Essentials of Diagnosis
- Enteritis: diarrhea, which may be watery, bloody, or dysenteric; abdominal pain; and fever and/or;
- Systemic disease: highly variable presentations that may include enteric fever, hemolytic uremic syndrome, or bacteremia with infectious foci in distant sites.
- History of exposure, possibly in known endemic areas or associated with an outbreak, through the ingestion of unclean water, unpasteurized juice or milk, undercooked meats, or other possibly contaminated food.
- Microbiologic isolation and identification of enteric pathogens or molecular detection.
General Considerations
The Enterobacteriaceae are a diverse family of bacteria that, in nature, exist in soil, on plant material, and in the intestines of humans and other animals. Another ecological niche in which these organisms thrive is the hospital. Many of these organisms cause a wide variety of extraintestinal diseases that are often nosocomial and commonly present in debilitated or immunocompromised hosts. These manifestations have been examined previously in this volume and include urinary tract infections (site), skin and soft tissue infections (site), lower respiratory infections and pneumonia (site), and infective endocarditis and sepsis syndrome. The genera most frequently associated with extraintestinal disease are Escherichia, Enterobacter, Klebsiella, Proteus, Citrobacter, and Serratia.
Some members of the Enterobacteriaceae, however, cause primarily enteric disease or enteric-associated systemic disease (Box 1). These are Shigella and Salmonella species and particular strains of E coli and Yersinia enterocolitica. This SITEis devoted to enteritis and enteric-associated systemic disease caused by diarrheagenic strains of E coli and of Shigella and Salmonella species. Enteritis and associated mesenteric lymphadenitis caused by Y enterocolitica are covered separately (see site).
The family Enterobacteriaceae consists of at least 27 definitive genera and numerous enteric groups. The final classification of the enteric groups has yet to be resolved. Although there is diversity within this group, members have several common, characteristic features. All Enterobacteriaceae are gram-negative, facultative anaerobic bacilli that have the ability to reduce nitrate to nitrite. They produce catalase, ferment D-glucose with or without gas production, and do not produce oxidase. This latter characteristic is useful in differentiating this group of organisms from other nosocomial gram-negative pathogens, such as Pseudomonas aeruginosa, which is oxidase positive.
Traditionally, phenotypic characterization has been the method of choice for differentiating the members of the Enterobacteriaceae, but, with increasing frequency, genotypic methods are being used to detect particular genera and pathogenic varieties. Phenotypic methods, however, remain the standard for routine identification of these organisms in the clinical microbiology laboratory. The characteristics that are most useful for identification include colony morphology (particularly distinctive for some Proteus strains), indole production from tryptophan, reactions of the methyl red and Voges-Proskauer tests, motility, the ability to produce hydrogen sulfide, and the ability to use various organic substances. Several pathogenic Enterobacteriaceae, particularly many of the diarrheagenic E coli, fail to demonstrate unique phenotypic characteristics and continue to pose a challenge for microbiologists.
SALMONELLA ENTERITIS
Clinical Findings
Signs and Symptoms
Salmonella enteritis, frequently caused by S enteritidis, S cholerasuis, or S typhimurium, occurs between 12 and 48 h after the consumption of contaminated food. Patients experience fever, abdominal cramping, and diarrhea that may be accompanied by nausea and vomiting. The diarrhea varies in consistency from watery to dysenteric.
Laboratory Findings
Microscopic examination of the stool usually discloses nonspecific neutrophils.
Differential Diagnosis
The differential diagnosis of infectious diarrhea includes parasitic, viral, and bacterial etiologies. Noninfectious causes of diarrhea, such as inflammatory-bowel disease, lymphocytic/collagenous colitis, neoplasia, and numerous other disorders, must be considered. Patients with inflammatory-bowel disease may also have fecal leukocytes, further limiting the usefulness of this test. An accurate diagnosis can be achieved with a thorough history and physical examination, excluding enteric pathogens by appropriate microbiologic studies, and obtaining and reviewing gastrointestinal biopsies by using endoscopy and histopathologic studies.
Complications
In immunocompetent individuals, the disease usually lasts = 1 week and resolves without specific antimicrobial therapy. Neonates and young children, the elderly, and pregnant women are at increased risk for severe disease. In addition, immunocompromised individuals and patients with sickle cell disease or other hemoglobinopathies are at increased risk for bacteremia and the establishment of metastatic foci of infection. The complications of Salmonella infections may be separated into four categories: (i) dehydration and electrolyte abnormalities, (ii) local inflammatory response, (iii) bacteremia with the spread of organisms to distant sites, and (iv) postinfectious arthritis.
- Extensive diarrhea. Regardless of the cause, extensive diarrhea may lead to fluid and electrolyte abnormalities. Dehydration and electrolyte imbalance may cause tissue ischemia, central nervous system changes, and fatal dysrhythmias. Young children and the elderly, especially if malnourished, often suffer the greatest morbidity and mortality.
- Mesenteric lymphoid hypertrophy. Mesenteric lymphoid hypertrophy is associated with enteric fever, but patients with Salmonella enteritis may develop mesenteric lymphadenitis. These patients develop severe abdominal pain that may mimic acute appendicitis. Although mesenteric lymphadenitis is most commonly associated with Y enterocolitica, it may also occur in patients with bacterial enteritis of other etiologies.
- Bacteremia. By definition, bacteremia is a part of the disease process in enteric fever, but patients with Salmonella enteritis also occasionally develop bacteremia. Salmonella bacteremia may result in dissemination of bacteria and foci of infection into virtually any organ. The spread of bacteria to distant sites has resulted in a wide variety of diseases, including abscesses of the liver and spleen, acute and chronic cholecystitis, soft-tissue infections, urogenital infections, pneumonia and empyema, meningoencephalitis, and osteomyelitis. Osteomyelitis may be associated with areas of prior trauma or underlying bony abnormalities or, classically, has been associated with sickle cell anemia or other hemoglobinopathies. Atherosclerotic plaques may also become infected during Salmonella bacteremia. These are serious infections, because infected plaque material is almost impossible to sterilize with antibiotics alone. These plaques become an intravascular focus of infection and continually seed the bloodstream. In the laboratory, intravascular infections, including plaque infections, are detected as high-grade bacteremia, wherein > 50% of three or more blood cultures are positive. The abdominal aorta is a common site for atherosclerotic disease and is the vessel most commonly infected. Abdominal aortic plaque infections may result in a life-threatening aortoduodenal fistula or in mycotic aneurysms. Intravascular infections usually require combined medical and surgical therapy. If the patients are not surgical candidates, they may require long-term, suppressive antimicrobial therapy. Endocarditis is not common in either Salmonella enteritis-associated bacteremia or typhoid fever. Patients with structural cardiac anomalies, such as previous rheumatic heart disease or ventricular aneurysm, are at higher risk for developing endocarditis, regardless of the etiologic agent.
- Post-infectious arthritis. As with other bacterial etiologies, patients with salmonellosis may develop a post-infectious arthritis. The joint pain usually begins about 2 weeks after the diarrheal illness, and multiple joints are affected. This reactive, immune-mediated arthritis may last for months. Like patients with Reiter’s syndrome, individuals with an HLA-B27 phenotype are at increased risk for developing this complication.
Diagnosis
Patients with Salmonella enteritis have positive stool cultures and occasionally positive blood cultures. Apart from the agents of enteric fever, Salmonella cholerasuis is more likely to result in bacteremia than other Salmonella species. After isolation, Salmonella species are rapidly grouped by using antisera and are differentiated by various biochemical reactions.
Over the past decade, several molecular methods have been explored for the rapid detection of Salmonella species, including enzyme-linked immunosorbent assays, indirect immunofluorescence, and polymerase chain reactions. Advances in molecular diagnostics should permit the rapid detection of antigens or nucleic acids that are unique to these organisms. Many of these tests, however, are not commercially available and may be cost prohibitive compared with culture.
Treatment
Uncomplicated enteritis caused by Salmonella species should not be treated with antimicrobial agents. Antimicrobial agents may prolong bacteria shedding and promote antimicrobial resistance. Fluid and electrolyte replacement should be used to treat dehydration. In most instances, oral rehydration is sufficient, but, if severe electrolyte anomalies exist, intravenous rehydration may be necessary. Antimotility agents should not be used, because these agents inhibit the clearance of pathogenic bacteria and their toxins. Patients at risk for or with systemic disease/complications should be treated. A third-generation cephalosporin, such as ceftriaxone, may be used for patients with severe disease, until antimicrobial susceptibility data are available (see Box 5). Prophylactic therapy is appropriate for individuals at increased risk for severe disease (Box 6). In the absence of an antimicrobial-susceptibility profile, empiric therapy should be used.
Systemic infections should be treated with antimicrobial agents based on the particular isolate’s susceptibility profile. Intravascular infections and osteomyelitis may require long-term antimicrobial therapy, possibly combined with surgery to effect a cure.
Prevention & Control
The prevention of all Salmonella infections requires an interruption of the fecal-oral cycle (see Box 3). Developed countries with adequate sewage disposal, clean drinking water, and an effective public health service have dramatically lowered the prevalence and incidence of enteric fever. Infections by S typhi have been particularly affected, because humans are the only known reservoir for this organism. Diminishing infections caused by other Salmonella strains are more difficult, because these organisms are commensals in the intestinal tracts of a wide variety of animals. Infections by these organisms are usually associated with contaminated or incompletely cooked foods. The control of these infections may be effected through education and efforts that stress the importance of rinsing meats when appropriate, avoiding cross-contamination of food preparation utensils, avoiding raw-egg-containing products, and thoroughly cooking meats.
Of particular public health interest is the association of S enteritidis with chicken eggs. Ovarian infections in chickens may result in the transovarial passage of Salmonella species. Therefore, even thoroughly washed eggs with intact shells may transmit S enteritidis. Foods that require uncooked egg whites and/or yolks should be prepared by using pasteurized egg products. For this reason, raw eggs and foods or beverages that contain raw eggs should not be ingested. Additionally, cracked eggs should never be consumed, because these are even more likely to be contaminated with Salmonella species. The thorough cooking of eggs renders them safe for consumption.
Beef and poultry may become contaminated with feces during the slaughter process. If possible, these products should be washed with free-flowing water and cooked thoroughly before consumption. Knives, cutting boards, and other utensils become contaminated during contact with uncooked foods. These fomites may cross-contaminate other foods and thereby transmit Salmonella species. Utensils and food preparation surfaces that have been used to process uncooked food should be washed thoroughly before they are used to process other foods. The thorough cooking of food and pasteurization of milk and other liquids substantially reduce the risk of Salmonella enteritis.
Vaccinations are available for individuals at risk for typhoid fever; prophylactic antimicrobial agents are not recommended. Current recommended candidates for vaccination include travelers to endemic areas and people who are household contacts of infected persons. In the United States, the traditional vaccine consists of heat-killed, phenol-treated organisms. This vaccine offers 55%-77% protection, but its usefulness is limited by side effects. The minor side effects include fever, headache, and local pain at the site of injection and may last from hours to several days, but more severe reactions may occur. This vaccine requires two injections 4 weeks apart. The minimum age for vaccination is 6 months, and a booster is required every 3 years.
A newer, capsular polysaccharide vaccine, ViCPS, appears to offer similar protection after a single injection and has fewer side effects. This vaccine has a minimum age requirement of 2 years and requires a booster every 2 years.
An attenuated, live-bacteria, oral vaccine has been licensed in the United States and may rapidly become the vaccine of choice for many individuals. This vaccine, Ty21a, appears to be safe and effective, with no serious side effects. It relies on the development of natural immunity by using an attenuated S typhi strain. Therefore, patients on antimicrobial therapy should not be given this vaccine concomitantly. As with other “live” vaccines, this vaccine should not be given to persons that are immunocompromised. It is not recommended for children < 6 years old. Because of these limitations, the oral vaccine will not completely replace the injectable vaccines. A booster dose is needed every 5 years.
None of the typhoid vaccines offer long lasting protection, and booster doses are required to maintain protective antibody levels. In addition, none of the vaccines are 100% effective and should be used in conjunction with other preventive measures. Information regarding typhoid fever prevention and the prevention of other travel-associated diseases is available from the Centers for Disease Control and Prevention toll free at 1-888-232-3228 or on the internet at http://www.cdc.gov/travel.
Future directions for vaccine development include vaccines that elicit longer lasting immunity and confer immunity to more than one enteric pathogen. Such vaccines have been created, using molecular techniques. The insertion into Salmonella strains of genetic material that encodes for the somatic antigens of S sonnei and V cholera has allowed for the genetic construction of bacteria with multiple somatic antigens. It is hoped that vaccination with these genetically engineered bacteria will confer protection to several enteric pathogens.
BOX 1. Enterobacteriaceae Syndromes
Children
Adults
More Common
- Enterocolitis
- Enterocolitis
Less Common
- Hemolytic uremic syndrome [with EHEC (more common in children than adults)]
- Enteric fever (with Salmonella)
- Dysentery (with Shigella)
- Hemolytic uremic syndrome (with EHEC)
- Enteric fever (with Salmonella)
- Dysentery (with Shigella)
BOX 2. Empiric Therapy for Diarrheagenic, Non-EHEC, E coli Infection
Children
Adults
First Choice
Trimethoprim-sulfamethoxazole (TMP/SMX) > 1 month: TMP, 10 mg/kg/d, + SMX, 50 mg/kg/d orally twice daily for 3-5 d
Ciprofloxacin, 500 mg orally twice daily (or another quinolone)
1) In most instances, disease secondary to diarrheagenic E coli infection resolves without therapy. If disease becomes chronic, a trial of antimicrobial therapy is warranted, but other etiologies of chronic diarrhea should also be considered.
BOX 3. Prevention & Control of Bacterial Gastroenteritis/Enteric Fever
Prophylactic Measures
- Appropriate sewage disposal and waste treatment
- Treatment of drinking water (ie, chlorination)
- Good personal hygiene
- Thorough cooking of food, especially eggs and hamburger
- Good food preparation skills (ie, avoid cross-contamination)
- Bismuth subsalicylate for travelers may aid other prophylactic measures
Isolation Precautions
- Good handwashing necessary, especially if the infecting organism is Salmonella typhi, Salmonella paratyphi, Shigella spp., or E coli O157:H7.
- Patients recovering from enteric fever (S typhi or S paratyphi) should not work as food preparers until stool cultures are negative.
BOX 4. Treatment of Shigella Gastroenteritis
Children
Adults
First Choice
Trimethoprim-sulfamethoxazole (TMP/SMX)
• > 1 month: TMP, 10 mg/kg/d, + SMX 50 mg/kg/d orally, divided every 12 h
Ciprofloxacin: 500 mg orally every 12 h (or another quinolone)
Second Choice
Ampicillin:
- > 1 month: 25 mg/kg every 6 h
- 1-4 wk: 25 mg/kg every 8 h
- < 1 wk: 25 mg/kg every 12 h
Ampicillin: 0.5-1 g orally every 6 h or 1-2 g IV every 4-6 h
Penicillin Allergic
- TMP/SMX (as above) OR Nalidixic acid, 55 mg/kg/day, orally, divided every 4 h
Trimethoprim-sulfamethoxazole: 160/800 mg orally every 12 h or 3-5 mg/kg IV every 6-8 h
The recommended duration of therapy for all treatment regimens is 3-5 d
BOX 5. Treatment of Enteric Fever
Children
Adults
First Choice
Ceftriaxone:
- > 4 wk: 50-100 mg/kg/d IV every 12-24 h
- < 1 wk: 50 mg/kg/d IV every 24 h
- 1-4 wk: 50-75 mg/kg d IV every 24 h
Ceftriaxone, 1-2 g IV every 12 h
Second Choice
Ampicillin:
- > 1 month: 25 mg/kg IV or orally every 6 h
- 1-4 wk: 25 mg/kg IV every 8 h
- < 1 wk: 25 mg/kg IV every 12 h
Ciprofloxacin, 500-750 mg orally every 12 h or 200-400 mg IV every 8-12 h (or another quinolone)
OR
Ampicillin, 0.5-1 g orally every 6 h or 1-2 g IV every 4-6 h
Penicillin Allergic
Trimethoprim-sulfamethoxazole (TMP/SMX)
- > 1 month: TMP, 10 mg/kg/d + SMX, 50 mg/kg/d orally divided every 12 h
Trimethoprim-sulfamethoxazole, 160/800 mg orally every 6 h or 8-10 mg/kg IV trimethoprim equivalent every 6 h
Chloramphenicol: 0.25-0.75 g orally every 6 h or = 1 g IV every 6 h for severe infections
Empiric therapy should be based on known antimicrobial susceptibility profiles and should be modified, based on the antimicrobial susceptibility profile of the infecting isolate. In areas of known multidrug resistance, children should be treated with ceftriaxone, and adults should be treated with ceftriaxone or a quinolone. In areas without known resistance, ampicillin, trimethoprim-sulfamethoxazole, or chloramphenicol may be used. Two weeks of antimicrobial therapy are usually required.
BOX 6. Prophylaxis for Salmonella Enteritis
Children
Adults
First Choice
Trimethoprim-sulfamethoxazole (TMP/SMX)
- > 1 month: TMP, 8 mg/kg/d + SMX, 40 mg/kg/d orally every 8 h
- Ciprofloxacin: 500 mg orally every 12 h (or an other quinolone)
Second Choice
- Amoxicillin: 6.7-13.3 mg/kg orally every 8 h
- Amoxicillin: 250-500 mg orally every 8 h
OR
- Trimethoprim-sulfamethoxazole, 160/800 mg orally every 12-24 h or 3-5 mg/kg IV every 6-8h
For groups at high risk for bacteremia or metastatic spread. Uncomplicated enteritis caused by Salmonella spp. should not be treated with antimicrobial agents.