Elizabeth D. Hermsen and Ziba Jalali
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Describe the epidemiology and clinical presentation of the various GI infections.
2. Develop an individualized treatment plan given a patient with each of the GI infections.
3. Understand the impact of resistance on the treatment of the various GI infections.
4. Recognize the effect of immunosuppression on GI infections.
5. Educate patients on appropriate prevention measures.
6. Describe the role of antimicrobial prophylaxis and/or vaccination for GI infections.
KEY CONCEPTS
Rehydration is the foundation of therapy for GI infections.
Blood in the stool indicates the possibility of inflammatory mucosal disease of the colon such as enterohemorrhagic Escherichia coli (EHEC), which is an important cause of bloody diarrhea in the United States.
Traveler’s diarrhea is most commonly caused by bacteria such as Shigella, Salmonella, Campylobacter, and E. coli, although viruses are being recognized increasingly as a significant cause of traveler’s diarrhea as well.
Education of travelers about high-risk food items is the key to the prevention of traveler’s diarrhea.
Nosocomial Clostridium difficile– associated diarrhea (CDAD) is almost always associated with antimicrobial use; therefore, unnecessary and inappropriate antibiotic therapy should be avoided. Almost all antibiotics except aminoglycosides have been associated with CDAD.
Viruses are the most common cause of diarrheal illness in the world. A live, oral vaccine is licensed and recommended for use in infants for the prevention of rotavirus infection.
INTRODUCTION
One of the primary concerns related to GI infection, regardless of the cause, is dehydration, which is the second leading cause of worldwide morbidity and mortality.1 Worldwide, dehydration is especially problematic for children younger than age 5. However, the highest rate of death in the United States occurs among the elderly.1 
Rehydration is the foundation of therapy for GI infections, and oral rehydration therapy (ORT) is usually preferred (Table 76–1).
BACTERIAL INFECTIONS
SHIGELLOSIS
Epidemiology
Shigella causes bacillary dysentery, which refers to diarrheal stool containing pus and blood. Worldwide, there are an estimated 165 million cases of shigellosis annually with 1 million associated deaths.2Shigellosis mostly affects children 6 months to 10 years of age. In the United States, shigellosis is a serious problem in daycare centers and areas with crowded living conditions such as urban centers. Most cases of shigellosis are a result of person-to-person transmission. Shigella transmission from contaminated food and water, although less common, is associated with large outbreaks.
Pathogenesis
Shigellas are nonmotile, gram-negative, nonlactose-fermenting rods and are members of the family Enterobacteriaceae. There are four species of Shigella: S. dysenteriae (serogroup A), S. flexneri (serogroup B), S. boydii (serogroup C), and S. sonnei (serogroup D). Infection with Shigella occurs after ingestion of as few as 10 to 100 organisms.3 This low dose of organisms probably explains the person-to-person spread and the high secondary attack rate when an index case is introduced into a family.
Shigella strains invade intestinal epithelial cells with subsequent multiplication, inflammation, and destruction.4 The organism infects the superficial layer of the gut, rarely penetrates beyond the mucosa, and seldom invades the bloodstream. However, bacteremia can occur in malnourished children and immunocompromised patients.
Table 76–1 Clinical Assessment of Degree of Dehydration in Children Based on Percentage of Body Weight Loss
Clinical Presentation and Diagnosis of Shigellosis
• Biphasic illness
• Early—high fever, watery diarrhea without blood
• Later—after approximately 48 hours, colitis develops with urgency, tenesmus, and dysentery.
• Low-grade fever
• More frequent small-volume stools (“fractional stools”)
• Abdominal cramping
• Major complications of shigellosis include
• Proctitis or rectal prolapse (infants and young children)
• Toxic megacolon (primarily in the setting of S. dysenteriae 1 infection)
• Intestinal obstruction
• Colonic perforation
• Bacteremia (more common in children)
• Metabolic disturbances
• Leukemoid reaction
• Neurologic disease
• Reactive arthritis or Reiter’s syndrome
• Hemolytic-uremic syndrome (HUS)
• Microscopic examination of stool is extremely useful and reveals multiple polymorphonuclear leukocytes and red blood cells (RBCs). Diagnosis is usually confirmed by stool culture
Treatment and Monitoring
Although infection with Shigella generally is self-limited and responds to supportive care, antibiotic therapy is indicated because it shortens the duration of illness and shedding and consequently reduces the risk of transmission. Antibiotic resistance is a worldwide concern and growing problem for enteric bacterial pathogens. The treatment of choice is a fluoroquinolone when the antibiotic susceptibility of the organism is unknown5 (Table 76–2). Cephalosporins or azithromycin can be used in the management of pediatric shigellosis. Rifaximin is likely to be effective in the treatment of milder forms of shigellosis and is effective at preventing infection with S. flexneri.6Antimotility agents are not recommended because they can worsen dysentery and may be related to the development of toxic megacolon. No vaccines are licensed currently for the prevention of shigellosis.
Patient Encounter 1
A 55-year-old man presents with headache, fever, abdominal pain, and bloody diarrhea for 48 hours. He states that his wife had similar symptoms several days ago. His stool Gram stain reveals the presence of leukocytes, and his WBC is 52 × 103/mm3 (52 × 109/L).
What test should you send?
Stool culture showed many Shigella sonnei.
What treatment do you recommend?
Table 76–2 Antibacterial Therapy for Shigellosis
SALMONELLOSIS
Epidemiology
Salmonella typhi and Salmonella paratyphi, which cause typhoid fever, have high host specificity for humans. In the United States, typhoid fever has become less prevalent and is associated primarily with international travel, especially to developing countries. Nontyphoidal Salmonella are important causes of reportable food-borne infection. There are an estimated 1.4 million cases of nontyphoid Salmonellaillness annually in the United States.7 The highest incidence is in those younger than 1 year of age and older than 65 years of age or in those with HIV/AIDS. Outbreaks of intestinal salmonellosis have been associated with unpasteurized orange juice, tomatoes, cantaloupe, alfalfa sprouts, and cilantro, among others. Exotic pets, especially reptiles (e.g., snakes, turtles, and iguanas), are an increasing source of human salmonellosis, accounting for 3% to 5% of all cases.
Risk factors for salmonellosis include extremes of age, alteration of the endogenous bowel flora of the intestine (e.g., as a result of antimicrobial therapy or surgery), diabetes, malignancy, rheumatologic disorders, HIV infection, and therapeutic immunosuppression of all types.
Pathogenesis
Salmonella are motile, nonlactose-fermenting, gram-negative bacilli. In salmonellosis, the organisms penetrate the epithelial lining to the lamina propia with production of diffuse inflammation. The distal ileum and colon are sites of infection.
Treatment and Monitoring
Gastroenteritis
Salmonella gastroenteritis is usually self-limited, and antibiotics have no proven value. Patients respond well to ORT. Symptoms typically diminish in 3 to 7 days without sequelae. Antibiotic use may result in a higher rate of chronic carriage and relapse. Antimicrobial use should be limited to pre-emptive therapy among patients at higher risk for extraintestinal spread or invasive disease (Table 76–3). Antimotility agents should not be used.
Enteric Fever
The current drug of choice for typhoid fever is a fluoroquinolone, such as ciprofloxacin. The recommended adult dose of ciprofloxacin for uncomplicated typhoid is 500 mg orally twice daily for 5 to 7 days. Drug resistance is a recognized problem in the Indian subcontinent, Southeast Asia, Mexico, the Arabian Gulf, and Africa. All S. typhi isolates should be screened for nalidixic acid and fluoroquinolone resistance. If nalidixic acid resistance is present, the patient should be given higher doses of ciprofloxacin or ofloxacin (10 mg/kg twice daily) for 10 to 14 days. A third-generation cephalosporin and azithromycin (1,000 mg once on day 1 followed by 5 days of 500 mg daily) are alternative agents for S. typhi strains, with minimum inhibitory concentration (MIC) values for ciprofloxacin of 2 mcg/mL or greater.8 Children may receive intravenous ceftriaxone 75 mg/kg daily or oral azithromycin 20 mg/kg (up to 1 g) daily, although relapse rates are higher with ceftriaxone.
Table 76–3 Antimicrobial Indications for Nontyphoidal Salmonellosis
|
Age 3 months or less; 65 years or more |
Clinical Presentation and Diagnosis of Salmonellosis
Gastroenteritis
• Onset 8 to 48 hours after ingestion of contaminated food.
• Fever, diarrhea, and cramping
• Stools are loose, of moderate volume, and without blood.
• Headache, myalgias, and other systemic symptoms can occur.
• Diagnosis relies on isolation of the organism from stool or ingested food.
• Certain underlying conditions (e.g., AIDS, inflammatory bowel disease, and prior gastric surgery) predispose the patient to more severe disease.
Enteric Fever
• Febrile illness 5 to 21 days after ingestion of contaminated food or water
• Chills, diaphoresis, headache, anorexia, cough, weakness, sore throat, dizziness, and muscle pains are frequently present before the onset of fever.
• Diarrhea is an early symptom and occurs only in 50% of cases. Intestinal hemorrhage or perforation, leukopenia, anemia, and subclinical disseminated intravascular coagulopathy may be seen.
• Culture of stool, blood, or bone marrow for Salmonella species is helpful.
Vascular Infection and Bacteremia
S. choleraesuis and S. dublin are the most common causative organisms. The risk of bacteremia is greater for infants, the elderly, and the immunocompromised.
Localized Infections
Localized infections occur in 5% to 10% of cases with Salmonella bacteremia. Sites for extraintestinal complications of salmonellosis include endocarditis, arteritis, central nervous system, lung, bone, joints, muscle/soft tissue, splenic, and genitourinary.
Chronic Carriers
The chronic carrier state, defined as positive stool or urine cultures for more than 12 months, develops in 1% to 4% of adults with typhoid fever. Persistence of the organism, in many cases, is due to billiary tract carriage, and the frequency of chronic carriage is higher in persons with biliary abnormalities.
Salmonella and HIV Infection
Salmonella is more likely to cause severe invasive infection in the HIV-infected population. Recurrent nontyphoidal Salmonella bacteremia is an AIDS-defining illness.
Patients with complicated typhoid fever (i.e., metastatic foci, ileal perforation, etc.) should receive parenteral therapy with ciprofloxacin 400 mg twice daily or ceftriaxone 2,000 mg once daily. Antimicrobial therapy can be completed with an oral agent after initial control of the symptoms of typhoid fever. In persons with AIDS and a first episode of Salmonella bacteremia, a longer duration of antibiotic therapy (1–2 weeks of parenteral therapy followed by 4 weeks of oral fluoroquinolone) is recommended to prevent relapse of bacteremia.
Three typhoid vaccines are available currently for use in the United States: (a) an oral live-attenuated vaccine (Vivotif Berna-TM vaccine, Swiss Serum and Vaccine Institute), (b) a parenteral heat-phenol-inactivated vaccine (Typhoid Vaccine, Wyeth-Ayerst), and (c) a parenteral capsular polysaccharide vaccine (Typhim Vi, Pasteur Merieux). Immunization is recommended only for travelers going to endemic areas such as Latin America, Asia, and Africa; household contacts of a chronic carrier; and laboratory personnel who frequently work with S. typhi.9
Chronic Carriers
In patients with normal gallbladder function, effective agents for eradication of chronic carriage include amoxicillin (3 g divided three times a day in adults for 3 months), trimethoprim-sulfamethoxazole (one double-strength tablet twice a day for 3 months), and ciprofloxacin (750 mg twice daily for 4 weeks). In patients with anatomic abnormalities, such as biliary or kidney stones, surgery combined with antibiotic therapy is indicated.
Patient Encounter 2
A 45-year-old Hispanic man with AIDS presents to the emergency department (ED) with fever, nausea, two episodes of vomiting, abdominal pain, and nonbloody diarrhea for 2 days. He reports that his diarrhea is improving, but he developed fever and chills a few hours before he came to the ED. Other history is noncontributory. His physical examination is positive for fever and diffuse abdominal pain. An abdominal ultrasound did not show any abnormal findings. Two sets of blood cultures were sent. He was admitted to the hospital.
What GI pathogen(s) do you suspect in this patient given that his blood cultures came back positive for nontyphoidal Salmonella?
What treatment do you recommend? Do any further tests need to be performed before you can decide on treatment recommendation? Are there any special considerations owing to this patient’s HIV infection?
CAMPYLOBACTERIOSIS
Epidemiology
Campylobacter jejuni is the most commonly identified bacterial cause of diarrhea worldwide. The organism accounts for 2.1 to 2.4 million cases of illness in the United States each year. Risk factors for Campylobacter infection include consumption of chicken, sausage, red meat, and contaminated water; foreign travel; receipt of an antimicrobial agent; household exposure to chickens; and contact with pets (especially birds and cats). Between 25% and 50% of C. jejuni infections in the United States appear to be related to chicken exposure or consumption.
The age and sex distributions of Campylobacter infections are unique among bacterial enteric pathogens. In developed countries, there are two age peaks: younger than 1 year of age and 15 to 44 years of age. There is a mild male predominance among infected persons. The reason for this distinct age and sex distribution remains unknown. The epidemiology of Campylobacter infections is quite different in developing countries; Campylobacter diarrhea is primarily a pediatric disease in developing countries.
Pathogenesis
Campylobacter spp. are gram-negative bacilli that have a curved or spiral shape. Campylobacter are sensitive to stomach acidity; as a result, diseases or medications that buffer gastric acidity may increase the risk of infection. The infectious dose for C. jejuni is low, similar to that for Salmonella spp. After an incubation period, infection is established in the jejunum, ileum, colon, and rectum.
Treatment and Monitoring
Hydration and electrolyte balance, often with ORT, are the cornerstone of treatment. The specific circumstances for which antibiotics should be considered include high fevers, bloody stools, symptoms longer than 1 week, pregnancy, infection with HIV, and other immunocompromised hosts.
Until a few years ago, fluoroquinolones were the drug of choice for campylobacteriosis. However, a major problem among Campylobacter strains is growing resistance, occurring worldwide. Fluoroquinolone resistance in human isolates of C. jejuni in the United States occurs at a rate of 18%, and resistance levels in Barcelona and Thailand are over 80%. Fluoroquinolones should not be used unless susceptibility is confirmed.
Macrolides are considered the optimal drug class for treatment of Campylobacter infections. The rate of resistance of Campylobacter to macrolides remains low. Other advantages include ease of administration, low cost, lack of major toxicity, and narrow spectrum of activity.10 The recommended dosage of azithromycin for adults is 500 mg orally daily for 3 days and for erythromycin is 500 mg orally four times daily for 5 days. The recommended regimen for children is azithromycin 20 mg/kg (up to 1 g) orally daily. For very ill patients, treatment with gentamicin, imipenem, cefotaxime, or chloramphenicol is indicated, but susceptibility tests should be performed.
Clinical Presentation and Diagnosis of Campylobacteriosis
• Incubation period of 1 to 7 days
• Abdominal cramps, fever, and diarrhea
• Dysentery is seen in approximately 50% of cases.
• Diarrhea is either loose and watery or grossly bloody.
• Some patients present mainly with abdominal cramps and pain and minimal diarrhea.
• Fecal leukocytes and red blood cells (RBCs) are detected in the stools of 75% of infected individuals. Diagnosis of Campylobacter is established by stool culture.
• Extraintestinal C. jejuni infection, including septic arthritis, cholecystitis, pancreatitis, meningitis, endocarditis, osteomyelitis, and neonatal sepsis, can present in three different ways:
• Transient bacteremia with acute campylobacter enteritis in a normal host with benign course
• Sustained bacteremia or deep focus of infection in a previously normal host that responds to antimicrobial therapy
• Sustained bacteremia or deep infection in a compromised host
• The most important postinfectious complication of C. jejuni is Guillain-Barré syndrome (GBS). The risk of developing GBS is very small (less than one case of GBS per 1,000 C. jejuni). GBS typically occurs 1 to 3 weeks after diarrhea.
Patient Encounter 3
A 55-year-old woman presents with a 3-day history of high fevers, headaches, and diarrhea. She reports having 7 to 10 loose watery stools per day. She had chicken for lunch in a local restaurant last week, which she really liked. Otherwise, she denies any unusual foods, any recent travel, or any sick contacts. She doesn’t have any pets at home. She is able to keep food down. The only positive physical findings are diffuse abdominal tenderness, fever, and high blood pressure. Fecal leukocytes were negative. A stool culture was sent, which showed moderate Campylobacter jejuni.
How would you treat this patient?
ENTEROHEMORRHAGIC ESCHERICHIA COLI
Epidemiology
Enterohemorrhagic E. coli (EHEC) are the pathogenic subgroup of shiga toxin-producing E. coli (STEC). Acute hemorrhagic colitis has been associated mainly with the O157:H7 serotype. This serotype has been responsible for larger outbreaks of infection, has higher rates of complications, and appears to be more pathogenic than non-EHEC STEC strains. The spectrum of disease associated with E. coli O157:H7 includes bloody diarrhea, which is seen in as many as 95% of patients, nonbloody diarrhea, HUS, and thrombotic thrombocytopenic purpura.
Approximately 70,000 cases of EHEC illness occur every year in the United States. The highest incidence is in patients aged 5 to 9 years and 50 to 59 years. Outbreaks of diarrhea due to E. coli O157:H7 and other STECs have occurred from contaminated beef, classically hamburgers served at fast-food chains, unpasteurized milk and other dairy products, vegetables (e.g., alfalfa sprouts, coleslaw, and lettuce), and apple juice. The most important reservoir for E. coli O157:H7 is the GI tract of cattle. Person-to-person transmission is also possible because of the low infectious dose required. Swimming in infant pools or contaminated lakes or drinking municipal water also appears to be a risk factor. The incidence of diagnosed E. coli O157:H7 infections in the United States are greater among rural than urban populations, and E. coli O157:H7 infections occur in summer and autumn.
Clinical Presentation and Diagnosis of EHEC
• Incubation period of 3 to 5 days
• Bloody stools
• Fever usually absent
• Leukocytosis
• Abdominal tenderness
• HUS in 2% to 10% of patients (especially children 1–5 years of age and the elderly in nursing homes); develops on average 1 week after the onset of diarrhea.
• EHEC belonging to serotype 0157:H7 characteristically do not ferment sorbitol, whereas more than 70% of intestinal floral E. coli do. To properly screen EHEC strains in cases of diarrhea, stool should be placed on special sorbitol-MacConkey agar. Colonies of E. coli 0157:H7, which do not ferment the sorbitol, can be identified readily and confirmed by serotyping with specific antisera. In addition, stool should be tested directly for the presence of Stx I and II by enzyme immunoassay (EIA).
Patient Encounter 4
A very pleasant 73-year-old white female with a 48-hour history of hematochezia and hemoptysis presents to the ED. She denies any recent travel, exotic foods, raw foods, or sick contacts. She does note that she ate cold-cut sandwiches at a fundraiser approximately 3 days before her symptoms started. She also noticed that she has three friends who developed bloody diarrhea who also ate at this same fundraiser. She denies any fevers, shakes, chills, cough, sore throat, shortness of breath, chest pain, nausea or vomiting, dysuria, hematuria, edema, or night sweats. On her initial presentation, she had a CT that showed pan-colitis and terminal ileitis. She was started on antibiotic therapy including ciprofloxacin and metronidazole. Fecal leukocytes were negative. A stool culture was sent and was positive for Stx. The final culture result was positive for Escherichia coli O157:H7.
What would be your next step for this patient?
Two days later, she develops acute kidney injury and thrombocytopenia. What is the most likely diagnosis?
Pathogenesis
The infectious dose of EHEC is very low, between 1 and 100 colony-forming units (CFUs).11 The two major virulence factors for EHEC are the production of two Shiga-like cytotoxins (Shiga toxin [Stx] I and II) and adhesion-causing attachment-effacement (A/E) lesions. These Stx cytotoxins are responsible for vascular damage and systemic effects such as HUS. Adhesion mediates initial attachment of EHEC to intestinal epithelial cells. Following attachment, these organisms produce A/E lesions on individual intestinal epithelial cells. A/E lesions infect the small or large intestine and cause diarrhea.
Treatment and Monitoring
The only recommended treatment of EHEC infection is supportive, including fluid and electrolyte replacement, often in the form of ORT. Most illnesses resolve in 5 to 7 days. Patients should be monitored for the development of HUS. Antibiotics are currently contraindicated because they can induce the expression and release of toxin. Antimotility agents should be avoided because they may delay clearance of the pathogen and toxin. This, in turn, may increase the risk of systemic complications.
Proper cooking of foods is essential. Supervision of hand washing by children in daycare centers and exclusion of symptomatic children may reduce person-to-person spread.
CHOLERA
Epidemiology
Cholera, the first reportable disease, is endemic in South Asia, particularly in the Ganges delta region.12 The biotypes of Vibrio cholerae responsible for pandemics are serogroup O1 (El Tor) and serogroup O139.13,14 Although not associated with pandemics, serogroups O75 and O141 have caused small outbreaks of severe diarrhea in the United States. Cholera can be transmitted by water or by food contaminated with contaminated water, particularly undercooked seafood. V. cholerae grows well in warm temperatures, causing marked seasonality in the incidence of cholera.12
People of blood type O are more susceptible to El For vibrios than people of other blood types.15 Inoculum size affects the likelihood and severity of cholera infection. The infectious dose is lower in patients who are taking antacids owing to the neutralization of gastric acid.16
Pathogenesis
V. cholerae is a gram-negative bacillus. Vibrios pass through the stomach to colonize the upper small intestine. Vibrios have filamentous protein extensions that attach to receptors on the intestinal mucosa, and their motility assists with penetration of the mucus layer.12 The cholera enterotoxin consists of two subunits, one of which (subunit A) is transported into the cells and causes an increase in cyclic adenosine mono-phosphate (cAMP), which leads to a deluge of fluid into the small intestine.17 This large volume of fluid results in the watery diarrhea that is characteristic of cholera. The stools are an electrolyte-rich isotonic fluid, the loss of which results in blood volume depletion followed by low blood pressure and shock.12 Of note, the diarrheal fluid is highly infectious.
Treatment and Monitoring
The cornerstone of cholera treatment is fluid replacement. Without treatment, the case-fatality rate for severe cholera is approximately 50%. For cholera, rice-based ORT is better than glucose-based ORT because it reduces the number of stools.18 Patients with significant disease should receive a short antibiotic course to shorten the duration of illness and decrease the number of stools. Azithromycin 1 g (20 mg/kg for children) orally given once is the regimen of choice. Ciprofloxacin 1 g (20 mg/kg for children) orally given once is an alternative but is associated with higher failure rates. Ciprofloxacin is associated with joint damage in children and should not be given to children under 18 years of age unless they cannot be treated with other antibiotics. Antibiotic resistance has been documented in V. choleraesince 1977.12 Antibiotic prophylaxis is not warranted.
Clinical Presentation and Diagnosis of Cholera12
• Incubation period of 18 hours to 5 days
• Abrupt onset of watery diarrhea and vomiting
• Large volumes of rice-water stools
• Dehydration, may be severe. Patients suffering from severe dehydration owing to rapid fluid loss are at risk for death within several hours of disease onset.
• Severe muscle cramps in extremities owing to the electrolyte imbalance are caused by the fluid loss. These cramps should resolve with treatment.
• Metabolic acidosis
The main prevention strategies include ensuring a safe water supply and safe food preparation, improving sanitation, and patient education. Several oral vaccines are in development, and two are available in countries outside the United States.19–24 However, these vaccines do not provide protection against all cases of cholera because the immunity may be overcome by high inocula.12
TRAVELER’S DIARRHEA
Epidemiology
Traveler’s diarrhea occurs commonly when visitors from developed countries travel to developing countries. Over 50 million people are at risk for traveler’s diarrhea each year.25 Traveler’s diarrhea can occur following the consumption of food or water contaminated with bacteria, viruses, or parasites. Bacteria such as Shigella, Salmonella, Campylobacter, and E. coli are responsible for 60% to 85% of the traveler’s diarrhea cases.25 Noroviruses are being recognized increasingly as a significant cause of traveler’s diarrhea as well.26
Risky foods include tap water; uncooked foods, including seafood, fruits, and vegetables; and foods that are stored inadequately, particularly buffet-style meals. Additionally, alcohol consumption of more than five drinks per day has been demonstrated to be a risk factor, especially in males.27 Education about the types of foods to avoid during travel can be an effective method of prevention.
Pathogenesis
Refer to the specific microorganism sections of this chapter for pathogenesis information.
Treatment and Monitoring
The goal of treatment is to maintain hydration and functional status to prevent disruption of travel plans. For travelers with mild cases of diarrhea, ORT is often all that is needed. However, antibiotics are effective at reducing the duration of illness. The use of trimethoprim-sulfamethoxazole has fallen out of favor because of the development of resistance in many regions. In general, fluoroquinolones, specifically levofloxacin (500 mg once daily for adults) and ciprofloxacin (500 mg twice daily for adults), are the drugs of choice for traveler’s diarrhea. A 24-hour regimen can be used unless the traveler has a fever or bloody stools, in which case a 3-day regimen is necessary.25Alternatives to fluoroquinolones should be used in Asia, where resistance is high among Campylobacter. Azithromycin, as a single adult dose of 1,000 mg, represents an alternative to the fluoroquinolone class.25 The recommended regimen for children is azithromycin 5 to 10 mg/kg orally as a single dose. Additionally, the FDA recently approved rifaximin for the treatment of traveler’s diarrhea at an adult dose of 200 mg three times daily for 3 days; rifaximin is not indicated for use in children under the age of 12 years. Rifaximin is not effective against C. jejuni, and efficacy has not been documented against Salmonella.
Clinical Presentation and Diagnosis of Traveler Diarrhea
• Frequent, loose stools
• Associated with nausea and vomiting
• Abdominal pain
• Fecal urgency
• Dysentery
• Signs and symptoms related to specific causative pathogen
Although antimotility agents are effective at shortening the duration of illness, they do not eradicate microorganisms and should not be used in moderate to severe cases with systemic symptoms unless in combination with an antibiotic. The combination of an antimotility agent and an antibiotic can reduce the duration of illness to a few hours.25
Education of travelers about high-risk food items is the key to the prevention of traveler’s diarrhea. Slogans such as “Peel it, boil it, cook it, or forget it” can help to remind travelers of the foods that may be contaminated. Prophylaxis of traveler’s diarrhea with antibiotics is effective but should be restricted to individuals who have a repeated history of traveler’s diarrhea; cannot afford to make travel alterations (e.g., business trip, competitors, or politicians); have a predisposing factor for traveler’s diarrhea, such as achlorhydria, gastrectomy, or inflammatory bowel disease; or are immunosuppressed.25 The use of antibiotics for prophylaxis is not widely recommended because of the selective pressure for the development of resistance, adverse effects, effect on the normal flora of the GI tract, and cost. The fluoroquinolones are used when prophylaxis is necessary. However, rifaximin may represent an ideal option for prophylaxis of traveler’s diarrhea, with virtually no systemic absorption and an excellent safety profile, although it is not approved by the FDA for this indication. Bismuth subsalicylate 525 mg one to four times daily is also effective for traveler’s diarrhea prophylaxis. No effective vaccines exist for traveler’s diarrhea.
CLOSTRIDIUM DIFFICILE–ASSOCIATED DIARRHEA
Epidemiology
C. difficile is the leading cause of nosocomial enteric infection. Notably, the incidence and severity of illness associated with C. difficile has been increasing. C. difficile toxins can be found in the stool of 15% to 25% of patients with antibiotic-associated diarrhea (AAD) and more than 95% of patients with pseudomembranous colitis.28 More than 90% of health care–associated clostridium difficile–associated diarrhea (CDAD) occur after or during antimicrobial therapy. Clindamycin, cephalosporins, and penicillins are the antibiotics most associated with CDAD, but almost all antimicrobial agents except aminoglycosides have been associated with CDAD.29 Fluoroquinolones are strongly associated with CDAD.30,31 Other risk factors for CDAD include increasing age, severe underlying disease, nonsurgical GI procedures, presence of a nasogastric tube, receipt of antiulcer medications, hospitalization in an intensive care unit (ICU), long duration of hospital stay, long duration of antibiotic, and receiving multiple antibiotics.32
The incidence of community-associated C. difficile infection (defined as occurring in patients not hospitalized in the year prior to diagnosis) is increasing.33 In addition to antibiotic use, community-associated C. difficile cases are associated with the use of gastric acid-suppressive agents (e.g., proton pump inhibitors and H2-receptor antagonists).
Pathogenesis
C. difficile is spread by the fecal-oral route, and patient-to-patient transmission has been documented. C. difficile is a gram-positive, spore-forming anaerobe. The organism is ingested either as the vegetative form or spores, which can survive for long periods in the environment and can traverse the acidic stomach. In the small intestine, spores germinate into the vegetative form. In the large intestine, CDAD can develop if the normal flora is disrupted by antibiotic therapy. Toxin production is essential for disease to occur. The main virulence factor for disease related to C. difficile is the production of toxins A and B. These toxins are responsible for inflammation, fluid and mucus secretion, and mucosal damage, which lead to diarrhea or colitis.
Treatment and Monitoring
Stopping the inciting antibiotic is the most important step in the initial treatment of CDAD. If stopping antibiotic therapy is not effective or not practical, antimicrobial therapy directed specifically against C. difficile should be given for 10 days. Oral metronidazole (adult dosing: 500 mg three times daily or 250 mg four times daily; pediatric dosing: 30 mg/kg/day divided four times daily, not to exceed 4 g/day) and oral vancomycin (adult dosing: 125 mg four times daily; pediatric dosing: 40 mg/kg/day divided four times daily, not to exceed 2 g/day) have similar rates of efficacy, but metronidazole is considered the drug of choice for most cases because of cost and concerns regarding the emergence of vancomycin-resistant enterococcus (VRE). Rifaximin and nitazoxanide have demonstrated the potential for treatment of CDAD, although further study is recommended.
Severe disease occurs when patients with CDAD also have marked leukocytosis and/or new onset renal insufficiency. Severe complicated disease is defined as severe disease plus the presence of colitis complications, such as sepsis, volume depletion, electrolyte imbalance, hypotension, paralytic ileus, and toxic megacolon. Patients with signs of severe disease should receive oral vancomycin as initial therapy. Severe complicated disease should be treated with a combination of oral vancomycin and intravenous metronidazole. Surgical intervention may be indicated and lifesaving, particularly in cases complicated by toxic megacolon or colonic perforation.
Clinical Presentation and Diagnosis of CDAD
• Symptoms can start as early as the first day of antimicrobial therapy or several weeks after antibiotic therapy is completed.
• Asymptomatic carriage
• Diarrhea
• Acute watery diarrhea with lower abdominal pain, lowgrade fever, and mild or absent leukocytosis
• Mild, with only three or four loose watery stools per day
• C. difficile toxins are present in stool, but sigmoidoscopic examination is normal.
• Colitis
• Profuse, watery diarrhea with 5 to 15 bowel movements per day, abdominal pain, abdominal distention, nausea, and anorexia
• Left or right lower quadrant abdominal pain and cramps that are relieved by passage of diarrhea.
• Dehydration and low-grade fever
• Sigmoidoscopic examination may reveal a nonspecific diffuse or patchy erythematous colitis without pseudomembranes.
• Pseudomembranous colitis: Same symptoms as colitis, but sigmoidoscopic examination reveals a characteristic membrane with adherent yellow or off-white plaques, usually in distal colon.
• Toxic megacolon: Suggested by acute dilation of the colon to a diameter greater than 6 cm, associated systemic toxicity, and the absence of mechanical obstruction. It carries a high mortality rate.
• Fulminant colitis: Acute abdomen and systemic symptoms such as fever, tachycardia, dehydration, and hypotension. Some patients have marked leukocytosis (up to 40 × 103 white blood cells/mm3 [40 × 109/L]). Diarrhea is usually prominent but may not occur in patients with paralytic ileus and toxic megacolon.
• Relapsing colitis
• Risk factors include increased age, recent abdominal surgery, increased number of C. difficile diarrheal episodes, and leukocytosis.
• 12% to 24% of patients develop a second episode of CDAD within 2 months of the initial diagnosis.
• In most instances, C. difficile toxin testing of a single stool specimen effectively establishes the diagnosis. Various enzyme-linked immunosorbent assay (ELISA) kits are available to detect toxin A or toxin B or both. Those that detect both toxin A and B are preferred. Repeated testing can boost sensitivity.
• Leukocytosis, hypoalbuminemia, and fecal leukocytes are nonspecific but suggestive of C. difficile infection.
• In selected patients, sigmoidoscopy, colonoscopy, or abdominal CT scan can provide useful diagnostic information.
Patient Encounter 5
A 70-year-old man presents to the ED because of diffuse abdominal pain and nonbloody diarrhea. One day earlier he had been discharged from the hospital, where he had received ceftriaxone and levofloxacin for 7 days for an upper respiratory infection. Soon after going home, he passed numerous liquid brown stools. A few hours later, the patient became disoriented, and an ambulance was called. His medical history is unremarkable. Laboratory values: WBC count 50 × 103/mm3 (50 × 109/L)/mm3, hematocrit 43%, sodium 125 mEq/L (125 mmol/L), potassium 5.6 mEq/L (5.6 mmol/L), CO2 14 mEq/L (14 mmol/L), and metabolic acidosis. An abdominal radiograph series show no evidence of obstruction. The patient was admitted to the hospital.
What GI disease do you suspect based on this information? From your suspicion, what diagnostic tests and treatment would you recommend for this patient?
In the hospital, he receives fluids and vancomycin 125 mg orally four times daily. Stool was sent for C. difficile toxin assay, which came back positive. The patient continues to have abdominal pain but no bowel movement. On day 3 of hospitalization, his abdomen is distended with diffuse pain. His WBC count remains elevated. A CT scan of the abdomen showed colonic dilation to greater than 6 cm. The patient became febrile and hypotensive, requiring multiple pharmacologic support for hypotension.
What are this patient’s risk factors for Clostridium difficile–associated diarrhea (CDAD)?
What do these new findings suggest?
How does this progression change your treatment recommendations?
In circumstances where oral therapy cannot be given, intravenous metronidazole (500 mg every 6–8 hours in adults), vancomycin retention enemas (500 mg every 4–8 hours in adults), or vancomycin via colonic catheter should be considered.34 Antiperistaltic agents should not be given because the use of these agents is associated with the development of toxic megacolon.
Therapeutic response should be based on clinical signs and symptoms. A repeat toxin assay as a “test of cure” is not recommended because some patients may remain colonized with this organism following recovery. Treatment of asymptomatic colonized patients is not recommended as an infection-control measurement.
Relapse is suggested by the returning of symptoms 3 to 21 days after stopping metronidazole or vancomycin. Since antibiotic resistance is not a factor in relapse, most relapses usually respond to another course of either metronidazole or vancomycin. Currently, metronidazole is recommended for treatment of the first recurrence, while vancomycin pulse dosing (125 mg orally every 3 days for 3 weeks) or tapered dosing (125 mg orally four times daily for 10–14 days, then 125 mg orally twice daily for 7 days, then 125 mg orally daily for 7 days) is recommended for treatment of subsequent recurrences.
Vigilant hand washing and isolation precautions are keys to controlling C. difficile. Use of antimicrobial hand gel instead of soap and water is not a recommended alternative for patients infected with C. difficile.
PARASITIC INFECTIONS
Please refer to Chapter 75 for information regarding giardiasis.
CRYPTOSPORIDIOSIS
Epidemiology
Cryptosporidiosis has been recognized as a human disease since the 1970s, with increasing importance in the 1980s and 1990s because of its relationship with HIV/AIDS. Cryptosporidium accounts for 2.2% and 6.1% of diarrhea cases in immunocompetent people in developed and developing countries, respectively.35 These percentages increase to 7% and 12% in children in developed and developing countries, respectively, and to 14% and 24% in immunocompromised persons in developed and developing countries, respectively.35
Infection is spread person-to-person, usually via the fecal-oral route; by animals, particularly cattle and sheep; and through the environment, especially water. People at increased risk of contracting cryptosporidiosis include household and family contacts and sexual partners of someone with the disease, health care workers, daycare workers, users of public swimming areas, and people traveling to regions of high endemicity.35
Clinical Presentation and Diagnosis of Cryptosporidiosis35,36
General
• 7- to 10-day incubation period
• Profuse, watery diarrhea with mucus but not blood or leukocytes that lasts for approximately 2 weeks
• Nausea, vomiting, and abdominal cramps often accompany the diarrhea.
• Fever may be present.
• Simplest method of diagnosis is detection of oocysts by modified acid-fast staining of a stool specimen. Standard ova and parasite test does not include Cryptosporidium.
Immunocompetent
• May manifest as asymptomatic disease, acute diarrhea, or persistent diarrhea lasting for several weeks
• Usually self-limiting
Immunocompromised
• May manifest as asymptomatic disease; transient infection for less than 2 months; chronic diarrhea lasting at least 2 months, or fulminant infection, with at least 2 L of watery stool per day
• Asymptomatic disease more common in those with a CD4+ cell count greater than 200 cells/mm3, and fulminant infection more common in those with a CD4+ cell count of less than 50 cells/mm3
Pathogenesis
Cryptosporidium is an intracellular protozoan parasite that is capable of completing its entire life cycle within one host. Humans become infected on ingestion of the oocysts, and autoinfection and persistent infections are possible owing to repeated life cycles within the GI tract.35 As few as 10 to 100 oocysts can cause infection.35
Treatment and Monitoring
There is no antimicrobial available that is effective at consistently eradicating Cryptosporidium, particularly in immunocompromised hosts. In general, immunocompetent persons and those with asymptomatic infection do not require antimicrobial therapy. In patients with HIV/AIDS, the optimal therapy is restoration of immune function through the use of antiretroviral therapy (ART). In persons in whom antimicrobial therapy is deemed necessary or in HIV/AIDS patients in whom ART is ineffective, a combination of an antimicrobial and an antidiarrheal agent is recommended.35 Azithromycin and clarithromycin have shown some treatment success for cryptosporidiosis, even in HIV-positive patients.36 However, the most promising agent is nitazoxanide, which is approved by the FDA for the treatment of cryptosporidiosis in adults and children. In randomized, placebo-controlled trials, nitazoxanide has demonstrated efficacy in cryptosporidiosis in immunocompetent persons, malnourished children, and HIV/AIDS patients with CD4+ cell counts above 50 cells/mm3.37 Limited evidence suggests that patients with CD4+ cell counts of less than 50 cells/mm3 may benefit from higher doses, longer durations, or both.37
Patient Encounter 6
A 35-year-old man with a past medical history significant for recent kidney transplant presents with diarrhea for one month. He reports 4 to 5 watery stools per day. He also complains of abdominal pain and weight loss. He denies any fever, nausea, and vomiting. Stool studies including fecal leukocytes, culture, and ova and parasites were all negative.
What additional diagnostic test should you order and why?
An acid-fast staining of stool was positive for Cryptosporidium parvum. What treatment would you recommend for this patient?
Prevention of cryptosporidiosis can prove difficult because the oocysts are resilient to many disinfectants and antiseptics, including ammonia, alcohol, and chlorine.35 Therefore, most traditional water-treatment methods, including filtration, do not eradicate all oocysts, which is problematic in the face of the small infective dose of Cryptosporidium. Routine screening of drinking water should be considered for water-treatment plants, and severely immunocompromised individuals should be advised to avoid water in lakes and streams and contact with young animals.35 For these persons, drinking water should be brought to a boil and cooled before ingestion.
VIRAL GASTROENTERITIS
Viruses are the most common cause of diarrheal illness in the world, resulting in about 450,000 and 160,000 hospitalizations for adults and children, respectively, and over 4,000 deaths.38,39 Many viruses may cause gastroenteritis, including rotaviruses, noroviruses, astroviruses, enteric adenoviruses, and coronoviruses (Table 76–4). This chapter will focus on rotaviruses.
ROTAVIRUS
Epidemiology
Rotavirus causes between 600,000 and 875,000 deaths each year, with the highest rates in the very young and in developing countries.40 Rotavirus is the leading cause of childhood gastroenteritis and death worldwide. Most infections occur in children between 6 months and 2 years old, typically during the winter season, but adults may be infected as well. Rotavirus causes over 2 million hospitalizations and 600,000 deaths per year in children younger than 5 years of age.41 Person-to-person transmission occurs through the fecal–oral route.
Pathogenesis
The mechanism of diarrhea has not been clearly elucidated, but theories include a reduction in the absorptive surface along with impaired absorption owing to cellular damage, enterotoxigenic effects of a rotavirus protein, and stimulation of the enteric nervous system.42
Clinical Presentation and Diagnosis of Rotavirus Infection40
• Incubation period of 2 days
• 2- to 3-day prodrome of fever and vomiting
• Profuse diarrhea without blood or leukocytes (up to 10–20 stools per day)
• Severe dehydration
• Anorexia
• Fever may be present.
• Presentation in adults may vary from asymptomatic to nonspecific symptoms of headache, malaise, and chills to severe diarrhea, nausea, and vomiting.
• Diagnosis can be made by polymerase chain reaction (PCR) of the stool.
Table 76–4 Agents Responsible for Acute Viral Gastroenteritis and Diarrhea
Patient Encounter 7
A 12-month-old female was brought to the ED for 10 watery stools in the last 36 hours. She attends a home daycare. Her mom reports that three other kids at the same daycare developed the same symptoms. She also vomited four times today. Positive physical findings include low-grade fever plus hyperactive bowel sounds.
What diagnostic test would you recommend?
What treatment would you recommend for this patient? How can you prevent this infection?
Treatment and Monitoring
The cornerstone of rotavirus treatment is supportive care and rehydration with ORT or intravenous fluids if necessary. Antimotility and antisecretory agents should not be used owing to their potential side effects in children and the self-limited nature of the disease. A live oral rotavirus vaccine is approved by the FDA for use in infants aged 6 weeks to 32 weeks and provides protection against rotavirus infection for at least 24 months.43 The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices recommends vaccination at 2, 4, and 6 months.
FOOD POISONING
Each year in the United States, approximately 76 million food-borne illnesses occur, leading to 325,000 hospitalizations and over 5,000 deaths.38 Many bacterial and viral pathogens that have been discussed previously in this chapter (e.g., Salmonella, Shigella, Campylobacter, E. coli, and noroviruses) can cause food poisoning. Other bacteria that can cause food-borne illness include Staphylococcus aureus, C. perfringens, C. botulinum, and Bacillus cereus(Table 76–5). Food poisoning should be suspected if at least two individuals present with similar symptoms after the ingestion of a common food in the prior 72 hours.
Patient Care and Monitoring
1. Observe the patient for signs and symptoms of dehydration, and rehydrate as necessary (see Tables 76–1 and 76–2).
2. Monitor for increase in stool consistency and decrease in stool frequency.
3. If pharmacologic agents are used, monitor for any adverse effects.
4. Evaluate the patient for any complications or effects specific to the afflicting pathogen.
OUTCOME EVALUATION
Patients with GI infections should be evaluated for resolution of GI symptoms, as well as any related systemic signs and symptoms. If antimicrobial therapy was used, completion of the course of therapy should be assessed. Documented clearance of the offending microorganism is not necessary.
Abbreviations Introduced in This Chapter
Table 76–5 Food Poisonings
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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