Pyogenic cocci

Various microscopically spherical bacteria are known causes of purulent disease in man. They include both Gram positive—Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae—and Gram-negative—Neisseria gonorrhoeae and N. meningitidis—species. The Gram-positive cocci are the leading pathogens of man, causing an estimated one-third of all bacterial infections of humans.¹

My focus here will be on the Streptococci, facultative anaerobic cocci not infrequently found as commensals but with significant virulent potential:

Acute Streptococcus pyogenes infections may take the form of pharyngitis, scarlet fever (rash), impetigo, cellulitis, or erysipelas. Invasive infections can result in necrotizing fasciitis, myositis and streptococcal toxic shock syndrome. Patients may also develop immune-mediated sequelae such as acute rheumatic fever and acute glomerulonephritis. S agalactiae may cause meningitis, neonatal sepsis, and pneumonia in neonates; adults may experience vaginitis, puerperal fever, urinary tract infection, skin infection, and endocarditis. Viridans streptococci can cause endocarditis, and Enterococcus is associated with urinary tract and biliary tract infections. Anaerobic streptococci participate in mixed infections of the abdomen, pelvis, brain, and lungs.²

Streptococcal Sore Throat

• malaise
• fever
• headache
• dysphagia with pus on tonsils that can be easily removed
  • throat swab cultured on blood agar
  • Rx with Penicillin (DOC) or erythromycin if penicillin allergy
    • otherwise risk of complications

Blood agar

Small (0.5 mm φ) colonies surrounded by clear halo from the lysis of red blood cells (β-effect). This complete destruction of red cells around the colony leaves a clear-colourless area sharply demarcated from the surrounding agar suggestive for, for instance, Streptococcus pyogenes.

Differential diagnosis

• Tonsillitis
• Pharyngitis
• Glandular Fever: viral
• Diphtheria: membrane on tonsils / pharynx not easily removed >> bleeding
• Thrush: fungal

Sore throat is not a trivial matter, particularly in a child, as it can lead to two important (autoimmune) complications—the host responds to antigen of coccus and cross-reacts with host tissues: glomerulonephritis (GMN); and Rheumatic Fever.

In occasional cases the organism is not isolated yet the clinical syndrome fits. In such cases, treat with antibiotics:

Throat swab – technique:

• Swab both tonsils and uvula
• Avoid tongue
• Swabbing saliva is of little aid

Lancefield grouping: Antigenic types

The cell surface structure of Group A streptococci is among the most studied of any bacteria – the cell wall is composed of repeating units of N-acetylglucosamine and N-acetylmuramic acid, the standard peptidoglycan. Historically, the definitive identification of streptococci has rested on the serologic reactivity of cell wall polysaccharide antigens as originally described by Rebecca Lancefield into eighteen group-specific antigens (Lancefield groups). The Group A polysaccharide is a polymer of N-acetylglucosamine and rhamnose. Some group antigens are shared by more than one species. This polysaccharide is also called the C substance or group carbohydrate antigen.³

Group A Streptococci

• Uniquely human pathogens: but because they do not affect animals, they are harder to study
• Present as commensals in throat of variable percent of healthy adults and children
• Subdivided according to M-protein into > 50 antigenic types

Streptococcus pyogenes

• Group A: Strep throat, Cellulitis, Scarlet fever, Streptococcal toxic shock syndrome, impetigo, rheumatic fever, necrotising fasciitis, post-streptococcal glomerulonephritis
  • Type 1 – these have nephritogenic potential
    • e.g. Scarlet fever – serious but rare today
      • erythrogenic toxin produced by S. pyogenes when infected by phage (φ)

The term Group A Strep is synonymous with the Streptococcus pyogenes species and the clinical syndrome of “Strep throat.” Patients with Strep throat present with a sudden onset of sore throat, painful swallowing (odynophagia) and fever, with or without headache and, in children, abdominal pain, nausea and vomiting.

Cough, runny nose, hoarse voice, oral ulcers, or conjunctivitis, however, would all suggest a viral cause for the sore throat. On examination, Strep throat will not only demonstrate pharyngeal and tonsillar erythema but also tonsillar hypertrophy, often with exudate, palatal petechiae, and often tender cervical lymphadenopathy. If the patient also has a scarlatiniform rash, then they have scarlet fever (rarer).

Younger children with Group A Strep infection, however, more usually present subacutely with mucopurulent rhinitis associated with a fever, irritability and anorexia [4]. Person-to-person transmission is the rule for Strep, although foodborne outbreaks have been documented and fomite transmission is theoretically possible. The incubation period is relatively short, about 2-5 days, and usually follows close contact with a person with Strep throat. Therefore, quarantine the patient until they are afebrile and have had at least 24 hours of antibiotic treatment; after which they do not transmit the bacteria.

Overall, Strep throat probably causes about 30% of sore throat in older children and about 10% of sore throat in adults. In the absence of viral symptoms, a rapid antigen detection test (RADT) can help distinguish a case of Strep throat from the manifold viral causes of sore throat. Treat with Penicillin or amoxicillin as drug of choice: “There has never been a report of a clinical isolate of group A strep that is resistant to penicillin”.[4] Macrolides can be used for penicillin-allergic patients.

Other infections caused by Streptococcus pyogenes

• Puerperal (Childbed) Fever: An ascending infection from the uterus → pelvis, now believed to be caused by a Group A β-haemolytic strep
• Burns / Wounds: septicaemia – swab early to confirm carriage first
• Impetigo (School Sores): very infectious/ contagious; nephritogenic potential
• Erysipelas: Strep. enter skin → infection/ blisters → bloodstream / systemic
• Poststreptococcal complications
  • Poststreptococcal Glomerulonephritis (PSGN)
  • Rheumatic Fever: occasionally seen in older children (i.e. rare < 3 years old and rare in adults)³

Bacterial production of lipoteichoic acid affords a concrete link between inanimate object and host, the link to the latter through receptors involving fibronectin. Production of an M-protein enables the organism to evade phagocytosis. Further, some pyogenic cocci have pili which help with adherence.³Although they can survive on fomites, like books and clothing, Streptococci can multiply only on their host because pyogenic cocci have lost the ability to synthesise proteins and some enzymes and depend on their host for reproduction. But extracellular enzymes they do produce enable the organism to break down host defences and spread rapidly: including more than 13 enzymes which partially collapse host defenses, such as chemotaxins, PMNL-destroying leucocidins, and haemolysins. Other pyogenic cocci virulence factors include the fermentation of glucose to lactic acid with a commensurate large fall in local tissue pH, and the activating bacterial lysosomes for greater host-tissue destruction.³

Two types of haemolysins are produced. The oxygen-labile type, Streptolysin, lyses the PMNL/macrophage membranes causing release of lysosomal enzymes (pH 4.5 – 5.5) that lead to tissue destruction. The oxygen-stable type, haemolysins, are responsible for the β-effect.³

Other factors that destroy tissue allowing the organism to spread:

• Proteinases
• Streptokinase
  • Plasminogen ➔ plasmin ➔ fibrinolysis
• Hyaluronidase
• Nucleases – dissolution of depolymerisation of nucleic acids
  • nephrotoxins and cardiotoxins also produced

Mode of spread

Before the throat becomes infected, the host skin is first colonized and the host acts as a self-same reservoir of auto-infection.

Reservoir (carriers)

While Streptococci need a human host to thrive—ideally a humid respiratory tract—they can and do survive away from the host, including on fomites. Notably, skin colonisation  precedes respiratory colonisation by about 20 days (three weeks) from initial exposure to a carrier.

Those with symptomatic pharyngitis are more likely than asymptomatic carriers to transmit group A strep to others.

Complications

In the antibiotic era, the local complications of peritonsillar and retropharyngeal abscess, cervical lymphadenitis, and mastoiditis, are all rare as are the complications more remote in time and space; the autoimmune complications of acute rheumatic fever and glomerulonephritis.

Other streptococci of medical importance

Streptococci are part of normal flora. Virulence factors of group A streptococci include (1) M protein and lipoteichoic acid for attachment; (2) a hyaluronic acid capsule that inhibits phagocytosis; (3) other extracellular products, such as pyrogenic (erythrogenic) toxin, which causes the rash of scarlet fever; and (4) streptokinase, streptodornase (DNase B), and streptolysins. Some strains are nephritogenic. Immune-mediated sequelae are just that, immune mediated, and do not reflect dissemination of bacteria. Nongroup A strains have no defined virulence factors.²

Streptococcus viridans

Part of the normal flora of the upper respiratory tract, virulent strains of Viridans Strep will grow on blood agar; producing the so-called alpha-effect. Especially where prior S. pyogenes infection, occasioning Rheumatic Fever, patients remain especially susceptible to viridans infection from a showering bacteraemia originating in the oral cavity to colonise damaged heart valves, causing a potentially life-threatening endocarditis, subacute bacterial endocarditis (SBE).

Most streptococci are facultative anaerobes, but some are obligate (strict) anaerobes. Most require enriched media (blood agar) to grow in laboratory conditions. Group A streptococci have a hyaluronic acid capsule to help with their microbiological identification.

Streptococci are classified on the basis of colony morphology, hemolysis, biochemical reactions, but most definitively their serologic specificity: they are divided into three groups by the type of hemolysis on blood agar:

• β-hemolytic (clear, complete lysis of red cells)
• α hemolytic (incomplete, green hemolysis), and
• γ hemolytic (no hemolysis).

Serologic grouping is based on antigenic differences in cell wall carbohydrates (groups A to V), in cell wall pili-associated protein, and in the polysaccharide capsule in group B streptococci. [5]

Patients with a history of Rheumatic Fever who undergo dental treatment require antibiotic prophylaxis. Antibiotic prophylaxis is also indicated for those with congenital heart (valve) defects, prosthetic heart valves, and often prior to childbirth (Group B Strep, or GBS). Think of GBS as modern-day “puerperal fever”.

Pneumococcus – Streptococcus pneumoniae

Pneumococcal infection in humans is mostly opportunistic, often following prior influenza or in alcoholics. Pneumococci are commensals of the upper respiratory tract. Non-toxic, they are encapsulated (virulence factor) with more than 80 different capsular types (serotypes). By evading phagocytosis, the capsule allows the organism to become established: they can be engulfed only once specific antibodies to the capsule have been formed. This usually buys the bacteria some time, about 5-7 days, allowing it to thrive in its host. The pathophysiology of infection, however, is not related to the pneumococcal capsule but rather its production of lgA1 protease, an antigenic enzyme that cleaves IgA.

Although most people have anti-IgA1 protease antibodies, they are not protective because they are not directed at the capsule: Ag-Ab complex (or cell wall via alternate pathway) ➔ activates Complement ➔ C3 + Cs ➔ coagulation cascade; basophils etc. (PAF ➔ shock). Pneumococcal pathophysiology relates to this activation of complement, the response does most of the damage and the patient may still develop a disseminated intravascular coagulation (DIC) despite antibiotic treatment.³

Enterococcus – formerly Streptococcus faecalis

Enterococcus faecalis has no effect on blood agar, in such cases it is given the term “γ-effect”.

Streptococcus	Haemolysis	Appearance	Designation
S. Pyogenes (Pneumococcus)	Complete	Clear zone	“β”
Viridans / Pneumoniae	Partial	Green zone	“a”
S. salivarius / Enterococci (previously S. faecalis)	None	No change	“γ”

“Streptococci are classified based on colony morphology, hemolysis, biochemical reactions, but most definitively on serologic specificity. Three groups are distinguished according to hemolysis of blood agar: β-hemolytic (clear, complete lysis of red cells), α hemolytic (incomplete, green hemolysis), and γ hemolytic (no hemolysis). Serologic grouping is based on antigenic differences in cell wall carbohydrates (groups A to V), in cell wall pili-associated protein, and in the polysaccharide capsule in group B streptococci”.²

The beta-haemolytic strep

Group A: pyogenes

Group B: S. agalactiae – normal flora, transferred from female gut to cause neonatal meningitis; S. milleri.

Acute glomerulonephritis and acute rheumatic fever may be identified by anti-streptococcal antibody titers. In addition, acute rheumatic fever is diagnosed by clinical criteria.

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References

1. Todar, Kenneth. “Bacterial Pathogens of Humans”. Todar’s Online Textbook of Bacteriology. Available at http://textbookofbacteriology.net/medical_4.html. Accessed 12 August 2020.
2. Baron S (Ed.). “Chapter 13. Streptococcus”. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996.
3. Kearney, R. “Pyogenic cocci.” (Lecture, University of Sydney, Sydney, July 24, 1990).
4. https://www.cdc.gov/groupastrep/diseases-hcp/strep-throat.html

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Further Reading

Evaluating the febrile patient with a rash. Am Fam Physician. 2000 Aug 15;62(4):804-816.

Martin, Judith M. The Mysteries of Streptococcal Pharyngitis. Curr Treat Options Pediatr. 2015 Jun; 1(2): 180–189. Published online 2015 Apr 7. doi: 10.1007/s40746-015-0013-9.

Scarlet fever, DermNet NZ. Available at https://dermnetnz.org/topics/scarlet-fever/. [Excellent images of scarlet fever].