Salmonella

Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Transmission occurs through the fecal-oral route and consumption of contaminated foods and water. Bacteria penetrate the intestinal cells through microfold cells of Peyer’s patches and cause abdominal symptoms. Pathogens can also disrupt sodium and chloride transport in the intestine (causing diarrhea) and invade the bloodstream (causing sepsis and nonintestinal infection). Major clinical presentations include typhoid or enteric fever, foodborne enterocolitis, and bacteremia. Antibiotic treatment is considered in severe illness and chronic carrier states.

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Classification

Gram negative bacteria classification flowchart

Gram-negative bacteria:
Most bacteria can be classified according to a lab procedure called Gram staining.
Bacteria with cell walls that have a thin layer of peptidoglycan do not retain the crystal violet stain utilized in Gram staining. These bacteria do, however, retain the safranin counterstain and thus appear as pinkish-red on the stain, making them gram negative. These bacteria can be further classified according to morphology (diplococci, curved rods, bacilli, and coccobacilli) and their ability to grow in the presence of oxygen (aerobic versus anaerobic). The bacteria can be more narrowly identified by growing them on specific media (triple sugar iron (TSI) agar) where their enzymes can be identified (urease, oxidase) and their ability to ferment lactose can be tested.
* Stains poorly on Gram stain
** Pleomorphic rod/coccobacillus
*** Require special transport media

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General Characteristics

Salmonella spp.

  • Features:
    • Gram stain and structure: gram-negative bacilli
    • Motility: motile and flagellated
    • Non-lactose-fermenting microbes; ferment glucose and mannose
    • Oxidase-negative bacilli
    • Inactivated by acids
    • Ability to produce hydrogen sulfide (H2S)
    • Growth medium:
      • Eosin methylene blue (EMB), MacConkey, or deoxycholate medium used to detect non-lactose-fermenting microbes
      • Selective for Salmonella-Shigella (SS): Hektoen enteric (HE) agar, SS agar
  • Associated diseases: typhoid fever, gastroenteritis/enterocolitis, bacteremia

Clinically relevant species

Salmonella enterica is the primary species and has the following serotypes:

  • Typhoidal (serotypes that cause typhoid or enteric fever):
    • S. enterica serotype typhi (formerly S. typhi)
    • S. paratyphi
  • Nontyphoidal (all other serotypes associated with foodborne gastroenteritis, most common in the United States):
    • S. enteritidis
    • S. typhimurium
Salmonella enterica serotype Typhimurium

Salmonella enterica serotype typhimurium: one of the causes of foodborne diseases

Image: “A Novel Data-Mining Approach Systematically Links Genes to Traits” by Volker Brinkmann. License: CC BY 4.0

Pathogenesis

Transmission and virulence

  • Reservoirs:
    • Typhoidal: human GI tract
    • Nontyphoidal: 
      • Farm animals: poultry, cattle, and pigs
      • Pets: turtles, parrots, rodents, cats, and dogs
  • Transmission:
    • Fecal-oral route
    • Ingestion of food products (commonly contaminated or undercooked foods, including poultry and eggs)
    • Infecting dose of S. enterica infection:
      • Varies with serotype
      • Considerably higher than Shigella (human-to-human transmission by direct contact unlikely)
    • S. enterica is inactivated by acids. Smaller inocula can infect individuals on antacids or patients with achlorhydria.
  • Virulence:
    • Vi capsular polysaccharide antigen: 
      • Surface polysaccharide in Salmonella typhi 
      • Interferes with phagocytosis
    • H (flagellar) antigen: required for motility
    • O (lipopolysaccharide) antigen: produces smooth colonies on agar
    • Pili: 
      • Bind to D-mannose receptors on eukaryotic cell types
      • Similar to Escherichia coli type 1 pili in function and morphology

Disease process

  • Entry in humans via ingestion:
    • Some organisms survive gastric-acid exposure → small bowel
    • From the lumen, Salmonella spp., mediated by their pili, can:
      • Penetrate M (microfold) cells of Peyer’s patches (gut-associated lymphoid system)
      • Penetrate epithelial cells of the bowel
  • In the bowel:
    • Organisms proliferate → Peyer’s patch hyperplasia and inflammation (fever, abdominal symptoms)
    • Salmonella spp. go further into the lamina propria.
    • Proliferation leads to:
      • Further invasion and recruitment of mononuclear cells and lymphocytes → may cause ulcerations
      • Disruption of sodium and chloride transport between cells and intestinal lumen → diarrhea
  • In severe cases:
    • Replication persists in the reticuloendothelial system → hepatosplenomegaly
    • Invading pathogens enter bloodstream → sepsis
Pathogenesis of Salmonella

Pathogenesis of Salmonella:
In the small bowel, Salmonella spp. (pink, oval spots) penetrate the mucosal barrier and enter the microfold cells (blue) and epithelial cells (purple) by bacteria-mediated endocytosis.
Microbes are released deep into the lamina propria. Sodium chloride (NaCl) imbalance is induced, resulting in diarrhea. An inflammatory response is elicited, recruiting mononuclear cells (e.g., dendritic cells) and lymphocytes. With further invasion, bacteria continue to replicate and spread in the bloodstream.

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Diseases Caused by Salmonella

Typhoidal species (Salmonella typhi and paratyphi)

Typhoid fever or enteric fever:

  • Description:
    • Severe systemic illness in which bacteria enter the bloodstream and disseminate in organs and lymphoid tissue
    • More common in:
      • Children, young adults
      • Impoverished regions
      • Travelers (to endemic areas)
  • Course of disease:
    • 1st week: 
      • Gradually rising fever
      • Relative bradycardia
      • Pulse-temperature dissociation
      • Constipation
    • 2nd week: 
      • Persistent fever
      • Abdominal pain (diarrhea or constipation)
      • Rose spots: salmon-colored macules (trunk)
    • 3rd week:
      • Ileocecal lymphatic hyperplasia of Peyer’s patch (can lead to perforation)
      • Peritonitis
      • Bacteremia
      • Intestinal bleeding
      • Hepatosplenomegaly
      • Altered mental status (toxic encephalopathy)
    • If no complications, symptoms resolve over weeks
  • Treatment:
    • Fluoroquinolones (check susceptibility as resistance is a possibility)
    • Other options: azithromycin or 3rd-generation cephalosporins
    • In severe systemic illness (e.g., delirium, stupor): addition of dexamethasone

Chronic carrier state:

  • Description:
    • Excretion of Salmonella in stool or urine > 12 months post infection
    • More frequent in:
      • Women
      • Patients with cholelithiasis/biliary-tract disease (can ↑ risk of gallbladder cancer)
      • Patients with urinary tract abnormalities or Schistosoma bladder infection (rare)
  • Course of disease:
    • Asymptomatic carriers
    • Carriers can transmit bacteria in cases of improper handwashing.
    • High risk of transmission via foods (e.g., Mary Mallon, or “Typhoid Mary”)
  • Treatment: 
    • Fluoroquinolone for 4 weeks (if susceptible)
    • Limited evidence with amoxicillin and trimethoprim-sulfamethoxazole (TMP-SMX)
    • Cholecystectomy in some cases

Nontyphoidal species (Salmonella enteritidis and typhimurium)

Enterocolitis/gastroenteritis:

  • Description: 
    • Most common presentation of Salmonella infection
    • Most common occurrence:
      • Consumption of poultry, eggs, and egg products (Salmonellae passed from chicken to eggs transovarially)
      • Consumption of contaminated water, meat, and other food products
      • Contact with animal reservoirs (especially pets) also increases the risk.
  • Course of disease:
    • From 8–72 hours after exposure:
      • Nausea, vomiting, fever
      • Abdominal pain and diarrhea
      • ↑ Ingested dose of bacteria: ↑ severity and duration of illness
    • Fever resolves by the 3rd day.
    • Diarrhea can take up to 10 days to resolve.
    • Chronic carrier state is rare (but may occur in patients with gallstones).
  • Treatment:
    • Hydration and electrolyte replacement
    • For mild symptoms and immunocompetent patients: antibiotics not used, disease is self-limiting
    • For severe illness (e.g., diarrhea 9–10 times/day) and/or immunocompromised individuals:
      • Fluoroquinolones (caution in children, may result in cartilage abnormalities)
      • Other options: TMP-SMX, azithromycin, 3rd-generation cephalosporins
    • For chronic carriers:
      • 4–6 weeks of antibiotics
      • Cholecystectomy in some cases

Bacteremia:

  • Description:
    • < 1% of Salmonella gastroenteritis, with majority of bacteremia cases in individuals < 5 years of age
    • Involves more invasive species (such as serotypes choleraesuis, heidelberg)
    • More common in:
      • Immunocompromised patients
      • Infants and the elderly
      • Hemoglobinopathies
      • Schistosomiasis, malaria
      • Chronic granulomatous disease
  • Course of disease: 
    • Can include septic arthritis, endocarditis, osteomyelitis, and meningitis
    • Endovascular infection (most common in abdominal aorta): 
      • Rare but serious complication
      • Causes aneurysms and atherosclerotic plaques
  • Treatment (longer course):
    • Fluoroquinolones
    • Alternatives: 3rd-generation cephalosporins, TMP-SMX, ampicillin

Comparison with Shigella

Both Salmonella and Shigella can invade the GI tract and cause diarrhea.

ShigellaSalmonella
Gram stain/structureGram-negative bacilliGram-negative bacilli
Lactose fermentationNon-fermenting microbesNon-fermenting microbes
OxidaseNegativeNegative
H2S productionNoYes
MotilityNoYes (with flagella)
Virulence factorsEndotoxin, Shiga toxinEndotoxin, Vi capsular antigen
ReservoirHumansHumans (S. typhi), animals
Dose to produce diseaseSmall inoculum (acid stable)Large dose (inactivated by acids)
Infection spreadCell to cell (no hematogenous spread)Can spread hematogenously

References

  1. Hohmann, E. (2019). Nontyphoidal Salmonella: Microbiology and epidemiology. UpToDate. Retrieved 31 January 2021, from https://www.uptodate.com/contents/nontyphoidal-salmonella-microbiology-and-epidemiology
  2. Hohmann, E. (2020). Nontyphoidal Salmonella: Gastrointestinal infection and carriage. UpToDate. Retrieved 5 Feb 2021, from https://www.uptodate.com/contents/nontyphoidal-salmonella-gastrointestinal-infection-and-carriage
  3. Hohmann, E. (2020). Nontyphoidal Salmonella bacteremia. UpToDate. Retrieved 5 Feb 2021, from https://www.uptodate.com/contents/nontyphoidal-salmonella-bacteremia
  4. Kotton, C., Hohmann, E. (2019). Pathogenesis of Salmonella gastroenteritis. UpToDate. Retrieved 5 Feb 2021, from https://www.uptodate.com/contents/pathogenesis-of-salmonella-gastroenteritis
  5. Riedel, S., Jawetz, E., Melnick, J. L., & Adelberg, E. A. (2019). Jawetz, Melnick & Adelberg’s Medical Microbiology (pp. 235–238 and 245–250). New York: McGraw-Hill Education.
  6. Ryan, E., Andrews, J. (2019). Pathogenesis of enteric (typhoid and paratyphoid) fever. UpToDate. Retrieved 5 Feb 2021, from https://www.uptodate.com/contents/pathogenesis-of-enteric-typhoid-and-paratyphoid-fever
  7. Ryan, E., Andrews, J., John, J. (2020). Epidemiology, microbiology, clinical manifestations and diagnosis of enteric (typhoid and paratyphoid) fever. UpToDate, Retrieved 5 Feb 2021, from https://www.uptodate.com/contents/epidemiology-microbiology-clinical-manifestations-and-diagnosis-of-enteric-typhoid-and-paratyphoid-fever
  8. Ryan K.J. (2017). Enterobacteriaceae. Sherris Medical Microbiology, 7e. McGraw-Hill.

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