a secondary cause from contact with sick children or travelers, but in an institutional fashion like
74
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
calicivirus. Rotavirus causes diarrhea in adults. Death has been reported in the elderly. Rotavirus is a well-known cause of waterborne and food-borne gastroenteritis. Diagnosis of a specific virus as a source of gastroenteritis is not required for management. Clinical features are helpful in distinguishing between bacterial and viral causes. The diagnosis of rotavirus can be made by rapid antigen testing of stool by enzyme immunoassay (>98% sensitive and specific) or latex agglutination tests (less sensitive and specific). Antirotavirus antibodies (IgM and IgA) are excreted in the stool after the first day of illness. Antibodies can remain positive for 10 days after the primary infection. A rise in antiviral antibody can be a diagnostic tool for Norwalk viruses. In immunocompromised patients, the most common viruses responsible for diarrhea are cytomegalovirus, Epstein-Barr virus, and rarely, astrovirus, picorbinovirus, calicivirus, and adenovirus.
Traveler’s diarrhea Traveler’s diarrhea is defined as the passage of three or more loose stools in a 24-hour period after travel to a foreign country. Associated symptoms include nausea, vomiting, abdominal pain, or fever. Symptoms commonly last only 2 to 5 days. If symptoms persist for more than 2 weeks, traveler’s diarrhea is unlikely. The most common offending organism is E. coli (toxigenic or nontoxigenic). The occurrence of fever with bloody or mucoid stool indicates a severe dysenteric syndrome related to infection with a more invasive organism.
Antibiotic-associated colitis Antibiotics are used commonly for a variety of illnesses. They alter the normal colonic microflora, leading to overgrowth of other bacteria, especially Clostridium difficile. Antibiotic-associated diarrhea or colitis can be caused by other enteric pathogens, including Salmonella, Clostridium perfringens type A, Staphylococcus aureus, and possibly Candida albicans. The protective effect of the normal intestinal flora is frequently referred to as colonization resistance. The disturbance of this barrier leads to growth of more harmful organisms. Antibiotic-associated diarrhea is defined as an otherwise unexplained diarrhea that occurs in association with administration of antibiotics [25]. The spectrum of findings in antibiotic-associated diarrhea ranges from colitis, which is a potential source of serious progressive disease, to diarrhea, which is defined as frequent loose and watery stools with no other complications. Clinical manifestations include abdominal cramping, fever, leukocytosis, fecal leukocytes, hypoalbuminemia, colonic thickening seen on CT scans, and characteristic changes apparent on endoscopy (multiple small, whitish-yellow plaques covering
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
75
hyperemic, prolapsing, and edematous colonic mucosa). Although infection with C. difficile accounts for only 10% to 20% of the cases of antibioticassociated diarrhea, it accounts for most colitis cases associated with antibiotic therapy [26]. Almost all antibiotics have been associated with C. difficile colitis, including vancomycin and metronidazole. The precise risk associated with individual agents is difficult to establish. The frequency of association is related to use, route of administration, and impact of colonic microflora. Antibiotics most frequently associated with C. difficile diarrhea include clindamycin, cephalosporin, ampicillin, and amoxicillin [26]. Meta-analysis shows that these agents were associated with the highest risks of C. difficile diarrhea, even after adjustment for other risk factors in multivariate analyses. Cancer chemotherapy agents that pose antibacterial properties and bowel-preparation regimens may result in sufficient disturbance of the intestinal microflora to allow colonization of C. difficile. Predisposing risk factors for Clostridium difficile infections Antibiotics are the major risk factor for C. difficile infection, and the hospital environment is the main source of C. difficile. The endogenous carriage rate in adults is low (0%–3% in American and European populations). In contradistinction, after admission to the hospital and treatment with antibiotics, 15% to 21% of patients become colonized with C. difficile. Asymptomatic carriers develop C. difficile–associated diarrhea, but they can contaminate the hospital environment. C. difficile spores may persist for many months in hospital wards because they are resistant to oxygen, desiccation, and many disinfectants. Others risk factors include older age and other disease states. Independent of age, debilitated patients are more likely to acquire C. difficile. Other reported risk factors are nasogastric tube, gastrointestinal procedures, antisecretory medications, intensive care unit stay, and duration of hospital stay. Pathophysiology of Clostridium difficile colitis Clostridium difficile produces toxin A and toxin B, two potent protein enterotoxins. These toxins are encoded by two distinct genes in close proximity on the bacterial genome. They are structurally similar. Specific cell-surface receptors for toxins A and B have not been characterized. Both toxins potently activate cell-signaling molecules, leading to the production of proinflammatory cytokines, including interleukin-1b, tumor necrosis factor-a, and interleukin-8. These proinflammatory mediators precede toxin internalization and subsequently lead to disorganization of cytoskeleton, disruption of protein synthesis, cell rounding, and cell death. Toxin A is an inflammatory enterotoxin that induces fluid secretion, increases fluid permeability, and induces marked enteritis and colitis when
76
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
injected into the intestinal lumen of animals. Although it was initially believed that toxin B does not participate in the pathogenesis of C. difficile because of its lack of enterotoxin effects in animals, toxin B is 10 times more potent than toxin A, inducing these changes in human colonic strips in vitro. Clinical features Infection with C. difficile produces a wide range of clinical manifestations, including asymptomatic carriage, mild to moderate diarrhea, and life-threatening pseudomembranous colitis. Asymptomatic carriage is common in hospitalized patients (10%–16%). These patients may develop antitoxin antibodies, which play a role in protecting from C. difficile diarrhea or colitis. The incubation period is likely to be less than 1 week, with median time of onset within 2 days. Colonization may occur during antibiotic treatment or during weeks after a course of antibiotics. It starts with passage of frequent, loose bowel movements consistent with proctocolitis. Mucous or occult blood may be present, but gross blood is rare. Some patients may present with fever, leukocytosis, and abdominal pain. Patients present with severe disability with or without diarrhea. In the absence of diarrhea, the only clue may be high fever, moderate or marked leukocytosis, lower or diffuse abdominal pain, tenderness, or distention. Extraintestinal manifestations of C. difficile infection are septic arthritis, bacteremia, and splenic abscess. More frequently seen is an oligoarticular, asymmetric, nondeforming large-joint arthropathy, similar to that seen in other infectious colitides. Complications of a severe form of disease include dehydration, hypoalbuminemia, electrolyte disturbances, toxic megacolon, bowel perforation, and death.
Diagnosis The diagnosis of C. difficile should be suspected in any patient with diarrhea who has received antibiotics within the previous 3 months or whose diarrhea began 72 hours or more after hospitalization. The testing of nondiarrheal stools for C. difficile is not recommended because many hospitalized patients may be asymptomatic carriers. Nonspecific findings such as leukocytosis, hypoalbuminemia, and fecal leukocytes can be helpful. Freshly passed stool samples should be submitted immediately in a clear water-tight container for detection of C. difficile toxins (A and B). Anaerobic cultures do not enhance recovery of the organism. Enzyme-linked immunoassay test Enzyme immunoassay to detect C. difficile toxins A and B antigens in the stool is used increasingly in clinical practice. Enzyme immunoassay is easy
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
77
to perform, highly specific (75%–100%), and relatively inexpensive, and results are available in 2 to 6 hours. False-positive results are rare. If the stool is tested for toxin A only, C. difficile diarrhea secondary to toxin A– negative or toxin B–positive results will not be diagnosed. It may be useful to test more than one stool sample for toxins with enzyme immunoassays. Performing enzyme immunoassays on two or three specimens rather than one increases the diagnostic yield by 5% to 10%. Tissue-culture cytology assay Tissue-culture cytology assay is considered the gold-standard diagnostic test for identification of C. difficile toxins in stool samples of patients with antibiotic-associated colitis. It is more sensitive (67%–100%) and specific (85%–100%), leading to greater diagnostic accuracy. Its disadvantage is that it requires a tissue-culture facility, which is more costly and time consuming, requiring incubation of fecal filtrate for 24 to 48 hours. Latex agglutination test This test detects only toxin A. Because of its recognition of other toxins and low sensitivity and nonspecificity, it is not recommended. Clostridium difficile culture The stool culture is sensitive but not specific for toxins producing C. difficile. An advantage is that it permits typing of individual isolates, helping in recognition of outbreaks. Polymerase chain reaction, with the use of specific primers based on the genes for toxins A and toxin B, is highly sensitive and specific, but it requires expertise in molecular diagnostic technique and is relatively expensive. Endoscopy Sigmoidoscopy or colonoscopy is not essential in the diagnosis of C. difficile colitis. Endoscopy is helpful in special situations, such as when the diagnosis is in doubt or the clinical situation demands rapid diagnosis. The finding of pseudomembranes in a patient with antibiotic-associated diarrhea is almost diagnostic for C. difficile colitis (Figs. 1 and 2). Other findings include normal colonoscopy in mild diarrhea to erythema, edema, friability, and nonspecific colitis with small ulceration or erosions. Radiology CT scans of the abdomen may facilitate the diagnosis but are nonspecific. Abdominal radiography may reveal toxic megacolon (>10 cm in its greatest diameter). CT scans may show mucosal edema, thumb printing, thickened colon, pancolitis, and pericolic inflammation.
78
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
Fig. 1. Antibiotic-associated pseudomembranous colitis.
Therapy of antibiotic-associated colitis The initial step in the management of C. difficile diarrhea and colitis is to discontinue the offending antibiotics if possible or to switch to other antibiotics that are less likely to exacerbate C. difficile diarrhea. Conservative management should be used in mild diarrhea. Anyone with moderately severe disease should be treated with metronidazole or vancomycin along with supportive measures, including intravenous fluid replacement and electrolyte imbalance correction. These patients have leukocytosis, fever, and severe diarrhea along with CT or endoscopic findings. Oral metronidazole (500 mg three times a day or 250 mg four times a day) and oral vancomycin (125 mg four times a day) have a similar rate of efficacy, with a response rate of 90% to 97%. The usual duration of therapy is 10 days, although a few studies have mentioned merits of longer or shorter courses [25]. If intravenous treatment is required, only metronidazole (not vancomycin) is effective, because this approach will still result in moderate concentration of the drug in the colon. The anticipated response to treatment is resolution of fever in 1 day and resolution of diarrhea in 4 to 5 days. Other antibiotics, such as bacitracin, have been studied but are less effective with a higher relapse rate [25]. Severe pseudomembranous colitis occurs in only 3% to 5% of patients with C. difficile–associated disease and is associated with a significant
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
79
Fig. 2. Severe pseudomembranous colitis.
mortality rate. Many patients who develop this extreme condition have substantial comorbid disease and are often critically ill. Diarrhea may be minimal or absent. Patients may present with abdominal pain, distention, peritoneal signs, colonic dilation, or the clinical picture of progressive sepsis. After discontinuing the precipitating antibiotics, therapy with metronidazole or vancomycin is started. Some studies recommended vancomycin as a first-line agent if the patient is critically ill because a more rapid response is anticipated. Intravenous vancomycin is not recommended. For patients with ileus, a nasogastric tube may be used with intermittent clamping. A combination of antibiotics using various routes can be tried in critically ill patients. Emergency surgery with colectomy is rarely required to prevent death in patients with severe colitis who have failed to respond to medical therapy and have established or impending bowel perforation. Approximately 20% to 25% of cases of C. difficile relapse [26]. Relapse is suggested by recurrence of symptoms, usually 3 to 21 days after metronidazole or vancomycin is discontinued. The assay of C. difficile toxin is unnecessary immediately after completion of treatment, and the result may be misleading, because one third of patients for whom therapy is successful have positive assays. Treatment lasting up to 4 to 6 weeks has been recommended, with antibiotics to control C. difficile infection while the normal flora become reestablished. Other proposed treatments are probiotics, intravenous immunoglobulin, and the use of anion-binding resins, but data to support their use are limited.
80
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
References [1] Centers for Disease Control and Prevention. Surveillance for food-borne disease outbreaks, United States, 1988–1992. CDC Surveillance Summaries 1996;45(Suppl):(SS-5). [2] Gangarosa RE, Glass RI, Lew JF, et al. Hospitalizations involving gastroenteritis in the United States, 1985: the special burden of the disease among the elderly. Am J Epidemiol 1992;135:281–90. [3] Ryan C, Nickels M, Hargrett-Bean N, et al. Massive outbreak of antimicrobial-resistant salmonellosis traced to pasteurized milk. JAMA 1987;258:3296. [4] MacKenzie R, Schell W, Blair K, et al. Massive outbreak of waterborne cryptosporidium infection in Milwaukee, Wisconsin. Clin Infect Dis 1995;21:57. [5] Davis M, Osaki G, Gordon G, et al. Update: multistate outbreak of Escherichia coli O157:H7 infection from hamburgers—Western United States, 1992–1993. MMWR 1983;42:258. [6] Farthing M. Acute diarrhea: pathophysiology. In: Graccey M, Walker-Smith J, editors. Diarrheal disease. Philadelphia: Lippincott-Raven; 1997. p. 55. [7] Oldfield CE. Emerging foodborne pathogens: keeping your patients and your families safe. Rev Gastroenterol Disord 2001;4:177–86. [8] Calderwood SD, Achesonn WDK, Keusch GT, et al. Proposed new nomenclature for shiga-like toxin family. ASM News 1996;62:118. [9] Riley LW, Remis RS, Helgerson SD, et al. Hemorrhagic colitis associated with a rare Escherichia coli serotype. N Engl J Med 1983;308:681–5. [10] Carter A, Borezyk A, Carlson J, et al. A severe outbreak of E coli O157:H7-associated hemorrhagic colitis in nursing home. N Engl J Med 1987;317:1496–500. [11] Oldfield CE, Wallace MR, Hopson SC. Emerging infections in the gastrointestinal tract. Clin Perspect Gastroenterol 2001;4:200–12. [12] Khel KS, Havens P, Behnke CE, et al. Evaluation of the premier EHEC assay for detection of shiga toxin-producing Escherichia coli. J Clin Microbiol 1997;35:2051–4. [13] Wong CS, Jelacic S, Habeeb RL, et al. The risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000;342:1930. [14] Allos BM, Blaser MJ. Campylobacter jejuni and the expanding spectrum of related infections. Clin Infect Dis 1995;20:1092. [15] Goldsweig DC, Pacheco PA. Infectious colitis excluding E.coli O157:H7 and C. difficile. Gastroenterol Clin N Am 2001;30:709–33. [16] Wolf DC, Gianella RA. Antibiotic therapy for bacterial enterocolitis: a comprehensive review. Am J Gastroenterol 1993;88:1667. [17] Pickering LK, Bartlett AV, Woodward WE. Acute infectious diarrheas among children in day care: epidemiology and control. Rev Infect Dis 1986;8:539. [18] DuPont HL, Levin MM, Hornick RB, et al. Inoculum size of shigellosis and implication for expected mode of transmission. J Infect Dis 1989;159:1126. [19] Salam MA, Bennish ML. Antimicrobial therapy of shigellosis. Rev Infect Dis 1991;13:S332. [20] Greenough WB. Vibrio cholera and cholera. In: Mandell GL, Bennet JE, Dolin R, editors. Principles and practice of infectious diseases, ed 4. New York: Churchill Livingstone; 1995. p. 1933–45. [21] Khan WB, Bennish M, Seas C, et al. Randomized controlled comparison of single-dose ciprofloxacin and doxycycline for cholera caused by vibrio cholerae 01 or 0139. Lancet 1996;348:296. [22] Bolen JL, Zamiska SA, Grenough WB III. Clinical features in enteritis due to vibrio parahemolyticus. Am J Med 1974;57:638. [23] Holmberg SD, Blake PA. Staphylococcal food poisoning in the United States: new facts and old misconceptions. JAMA 1984;251:487. [24] Goodgame RW. Virus causes of diarrhea. Gastroenterol Clin N Am 2001;30:779. [25] Bartlett JG. Antibiotic-associated diarrhea. N Engl J Med 2002;346(5):334–7. [26] Kyne L, Farrell RJ, Kelly CP. Clostridium difficile. Gastroenterol Clin N Am 2001;30:753.
Gastroenteritis and antibiotic-associated diarrhea Abdul Jabbar, MD*, Richard A. Wright, MD Division of Gastroenterology/Hepatology, Department of Medicine, University of Louisville, 530 South Jackson Street, Digestive Health Center, Louisville, KY 40292, USA
Acute gastroenteritis consists of mucosal inflammation of the stomach and the intestine and is characterized by a syndrome of acute anorexia, nausea, vomiting, abdominal cramps, bloating, and diarrhea. More profound gastroenteritis may present with severe dehydration, orthostatic hypotension, or neurologic deficits. Acute gastroenteritis frequently is labeled as food poisoning. The actual causes of this syndrome are numerous and include viral or bacterial infection, food allergies (eosinophilic), food poisoning, and organic or inorganic chemical agents. Ingestion can occur by way of person-to-person contact, airborne transmission (especially with virus), or more commonly, contaminated food or water. Symptoms of gastroenteritis usually begin abruptly, with the patient typically documenting the hour of onset. With few exceptions, gastroenteritis is self-limited, and patients recover within 1 to 5 days. There have been multiple outbreaks of gastroenteritis due to different infectious agents. The incidence varies from year to year. The true incidence is never known because most cases are not reported. Of 2423 reported outbreaks investigated by the Centers for Disease Control from 1988 to 1992, the cause was established for only 41% [1], which shows the current limitation in diagnostic capabilities, particularly for identifying presumptive viral pathogens. Gangarosa et al [2] analyzed hospitalizations in the McDonnell-Douglas Health information database from 1985. Gastroenteritis, as one of the top three diagnoses, was recorded as the discharge diagnosis in 98,185 hospitalizations and resulted in 1130 deaths. Analysis showed that age was the most important risk factor for death during hospitalization involving gastroenteritis. Individuals 80 years of age or older have a 3% fatality rate compared with 0.05% for children younger than * Corresponding author. E-mail address: [email protected] (R.A. Wright). 0095-4543/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0095-4543(02)00060-X
64
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
5 years. The authors of this study concluded that gastroenteritis is a large, underemphasized public health problem among the elderly. Higher mortality in gastroenteritis in elderly patients is due to concomitant myocardial, renal, cerebrovascular, and intestinal ischemia.
Etiologic agents Multiple agents have been implicated for gastroenteritis and can be classified as bacterial, viral, food intolerance (eosinophilic), and others. Bacterial infections Bacterial infection is caused by the fecal-oral route and direct contact, particularly in areas where people are housed together with poor hygiene, such as day care centers or nursing homes. The ingestion of water and food contaminated with pathogenic microorganisms is a significant source of disease transmission and can cause large outbreaks of disease. A massive salmonella outbreak was reported in Illinois in 1987 as a result of milk contamination at one plant site during the pasteurization process. More than 16,000 culture-confirmed cases were documented [3]. Cryptosporidiosis contamination of the Milwaukee water supply resulted in a large waterborne outbreak [4]. In 1993, 500 cases were identified from the western United States related to contaminated hamburger with Escherichia coli O157-H7 [5]. In developing regions of the world, acute diarrhea is epidemic, whereas in developed countries, comprehensive standards for food, water, and sewage make endemic outbreaks uncommon. A seasonal distribution is definitely seen with gastroenteritis due to bacterial and viral causes. The highest incidence for hospital admissions owing to bacterial causes is in August and September.
Pathogenesis In most intestinal infections, a pathogen enters and colonizes the intestine. There are some exceptions when colonization is not required, such as with ingestion of preformed toxins, which results in activation of cyclic adenosine monophosphate or adenylate cyclase enzymes causing secretory diarrhea. A pivotal step in colonization is adherence of the pathogen to intestinal epithelium with bacterial pilli–containing adhesions, a lectin-like molecule that interacts with sugar moieties on the microvillous membrane of intestinal mucosa, allowing attachment [6]. Pathogens produce diarrhea by three different mechanisms. (1) Some pathogens do not disrupt the mucosa but lead to diarrhea secondary to release of enterotoxins, which promote intestinal secretion (Staphylococcus aureus, Bacillus cereus, Clostridium botulinum). (2) Some bacteria disrupt
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
65
mucosal integrity through cytotoxic mediators, which may or may not invade the tissue. (3) Some pathogens have the capacity to express invasins, which trigger the host cell to initiate an energy-dependent endocytotic process that uses the host cell microfilament system. This process leads to tissue invasion by the organism and destruction of the mucosa. In general, the mechanism of the diarrhea is due to increased intestinal secretion as a result of enterotoxins, cytotoxic mediators, or decreased intestinal absorption secondary to intestinal damage or inflammation. Infection in different regions of the gastrointestinal tract can influence the character of diarrhea. Noninflammatory diarrhea is caused by impaired electrolyte and fluid absorption of the small intestine. Noninflammatory diarrhea is self-limited and requires supportive therapy only. Alternatively, antibiotics may benefit inflammatory diarrhea.
Foodborne bacterial pathogens Foodborne illness is a significant and growing global problem, with 200 different diseases currently known to be transmitted by food. Worldwide, an estimated 1 billion episodes of diarrhea are caused by foodborne pathogens annually, accounting for 70% of all human diseases [7]. Escherichia coli O157-H7 E. coli O157:H7 is so named because it possesses the one hundred fiftyseventh described somatic or O antigen and the seventh flagellar or H antigen. The organism is believed to have acquired its pathogenicity recently, when it acquired two shiga-like toxins [8]. It was first recognized as a cause of hemorrhagic colitis when it was associated with the consumption of undercooked hamburger at fast-food restaurants in 1982 [9]. In 1983, hemolytic uremic syndrome (HUS) manifested by thrombocytopenia, microangiopathic hemolytic anemia, and renal failure was first reported in children as a complication of E. coli O157:H7. Currently, E. coli O157:H7 is estimated to be responsible for 73,000 cases of diarrheal disease, resulting in 2100 hospitalizations and 60 deaths annually in the United States [7]. Hemolytic uremic syndrome is now the leading cause for dialysis in children and 50% of thrombotic thrombocytopenic purpura cases in adults in the United States. E. coli is a part of normal flora in cattle. Fifty percent of all feedlot cattle are colonized with E. coli O157:H7. Up to 90% of hamburger is contaminated. Most cases of gastroenteritis are due to contamination of beef products, fruits, or cross-contaminated infected beef products during food preparation. This organism requires a low dose of colony-forming units (10–100), similar to that of shigella. This low infectious dose has resulted in significant secondary spread in nursing home and day care centers [10].
66
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
The pathogenicity of E. coli O157:H7 is attributable to production of shiga toxins. These toxins also are termed verocytotoxins because Vero cells have been used most frequently in vitro assays of toxin detection. E. coli O157:H7 produces two types of toxins: shiga toxin 1 and shiga toxin 2, or both. E. coli O157:H7 also has the ability to attach to the intestinal mucosa surface. These toxins inhibit protein synthesis and destroy epithelial cells with resultant necrosis and edema. They bind to globotrioasosylceramide, a membrane surface receptor. These receptors are expressed highly in the cortex of human kidney, which may explain the predilection for renal involvement. These toxins also have a direct effect on vascular epithelium, creating intravascular thrombi with platelet and fibrin deposition leading to ischemic changes in the colonic microvasculature and resultant hemorrhagic colitis [11]. The incubation period averages 3 to 4 days after consumption of contaminated food. Initially, the patient has watery diarrhea for 1 to 2 days, followed by severe abdominal cramping and bloody diarrhea. Fever is low grade or absent. The absence of fever with marked abdominal pain and bloody diarrhea can be confused with ischemic colitis, intussusception, or inflammatory bowel disease. An estimated 5% of cases progress to HUS or thrombotic thrombocytopenic purpura, with a propensity for children and the elderly. The onset of HUS is usually within 1 week of the onset of diarrhea. Patients have pallor, oliguria or anuria, and edema. In elderly patients, thrombotic thrombocytopenic purpura may present with neurologic manifestations, including lethargy, agitation, seizures, or coma. Most patients have bloody diarrhea. The diagnosis is made by stool culture on sorbitol MacConkey agar (SMAC agar). The yield is 90% with acute bloody diarrhea. Another sensitive test is the EHEC assay (Meridian Diagnostic, Cincinnati, OH), which identifies the toxins in the stool. It has a sensitivity of 100% and a specificity of 99.7%, whereas culture on SMAC agar has a sensitivity of 60% and a specificity of 100% [12]. Stool examination shows abundant blood, but fecal leukocytes are either absent or rare. Plain abdominal films show predominantly right-sided findings with dilated ascending and transverse colon with ileus in 60% to 100% of cases. Colonoscopy reveals patchy erythema, edema, and superficial ulceration. Histopathology shows a mixture of ischemic and infectious changes. The treatment of E. coli O157:H7 is supportive. An accumulating body of data suggests that antibiotics are not only ineffective in ameliorating illness but also increase the risk of HUS [13]. This risk is greatest in children. In a southwestern Ontario nursing home outbreak with E. coli O157:H7, adults who received antibiotics for diarrhea were at a statistically increased risk for HUS. Physicians should not use antibiotics to treat other pathogens unless it is confirmed that E. coli O157:H7 is not present. The use of antitoxins is currently under investigation. Antimotility agents and opioids should be avoided.
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
67
Because there is no effective treatment for E. coli O157:H7, prevention becomes a matter of paramount importance. Hamburger should be cooked to an internal temperature of 155F. Irradiation of meat is now Food and Drug Administration–approved, effectively eliminating E. coli O157:H7. Contact isolation is effective in preventing spread in day care centers. Children should have two negative stool culture results before returning to day care centers.
Diarrheogenic Escherichia coli The diarrheogenic E. coli strains cause diarrhea as result of enterotoxin production, adherence, or invasion. They are divided into the following. Enterotoxigenic-producing Escherichia coli Enterotoxigenic-producing E. coli (ETEC) is the most common cause of traveler’s diarrhea. Enterotoxigenic-producing E. coli carries a virulencerelated plasmid. These strains elaborate either heat-sensitive or heat-labile toxin. Enterotoxigenic-producing E. coli adheres to and colonizes the mucosa with the help of surface fimbriae called colonization factors. Toxins are delivered through the colonization factor, leading to activation of cyclic adenosine monophosphate and subsequently leading to active water and electrolyte secretion and diarrhea. The development of vaccines against colonization factors could lead to cost-effective management of this highly prevalent public health problem. Fecal contamination of water and food is the primary reason for the high prevalence of ETEC in developing parts of the world. Enterohemorrhagic Escherichia coli Enterohemorrhagic E. coli is a relatively less common cause of diarrhea. It usually presents as self-limited watery diarrhea. Occasionally, bloody diarrhea associated with HUS can present a management problem. Enteroaggregative Escherichia coli Enteroaggregative E. coli is an unrecognized cause of traveler’s diarrhea. In one study, enteroaggregative E. coli was isolated in 29 of 64 travelers to Jamaica and Mexico. Ciprofloxacin is beneficial in this group. The presentation resembles that of enterohemorrhagic E. coli. Campylobacter In the United States and developed countries, Campylobacter is the most commonly identified bacterial organism in infectious diarrhea, with more
68
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
than 2.4 million cases occurring annually in the United States [14]. Campylobacter jejuni is responsible for 99% of these cases. Campylobacter-related gastroenteritis is most commonly due to consumption of poultry. Recent surveys have shown that 88% of chickens in the retail market are culture positive for Campylobacter, with the highest colony counts in the skin and giblets. The peak incidence occurs in infants. A second peak occurs between 15 and 30 years of age. Infections are seasonal, with peak incidence from May to August. Campylobacter invades the small and large intestine and can produce neurotoxins. It is clinically indistinguishable from salmonella and shigella infections. The most common symptoms are fever, abdominal pain, diarrhea, vomiting, systemic motor paralysis, and cranial nerve and respiratory muscle paralysis. Symptoms usually resolve in 1 week without antibiotic therapy, but symptoms may persist for 1 to 3 weeks in 20% of sick patients. Complications include cholecystitis, pancreatitis, and peritonitis. Immunologic sequelae include reactive arthritis and Guillain-Barre´ syndrome [14]. Diagnosis is by culture of Campylobacter in the stool, blood, or toxins in the stool. Occult or gross blood is present in most cases, with fecal leukocytes present in 75% of patients. Massive gastrointestinal bleeding is rare. Colonoscopy findings range from segmental colonic ulceration to diffuse colitis. The small intestine also can be affected, but to a much lesser extent. Antibiotics are beneficial in those patients with symptoms prolonged more than 1 week or with worsening fever and bloody diarrhea. Patients with human immunodeficiency virus or other immunocompromised conditions also should receive antibiotics [14]. Antibiotics can reduce the duration of Campylobacter excretion in the stool but may not shorten the uncomplicated enteritis course [14]. Erythromycin is the treatment of choice because resistance is rare. Ciprofloxacin is effective and has been shown to reduce the duration of clinical symptoms and to eradicate Campylobacter from stool, but resistance is common. Avoidance of raw chicken can prevent infection.
Salmonella Salmonella causes an estimated 3.7 million cases of gastroenteritis infections in the United States annually. Multiple outbreaks have been reported. Sporadic infections are common. The most common types in the United States are Salmonella enteritidis followed by S. typhimurium, S. newport, and S. hadar. S. enteritidis accounts for 2.4 million infections in the United States. The greatest prevalence is in children less than 1 year of age. There is significant risk of mortality and morbidity in the elderly. Almost 50% of the cases are caused by contaminated poultry, meats, eggs,
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
69
and dairy products. Gastrointestinal endoscopy is rarely implicated in the spread of this infection [15]. The pathogenicity is secondary to invasion of mucosa in the small and large intestine. Histologic findings include edema of the lamina propria and diffuse or focal acute inflammatory infiltrations with disruption of the mucosa changes with microabscesses. Predisposing conditions are sickle cell, neoplasm, corticosteroids, chemotherapy, and immunodeficient states. Gastric acid is the most important host defense. With normal acidity, greater than 99.9% of gram-negative bacteria are destroyed. Patients usually present with symptoms of nausea, vomiting, abdominal pain, and bloody diarrhea. Symptoms last 2 to 4 days with gastroenteritis and 2 to 3 weeks for hemorrhagic colitis. Toxic megacolon rarely has been reported. A carrier state of greater than 1 year has been reported, with the organism harbored in the gallbladder. This carrier state has an incidence of less than 1% [15]. Salmonella cholecystitis is rare. Diagnosis can be made by stool culture. The median duration of organism excretion is 5 weeks. Sensitivity of stool culture in adults ranges from 36% to 58%. Treatment is not recommended in uncomplicated salmonella gastroenteritis. Treating with antibiotics, particularly ciprofloxacin, may prolong fecal excretion of Salmonella. There are no prospective trials evaluating antibiotic therapy in S. colitis. Antibiotics should be given to patients with lymphoproliferative disorder, malignancy, immunosuppression, post-transplant status, and sickle cell disease; and to those who are pregnant, in early childhood, or elderly [16]. Antibiotics can be used if the patient has severe symptoms or persistent disease. Preferred antibiotics include ampicillin and trimethoprim-sulfamethoxazole. In patients with extra-intestinal manifestations (ie, osteomyelitis, pneumonia, arteritis, or meningitis), therapy with ampicillin, amoxicillin, or third-generation cephalosporins is indicated. In the carrier state, antibiotic treatment is controversial. Quinolone antibiotics are the agents of choice, although they may prolong the carrier state after acute salmonella gastroenteritis. Cholecystectomy offers the definite cure. Shigella Shigella is a gram-negative bacillus with four species: S. dysenteriae, S. flexneri, S. boydi, and S. sonnei. The dysenteri species produce a potent protein synthesis–inhibiting cytotoxin called shiga toxin. It has been associated with food and water outbreaks, but in most cases, transmissions are by way of person-to-person contact. Shigella has an estimated 0.22 cases per 1000 children per year in the United States [17]. Incidence is much higher in American Indians. Small inocula of organisms are necessary to cause the disease: 10 to 100 organisms of S. dysenteri type 1 in otherwise healthy adults. This small dose could be secondary to acid resistance [18]. Children in day care centers
70
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
and homosexual men are the two populations in developed countries that are at higher risk; S. flexneri is the most common species in male homosexuals. Symptoms begin with fever, fatigue, malaise, and anorexia. Later, watery or bloody diarrhea develops. The stool frequency ranges from 8 to 10 bowel movements per day, and the volume is high, with subsequent dehydration. Clinical dysentery is most common with S. dysenteri as compared with other species. Toxic megacolon occurs more frequently with S. dysenteriae type 1 infection. Hemolytic uremic syndrome has been reported with S. dysenteriae. Neurologic manifestations, such as seizures, rarely occur. Reiter’s syndrome has been reported as a sequelae. The diagnosis is made by stool cultures. The stool is loaded with polymorphonuclear leukocytes. Colonoscopy shows findings of erythema, edema, loss of vascular pattern, focal hemorrhages, mild friability, and adherent white mucopurulent layers, with predominant involvement of the distal colon (rectum and sigmoid). Antibiotics lower the mortality rate and shorten the illness. Suggested antibiotics are trimethoprim-sulfamethoxazole and ciprofloxacin [19]. Antidiarrheal agents predispose to toxic dilation of the colon. Prophylaxis is the most important factor in shigella infection. Handwashing with bactericidal soap can prevent transmission. Shigella can be transmitted by insects to food. Pesticides in areas of endemicity reduce incidence. Vaccines do not afford significant protection.
Vibrio cholerae and Vibrio parahaemolyticus Vibrio cholerae is a major cause of epidemic diarrhea in Asia, Africa, and Latin America. Only serogroups 01 and 0139 are associated with cholera. V. cholerae primarily infects the small intestine by production of enterotoxins that produce watery diarrhea, nausea, vomiting, circulatory collapse, and shock. If the condition is not treated, the patient can become hypotensive within 1 hour and die within 2 to 3 hours. Rapid diagnosis can be made by stool specimens, which show large numbers of bacilli with ‘‘shooting-star’’ motility and immobilize motile vibrios with Inaba antisera. Diagnosis is accomplished best by culturing the stool or rectal swab on thiosulfate citrate bile salts sucrose–selective agar. With advances in molecular biology, rapid diagnosis of cholera can be made by using AP-labeled, cytotoxin-specific oligonucleotide to identify V. cholerae from the stool specimen [20]. Cholera is a self-limited, noninvasive disease, but its capacity to cause voluminous diarrhea and its efficient fecal-oral transmission make it one of the most persistent scourges of humankind. Primary treatment is rehydration. Initial assessment should include calculation of fluid requirement and replacement of electrolytes. Antibiotics such as tetracycline or single-dose
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
71
doxycycline can reduce stool frequency, duration of illness, and fecal shedding of V. cholerae by 50% [21]. Trimethoprim-sulfamethoxazole, erythromycin, and ampicillin are alternatives. Single-dose quinolones are extremely effective in cholera therapy, and quinolone-resistant cholera are extremely rare at present. Vibrio parahaemolyticus and Vibrio mimicus outbreaks usually are associated with consumption of oysters. V. parahaemolyticus has been recognized as the major cause of acute diarrheal disease in Japan. It is reported to infect 16% of travelers to Southeast Asia. Approximately 30 to 40 cases of V. parahaemolyticus are seen in the Gulf Coast states of Alabama, Florida, Louisiana, and Texas. Sudden and profuse diarrhea and abdominal pain are the earliest and almost universal symptoms. Nausea, vomiting, headache, chills, fever, and blood and mucous in the stool are seen commonly. In rare instances, hypotension and shock have been reported [22]. The disease is self-limited and lasts only a few days. There is no controlled trial treating noncholera vibrio gastroenteritis with antibiotics. For the rare patient with prolonged diarrhea, a course of doxycycline or quinolone is reasonable. Other noncholera vibrios, such as Vibrio hollisae, V. fluvialis, and V. furnissi, are rarely if ever associated with gastroenteritis. Listeria monocytogenes There are at least 2500 cases of severe Listeria monocytogenes infections, with 500 deaths in the United States annually. More recently, L. monocytogenes has been increasingly implicated as a cause of febrile gastroenteritis in immunocompetent patients. Severe invasive infections occur predominantly in newborns, pregnant women, those who are immunocompromised, and in those older than 65 years of age. Its outbreak has been associated with hot dogs. L. monocytogenes grow well at refrigerator temperatures, making infection a special concern for foods with a longer shelf-life kept at such temperatures. Diarrhea and fever are the predominant symptoms. No effective treatment is available. The Food and Drug Administration has released a consumer advisory to reduce the incidence. Hot dogs and luncheon meats should be well reheated and steaming hot; soft cheeses and refrigerated pates should be avoided. Clostridium perfringens Clostridium is a ubiquitous organism found in human and animal feces and in soil. Meats are the most frequently contaminated food. Transmission of enough organisms to produce illness occurs typically with inadequately heated or reheated meats. Spores may survive at normal temperatures. The spores may germinate and multiply at warm temperatures
72
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
that do not inhibit bacterial growth. The incubation period is 8 to 16 hours. C. perfringens is a common contaminant of meat-related food. It produces toxins in food and feces. Enterotoxins are released during the sporulation in the large intestine. Symptoms start abruptly and include profuse diarrhea, occasional vomiting, and abdominal cramps. Culture of the suspected food is diagnostic. The clinical picture is self-limited, lasting 1 to 4 days. No treatment is necessary. Only symptomatic treatment is warranted. Staphylococcus aureus Staphylococcus aureus is a common contaminant of custard-filled pastries and processed meats. Contaminated foods contain enterotoxins. Individuals with skin or nasal mucosa colonization are the source of S. aureus [23]. Staphylococcal food poisoning occurs when contaminated food is allowed to stand long enough for the organism to multiply and produce enterotoxin. It mainly involves meats (ham, pork, beef, and poultry). The incubation period is short, ranging from 1 to 8 hours. The patient presents with vomiting, abdominal cramps, and diarrhea but no fever. In the first 24 hours, the patient has intense vomiting, with diarrhea later. Only symptomatic treatment is necessary. Bacillus cereus Bacillus cereus enterotoxin is produced in food or in the intestine. The most commonly contaminated foods are rice and bean sprouts. The incubation period is 2 to 4 hours. If pre-existing toxins are in the food, vomiting is the predominant symptom. If the toxins are formed by bacterial production in the intestine, diarrhea is the main symptom. Rhabdomyolysis and liver failure have been reported. Vomiting and diarrhea are self-limited, lasting less than 24 hours. Yersinia enterocolitica Yersinia enterocolitica is found more frequently in northern Europe than in the United States. It is found in streams, lakes, and animals. Cows, chickens, horses, cats, and dogs have been implicated. The most common clinical symptoms are abdominal pain and diarrhea. Other symptoms are nausea, vomiting, fever, and arthralgias. Approximately 40% of patients present with symptoms suggestive of appendicitis. Yersinia infection is more common in the winter. The diagnosis is made by stool culture or serology. Patients occasionally have leukocytosis, an elevated erythrocyte sedimentation rate (ESR), or occult blood in the stool. Antibiotics have not been shown to alter the disease process. Current recommendations include the use of
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
73
trimethoprim-sulfamethoxazole, tetracycline, and ciprofloxacin for treatment of severe yersinia enteritis or complications such as mesenteric adenitis, erythema nodosum, and arthritis. Viral gastroenteritis Viral gastroenteritis usually presents with diarrhea accompanied by prominently upper gastrointestinal symptoms for 1 to 4 days. It is easily confused with bacterial enteritis because symptoms are identical. Viral enteritis is most likely present when vomiting is prominent. The incubation period is longer than 14 hours, and duration of symptoms is more than 72 hours. Viral pathogens are likely when there are no warning signs of bacterial infection (ie, high fever, bloody diarrhea, abdominal pain, more than six stools per 24 hours) and there are no epidemiologic clues from the history, including sexual contact or antibiotic use [24]. In acute viral gastroenteritis, an etiologic diagnosis is suspected from clinical features and knowledge of the epidemiology. Following are the most common viruses responsible for gastroenteritis: acute sporadic and endemic childhood and adult diarrhea (rotavirus, calicivirus, Astrovirus, adenovirus, Torovirus); epidemic diarrhea (calicivirus, Astrovirus, adenovirus, diarrhea in immunocompromised hosts); cytomegalovirus; Epstein-Barr virus; adenovirus; Astrovirus; and picornavirus. The pathogenesis of diarrhea in rotavirus infection is understood poorly. The virus attaches and enters mature enterocytes at the tips of the small intestinal villi. It may lead to structural changes to the mucosa, leading to villus shortening and mononuclear infiltrates in the lamina propria. Viral attachment and entry into the cells can lead to diarrhea. Studies have suggested that one of the nonstructural viral proteins (NSP4) may act as an enterotoxin, promoting active chloride secretion mediated through increases in intracellular calcium concentration. In adults, the most important cause of viral gastroenteritis is calicivirus, also referred to as the Norwalk-like virus or small, round, structured virus. There are more than 100 different strains of Norwalk-like viruses, certain strains being predominant in any given time period or regions. When acute gastroenteritis sweeps through a semiclosed community (ie, family, school, residential home, or hospital), affecting adults and children with high attack rate, the illness is most likely due to calicivirus. According to the Centers for Disease Control, 9.2 million cases of food-related illnesses are caused by these viruses each year in the United States. Transmission of these viruses varies from contaminated food, person-to-person contact, raw oysters, and contaminated water. The frequency of rotavirus as a cause of sporadic adult gastroenteritis is not known. Adult infection usually occurs as a secondary cause from contact with sick children or travelers, but in an institutional fashion like
74
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
calicivirus. Rotavirus causes diarrhea in adults. Death has been reported in the elderly. Rotavirus is a well-known cause of waterborne and food-borne gastroenteritis. Diagnosis of a specific virus as a source of gastroenteritis is not required for management. Clinical features are helpful in distinguishing between bacterial and viral causes. The diagnosis of rotavirus can be made by rapid antigen testing of stool by enzyme immunoassay (>98% sensitive and specific) or latex agglutination tests (less sensitive and specific). Antirotavirus antibodies (IgM and IgA) are excreted in the stool after the first day of illness. Antibodies can remain positive for 10 days after the primary infection. A rise in antiviral antibody can be a diagnostic tool for Norwalk viruses. In immunocompromised patients, the most common viruses responsible for diarrhea are cytomegalovirus, Epstein-Barr virus, and rarely, astrovirus, picorbinovirus, calicivirus, and adenovirus.
Traveler’s diarrhea Traveler’s diarrhea is defined as the passage of three or more loose stools in a 24-hour period after travel to a foreign country. Associated symptoms include nausea, vomiting, abdominal pain, or fever. Symptoms commonly last only 2 to 5 days. If symptoms persist for more than 2 weeks, traveler’s diarrhea is unlikely. The most common offending organism is E. coli (toxigenic or nontoxigenic). The occurrence of fever with bloody or mucoid stool indicates a severe dysenteric syndrome related to infection with a more invasive organism.
Antibiotic-associated colitis Antibiotics are used commonly for a variety of illnesses. They alter the normal colonic microflora, leading to overgrowth of other bacteria, especially Clostridium difficile. Antibiotic-associated diarrhea or colitis can be caused by other enteric pathogens, including Salmonella, Clostridium perfringens type A, Staphylococcus aureus, and possibly Candida albicans. The protective effect of the normal intestinal flora is frequently referred to as colonization resistance. The disturbance of this barrier leads to growth of more harmful organisms. Antibiotic-associated diarrhea is defined as an otherwise unexplained diarrhea that occurs in association with administration of antibiotics [25]. The spectrum of findings in antibiotic-associated diarrhea ranges from colitis, which is a potential source of serious progressive disease, to diarrhea, which is defined as frequent loose and watery stools with no other complications. Clinical manifestations include abdominal cramping, fever, leukocytosis, fecal leukocytes, hypoalbuminemia, colonic thickening seen on CT scans, and characteristic changes apparent on endoscopy (multiple small, whitish-yellow plaques covering
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
75
hyperemic, prolapsing, and edematous colonic mucosa). Although infection with C. difficile accounts for only 10% to 20% of the cases of antibioticassociated diarrhea, it accounts for most colitis cases associated with antibiotic therapy [26]. Almost all antibiotics have been associated with C. difficile colitis, including vancomycin and metronidazole. The precise risk associated with individual agents is difficult to establish. The frequency of association is related to use, route of administration, and impact of colonic microflora. Antibiotics most frequently associated with C. difficile diarrhea include clindamycin, cephalosporin, ampicillin, and amoxicillin [26]. Meta-analysis shows that these agents were associated with the highest risks of C. difficile diarrhea, even after adjustment for other risk factors in multivariate analyses. Cancer chemotherapy agents that pose antibacterial properties and bowel-preparation regimens may result in sufficient disturbance of the intestinal microflora to allow colonization of C. difficile. Predisposing risk factors for Clostridium difficile infections Antibiotics are the major risk factor for C. difficile infection, and the hospital environment is the main source of C. difficile. The endogenous carriage rate in adults is low (0%–3% in American and European populations). In contradistinction, after admission to the hospital and treatment with antibiotics, 15% to 21% of patients become colonized with C. difficile. Asymptomatic carriers develop C. difficile–associated diarrhea, but they can contaminate the hospital environment. C. difficile spores may persist for many months in hospital wards because they are resistant to oxygen, desiccation, and many disinfectants. Others risk factors include older age and other disease states. Independent of age, debilitated patients are more likely to acquire C. difficile. Other reported risk factors are nasogastric tube, gastrointestinal procedures, antisecretory medications, intensive care unit stay, and duration of hospital stay. Pathophysiology of Clostridium difficile colitis Clostridium difficile produces toxin A and toxin B, two potent protein enterotoxins. These toxins are encoded by two distinct genes in close proximity on the bacterial genome. They are structurally similar. Specific cell-surface receptors for toxins A and B have not been characterized. Both toxins potently activate cell-signaling molecules, leading to the production of proinflammatory cytokines, including interleukin-1b, tumor necrosis factor-a, and interleukin-8. These proinflammatory mediators precede toxin internalization and subsequently lead to disorganization of cytoskeleton, disruption of protein synthesis, cell rounding, and cell death. Toxin A is an inflammatory enterotoxin that induces fluid secretion, increases fluid permeability, and induces marked enteritis and colitis when
76
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
injected into the intestinal lumen of animals. Although it was initially believed that toxin B does not participate in the pathogenesis of C. difficile because of its lack of enterotoxin effects in animals, toxin B is 10 times more potent than toxin A, inducing these changes in human colonic strips in vitro. Clinical features Infection with C. difficile produces a wide range of clinical manifestations, including asymptomatic carriage, mild to moderate diarrhea, and life-threatening pseudomembranous colitis. Asymptomatic carriage is common in hospitalized patients (10%–16%). These patients may develop antitoxin antibodies, which play a role in protecting from C. difficile diarrhea or colitis. The incubation period is likely to be less than 1 week, with median time of onset within 2 days. Colonization may occur during antibiotic treatment or during weeks after a course of antibiotics. It starts with passage of frequent, loose bowel movements consistent with proctocolitis. Mucous or occult blood may be present, but gross blood is rare. Some patients may present with fever, leukocytosis, and abdominal pain. Patients present with severe disability with or without diarrhea. In the absence of diarrhea, the only clue may be high fever, moderate or marked leukocytosis, lower or diffuse abdominal pain, tenderness, or distention. Extraintestinal manifestations of C. difficile infection are septic arthritis, bacteremia, and splenic abscess. More frequently seen is an oligoarticular, asymmetric, nondeforming large-joint arthropathy, similar to that seen in other infectious colitides. Complications of a severe form of disease include dehydration, hypoalbuminemia, electrolyte disturbances, toxic megacolon, bowel perforation, and death.
Diagnosis The diagnosis of C. difficile should be suspected in any patient with diarrhea who has received antibiotics within the previous 3 months or whose diarrhea began 72 hours or more after hospitalization. The testing of nondiarrheal stools for C. difficile is not recommended because many hospitalized patients may be asymptomatic carriers. Nonspecific findings such as leukocytosis, hypoalbuminemia, and fecal leukocytes can be helpful. Freshly passed stool samples should be submitted immediately in a clear water-tight container for detection of C. difficile toxins (A and B). Anaerobic cultures do not enhance recovery of the organism. Enzyme-linked immunoassay test Enzyme immunoassay to detect C. difficile toxins A and B antigens in the stool is used increasingly in clinical practice. Enzyme immunoassay is easy
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
77
to perform, highly specific (75%–100%), and relatively inexpensive, and results are available in 2 to 6 hours. False-positive results are rare. If the stool is tested for toxin A only, C. difficile diarrhea secondary to toxin A– negative or toxin B–positive results will not be diagnosed. It may be useful to test more than one stool sample for toxins with enzyme immunoassays. Performing enzyme immunoassays on two or three specimens rather than one increases the diagnostic yield by 5% to 10%. Tissue-culture cytology assay Tissue-culture cytology assay is considered the gold-standard diagnostic test for identification of C. difficile toxins in stool samples of patients with antibiotic-associated colitis. It is more sensitive (67%–100%) and specific (85%–100%), leading to greater diagnostic accuracy. Its disadvantage is that it requires a tissue-culture facility, which is more costly and time consuming, requiring incubation of fecal filtrate for 24 to 48 hours. Latex agglutination test This test detects only toxin A. Because of its recognition of other toxins and low sensitivity and nonspecificity, it is not recommended. Clostridium difficile culture The stool culture is sensitive but not specific for toxins producing C. difficile. An advantage is that it permits typing of individual isolates, helping in recognition of outbreaks. Polymerase chain reaction, with the use of specific primers based on the genes for toxins A and toxin B, is highly sensitive and specific, but it requires expertise in molecular diagnostic technique and is relatively expensive. Endoscopy Sigmoidoscopy or colonoscopy is not essential in the diagnosis of C. difficile colitis. Endoscopy is helpful in special situations, such as when the diagnosis is in doubt or the clinical situation demands rapid diagnosis. The finding of pseudomembranes in a patient with antibiotic-associated diarrhea is almost diagnostic for C. difficile colitis (Figs. 1 and 2). Other findings include normal colonoscopy in mild diarrhea to erythema, edema, friability, and nonspecific colitis with small ulceration or erosions. Radiology CT scans of the abdomen may facilitate the diagnosis but are nonspecific. Abdominal radiography may reveal toxic megacolon (>10 cm in its greatest diameter). CT scans may show mucosal edema, thumb printing, thickened colon, pancolitis, and pericolic inflammation.
78
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
Fig. 1. Antibiotic-associated pseudomembranous colitis.
Therapy of antibiotic-associated colitis The initial step in the management of C. difficile diarrhea and colitis is to discontinue the offending antibiotics if possible or to switch to other antibiotics that are less likely to exacerbate C. difficile diarrhea. Conservative management should be used in mild diarrhea. Anyone with moderately severe disease should be treated with metronidazole or vancomycin along with supportive measures, including intravenous fluid replacement and electrolyte imbalance correction. These patients have leukocytosis, fever, and severe diarrhea along with CT or endoscopic findings. Oral metronidazole (500 mg three times a day or 250 mg four times a day) and oral vancomycin (125 mg four times a day) have a similar rate of efficacy, with a response rate of 90% to 97%. The usual duration of therapy is 10 days, although a few studies have mentioned merits of longer or shorter courses [25]. If intravenous treatment is required, only metronidazole (not vancomycin) is effective, because this approach will still result in moderate concentration of the drug in the colon. The anticipated response to treatment is resolution of fever in 1 day and resolution of diarrhea in 4 to 5 days. Other antibiotics, such as bacitracin, have been studied but are less effective with a higher relapse rate [25]. Severe pseudomembranous colitis occurs in only 3% to 5% of patients with C. difficile–associated disease and is associated with a significant
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
79
Fig. 2. Severe pseudomembranous colitis.
mortality rate. Many patients who develop this extreme condition have substantial comorbid disease and are often critically ill. Diarrhea may be minimal or absent. Patients may present with abdominal pain, distention, peritoneal signs, colonic dilation, or the clinical picture of progressive sepsis. After discontinuing the precipitating antibiotics, therapy with metronidazole or vancomycin is started. Some studies recommended vancomycin as a first-line agent if the patient is critically ill because a more rapid response is anticipated. Intravenous vancomycin is not recommended. For patients with ileus, a nasogastric tube may be used with intermittent clamping. A combination of antibiotics using various routes can be tried in critically ill patients. Emergency surgery with colectomy is rarely required to prevent death in patients with severe colitis who have failed to respond to medical therapy and have established or impending bowel perforation. Approximately 20% to 25% of cases of C. difficile relapse [26]. Relapse is suggested by recurrence of symptoms, usually 3 to 21 days after metronidazole or vancomycin is discontinued. The assay of C. difficile toxin is unnecessary immediately after completion of treatment, and the result may be misleading, because one third of patients for whom therapy is successful have positive assays. Treatment lasting up to 4 to 6 weeks has been recommended, with antibiotics to control C. difficile infection while the normal flora become reestablished. Other proposed treatments are probiotics, intravenous immunoglobulin, and the use of anion-binding resins, but data to support their use are limited.
80
A. Jabbar, R.A. Wright / Prim Care Clin Office Pract 30 (2003) 63–80
References [1] Centers for Disease Control and Prevention. Surveillance for food-borne disease outbreaks, United States, 1988–1992. CDC Surveillance Summaries 1996;45(Suppl):(SS-5). [2] Gangarosa RE, Glass RI, Lew JF, et al. Hospitalizations involving gastroenteritis in the United States, 1985: the special burden of the disease among the elderly. Am J Epidemiol 1992;135:281–90. [3] Ryan C, Nickels M, Hargrett-Bean N, et al. Massive outbreak of antimicrobial-resistant salmonellosis traced to pasteurized milk. JAMA 1987;258:3296. [4] MacKenzie R, Schell W, Blair K, et al. Massive outbreak of waterborne cryptosporidium infection in Milwaukee, Wisconsin. Clin Infect Dis 1995;21:57. [5] Davis M, Osaki G, Gordon G, et al. Update: multistate outbreak of Escherichia coli O157:H7 infection from hamburgers—Western United States, 1992–1993. MMWR 1983;42:258. [6] Farthing M. Acute diarrhea: pathophysiology. In: Graccey M, Walker-Smith J, editors. Diarrheal disease. Philadelphia: Lippincott-Raven; 1997. p. 55. [7] Oldfield CE. Emerging foodborne pathogens: keeping your patients and your families safe. Rev Gastroenterol Disord 2001;4:177–86. [8] Calderwood SD, Achesonn WDK, Keusch GT, et al. Proposed new nomenclature for shiga-like toxin family. ASM News 1996;62:118. [9] Riley LW, Remis RS, Helgerson SD, et al. Hemorrhagic colitis associated with a rare Escherichia coli serotype. N Engl J Med 1983;308:681–5. [10] Carter A, Borezyk A, Carlson J, et al. A severe outbreak of E coli O157:H7-associated hemorrhagic colitis in nursing home. N Engl J Med 1987;317:1496–500. [11] Oldfield CE, Wallace MR, Hopson SC. Emerging infections in the gastrointestinal tract. Clin Perspect Gastroenterol 2001;4:200–12. [12] Khel KS, Havens P, Behnke CE, et al. Evaluation of the premier EHEC assay for detection of shiga toxin-producing Escherichia coli. J Clin Microbiol 1997;35:2051–4. [13] Wong CS, Jelacic S, Habeeb RL, et al. The risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000;342:1930. [14] Allos BM, Blaser MJ. Campylobacter jejuni and the expanding spectrum of related infections. Clin Infect Dis 1995;20:1092. [15] Goldsweig DC, Pacheco PA. Infectious colitis excluding E.coli O157:H7 and C. difficile. Gastroenterol Clin N Am 2001;30:709–33. [16] Wolf DC, Gianella RA. Antibiotic therapy for bacterial enterocolitis: a comprehensive review. Am J Gastroenterol 1993;88:1667. [17] Pickering LK, Bartlett AV, Woodward WE. Acute infectious diarrheas among children in day care: epidemiology and control. Rev Infect Dis 1986;8:539. [18] DuPont HL, Levin MM, Hornick RB, et al. Inoculum size of shigellosis and implication for expected mode of transmission. J Infect Dis 1989;159:1126. [19] Salam MA, Bennish ML. Antimicrobial therapy of shigellosis. Rev Infect Dis 1991;13:S332. [20] Greenough WB. Vibrio cholera and cholera. In: Mandell GL, Bennet JE, Dolin R, editors. Principles and practice of infectious diseases, ed 4. New York: Churchill Livingstone; 1995. p. 1933–45. [21] Khan WB, Bennish M, Seas C, et al. Randomized controlled comparison of single-dose ciprofloxacin and doxycycline for cholera caused by vibrio cholerae 01 or 0139. Lancet 1996;348:296. [22] Bolen JL, Zamiska SA, Grenough WB III. Clinical features in enteritis due to vibrio parahemolyticus. Am J Med 1974;57:638. [23] Holmberg SD, Blake PA. Staphylococcal food poisoning in the United States: new facts and old misconceptions. JAMA 1984;251:487. [24] Goodgame RW. Virus causes of diarrhea. Gastroenterol Clin N Am 2001;30:779. [25] Bartlett JG. Antibiotic-associated diarrhea. N Engl J Med 2002;346(5):334–7. [26] Kyne L, Farrell RJ, Kelly CP. Clostridium difficile. Gastroenterol Clin N Am 2001;30:753.