Streptococcus

Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci (e.g., S. mutans, S. mitis, and S. sanguinis). Streptococcal infections cause a wide array of clinical manifestations, including pharyngitis, pneumonia, skin and soft tissue infections, endocarditis, septicemia, meningitis, and streptococcal toxic shock syndrome. They are also responsible for the postinfectious syndromes of acute rheumatic fever and poststreptococcal glomerulonephritis. Most streptococci are sensitive to penicillin.

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General Characteristics

Shared characteristics

  • Gram-positive cocci: Some may lose positive staining after overnight incubation or if the culture ages and bacteria die.
  • Grow in pairs or chains: Classic long chains are best seen when grown in liquid medium.
  • Nonmotile
  • Non–spore-forming
  • Facultative anaerobes (oxygen tolerant)
  • Catalase negative:
    • Catalase is an enzyme that splits hydrogen peroxide into water and oxygen.
    • The state of being catalase negative is a key finding that differentiates streptococci from staphylococci, which are catalase positive.
  • Habitats: skin and mucous membranes of humans and animals

Capsule

  • Important virulence factor
  • Encapsulated streptococci:
    • Hyaluronic acid: group A (S. pyogenes)
    • Polysaccharide:
      • Group B (S. agalactiae)
      • S. pneumoniae
      • Group D (Enterococcus)
  • Nonencapsulated streptococci: 
    • Viridans streptococci 
      • S. viridans is not a true or single species; rather, it is a pseudo-taxonomic term.
      • Represents different groups of streptococci, including the S. bovis group (e.g., S. gallolyticus), S. mitis, the S. mutans group, S. sanguinis, the S. anginosus group, S. constellatus, S. intermedius, and the S. salivarius group.
    • Nonencapsulated S. pneumoniae:
      • Some natural nonencapsulated phenotypes exist and cause disease.
      • Capsular production is lost by all encapsulated pneumococci after passing through a few subcultures on agar, but they will again produce capsules (and have enhanced virulence) if injected into mice.

Biofilm

Streptococci have the ability to form biofilms:

  • Densely packed bacterial communities 
  • Grow on surfaces or human tissues
  • Bacteria secrete and surround themselves with a slimy matrix composed of polymers (polysaccharides in streptococcal species).
  • Examples of biofilms:
    • Dental plaque
    • Bacterial colonization of chronic wounds

Significance:

  • More resistant to host immune defenses
  • More resistant to antibiotics

Differentiation of Streptococcus Species

Gram-positive bacteria:
Most bacteria can be classified according to a lab procedure called Gram staining.
Bacteria with cell walls that have a thick layer of peptidoglycan retain the crystal violet stain utilized in Gram staining but are not affected by the safranin counterstain. These bacteria appear as purple-blue on the stain, indicating that they are gram positive. The bacteria can be further classified according to morphology (branching filaments, bacilli, and cocci in clusters or chains) and their ability to grow in the presence of oxygen (aerobic versus anaerobic). The cocci can also be further identified. Staphylococci can be narrowed down on the basis of the presence of the enzyme coagulase and on their sensitivity to the antibiotic novobiocin. Streptococci are grown on blood agar and classified on the basis of which form of hemolysis they employ (α, β, or γ). Streptococci are further narrowed on the basis of their response to the pyrrolidonyl-β-naphthylamide (PYR) test, their sensitivity to specific antimicrobials (optochin and bacitracin), and their ability to grow on sodium chloride (NaCl) media.

Image by Lecturio.

Serologic (Lancefield) classification

  • Groups A–V are identified on the basis of the antigens in the cell wall, pili, or capsule.
  • Now mostly of historic interest, as many more species have been described
  • Some streptococcal species are still traditionally referred to by their serologic types (groups A, B, and D).
    • Group A: S. pyogenes
    • Group B: S. agalactiae
    • Group C: S. equisimilis, S. equi, S. zooepidemicus
    • Group D: Enterococcus faecalis, E. faecium, E. durans, S. bovis
    • Groups F, G, and L: S. anginosus
    • Group H: S. sanguis
    • Group K: S. salivarius
    • Group L: S. dysgalactiae
    • Groups M and O: S. mitis
    • Group N: Lactococcus lactis
    • Groups R and S: S. suis

Hemolytic classification

Streptococci grow well on blood agar. Streptococcus species are divided into 3 groups on the basis of their hemolysis pattern:

  • β-Hemolytic: complete hemolysis (clear zone of hemolysis):
    • S. pyogenes
    • S. agalactiae
  • α-Hemolytic: partial hemolysis (green zone of hemolysis):
    • S. pneumoniae
    • Viridans streptococci (variable hemolytic patterns in some species)
  • γ-Hemolytic: no hemolysis:
    • S. gallolyticus (a member of the S. bovis group)
    • S. faecalis and S. faecium have been reclassified into the distinct genus of Enterococcus as E. faecalis and E. faecium.

Blood agar plate showing β-hemolytic colonies of S. pyogenes:
Note the complete (beta-type) hemolysis around each colony.

Image: “Lancefield Group A” by Nathan Reading. License: CC BY 2.0

Distinguishing factors of the pathogenic streptococci

Distinguishing factors of the pathogenic streptococci
SpeciesMorphologyUsual habitatDistinguishing features
S. pyogenes (group A strep)Appear in pairs of chainsThroat, skin
  • Encapsulated by hyaluronic acid
  • β-Hemolytic
  • Inhibited by bacitracin
  • PYR positive
S. agalactiae (group B strep)Appear in pairs or chainsVagina, lower gastrointestinal tract
  • Encapsulated by polysaccharide capsule
  • β-Hemolytic
  • Hippurate positive
  • cAMP test positive: Increasing zone of hemolysis when plated with S. aureus
  • Bacitracin resistant
S. pneumoniaeLancet-shaped diplococciNasopharynx
  • Encapsulated by polysaccharide capsule
  • α-Hemolytic
  • Optochin sensitive
  • Bile soluble: cannot grow in bile
Viridans streptococci: S. mutans, S. mitis, S. sanguinisAppear in pairs or chainsOral cavity, colon (S. bovis)
  • Nonencapsulated
  • α-Hemolytic
  • Optochin resistant
  • Bile resistant: can grow in bile
Enterococci (formerly group D strep, reclassified as the distinct genus Enterococcus): E. faecalis, E. faecium
S. gallolyticus (in group D and a member of the S. bovis group)
Appear in pairs, short chains, or singlyMostly in intestine, but oral cavity and vagina can be colonized
  • Ɣ-Hemolytic (nonhemolytic)
  • Grow in 6.5% NaCl
PYR: pyrrolidonyl-β-naphthylamide

Pathogenesis

Each pathogenic species of streptococci has key virulence factors that relate to their spread and clinical manifestations. See the charts below for a summary of these features in selected species:

Virulence factors and functions of S. pyogenes (group A strep)
Virulence factorsFunction
CapsuleInhibits phagocytosis
M protein (involved in rheumatic fever)
  • Antiphagocytic
  • Molecular mimicry (type II hypersensitivity reaction) of myosin in heart valves: The mitral valve is affected most often and the aortic valve less commonly.
Streptolysin OLyses RBCs
Streptokinase (fibrinolysin)Converts plasminogen to plasmin and lyses blood clots, allowing bacteria to escape from the clot
DNAse
  • Depolymerizes DNA
  • Aids in spread by liquefying pus, which owes its viscosity to DNA (mostly from dead neutrophils)
HyaluronidaseAids in spread by splitting hyaluronic acid, an important component of the ground substance of connective tissue
Lipoteichoic acid (covers hairlike pili that project through capsule)Adhere to epithelial cells
3 types of streptococcal pyrogenic exotoxins:
  • SpeA: involved in scarlet fever and streptococcal toxic shock syndrome
  • SpeB: protease, involved in poststreptococcal glomerulonephritis (bacterial infection-related glomerulonephritis)
  • SpeC: involved in scarlet fever and streptococcal toxic shock syndrome
SpeA and SpeC are called superantigens because they stimulate T cells to produce cytokines by binding to the V-beta region of the T-cell receptor.
  • In scarlet fever: Blood vessels are dilated because the cutaneous cytokine milieu is altered.
  • In toxic shock syndrome: The overwhelming release of inflammatory cytokines by T cells mediates shock.
  • In poststreptococcal glomerulonephritis: Antigen–antibody complexes form on the glomerular basement membrane. The two most important group A strep antigens are SpeB and nephritis-associated plasmin receptor.
2 types of hemolysins:
  • Streptolysin O: stimulates production of antibody anti–streptolysin O (ASO); inactivated by oxygen
  • Streptolysin S: not antigenic
Lyse RBCs and also damage the membranes of other cells
Spe: Streptococcal pyrogenic exotoxins
Virulence factors and functions of S. agalactiae (group B strep)
Virulence factorsFunction
CapsuleInhibits phagocytosis
Virulence factors and functions of S. pneumoniae
Virulence factorsFunction
CapsuleInhibits phagocytosis
IgA proteaseMucosal invasion
Virulence factors and functions of S. mutans
Virulence factorsFunction
DextransPlatelet adhesion
In vivo biofilm productionAdhesion

Diseases Caused by β-Hemolytic Streptococci

Streptococcus pyogenes

Streptococcus pyogenes is the most virulent pathogen in the Streptococcus family.

Pharyngitis:

  • Most common infection caused by S. pyogenes 
  • In infants and small children: subacute nasopharyngitis, palatal petechiae, cervical lymphadenopathy; may lead to middle-ear infection
  • In older children and adults: intense nasopharyngitis, tonsillitis, purulent exudates, high fever, cervical lymphadenopathy
  • Asymptomatic infections: 20%
  • Many other etiologies of pharyngitis: adenovirus, infectious mononucleosis, gonococcal infection, diphtheria

Streptococcal pharyngitis:
Redness and edema of the throat and palatal petechiae

Image: “Streptococcal pharyngitis” by CDC/Dr. Heinz F. Eichenwald. License: Public Domain

Skin and soft tissue infections:

  • Impetigo: 
    • “Honey-crusted” skin lesions
    • Mostly affects children 2–5 years of age
    • Highly communicable, especially in hot, humid climates
    • May progress to cellulitis
    • May also be caused by Staphylococcus aureus
  • Erysipelas: 
    • Infection of upper dermis and superficial lymphatics
    • Red, raised, rapidly advancing, and well-demarcated margin of infection (being raised and well demarcated differentiates it from cellulitis)
  • Cellulitis: 
    • Infection of deep dermis and subcutaneous fat
    • Red, not raised, and not well-demarcated margin of infection (not being raised and not being well demarcated differentiates it from erysipelas)
  • Abscess: 
    • Localized collection of pus in a newly created cavity
    • S. pyogenes and Staphylococcus aureus (MRSA) are the most common causes of abscesses on the trunk, extremities, axillae, or head and neck.
  • Necrotizing fasciitis (“flesh-eating bacteria” or “streptococcal gangrene”)
    • A necrotizing soft tissue infection [NSTI] that also includes necrotizing forms of myositis and cellulitis  
    • Fulminant tissue destruction, systemic signs of toxicity, and high mortality; usually polymicrobial, with aerobic and anaerobic bacteria
    • Overlying skin may seem only mildly warm, with no clear portal of entry.
    • Predisposing factors: diabetes, trauma, immunosuppression
    • Pyrogenic exotoxins most likely contribute to shock via cytokines.
    • Surgical emergency: debridement and administration of antibiotics urgently needed

Impetigo in a child:
The image shows characteristic “honey-crusted” lesions around the mouth.

Image: “Microbio 21 02 impetigo” by CNX OpenStax. License: CC BY 4.0

Puerperal fever: occurs when S. pyogenes enters uterus after delivery, causing endometritis and bacteremia

Bacteremia or sepsis caused by:

  • Infected traumatic or surgical wounds
  • Skin infections (e.g., cellulitis)
  • Pharyngitis (rare)

Toxin-mediated diseases

Scarlet fever:

  • Usually in association with pharyngitis
  • Mediated by toxins (superantigen A or C) 
  • Diffuse papular erythematous rash; palms, soles, and face usually spared
  • “Strawberry tongue”
  • Circumoral pallor

Rash of scarlet fever

Image: “The rash of scarlet fever” by Alicia Williams. License: CC BY 2.5

Toxic shock syndrome (TSS):

  • Early-onset shock, bacteremia, respiratory failure, and multiorgan failure
  • Fatal in 30% of cases
  • May be preceded by minor trauma with local signs of infection
  • Mediated by superantigen toxins
  • Toxic shock syndrome can also be caused by Staphylococcus aureus, which can also express superantigen toxins.

Postinfectious sequelae

Rheumatic fever:

  • 2–3 weeks after pharyngitis
  • Early antibiotic treatment of pharyngitis decreases the incidence.
  • Associated with antibodies to streptolysin O, hyaluronidase, and streptokinase
  • J♡NES criteria:
    • Joint involvement (polyarthritis)
    • (mitral valve stenosis, myocarditis, pericarditis)
    • Nodules (subcutaneous; on extensor surfaces)
    • Erythema marginatum (rash)
    • Sydenham’s chorea (neurologic)

Poststreptococcal glomerulonephritis (PSGN):

  • Caused by specific nephritogenic strains that have the 2 most important antigens (SpeB and nephritis-associated plasmin receptor)
  • Occurs 2–3 weeks after pharyngitis or impetigo
  • Deposition of immune complexes within glomerular basement membrane (type 3 hypersensitivity reaction)
  • Hematuria/proteinuria, edema, hypertension
  • Usually (but not always) benign and self-limited

Streptococcus agalactiae: The Group B Streptococci (GBS)

  • Frequently colonize genital (in 5%–30% of women) and GI tracts 
  • In older adults with chronic medical conditions:
    • Most common infection: cellulitis
    • Sepsis
    • Less common: cystitis, pyelonephritis, pneumonia, septic arthritis, endocarditis, meningitis
  • In pregnant women:
    • Urinary tract infection (or asymptomatic bacteriuria)
    • Chorioamnionitis
    • Postpartum endometritis
  • In neonates:
    • Acquired in utero by ascending infection or during passage through vagina
    • Early (within 6 days) or late (up to 90 days) onset
    • Can present with:
      • Bacteremia (without focus)
      • Sepsis
      • Meningitis
      • Pneumonia
      • Respiratory distress syndrome

Diseases Caused by α-Hemolytic Streptococci

Streptococcus pneumoniae

  • Most common bacterial cause of community-acquired pneumonia
    • Presents with hypoxia, cough, tachypnea, tachycardia, fever
    • Human-to-human transmission by aerosols or close contact
  • Nasopharyngeal colonization is common (5%–40%). Aspiration of nasopharyngeal secretions into the lungs can lead to pneumonia if:
    • Very large bacterial inoculum
    • Normal clearance mechanisms impaired by smoking, viral infections, alcohol or drug intoxication, systemic illness, heart failure
  • Can also spread and cause bacteremia, which can result in bacterial seeding of other organs:
    • CNS: meningitis, otitis media, 
    • Cardiac: endocarditis, pericarditis
    • Rheumatic: septic arthritis, osteomyelitis

Infective endocarditis:
A bacterial vegetation (arrow) is seen on the tricuspid valve on an echocardiogram.

Image: “Endocarditis ultrasound” by Daisuke Koya et al. License: CC BY 2.0

Viridans Streptococci

  • Most prevalent bacteria of the normal microbiota of the upper respiratory tract
  • Important for the healthy state of the mucous membranes
  • Most commonly get into the bloodstream through breaks in oral mucosa (e.g., during dental procedures)
  • Have been associated with:
    • Sinusitis in immunocompromised patients
    • S. mutans: dental caries, endocarditis
    • S. mitis: endocarditis, bacteremia, high level of resistance to penicillin
    • S. bovis: endocarditis, biliary disease, common blood isolate in colon cancer
    • S. anginosus group: pyogenic infections in brain, liver, lung
    • S. salivarius group: bacteremia, endocarditis, meningitis

Enterococci

  • Reclassified into their own genus, Enterococcus
  • Very similar to Streptococcus in physical appearance and characteristics
  • Commensal organisms in human intestines
  • Have been associated with:
    • Urinary tract infections
    • Diverticulitis
    • Spontaneous bacterial peritonitis
    • Endocarditis (commonly after manipulation of GI or urinary tract)
    • Meningitis (rare)

Identification and Prevention

Identification and prevention
SpeciesIdentificationPrevention
S. pyogenes Group A strep (GAS)
  • Gram stain (cannot differentiate from a viridans streptococcus)
  • Rapid streptococcal antigen test (“strep test”): specificity high, but sensitivity 77%–92%
  • Throat culture: 24–48 hours
  • Beta-hemolysis
  • PCR testing: not always available
  • ASO titer, anti-DNAse titer: if rheumatic fever or acute poststreptococcal glomerulonephritis is suspected
Early (before day 8) antibiotic treatment of pharyngitis to prevent rheumatic fever (RF) and continued chemoprophylaxis for years in persons who have had an attack of RF to prevent relapse of RF activity
S. agalactiae group B strep (GBS)
  • PCR-based tests on urine
  • Cultures: beta-hemolysis and biochemical testing
Screen all pregnant women at 35–37 weeks for GBS and administer IV antibiotics (penicillin) during labor to prevent neonatal infection
S. pneumoniae
  • Sputum Gram stain and culture
  • Blood culture: alpha-hemolysis, then biochemical testing, molecular testing, or a mass spectrometry method
Immunization, following U.S. Advisory Committee on Immunization Practices (ACIP) guidelines for different ages and medical conditions, with:
  • Pneumococcal conjugate vaccine (Prevnar 13)
  • Pneumococcal polysaccharide vaccine (Pneumovax 23)
Viridans streptococci: S. mutans, S. bovis, S. mitisBlood cultures, then biochemical testing (often unreliable for viridans species, so molecular testing or a mass spectrometry method increasingly being used)Prophylactic antibiotics in patients with high-risk conditions (e.g., prosthetic heart valves, unrepaired cyanotic congenital heart disease) who are undergoing a dental procedure
EnterococcusCultures (growth in 6.5% NaCl), then biochemical testing, molecular testing, or mass spectrometry methods

References

  1. Group A Streptococcal Disease (GAS). Centers for Disease Control and Prevention. Accessed December 27, 2020.
  2. Haslam DB, St Gemelli JW (2018). Viridans Streptococci, Abiotrophia and Granulicatella Species, and Streptococcus bovis Group. Retrieved December 27, 2020, from https://www.sciencedirect.com/topics/medicine-and-dentistry/viridans-streptococci
  3. Patterson MJ (1996). Streptococcus. Retrieved December 26, 2020, from https://www.ncbi.nlm.nih.gov/books/NBK7611/
  4. Puopolo KM, Baker CJ (2019). Group B streptococcal infection in neonates and young infants. Retrieved December 26, 2020, from https://www.uptodate.com/contents/group-b-streptococcal-infection-in-neonates-and-young-infants
  5. Stevens DL (2020). Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis. Retrieved December 26, 2020, from https://www.uptodate.com/contents/invasive-group-a-streptococcal-infection-and-toxic-shock-syndrome-epidemiology-clinical-manifestations-and-diagnosis
  6. Tuomanen EI (2019). Microbiology and pathogenesis of Streptococcus pneumoniae. Retrieved December 26, 2020, from https://www.uptodate.com/contents/microbiology-and-pathogenesis-of-streptococcus-pneumoniae
  7. Wald ER (2020). Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis. Retrieved 26 December 2020, from https://www.uptodate.com/contents/group-a-streptococcal-tonsillopharyngitis-in-children-and-adolescents-clinical-features-and-diagnosis
  8. Martin CS, Bradshaw JL, Pipkins HR, McDaniel LS (2018). Pulmonary disease associated with nonencapsulated streptococcus pneumoniae. Open Forum Infectious Diseases. 2018;5(7). https://doi.org/10.1093/ofid/ofy135
  9. Riedel S, Hobden JA (2019). In Riedel, S, Morse, S.A., Mietzner, T., Miller, S. (Eds.), Jawetz, Melnick, & Adelberg’s Medical Microbiology (28th ed., pp. 215-233).
  10. Advisory Committee on Immunization Practices (ACIP). CDC. (2020, December 22). https://www.cdc.gov/vaccines/acip/index.html

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