Or, Streptococcus pyogenes and the

Bacteria Flesh-Eating Phenomenon

This is the gruesome tale of a vicious disease that has a preference for human flesh, a pestilence that surpasses the worst of nightmares. However, unlike a nasty Hollywood horror story that keeps you up all night in terrified fascination, this one is made by Nature, and it is very, very real.

A rogue microbe

The most infamous flesh-eating* bacteria is Streptococcus pyogenes***. Normally a harmless inhabitant of the mouth and upper respiratory tract, rogue S. pyogenes are immensely destructive. They cause, among other things – strep throat (streptococcal pharyngitis), acne, rheumatic fever, toxic shock syndrome and – most horrifyingly – necrotizing fasciitis.

Invasion and Infection

Streptococcus pyogenes’s invasion strategy is somewhat direct – and brutal. It usually enters the human body where there is a break in the skin caused by injury*. Once inside the bloodstream, the bacteria moves rapidly through tissue in a path along the fascia, which is the subcutaneous² tissue surrounding the muscle. Rapid multiplication of this invading army causes antibodies to recognize them and to release chemicals called cytokines* that signal white blood cells to swallow the bacteria*. However, all pathogenic* strains of S. pyogenes have a protein called M protein, which enables them to escape from being eaten*** and continue along its path of invasion. At the same time, S. pyogenes also releases a torrent of toxins that cause massive tissue damage. This extensive tissue damage manifests itself as "necrotizing fasciitis". If the disease is allowed to progress, the body can go into systemic shock, resulting in multiple organ failure, collapse of the circulatory system due to disseminated³ intravascular⁴ coagulation⁵**, and imminent death.

The Warning Signs

The symptoms of necrotizing fasciitis caused by Streptococcus pyogenes includes:

1. Trauma (Day 0)
2. Discomfort in the general region of the trauma (Day 0)
3. Pain that is out of proportion with the severity of the injury, or pain that is not restricted to the immediate area of the injury
4. Influenza-like symptoms such as vomiting, diarrhoea, dehydration, malaise, weakness, muscle pain, and fever
5. Swelling or sunburn-type redness in the general region of the injured area (Day +2)
6. Worsening of condition
7. Less frequent urination
8. Large, boil-like blisters (bullae) containing foul-smelling pus (Day +2 to Day +3)
9. Haemorrhage from the bullae
10. Gangrene (Day +4)

The War against the Invaders

Early diagnosis of necrotizing fasciitis increase the chances of the victim surviving this disease. Once detected, rapid treatment must begin in order to both save the patient’s life and to reduce damage to the patient*. This treatment will include:

• Aggressive combination regime antibiotics therapy. A broad spectrum of drugs will be used, including cefazolin, clindamycin, gentamycin, penicillin and metronidazole* However, because antibiotics therapy sometimes does not work, ** *** doctors are pressured to either prevent shock from happening at all, or to catch it in the early – and more easily treatable – stages.

• Surgical debridement i.e. Cutting away dead or infected tissue or removal of foreign matter from the flesh. This involves surgical excision and drainage to remove all infected, necrotic tissue and fascia until clean, healthy, pearly grey fascia is identified in all margins of the wound. This will be carried out as soon as the patient is diagnosed with necrotizing fasciitis to prevent further spreading of the disease. If diagnosed early, tissue loss can be relatively small, and only flesh, subcutaneous tissue and fat will be removed. If the disease is allowed to progress, however, amputation of affected limbs may be necessary if the victim is to survive.

• Treatment may also include usage of a hyperbaric⁶ oxygen chamber. This is to increase the partial pressure of oxygen in the blood, thus enabling wounds to heal better by reducing oedema due to vasoconstriction of the arterioles, and hypoxia. The white blood cells are also strengthened in their ability to fight the invading bacteria. However, this treatment is more commonly used in the case of gas gangrene, which is typically caused by Clostridium perfringens.

These are only essential treatment measures; however, because of the complication of necrotizing fasciitis, subsidiary patient management is needed to deal with the excruciating pain experienced by patients during dressing changes, and to encourage the body to heal. The caloric intake of patients recovering from massive trauma is usually increased twofold or threefold, often with dietetic recommendations by a dietician. The emotional trauma suffered by the patients due to pain, severe disfigurement following surgery, and intense emotions must also be handled to ensure complete recovery.

Risks

Since Streptococcus pyogenes is such a common bacteria in our lives, it is entirely fortunate for us that the occurrence of necrotizing fasciitis is so rare. A 1996 CDC report estimates from 500 to 1500 cases per year of necrotizing fasciitis of which 20% die. Most of us will repeatedly come into contact with this bacteria, and in most cases, will experience infection. However, most of these infections tend towards routine strep throat (pharyngitis) or skin infection (impetigo). Only a very small percentage of people will develop so serious a disease as necrotizing fasciitis. Many of the affected are the elderly and those who suffer disease of some sort – for example, cardiovascular or renal disease, cancer, diabetes or severe weight disorder*. Children with chickenpox are an especially high risk group, and those who are below 10 are 39 times more likely to develop invasive GAS infections (including necrotizing fasciitis), the attack rate being 4.4 per 100,000 cases of chickenpox.

Recently, however, it has been established that the usage of pain-relieving nonsteroidal anti-inflammatory drugs (ibuprofen) greatly increases the risk of developing necrotizing fasciitis, especially among children with varicella-zoster virus infection (a.k.a. chickenpox). Because these drugs prevent inflammation, which is important for fighting microbes, it also messes up the body's defense mechanism*** thus causing multiple organ system failure.

What you can do to help protect yourself against necrotizing fasciitis

There is very little that you can do by way of prophylaxis to prevent infection and intra-family spread; however, very little is still more than none at all. The most important preventive measure is to keep your skin intact. If your skin is broken by injury, clean the wound thoroughly with disinfectant and cover it up with clean dressing so that it does not become exposed to the environment. Wound dressings should be changed regularly, and the wounds should be monitored for possible signs of infection (see The Warning Signs). If you should develop the symptoms listed, immediately seek medical help. It may be disgustingly fascinating to watch the disease run its full course, but it could also cost you your life. If your child has chickenpox, avoid giving them nonsteroidal anti-inflammatory drugs to ease the pain. Athletes should also be cautious about using the said drugs.

And do not panic unnecessarily. You should, of course, exert caution, but you should also realize that the chances of you developing necrotizing fasciitis in your lifetime (if you are a healthy individual) are very, very small.

For Further Reading

1. Davies H. D., McGeer A., Schwartz B., Green K., Cann D., Simor A. E., Low D. E., The Ontario Group A Streptococcal Study Group. 1996.
Invasive Group A Streptococcal Infections in Ontario, Canada. N Engl J Med; 335:547-554

2. A lot of information can also be found at the National Necrotizing Fasciitis Foundation.

3. To read a story about a survivor’s battle against necrotizing fasciitis, go to http://www.nnff.org/survivors/cassi_moore/cassi.htm.

(For those of you who are interested in pathogenecity of Streptococcus pyogenes

Virulence Factors of Streptococcus pyogenes)

Streptococcus pyogenes possesses a number of somatic⁷cellular constituents as well as extracellular * enzymes and toxins that are responsible for its pathogenesity*. These include:

M protein: The ability of S. pyogenes to cause disease greatly depends upon this protein. It is anchored to the bacteria’s cell membrane. It serves to inhibit the activation of the complement cascade* and protects the bacteria from being gobbled up by phagocyte*. There are 80 different types of this protein. Antibodies are generated against the M protein and help to destroy it as well as to protect from infection against other S. pyogenes that possess the same M protein; however, they are useless against other M types. Non-pathogenic strains usually do not have this protein.

Hyaluronic acid capsule: Most strains of S. pyogenes are enveloped in this. It protects the bacteria from being phagocytosed. Hyaluronidase is an enzyme that liquefies the hyaluronic acid⁸component of the connective tissue matrix.

Lipoteichoic acid⁹ and protein F: These enable the bacteria to stick to fibronectin* on the surface of human epithelial¹⁰ cells – this is crucial if the bacteria is to succeed in its invasion.

Streptolysin: These enzymes are responsible for the bacteria’s haemolytic activity. There are two types of streptolysin –

• Streptolysin O: This enzyme is sensitive to oxygen and can be inactivated by it. It not only destroys both red and white blood cells, but also provokes an immune response i.e. it is antigenic. It is toxic to a wide variety of cells, including the myocardium*.
• Streptolysin S: This enzyme is oxygen-stable. It is also responsible for beta-haemolysis, but is not antigenic.

A large number of other toxins and extracellular products also play a role in tissue damage and the spread of S. pyogenes; however, they will not be discussed here.

The Superantigen Phenomenon

Usually when the immune system encounters an antigen, this provokes typical antigen-specific interference, such as phagocytosis. However, there are certain types of antigens that causes a different sort of response. These are called superantigens, and S. pyogenes is one of the bacteria that produces this type of antigen.

Under normal circumstances, antigen presenting cells (APCs) such as macrophages that have engulfed bacteria process protein antigens by cutting them up and presenting one of the pieces on the cell surface. Only a few T cells will be able to recognize these pieces, and therefore only a few will be stimulated to produce cytokines that lead to antibody production (about 1 in 10,000 T cells).

Superantigens, however, are not chopped up but will bind directly to the APC’s surface. Because they do this indiscriminately, many APCs will have these superantigen molecules bound to their surfaces. Also, these superantigens bind indiscriminately to T cells as well, and therefore will stimulate as many as 1 in 5 T cells. This causes release of excessively high levels of the cytokine IL-2, thus giving rise to a variety of symptoms such as nausea, vomiting, malaise and fever. This also leads to excess production of other cytokines, which will subsequently cause shock.

BIBLIOGRAPHY

1. Davies H. D., McGeer A., Schwartz B., Green K., Cann D., Simor A. E., Low D. E., The Ontario Group A Streptococcal Study Group. 1996.
   Invasive Group A Streptococcal Infections in Ontario, Canada. N Engl J Med; 335:547-554
2. Fink, A and G DeLuca. 2002. Necrotizing fasciitis: pathophysiology and treatment. Medsurg Nursing. 11:33-36.
3. Foth, J. 2002. Necrotizing Fasciitis: “The Flesh-Eating Bacteria”. Science Education.
4. Gladwin, M and B Trattler. 1997. Streptococci. IN Clinical Microbiology Made Ridiculously Simple. McGraw Hill International Editions.
5. Mims, CA, NJ Dimmock, A Nash and J Stephen. 1995. Mechanisms of Cell and Tissue Damage. IN Mims’ Pathogenesis of Infectious Disease, 4th ed. Academic Press Limited, London.
6. Mims, CA, NJ Dimmock, A Nash and J Stephen. 1995. The Immune Response to Infection. IN Mims’ Pathogenesis of Infectious Disease, 4th ed. Academic Press Limited, London.
7. Mims, CA, NJ Dimmock, A Nash and J Stephen. 1995. The Spread of Microbes through the Body. IN Mims’ Pathogenesis of Infectious Disease, 4th ed. Academic Press Limited, London.
8. Salyers, AA and DD Whitt. 1994. Host Defenses Against Bacterial Pathogens: Defenses in Tissue and Blood. IN Bacterial Pathogenesis: A Molecular Approach. ASM Press, Washington DC.
9. Salyers, AA and DD Whitt. 1994. Scarlet Fever, Toxic Shock Syndrome, and the Return of Severe, Invasive Streptococcal Disease. IN Bacterial Pathogenesis: A Molecular Approach. ASM Press, Washington DC.
10. Salyers, AA and DD Whitt. 1994. Virulence Factors that Damage the Host. IN Bacterial Pathogenesis: A Molecular Approach. ASM Press, Washington DC.
11. Schleiss, MR. 2002. Streptococcal infection, Group A. EMedicine.
12. Seachrist, L. 1995. The once and future scourge. Science News. 148:234-5.
13. Stevens, DL et al. 1989. Severe Group A Streptococcal Infections Associated with a Toxic Shock-like Syndrome and Scarlet Fever Toxin. NEJM 321:2-7.
14. Flesh-Eating Bacteria: Facts Behind the Bug.
15. Necrotizing Fasciitis.
16. National Necrotizing Fasciitis Foundation Factsheet

Definitions obtained from:

17. Webster’s New World Dictionary, Third College Edition (1994).

18. Mims, CA, NJ Dimmock, A Nash and J Stephen. 1995. Glossary. IN Mims’ Pathogenesis of Infectious Disease, 4th ed. Academic Press Limited, London.