Microbiology and Pathogenesis

Salmonellae are facultatively anaerobic gram-negative bacilli that cause infection when between 200 and 10⁶ organisms are ingested.

• Conditions that reduce gastric acidity or intestinal integrity increase susceptibility to infection.
• Organisms penetrate the small-intestinal mucus layer and traverse the intestinal epithelium through M cells overlying Peyer's patches.
  • - S. Typhi and S. Paratyphi survive within macrophages, then disseminate throughout the body via lymphatics, and ultimately colonize reticuloendothelial tissues.
  • Nontyphoidal salmonellae most commonly cause gastroenteritis, invading the large- and small-intestinal mucosa and resulting in massive PMN infiltration (as opposed to the mononuclear-cell infiltration seen with typhoid fever).

Epidemiology and Clinical Manifestations

Depending on the specific species, salmonellosis results in typhoid fever or gastroenteritis.

• Typhoid (enteric) fever: Typhoid fever is a systemic disease characterized by fever and abdominal pain and caused by dissemination of S. Typhi or S. Paratyphi, for which humans are the only hosts.
  • Disease results from ingestion of food or water contaminated by chronic carriers and is rare in developed nations. Worldwide, there are ∼21-27 million cases, with 200,000-600,000 deaths annually.
  • After an incubation period of 5-21 days, prolonged fever (>75% of cases), headache (80%), chills (35-45%), anorexia (55%), and abdominal pain (30-40%) are common. Other signs and symptoms may include sweating, cough, malaise, arthralgias, nausea, vomiting, and diarrhea-or, less often, constipation.
  • Physical findings include rose spots (a faint, salmon-colored, blanching, maculopapular rash), hepatosplenomegaly, epistaxis, and relative bradycardia.
  • Intestinal perforation and/or GI hemorrhage can occur in the third and fourth weeks of illness; neurologic manifestations (e.g., meningitis, Guillain-Barré syndrome) occur in 2-40% of pts.
  • Long-term Salmonella carriage (i.e., for >1 year) in urine or stool develops in 2-5% of pts.
• Nontyphoidal salmonellosis (NTS): Most commonly caused by S. Typhimurium or S. Enteritidis, NTS typically presents within 6-48 h of exposure as gastroenteritis (nausea, vomiting, nonbloody diarrhea, abdominal cramping, and fever) that lasts 3-7 days.
  • In the United States, NTS causes ∼12 million illnesses annually.
  • Disease is acquired from multiple animal reservoirs. The main mode of transmission is via contaminated food products, such as eggs (S. Enteritidis), poultry, undercooked meat, dairy products, manufactured or processed foods, and fresh produce. Infection is also acquired during exposure to pets, especially reptiles.
  • Stool cultures remain positive for 4-5 weeks and-in rare cases of chronic carriage-for >1 year.
  • Bacteremia, usually due to S. Choleraesuis and S. Dublin, develops in 8% of pts; of these pts, 5-10% develop localized infections (e.g., hepatosplenic abscesses, meningitis, pneumonia, osteomyelitis).
  • Reactive arthritis can follow Salmonella gastroenteritis, particularly in persons with the HLA-B27 histocompatibility antigen.

Diagnosis

Positive cultures of blood, stool, or other specimens are required for diagnosis.

Microbiology

Campylobacters are motile, curved gram-negative rods that are a common bacterial cause of gastroenteritis in the United States. Most cases are caused by Campylobacter jejuni.

Epidemiology

Campylobacters are common commensals in the GI tract of many food animals and household pets. In developed countries, ingestion of contaminated poultry accounts for 30-70% of cases. Transmission to humans occurs via contact with or ingestion of raw or undercooked food products or direct contact with infected animals.

Clinical Manifestations

An incubation period of 2-4 days (range, 1-7 days) is followed by a prodrome of fever, headache, myalgia, and/or malaise. Within the next 12-48 h, diarrhea (with stools containing blood in ∼10% of cases in adults), cramping abdominal pain, and fever develop.

• Most cases are self-limited, but illness persists for >1 week in 10-20% of pts and may be confused with inflammatory bowel disease.
• Species other than C. jejuni (e.g., C. fetus) can cause a similar illness in normal hosts or prolonged relapsing systemic disease without a primary focus in immunocompromised pts.
  • The course may be fulminant, with bacterial seeding of many organs, particularly vascular sites.
  • Fetal death can result from infection in a pregnant pt.
• Three patterns of extraintestinal infection have been noted: (1) transient bacteremia in a normal host with enteritis (benign course, no specific treatment needed); (2) sustained bacteremia or focal infection in a normal host; and (3) sustained bacteremia or focal infection in a compromised host.
• Complications include reactive arthritis (particularly in persons with the HLA-B27 phenotype) and Guillain-Barré syndrome (in which campylobacters are associated with 20-40% of cases).

Diagnosis

The diagnosis is confirmed by cultures of stool, blood, or other specimens on special media and/or with selective techniques.

Microbiology and Epidemiology

Shigellae are small, gram-negative, nonmotile bacilli that are very closely related to E. coli. The four most common Shigella serotypes are S. dysenteriae type 1, S. flexneri, S. boydii, and S. sonnei (which is more prevalent in the industrialized world). Humans are the major reservoir, but Shigella can be found in other higher primates. Shiga-toxin producing E. coli (STEC) and enterohemorrhagic E. coli (EHEC) can be found in cows.

• Person-to-person spread via the fecal-oral route is most common for Shigella (and is occasionally the route for STEC, EHEC, and Shiga toxin-producing enteroaggregative E. coli [ST-EAEC]); ingestion of contaminated food and water is the more common route of transmission of STEC/EHEC/STEAEC (and is occasionally the route for Shigella).
• The ability of as few as 100 organisms to cause infection helps explain the high rate of secondary household transmission.
• Shiga toxin and Shiga-like toxins produced by some strains of E. coli (including O157:H7) are important factors in disease severity. The toxins target endothelial cells and play a significant role in the microangiopathic complications of Shigella and E. coli infections, such as hemolytic-uremic syndrome (HUS; i.e., Coombs-negative hemolytic anemia, thrombocytopenia, and acute renal failure) and thrombotic thrombocytopenic purpura.
• An analysis of Shigella cases occurring in 1966-1997 revealed an annual incidence of 165 million cases (of which 69% affected children <5 years of age) with 0.5-1.1 million deaths; the mortality rates have decreased since then, but multidrug-resistant strains have emerged.

Clinical Manifestations

After an incubation period of 1-4 days, shigellosis evolves through three phases: watery diarrhea, dysentery (bloody mucopurulent stools), and the postinfectious phase.

• Most episodes resolve in 1 week without treatment; with appropriate treatment, recovery takes place within a few days, with no sequelae.
• Complications are largely intestinal (e.g., toxic megacolon, intestinal perforation, rectal prolapse) or metabolic (e.g., hypoglycemia, hyponatremia). Shiga toxin produced by S. dysenteriae type 1 is linked to HUS in developing countries but is rare in industrialized countries, where E. coli O157:H7 is a more common cause.

Diagnosis

Shigellosis is diagnosed directly by stool culture. STEC/EHEC infection is diagnosed by simultaneous culture (assaying for E. coli strains that do not ferment sorbitol, with subsequent serotyping for O157) and assay for the detection of Shiga toxin (which can rapidly detect non-O157 STEC/EHEC and sorbitol-fermenting strains of O157:H7).

Microbiology and Clinical Manifestations

Yersinia enterocolitica and Y. pseudotuberculosis are nonmotile gram-negative rods that cause enteritis or enterocolitis with self-limited diarrhea that lasts an average of 2 weeks as well as mesenteric adenitis (especially common with Y. pseudotuberculosis) and terminal ileitis (especially common with Y. enterocolitica), either of which can resemble acute appendicitis. Septicemia can occur in pts with chronic liver disease, malignancy, diabetes mellitus, and other underlying illnesses. Infection has been linked to reactive arthritis in HLA-B27-positive pts.

Diagnosis

Stool culture studies for Yersinia must be specifically requested and require the use of special media.

Microbiology and Epidemiology

Entamoeba histolytica, the cause of amebiasis, infects ∼10% of the world's population and is the second most common cause of death from parasitic disease (after malaria). Infection follows ingestion of cysts from fecally contaminated water, food, or hands. Motile trophozoites are released from cysts in the small intestine and then cause infection in the large bowel. Trophozoites may be shed in stool (in active dysentery) or encyst. Excreted cysts survive for weeks in a moist environment.

Clinical Manifestations

Most pts harboring Entamoeba species are asymptomatic, but some pts develop inflammatory colitis 2-6 weeks after ingestion of amebic cysts.

• Dysentery may develop, with daily passage of 10-12 small stools consisting mostly of blood and mucus. Fewer than 40% of pts have fever.
• Fulminant amebic colitis-characterized by more profuse diarrhea, severe abdominal pain with peritoneal signs, and fever-is more common among children.
• Liver abscess is the most common type of extraintestinal infection and can arise months (usually ≤5 months) after exposure to E. histolytica. Pts present with RUQ pain, fever, right-sided pleural effusion, and hepatic tenderness and typically do not have active colitis. The abscess can rupture through the diaphragm and metastasize elsewhere (e.g., lung, heart).

Diagnosis

Microscopic examination of three stool samples, often combined with serologic testing, remains the standard diagnostic approach.

• Up to 10% of pts with acute amebic liver abscess may have negative serologies; testing should be repeated in 1 week if clinical suspicion remains high.

Microbiology and Epidemiology

C. difficile is an obligately anaerobic, gram-positive, spore-forming bacillus and causes diarrheal illness that is most commonly acquired in the hospital. The disease is typically acquired in association with antimicrobial treatment; virtually all antibiotics carry a risk of CDI.

• After C. difficile colonizes the gut, its spores vegetate, multiply, and secrete toxin A (an enterotoxin) and toxin B (a cytotoxin), causing diarrhea and pseudomembranous colitis. The rate of fecal colonization is often ≥20% among adult pts hospitalized for >2 weeks; in contrast, the rate is 1-3% among community residents.
• Spores can persist on environmental surfaces in the hospital for months and on the hands of hospital personnel who do not practice adequate hand hygiene.
• Rates and severity of CDI in the United States, Canada, and Europe have increased markedly since the year 2000. The epidemic NAP1/BI/027 strain accounts for much of the increase and is characterized by production of 16-23 times as much toxin A and toxin B as is documented for control strains, by the presence of a third toxin (binary toxin), and by high-level resistance to fluoroquinolones; however, the incidence of this particular epidemic strain has been decreasing over the past few years, with concomitant decreases in rates of CDI.

Clinical Manifestations

Most commonly, pts develop diarrhea, with stools that are not grossly bloody and are soft to watery, with a characteristic odor. Pts may have up to 20 bowel movements per day. Fever, abdominal pain, and leukocytosis are common.

• Constipation due to an adynamic ileus can occur. Unexplained leukocytosis (≥15,000 WBCs/µL) in this setting should prompt evaluation for CDI. These pts are at high risk for complications such as toxic megacolon and sepsis.
• C. difficile diarrhea recurs after treatment in ∼15-30% of cases.

Diagnosis

CDI is diagnosed in a pt with diarrhea (≥3 unformed stools per 24 h for ≥2 days) by detection of toxin-producing organism, toxin A, or toxin B in stool or identification of pseudomembranes in the colon.

• Most laboratory tests for toxin (e.g., EIAs) lack sensitivity, but repeat testing is not recommended. PCR assays are rapid, sensitive, and highly specific.
• Testing of asymptomatic pts (including a test of cure for those who have completed therapy) is not recommended.