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138 Acute Infectious Diarrheal Diseases and Bacterial Food Poisoning

of enteric organisms including aerobic and anaerobic gram-negative bacilli is usually isolated from psoas abscesses in the United States. S. aureus is most likely to be isolated when a psoas abscess arises from hematogenous spread or a contiguous focus of osteomyelitis; a mixed enteric flora is the most likely etiology when the abscess has an intraab­ dominal or pelvic source. Patients with psoas abscesses frequently pres­ ent with fever, lower abdominal or back pain, or pain referred to the hip or knee. CT is the most useful diagnostic technique.

TREATMENT Psoas Abscesses Treatment includes surgical drainage and the administration of an antibiotic regimen directed at the inciting organism(s). Pancreatic Abscesses  See Chap. 359. ■ ■FURTHER READING Biggins SW et al: Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome: 2021 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 74;1014.2021. De Pascale G et al: Poor timing and failure of source control are risk factors for mortality in critically ill patients with secondary peritonitis. Intensive Care Med 48:1593, 2022. Li PK et al: ISPD peritonitis recommendations: 2016 update on prevention and treatment. Perit Dial Int 36:481, 2016. Oliver A et al: Role of rifaximin in spontaneous bacterial peritonitis PART 5 Infectious Diseases prevention. South Med J 111:660 2018. Roediger R, Lisker-Melman M: Pyogenic and amebic infections of the liver. Gastroenterol Clin North Am 49:361, 2020. Ross JT et al: Secondary peritonitis: Principles of diagnosis and intervention. BMJ 361:k1407, 2018. Van Hooste W et al: Infections caused by hypervirulent Klebsiella pneumoniae in non-endemic countries: Three case reports and review of the literature. Acta Clin Belg 78:229, 2023. Ana A. Weil, Regina C. LaRocque

Acute Infectious

Diarrheal Diseases and

Bacterial Food Poisoning Diarrheal disease mortality has decreased substantially in the past three decades. Nevertheless, acute diarrheal disease is still a leading cause of illness globally and is associated with an estimated 1.57 million deaths per year. Across low-income and middle-income countries, one in ten deaths among children <5 years of age is attributable to diar­ rhea, with substantial variation in incidence and mortality between countries. The morbidity from diarrhea also is significant. Recurrent intestinal infections are associated with physical and mental stunting, wasting, micronutrient deficiencies, and malnutrition. In short, diar­ rheal disease is a driving factor in global morbidity and mortality. The wide range of clinical manifestations of acute gastrointestinal illnesses is matched by the wide variety of infectious agents involved, including viruses, bacteria, and parasites (Table 138-1). This chapter discusses factors that enable gastrointestinal pathogens to cause dis­ ease, reviews host defense mechanisms, and delineates an approach to the evaluation and treatment of patients presenting with acute

diarrhea. Individual organisms causing acute gastrointestinal illnesses are discussed in detail in subsequent chapters. PATHOGENIC MECHANISMS Enteric pathogens have developed a variety of tactics to overcome host defenses. Understanding the virulence factors employed by these organisms is important in the diagnosis and treatment of clinical disease. ■ ■INOCULUM SIZE The number of microorganisms that must be ingested to cause disease varies considerably from species to species. For Shigella, enterohemor­ rhagic Escherichia coli, Giardia lamblia, or Entamoeba, as few as 10–100 bacteria or cysts can produce infection, while 105−108 Vibrio cholerae organisms must be ingested to cause disease. The infective dose of Sal­ monella varies widely, depending on the species, host, and food vehicle. The ability of organisms to overcome host defenses has important implications for transmission; Shigella, enterohemorrhagic E. coli, Ent­ amoeba, and Giardia can spread by person-to-person contact, whereas under some circumstances, Salmonella may need to grow in food for several hours before reaching an effective infectious dose. ■ ■ADHERENCE Many organisms must adhere to the gastrointestinal mucosa as an initial step in the pathogenic process; thus, organisms that can com­ pete with the normal bowel flora and colonize the mucosa have an important advantage in causing disease. Specific cell-surface proteins involved in attachment of bacteria to intestinal cells are important virulence determinants. V. cholerae, for example, adheres to the brush border of small-intestinal enterocytes via specific surface adhesins, including the toxin-coregulated pilus and other accessory coloniza­ tion factors. Enterotoxigenic E. coli, which causes watery diarrhea, produces an adherence protein called colonization factor antigen that is necessary for colonization of the upper small intestine by the organism prior to the production of enterotoxin. Enteropathogenic E. coli, an agent of diarrhea in young children, and enterohemor­ rhagic E. coli, which causes hemorrhagic colitis and the hemolyticuremic syndrome, produce virulence determinants that allow these organisms to attach to and efface the brush border of the intestinal epithelium. ■ ■TOXIN PRODUCTION The production of one or more exotoxins is important in the pathogen­ esis of numerous enteric organisms. Such toxins include enterotoxins, which cause watery diarrhea by acting directly on secretory mecha­ nisms in the intestinal mucosa; cytotoxins, which cause destruction of mucosal cells and associated inflammatory diarrhea; and neurotoxins, which act directly on the central or peripheral nervous system. The prototypical enterotoxin is cholera toxin, a heterodimeric pro­ tein composed of one A and five B subunits. The A subunit contains the enzymatic activity of the toxin, while the B subunit pentamer binds holotoxin to the enterocyte surface receptor, the ganglioside GM1. After the binding of holotoxin, a fragment of the A subunit is translocated across the eukaryotic cell membrane into the cytoplasm, where it catalyzes the adenosine diphosphate ribosylation of a guano­ sine triphosphate (GTP)–binding protein and causes persistent activa­ tion of adenylate cyclase. The result is an increase of cyclic adenosine monophosphate in the intestinal cell, which increases Cl– secretion and decreases Na+ absorption, leading to a loss of fluid and the production of diarrhea. Enterotoxigenic strains of E. coli may produce a protein called heatlabile enterotoxin (LT) that is like cholera toxin and causes secretory diarrhea by the same mechanism. Alternatively, enterotoxigenic strains of E. coli may produce heat-stable enterotoxin (ST), one form of which causes diarrhea by activation of guanylate cyclase and elevation of intracellular cyclic guanosine monophosphate. Some enterotoxigenic strains of E. coli produce both LT and ST. Bacterial cytotoxins, in contrast, destroy intestinal mucosal cells and produce the syndrome of dysentery, with bloody stools containing

TABLE 138-1  Gastrointestinal Pathogens Causing Acute Diarrhea MECHANISM LOCATION ILLNESS STOOL FINDINGS EXAMPLES OF PATHOGENS INVOLVED Noninflammatory (enterotoxin) Proximal small bowel Watery diarrhea No fecal leukocytes; mild or no increase in fecal lactoferrin Inflammatory (invasion or cytotoxin) Colon or distal small bowel Dysentery or inflammatory diarrhea Fecal polymorphonuclear leukocytes; substantial increase in fecal lactoferrin Penetrating Distal small bowel Enteric fever Fecal mononuclear leukocytes Abbreviations: LT, heat-labile enterotoxin; ST, heat-stable enterotoxin. inflammatory cells. Enteric pathogens that produce such cytotoxins include Shigella dysenteriae type 1, Vibrio parahaemolyticus, and Clos­ tridioides difficile. S. dysenteriae type 1 and Shiga toxin–producing strains of E. coli produce potent cytotoxins and have been associated with outbreaks of hemorrhagic colitis and hemolytic-uremic syndrome. Neurotoxins are usually produced by bacteria outside the host and therefore cause symptoms soon after ingestion. Included are the staph­ ylococcal and Bacillus cereus toxins, which act on the central nervous system to produce vomiting. ■ ■INVASION Dysentery may result not only from the production of cytotoxins but also from bacterial invasion and destruction of intestinal mucosal cells. Infections due to Shigella and enteroinvasive E. coli are characterized by the organisms’ invasion of mucosal epithelial cells, intraepithelial mul­ tiplication, and subsequent spread to adjacent cells. Salmonella causes inflammatory diarrhea by invading the bowel mucosa but generally is not associated with the destruction of enterocytes or the full clinical syndrome of dysentery. Salmonella enterica serovar Typhi and Yersinia enterocolitica can penetrate intact intestinal mucosa, multiply intra­ cellularly in Peyer patches and intestinal lymph nodes, and then dis­ seminate through the bloodstream to cause enteric fever—a syndrome characterized by fever, headache, relative bradycardia, abdominal pain, splenomegaly, and leukopenia. HOST DEFENSES Given the enormous number of microorganisms ingested with every meal, the normal host must combat a constant influx of potential enteric pathogens. Studies of infections in patients with alterations in defense mechanisms have led to a greater understanding of the variety of ways in which the normal host can protect itself against disease. ■ ■INTESTINAL MICROBIOTA The large numbers of bacteria that normally inhabit the intestine (the intestinal microbiota) act as an important host defense mechanism, preventing colonization by potential enteric pathogens. Mechanisms of colonization resistance are not fully understood but include geographic and nutritional exclusion at the mucosal surface. Persons with fewer intestinal bacteria, such as infants who have not yet developed normal enteric colonization or patients receiving antibiotics, are at greater risk of developing infections with enteric pathogens. The bacterial com­ munity composition of the intestinal microbiota is as important as abundance of organisms present. More than 99% of the normal colonic microbiota is made up of anaerobic bacteria, and the acidic pH and volatile fatty acids produced by these organisms appear to be critical elements in resistance to colonization. ■ ■GASTRIC ACID The acidic pH of the stomach is an important barrier to enteric patho­ gens, and an increased frequency of infections due to Salmonella,

G. lamblia, and a variety of helminths has been reported among patients who have undergone gastric surgery or are achlorhydric for some other reason. Neutralization of gastric acid with antacids, proton pump

Vibrio cholerae, enterotoxigenic Escherichia coli (LT and/or ST), enteroaggregative E. coli, Clostridium perfringens, Bacillus cereus, Staphylococcus aureus, Aeromonas hydrophila, Plesiomonas shigelloides, rotavirus, norovirus, enteric adenoviruses, Giardia lamblia, Cryptosporidium spp., Cyclospora spp., microsporidia Shigella spp., Salmonella spp., Campylobacter jejuni, enterohemorrhagic E. coli, enteroinvasive E. coli, Yersinia enterocolitica, Listeria monocytogenes, Vibrio parahaemolyticus, Clostridium difficile, A. hydrophila, P. shigelloides, Entamoeba histolytica, Klebsiella oxytoca Salmonella Typhi, Y. enterocolitica inhibitors, or H2 blockers—a common practice in the management of hospitalized patients—similarly increases the risk of enteric coloniza­ tion. In addition, some microorganisms can survive the extreme acid­ ity of the gastric environment; rotavirus and Shigella, for example, are highly stable to acidity. ■ ■INTESTINAL MOTILITY Peristalsis is the major mechanism for clearance of bacteria from the proximal small intestine. When intestinal motility is impaired (e.g., by treatment with opioids or other antimotility drugs, anatomic abnor­ malities, or hypomotility states), the frequency of bacterial overgrowth and infection of the small bowel with enteric pathogens is increased. Some patients whose treatment for Shigella infection consists of diphenoxylate hydrochloride with atropine (Lomotil) experience pro­ longed fever and shedding of organisms, while patients treated with opioids for mild Salmonella gastroenteritis have a higher frequency of bacteremia than those not treated with opioids. CHAPTER 138 ■ ■INTESTINAL MUCIN A complex layer of mucus, produced by specialized secretory cells, covers the stomach, small intestine, and large intestine, and separates the lumenal commensal microbiota from the epithelium. The thickness and constituents of this mucus barrier vary throughout the gastro­ intestinal tract. The mucus barrier turns over rapidly and comprises glycoproteins and a range of antimicrobial molecules and secreted immunoglobulins directed against specific microbial antigens. Enteric pathogens have evolved a wide range of strategies to overcome this barrier and thus to reach the underlying epithelium and cause disease. For example, pathogens can penetrate the mucus layer by secreting enzymes to degrade the mucus or through flagella-mediated motil­ ity. Some organisms, such as Shigella, secrete toxins that can diffuse through the mucus layer and disrupt the underlying epithelium. The resulting reduction of mucus production allows the pathogen to reach the cell surface. Acute Infectious Diarrheal Diseases and Bacterial Food Poisoning
■ ■IMMUNITY Both cellular immune responses and antibody production play impor­ tant roles in protection from enteric infections. Humoral immunity to enteric pathogens consists of systemic IgG and IgM as well as secre­ tory IgA. The mucosal immune system may be the first line of defense against many gastrointestinal pathogens. The binding of bacterial antigens to the lumenal surface of M cells in the distal small bowel and the subsequent presentation of antigens to subepithelial lymphoid tis­ sue leads to the proliferation of sensitized and specialized lymphocytes. These lymphocytes circulate and populate all of the mucosal tissues of the body as IgA-secreting plasma cells. ■ ■GENETIC DETERMINANTS Host genetic variation influences susceptibility to diarrheal dis­ eases. People with blood group O show increased susceptibility to disease due to V. cholerae, Shigella, E. coli O157, and norovirus. Polymorphisms in genes encoding inflammatory mediators have been associated with the outcome of infection with enteroaggregative E. coli, enterotoxin-producing E. coli, Salmonella, C. difficile, and V. cholerae.

APPROACH TO THE PATIENT Infectious Diarrhea or Bacterial Food Poisoning The approach to the patient with possible infectious diarrhea or bacterial food poisoning is shown in Fig. 138-1. HISTORY Diarrhea is defined as the passage of loose or watery stools that conform to the shape of a container three or more times in a 24-h period. The answers to questions with high discriminating value can quickly narrow the range of potential causes of diarrhea and help determine whether treatment is needed. Important elements of the narrative history are detailed in Fig. 138-1. Diarrhea, Nausea, or Vomiting Symptomatic therapy Oral rehydration therapy (see Table 138-5) Assess: Duration (>1 day) Severity (see text) Yes PART 5 Infectious Diseases Obtain history: Duration1 Fever2 Appearance of stool3 Frequency of bowel movements4 Abdominal pain5 Tenesmus6 Vomiting7 Common source8 Antibiotic use9 Travel10 and

Obtain stool to be examined for WBCs (and, if >10 days, for parasites) Inflammatory (WBCs; see Table 138-1) Examine stool for parasites Noninflammatory (no WBCs; see Table 138-1) Continue symptomatic therapy (Table 138-5); further evaluation if no resolution Culture for: Shigella, Salmonella, Campylobacter jejuni Consider: Clostridioides difficile cytotoxin Consider: Empirical antimicrobial therapy (Table 138-5) FIGURE 138-1  Clinical algorithm for the approach to patients with community-acquired infectious diarrhea or bacterial food poisoning. Key to superscripts: 1. Diarrhea lasting >2 weeks is generally defined as chronic; in such cases, many of the causes of acute diarrhea are much less likely, and a new spectrum of causes needs to be considered. 2. Fever often implies invasive disease, although fever and diarrhea may also result from infection outside the gastrointestinal tract, as in malaria. 3. Stools that contain blood or mucus indicate ulceration of the large bowel. Bloody stools without fecal leukocytes should alert the laboratory to the possibility of infection with Shiga toxin–producing enterohemorrhagic Escherichia coli. Bulky white/gray stools suggest a small-intestinal process that is causing malabsorption. An acute illness with profuse “rice-water” stools, with an appearance of water after rice has been cooked, suggests cholera or a similar toxigenic process. 4. Frequent stools over a given period can provide the first warning of impending dehydration. 5. Abdominal pain may be most severe in inflammatory processes like those due to Shigella, Campylobacter, and necrotizing toxins. Painful abdominal muscle cramps, caused by electrolyte loss, can develop in severe cases of cholera. Bloating is common in giardiasis. An appendicitislike syndrome should prompt a culture for Yersinia enterocolitica with cold enrichment. 6. Tenesmus (painful rectal spasms with a strong urge to defecate but little passage of stool) may be a feature of cases with proctitis, as in shigellosis or amebiasis. 7. Vomiting implies an acute infection (e.g., a toxin-mediated illness or food poisoning) but can also be prominent in a variety of systemic illnesses (e.g., malaria) and in intestinal obstruction. 8. Asking patients whether anyone they know is sick is a more efficient means of identifying a common source than is constructing a list of recently eaten foods. If a common source seems likely, specific foods can be investigated. See text for a discussion of bacterial food poisoning. 9. Current antibiotic therapy or a recent history of treatment suggests Clostridioides difficile diarrhea (Chap. 139). Stop antibiotic treatment if possible and consider tests for C. difficile toxins. Antibiotic use may increase the risk of chronic intestinal carriage following salmonellosis. 10. See text (and Chap. 130) for a discussion of traveler’s diarrhea. (From The New England Journal of Medicine. Bacterial and Protozoal Gastroenteritis. RL Guerrant, DA Bobak 325:327-340. Copyright @1991 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

PHYSICAL EXAMINATION The examination of patients for signs of dehydration provides essential information about the severity of the diarrheal illness and the need for rapid therapy. Mild dehydration is indicated by thirst, dry mouth, decreased axillary sweat, decreased urine output, and slight weight loss. Signs of moderate dehydration include an ortho­ static fall in blood pressure, skin tenting, and sunken eyes (or, in infants, a sunken fontanelle). Signs of severe dehydration include lethargy, obtundation, feeble pulse, hypotension, and shock. DIAGNOSTIC APPROACH After assessing severity of illness, the clinician must distinguish between inflammatory and noninflammatory disease. Using the Resolution No Continued illness Specific antiparasitic therapy

history and epidemiologic features of the case, the clinician can then rapidly evaluate the need for further efforts to define a specific etiology and for therapeutic intervention. Examination of a stool sample may supplement the narrative history. Grossly bloody or mucoid stool suggests an inflammatory process. A test for fecal leukocytes (preparation of a thin smear of stool on a glass slide, addition of a drop of methylene blue, and examination of the wet mount) can suggest inflammatory disease in patients with diarrhea, although the predictive value of this test is still debated. A test for fecal lactoferrin, which is a marker of fecal leukocytes, is more sensitive and is available in latex agglutination and enzyme-linked immunosorbent assay formats. Stool culture or molecular testing is useful for diagnosing a causative organism, particularly in patients with severe illness or high-risk comorbidities. Causes of acute infec­ tious diarrhea, categorized as inflammatory and noninflammatory, are listed in Table 138-1. POST DIARRHEA COMPLICATIONS Short- or long-term complications may follow the resolution of an acute diarrheal episode. The clinician should inquire about prior diarrheal illness if the conditions listed in Table 138-2 are observed. EPIDEMIOLOGY ■ ■TRAVEL HISTORY Of the several million people who travel from temperate industrialized countries to tropical regions of Asia, Africa, and Central and South America each year, 20–50% experience a sudden onset of abdominal cramps, anorexia, and watery diarrhea; thus, traveler’s diarrhea is the most common travel-related infectious illness (Chap. 130). The time of onset is usually 3 days to 2 weeks after the traveler’s arrival in a resource-poor area; most cases begin within the first 3–5 days. The illness is generally self-limited, lasting 1–5 days. The high rate of diar­ rhea among travelers is related to the ingestion of contaminated food or water. The pathogens that cause traveler’s diarrhea vary considerably with location (Table 138-3), as does the pattern of antimicrobial resistance. In all areas, enterotoxigenic and enteroaggregative E. coli are the most common pathogens among persons with the classic secretory traveler’s diarrhea syndrome. Infection with Campylobacter jejuni is especially common in areas of Asia. ■ ■LOCATION Closed and semi-closed communities, including day-care centers, schools, residential facilities, and cruise ships, are important settings TABLE 138-2  Postdiarrhea Complications of Acute Infectious Diarrheal Illness COMPLICATION COMMENTS Chronic diarrhea (diarrhea lasting

4 weeks) • Lactase deficiency • Small-bowel bacterial overgrowth • Malabsorption syndromes (tropical Occurs in ~1% of travelers with acute diarrhea Protozoa account for approximately one-third of cases and celiac sprue) Initial presentation or exacerbation of inflammatory bowel disease May be precipitated by traveler’s diarrhea Irritable bowel syndrome Occurs in ~10% of travelers with traveler’s diarrhea Reactive arthritis Particularly likely after infection with invasive organisms (Shigella, Salmonella, Campylobacter, Yersinia) Hemolytic-uremic syndrome (hemolytic anemia, thrombocytopenia, and renal failure) Follows infection with Shiga toxin–producing bacteria (Shigella dysenteriae type 1 and enterohemorrhagic Escherichia coli) Guillain-Barré syndrome Particularly likely after Campylobacter infection

TABLE 138-3  Causes of Traveler’s Diarrhea APPROXIMATE PERCENTAGE OF CASES COMMENTS ETIOLOGIC AGENT Bacteria 50–75 Enterotoxigenic Escherichia coli 10–45 Single most important agent Enteroaggregative E. coli 5–35 Emerging enteric pathogen with worldwide distribution Campylobacter jejuni 5–25 More common in Asia Shigella 0–15 Major cause of dysentery Salmonella 0–15 — Others 0–5 Including Aeromonas, Plesiomonas, and Vibrio cholerae Viruses 0–20 Norovirus 0–10 Associated with cruise ships Rotavirus 0–5 Particularly common among children Parasites 0–10 Giardia lamblia 0–5 Affects hikers and campers who drink from freshwater streams Cryptosporidium 0–5 Resistant to chlorine treatment of water sources Entamoeba histolytica <1 — Cyclospora <1 — CHAPTER 138 Other 0–10 Acute food poisoninga 0–5 — No pathogen identified 10–50 — aFor etiologic agents, see Table 138-4. Source: After DR Hill et al: The practice of travel medicine: Guidelines by the Infectious Diseases Society of America. Clin Infect Dis 43:1499, 2006. Acute Infectious Diarrheal Diseases and Bacterial Food Poisoning
for outbreaks of enteric infections. Norovirus, which is highly con­ tagious and robust in surviving on surfaces, is the most common etiologic agent associated with outbreaks of acute gastroenteritis. Other common organisms, often spread by fecal–oral contact in such communities, are Shigella, C. jejuni, and Cryptosporidium. Rotavirus is rarely a cause of pediatric diarrheal outbreaks in the United States since rotavirus vaccination was broadly recommended in 2006. Simi­ larly, hospitals are sites in which enteric infections are concentrated. Diarrhea is one of the most common manifestations of nosocomial infections. C. difficile is the predominant cause of nosocomial diar­ rhea among adults in the United States, and outbreaks of norovirus infection are common in health care settings. Klebsiella oxytoca has been identified as a cause of antibiotic-associated hemorrhagic colitis. Enteropathogenic E. coli has been associated with outbreaks of diarrhea in nurseries for newborns. One-third of elderly patients in chronic-care institutions develop a significant diarrheal illness each year; more than one-half of these cases are caused by cytotoxin-producing C. difficile. Antimicrobial therapy can predispose to pseudomembranous colitis by altering the normal colonic microbiota, which then permits the multi­ plication of C. difficile (Chap. 139). ■ ■AGE Globally, most morbidity and mortality from enteric pathogens involve children <5 years of age. Breast-fed infants are protected from patho­ gens in contaminated food and water and derive some protection from maternal antibodies, but their risk of infection rises dramatically when they begin to eat solid foods. Exposure to rotavirus is universal, with most children experiencing their first infection in the first or second year of life if not vaccinated. Older children and adults are more com­ monly infected with norovirus. Other organisms with higher attack rates among children than among adults include enterotoxigenic, enteropathogenic, and enterohemorrhagic E. coli; Shigella; C. jejuni; and G. lamblia.

■ ■HOST IMMUNE STATUS Immunocompromised hosts are at elevated risk of acute and chronic infectious diarrhea. Individuals with defects in cell-mediated immu­ nity (including those with AIDS) are at particularly high risk of invasive enteropathies, including salmonellosis, listeriosis, and cryp­ tosporidiosis. Individuals with hypogammaglobulinemia are at par­ ticular risk of C. difficile colitis and giardiasis and can develop chronic infections with viral pathogens such as norovirus. Patients with cancer are more likely to develop C. difficile infection due to chemo­ therapy-associated antibiotic exposure and frequent hospitalizations. Infectious diarrhea can be life-threatening in immunocompromised hosts, with complications including persistent infection, bacteremia, and metastatic seeding of infection. Furthermore, dehydration may compromise renal function and increase the toxicity of immunosup­ pressive drugs.

■ ■BACTERIAL FOOD POISONING If the history and the stool examination indicate a noninflammatory etiology of diarrhea and there is evidence of a common-source out­ break, questions concerning the ingestion of specific foods and the time of onset of diarrhea after a meal can provide clues to the bacterial cause of the illness. Potential causes of bacterial food poisoning are shown in Table 138-4. Bacterial disease caused by an enterotoxin elaborated outside the host, such as that due to Staphylococcus aureus or B. cereus, has the shortest incubation period (1–6 h) and generally lasts <12 h. Most cases of staphylococcal food poisoning are caused by contamination from Staphylococcus-infected human carriers. Staphylococci can multiply at a wide range of temperatures; thus, if food is left to cool slowly and remains at room temperature after cooking, the organisms will have the opportunity to form enterotoxin. Outbreaks following picnics where potato salad, mayonnaise, and cream pastries have been served offer classic examples of staphylococcal food poisoning. Diarrhea, nausea, vomiting, and abdominal cramping are common, while fever is rare. PART 5 Infectious Diseases B. cereus can produce either a syndrome with a short incuba­ tion period—the emetic form, mediated by a staphylococcal type of enterotoxin—or one with a longer incubation period (8–16 h)—the diarrheal form, caused by an enterotoxin resembling E. coli LT, in which TABLE 138-4  Bacterial Food Poisoning INCUBATION PERIOD, ORGANISM SYMPTOMS COMMON FOOD SOURCES 1–6 h Staphylococcus aureus Nausea, vomiting, diarrhea Ham, poultry, potato or egg salad, mayonnaise, cream pastries Bacillus cereus Nausea, vomiting, diarrhea Fried rice 8–16 h Clostridium perfringens Abdominal cramps, diarrhea (vomiting rare) Beef, poultry, legumes, gravies B. cereus Abdominal cramps, diarrhea (vomiting rare) Meats, vegetables, dried beans, cereals

16 h Vibrio cholerae Watery diarrhea Shellfish, water Enterotoxigenic Escherichia coli Watery diarrhea Salads, cheese, meats, water Enterohemorrhagic

E. coli Bloody diarrhea Ground beef, roast beef, salami, raw milk, raw vegetables, apple juice Salmonella spp. Inflammatory diarrhea Beef, poultry, eggs, dairy products Campylobacter jejuni Inflammatory diarrhea Poultry, raw milk Shigella spp. Dysentery Potato or egg salad, lettuce, raw vegetables Vibrio parahaemolyticus Dysentery Mollusks, crustaceans

diarrhea and abdominal cramps are characteristic but vomiting is uncommon. The emetic form of B. cereus food poisoning is associated with contaminated fried rice; the organism is common in uncooked rice, and its heat-resistant spores survive boiling. If cooked rice is not refrigerated, the spores can germinate and produce toxin. Frying before serving may not destroy the preformed, heat-stable toxin. Food poisoning due to Clostridium perfringens also has a slightly longer incubation period (8–14 h) and results from the survival of heat-resistant spores in inadequately cooked meat, poultry, or legumes. After ingestion, toxin is produced in the intestinal tract, causing mod­ erately severe abdominal cramps and diarrhea; vomiting is rare, as is fever. The illness is self-limited, rarely lasting >24 h. Not all food poisoning has a bacterial cause. Nonbacterial agents of short-incubation food poisoning include capsaicin, which is found in hot peppers, and a variety of toxins found in fish and shellfish (Chap. 471). ■ ■LABORATORY EVALUATION Many cases of noninflammatory diarrhea are self-limited or can be treated empirically, and in these instances, the clinician may not need to determine a specific etiology. Potentially pathogenic E. coli cannot be distinguished from normal fecal flora by routine culture, and tests to detect enterotoxins are not available in most clinical laboratories. In situations in which cholera is a concern, stool should be cultured on selective media such as thiosulfate–citrate–bile salts–sucrose (TCBS) or tellurite–taurocholate–gelatin (TTG) agar; rapid diagnostic tests are also available. A latex agglutination test has made the rapid detection of rotavirus in stool practical for many laboratories, while reverse-transcriptase polymerase chain reaction (PCR) and specific antigen enzyme immunoassays have been devel­ oped for the identification of norovirus. Stool specimens should be examined by immunofluorescence-based rapid assays, PCR, or (less sensitive) standard microscopy for Giardia cysts or Cryptosporidium if the level of clinical suspicion regarding the involvement of these organisms is high. All patients with fever and evidence of inflammatory diarrhea acquired outside the hospital should be evaluated for Salmonella, Shigella, and Campylobacter. Salmonella and Shigella can be selected on MacConkey agar as non-lactose-fermenting (colorless) colonies or can be grown on Salmonella–Shigella agar or in selenite enrichment broth, both of which inhibit most organisms except these pathogens. Evalua­ tion of nosocomial diarrhea should initially focus on C. difficile; stool culture for other pathogens in the hospital setting is extremely low yield and is not cost-effective. Toxins A and B produced by pathogenic strains of C. difficile can be detected by rapid enzyme immunoassays, latex agglutination tests, or PCR (Chap. 139). Isolation of C. jejuni requires inoculation of fresh stool onto selective growth medium and incubation at 42°C in a microaerophilic atmosphere. In many labora­ tories in the United States, E. coli O157:H7 is among the most common pathogens isolated from visibly bloody stools. Shiga-toxin containing strains of this enterohemorrhagic serotype can be identified by PCR or in specialized laboratories by serotyping, but also can be identified presumptively as lactose-fermenting, indole-positive colonies of sor­ bitol nonfermenters (white colonies) on sorbitol MacConkey plates. If the clinical presentation suggests the possibility of intestinal amebiasis, stool should be examined by a rapid antigen detection assay or by (less sensitive and less specific) microscopy. Multiplex nucleic acid amplifi­ cation methods for detection of many stool pathogens (viral, bacterial, and parasitic) are increasingly being used in clinical microbiology laboratories to decrease the time to detection of a pathogen. These tests are more sensitive and rapid than standard culture methods and may detect multiple pathogens, which may lead to challenges in interpreta­ tion. For bacterial enteric infections, the lack of a microbial isolate prevents determination of antimicrobial susceptibility and typing of strains by public health authorities in order to detect and respond to common-source outbreaks. For this reason, the Centers for Disease Control and Prevention suggests that diagnosis of an enteric bacterial infection by a nucleic acid amplification method should be followed by attempted isolation of the pathogen by culture.

TREATMENT Infectious Diarrhea or Bacterial Food Poisoning In many cases, a specific diagnosis is not necessary or not available to guide treatment. The clinician can proceed with the informa­ tion obtained from the history, stool examination, and evaluation of dehydration severity. Empirical regimens for the treatment of traveler’s diarrhea are listed in Table 138-5. The mainstay of treatment is adequate rehydration. The treat­ ment of cholera and other dehydrating diarrheal diseases was revolutionized by the development and promotion of oral rehydra­ tion solution (ORS), the efficacy of which depends on the fact that glucose-facilitated absorption of sodium and water in the small intestine remains intact in the presence of cholera toxin. The use of ORS has reduced cholera mortality rates from >50% (in untreated cases) to <1%. Several ORS formulas have been developed and tested. Initial preparations were based on the treatment of patients with cholera and included a solution containing 3.5 g of sodium chloride, 2.5 g of sodium bicarbonate (or 2.9 g of sodium citrate), 1.5 g of potassium chloride, and 20 g of glucose (or 40 g of sucrose) per liter of water. Such a preparation can still be used for the treat­ ment of severe cholera. Many causes of secretory diarrhea, however, are associated with less electrolyte loss than occurs in cholera. Beginning in 2002, the World Health Organization recommended a reduced-osmolarity/reduced-salt ORS that is better tolerated and TABLE 138-5  Treatment of Traveler’s Diarrhea on the Basis of Clinical Featuresa CLINICAL SYNDROME SUGGESTED THERAPY Watery diarrhea (no blood in stool, no fever), 1 or 2 unformed stools per day without distressing enteric symptoms Oral fluids (oral rehydration solution, Pedialyte, Lytren, or flavored mineral water) and saltine crackers Watery diarrhea (no blood in stool, no fever), 1 or 2 unformed stools per day with distressing enteric symptoms Bismuth subsalicylate (for adults): 30 mL or 2 tablets (262 mg/tablet) every 30 min for 8 doses; or loperamideb: 4 mg initially followed by 2 mg after passage of each unformed stool, not to exceed 8 tablets (16 mg) per day (prescription dose) or 4 caplets (8 mg) per day (over-the-counter dose); drugs can be taken for 2 days. Antibacterial drugc can be considered in selected circumstances. Dysentery (passage of bloody stools) or fever (>37.8°C) Antibacterial drugc Vomiting, minimal diarrhea Bismuth subsalicylate (for adults; see dose above) Diarrhea in infants (<2 years old) Fluids and electrolytes (oral rehydration solution, Pedialyte, Lytren); continue feeding, especially with breast milk; seek medical attention for moderate dehydration, fever lasting >24 h, bloody stools, or diarrhea lasting more than several days aAll patients should take oral fluids (Pedialyte, Lytren, or flavored mineral water) plus saltine crackers. If diarrhea becomes moderate or severe, if fever persists, or if bloody stools or dehydration develops, the patient should seek medical attention. bLoperamide should not be used by patients with fever or dysentery; its use may prolong diarrhea in patients with infection due to Shigella or other invasive organisms. cThe recommended antibacterial drugs are as follows: If the level of suspicion is low for fluoroquinolone-resistant Campylobacter: Adults: (1) A fluoroquinolone such as ciprofloxacin, 750 mg as a single dose or 500 mg bid for 3 days; levofloxacin, 500 mg as a single dose or 500 mg qd for 3 days; or norfloxacin, 800 mg as a single dose or 400 mg bid for 3 days. (2) Azithromycin, 1000 mg as a single dose or 500 mg qd for 3 days. (3) Rifaximin, 200 mg tid or 400 mg bid for 3 days (not recommended for use in dysentery). Children: Azithromycin, 10 mg/kg on day 1, 5 mg/kg on days 2 and 3 if diarrhea persists. If fluoroquinolone-resistant Campylobacter is suspected (for example, following travel to Southeast Asia): Adults: Azithromycin (at above dose for adults). Children: Same as for children traveling to other areas (see above). Source: After DR Hill et al: The practice of travel medicine: Guidelines by the Infectious Diseases Society of America. Clin Infect Dis 43:1499, 2006.

more effective than classic ORS. This preparation contains 2.6 g of sodium chloride, 2.9 g of trisodium citrate, 1.5 g of potassium chloride, and 13.5 g of glucose (or 27 g of sucrose) per liter of water. ORS formulations containing rice or cereal as the carbohydrate source may be even more effective than glucose-based solutions. Patients who are severely dehydrated, are unable to drink, or in whom vomiting precludes oral therapy should receive IV solutions such as Ringer’s lactate in addition to ORS when the patient can ingest it safely.

Most cases of traveler’s diarrhea (usually due to enterotoxigenic or enteroaggregative E. coli or to Campylobacter) can be treated effectively with rehydration, bismuth subsalicylate, or antiperistal­ tic agents. Antimicrobial agents can shorten the duration of illness from 3–4 days to 24–36 h but may be associated with the acquisi­ tion of multidrug-resistant organisms; their use should therefore be reserved for severe cases. Changes in diet have not been shown to have an impact on the duration of illness, and the efficacy of probi­ otics to hasten recovery continues to be debated. Most individuals who present with dysentery (bloody diarrhea and fever) should be treated empirically with an antimicrobial agent (e.g., a fluoroquino­ lone or a macrolide, depending on local antimicrobial susceptibility patterns) pending diagnostic testing. Individuals with shigellosis should receive a 3- to 7-day course. Patients with severe or pro­ longed Campylobacter infection often benefit from antimicrobial treatment. Because of widespread resistance of Campylobacter to fluoroquinolones, especially in parts of Asia, a macrolide antibiotic such as erythromycin or azithromycin is preferred for this infection. Treatment of salmonellosis must be tailored to the individual patient. Since administration of antimicrobial agents often prolongs intestinal colonization with Salmonella, these drugs are usually reserved for individuals at high risk of complications from dis­ seminated salmonellosis, such as infants, patients with prosthetic devices, patients over age 50, and immunocompromised persons. Antimicrobial agents should not be administered to individuals (especially children) in whom enterohemorrhagic E. coli infection is suspected. Laboratory studies of enterohemorrhagic E. coli strains have demonstrated that many antibiotics induce replication of Shiga toxin–producing lambdoid bacteriophages, thereby significantly increasing toxin production by these strains. Clinical studies have supported these laboratory results, and antibiotics may increase by 20-fold the risk of hemolytic-uremic syndrome and renal failure during enterohemorrhagic E. coli infection. A clinical clue in the diagnosis of the latter infection is bloody diarrhea in a patient with a low-grade fever or who is afebrile. CHAPTER 138 Acute Infectious Diarrheal Diseases and Bacterial Food Poisoning
PROPHYLAXIS Improvements in safe water infrastructure to limit fecal–oral spread of enteric pathogens will be necessary if the prevalence of diarrheal dis­ eases is to be significantly reduced in resource-poor countries. Travelers can reduce their risk of diarrhea by eating only hot, freshly cooked food; by avoiding raw vegetables, salads, and unpeeled fruit; and by drinking only boiled or treated water and avoiding ice. Historically, few travelers to tourist destinations adhere to these dietary restrictions, even after pretravel counseling. Bismuth subsalicylate is an inexpensive agent for the prophylaxis of traveler’s diarrhea; it is taken at a dosage of 2 tablets (525 mg) four times a day. Treatment appears to be effective and safe for up to 3 weeks, but adverse events such as temporary darkening of the tongue, constipation, and tinnitus can occur. A meta-analysis sug­ gests that probiotics may lessen the likelihood of traveler’s diarrhea by ~15%, but further studies are needed. Prophylactic antimicrobial agents, although effective, are not generally recommended for the prevention of traveler’s diarrhea except when travelers are immunosuppressed or have underlying illness that places them at high risk for morbidity from gastrointestinal infection. If prophylaxis is indicated, the nonabsorbed antibiotic rifaximin can be considered. The possibility of exerting a major impact on the worldwide mor­ bidity and mortality associated with diarrheal diseases has led to inten­ sive efforts to develop effective vaccines against common bacterial and