Home Educatione-Learning Necrotizing Fasciitis and Deep Soft Tissue Infections in the ICU
  • Specialties
  • Critical Care, Pulmonary
  • Learning Categories
  • Learning Category 2: Self-Directed Learning
  • CME Credit
  • Credit not available as of July 1, 2013

Necrotizing Fasciitis and Deep Soft Tissue Infections in the ICU

PCCSU Volume 25, Lesson 20

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

Hardware/software requirements: Web browsing device with working Web browser.

PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Oluwaseun Falade-Nwulia, MD, MPH; and Naomi P. O’Grady, MD

Dr. Falade-Nwulia is Clinical Fellow, Critical Care Medicine Department; and Dr. O’Grady is Staff Clinician and Medical Director, Procedures, Vascular Access, and Conscious Sedation Services, National Institutes of Health, Bethesda, Maryland.

Dr. Falade-Nwulia and Dr. O’Grady have disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this chapter.

Objectives

  1. Describe the epidemiology and microbiology of necrotizing fasciitis and deep soft tissue infections.
  2. Review common clues to the diagnosis of necrotizing soft tissue infections.
  3. Review diagnostic tools used for necrotizing soft tissue infections.
  4. Describe the management of deep soft tissue infections.
  5. Review the role of IV immunoglobulin and hyperbaric oxygen therapy in the management of necrotizing soft tissue infections.

Key words: necrotizing fasciitis, necrotizing soft tissue infection

Abbreviations: CA-MRSA = community-associated methicillin-resistant Staphylococcus aureus; GAS = group A streptococcus; IVIG = IV immunoglobulin; NSTI = necrotizing soft tissue infection

Introduction

Necrotizing soft tissue infections (NSTIs) are infrequent but highly lethal infections associated with necrotizing changes of any of the layers within the soft tissue compartment. These infections may affect the dermis, subcutaneous tissue, superficial fascia, deep fascia, or muscle. The clinical spectrum ranges from invasive cellulitis to myonecrosis. Necrotizing fasciitis is characterized by widespread fascial necrosis with relative sparing of skin and underlying muscle. Many terms have been used interchangeably to describe this spectrum of disease. For example, necrotizing fasciitis limited to the perineal, genital, or perianal regions is referred to as Fournier’s gangrene. Clostridial myonecrosis has been termed “gas gangrene” and primarily affects skeletal muscle. Though sometimes seen as discrete clinical syndromes, all NSTIs are associated with rapid progression of tissue necrosis due to angiothrombotic microbial invasion, and all are associated with a predilection for development of multiorgan dysfunction and death in the absence of early diagnosis and appropriate treatment. These similarities in the pathophysiology, clinical characteristics, and management strategy permit a common discussion of these clinical syndromes.

Epidemiology and Microbiology

About 500 to 1,500 cases of NSTI occur per year in the United States.1 Although NSTIs occur in all age groups, they are most likely to occur in patients older than 50 years with comorbid medical conditions such as diabetes, hypertension, peripheral vascular disease, alcoholism or cardiopulmonary disease.2-5 Other known predisposing factors include HIV infection, history of IV drug abuse, cancer, and corticosteroid use.6 Surgical procedures, especially those involving the bowel, and blunt abdominal trauma may also increase the risk of NSTI.7

The majority of NSTIs are synergistic polymicrobial infections, often referred to as type I necrotizing fasciitis. A recent single-center review5 of 89 patients treated for necrotizing fasciitis between 1997 and 2002 revealed multiple organisms in 54% of patients, a single organism in 28% of patients, and no organisms in 18% of patients. Streptococcal species were the most commonly associated isolates in this series (42% of positive culture results), consistent with other published data.5,8 The majority of the positive culture results (66%) in this series were polymicrobial. Other organisms commonly recovered in NSTIs include Staphylococcus species, Enterococcus species, Enterobacteriaceae, Bacteroides species, anaerobic gram-positive cocci, various Clostridium species, and fungal species. Another study4 of 182 confirmed cases of necrotizing soft tissue infections in a single center between 1985 and 1993 reported an average of 4.4 organisms in 154 (84.6%) of 182 original wound cultures. In recent years, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a prominent causative pathogen in community-acquired necrotizing fasciitis, occurring in 9 of 31 cases of necrotizing fasciitis over 15 months in one series.9,10 All isolates were the USA 3000 CA-MRSA clone and carried the Panton-Valentine leukocidin virulence genes.9 Other organisms associated with community acquired NSTIs include Aeromonas species and Vibrio species, including Vibrio cholera, Vibrio vulnificus, and Vibrio parahaemolyticus, and they are found classically in patients with cirrhosis with water or marine animal exposure.11 Candida, Aspergillus, Cryptococcus, Rhizopus, and Apophysomyces have all been cultured from NSTI.8

Monomicrobial NSTIs, sometimes called type II necrotizing fasciitis, are most commonly associated with Streptococcus pyogenes, S aureus, V vulnificus, and anaerobic streptococci.7 Group B streptococcus, classically associated with obstetric complications, is increasingly being reported as a causative organism in patients with diabetes who are not pregnant.5 Among patients with liver disease, data suggest high rates of monomicrobial infections with gram-negative rods; 97% of 42 episodes in one series from Taiwan,12 with majority of infections caused by Vibrio species (36%), Klebsiella species (21%), and Aeromonas species (14%). Monomicrobial Klebsiella-related necrotizing infections are associated with diabetes mellitus, and patients often have other septic foci of infection, such as liver abscesses and endogenous endolphthalmitis.13,14 Multidrug-resistant Acinetobacter is also being increasingly reported as a causative organism in NSTIs.15,16

The wide spectrum of organisms associated with NSTI necessitate initial broad-spectrum antimicrobial coverage and wound cultures at initial surgical debridement to confirm involved pathogens in order to ensure appropriate antimicrobial coverage.

Clinical Diagnosis

Clinical diagnosis of NSTIs can be difficult because patients may have signs and symptoms of a simple soft tissue infection, or they may lack any symptoms whatsoever. Physical examination of patients with mental status changes or sepsis should include a complete skin exam. Although the groin, perineum, extremities, abdomen, and traumatic wounds are the most common sites of NSTIs,4 there are increasing reports of NSTIs in atypical sites of the head and neck, such as the eyelids, face, scalp, and ear.17 These atypical cases are most commonly linked to dental infections and skin or mucosal injuries.17

Typical initial signs and symptoms include swelling, erythema, exquisite pain, and tachycardia that rapidly progresses to tense edema of the area surrounding compromised skin, pain out of proportion to lesions, skin discoloration, blisters/bullae and necrosis, crepitus, and subcutaneous gas.18 As the disease progresses, patients become increasingly febrile and tachycardic, progressing to hypotension and shock.

Shock associated with NSTIs caused by group A streptococcus (GAS) is classically referred to as streptococcal toxic shock syndrome (STSS). Clinical criteria for a diagnosis of STSS requires the presence of at least one of the following: renal impairment, coagulopathy, liver dysfunction, acute respiratory distress syndrome, or a generalized erythematous macular rash.14 STSS is believed to be caused by production of superantigens, notably pyrogenic exotoxins A, B, or C, and most commonly by M1 and M3 strains of GAS.19 Toxic shock-like syndromes have also been associated with Clostridium sordelli infections secondary to obstetric complications and black tar heroin use among injection drug users.11,20,21

Findings of hypotension, skin crepitance or necrosis, bullae, or subcutaneous air are considered most specific of NSTIs but are only seen in less than 40% of patients.4 Of 89 patients in a single-center study,5 fever and hypotension were found in only 53% and 18% of patients, respectively, at presentation. Relative immunodeficiency associated with poorly controlled diabetes may blunt the immunologic response to these infections and account for the relatively low rates of a systemic inflammatory response at presentation. The most consistent finding in most cases is pain out of proportion to physical findings.5 Bullae filled with serous fluid have also been suggested as a diagnostic clue that should raise suspicion for the disease.5 Presence of risk factors or predisposing factors for NSTIs such as diabetes mellitus, immune suppression, or obesity should raise suspicion and prompt evaluation for a necrotizing component of soft tissue infections in these patients. Unfortunately, this is not enough to guarantee an early diagnosis because no clear etiology is found in ≥20% of patients eventually found to have NSTIs.3 These cases without associated predisposing factors are more likely to be caused by GAS or CA-MRSA.1,9

Diagnostic Tools

Difficulties with clinical diagnosis have led to evaluation of a number of diagnostic tools to aid rapid and accurate diagnosis of NSTIs. These include the use of common laboratory findings, imaging studies, and tissue-based methods.

Laboratory Findings
Basic laboratory values may provide clues to the presence of a necrotizing soft tissue infection. In one retrospective analysis, Wall and colleagues22 compared admission variables of patients with NSTI and non-necrotizing soft tissue infections, and found that a WBC count >15,400 cells/mm3 or a sodium level <135 mmol/L was associated with NSTI. The combination of both was found to be a very sensitive tool with a negative predictive value of 99%. However, it is nonspecific with a positive predictive value of only 26%. This would suggest that the absence of leukocytosis or hyponatremia may reduce suspicion of NSTI, but their presence does not confirm diagnosis. The laboratory risk indictor for necrotizing fasciitis (LRINEC) score has been proposed for use as a model for predicting a necrotizing component to a soft tissue infection (Table 1). This model is based on a 13-point scale with weighted scores assigned to each of the following values: C-reactive protein, hemoglobin, WBC count, and serum sodium, creatinine, and glucose. After external validation, a score of >6 had a positive predictive value of 92% and a negative predictive value of 96% in intermediate- and high-risk patients.23 This tool, however, has not done as well in other validation studies.24


Table 1The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) Score

Parameter Value Score
Serum C-reactive protein (mg/L) ≥150 4 points
WBC count (cells/μL) 15,000-25,000 1 point
  >25,000 2 points
Hemoglobin (g/dL) 11-13.5 1 point
  <11 2 points
Serum sodium (mmol/L) <135 2 points
Serum creatinine (mg/dL) >1.6 2 points
Serum glucose (mg/dL) >180 1 point

Adapted from Wong et al.23


Imaging Studies
Imaging should never delay surgical intervention when clinical suspicion is high for NSTI. In equivocal cases, imaging may be useful. Plain radiography may detect subcutaneous gas.25 Though specific, subcutaneous gas on radiographs is not very sensitive; in one series, it was found in only 17% of patients, and it is often a late finding.5,6 CT scanning is more sensitive and has the advantage of being able to identify other causes of deep infection such as abscesses.1 Although MRI studies have reported high sensitivity rates of 93% to 100%, it also is nonspecific. More importantly, it is time consuming and may delay needed surgical intervention. Reported findings on MRI include subcutaneous thickening, with fluid collections and hyperintense signal of subcutaneous tissue and superficial fascia on T2- weighted images.26 In patients in whom there is a low index of suspicion, ultrasound, CT scan, and MRI have the advantage of providing additional anatomic information and possibly identifying other sources of infection.

Tissue-Based Methods
Examination of frozen section biopsy specimens from affected sites has been evaluated and is associated with a decrease in mortality compared with historical controls.27,28 The “finger test” is often seen in the literature in relation to necrotizing fasciitis. It involves the creation of a small surgical opening through which one can use a probe or finger to bluntly dissect to deep fascia. Ease of dissection of subcutaneous tissue to deep fascia is believed to be consistent with a diagnosis of necrotizing fasciitis.3 The gold standard for detection of necrotizing soft tissue infections is tissue biopsy obtained at the time of wound exploration and surgical debridement. Overall, clinical suspicion remains central to making a diagnosis of NSTI regardless of any other ancillary tools of diagnosis.

Treatment

The management of NSTIs includes source control, antimicrobial therapy, close monitoring, and supportive care usually in an ICU setting. Early and complete debridement is required for source control and is the cornerstone of management of NSTI. Broad-spectrum antimicrobial therapy should also be started early in conjunction with close monitoring and appropriate supportive care.

Surgery

Early and adequate surgical debridement is the most important determinant of survival in NSTIs. Delay in debridement and inadequacy of the first debridement has been linked to an increased risk of death.2,5,29,30 In one series,5 a 24-h or greater delay from admission to surgical debridement was associated with a mortality risk over nine times that of patients who received earlier surgical intervention. Immediate resection of all compromised tissue to healthy, viable bleeding tissue is essential for definitive management.6 Repeat debridement in the days following initial debridement is generally necessary to control the necrotizing process. Many experts advocate for a second-look surgery within 24-36 h of the first surgery, and daily thereafter, until there is no longer a need for surgical debridement.7 Patients require frequent wound checks through the course of care with surgical evaluation for further debridement if concerns arise for disease extension. Close management and follow-up with a surgical team is essential for management of all cases of NSTIs.

Antibiotic Therapy

Antimicrobial therapy is an important adjunct in the management of NSTIs. Initial antibiotic coverage should be broad and include coverage for gram-positive, gram-negative, and anaerobic organisms. Options for initial empiric coverage include β-lactam/β-lactamase inhibitor combinations (eg, piperacillin/tazobactam) or carbapenems (eg, imipenem, meropenem, or ertapenem) to cover gram-negative organisms and anaerobes. This should be combined with either vancomycin, linezolid, or daptomycin to cover for methicillin-resistant staphylococcal infection until it has been excluded. If GAS is suspected, clindamycin should be added to the regimen because it is not affected by inoculum size or the stage of bacterial growth; it suppresses toxin production31; it has inhibitory actions on protein synthesis, including streptococcal superantigens; and it has a long postantibiotic effect. This makes it an important component of initial NSTI regimens until streptococcal and clostridial infections have been excluded.32 Inhibition of toxin production by clindamycin may also exert a beneficial effect for control of the inflammatory response in NSTI.33 There are some data to suggest that linezolid may suppress production of GAS virulence proteins in a manner similar to clindamycin.34 In patients who are allergic to penicillin, options for antibiotic coverage include vancomycin combined with a fluoroquinolone (eg, ciprofloxacin or levofloxacin) and clindamycin or metronidazole. Although blood culture results may be positive in about 20% of polymicrobial necrotizing infections, blood culture results may not completely reflect all organisms present in infected tissues.5 Initial coverage should be tailored down based on microbiology data from initial debridement. High-dose penicillin plus clindamycin remain the drugs of choice for S pyogenes and clostridial necrotizing infections.7,14 Antibiotics should be continued until no further surgical debridements are necessary. Continuing antibiotic therapy beyond that is arbitrary and may expose patients to an unnecessary prolonged course of antibiotics with the attendant risks of developing resistant infections.

Despite appropriate antibiotic therapy, thrombosis of blood vessels in many instances prevents effective antibiotic penetration, permitting accumulation of bacteria and bacterial toxins.29 As such, in the absence of complete surgical debridement, sepsis will develop.

Supportive Care

These patients will invariably have ICU care needs both for monitoring and supportive care. Overwhelming sepsis with attendant respiratory, renal, or multiorgan failure is responsible for majority of the mortality in NSTI.29 Shock syndromes should be managed appropriately with aggressive fluid resuscitation and vasopressors when indicated. Respiratory support, central cardiovascular monitoring, and hemodialysis may also be indicated. Adequate nutritional support may also improve outcomes, with a recommendation of twice the basic caloric requirements in the acute phase of management of NSTIs by some authors.3,4,35

Adjunctive Therapies

IV Immunoglobulin
Neutralization of streptococcal toxins by antibodies present in IV immunoglobulin (IVIG) may improve outcomes in patients with STSS. The role of IVIG in management of invasive group A streptococcal infection is supported both by case reports and case series, the largest of which showed an increase in 30-day survival from 34% to 67% in 21 patients with streptococcal toxic shock syndrome who received IVIG at a median dose of 2g/kg compared with historical control subjects.36 Patients receiving IVIG were, however, more likely to have had surgical intervention and more likely to have received clindamycin. A subsequent double blind, placebo-controlled trial37 of IVIG to placebo in 21 patients with STSS suggested a 3.6-fold higher mortality in the placebo group compared with the IVIG group. However, statistical significance was not achieved, and in the 13 patients with necrotizing soft tissue infections, there was no difference in time to stop further progression of necrotizing infection (69 h for the IVIG group vs 36 h for the placebo group).37 Although primarily given as therapy for STSS, the use of IVIG in streptococcal NSTI remains controversial, with no consensus on optimal dosing or therapeutic window.6

Hyperbaric Oxygen Therapy
Like IVIG, the use of hyperbaric oxygen therapy in necrotizing soft tissue infections remains controversial. Some observational studies suggest a need for fewer debridements and lower mortality rates in patients treated with hyperbaric oxygen compared with untreated patients, with mortality rates of 7% vs 42% in one study38 of 26 patients and rates of 23% vs 66% in another study39 of 29 patients. In contrast, use of hyperbaric oxygen was associated with increased mortality, morbidity, and cost of therapy in a subsequent larger observational study of 42 patients with Fournier gangrene.40 Use of hyperbaric oxygen is further limited by unavailability at most institutions and the difficulties of managing a critically ill patient in a pressurized chamber.

Conclusions

NSTIs, though relatively uncommon, are still associated with high mortality rates. A high index of suspicion is needed to make an early diagnosis given the paucity of signs on presentation in many cases. The most common diagnostic clues are pain out of proportion to physical findings, fever, and signs of systemic toxicity. While antibiotics, monitoring, and supportive care in a critical care setting are important components of care for patients with NSTIs, early and complete surgical debridement is necessary to reduce the significant morbidity and mortality associated with these infections.


References

  1. Anaya DA, Dellinger EP. Necrotizing soft-tissue infection: diagnosis and management. Clin Infect Dis. 2007;44:705-710.
  2. McHenry CR, Piotrowski JJ, Petrinic D, Malangoni MA. Determinants of mortality for necrotizing soft-tissue infections. Ann Surg. 1995;221:558-565.
  3. Childers BJ, Potyondy LD, Nachreiner R, et al. Necrotizing fasciitis: a fourteen-year retrospective study of 163 consecutive patients. Am Surg. 2002;68:109-116.
  4. Elliott DC, Kufera JA, Myers RA. Necrotizing soft tissue infections: risk factors for mortality and strategies for management. Ann Surg. 1996;224:672-683.
  5. Wong CH, Chang HC, Pasupathy S, Khin LW, Tan JL, Low CO. Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality. J Bone Joint Surg Am. 2003;85-A:1454-1460.
  6. Young MH, Engleberg NC, Mulla ZD, Aronoff DM. Therapies for necrotising fasciitis. Expert Opin Biol Ther. 2006;6:155-165.
  7. Stevens DL, Bisno AL, Chambers HF, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-1406.
  8. Elliott D, Kufera JA, Myers RA. The microbiology of necrotizing soft tissue infections. Am J Surg. 2000;179:361-366.
  9. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med. 2005;352:1445-1453.
  10. Young LM, Price CS. Community-acquired methicillin-resistant Staphylococcus aureus emerging as an important cause of necrotizing fasciitis. Surg Infect (Larchmt). 2008;9:469-474.
  11. Vinh DC, Embil JM. Severe skin and soft tissue infections and associated critical illness. Curr Infect Dis Rep. 2007;9:415-421.
  12. Lee CC, Chi CH, Lee NY, et al. Necrotizing fasciitis in patients with liver cirrhosis: predominance of monomicrobial Gram-negative bacillary infections. Diagn Microbiol Infect Dis. 2008;62:219-225.
  13. Kelesidis T, Tsiodras S. Postirradiation Klebsiella pneumoniae-associated necrotizing fasciitis in the western hemisphere: a rare but life-threatening clinical entity. Am J Med Sci. 2009;338:217-224.
  14. Vinh DC, Embil JM. Rapidly progressive soft tissue infections. Lancet Infect Dis. 2005;5:501-513.
  15. Charnot-Katsikas A, Dorafshar AH, Aycock JK, David MZ, Weber SG, Frank KM. Two cases of necrotizing fasciitis due to Acinetobacter baumannii. J Clin Microbiol. 2009;47:258- 263.
  16. Sullivan DR, Shields J, Netzer G. Fatal case of multi-drug resistant Acinetobacter baumannii necrotizing fasciitis. Am Surg. 2010;76:651-653.
  17. Mastronikolis NS, Stathas T, Naxakis SS, et al. Necrotizing fasciitis of the head and neck: report of 5 cases and review of the literature. Eur Rev Med Pharmacol Sci. 2010;14:123-134.
  18. Wong CH, Wang YS. The diagnosis of necrotizing fasciitis. Curr Opin Infect Dis. 2005;18:101-106.
  19. Bisno AL, Brito MO, Collins CM. Molecular basis of group A streptococcal virulence. Lancet Infect Dis. 2003;3:191-200.
  20. Fischer M, Bhatnagar J, Guarner J, et al. Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med. 2005;353:2352-2360.
  21. Kimura AC, Higa JI, Levin RM, Simpson G, Vargas Y, Vugia DJ. Outbreak of necrotizing fasciitis due to Clostridium sordellii among black-tar heroin users. Clin Infect Dis. 2004;38:e87-e91.
  22. Wall DB, Klein SR, Black S, de Virgilio C. A simple model to help distinguish necrotizing fasciitis from nonnecrotizing soft tissue infection. J Am Coll Surg. 2000;191:227-231.
  23. Wong CH, Khin LW, Heng KS, Tan KC, Low CO. The LRINEC (laboratory risk indicator for necrotizing fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections. Crit Care Med. 2004;32:1535-1541.
  24. Holland MJ. Application of the laboratory risk indicator in necrotising fasciitis (LRINEC) score to patients in a tropical tertiary referral centre. Anaesth Intensive Care. 2009;37:588-592.
  25. Fisher JR, Conway MJ, Takeshita RT, Sandoval MR. Necrotizing fasciitis: importance of roentgenographic studies for soft-tissue gas. JAMA. 1979;241:803-806.
  26. Rieger UM, Gugger CY, Farhadi J, et al. Prognostic factors in necrotizing fasciitis and myositis: analysis of 16 consecutive cases at a single institution in Switzerland. Ann Plastic Surg. 2007;58:523-530.
  27. Majeski J, Majeski E. Necrotizing fasciitis: improved survival with early recognition by tissue biopsy and aggressive surgical treatment. South Med J. 1997;90:1065-1068.
  28. Stamenkovic I, Lew PD. Early recognition of potentially fatal necrotizing fasciitis: the use of frozen-section biopsy. N Engl J Med. 1984;310:1689-1693.
  29. Green RJ, Dafoe DC, Raffin TA. Necrotizing fasciitis. Chest. 1996;110:219-229.
  30. Voros D, Pissiotis C, Georgantas D, Katsaragakis S, Antoniou S, Papadimitriou J. Role of early and extensive surgery in the treatment of severe necrotizing soft tissue infection. Br J Surg. 1993;80:1190-1191.
  31. Stevens DL, Gibbons AE, Bergstrom R, Winn V. The Eagle effect revisited: efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis. J Infect Dis. 1988;158:23-28.
  32. Johansson L, Thulin P, Low DE, Norrby-Teglund A. Getting under the skin: the immunopathogenesis of Streptococcus pyogenes deep tissue infections. Clin Infect Dis. 2010;51:58-65.
  33. Stevens DL, Bryant AE, Hackett SP. Antibiotic effects on bacterial viability, toxin production, and host response. Clin Infect Dis. 1995;20 Suppl 2:S154-157.
  34. Coyle EA, Cha R, Rybak MJ. Influences of linezolid, penicillin, and clindamycin, alone and in combination, on streptococcal pyrogenic exotoxin a release. Antimicrob Agents Chemother. 2003;47:1752-1755.
  35. Majeski JA, Alexander JW. Early diagnosis, nutritional support, and immediate extensive debridement improve survival in necrotizing fasciitis. Am J Surg. 1983;145:784-787.
  36. Kaul R, McGeer A, Norrby-Teglund A, et al. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome: a comparative observational study—the Canadian Streptococcal Study Group. Clin Infect Dis. 1999;28:800-807.
  37. Darenberg J, Ihendyane N, Sjolin J, et al; Streptig Study Group. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2003;37:333-340.
  38. Hollabaugh RS Jr, Dmochowski RR, Hickerson WL, Cox CE. Fournier’s gangrene: therapeutic impact of hyperbaric oxygen. Plast Reconstr Surg. 1998;101:94-100.
  39. Riseman JA, Zamboni WA, Curtis A, Graham DR, Konrad HR, Ross DS. Hyperbaric oxygen therapy for necrotizing fasciitis reduces mortality and the need for debridements. Surgery. 1990;108:847-850.
  40. Mindrup SR, Kealey GP, Fallon B. Hyperbaric oxygen for the treatment of Fournier's gangrene. J Urol. 2005;173:1975-1977.