Steven Martin and Rose Jung
KEY CONCEPTS
The etiology of infectious diarrhea includes bacteria, viruses, and protozoans. Viral infections are the leading cause of diarrhea in the world.
The common pathogens responsible for watery diarrhea are norovirus and enterotoxigenic Escherichia coli. The pathogens that produce dysentery or bloody diarrhea are Shigella spp., Campylobacter jejuni, nontyphoid Salmonella, and enterohemorrhagic E. coli.
Fluid and electrolyte replacement is the cornerstone of therapy for diarrheal illnesses. Oral rehydration therapy is preferred in most cases of mild and moderate diarrhea.
Antibacterial therapy often is not indicated for gastroenteritis because many cases are mild and self-limited or are viral in nature. Antibiotic therapy is recommended in severe cases of diarrhea, moderate-to-severe cases of traveler’s diarrhea, most cases of febrile dysenteric diarrhea, and culture-proven bacterial diarrhea.
Loperamide offers symptomatic relief in patients with moderate watery diarrhea. However, the use of antimotility agents should be avoided in patients with dysentery diarrhea.
Diarrheal illness can be largely prevented by following simple rules of personal hygiene and safe food preparation.
Metronidazole is the drug of choice for mild to moderate Clostridium difficile infection (CDI). In patients with severe disease, contraindication or intolerance to metronidazole, and inadequate response to metronidazole, oral vancomycin or fidaxomicin, is recommended.
The most common pathogens for traveler’s diarrhea include enterotoxigenic E. coli, Shigella, Campylobacter, Salmonella, and viruses.
Patient education in prevention strategies and self-treatment of traveler’s diarrhea is recommended. Prophylaxis with antibiotics is not recommended in most situations.
Common pathogens responsible for food poisoning include Staphylococcus, Salmonella, Shigella, and Clostridium.
GI infections and enterotoxigenic poisonings encompass a wide variety of medical conditions characterized by inflammation of the GI tract. Vomiting and diarrhea are commonly associated with GI inflammation. The resulting dehydration is responsible for much of the morbidity and mortality. Diarrhea is defined as a decrease in consistency of bowel movements (i.e., unformed stool) and an increase in frequency of stools to ≥3 per day.1 Acute disease is commonly associated with diarrhea lasting ≤14 days in duration while persistent diarrhea lasts >14 days.
This chapter focuses on infectious etiologies of acute GI infections and enterotoxigenic poisonings. A wide variety of viral, bacterial, and parasitic pathogens are responsible for this disease. Chapter 93discusses the common protozoans that cause gasteroenteritis. Therefore, this chapter focuses on common viral and bacterial etiologies. Because the clinical consequences of bloody or dysenteric diarrhea can be more severe compared with cases of watery or nonbloody diarrhea, the chapter is organized accordingly. Epidemiology, clinical presentation, diagnosis, treatment, and prevention strategies are discussed for all GI infections, and further elaborated in subsequent sections in regards to specific diseases such as Clostridium difficile–associated diarrhea, traveler’s diarrhea, and foodborne illnesses.
EPIDEMIOLOGY
Dehydration resulting from acute diarrhea is the second leading cause of morbidity and mortality worldwide, and infants and children younger than 5 years of age are at the highest risk. Among the 139 low- to middle-income countries, there were approximately 1.7 billion episodes of childhood diarrhea in 2010. The incidence of diarrhea for all children younger than age 5 years was estimated to be 2.9 episodes per child per year. The incidence of diarrhea was higher in younger children, with 4.5 episodes per child per year among children aged 6 to 11 months, compared with 2.3 episodes per child per year for children 24 to 59 months of age.2 Younger children also had a higher risk of death from acute dehydrating diarrhea. For children younger than age 1 year and those aged 1 to 4 years, the median mortality rates were 8.5 and 3.8 per 1,000 children per year, respectively.3 Although incidence of childhood diarrhea has been declining, diarrhea remains a major health problem in children, especially in those younger than 1 year.
In the United States, 179 million episodes of acute gastroenteritis occur each year, resulting in more than 600,000 hospitalizations and more than 5,000 deaths.4,5 In contrast to the developing world where the risk of death is highest among young children, most of those who die of diarrheal illness in the United States are elderly. During 1979 to 1987, 51% of deaths caused by diarrheal illness were among patients older than age 74 years, and 27% were among the ages of 55 to 74 years; only 11% of deaths were in those younger than age 5 years.6 Similarly, a study of the McDonnell-Douglas Health Information System database revealed that 25% of all hospitalizations and 85% of all mortality associated with diarrhea involved the elderly (≥age 60 years).4 In addition to children and elderly, other groups at risk for GI infections include travelers and campers, patients in chronic care facilities, military personnel assigned overseas, and immunocompromised patients such as those with acquired immunodeficiency syndrome (AIDS).
Etiology
The etiology of GI infections and enterotoxigenic poisonings includes a wide variety of virus, bacteria, and parasites, but contribution of each is unknown. Etiologic agents are rarely identified due to the infrequency of stool samples collected, or inability of many laboratories to detect the full range of pathogens, especially viruses. In this chapter, discussions of pathogens responsible for watery diarrhea focus on virus (rotavirus and norovirus), enterotoxigenic Escherichia coli (ETEC), and cholera. Pathogens commonly associated with dysenteric or bloody diarrhea are Shigella spp., Salmonella spp., Campylobacterspp., enterohemorrhagic E. coli (EHEC), Yersinia enterocolitica, and C. difficile. Characteristics of watery and dysenteric diarrhea and common pathogens responsible for them are outlined in Table 91–1.
TABLE 91-1 Acute Infectious Diarrhea Clinical Syndromes: Watery versus Dysentery
Viruses are now recognized as the leading cause of diarrhea in the world. In Asia, Africa, and Latin America, viral gastroenteritis accounts for 3 to 5 billion cases and is associated with 5 to 10 million deaths.7Noroviruses, previously known as Norwalk-like viruses, account for greater than 90% of viral gastroenteritis among all age groups and 50% of outbreaks worldwide. In the United States, noroviruses have been estimated to cause 21 million cases of acute gastroenteritis annually including >70,000 hospitalizations and nearly 800 deaths.5 Outbreaks occur throughout the year and have been documented in families, healthcare systems, cruise ships, and college dormitories.
In infants and children, rotavirus, a double-stranded, wheel-shaped, RNA virus, is the most common cause of diarrhea worldwide, and 1 million people die annually from the infection. In the United States, approximately 3.5 million cases of diarrhea, 500,000 physician visits, 50,000 hospitalizations, and 20 deaths occur each year in children younger than age 5 years.7 Nearly all children are infected by age 5 years. After the initial infection with rotavirus, 40% of children are protected against subsequent infection, 75% are protected against subsequent gastroenteritis, and up to 88% are protected against severe gastroenteritis. Other viruses, enteric adenovirus, and astrovirus, coronaviruses, enteroviruses, and pestiviruses, are being identified increasingly as causative agents of diarrhea. Characteristics of viral pathogens causing gastroenteritis are outlined in Table 91–2.
TABLE 91-2 Characteristics of Agents Responsible for Acute Viral Gastroenteritis
In the United States, bacterial causes of acute gastroenteritis account for more than 5.2 million cases of diarrhea annually including 46,000 hospitalizations and 1,500 deaths.4 However, there appears to be substantial underreporting and the cause is identified in less than 3% of cases. In the United States, common pathogens responsible for watery diarrhea are norovirus and ETEC while those associated with dysentery or bloody diarrhea are Shigella spp. (15.3%), Campylobacter spp. (6.2%), Salmonella spp. (5.8%), EHEC (2.6%), and others (0.6%).8 Other organisms that are responsible for dysentery include Aeromonas species, noncholera Vibrio, and Y. enterocolitica. Characteristics of acute bacterial pathogens causing gastroenteritis are summarized in Table 91–3.
TABLE 91-3 Characteristics of Acute Bacterial Gastroenteritis
Cholera has been rare in the United States because of advanced water and sanitation systems. However, the disease that causes profuse watery diarrhea is endemic in the Indian subcontinent and sub-Saharan Africa. Vibrio cholerae is a gram-negative bacillus sharing similar characteristics with the family Enterobacteriaceae, and the disease is caused by toxigenic V. cholerae serogroups O1 or O139. Approximately half of the people infected with V. cholerae O1 are symptomatic, whereas only 1% to 5% of those infected with V. cholerae O139 manifest symptoms.9
E. coli is a gram-negative bacillus commonly found in the human GI tract, and diarrheagenic E. coli is differentiated into several distinct categories based on pathogenic features of diarrheal disease: ETEC, enteroinvasive E. coli(EIEC), enteropathogenic E. coli (EPEC), enteroaggregative E. coli (EAEC), and EHEC. ETEC occurs most commonly, and accounts for about half of all cases of E. coli diarrhea. There are an estimated 79,000 cases of ETEC in the United States each year.4 ETEC is also the most common cause of traveler’s diarrhea and a common cause of food- and water-associated outbreaks. Infections with EIEC and EPEC are primarily a disease of children in developing countries.10,11 EAEC strains are implicated in persistent diarrhea (≥14 days) in human immunodeficiency virus (HIV)-infected patients.12EHEC, also known as Shiga toxin–producing E. coli (STEC), causes watery diarrhea that becomes bloody in 1 to 5 days in 80% of patients.10
Approximately 165 million cases of shigellosis occur worldwide with 450,000 cases from the United States annually.13 Shigella species are gram-negative bacilli belonging to the family Enterobacteriaceae. Four species most often associated with disease are Shigella dysenteriae type 1, Shigella flexneri, Shigella boydii, and Shigella sonnei.13 In the United States, S. sonnei and S. flexneri are the most common causes of gastroenteritis. The other two Shigella species are commonly acquired during travel to developing countries. Poor sanitation or personal hygiene, inadequate water supply, malnutrition, and increased population density are associated with an increased risk of Shigella gastroenteritis epidemics, even in developed countries.
The Campylobacter species are flagellated, curved, gram-negative rods. Although there are 14 different species, Campylobacter jejuni is the species responsible for more than 99% of Campylobacter-associated gastroenteritis. Approximately 2.4 million persons are affected each year in the United States, involving almost 1% of the entire population.4
Salmonella enterica are gram-negative bacilli belonging to the family Enterobacteriaceae. The most prevalent S. enterica serotypes are Typhi and Paratyphi, which cause enteric fever. Gastroenteritis is caused by S. entericaserotypes Typhimurium or Enteritidis. In the United States, the largest burden of Salmonella infection is due to nontyphoidal serotypes, causing approximately 1.4 million cases of salmonellosis, 16,000 hospitalizations, and 600 deaths, occurring annually.14
Recognized as a common and potentially deadly cause of infectious diarrhea, EHEC is believed to be the major etiologic factor responsible for the development of hemorrhagic colitis and hemolytic uremic syndrome (HUS). The annual disease burden of E. coli O157:H7 in the United States is more than 20,000 infections and as many as 250 deaths; however, the failure of many clinical laboratories to screen for this organism greatly complicates any estimates.15 In the United States, serotype O157:H7 causes 50% to 60% of all EHEC infections, but in the southern hemisphere, including Argentina, Australia, Chile, and South Africa, non-O157:H7 serotypes are often more prevalent. Non-O157 STEC strains in general produce a lower frequency of dysentery than O157 positive strains (62% vs. 85%).
Yersinia species are non–lactose-fermenting gram-negative coccobacilli that are widely distributed in nature. The genus Yersinia includes six species known to cause disease in humans. Y. enterocolitica and, to a lesser extent, Yersinia pseudotuberculosis are most likely associated with intestinal infection, but overall both are a relatively infrequent cause of diarrhea and abdominal pain. More than 50 serotypes of Y. enterocolitica exist; of these, serotypes 0:3, 0:8, and 0:9 are associated most frequently with enterocolitis.16 Children are the most likely to experience illness with Y. enterocolitica infection.
PATHOPHYSIOLOGY
Acute gastroenteritis and its resulting diarrhea are caused by altered movement of ions and water resulting in increased colonic secretion. Under normal conditions, the GI tract has the tremendous capacity to absorb fluid and electrolytes allowing only 100 to 200 mL of fluid to be excreted in the stool daily.17 The classic enteric pathogen that causes secretary diarrhea is V. cholerae, but ETEC and rotavirus are also responsible for watery diarrhea.
V. cholerae is an enteric pathogen that causes classical secretory diarrhea due to changes in ion secretion and absorption. Among the toxins produced by V. cholerae, the most important is cholera toxin.9Cholera toxin consists of two subunits, A and B. The B subunits are responsible for delivery of the A subunit into the cell. The A subunit stimulates adenylate cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP) and results in protein kinase A (PKA)-mediated activation of cystic fibrosis transmembrane conductance regulator (CFTR). This leads to increased chloride secretion and decreased sodium absorption producing the severe watery diarrhea characteristic of the disease.18 The toxin likely acts along the entire intestinal tract, but most fluid loss occurs in the duodenum. The net effect of the cholera toxin is isotonic fluid secretion (primarily in the small intestine) that exceeds the absorptive capacity of the intestinal tract (primarily the colon).
ETEC also causes watery diarrhea characterized by severe intestinal water secretion by producing plasmid-mediated enterotoxins: heat-labile toxin and heat-stable toxin. The heat-labile toxin has two subunits (A and B) that have similar antigenic properties and action on the gut mucosa as cholera toxin. Heat-labile toxins increase chloride secretion via activation of cAMP. The net effect is luminal accumulation of electrolytes that draws water into the intestine, and production of a cholera-like secretory diarrhea.19 Heat-stable toxin is thought to be nonantigenic and produces watery diarrhea by acting on the small intestine.
Rotavirus induces changes in transepithelial fluid balance, and causes malabsorption as a consequence of destruction of epithelial lining of intestine, and vascular damage and ischemia of villi. Once rotavirus infects small intestinal villus cells, viroplasms are formed and its toxin, nonstructural protein 4 (NSP4), is released. The viral enterotoxin increases intracellular calcium, and the increase in calcium disrupts microvillus cytoskeleton, as well as barrier function. Changes to the villi include shortening of villus height, crypt hyperplasia, and mononuclear cell infiltration of the lamina propria.20
Inflammatory diarrhea is caused by two groups of organisms—enterotoxin-producing, noninvasive bacteria (e.g., EAEC, EHEC) or invasive organisms (e.g., Salmonella spp., Shigella spp., Campylobacterspp.). The enterotoxin-producing organisms adhere to the mucosa, activate cytokines, and stimulate the intestinal mucosa to release inflammatory mediators. Invasive organisms, which can also produce enterotoxin, invade the intestinal mucosa to induce an acute inflammatory reaction, involving the activation of cytokines and inflammatory mediators.
Ingestion of as few as 10 to 200 viable organisms of the Shigella species causes disease in healthy adults.13 Shigella multiply and spread within the submucosa of the small bowel, but they rarely extend beyond the mucosa. Inflammatory diarrhea is caused by the pathogens invading the epithelial barrier through M cells where they encounter and eliminate macrophages. The destruction of macrophages after emergence from M cells causes an initial release of interleukin (IL)-1β. This initial inflammatory process is exacerbated by free bacteria binding to toll-like receptor (TLR4) that causes the production of IL-6 and IL-8. Both IL-1β and IL-8 attract polymorphonucleocytes.21Release of polymorphonucleocytes activates chloride secretion and subsequent diarrhea. Degranulation and release of toxic substances by neutrophils cause ulceration of the epithelium, distortion of the crypts, death to intestinal epithelium, sloughing of mucosal cells, bloody mucoid exudate into the gut lumen, and submucosal accumulation of inflammatory cells with microabscess formation.22 Microabscesses eventually may coalesce, forming larger abscesses. Infection frequently involves the entire colon. In addition to the virulence characteristics of invasiveness, S. dysenteriae type 1 and, to a lesser degree, S. flexneri and S. sonnei produce a cytotoxin or Shiga toxin, which can lead to HUS.10
The pathogenicity of EHEC is related to the production of Shiga-like toxins, so named because of their resemblance to the Shiga toxin of S. dysenteriae.17 The cytotoxic effect of Shiga-like toxins disrupts the mucosal integrity of the large intestine, causing diarrhea. In addition, the toxin is able to pass through the intestinal epithelium to reach the endothelial cells lining small blood vessels that supply the gut, kidney, and other viscera, causing the myriad metabolic events that eventually lead to HUS.
CLINICAL PRESENTATION AND DIAGNOSIS
Gastroenteritis is an illness characterized by diarrhea, which may be accompanied by nausea, vomiting, fever, and abdominal pain. For the best diagnosis and management, it is important to distinguish secretory diarrhea that produces watery diarrhea from inflammatory diarrhea or dysentery. Most enteric pathogens produce acute diarrhea. Dysentery is defined as passing grossly bloody stools. Not all stools in dysenteric illness may contain visible blood, while most stools contain mucus. Systemic toxicity such as fever is often associated with dysentery of infectious origin. Symptoms of enteric pathogens that cause watery and dysentery diarrhea are listed in Table 91–1.
A physical examination and careful history that includes information about symptoms, the length of time the patient has been sick, the number of individuals affected, and recent history of travel, diet, and medications are important factors in making a diagnosis. Infections with norovirus or ETEC result in mild, self-limiting disease. Cholera produces severe dehydrating diarrhea. Infections with enteric pathogens such as Shigella spp., Salmonella spp., Campylobacter spp., EHEC, and Y. enterocolitica can result in dysentery diarrhea and severe complications. The clinical presentation of acute viral and bacterial gastroenteritis is summarized in Tables 91–2 and 91-3, respectively.
Stool culture is an important tool in making an organism-specific diagnosis and determining susceptibility to antimicrobial agents. Due to the low yield, stool cultures are not recommended in most mild to moderate watery diarrhea. Instead, indications for stool cultures include dysenteric diarrhea, persistent diarrhea especially in immunocompromised patients (i.e., persons aged 65 years and older with comorbid diseases, neutropenia, or HIV infection), and diarrhea where an outbreak is suggested.1 A routine stool culture identifies the presence of Campylobacter, Salmonella, and Shigella species. The yield of stool cultures for other pathogens is increased if the test is ordered specifically based on history and physical examination. For dysenteric diarrhea, the laboratory should be instructed to look for EHEC including E. coli O157:H7. In hospitalized patients who develop diarrhea 3 days after hospitalization or in those with recent exposure to antimicrobials or chemotherapy, stool specimen should be sent for C. difficile toxins A and B. In addition to stool cultures, microscopic examination for fecal polymorphonuclear cells, or a simple immunoassay for the neutrophil marker lactoferrin, can further provide evidence of an inflammatory process and increase the yield of cultures in patients presenting with dysenteric diarrhea.
Complications
Complications associated with acute watery diarrhea most likely result from dehydration and, therefore, Treatment below focuses on rehydration therapy. Dysenteric diarrhea is more likely to have severe complications, especially in children less than 5 years of age and in elderly. Enteric pathogens responsible for complications include Shigella spp., Salmonella spp., Campylobacter spp., EHEC, and Y. enterocolitica.
Bacteremia is the most common complication of gastroenteritis and can be seen after infections with nontyphoid Salmonella, C. jejuni or C. fetus, and Y. enterocolitica.15 Nontyphoid Salmonella is most common in children less than 5 years of age, elderly, and patients with hemoglobinopathy, malaria, or immunosuppression. Bacteremia due to Campylobacter spp. has been reported in patients with HIV infection, malignancy, transplantation, and hypogammaglobulinemia. Although rare, Y. enterocolitica bacteremia has been reported in patients with diabetes mellitus, severe anemia, hemochromatosis, cirrhosis, and malignancy, the elderly, and those who have received frequent red blood cell transfusions (iron overload).23 The clinical syndrome is characterized by persistent bacteremia and prolonged intermittent fever with chills. Stool cultures frequently are negative. Leukocyte counts are often within the normal range. Vascular complications such as seeding of atherosclerotic plaques or aneurysms in arterial vessels occur in 10% to 25% of adults with bacteremia. Localized infections involving bone, cysts, heart, kidney, liver, lungs, pericardium, and spleen develop in 5% to 10% of patients with bacteremia.
Severe complication in patients infected with EHEC is HUS. HUS is defined by the triad of acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia.24 This syndrome is commonly observed in children less than 5 years of age and the elderly. Approximately 2% to 7% of cases infected with O157:H7 strains are complicated by development of HUS. Death may occur rarely, usually as a result of HUS. S. dysenteriae type 1 can also cause HUS, although more rarely than observed with EHEC.13
Shigella infection may also lead to complications such as generalized seizures, sepsis, toxic megacolon, perforated colon, arthritis, and protein-losing enteropathy. Mortality is rare, but it may be more likely with S. dysenteriaetype I. Less than 3% of persons who are infected with S. flexneri will later develop Reiter’s syndrome, characterized by pains in the joints, irritation of the eyes, and painful urination. This can lead to chronic arthritis.25
Infection with C. jejuni has been associated with Guillain-Barré syndrome (GBS), but the relationship is not well understood.26 The risk of developing GBS after C. jejuni infection appears to be low (approximately 1 case of GBS per 1,000 C. jejuni infections). The weakness usually starts in the legs with difficulty in walking and may progress to a complete paralysis of all extremities that lasts several weeks and usually requires intensive care.
Approximately 10% to 30% of adult patients develop a reactive arthritis 1 to 2 weeks after recovery from gastroenteritis secondary to S. flexneri, Salmonella spp., C. jejuni, and Y. enterocolitica. This arthritis, involving the knees, ankles, toes, fingers, and wrists, usually resolves in 1 to 4 months but may persist in approximately 10% of patients.26 This complication is more common in persons with the HLA-B27 antigen.
TREATMENT
Fortunately, diarrheal mortality has declined substantially in the past 2 decades, especially among children younger than 1 year of age. Interventions for diarrheal disease such as improved sanitation, increased use of oral rehydration therapy (ORT), breast-feeding, and better weaning practices are responsible for the decrease in case-fatality rates.
General Approach to Treatment
The cornerstone of management for all GI infections and enterotoxigenic poisonings is to prevent dehydration by correcting fluid and electrolyte imbalances. In mild, self-limiting acute gastroenteritis, a diet of oral fluids and easily digestible foods such as chicken soup and crackers is recommended. In patients with severe dehydrating watery diarrhea and dysenteric diarrhea, IV rehydration therapy, antibiotics, and/or antimotility treatments are needed.
Rehydration Therapy
Initial assessment of fluid loss is essential for successful rehydration therapy and should include acute weight loss, as it is the most reliable means of determining the extent of water loss. However, if accurate baseline weight is not available, clinical signs are helpful in determining approximate deficits (Table 91–4). Physical assessment generally is more reliable in young children and infants than in adults.
TABLE 91-4 Clinical Assessment of Degree of Dehydration in Children Based on Percentage of Body Weight Lossa
Fluid replacement is the cornerstone of therapy for dehydration due to diarrhea regardless of etiology. For the treatment of mild to moderate dehydration, ORT is superior to administration of IV fluids. ORT reverses dehydration in nearly all patients with mild to moderate diarrhea with 94% to 97% efficacy.27 It offers the advantages of being inexpensive and noninvasive, and does not require hospitalization for administration. Moreover, thirst drives use of ORT and provides a safeguard against overhydration. Therefore, treatment of dehydration consists of ORT for rehydration and replacement of ongoing losses as well as continuation of normal feeding.
The necessary components of oral rehydration solutions (ORS) include carbohydrates (typically glucose), sodium, potassium, chloride, and water. In 1979, the World Health Organization (WHO) introduced a glucose-based ORS formulation that is 310 mOsm/L. This original formation known as ORS ≥310 takes advantage of glucose-coupled sodium transport in the small bowel and enhances sodium and subsequently water transport across intestinal walls. Therefore, this glucose-based ORS is effective in replacing the fluid from acute diarrhea but does not reduce stool output or shorten duration of diarrhea. In 2002, the World Health Organization/United Nations Children’s Fund (WHO/UNICEF) changed its recommendation to a reduced osmolarity solution (osmolarity = 245 mOsm/L). The use of ORS ≤270 reduced stool volume, shortened duration of diarrhea, and decreased need for unscheduled IV therapy when compared with ORS ≥310.28 The newer formulation of ORS ≤270 mOsm/L was, however, more likely to cause hyponatremia (blood sodium levels <130 mmol/L).29
In restoring fluid and electrolyte balance in cholera infections, polymer-based ORS may be more efficacious than glucose-based ORS. Polymer-based ORS contains rice, wheat, sorghum, or maize. This polymer-based ORS releases glucose more slowly after digestion, and when absorbed in the small bowel, enhances the reabsorption of water and electrolyte secreted into the bowel lumen during diarrhea. In a meta-analysis of 34 trials, polymer-based ORS has been shown to reduce the duration of diarrhea in adults with cholera when compared with glucose-based ORS ≥310 and ≤270.30
Guidelines on rehydration therapy based on the degree of dehydration and replacement of ongoing losses are outlined in Table 91–4. ORS should be given in small and frequent volumes (5 mL every 2 to 3 minutes in a teaspoon or oral syringe). Nasogastric administration of ORT is an alternative method of administration in a child with persistent vomiting. For breastfed infants, nursing should be continued. The composition of commercial ORS and commonly consumed beverages is listed in Table 91–5. Clear fluids, such as soft drinks, sweetened fruit drinks, broth, and sports drinks, should be avoided in the treatment of dehydration. Those solutions may cause an osmotic diarrhea and hypernatremia.
TABLE 91-5 Comparison of Common Solutions Used in Oral Rehydration and Maintenance
In the treatment of severe dehydration, the primary goal of therapy is rapid restoration of fluid losses, correction of metabolic acidosis, and replacement of potassium deficiency. Severely dehydrated patients should be resuscitated initially with lactated Ringer’s solution or normal saline IV to restore hemodynamic stability. Lactated Ringer’s solution is preferred over normal saline because normal saline does not correct metabolic acidosis. Rapid IV rehydration is preferred over more prolonged replacement regimens for restoring extracellular fluids and electrolytes because it more effectively reestablishes GI and renal perfusion. After rehydration, maintenance fluid is given based on accurate recording of intake and output volumes. ORT should be instituted as soon as it can be tolerated.
Early refeeding with age-appropriate unrestricted diet is recommended in children. Previously, the proponents of late refeeding recommended variable periods of fasting followed by gradual reintroduction of food in order to prevent complications. A meta-analysis of 12 trials showed that early refeeding during or immediately following the start of rehydration did not increase the risk of complications such as unscheduled IV fluids, vomiting, or development of persistent diarrhea compared with late refeeding that ranged from 20 to 48 hours after start of rehydration.31 Initially, easily digested foods such as bananas, applesauce, and cereal should be introduced. Foods high in fiber, sodium, and sugar should be avoided. Lactase deficiency may be exacerbated among known lactase-deficient patients and may persist up to 10 days.
Antimicrobial Therapy
The indiscriminate use of antimicrobial therapy produces increases in antimicrobial resistance, side effects of antimicrobial agents, and the threat of superinfections owing to eradication of normal flora. Increasing fluoroquinolone resistance in Campylobacter and multidrug resistance in Salmonella species worldwide reinforces the importance of judicious use of antibiotics and prudent infection control measures.32,33 Antibiotic therapy is recommended in severe cases of diarrhea, moderate-to-severe cases of traveler’s diarrhea, most cases of febrile dysenteric diarrhea, and culture-proven bacterial diarrhea. Antimicrobial therapy is not recommended in EHEC diarrhea.
Antibiotic therapy is recommended in severe cases of cholera and ETEC diarrhea. In cases of cholera, antibiotics shorten the duration of diarrhea, decrease fluid loss, and shorten the duration of the carrier state.9 It is important to take local susceptibility patterns into consideration in the selection of the antimicrobial regimen. In areas of high fluoroquinolone resistance, azithromycin has been effective in patients with cholera. In patients with ETEC diarrhea, empiric antibiotics reduce severity and duration of diarrhea. A short course of therapy with fluoroquinolones (e.g., ciprofloxacin and levofloxacin) is the most commonly recommended therapy due to increased resistance among other drug classes.34 Rifaximin has been effective for ETEC when traveling in Mexico.35 Further discussions of antibiotic prophylaxis and treatment can be found in Traveler’s Diarrhea below. Table 91–6 summarizes antibiotic recommendations. Further details regarding treatment of C. difficile–associated diarrhea, traveler’s diarrhea, and foodborne illnesses are discussed in respective sections.
TABLE 91-6 Recommendations for Antibiotic Therapy
Antibiotic therapy is indicated in most febrile dysenteric diarrhea. In shigellosis, antibiotics shorten the period of fecal shedding and attenuate the clinical illness. Antibiotic therapy is reserved for the elderly, those who are immunocompromised, children in daycare centers, malnourished children, and healthcare workers. In the United States, Shigella spp. remain susceptible to fluoroquinolones. Fluoroquinolone resistance among Shigella spp. is of increasing concern in developing countries, and azithromycin may be a better choice in patients with a recent history of travel to a developing region.15 Similar antibiotic regimens can be used for high-risk patients who develop Yersinia bacteremia (i.e., infants younger than age 3 months and patients with cirrhosis or iron overload) or in patients with bone and joint infections.36In Campylobacteriosis, antibiotics are not useful unless started within 4 days of the start of the illness because they do not shorten the duration or severity of diarrhea and only shorten the duration of bacterial excretion. Antibiotics are warranted in patients with high fevers, severe bloody diarrhea, prolonged illnesses (>1 week), pregnancy, and immunocompromised states, including HIV infection. Fluoroquinolone resistance among Campylobacter spp. has increased, and is now 10% to 13% in the United States and 41% to 88% in Europe and Asia. Resistance may be the result of the use of fluoroquinolone antibiotics in poultry and other animal feed, and the frequent use of these agents internationally in treating enteric infections. Macrolides such as erythromycin and azithromycin are recommended especially in patients with a recent history of travel to Asia.34
Nontyphoid Salmonella infection leads to bacteremia in approximately 8% of otherwise healthy adults. Risk of bacteremia is increased in some patient populations and should be treated with antibiotics. High-risk patients include neonates or infants younger than 1 year, persons older than 50 years, and patients with primary or secondary immunodeficiency such as AIDS or chemotherapy-induced inflammatory bowel disease, sickle cell disease, vascular abnormalities (prostatic heart valve or abdominal aneurysm), or prosthetic joints.15 Susceptibility testing is recommended due to increased resistance.
Outcomes of some bacterial diarrheal illnesses may be worsened by the use of antibiotics, therefore precluding their use. In patients infected with EHEC, use of an antimicrobial agent such as a fluoroquinolone or trimethoprim–sulfamethoxazole may increase the risk of HUS by increasing the production of Shiga-like toxin.36 Empiric antimicrobial therapy should be withheld when clinical suspicion is high due to the high prevalence of the disease in the region, patient clinical presentation suggestive of EHEC infection, or a known foodborne outbreak of dysentery with an incubation period of longer than 2 days. Antibiotics should not be given to infants or children due to a higher incidence of HUS in this population. Treatment of EHEC infection is primarily limited to supportive care, which may include fluid replacement therapy, hemodialysis, hemofiltration, transfusion of packed erythrocytes, platelet infusions, and other interventions as indicated clinically. Severe disease may cause chronic kidney failure and require renal transplantation.
Antimotility Agents
Antimotility drugs such as diphenoxylate and loperamide offer symptomatic relief in patients with watery diarrhea by reducing the number of stools. In dysenteric diarrhea, slowing of fecal transit time with these agents is thought to result in extended toxin-associated damage, worsening diseases such as HUS. Therefore, antimotility drugs are not recommended in patients with many toxin-mediated dysenteric diarrhea (i.e., EHEC, pseudomembranous colitis, shigellosis). However, evidence suggests that in adults with dysenteric diarrhea these agents do not appear to be harmful if given concomitantly with antibacterial therapy.36
Clinical Controversy…
Loperamide should not be used in patients with fever or bloody stool. There is evidence that the use of such agents can increase the risk for development of HUS, possibly by delaying intestinal clearance of the organism and thereby increasing toxin absorption.
Probiotics
Probiotics are preparations of microorganisms and most commercial products have been derived from food sources, particularly cultured milk products. Several systematic reviews and meta-analyses have shown an overall reduction in the duration of diarrhea by approximately 17 to 30 hours with the use of probiotics.37 No serious adverse effects have been reported in otherwise healthy persons. Probiotics that were effective in at least one controlled trial included Lactobacillus rhamnosus GG, Lactobacillus reuteri, combination L. rhamnosus, L. reuteri, and Bifidobacterium animalis subsp. lactis, and combination Lactobacillus acidophilus and Lactobacillus bifidus. Unfortunately, the data do not clearly define type, dose, or duration of probiotic treatment that would result in clinical benefit.
Oral Zinc Supplementation
Zinc deficiency is largely due to inadequate dietary intake and is common in many developing countries where morbidity and mortality associated with acute diarrhea in children remain high. In children older than 6 months of age with moderate signs of malnutrition, zinc supplementation may shorten the duration of diarrhea by approximately 27 hours (MD –26.98 hours, 95% CI –14.62 to –39.34).38 Therefore, oral zinc supplementation of 20 mg/day for 1 to 2 weeks may have an additional benefit over ORS in reducing children mortality in developing countries. Common side effects include metallic taste and vomiting. At high doses, zinc supplementation may cause epigastric pain, lethargy, and fatigue.
PREVENTION OF GASTROINTESTINAL INFECTIONS
Public health measures of improved water supply and sanitation facilities and the quality control of commercial products are important for the control of the majority of enteric infections. In addition, many diarrheal diseases can be prevented by following simple rules of personal hygiene and safe food preparation. Hand washing with soap and running water is instrumental in preventing the spread of illness and should be emphasized for caregivers and persons with diarrheal illnesses. Safe food handling and preparation practices can significantly decrease the incidence of certain types of enteric infections.
Reporting suspected outbreaks and cases of notifiable illness to local health authorities is vital to investigation of threats of enteric infection arising from increasingly global and industrialized food supplies. The reporting of specific infectious diseases to the appropriate public health authorities is the cornerstone of public health surveillance, outbreak detection, and prevention and control efforts.
Vaccines are used to boost specific immune processes directed against the bacteria themselves or against adherence appendages, cytotoxins, or enterotoxins. Unfortunately, there are only a few vaccines available for prevention of gastroenteritis. Vaccines for typhoid fever are the parenteral Vi capsular polysaccharide vaccine (ViCPS) and the oral live-attenuated Ty21a vaccine.39 Efficacy rates for both vaccines range from 50% to 80%. The ViCPS is indicated for children who are ≥2 years of age and a booster dose is administered 2 years later. The Ty21a vaccine is indicated for children ≥6 years of age; one capsule should be swallowed whole every other day for a total of four doses at least 1 week before the potential exposure. A booster should be taken every 5 years if continued protection is needed.
In the United States, routine rotavirus vaccination is recommended for all infants beginning at age 2 months. There are two vaccines, RotaTeq (RV5) and Rotarix (RV1), available for reducing rotaviral gastroenteritis.40 The RV5 vaccine is a live, oral vaccine that offers 74% efficacy against gastroenteritis of any severity and 98% efficacy against severe disease. This vaccine also decreased office visits by 86%, emergency department visits by 94%, and hospitalizations by 96%. The RV1 vaccine is a live-attenuated human rotavirus vaccine. A trial of this vaccine has shown a clinical efficacy of 79% against gastroenteritis of any severity and 96% efficacy against severe rotavirus disease. Rotarix reduced hospitalizations by 100% and medically attended visits by 92% in the first rotavirus season, and reduced hospitalizations by 96% through two seasons.40 The RV5 vaccine is administered orally in a three-dose series at ages 2, 4, and 6 months while the RV1 vaccine is administered orally in a two-dose series at ages 2 and 4 months. The first dose may be given between 6 weeks and 14 weeks and 6 days of age and all doses should be given before 8 months of age.
Although not available in the United States, two oral vaccines are available in other countries. Dukoral (Crucell, Stockholm, Sweden) consists of killed V. cholerae O1 organisms and the cholera B subunit, and is licensed in over 60 countries. Shanchol (Shantha Biotechnics, Hyderabad, India) consists of killed whole cells from a mix of pathogenic strains of V. cholerae (O1 and O139) and is licensed in India.9 Both vaccines are given in two doses (three doses of Dukoral are required for children 2 to 5 years of age) and administered about 7 to 14 days apart (up to 42 days apart for Dukoral). Dukoral must be administered with a buffer that requires 75 to 150 mL of clean water while Shanchol does not require the buffer. Both vaccines demonstrated protective efficacy of 47% to 87% after two doses but almost none after a single dose. Protection is achieved in approximately 1 week following the last dose and persists for about 2 years. The common side effects were considered mild and included abdominal pain, headache, fever, and nausea. The WHO does not require vaccination for international travel to or from endemic areas because vaccines require two doses and provide incomplete protection for a relatively short period of time.
EVALUATION OF THERAPEUTIC OUTCOMES
Appropriate followup care of patients with acute diarrhea is based on successful restoration of fluid losses. The clinical signs and symptoms that lead to the diagnosis also can assess adequate rehydration, and should be monitored frequently. Since ORT is now preferred, routine laboratory testing often is unnecessary. Electrolytes should be measured in those receiving IV fluids, when oral replacement fails, or when signs of hypernatremia or hypokalemia are present. Followup stool samples to ensure complete evacuation of the infecting pathogen may be necessary only in patients who are at high risk to initiate or contribute to a community outbreak. All patients should be monitored for complications associated with the infecting pathogen, resolution of the diarrhea, and adverse reactions to the pharmacologic agents used. Prompt discharge of hospitalized patients is recommended when rehydration is achieved, IV fluids have not been required, oral intake equals or exceeds losses, or adequate education and medical followup are ensured. For most patients, discharge can occur in 16 to 24 hours.
C. difficile
Epidemiology
C. difficile is the most commonly known cause of infectious diarrhea in hospitalized patients in North America and Europe. C. difficile infection (CDI) is associated with use of broad-spectrum antimicrobials, including clindamycin, ampicillin, cephalosporins, and fluoroquinolones. Other agents that have been implicated, albeit at a lower incidence rate, include aminoglycosides, erythromycin, trimethoprim–sulfamethoxazole, vancomycin, and metronidazole. Although in most cases CDI occurs during or shortly after the completion of antimicrobial therapy, disease onset can be delayed for 2 or 3 months.41 CDI occurs most often in high-risk groups, such as the elderly, debilitated patients, cancer patients, surgical patients, patients receiving antibiotics, patients with nasogastric tubes, and patients who frequently use laxatives. A meta-analysis of 23 studies (~300,000 patients) suggests that proton pump inhibitors increase the incidence of CDI by 65%.42
Unfortunately attributable mortality from CDI increased from 5.7 to 23.7 deaths per 1 million persons in the United States from 1999 to 2004.43 Mortality from the infection has been reported as high as 38%, with many studies indicating a mortality rate of 15% or greater.44 Increased mortality is assumed to be due to the emergence of a single-strain type (North American pulsed-field type 1 [NAP-1]) in outbreaks.45 NAP-1 strain is highly resistant to fluoroquinolones and carries deletion mutations in a regulatory gene (tcdC) believed to inhibit toxin production, causing higher levels of toxin production responsible for more serious diseases. The NAP-1 strain is also refractory to standard therapy.
Pathogenesis
C. difficile is a gram-positive spore-forming anaerobic bacillus and causes a toxin-mediated disease. Once antibiotics disrupt normal colonic flora and colonization of C. difficile occurs, two toxins (A and B) are released to mediate diarrhea and colitis. This toxin production is essential in disease manifestation. Toxin A is the major pathogenic factor and has been characterized as an enterotoxin that causes intestinal fluid secretion, mucosal injury, and inflammation through actin disaggregation, intracellular calcium release, and damage to neurons. Toxin B is a nonenterotoxic cytotoxin that causes depolymerization of filamentous actin and mediates more potent damage to human colonic mucosa than toxin A. Initially, raised white and yellowish plaques form, and the surrounding mucosa may be inflamed. With progression of disease, these pseudomembranous plaques become enlarged and scatted over the colorectal mucosa.41
Clinical Presentation
Clinical diagnosis is based on the onset of diarrhea during or after antimicrobial use and often is associated with abdominal discomfort, fever, and polymorphonuclear leukocytosis. A spectrum of disease ranges from mild diarrhea to life-threatening toxic megacolon and pseudomembranous enterocolitis.41 In colitis without pseudomembrane formation, patients present with malaise, abdominal pain, nausea, anorexia, watery diarrhea, low-grade fever, and leukocytosis. Fulminant disease is characterized by severe abdominal pain, perfuse diarrhea, high fever, marked leukocytosis, and classic pseudomembrane formation evident with sigmoidoscopic examination.
CDI should be suspected in patients experiencing diarrhea with a recent history of antibiotic use (within the previous 3 months) or in those whose diarrhea began 72 hours after hospitalization. Diagnosis can be established by detection of toxin A or B, stool culture for C. difficile, or endoscopy. If the stool sample is negative, a second analysis is recommended because the testing sensitivity may be increased with repeat testing. Endoscopy should be reserved for situations where rapid diagnosis is needed, ileus is present, stool is not available, or other colonic diseases are in the differential diagnosis.
TREATMENT
Initial therapy should include discontinuation of the offending agent.41 Fluid and electrolyte replacement therapy is necessary. Although diarrhea will resolve in up to 25% of patients within 48 hours of discontinuing the offending agent without therapy, most patients require antibiotics. Metronidazole, vancomycin, and fidaxomicin are all effective agents for treating C. difficile diarrhea. Nitazoxanide, rifampin, and bacitracin have also been studied.
In head-to-head comparison studies, vancomycin and metronidazole were similar in duration of diarrhea and toxin or organism clearance, rate of initial cure of infection, rate of recurrence, mortality, and incidence of side effects.46–48 Vancomycin was superior to metronidazole in a subgroup analysis of 69 patients with severe C. difficile diarrhea.46 When vancomycin has been compared with agents other than metronidazole, including fidaxomicin, the rate of initial cure did not significantly differ between treatment groups. Recurrence was common, ranging from 9% to 37% in clinical trials. Only the comparison between vancomycin and fidaxomicin demonstrated a significant difference in recurrence, 25.4% versus 15.3% (P = 0.005).49
Metronidazole (250 mg four times daily or 500 mg three times daily) is the drug of choice for mild to moderate CDI because its oral formation is less expensive than that of vancomycin or fidaxomicin, and there are concerns for vancomycin-resistant enterococci with oral vancomycin use. In patients with severe disease, contraindication or intolerance to metronidazole, and inadequate response to metronidazole, oral vancomycin or fidaxomicin, is recommended. Vancomycin (125 mg four times daily) must be administered orally because IV vancomycin does not achieve gut lumen concentrations high enough for effective bacterial elimination. Due to cost, many institutions choose to use the injectable form of vancomycin to prepare an oral formulation. In patients with an ileus (where oral vancomycin reaching site of infection is questioned) vancomycin may be delivered by retention enema or adding IV metronidazole. Fidaxomicin is a macrocyclic oral antibiotic (200 mg administered twice daily) that has minimal bioavailability, and is bacteriostatic against C. difficile.
Recurrence of CDI occurs in approximately 20% of cases.50 Patients with one prior episode of relapse have a greater than 40% risk of additional recurrences, whereas those with two or more previous episodes have a greater than 60% risk.51 Risk factors for recurrent CDI include a history of recurrence, emergency hospital admission, previous GI hospital admission, recent (within 4 to 12 weeks) hospitalization, increasing age, use of additional antimicrobials, and an inadequate protective immune response to C. difficile toxins.50
Treatment of recurrence has not been well studied. In a subgroup analysis of 128 patients who developed relapse after initial therapy with either vancomycin or fidaxomicin, response to therapy (>90% cure) was similar for both drugs. However, there was significantly less recurrence within 28 days in those treated with fidaxomicin (35.5% vs. 19.7% vancomycin, P = 0.045). Management of the first relapse is identical to a primary episode because relapse is rarely due to resistance to the initial agent of treatment. Instead, relapse occurs because treatment fails to eradicate the spore forms of pathogen or treatment makes patients vulnerable to another infection by impairing normal flora. There are some data suggesting that fidaxomicin inhibits spore production in C. difficile.52
The optimal management of patients with multiple relapses is not clear. A prolonged tapered pulse dosing of oral vancomycin has been suggested for second relapses.51,53 Alternative regimens that have shown efficacy include drugs in rifamycin class: vancomycin + rifampin54 or vancomycin followed by rifaximin.55 Concern with these regimens includes drug interactions with rifampin and development of resistance, especially if either rifampin or rifaximin is used as monotherapy. Nitazoxanide is another alternative agent in patients with relapse following metronidazole therapy.56 There are two other modalities that have been shown to have efficacy against CDI: IVIG and fecal transplantation. Individuals with low concentration of circulating IgG antitoxin are susceptible to more severe disease and frequent relapses. In those with multiple relapses due to impaired antigenic response to toxins, IVIG 400 mg/kg may be a worthwhile intervention.56 It is, however, expensive and its efficacy is reported in case series and anecdotal reports. Fecal transplantation uses a small amount of fresh feces from a healthy donor, suspended in saline, filtered, and administered through a nasogastric tube or by retention enema.57 Although it was efficacious in a case series, it is a difficult option to offer to patients.
Agents that have lost favor due to poor efficacy or resistance include bacitracin, cholestyramine, colestipol, and fusidic acid. Probiotics using Saccharomyces boulardii or lactobacilli species to augment colonization resistance and prevent recurrent CDI have been studied in adults and children. A placebo-controlled trial of 204 patients demonstrated no benefit of S. boulardii for prevention of CDI in hospitalized adults.58 However, several trials suggest the probiotic may be effective in prevention of CDI in pediatric patients.59 Agents that are in clinical trials include ramoplanin (a new lipoglycodepsipeptide), rifamycins (including rifampin, rifaximin, and rifalazil), monoclonal antibodies to C. difficile toxins A and B, and CB-315 (a lipopeptide). Tolevamer (a large anionic polymer that binds C. difficile toxins A and B) was inferior to metronidazole and vancomycin in the treatment of the first episode of CDI, but the relapse rate was lower.60 A C. difficile toxoid vaccine (Sanofi Pasteur) has received fast-track status through the FDA, and is in phase II testing.
Drugs that inhibit peristalsis, such as diphenoxylate, are contraindicated in CDI.41 Slowing of fecal transit time is thought to result in extended toxin-associated damage. Strict hand washing and contact precautions are imperative measures in preventing the spread of the organism. C. difficile can be cultured in rooms of infected individuals up to 40 days after discharge.
Clinical Controversy…
Some investigators have found prophylaxis with competing, nonpathogenic organisms such as Lactobacillus spp. or Saccharomyces spp. to be helpful in preventing relapses in small numbers of patients with CDI. It is thought that these organisms help to restore the natural flora in the gut and make patients more resistant to colonization by C. difficile when used in conjunction with appropriate antibiotics.
TRAVELER’S DIARRHEA
Traveler’s diarrhea describes the clinical syndrome manifested by malaise, anorexia, and abdominal cramps followed by the sudden onset of diarrhea that incapacitates many travelers. It interferes with planned activities or work in 30% of those affected. In particular, an increased risk lies with North Americans and Northern Europeans traveling to Latin America, southern Europe, Africa, and Asia. The highest risk is observed with patients with immunocompromised conditions, achlorhydria, inflammatory bowel disease, and people with chronic debilitating medical conditions. Overall, 20% to 50% of people traveling to high-risk areas will develop the illness.34
The onset of symptoms usually occurs during the first week of travel but can occur anytime during the visit or after returning home. Traveler’s diarrhea is caused by contaminated food or water. The most common pathogens are bacterial in nature and include ETEC (20% to 72%), Shigella (3% to 25%), Campylobacter (3% to 17%), and Salmonella (3% to 7%).8 Viruses (up to 30%) are also potential causes, as are parasites, although they are rare during short-term travels, accounting for less than 5% of cases. Bacterial enteropathogens cause up to 80% of cases. The diarrhea-producing E. coli (ETEC) plays more important role in Latin America, Africa, and South Asia. The invasive enteric pathogens (Campylobacter spp., Shigella spp., and Salmonella spp.) are relatively more important causes of traveler’s diarrhea in Asia.
The severity of the syndrome is determined by the number of stools per day and the presence or absence of cramping, nausea, and vomiting. Mild diarrhea is defined as one to three loose stools per day that are associated with abdominal cramps lasting less than 14 days. Moderate diarrhea indicates more than four loose stools daily associated with dehydration, and severe diarrhea is defined as the presence of fever or blood in stools. Traveler’s diarrhea is rarely life-threatening and in most cases, symptoms resolve in several days without treatment. Travelers to high-risk areas should pack a kit that includes a thermometer, loperamide, 3 days of antibiotics (see Treatment below), ORS salts, and a water purification method.34
Prevention
Patient education in avoiding high-risk food and beverages should be the best method for minimizing the risk. High-risk foods and beverages include raw or undercooked meat and seafood, moist foods served at room temperature, fruits that cannot be peeled, vegetables, milk from a questionable source, hot sauces on the table, tap water, unsealed bottled water, iced drinks, and food from a street vendor. Slogans such as “Peel it, boil it, cook it, or forget it” remind travelers to avoid contaminated food and to use water purification or reliable bottled beverages. Unfortunately, a meta-analysis concluded that the incidence of diarrhea was similar in travelers who followed the old adage and those who engaged in riskier eating habits.61 A potential reason for a lack of difference may be due to the fact that cooking foods does not always kill pathogens and food should not be considered safe unless it is cooked until steaming hot. Nonetheless, advisement of avoidance measures regarding safe foods, beverages, and eating establishments is recommended to heighten awareness.
Bismuth subsalicylate 524 mg (two tablets or two tablespoonfuls) orally four times daily for up to 3 weeks is a commonly recommended prophylactic regimen.34 Bismuth subsalicylate may inhibit enterotoxin activity and prevent diarrhea. Persons taking this regimen should be informed of adverse events, including temporary black discoloration of tongue and stools, and, rarely, tinnitus.
Although the efficacy of prophylactic antibiotics has been documented, their use is not recommended for most travelers due to the potential side effects of antibiotics (e.g., photosensitivity), predisposition to other infections such as CDI or vaginal candidiasis, the increased risk of selection of drug-resistant organisms, cost, lack of data on the safety and efficacy of antibiotics given for more than 2 or 3 weeks, and availability of rapidly effective antibiotics for treatment. Prophylactic antibiotics are recommended only in high-risk individuals or in situations in which short-term illness could ruin the purpose of the trip, such as a military mission. A fluoroquinolone is the drug of choice when traveling to most areas of the world.34 Due to fluoroquinolone resistance among Campylobacter spp., azithromycin can be considered when traveling to South Asia and Southeast Asia.
Rifaximin is a nonabsorbed oral rifamycin that has activity against enteric pathogens and may have a role in the prevention of traveler’s diarrhea in select populations. A randomized, double-blind trial of rifaximin 200 mg once, twice, or three times daily with meals for 2 weeks resulted in equal protection of 72% for each of the three dosing regimens compared with placebo.35 Since rifaximin is effective against traveler’s diarrhea due to noninvasive strains of E. coli, this agent should be reserved for travel regions where E. coli predominates, such as Latin America and Africa. Rifaximin has a tolerability and safety profile comparable to that of placebo. The concern with the class rifamycin is the emergence of resistance when used as monotherapy.
TREATMENT
The goals of treatment are to avoid dehydration, reduce the severity and duration of symptoms, and prevent interruption to planned activities. Fluid and electrolyte replacement should be initiated at the onset of diarrhea. ORT is generally not required in otherwise healthy individuals; flavored mineral water ad libitum offers a good source of sodium and glucose. In infants and young children, elderly, and those with chronic debilitating medical conditions, ORT is recommended. For symptom relief, loperamide (preferred because of its quicker onset and longer duration of relief relative to bismuth) may be taken (4 mg orally initially and then 2 mg with each subsequent loose stool to a maximum of 16 mg/day in patients without bloody diarrhea and fever). Loperamide should be discontinued if symptoms persist for more than 48 hours. Other symptomatic therapy in mild diarrhea includes bismuth subsalicylate 524 mg every 30 minutes for up to eight doses.34 There is insufficient evidence to warrant the recommendation of probiotics.
Since behavioral modification has limited efficacy and chemoprophylaxis is not recommended in most travelers, the current recommendation relies on self-treatment. Most trials indicate that a single dose of antibiotic and up to 3 days of treatment will improve the condition within 24 to 36 hours, shortening the duration of diarrhea by 1 to 2 days.34 A single dose of fluoroquinolone is recommended initially and if diarrhea is improved within 12 to 24 hours, antibiotics should be discontinued. Otherwise, it can be continued for up to 3 days. A fluoroquinolone is recommended when traveling to most areas of the world. Where fluoroquinolone-resistant Campylobacter is common, such as in South Asia and Southeast Asia, azithromycin can be used.34 Azithromycin can also be used in pregnant women and children younger than age 16 years. Empiric treatment of young children should be cautioned.
Rifaximin was as effective as a 3-day course of ciprofloxacin in shortening the duration of diarrhea in noninvasive traveler’s diarrhea. However, rifaximin was not as effective in patients with fever and bloody diarrhea and in those with invasive pathogens. Therefore, a 3-day course of rifaximin has been approved for the treatment of traveler’s diarrhea caused by noninvasive strains of E. coli in people ≥12 years of age and can be considered when traveling to areas where E. coli–associated traveler’s diarrhea is common, such as Mexico and Jamaica.34
For rapid improvement in symptoms, antibiotic therapy with adjunctive treatment with loperamide has shown benefit.62 All clinical trials concluded that the combination therapy was safe, and the worsening of the disease with the use of antimotility treatment has not been encountered.
Clinical Controversy…
Most trials have shown that a short course of antibiotic therapy reduces the duration of traveler’s diarrhea by 1 to 2 days with mild side effects. Some clinicians advocate a self-treatment with antibiotics for moderate-to-severe traveler’s diarrhea, while others urge a more cautious approach. The final decision on self-treatment should rely on discussions with individual travelers, taking into consideration their ability and willingness to adhere to prevention strategies and to tolerate diarrheal illness during the trip.
FOOD POISONING
Foodborne illnesses result from the ingestion of food containing pathogenic microorganisms that cause GI infections or preformed toxins that were produced by microorganisms that cause enterotoxigenic poisonings. In the United States, foodborne diseases cause approximately 76 million illnesses, 325,000 hospitalizations, and 5,200 deaths each year.4 Foodborne transmission may account for up to 80% of acute gastroenteritis. Common enteric pathogens responsible for foodborne diseases have been discussed in the previous sections (norovirus, nontyphoidal Salmonella, Campylobacter spp., Shigella, E. coli). Common foodborne pathogens that cause enterotoxigenic poisonings include Staphylococcus aureus, Bacillus cereus, Clostridium perfringens, and Clostridium botulinum. Characteristics of pathogens responsible for foodborne illnesses are summarized in Table 91–7.
TABLE 91-7 Food Poisonings
Because foodborne disease can appear as sporadic cases or outbreaks, the diagnosis should be suspected whenever two or more people present with acute GI or neurologic manifestations after sharing a meal within the previous 72 hours. Important clues about etiologic agents can be gathered from demographic information (age, gender, etc.), the clinical syndrome, incubation period, and medical history, type of foods consumed, seasonality, and geographic location of the outbreak.
Enterotoxigenic poisonings result from ingestion of food contaminated by preformed toxins. Therefore, symptoms are rapid in onset, but most cases of food poisoning are of short duration with recovery occurring within 1 to 2 days. B. cereus causes two different types of clinical syndromes. The first one is caused by characterized by a short incubation period and mostly vomiting. The second syndrome has a longer incubation period and is characterized by diarrhea. Foodborne C. perfringens infection may present as two distinct syndromes. Type A organisms are seen in Western nations and result in a 24-hour illness characterized by watery diarrhea and epigastric pain. Type C organisms can be found in undercooked pork and occur in underdeveloped tropical regions. They can produce a toxin-related syndrome called enteritis necroticans, which is a coagulative transmural necrosis of the intestinal wall. This syndrome can result in intestinal perforation leading to sepsis and mortality in approximately 40% of victims.
Foodborne botulism results from the ingestion of food contaminated with preformed toxins or toxin-producing spores from C. botulinum. C. botulinum poisoning is relatively rare; only 110 cases are reported per year in the United States.63 Botulism is almost always associated with improper preparation or storage of food. Seven distinct toxins (A to G) have been described. The toxins prevent the release of acetylcholine at the peripheral cholinergic nerve terminal. Toxin activity has prompted the use of minute locally injected doses to treat select spastic disorders, such as blepharospasm, hemifacial spasm, and certain dystonias. Foodborne botulism is suspected when patients present with acute GI symptoms concurrently or just prior to the onset of a symmetric descending paralysis without sensory or central nervous system involvement. Diagnosis is made by culturing C. botulinum from the stool. The clinical presentation may resemble GBS associated with C. jejuni infection. The difference lies in the onset of neurologic symptoms, which typically occur 1 to 3 weeks after the onset of C. jejuni infection, and the condition usually is manifested by an ascending paralysis in C. jejuni–associated GBS.
Treatment consists primarily of respiratory support and use of botulinum antitoxin.64 If evaluation is performed within several hours of ingestion, gastric lavage or induction of vomiting is suggested. Cathartics and enemas also can be used to remove residual toxin from the bowel, but they are contraindicated in cases of ileus. Botulinum antitoxin is a concentrated preparation of equine globulins obtained from horses immunized with toxins A, B, and E. Because trivalent antitoxin is equine in origin, patients should be tested for hypersensitivity before receiving the product IV. Other agents used experimentally as adjunctive therapy are guanidine, which antagonizes the effect of botulinum toxin at the neuromuscular junction, and 4-aminopyridine, which increases acetylcholine release. Newer and more effective methods of treatment and prevention are under development, including a botulinum toxin vaccine consisting of nontoxic botulinum fragments. Prevention always should be stressed. Botulinum toxins are heat labile and readily destroyed by 10 minutes of boiling. All home-canned foods should be processed according to directions and boiled, not just warmed, prior to consumption.
In foodborne illnesses, the cornerstone of therapy remains supportive care. ORT is preferred in replenishing and maintaining fluid and electrolyte balance, and IV fluid therapy should be reserved for those who are severely ill and cannot tolerate oral therapy. Antiemetics and antiperistaltic agents offer symptomatic relief, but the latter should not be given in patients who present with high fever, bloody diarrhea, or fecal leukocytes. Antimicrobial therapy is not effective in the management of S. aureus, C. perfringens, or B. cereus food poisonings. In developed countries, many of the foodborne illnesses can be prevented with proper food selection, preparation, and storage. However, in developing countries, sanitation and clean water supply are larger concerns.
ABBREVIATIONS
REFERENCES
1. Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001;32(3):331–351.
2. Fischer Walker CL, Perin J, Aryee MJ, Boschi-Pinto C, Black RE. Diarrhea incidence in low- and middle-income countries in 1990 and 2010: A systematic review. BMC Public Health 2012;12:220.
3. Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bull World Health Organ 2003;81(3):197–204.
4. Jones TF, McMillian MB, Scallan E, et al. A population-based estimate of the substantial burden of diarrhoeal disease in the United States; FoodNet, 1996–2003. Epidemiol Infect 2007;135(2):293–301.
5. Scallan E, Griffin PM, Angulo FJ, Tauxe RV, Hoekstra RM. Foodborne illness acquired in the United States—Unspecified agents. Emerg Infect Dis 2011;17(1):16–22.
6. Scallan E, Hoekstra RM, Angulo FJ, et al. Foodborne illness acquired in the United States—Major pathogens. Emerg Infect Dis 2011;17(1):7–15.
7. Charles MD, Holman RC, Curns AT, Parashar UD, Glass RI, Bresee JS. Hospitalizations associated with rotavirus gastroenteritis in the United States, 1993–2002. Pediatr Infect Dis J 2006;25(6):489–493.
8. Talan D, Moran GJ, Newdow M, et al. Etiology of bloody diarrhea among patients presenting to United States emergency departments: Prevalence of Escherichia coli O157:H7 and other enteropathogens. Clin Infect Dis 2001;32(4):573–580.
9. Sack DA, Sack RB, Nair GB, Siddique AK. Cholera. Lancet 2004;363(9404):223–233.
10. Holtz LR, Neill MA, Tarr PI. Acute bloody diarrhea: A medical emergency for patients of all ages. Gastroenterology 2009;136(6):1887–1898.
11. Robins-Browne RM, Hartland EL. Escherichia coli as a cause of diarrhea. J Gastroenterol Hepatol 2002;17(4):467–475.
12. Flores J, Okhuysen PC. Enteroaggregative Escherichia coli infection. Curr Opin Gastroenterol 2009;25(1):8–11.
13. Niyogi SK. Shigellosis. J Microbiol 2005;43(2):133–143.
14. Voetsch AC, Van Gilder TJ, Angulo FJ, et al. FoodNet estimate of the burden of illness caused by nontyphoidal Salmonella infections in the United States. Clin Infect Dis 2004;38(Suppl 3):S127–S134.
15. Pfeiffer ML, DuPont HL, Ochoa TJ. The patient presenting with acute dysentery—A systematic review. J Infect 2012; 64(4):374–386.
16. Sabina Y, Rahman A, Ray RC, Montet D. Yersinia enterocolitica: Mode of transmission, molecular insights of virulence, and pathogenesis of infection. J Pathog 2011;2011:429069.
17. Hodges K, Gill R. Infectious diarrhea: Cellular and molecular mechanisms. Gut Microbes 2010;1(1):4–21.
18. Li C, Dandridge KS, Di A, et al. Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through CFTR-dependent protein interactions. J Exp Med 2005;202(7):975–986.
19. Lucas ML. Enterocyte chloride and water secretion into the small intestine after enterotoxin challenge: Unifying hypothesis or intellectual dead end? J Physiol Biochem 2008;64(1):69–88.
20. Greenberg HB, Estes MK. Rotaviruses: From pathogenesis to vaccination. Gastroenterology 2009;136(6):1939–1951.
21. Rallabhandi P, Awomoyi A, Thomas KE, et al. Differential activation of human TLR4 by Escherichia coli and Shigella flexneri 2a lipopolysaccharide: Combined effects of lipid A acylation state and TLR4 polymorphisms on signaling. J Immunol 2008;180(2):1139–1147.
22. Fernandez MI, Sansonetti PJ. Shigella interaction with intestinal epithelial cells determines the innate immune response in shigellosis. Int J Med Microbiol 2003;293(1):55–67.
23. Haverly RM, Harrison CR, Dougherty TH. Yersinia enterocolitica bacteremia associated with red blood cell transfusion. Arch Pathol Lab Med 1996;120(5):499–500.
24. Panos GZ, Betsi GI, Falagas ME. Systematic review: Are antibiotics detrimental or beneficial for the treatment of patients with Escherichia coli O157:H7 infection? Aliment Pharmacol Ther 2006;24(5):731–742.
25. Garg AX, Pope JE, Thiessen-Philbrook H, Clark WF, Ouimet J. Arthritis risk after acute bacterial gastroenteritis. Rheumatology (Oxford) 2008;47(2):200–204.
26. Allos BM. Campylobacter jejuni infections: Update on emerging issues and trends. Clin Infect Dis 2001;32(8):1201–1206.
27. Organization WH. The Treatment of Diarrhoea: A Manual for Physicians and Other Senior Health Workers. 2005, http://whqlibdoc.who.int/publications/2005/9241593180.pdf.
28. Hahn S, Kim S, Garner P. Reduced osmolarity oral rehydration solution for treating dehydration caused by acute diarrhoea in children. Cochrane Database Syst Rev 2002;(1):CD002847.
29. Musekiwa A, Volmink J. Oral rehydration salt solution for treating cholera: /= 310 mOsm/L solutions. Cochrane Database Syst Rev 2011; (12):CD003754.
30. Gregorio GV, Gonzales ML, Dans LF, Martinez EG. Polymer-based oral rehydration solution for treating acute watery diarrhoea. Cochrane Database Syst Rev 2009;(2):CD006519.
31. Gregorio GV, Dans LF, Silvestre MA. Early versus delayed refeeding for children with acute diarrhoea. Cochrane Database Syst Rev 2011;(7):CD007296.
32. Payot S, Bolla JM, Corcoran D, Fanning S, Megraud F, Zhang Q. Mechanisms of fluoroquinolone and macrolide resistance in Campylobacter spp. Microbes Infect 2006;8(7):1967–1971.
33. Parry CM, Threlfall EJ. Antimicrobial resistance in typhoidal and nontyphoidal salmonellae. Curr Opin Infect Dis 2008; 21(5):531–538.
34. Hill DR, Ericsson CD, Pearson RD, et al. The practice of travel medicine: Guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43(12):1499–1539.
35. DuPont HL, Jiang ZD, Okhuysen PC, et al. A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers’ diarrhea. Ann Intern Med 2005;142(10):805–812.
36. DuPont HL. Clinical practice. Bacterial diarrhea. N Engl J Med 2009;361(16):1560–1569.
37. Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev 2010;(11):CD003048.
38. Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev 2012;6:CD005436.
39. Steinberg EB, Bishop R, Haber P, et al. Typhoid fever in travelers: Who should be targeted for prevention? Clin Infect Dis 2004;39(2):186–191.
40. Cortese MM, Parashar UD. Prevention of rotavirus gastroenteritis among infants and children: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2009;58(RR-2):1–25.
41. Leffler DA, Lamont JT. Treatment of Clostridium difficile-associated disease. Gastroenterology 2009;136(6):1899–1912.
42. Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: A meta-analysis. Am J Gastroenterol 2012;107(7):1001–1010.
43. Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile-related mortality rates, United States, 1999–2004. Emerg Infect Dis 2007;13(9):1417–1419.
44. Mitchell BG, Gardner A. Mortality and Clostridium difficile infection: A review. Antimicrob Resist Infect Control 2012;1(1):20.
45. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005;353(23):2442–2449.
46. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45(3):302–307.
47. Wenisch C, Parschalk B, Hasenhundl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 1996;22(5):813–818.
48. Teasley DG, Gerding DN, Olson MM, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet 1983;2(8358):1043–1046.
49. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364(5):422–431.
50. Eyre DW, Walker AS, Wyllie D, et al. Predictors of first recurrence of Clostridium difficile infection: Implications for initial management. Clin Infect Dis 2012;55(Suppl 2): S77–S87.
51. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: Treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002; 97(7):1769–1775.
52. Babakhani F, Bouillaut L, Gomez A, Sears P, Nguyen L, Sonenshein AL. Fidaxomicin inhibits spore production in Clostridium difficile. Clin Infect Dis 2012;55(Suppl 2): S162–S169.
53. Kelly C. A 76-year-old man with recurrent Clostridium difficile-associated diarrhea. JAMA 2009;301(9):954–962.
54. Buggy BP, Fekety R, Silva J Jr. Therapy of relapsing Clostridium difficile-associated diarrhea and colitis with the combination of vancomycin and rifampin. J Clin Gastroenterol 1987;9:155–159.
55. Johnson S, Schriever C, Galang M, Kelly CP, Gerding DN. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis 2007;44:846–848.
56. Wilcox W. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhea. J Antimicrob Chemother 2004;53:882–884.
57. Aas J, Gessert C, Bakken JS. Recurrent Clostridium difficile colitis: Case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003;36:580–585.
58. Pozzoni P, Riva A, Bellatorre AG, et al. Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in adult hospitalized patients: A single-center, randomized, double-blind, placebo-controlled trial. Am J Gastroenterol 2012;107(6):922–931.
59. Johnston BC, Supina AL, Ospina M, Vohra S. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev 2007;(2):CD004827.
60. Louie TJ, Peppe J, Watt CK, et al. Tolevamer, a novel nonantibiotic polymer, compared with vancomycin in the treatment of mild to moderately severe Clostridium difficile-associated diarrhea. Clin Infect Dis 2006;43: 411–420.
61. Shlim D. Looking for evidence that personal hygiene precautions prevent traveler’s diarrhea. Clin Infect Dis 2005;41(Suppl 8):S531–S535.
62. Riddle MS, Arnold S, Tribble DR. Effect of adjunctive loperamide in combination with antibiotics on treatment outcomes in traveler’s diarrhea: A systematic review and meta-analysis. Clin Infect Dis 2008;47(8):1007–1014.
63. Sobel J, Tucker N, Sulka A, McLaughlin J, Maslanka S. Foodborne botulism in the United States, 1990–2000. Emerg Infect Dis 2004;10(9):1606–1611.
64. Sobel J. Botulism. Clin Infect Dis 2005;41(8):1167–1173.