OVERVIEW: What every clinician needs to know

Pathogen name and classification

Shigella is a nonmotile gram-negative bacillus that does not ferment lactose. It grows readily on standard media and can be easily isolated using selective media. It is a member of the Enterobacteriaceae family and is closely related to E. coli. Shigella contains a 220-kb virulence plasmid that carries the genes that mediate its ability to invade and cause disease in humans. There are four major serologic groups, A through D. In the United States S. sonnei (Group D) is most common (75% of cases) followed by S. flexneri (Group B). In developing countries S. flexneri is most common, followed by S. sonnei. S. dysenteriae (Group A) and S. boydii (Group C) are less common.

What is the best treatment?

  • For most patients the treatments of choice are:

    Ciprofloxacin 500mg po Q12H x 3 days

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    Levofloxacin 500mg po Q24H x 3 days


    Azithromycin 500mg po Q24H x 3 days

  • Alternatively trimethoprim-sulfamethoxazole can be administered (higher levels of resistance reported in many regions, 48% in the U.S.)

    160/800mg (one double strength) po Q12H x 5 days

  • In the very ill patient or a patient coming from Asia.

    Ceftriaxone is preferred 1-2gm IV Q24H x 5 days

  • Antibiotic resistance is a major problem when treating shigellosis.

    Plasmids (R plasmids) carrying resistance genes directed against ampicillin, tetracycline, trimethoprim-sulfamethoxazole, chloramphenicol, and streptomycin are common

    Transposons also transfer resistance genes

    In epidemics, mobile genes within chromosomes (integrons) can transfer resistance.

    High rates of resistance are found in Africa, Asia, and South America

    Resistance to nalidixic acid is found in 20% of isolates from Bangladesh.

    In the United States resistance to ampicillin, trimethoprim-sulfa and ampicillin are now extremely common. Resistance to ceftriaxone, ciprofloxacin and nalidixic acid are increasing.

  • Given the increasing risk of antibiotic resistant strains, whenever possible the organism should be cultured and antibiotic sensitivities determined.

  • Antibiotic treatment shortens symptomatic disease by 2 days and shortens the shedding of Shigella in the stools reducing person to person spread of the disease. Treatment has also been shown to reduce Shiga toxin levels in association with S. dysenteriae

How do patients contract this infection, and how do I prevent spread to other patients?

  • Epidemiology:

    The annual number of Shigella infections is estimated to be 165 million worldwide, with over 100 million occuring in developing countries; 1 million deaths occur annually, primarily in developing countries.

    Shigella is capable of resisting the acid environment of the stomach. As a consequence, ingestion of between 50 and 200 bacteria is sufficient to cause shigellosis. Salmonella and Campylobacter are acid sensitive and require the ingestion of 104-108 organisms to cause disease.

    Because of the low innoculum required to cause disease, Shigella readily spread from person to person, while Salmonella and Campylobacter are primarily spread via contaminated foods or water.

    Secondary cases are common. When an infant develops shigellosis, 40% of other children and 20% of adults in the household will contract the disease

    In custodial institutions, mentally challenged individuals commonly carry fecal flora on their hands and the spread of Shigella has been documented despite adequate washrooms and attempts at good personal hygiene.

    Day care centers are a common source of infection in the US. Shigella infection is common among school-aged children in Great Britain. Children with shigellosis commonly contaminate toilet seats.

    Infection has been spread by men having sex with men; infection is transmitted primarily through oral-anal contact.

    Shigellosis most commonly occurs in the summer months when the bacterium can readily survive in the environment; the pathogen has been shown to be spread by flies.

    Foodborne disease is uncommon in developed countries, but has been reported in association with potato and macaroni and other cold salads. In developing countries fecal contamination during cultivation can contaminate raw tomatoes and lettuce.

    In developing countries this pathogen is also be spread through contaminated water.

    Shigella can survive in water for 6 months

    Outbreaks can occur when wells are in close proximity to sewer systems, cesspools or outhouses.

    Chlorination kills Shigella and eliminates the risk of waterborne disease

  • Infection control issues:

    Handwashing with soap and water or treatment with alcohol based hand rubs can prevent person-to-person spread.

    Food handlers need to wash their hands after visits to the bathroom and before handling food.

    Food handlers with documented Shigella infection should not handle food until their stool culture is negative. Stool can be cleared by antibiotic therapy in most cases

    Improvement of sewage handling and a safe water supply are the key infection control measure required in developing countries. Other important control measures include:

    Control of flies through insecticides

    Proper handling and refrigeration of foods

    Cooking food thoroughly

    Breast feeding protects against infant Shigella dysentery.

    No vaccine is available.

    Antibiotic prophylaxis is discouraged because the risk of further selection of antibiotic resistant strains.

What host factors protect against this infection?

  • IgA antibodies directed against Shigella occur following Shigella infection.

  • Immunoglobulin can serve as an opsonin, enhancing phagocytosis by monocytes, macrophages and neutrophils.

  • Ingestion of Shigella by macrophages is accompanied by increases in levels of pro-inflammatory cytokines.

What are the clinical manifestations of infection with this organism?

  • Within 1-7 days after ingestion Shigella infects the small intestine where it initially stimulates high-volume watery diarrhea accompanied by cramps. Diarrhea is often accompanied by fever, anorexia, and fatigue.

  • Within several days the infection migrates to the lower gastrointestinal tract where it causes lower abdominal cramps accompanied by bilateral lower quadrant abdominal tenderness and small volume diarrheal stools.

  • Patients may experience tenesmus and in about half of patients the stools are bloody. Mucoid diarrhea is most common, being found in 70-85% of cases.

  • Approximately 1/3rd of patients experience vomiting.

  • The severity of disease varies depending on the serogroup:

    S. sonnei usually causes mild disease with primarily watery diarrhea but can cause bacteremia in patients with diabetes or malignancy.

    S. dysenteriae1 and S. flexneri usually cause bloody diarrhea

  • The disease is usually self-limited, lasting no more than 7 days in the absence of antibiotic treatment.

What common complications are associated with infection with this pathogen?

  • Bacteremia is uncommon, varying from 0-7% of patients, and is usually accompanied by leukocytosis and hyponatremia as well as high fever, lethargy and severe dehydration. In patients with HIV the incidence of bacteremia is much higher and is accompanied by severe illness and death.

  • Complications are rare, but can include:

    Proctitis or rectal prolapse. Usually seen in infants and young children

    Intestinal obstruction most commonly associated with S. dysenteriae 1, may be accompanied by a high peripheral WBC and decreased serum sodium.

    Toxic megacoloon is most commonly associated with S. dysenteriae 1, and is associated with pancolitis

    Hemolytic-uremic syndrome (HUS) is rare, but can be associated with infection due to S. dysenteriae 1 which can produce the same Shiga toxin as E. coli 0157:H7. Unlike the latter organism treatment with antibiotics decrease toxin production and reduces the likelihood of HUS.

  • Reactive arthritis (previously called Reiter’s syndrome) rarely develops 1-2 weeks after diarrhea. These patients are frequently HLA-B27 positive (70% of the time).

How should I identify the organism?

  • The stool would be expected to contain large numbers of neutrophils and red blood cells.

  • Stool culture provides the definitive diagnosis.

    Because Shigella is quite fastidious the stool should be promptly cultured

    A stool sample provides a higher yield than rectal swab.

    Mucoid material provides the highest yield.

    Lactose containing media combined with a color indicator helps identify suspicious colonies (Shigella does not ferment lactose and colonies will be lactose negative.) This bacterium does ferment glucose and is indole positive, and urea and oxidase negative

    Selective media is often helpful.

  • PCR – as few as 10 organisms can be detected by PCR. PCR is costly and presently is only available as a research tool.

How does this organism cause disease?

  • Shigella contains a type III secretion system that injects bacterial proteins into host cells that stimulate the host cell membrane to ruffle and capture bacteria in giant phagosomes.

  • Subsequently the bacterium lyses the confining membrane and escapes into the cytoplasm where the surface protein IcsA (VirG) attracts the host cell actin regulatory protein N-WASP. This protein in turn attracts and activates a protein complex that stimulates the assembly of new actin filaments called Arp2/3. These proteins result in the formation of actin filament rocket tails at one end of the bacterium. As these rocket tails elongate they push the bacterium through the cytoplasm eventually reaching the host cell peripheral membrane.

  • A large membrane protrusion with a single bacterium at tip is formed (recently termed a transpodia because this structure transports the bacterium from one cell to another). With the help of the host cell protein Myosin 10, the membrane protrusion pushes into an adjacent host cell where it is ingested and the bacterium than escapes into the cytoplasm of the new cell allowing Shigella to spread from cell to cell without ever coming in contact with the extracellular milieu.

  • Shigella toxins cause premature host cell apoptosis and result in zones of necrosis in the bowel wall, explaining the formation of bloody ulcerations that become infiltrated with neutrophils.

  • The ability to spread from cell to cell and cause cell necrosis can explain the accompanying bloody diarrhea, as well as the many neutrophils seen in the stools of patients with Shigella dysentery.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Bennish, ML, Khan, WA, Begum, M. “Low risk of hemolytic uremic syndrome after early effective antimicrobial therapy for Shigella dysenteriae type 1 infection in Bangladesh”. Clin Infect Dis. vol. 42. 2006. pp. 356-362. (Unlike infection with Ecoli 0157 in which antibiotic treatment increases Shiga toxin levels and the likelihood of Hemolytic Uremic Syndrome (HUS), administration of antibiotics decreases Shiga toxin levels in S. dysenteriae type 1 infection and reduces the likelihood of HUS.)

Bernardini, ML, Mounier, J, d’ Hauteville, H, Coquis-Rondon, M, Sansonetti, PJ. “Identification of icsA, a plasmid locus of Shigella flexneri that governs bacterial intra- and intercellular spread through interaction with F-actin”. Proc Natl Acad Sci U S A. vol. 86. 1989. pp. 3867-3871. (This is the first study to demonstrate that Shigella induces actin filament assembly and induces transpodia formation for cell-to-cell spread)

Hawkins, C, Taiwo, B, Bolon, M, Julka, K, Adewole, A, Stosor, V. “Shigella sonnei bacteremia: two adult cases and review of the literature”. Scand J Infect Dis. vol. 39. 2007. pp. 170-173. (S. sonnei usually causes mild disease; however patients with Diabetes Mellitus or malignancy can develop bacteremia and more severe clinical manifestations.)

Keddy, KH, Sooka, A, Crowther-Gibson, P. “Systemic shigellosis in South Africa”. Clin Infect Dis. vol. 54. 2012. pp. 1448-1454. (Female patients with HIV are more likely to develop bacteremia and fatal systemic shigelosis.)

Kuo, CY, Su, LH, Perera, J. “Antimicrobial susceptibility of Shigella isolates in eight Asian countries, 2001-2004”. J Microbiol Immunol Infect. vol. 41. 2008. pp. 107-111. (Increasing resistance to ciprofloxacin is now being seen in Hong Kong, the Philippines, Korea, Vietnam and Sri Lanka and to ceftriazone in Taiwan, Hong Kong and the Philippines.)

Mounier, J, Popoff, MR, Enninga, J, Frame, MC, Sansonetti, PJ, Van Nhieu, GT. “The IpaC carboxyterminal effector domain mediates Src-dependent actin polymerization during Shigella invasion of epithelial cells”. PLoS Pathog. vol. 5. 2009. pp. e1000271(Ipa C is injected into host cells by the type III secretion system of Shigella and induces actin-mediated host cell phagocytosis and entry.)

Shiferaw, B, Solghan, S, Palmer, A. “Antimicrobial susceptibility patterns of Shigella isolates in Foodborne Diseases Active Surveillance Network (FoodNet) sites, 2000-2010”. Clin Infect Dis. vol. 54. 2012. pp. S458-463. (Resistance to ampicillin, trimethoprim-sulfa, and tetracycline are common in the U.S. and multidrug resistance is increasingly being found.)