Holenarasipur R. Vikram, MD, FACP, FIDSA
What are the strains of diarrhea-causing Escherichia coli?
Enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), enteroinvasive E. coli (EIEC), enterohemorrhagic E. coli (EHEC, also known as Shiga toxin-producing E. coli or STEC), and enteroaggregative E. coli (EAEC).
What regions of the gastrointestinal tract do the strains of E. coli involve?
What clinical syndromes are associated with ETEC?
Dehydrating watery diarrhea in young children (< 2 years old) in the developing world, diarrhea in older individuals not previously exposed to this organism, and traveler’s diarrhea. ETEC can readily survive in food and water supplies.
How does EPEC cause disease?
It leads to adherence and effacement of enterocytes.
True/False: Stools from patients with ETEC are bloody.
False. They are watery without blood or fecal leukocytes.
What is the site of infection with EIEC?
The colonic mucosa. Ulceration may occur as a result of this infection. Clinical manifestations resemble those of shigellosis.
Which E. coli strain is associated with the hemolytic-uremic syndrome (HUS)?
EHEC belonging to the serotype O157:H7. Several non-O157 strains of EHEC, particularly seen outside the United States, can also cause HUS.
What are the clinical components of the classic triad of HUS?
The classic triad of HUS includes: 1) acute renal failure, 2) thrombocytopenia, and 3) microangiopathic hemolytic anemia.
What is the characteristic colonic histopathology in patients with EHEC infection?
Hemorrhage and edema in the lamina propria of the colon. Focal necrosis, neutrophilic infiltration, and pseudomembranes may also be seen.
What is the major virulence factor of EHEC?
Shiga toxin. Following attachment to the intestinal epithelial cells, secretion of bacterial proteins into these cells and elaboration of Shiga toxins takes place. Shiga toxins enter the systemic circulation and are bound to polymorphonuclear leukocytes, which are responsible for endothelial cell injury in various organs, bloody diarrhea, and in some cases, manifestations of HUS.
How is E. coli O157:H7 transmitted?
The GI tract of cattle is the most important reservoir for E. coli O157:H7. Undercooked ground beef has traditionally been the major source of transmission. Other sources of food-borne transmission have included raw milk, green onions, shredded lettuce, and apple juice. Person-to-person transmission, as well as exposure to animals in county fairs, petting zoos, and farms, has led to O157:H7 outbreaks due to inadequate hand hygiene practices. The exact source of the May 2011 outbreak of O104:H4 in Germany remains uncertain.
True/False: There is a seasonal pattern associated with EHEC infection.
True. In the United States, majority of cases occur between the months of June and September.
What is the infectious dose of E. coli O157:H7 for humans?
Ten to 100 organisms are sufficient to cause infection. This is similar to Shigella, and is very low in comparison to other diarrhea-causing bacterial pathogens.
What are the most common clinical manifestations of E. coli O157:H7 infection?
The incubation period following exposure to EHEC is usually 3–4 days. Bloody diarrhea, leukocytosis, absence of fever, and abdominal tenderness are the most common clinical manifestations. Up to half of symptomatic patients might require hospitalization with a mortality rate of 1%–2%, especially the elderly and those who develop HUS.
What percentage of patients infected with E. coli O157:H7 develop HUS?
Approximately 6%–9% of all cases of EHEC infections (15% in those under the age of 10) are complicated by HUS. In 2008, two-thirds of all cases of postdiarrheal HUS occurred in children less than 5 years of age. In a recent outbreak of EHEC O104:H4 in Germany (May 2011), more than 80% of infected patients were >18 years of age, and HUS was observed in 30% of these infections.
True/False: All individuals with E. coli O157:H7 should be treated with antibiotics.
False. Observational studies have reported an increased risk of HUS if antibiotics are administered during the phase of bloody diarrhea, probably due to increased expression and release of Shiga toxin. Furthermore, antibiotic therapy does not alter the duration of illness. Likewise, antimotility drugs also seem to enhance the risk of HUS in patients with EHEC infection. Therefore, both antibiotics and antimotility agents should be avoided.
What is the clinical outcome in patients with postdiarrheal HUS?
Among those who develop postdiarrheal HUS, up to 50% of patients might require dialysis during the acute phase and 5%–10% may have residual renal or neurologic sequelae. Overall mortality is 3%–5%.
How is E. coli O157:H7 detected in the laboratory?
The Center for Disease Control and Prevention recommends all stool samples submitted for culture be screened for E. coli O157:H7. However, > 90% of positive stool cultures for E. coli O157:H7 come from visibly bloody stool or those with a recent history of bloody diarrhea. Sorbitol-MacConkey (SMAC) agar is the medium used for this purpose. E. coli O157:H7 produces colorless colonies on SMAC agar. The colonies can then be tested with antisera to the O157 antigen. Newer diagnostic techniques can directly detect Shiga toxins in stool.
What are the four species of Shigella?
Shigellae are nonmotile, facultatively anaerobic, nonlactose fermenting Gram-negative rods. The four species (and serogroups) are as follows:
1. S. dysenteriae (serogroup A)
2. S. flexneri (serogroup B)
3. S. boydii (serogroup C)
4. S. sonnei (serogroup D)
Which species of Shigella is the most common isolate in the United States?
S. sonnei accounts for about 75% of cases of Shigellosis in the United States, followed by S. flexneri.
How does Shigella produce dysentery?
Ingestion of as few as 10–100 viable organisms in contaminated food and water can cause disease. They multiply several-fold in the small intestine (relatively resistant to gastric acid) and reach the colon, where they invade the colonic mucosa causing cell death, an intense inflammatory reaction, ulcerations, and abscesses. Shigella strains also elaborate three distinct enterotoxins. Shiga toxin is produced by S. dysenteriae type 1. The relative contribution of these toxins to disease is unknown, as nontoxigenic strains of Shigella are also pathogenic.
True/False: Blood cultures are usually positive with Shigella infection.
False. The organism rarely invades beyond the mucosa. Although uncommon, bacteremia can occasionally be seen in children < 5 years of age who present with severe disease.
What is the typical clinical course of Shigella infection?
The average incubation period is 3 days. Initial manifestations include fever and abdominal cramping followed by watery diarrhea. Subsequently, bloody mucoid diarrhea and tenesmus are noted. Disease severity also varies by serogroup: S. dysenteriae type 1 and S. flexneri commonly cause dysenteric symptoms, while S. sonnei often leads to a mild illness with watery diarrhea. The course of the disease is typically self-limited in healthy adults.
What are the laboratory findings in patients with Shigella infection?
The peripheral white blood cell count can be elevated. Microscopic evaluation of feces shows many polymorphonuclear leukocytes. Since Shigella does not ferment lactose, colonies appear colorless on lactose-containing media. Additional selective media can be utilized to work up suspicious lactose-negative colonies. Serologic studies are not helpful in establishing the diagnosis; however, they may serve as epidemiologic tools for defining the extent of an epidemic. Shigellae are nonmotile, indole-positive, urease- and oxidase-negative, and ferment glucose.
What are some of the described intestinal and systemic complications of Shigella infection?
Toxic megacolon, rectal prolapse, intestinal obstruction, and colonic perforation are uncommon intestinal complications in patients with severe disease. Profound dehydration, hyponatremia, protein-losing enteropathy, leukemoid reaction, bacteremia, seizures, and reactive arthritis are known systemic complications. HUS can be associated with shiga toxin-producing strains of S. dysenteriae type 1.
True/False: Patients with Shigella infections should receive antibiotic treatment.
True. Antibiotics have been shown to decrease the duration of fever and diarrhea by about 2 days. Even though Shigella infection is self-limiting in healthy individuals, treating anyone with a positive stool culture for Shigella is recommended to reduce the duration of shedding in the stool and to limit person-to-person spread.
What antibiotics are used to treat Shigella infections?
Ciprofloxacin (500 mg twice daily for 5 days) or another fluoroquinolone is the drug of choice for shigellosis acquired in the United States, while awaiting antimicrobial susceptibilities. Trimethoprim-sulfamethoxazole and azithromycin are alternatives (if susceptible). For strains of Shigella acquired in the Asian subcontinent, a third generation cephalosporin is preferable due to widespread resistance to ciprofloxacin. Trimethoprim-sulfamethoxazole and azithromycin are alternatives.
Untreated, how long can patients with Shigella gastroenteritis excrete the microorganism?
For up to 6 weeks.
What host factor lowers the infectious dose required in Salmonella infections?
Lack of gastric acid.
What are the major clinical syndromes caused by Salmonellae?
Gastroenteritis, enteric fever, chronic asymptomatic carrier state, endovascular infection (especially aortitis or vascular graft infections), and focal metastatic infections.
What are the main modes of acquisition of nontyphoidal Salmonella infection?
Eggs and poultry. Salmonellae can undergo transovarial transmission from chickens into intact shell eggs. Contaminated peanut butter, milk, ice cream, fresh produce, and meat have also been associated with outbreaks. Pet reptiles, snakes, frogs, iguanas, turtles, and rodents can also transmit Salmonella, especially to young children. Therefore, children under the age of 5 and immunocompromised hosts should avoid contact with reptiles.
What host factors predispose patients to infections with Salmonella?
AIDS, organ transplantation, chronic corticosteroid use, cancer chemotherapy, extremes of age, reduced gastric acidity, altered intestinal function due to prior antibiotic therapy or inflammatory bowel disease, impaired phagocytic function (eg, schistosomiasis, histoplasmosis, malaria, chronic granulomatous disease), and iron overload states (such as hemoglobinopathies) result in increased susceptibility to Salmonella infection.
Describe the clinical features of Salmonella gastroenteritis?
Symptoms (nausea, vomiting, and diarrhea) begin within 48 hours of ingestion of contaminated food or water. The diarrhea varies in volume; blood or mucus is usually absent. Fever and abdominal cramping are reported in about 90% of cases. Fever resolves in 2–3 days and the diarrhea is usually self-limiting.
Who are at risk for cardiovascular complications following nontyphoidal Salmonella bacteremia?
Older age (> 60 years), preexisting atherosclerotic disease or aortic aneurysm, and prosthetic cardiac valves predispose patients to develop mycotic (infected) aneurysms, aortitis, and endocarditis with resulting metastatic infection in the presence of Salmonella bacteremia. Older patients with Salmonella bacteremia and chest/abdominal/back pain should undergo urgent evaluation to exclude infective aortitis or aneurysm.
What does laboratory investigation of a patient with Salmonella infection typically reveal?
Fecal leukocytes are seen on microscopic evaluation of stools. Salmonella sp. are nonlactose fermenters; therefore, the colonies appear colorless on lactose-containing media. Less than 5% of immunocompetent individuals will have positive blood cultures with nontyphoidal Salmonella infections. S. typhimurium and S. enteritidis are the most frequently isolated serotypes in stool cultures in the United States. Most nontyphoidal salmonellae produce hydrogen sulfide.
How long can patients excrete Salmonella in their stool after resolution of an episode of gastroenteritis?
Asymptomatic fecal excretion of nontyphoidal Salmonella strains may occur for about 4–5 weeks. The influence of antimicrobial therapy on the risk of prolonged excretion is unclear. Stool shedding can be intermittent. The importance of hand washing cannot be overemphasized in healthcare workers and food handlers.
What are the recommendations for antimicrobial treatment of Salmonella gastroenteritis?
Otherwise healthy individuals with mild symptoms do not require antimicrobial therapy, as the illness is self-limited. Immunocompetent patients with severe diarrhea, persistent fever, and those requiring hospitalization should receive antibiotics. Immunocompromised patients, those at extremes of age, and patients with Salmonella bacteremia require antimicrobial therapy. Fluoroquinolones, trimethoprim-sulfamethoxazole and beta-lactam antibiotics are usually effective. Therapy can be modified based on antimicrobial susceptibility results.
What are the common reservoirs of Campylobacter jejuni?
Campylobacter is a zoonosis. It is most commonly acquired from poultry but also may be transmitted through raw milk, other dairy products, or undercooked meat. The two most important species are C. jejuni and C. coli.
True/False: Campylobacter is one of the leading causes of acute diarrheal disease worldwide.
What are the sites of tissue injury in Campylobacter infections?
Jejunum, ileum, colon, and rectum. Histologic appearance is indistinguishable from shigellosis and salmonellosis.
What does laboratory investigation of a patient with C. jejuni infection typically reveal?
Gram stain of a stool specimen can reveal faint-curved, Gram-negative (gull-wing) bacteria. The sensitivity of stool Gram stain is 50%–75%. Stool culture must be undertaken with selective media under microaerophilic conditions. Blood cultures are positive in less than 1%.
What are some of the unique manifestations of C. jejuni infection?
Most patients have a self-limited diarrhea that lasts for a mean of 7 days. Some patients can manifest with bloody diarrhea and acute colitis that can be mistaken for inflammatory bowel disease. Acute ileocecitis from Campylobacter can mimic acute appendicitis. Other acute complications that can result from Campylobacter infections include massive hemorrhage, HUS, cholecystitis, pancreatitis, hepatitis, peritonitis in patients on continuous ambulatory peritoneal dialysis, and infected pseudoaneurysm. Patients with HIV/AIDS can develop long-term carriage leading to recurrent episodes of enteritis and sometimes bacteremia.
What are the two major late sequelae following C. jejuni infection?
Reactive arthritis and Guillain–Barrè syndrome (GBS). Reactive arthritis can also occur following other bacterial diarrheal infections, and is more common in patients with the HLA-B27 phenotype. Up to 40% of GBS cases are attributable to recent Campylobacter infection (overt or asymptomatic). The onset of GBS is usually 1–2 weeks after Campylobacter infection.
Which antimicrobial agents are utilized to treat Campylobacter infections?
Since Campylobacter gastroenteritis is a mild self-limited infection, most patients do not need antimicrobial therapy. However, antibiotics may be necessary in those with severe or extraintestinal disease, in the elderly, during pregnancy, and in the immunocompromised host. C. jejuni is inherently resistant to beta-lactams and trimethoprim. The incidence of fluoroquinolone resistance among Campylobacter is increasing throughout the world. Macrolides or tetracyclines are the preferred agents. If the person cannot tolerate oral medications, either an aminoglycoside or a carbapenem should be administered. The final choice of antibiotic therapy should be based on susceptibility testing.
Describe the histopathologic findings in patients with intestinal Entamoeba histolytica infection (amebiasis).
Majority of infections (up to 90%) are asymptomatic. It exists in two forms: a cyst stage (infective form) and a trophozoite stage (causes invasive disease). Colonic lesions range from nonspecific thickening of the mucosa to the classic flask-shaped ulcer. Twenty to 50% of patients have classic ulcers extending through the mucosa and muscularis layer into the submucosa. Colonoscopy is not routinely recommended in patients with active amebic colitis due to the risk of perforation.
What tests are available to diagnose intestinal amebiasis?
Stool examination to demonstrate cysts or trophozoites, fecal and serum antigen detection assays, and serology. Antigen detection is more sensitive than stool examination. It can help with diagnosis during early infection and in endemic areas where serology is of limited utility.
Describe the extraintestinal manifestations of amebiasis.
Amebic liver abscess is the most common extraintestinal manifestation, with infection reaching the liver via the portal venous system. Pleuropulmonary amebiasis can occur as a complication of amebic liver abscess. Intraperitoneal rupture of liver abscesses can also occur. Rarely, pericardial, genitourinary, and cerebral amebiasis have been described.
How is infection with E. histolytica treated?
The goal of therapy is to eliminate trophozoites causing invasive colitis and to eradicate intestinal cyst carriage. A 10-day course of metronidazole followed by a 7–10 day course of an intraluminal agent such as diloxanide furoate or paromomycin is recommended. Extraintestinal amebiasis may require a longer course of metronidazole therapy.
What is the most common infectious cause of healthcare-associated diarrhea?
Clostridium difficile is the most common cause of infectious diarrhea in healthcare settings. It accounts for 20%–30% of all cases of antibiotic-associated diarrhea.
What are the risk factors for C. difficile infection (CDI)?
Advanced age (> 64 years), duration of hospitalization, exposure to antimicrobial agents, cancer chemotherapy, gastrointestinal surgery, tube feeding, and gastric acid suppression are known risk factors for CDI.
True/False: Alcohol-based hand sanitizers and hand washing with soap and water are equally effective in the prevention of nosocomial transmission of C. difficile.
False. The spores of C. difficile are highly resistant to killing by alcohol. Therefore, alcohol-based hand sanitizers are ineffective. Hand washing with soap and running water mechanically removes C. difficile spores from the hands of healthcare workers and is the recommended option for hand hygiene in this setting.
What are the various tests available for the diagnosis of CDI?
C. difficile toxins A and B testing by enzyme immunoassay (EIA), polymerase chain reaction (PCR), cell cytotoxicity assay, toxigenic culture, and C. difficile common antigen (glutamate dehydrogenase) are available for the diagnosis of CDI.
How is an initial episode of CDI treated?
The offending antimicrobial agent should be discontinued as soon as possible. For an initial episode of CDI (mild-to-moderate), metronidazole 500 mg orally three times per day for 10–14 days is recommended. For an initial episode of severe CDI, vancomycin 125 mg orally 4 times per day for 10–14 days is the treatment of choice. With an initial episode of severe, complicated CDI (hypotension or shock, ileus, megacolon), vancomycin 500 mg 4 times per day by mouth (or nasogastric tube), PLUS metronidazole 500 mg every 8 hours intravenously is recommended. If there is complete ileus, rectal instillation of vancomycin should be considered. Colectomy can be life-saving for selected patients. The newly approved agent fidaxomicin was demonstrated to be noninferior to vancomycin for the treatment of CDI and was associated with a significantly lower rate of CDI recurrence. Antimotility agents and opiate antagonists should be avoided in patients with CDI as they may precipitate toxic megacolon.
What options are available for the management of patients with recurrent CDI?
The first step would be to minimize and avoid antimicrobial therapy in patients with a history of recurrent CDI. First recurrence of CDI can be treated with the same regimen as the initial episode. In patients with multiple recurrences, a tapered or pulsed regimen of vancomycin can be tried. Other modalities with reported success in patients with recurrent CDI include: a) oral vancomycin followed by rifaximin, b) nitazoxanide, c) intravenous immunoglobulin, and d) fecal transplantation from a “healthy” donor. The addition of human monoclonal antibodies against C. difficile toxins A and B to those receiving either oral vancomycin or metronidazole significantly reduced recurrent CDI. The newly approved agent fidaxomicin was demonstrated to be noninferior to vancomycin for the treatment of CDI and was associated with a significantly lower rate of CDI recurrence.
Who are at risk for developing typhlitis?
Typhlitis is a life-threatening enterocolitis that develops most often in patients with hematologic malignancies following chemotherapy. Patients are usually profoundly neutropenic and present with fever and abdominal pain. It is also referred to as “neutropenic enterocolitis.” The cecum is almost always affected with involvement of the adjacent colon and ileum.
Describe conditions that predispose patients to develop cytomegalovirus (CMV) colitis.
AIDS, solid organ transplant recipients (especially those who are CMV mismatch [D+/R-]), following allogeneic stem cell transplantation, patients receiving chronic high-dose steroid therapy, and those with inflammatory bowel disease requiring high-dose immunosuppression can manifest CMV colitis. Colonoscopy with biopsy and immunohistochemical staining can provide a definitive diagnosis.
What is Strongyloides hyperinfection syndrome?
Strongyloides stercoralis can complete its entire life cycle within the human host. Such autoinfection can persist for decades and can be asymptomatic in immunocompetent hosts. However, in the setting of immunosuppression, the parasite burden is tremendously increased and can lead to hyperinfection syndrome. Filariform larvae penetrate the intestinal wall and enter the bloodstream with widespread dissemination. In the process, they can also cause bacteremia with enteric pathogens resulting in septic shock. Timely diagnosis can be life-saving. Stool examination, serology, or endoscopy can be utilized for diagnosis. Ivermectin and albendazole are the treatments of choice.
What is the treatment of choice for Balantidium coli infection?
B. coli is a protozoan that can cause acute colitis (trophozoite form) or lead to asymptomatic cyst excretion in humans. Tetracycline and metronidazole are the drugs of choice for B. coli.
What are the gastrointestinal manifestations of Chagas disease?
Chagas disease is caused by the protozoan Trypanosoma cruzi and is endemic in many South American countries. Gastrointestinal involvement is seen in the chronic phase of Chagas disease and manifests as megaesophagus and megacolon. This is due to a loss of neurons in the gastrointestinal tract. Most patients with gastrointestinal involvement also have concurrent chronic Chagas heart disease.
• • • SUGGESTED READINGS • • •
Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001;32: 331-350.
Goldsweig CD, Pacheco PA. Infectious colitis excluding E. coli O157:H7 and C. difficile. Gastroenterol Clin North Am. 2001;30: 709-733.
Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431-455.