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Fig 1: This is a presurgical picture of the leg of a patient with severe
necrotizing fasciitis of the lower leg. This picture was
part of an online essay by Katrina Tram Duong, and was
reproduced with permission.
Necrotizing Fasciitis(NF), commonly referred to as “flesh-eating bacteria,” is a rare yet debilitating disease involving a rapidly progressing bacterial infection(For particularly graphic pictures of what NF can do, visit the National Necrotizing Fasciitis Foundation, or the Armed Forces Infections Diseases Society). No single species of bacterium is responsible for NF, in fact, it usually consists of a combination of aerobic and anaerobic flora. The most common bacteria involved in NF is group A streptococcus, Streptococcus pyogenes, the bacterium responsible for common strep throat. Other bacteria frequently found in NF are Staphylococcus aureus, Escheria coli, Clostridium, Peptostreptococcus, Enterobacteriaceae, coliforms, Proteus, Pseudomonas, Klebsiella, Bacteroides Fragilis, and Vibrio vulnificus. This varied flora makes treatment more difficult.
It appears that NF starts as a small local infection by one or more of these bacteria, most frequently Streptococcus pyogenes, and/or Staphylococcus aureus. This local infection causes local hypoxia, under which conditions these facultative aerobes are still able to proliferate, while leukocytes are unable to function. The aerobic respiration of these bacteria produces a variety of gasses, which build up in tissue, causing what is referred to as “gas gangrene.” The rapid spread and necrotic activity of NF is enhanced by bacterial toxins, but appears to be largely due to the overwhelming release of cytokines, much like a localized version of Toxic Shock Syndrome(TSS). In fact, some researchers have recently identified some loci responsible for genetic predisposition, and protection from both NF and TSS. In 2000, a group determined that “Severe invasive cases suffering from toxic shock and/or necrotizing fasciitis had significantly higher frequencies of IL-2, IL-6, and TNF-alpha producing cells in their circulation as compared to non-severe invasive cases.”(Norrby-Teglund, et al., 2000) Two years later, the same group(plus some) determined that the Specific human leukocyte antigen class II locus, which is involved in the leukocyte antigen recognition/cytokine release pathway, was at least in part responsible for a genetic predisposition/protection for TSS/NF. Of the 11 major haplotypes they were able to identify in the healthy population, they apparently found one haplotype that confers protection, and one that confers predisposition to NF and/or TSS.(Kotb, et al., 2002)
Many other researchers have studied the mode of virulence of these bacteria, particularly Streptococcus pyogenes. The superantigen streptococcal pyrogenic exotoxin A(SPEA) appears to play some role in S.pyogenes virulence, with increased levels being associated with decreased survival in a mouse model. However, this cannot be the primary mode of virulence, as passive immunization against SPEA failed to exhibit protection.(Sriskandan, et al., 1996) S.pyogenes has a number of surface proteins that allow it to cross epithelial barriers, including M proteins, which bind complement control factors, an hyaluronic capsule, a cysteine protease, and fibronectin binding proteins. One group determined that “the group A streptococcal hyaluronic capsule, and M protein, but not the cysteine protease are critical for the development of tissue necrosis, secondary bacteremia, and lethal infection in a murine model of human necrotizing fasciitis.(Cameron, et al., 1998) Another group demonstrated quite dramatically that the hyaluronic capsule operates by binding CD44 in human epithelia. “Studies of bacterial translocation in two models of human skin[pharyngeal and skin] indicated that cell signaling triggered by interaction of the GAS capsule with CD44 opened intercellular junctions and promoted tissue penetration by GAS through a paracellular route.”(Cywes, Wessels, 2001)
For a positive patient outcome, treatment must be rapid, and aggressive. This is difficult to achieve since diagnosis is often delayed. Patients typically present with what appears to be a mild to moderate infection. However, within a period of days, or even hours, NF can traverse the length of a limb, or even become systemic(at which time it becomes TSS). Treatment typically consists of extensive surgical debridement, along with multiple broad range antibiotics. Penicillin G or Clindamycin are usually given to eradicate the aerobes, while metronidazole or a third generation cephalosporin are given concurrently to eliminate any anaerobes. More recently, Penicillin use has decreased, as resistance becomes more common. Penicillin works by interfering with cell wall synthesis, Clindamycin may block t-RNA release from ribosomes, halting protein synthesis. Metronidazole inhibits bacterial DNA synthesis, and third generation cehpalosporins such as Rocephin bind penicillin binding proteins.
Janeway CA, Travers P, Walport M, Shlomchik M. Immunobiology: The Immune System in Health and Disease. 5th Edition. New York: Garland Publishing.
Ashbaugh C, Carey V, Warren H, Wessels M. 1998. Molecular analysis of the role of group A streptococcal cysteine protease, hyaluronic acid capsule, and M protein in a murine model of human invasive soft tissue infection. J Clin Invers. 102(3):550-560.
Cywes C, Wessels M. 2001. Group A Streptococcus tissue invasion by CD44-mediated cell signaling. Nat. 414:648-51.
Kotb M, Norrby-Teglund A, McGreer A, El-Sherbini H, Dorak M, Khurshid A, Green K, Peeples J, Wade J, Thomson G, Schwartz B, Low D. An immunogenic and molecular basis for differences in outcomes of invasive group A streptococcal infections. Nat Med. 8(12):1398-1404.
Norrby-Teglund A, Chateller S, Low DE, McGreer A, Green K, Kotb M. 2000. Host variation in cytokine responses to superantigens determines the severity of invasive group A streptococcal infection. Eur J Immunol. 30(11):3247-55.
Sriskandan S, Moyes D, Buttery LK, Krausz T, Evans TJ, Polak J, Cohen J. 1996. Streptococcal pyrogenic exotoxin A release, distribution, and role in murine model of fasciitis and multiorgan failure due to Streptococcus pyogenes. J Infect Dis. 173(6):1399-407.
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Many thanks to Dr. A. Malcolm Campbell for his guidance in this endeavor as well as others. 1048266630-023226-915