Impetigo (see Impetigo): infection of superficial layers of the epidermis
Cellulitis (see Cellulitis): skin infection of deeper dermis and subcutaneous fat (resulting from bacterial breach of the skin) characterized by erythema, warmth, and edema without an underlying suppurative focus
Erysipelas (see Erysipelas): skin infection of upper dermis and superficial lymphatics (resulting from bacterial breach of the skin) characterized by erythema, warmth, and edema without an underlying suppurative focus
Furuncle (Boil) (see Skin Abscess): infection of hair follicle where purulent material extends through the dermis into the subcutaneous tissue, forming a small abscess
Carbuncle (see Skin Abscess): coalescence of several inflamed follicles into a single inflammatory mass with purulent drainage from multiple follicles
Skin Abscess (see Skin Abscess): collection of pus within dermis and deeper skin tissues
Necrotizing Soft Tissue Infection (see Necrotizing Soft Tissue Infection): deep tissue infection involving the hypodermis (and contained structures)
All of These are Characterized by Fulminant Tissue Destruction, Systemic Toxicity (Tachycardia >120 Beats/min, Hypotension, Elevated Creatine Kinase, CRP >15 mg/dL, LRINEC Score >6, etc), and High Mortality Rates
History
1861-1865 During the United States Civil War: first description of necrotizing fasciitis by the Confederate Army surgeon, Joseph Jones
1883: Fournier described necrotizing fasciitis in the perineal and genital region
1952: Wilson first used the term “necrotizing fasciitis”
Modern Era: lay press commonly refers to the organisms which cause necrotizing soft tissue infection as “flesh-eating bacteria”
Epidemiology
Incidence
Incidence of Necrotizing Fasciitis is Approximately 0.3-15 Cases per 100,000 Population (NEJM, 2017) [MEDLINE]
Diagnosis
Laboratory Risk Indicator for Necrotizing Soft Tissue Infection (LRINEC)
C-Reactive Protein (CRP) (mg/L)
CRP < 150: 0 points
CRP ≥ 150: 4 points
White Blood Cell (WBC) Count
WBC < 15: 0 points
WBC 15-25: 1 point
WBC >25: points
Hemoglobin (Hb) (g/dL)
Hb >13.6: 0 points
Hb 11-13.5 : 1 points
Hb < 10.9: 2 points
Sodium (Na) (mmol/L)
Na ≥ 135: 0 points
Na < 135: 2 points
Creatinine (Cr) (mg/dL)
Cr ≤ 1.6: 0 points
Cr >1.6: 2 points
Serum Glucose (Glc) (mg/dL)
Glc ≤ 180: 0 points
Glc >180: 1 point
LRINEC Score Represents the Probability of Necrotizing Fasciitis Being Present
Low Risk (<5 Points): <50% probability of necrotizing fasciitis
Intermediate Risk (6-7 Points): 50-75% probability of necrotizing fasciitis
High Risk (>8 points): >75% probability of necrotizing fasciitis
Plain Film Radiographic Studies, CT Scanning, and/or MRI Scanning May Be Useful to Image Soft Tissues (and to Detect Soft Tissue Gas)
CT Scan is More Sensitive than Plain Film Radiographic Studies for the Detection of Soft Tissue Gas
Crucially, Obtaining Radiographic Studies Should Not Delay the Definitive Surgical Diagnosis and/or Therapeutic Intervention in Patients with Frank Crepitus on Physical Exam and/or Rapid Clinical Deterioration
Ultrasound with Aspiration of Perifascial Fluid Collections
May Be Useful
“Dishwater” Appearance of Fluid
Finger Test
Procedure: local anesthesia, followed by a 2 cm incision down to the deep fascia with digital exploration
Lack of Bleeding from the Incision Suggests Necrotizing Fasciitis
If the Tissues at Level of the Deep Fascia Dissect with Minimal Resistance, the Finger Test is Positive, Suggesting Necrotizing Fasciitis
Tissue Biopsy with Rapid Frozen Section Analysis
May Demonstrate Obliterative Vasculitis of Subcutaneous Vessels, Acute Inflammation, and Subcutaneous Tissue Necrosis
Clinical
General Comments
Necrotizing Soft Tissue Infection Includes Any/All of the Following (NEJM, 2017) [MEDLINE]
Necrotizing Cellulitis
Involving the Epidermis/Dermis/Subcutaneous Tissue
Necrotizing Fasciitis
Distinguishing Necrotizing Fasciitis from Necrotizing Myositis May Be Difficult, Since Skeletal Muscle and Fascia Can Be Involved in Both Syndromes (NEJM, 1989) [MEDLINE] (Scand J Infect Dis, 1992) [MEDLINE] (Emerg Infect Dis, 1995) [MEDLINE]
Infection Typically Spreads Along the Muscle Fascia Due to its Relatively Poor Blood Supply (In Contrast to Muscle Tissue, Which is Frequently Spared Due to its Better Blood Supply) (Arch Surg, 1986) [MEDLINE]
Necrotizing Myositis
Differentiation of Necrotizing Fasciitis from Other Conditions
Radiologic Presence of Soft Tissue Gas May Allow Clinical Differentiation of Necrotizing Soft Tissue Infections (NEJM, 2017) [MEDLINE]
Absence of Soft Tissue Gas on Radiographic Studies
Most Cases Occur in Patients without Underlying Co-Morbid Conditions (in Contrast to Type I Necrotizing Fasciitis Cases) (J Bone Joint Surg Am, 2003) [MEDLINE]
Of the 3.5 Cases Per 100,00 Population of Invasive Streptococcus Pyogenes Cases in the US (8,950-11,500 Cases of Invasive Streptococcus Pyogenes Infections Annually in the US), Necrotizing Fasciitis Accounts for Approximately 6% of These Cases (Clin Infect Dis, 2007) [MEDLINE]
Important Risk Factor for Necrotizing Soft Tissue Infection Involving the Head and Neck Region, Lower Extremities, and Perineum (J Clin Microbiol, 1995) [MEDLINE] (J Bone Joint Surg Am, 2003) [MEDLINE]
Regardless of Their Association with Causation, NSAID’s May Mask the Clinical Symptoms/Signs in Necrotizing Soft Tissue Infection, Which May Delay Diagnosis
M-Protein is an Important Determinant of Virulence (with M Type 1 and 3 Being Associated with Streptococcal Toxic Shock Syndrome in 50% of Cases) (Clin Infect Dis, 2007) [MEDLINE]
Strains with These M-Proteins Can Produce Pyrogenic Exotoxins, Which Induce Cytokine Production (Contributing to Shock, Tissue Destruction, and Organ Failure)
Streptococcus Pyogenes is the Most Common Streptococcus Species Associated with Necrotizing Soft Tissue Infection
Concomitant Streptococcus Pyogenes and Staphylococcus Infection May Occur in Some Cases (see Staphylococcus Aureus)
Infection Usually Enters Through Penetrating Trauma or Cutaneous Site of Infection
Early Findings
Signs of Superficial Skin Infection
Later Findings
Purple (Violaceous) Bullae
Skin Sloughing
Once Infection Reaches the Deep Fascia, it Rapidly Spreads Along Fascial Planes, Through Venous Channels and Lymphatics
Cases with No Defined Portal of Entry: 50% of cases (NEJM, 2017) [MEDLINE]
Asymptomatic/Symptomatic Pharyngitis Likely Results in Subsequent Hematogenous Dissemination to a Site of Non-Penetrating Minor Trauma (Such as a Bruise or Muscle Strain)
Early Findings
Severe Pain
Fever (without Signs of Superficial Skin Infection) (see Fever)
Later Findings
Purple (Violaceous) Bullae
Skin Sloughing
Clinical Sites of Infection
Lower Extremities
Approximately 66% of Cases Occur in the Lower Extremities (Especially in Patients with Underlying Diabetes Mellitus and Peripheral Arterial Disease)
Necrotizing Fasciitis of the Head and Neck
While Most Head and Neck Necrotizing Soft Tissue Infections are Type I-Polymicrobial (See Below), Some Cases May Be Type II-Monomicrobial (Associated with Streptococcus Pyogenes)
Predisposed by Breach in the Oropharyngeal Mucous Membrane Due to Surgery, Instrumentation, or Odontogenic Infection (see Deep Neck Infection) (Head Neck, 2018) [MEDLINE]
Most Cases (78%) are of Dental Origin (Clin Infect Dis, 1995) [MEDLINE]
Fasciitis May Spread to Face, Lower Neck, or Mediastinum (Clin Infect Dis, 1995) [MEDLINE]
Mediastinal Spread is Predisposed by Prior Corticosteroid Use, Infection by Gas-Producing Organism, or Pharyngeal Focus of Infection (Ann Thorac Surg, 2012) [MEDLINE]
Clinical Manifestations
Early Findings
Early Anesthesia in the Affected Area May Occur (Due to in the thrombosis of Small Blood Vessels and Destruction of the Superficial Nerves in the Subcutaneous Tissues)
Initially, the Overlying Tissue May Appear Unaffected (For This Reason, Necrotizing Fasciitis is Difficult to Diagnose without Direct Visualization of the Fascia)
Erythema (Without Sharp Margins): present in 72% of cases (NEJM, 2017) [MEDLINE]
Severe Pain Over Skin and Underlying Muscle Out of Proportion to the Exam: present in 72% of cases (NEJM, 2017) [MEDLINE]
This is a Sensitive, Early Finding Which May Precede Development of Fever and Other Constitutional Symptoms (Chest, 2005) [MEDLINE]
Associated with Strains of Methicillin-Resistant Staphylococcus Aureus (MRSA) Which Produce the Panton-Valentine Leukocidin (PVL) Toxin
Concomitant Streptococcus Pyogenes and Staphylococcus Infection May Occur in Some Cases (As Noted Above)
Physiology
Once Infection Reaches the Deep Fascia, There is Rapid Spread Along Fascial Planes, Through Venous Channels and Lymphatics
Clinical
Early Findings
Severe Pain Over Skin and Underlying Muscle: sensitive, early finding that may precede development of fever and other constitutional symptoms [MEDLINE]
Peripheral Arterial Disease (PAD) (see Peripheral Arterial Disease): most commonly involving the lower extremity
Surgery/Trauma
Microbiology
General Comments
Mixed Aerobic and Anaerobic Infection: multiple organisms can be isolated from almost all of these cases (there is an average of 5 pathogens in each wound)
At Least One Anaerobe is Isolated in Conjunction with Enterobacteriaceae and One or More Non-Group A Facultative Anaerobic Streptococcus Species (J Clin Microbiol, 1995) [MEDLINE] (J Bone Joint Surg Am, 2003) [MEDLINE] (Clin Infect Dis, 2007) [MEDLINE]
Obligate Aerobes (Such as Pseudomonas Aeruginosa) are Rarely Present in Such Infections
Presence of Fungi in Polymicrobial Necrotizing Soft Tissue Infection Increases the Probability of Requiring ≥2 Surgical Interventions and is Associated with a 3-Fold Increase in Mortality Rate (Surg Infect-Larchmt, 2017) [MEDLINE]
Clinical Sites of Infection
Lower Extremity Necrotizing Fasciitis
Epidemiology
Most Common Site in Cases Associated with Diabetes Mellitus and Peripheral Arterial Disease
Necrotizing Fasciitis of the Head and Neck
Portal of Entry
Breach in the Oropharyngeal Mucous Membrane Due to Surgery, Instrumentation, or Odontogenic Infection (see Deep Neck Infection) (Head Neck, 2018) [MEDLINE]
Most Cases (78%) are of Dental Origin (Clin Infect Dis, 1995) [MEDLINE]
Microbiology
Most Cases are Due to Mixed Aerobic and Anaerobic Infection (Clin Infect Dis, 1995) [MEDLINE]
Fasciitis May Spread to Face, Lower Neck, or Mediastinum (Clin Infect Dis, 1995) [MEDLINE]
Mediastinal Spread is Predisposed by Prior Corticosteroid Use, Infection by Gas-Producing Organism, or Pharyngeal Focus of Infection (Ann Thorac Surg, 2012) [MEDLINE]
Breach in Gastrointestinal/Genitourinary Tract or Labia: by diverticulum, malignancy, hemorrhoid, anal fissure/perianal abscess, Bartholin abscess, episiotomy, vulvovaginal infection, decubitus ulcer, or urethral tear
Once Infection Reaches the Deep Fascia of Perineum, Rapid Spread Along Fascial Planes, Through Venous Channels and Lymphatics to Involve the Anterior Abdominal Wall/Gluteal Muscles/Scrotum/Penis
Surgical Exploration/Debridement is Required to Distinguish Anaerobic Cellulitis from Fasciitis and Myonecrosis
Clostridial Myonecrosis (Gas Gangrene)
Traumatic Gas Gangrene
Epidemiology
Trauma Accounts for 70% of Clostridial Gas Gangrene Cases and 80% of These are Due to Clostridium Perfringens (Mol Microbiol, 1995) [MEDLINE]
Traumatic Gas Gangrene was Common During the Civil War, World War I, and World War II (Due to Delayed Treatment of Injuries
In the Modern Era, Delayed Treatment of Injuries (During Earthquakes, etc) Still Results in High Traumatic Gas Gangrene Mortality Rates
In an Earthquake in China, the Average Time from Injury to Medical Treatment was 3.5 Days and 20% of Those with Open Wounds Developed Clostridium Perfringens Gas Gangrene (with a 50-8% Mortality Rate) (Chin Med J-Engl, 2013) [MEDLINE]
Risk Factors
Black Tar Heroin Injection (Skin Popping): associated with Clostridium Novyii and Clostridium Sordellii (MMWR Morb Mortal Wkly Rep, 2000) [MEDLINE] (Clin Infect Dis, 2006) [MEDLINE]
Bowel/Biliary Tract Surgery
Intramuscular Injection
Reproductive
Abortion
Pregnancy Loss/Miscarriage/Intrauterine Fetal Demise (see Pregnancy Loss)
Retained Placenta
Prolonged Rupture of Membranes
Trauma
Compound Fracture
Crush Injury
Gunshot Wound
Knife Wound
Microbiology: while traumatic gas gangrene may have other microbes isolated from the site of trauma, Clostridium are considered the major organisms causing tissue destruction
Trauma Introduces Clostridium Organisms (Vegetative or Spore Forms) Directly into Deep Tissue
Traumatic Vascular Injury with Compromised Blood Supply Creates an Anaerobic Environment (with Low Oxidation-Reduction Potential and an Acidic pH) Which Facilitates the Growth of Clostridium (Mol Microbiol, 1995) [MEDLINE]
Clostridium Perfringens Secretes Many Extracellular Toxins (Alpha Toxin is a Hemolytic Toxin with Both Phospholipase C and Sphingomyelinase Activities, Theta Toxin, aka Perfringolysin O, is a Pore-Forming Toxin)
Tissue Necrosis Can Occur within Hours of the Initial Injury and Progresses Rapidly (Inches Per Hour) in the Absence of Adequate Treatment
Severe Muscle Necrosis and Absent Neutrophils from the Site (In Contrast to Staphylococcus Aureus Infection, Where There is an Absence of Adjacent Tissue/Vascular Destruction and Neutrophils are Abundant)
Due to Large Heterotypic Aggregates of Activated Platelets (Caused by Alpha Toxin Activation of the Platelet Glycoprotein IIb/IIIa Fibrinogen Receptor), Neutrophils Accumulate Along the Capillary/Small Arteriole/Postcapillary Venule Endothelium, But are Unable to Cross the Vascular Endothelium into the Infected Tissue (Br Med J, 1917) [MEDLINE]
Alpha and Theta Toxins are Also Cytotoxic to Neutrophils
Alpha Toxin Directly Inhibits Myocardial Contractility, Resulting in a Decrease in Cardiac Output ( J Infect Dis, 1988) [MEDLINE] (J Infect Dis, 1995) [MEDLINE]
Theta Toxin Decreases Systemic Vascular Resistance (SVR) (Via the Actions of Vasodilatory Prostacyclin, Platelet Activating Factor, and Other Lipid Autocoids), Resulting in “Warm Shock” ( J Infect Dis, 1988) [MEDLINE] (J Biol Chem, 1989) [MEDLINE] (J Infect Dis, 1995) [MEDLINE]
The Combined Effects of Alpha Toxin Depressing Cardiac Output and Theta Toxin Causing Vasodilation Results in Severe Hemodynamic Compromise
Alpha and Theta Toxins Directly Cause Hemolysis (Ann Hematol, 1993) [MEDLINE] (J Infect Dis, 1995) [MEDLINE]
While Bacteremia Can Occur Transiently without Gas Gangrene, Most Clostridium Perfringens and Clostridium Septicum Blood Isolates are Associated with Clinically Significant Infection (J Infect Dis, 1975) [MEDLINE] (J Infect Dis, 1989) [MEDLINE]
X-Ray/CT Scan/MRI: useful to detect gas in soft tissues
Needle Aspiration/Punch Biopsy: diagnostic in 20% of cases (however, biopsy does not address the need for surgical debridement)
Clinical
Sudden Onset of Severe Pain at the Site of Surgery or Trauma (Due to Toxin-Mediated Ischemia) (NEJM, 1973) [MEDLINE]
Mean Incubation Period (Which Depends on the Size of the Bacterial Inoculum and the Degree of Vascular Compromise): <24 hrs (Range: 6 hrs-Several Days)
Skin Initially May Appear Pale
Then Rapidly Develops a Bronze Color, Followed by Purple-Red Discoloration
Skin Then Becomes Tense and Exquisitely Tender
Skin Crepitus (see Skin Crepitus): most sensitive and specific examination finding (Arch Surg, 1986) [MEDLINE]
Preferred Empiric Regimen is Piperacillin-Tazobactam (4.5 g IV q8hrs) (or Carbapenem) + Clindamycin (900 mg IV q8hrs)
Preferred Definitive Regimen is Penicillin (3-4 million U IV q4hrs) + Clindamycin (900 mg IV q8hrs) or Tetracycline (500 mg IV q6hrs)
Surgical Exploration: edematous and reddish/blue/black muscle, which does not bleed or contract when stimulated
Tissue Gram Stain and Culture: large gram-variable rods at site of injury (can appear as either Gram-positive and Gram-negative rods when stained directly from infected tissues, but stain as Gram-positive rods when obtained from culture media)
Tissue Pathology: widespread tissue destruction, muscle necrosis (necrosis of skin, fat, subcutaneous tissue, and fascia may also be present), presence of organisms, and absence of neutrophils in the tissue
Booster Tetanus Vaccine (if Not Received within the Last 5 Years)
Prognosis for Gas Gangrene of an Extremity is Better than for Gas Gangrene of the Trunk or Visceral Organs (Due to Ease of Debridement)
Survival Rate with Proper Antibiotics + Debridement + Hyperbaric Oxygen Has Been Reported to Be 81% (J Trauma, 1983) [MEDLINE]
Presence of Bacteremia and Hemolysis Predicts the Highest Likelihood of Progression to Shock and Death
Recurrent Gas Gangrene Due to Clostridium Perfringens Has Been Observed in Patients with Minor Trauma at a Site of Prior Gas Gangrene (Likely Related to Spores Residing for a Prolonged Period in Tissue Which was Not Adequately Debrided) (West J Med, 1988) [MEDLINE]
Spontaneous Gas Gangrene
Risk Factors
Advanced Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) (see Human Immunodeficiency Virus)
Clostridium Tertium (see Clostridium Tertium): typically resistant to penicillin, cephalosporins, and clindamycin, allowing survival in the gastrointestinal tract (especially in patients who have received broad-spectrum antibiotics)
Distinguishing Spontaneous Clostridial Gas Gangrene from Streptococcal Myonecrosis May Be Difficult, But the Presence of Tissues Crepitus Favors the Diagnosis of Clostridial Infection
Surrounding Skin Has Purplish Hue (Due to Vascular Compromise from Diffusion of Bacterial Toxins into Surrounding Area) (Rev Infect Dis, 1990) [MEDLINE]
Treatment
Empiric Antibiotics (to Cover for Streptococcus Pyogenes, Clostridium, and Mixed Aerobes/Anaerobes): preferred regimen is piperacillin-tazobactam (4.5 g IV q8hrs) + clindamycin (900 mg IV q8hrs)
Definitive Antibiotics for Clostridium Septicum: penicillin (3-4 million U IV q4hrs) + clindamycin (900 mg IV q8hrs) or tetracycline (500 mg IV q6hrs)
Definitive Antibiotics For Clostridium Tertium: vancomycin or metronidazole are preferred agents
Early Surgical Debridement
Prognosis: mortality of spontaneous gangrene is 67-100% ( Ann Chir Gynaecol, 1986) [MEDLINE] (Cancer, 1991) [MEDLINE]
Gallery
Example of Streptococcus Pyogenes Necrotizing Cellulitis
62 y/o Female with Left Forearm Cellulitis After Superficial Wound
Example of Type I Necrotizing Fasciitis
36 y/o Diabetic Caucasian Male (with HbA1C 13%) Who Presented with Ulcerating Left Foot Skin Lesions
Patient Underwent Immediate Surgical Incision and Drainage of the Left Foot/Distal Left Leg and Left Great Toe Amputation
12 hrs Later, He Developed Progressive Gangrene Adjacent to the Surgical Field (Picture Below), Requiring Repeat Surgical Debridement with Left Below the Knee Amputation
Blood Cultures were Positive for Streptococcus Agalactiae (Group B)
Wound Cultures were Positive for Escherichia Coli + Streptococcus Agalactiae (Group B)
Unlike penicillin, the efficacy of clindamycin is not affected by the inoculum size or stage of bacterial growth
Clindamycin suppresses bacterial toxin synthesis
Subinhibitory concentrations of clindamycin facilitate Strep Pyogenes phagocytosis
Clindamycin decreases the synthesis of penicillin-binding protein, which, in addition to being a target for penicillin, is also an enzyme involved in cell wall synthesis and degradation
Clindamycin has a longer postantibiotic effect than β-lactams (such as penicillin)
Clindamycin suppresses LPS-induced mononuclear synthesis of tumor necrosis factor-α
Vancomycin (see Vancomycin): or comparable agent, to cover for possible MRSA
Reported in the Treatment of Streptococcal Toxic Shock Syndrome (see Streptococcal Toxic Shock Syndrome): may have a role in Streptococcus-associated necrotizing faasciitis cases (although this is not an FDA-approved indication)
Prompt Surgical Debridement Down to Fascia with Wide Excision
Early surgical intervention has been demonstrated to improve mortality and decrease tissue loss (amputation, etc).
Delayed surgical intervention is associated with increased risk of death [MEDLINE]
Average latency from admission to surgery in survivors: 25 hrs
Average latency from admission to surgery in non-survivors: 90 hrs
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A 46-year-old man with excruciating shoulder pain. Chest. Mar 2005;127(3):1039-44 [MEDLINE]
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Group B streptococcal necrotizing fasciitis from a decubitus ulcer. Int J Emerg Med. 2010 Dec; 3(4): 519–520 [MEDLINE]
Factors associated with the mediastinal spread of cervical necrotizing fasciitis. Ann Thorac Surg. 2012 Jan;93(1):234-8 [MEDLINE]
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Necrotising soft tissue infection in a UK metropolitan population. Ann R Coll Surg Engl. 2015 Jan;97(1):46-51. doi: 10.1308/003588414X14055925058553 [MEDLINE]
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Diagnosis
Isolation of Clostridium in human infections: evaluation of 114 cases. J Infect Dis. 1975;131 Suppl:S81 [MEDLINE]
Anaerobic bacterial bacteremia: 12-year experience in two military hospitals. J Infect Dis. 1989;160(6):1071 [MEDLINE]
Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jul 15;59(2):e10-52. doi: 10.1093/cid/ciu444 [MEDLINE]
Treatment
Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jul 15;59(2):e10-52. doi: 10.1093/cid/ciu444 [MEDLINE]
