US Pharm. 2013;38(4):HS8-HS12.
ABSTRACT: Necrotizing soft-tissue infections are uncommon but aggressive infections with a potential for high morbidity and mortality. The basic pathology involves the invasion and rapid spread of microbial pathogens into the subcutaneous tissue, where bacteria release enzymes and toxins that cause local tissue ischemia and necrosis. Streptococcus and Staphylococcus species are the most common causative organisms. Concomitant stimulation of the production of inflammatory cytokines promotes systemic toxicity, shock, multisystem organ failure, and death. Effective treatment involves surgical debridement and empiric antibiotic therapy, with amputations as a last option. Patients should be managed for fluid and electrolyte imbalances and may be supported with IVIG and hyperbaric oxygen therapy.
Necrotizing soft-tissue infections (NSTIs) are life-threatening medical emergencies that require early aggressive treatment to reduce complications and improve survival rates.1-3 The features of these aggressive infections include extensive pain, rapidly spreading necrosis leading to gangrene of the skin, and underlying sterile structures.2 The infection can spread at an alarming rate of 1 inch of skin per hour even though there may be few visible effects on the skin.4 Consequently, NSTIs are associated with high rates of morbidity and mortality.1 They are caused by “flesh-eating bacteria” and include infections such as phagedena and gangrene (e.g., hospital, progressive bacterial synergistic, Fournier’s, hemolytic streptococcal).2,5
Between 500 to 1,500 cases of NSTIs have been recorded annually in the United States, although clinical experience suggests that the total number greatly exceeds this estimate.2,3 The difficulty in obtaining an accurate incidence is partly attributable to the fact that there is no clear definition and system of classification of NSTIs. Mortality rates from NSTIs are as high as 35%, even with medical advances.1
Etiology and Risk Factors
The source of NSTIs is commonly trauma or underlying tissue invasion; however, in >20% of cases, the etiology is unknown.6-8 NSTIs may be caused by aerobic or anaerobic organisms that differ from those that cause non-NSTIs. In many cases, the infection is caused by more than one microbe.2 Streptococcus and Staphylococcus species are the most common causative organisms.2 Others include Vibrio vulnificus, from seawater exposure; Aeromonas hydrophila, from freshwater exposure; Streptococcus iniae, from aquacultured fish; and Erysipelothrix rhusiopathiae, contracted by butchers, clam handlers, and veterinarians.9
Various patient factors place the individual at a higher risk of contracting an NSTI. These include injectable drug use, alcohol abuse, obesity, diabetes mellitus, peripheral vascular disease, immunosuppression, malignancy, cirrhosis, and increased age.2,3
Any untreated infection can result in local necrosis. NSTIs spread rapidly along skin and subcutaneous tissues, fascia, or muscles, causing vascular occlusion, ischemia, and tissue necrosis. Depending upon the bacteria involved, the necrosis may be directly mediated by toxins or indirectly due to vascular involvement.3 The ability of the infecting bacteria to produce various exotoxins enhances their virulence and accelerates the progression of infection.4
Streptococci: Beta-hemolytic streptococci are highly potent and cause a wide array of diseases of the throat and skin including pharyngitis, erysipelas, glomerulonephritis, scarlet fever, impetigo, and rheumatic fever. Group A streptococcal (GAS) infections, such as NSTIs, are caused by Streptococcus pyogenes.2,10 They are gram-positive, nonmotile, non–spore-forming, catalase-negative aerobic organisms. They are found either as pairs or as short-to-moderate–sized chains in clinical specimen that form long chains when grown in broth-rich media enriched with serum or blood.2 The annual incidence of GAS infections is 0.4 per 1,000 persons.3
Streptococci and staphylococci release a variety of virulent factors that contribute to their pathogenicity, including3:
• Surface proteins M-1 and M-3, which increase the microbe’s ability to adhere to tissue and escape phagocytosis.
• Exotoxins A and B, which damage the endothelium and cause loss of microvascular integrity and escape of plasma, resulting in tissue edema and impaired blood flow at the capillary level.
• Streptolysin O, which stimulates CD4 cells and macrophages to produce tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6. These cytokines produce the systemic inflammatory response syndrome that can lead to septic shock, multisystem organ dysfunction, and death.4 TNF-alpha also stimulates neutrophil degranulation, resulting in further injury to the vascular endothelium.4
• Superantigens, which directly stimulate T cells, thereby activating complement, the bradykinin-kallikrein system, and the coagulation cascade. This worsens small-vessel thrombosis and tissue ischemia, impedes oxidative destruction of bacteria by polymorphonuclear cells, and prevents adequate delivery of antibiotics.4
• Protein F, hyaluronidases, streptokinases, and cell-envelope proteinases.
The human skin and mucous membranes are the only known reservoir for GAS infection in nature.2 Predisposing patient factors that may lead to a GAS infection include minor skin cuts, splinters, penetrating injuries, varicella lesions, burns, surgical procedures, childbirth, and muscle strain.11 Initially, mild erythema that undergoes a rapid evolution with pronounced inflammation is observed at the site of injury. This is followed by a diffuse swelling and the appearance of bullae filled with clear fluid that rapidly progress to hemorrhagic or violaceous color suggestive of dermal necrosis.12-14 The systemic symptoms that characterize GAS infections include the early onset of shock and organ failure, high fever, and extreme prostration.
Clostridium Species: These species are anaerobic, gram-positive rods that can form endospores.2,15 Over 150 species of Clostridium have been identified, with C perfringens being the most prevalent. Other species include C novyi, C histolyticum, C bifermentans, C tertium, and C fallax.2,15 They are found naturally occurring in soil and sediments as well as the intestinal microflora of humans and animals.2
Clostridium species release alpha-toxin, a virulent protein that results in extensive necrosis of the tissue and cardiovascular collapse.4 Clostridial myonecrosis (gas gangrene) is a life-threatening muscle infection that develops most commonly following a traumatic injury that is contaminated by clostridial spores.2 It can also occur in the absence of trauma via hematogenous seeding of skeletal muscle by Clostridium septicum.2 It is characterized by profound toxemia, extensive edema, tissue death to a large extent, and the release of gas. Following an injury or surgery, the onset of the infection may occur between 1 and 6 hours, and symptoms usually begin within 24 to 72 hours.15 The patient typically experiences a sudden onset of severe pain even in the absence of obvious physical findings.2 There is initial redness at the site of the wound followed by a rapidly spreading brown to purple discoloration of the skin.2 Gas gangrene progresses rapidly, with gas being detected within underlying tissues.15 It is important to note, however, that gas in the wound is a relatively late finding, and in most cases the patient is near death at this stage.16 Bullae may develop on the overlying tense skin and be filled with clear, red, blue, or purple fluid.2 The discharge from the infected site has a characteristic mousy odor.17 In the early stages, the body temperature may be normal; however, it may rise rapidly concomitant to full-blown sepsis with hypotension and multiorgan failure.
Mortality rates from gas gangrene may be as high as 60%, making rapid diagnosis and proper intervention very important.2 Surgical debridement is frequently performed. Clostridium species are sensitive to penicillin, metronidazole, clindamycin, and carbapenems.2
Vibrio Vulnificus Species: This bacterium forms part of the natural flora of coastal marine environments worldwide and is acquired through a break in the skin and exposure to warm seawater.4 It has been isolated from water, sediments, and a variety of seafood, including shrimp, fish, oysters, and clams.18 In addition to exposure to marine life, individuals who have moderate-to-severe liver disease are at a high risk of contracting the infection.4 Infection with V vulnificus can result in multisystem organ failure and death if not treated within 24 hours.4
Aeromonas Species: These bacteria are gram-negative, nonsporulating aerobic rods that test positive in an oxidase test.2 They are found in fresh and brackish water as well as chlorinated tap water, including hospital water.2 These bacteria are more common in the warmer months and are associated with diarrheal disease including traveler’s diarrhea in individuals returning from Asia, Africa, and Latin America, as well as with soft-tissue infections.2 Most commonly associated with A hydrophila, infections typically occur on the extremities following traumatic aquatic injury or trauma followed by exposure to freshwater.2 The infection can range from mild to severe and may manifest as cellulitis, myonecrosis, or ecthyma gangrenosum.19 Cellulitis that develops within 8 to 48 hours is characterized by intense redness and induration at the site of injury, suppuration, and necrosis around the wound. Aeromonas species are resistant to penicillin and ampicillin but sensitive to aztreonam, carbapenems, and third-generation cephalosporins. In some cases, fluoroquinolones may also be effective, but resistance could develop easily. Aminoglycosides, especially tobramycin, are particularly useful in these infections.2
Various factors can be used to classify NSTIs, including the depth of tissue involvement, severity of infection, and microbiology. According to the FDA, NSTIs are classified as: 1) uncomplicated infections that respond to a simple course of antibiotics or incision and drainage, or 2) complicated infections that involve deeper tissues and may require surgery. Based on the organisms isolated, there are three types of NSTIs: type I, type II, and type III.1,2
Type I Infections: These are the most common type and usually involve four or more causative organisms, which are frequently a mix of aerobic and anaerobic bacteria.3 The most prominent aerobic organisms are streptococci; one may also find staphylococci, enterococci, and gram-negative rods. Bacteroides species are the most common anaerobes, followed by Peptostreptococcus.3 The presence of multiple pathogenic organisms is usually a sign of a compromised immune system, and patients with type I infections commonly have diabetes mellitus, obesity, peripheral vascular disease, chronic kidney disease, or alcohol abuse.3
Fournier’s gangrene is a type I NSTI involving the perineum or genital areas. It can arise from genitourinary, colorectal, or dermatologic sources.3 Ludwig’s angina (cervical necrotizing fasciitis) is another type I infection that involves the submandibular space. Common complications associated with it include stridor and airway obstruction.3
Type II Infections: These are much less common and account for 10% to 15% of NSTIs. They are increasingly caused by Staphylococcus aureus, specially methicillin-resistant strains. Additionally, streptococci may be isolated from such infections.3 Type II NSTIs are typically located on the extremities and normally originate from minor injuries that allow the entry for bacteria or create an environment that is conducive to the survival of hematogenously transported bacteria.4 Type II NSTIs may also be associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).4
Type III Infections: These are the least common type of NSTIs, but the cause of these infections has not been universally agreed upon.3 While some sources consider these infections to be caused by V vulnif-icus, others attribute them to clostridial myonecrosis.3,4 Type II infections typically occur as a result of a deeply penetrating wound or a crush injury accompanied by local devascularization, intestinal surgery, or “black tar” heroin injection.
Because the findings are nonspecific, it is difficult to establish diagnosis of NSTIs.4 Prior use of antibiotics and/or NSAIDs may mask the symptoms and make diagnosis even more difficult, while identification of risk factors may simplify this process somewhat.2 The presentation of NSTIs varies widely, ranging from cellulitis to fasciitis to myositis, depending upon the area and the depth of involvement.2 The classic clinical symptoms, including tense edema, pain disproportionate to the appearance, skin discoloration, blisters or bullae, necrosis, and crepitus, are present only in about 10% to 40% of patients.2,4 Other indications of an NSTI include unexplained tachycardia, marked left shift, and elevated creatine phosphokinase level.2
Different diagnostic tools such as imaging studies and biopsies may be useful in arriving at a diagnosis.2 Valuable imaging studies include plain radiography, ultrasonography, CT scan, and MRI. These may reveal soft-tissue gas, enhancement or thickening of the involved fascia, or abcesses.1 A frozen-section biopsy, when performed early, avoids a delayed diagnosis and decreases mortality.
The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) is a validated score that is used to group patients into those with high, moderate, and low risk based upon routine laboratory tests, including total white blood cell count, hemoglobin, sodium, creatinine, glucose, and C-reactive protein (TABLE 1).1,2 A total score of 8 or more is strongly predictive of an NSTI.
A finger test, whereby an incision is made to the deep fascia under local anesthesia and is gently probed with the index finger, may be ordered. Lack of bleeding, presence of characteristic dishwater pus, and lack of tissue resistance to the blunt finger are features of a positive finger test for necrotizing fasciitis. If the test is positive, the incision is extended to perform debridement.2
Aims of NSTI therapy include: 1) initiation of antimicrobial therapy (broad-spectrum therapy is recommended until the culture is confirmed); 2) fluid resuscitation and correction of electrolyte and acid base abnormalities; 3) debridement of necrotic tissues; and 4) support of failing tissues.2,3 If a streptococcal culture is confirmed, high-dose penicillin and clindamycin should be used in the antibiotic regimen.2 Following surgical debridement, antibiotic therapy can be de-escalated if the patient stabilizes.2
Antimicrobial Therapy: IV empiric broad-spectrum therapy directed against gram-positive cocci, gram-negative bacilli, and anaerobic bacteria should be initiated promptly to prevent the systemic manifestations of infection, including sepsis syndrome or septic shock (TABLE 2).3 The effectiveness of the antibiotics is limited by impaired delivery to the necrotic area.1
Streptococci respond well to high-dose benzylpenicillins.20 Clindamycin is a macrolide with activity against gram-positive and anaerobic organisms. It is useful in the suppression of endotoxin and superantigen production by S aureus, hemolytic streptococci, and clostridia, thereby enhancing phagocytosis, limiting toxin-mediated destruction, and inhibiting the systemic release of cytokines.1,3
Vancomycin or linezolid, which is now shown to be superior to vancomycin, can be prescribed for patients who cannot take clindamycin.1,3 It is becoming increasingly popular to include vancomycin, daptomycin, or linezolid in empiric therapy regimens to combat evolving methicillin-resistant S aureus (MRSA) strains.1,3
If a Vibrio or Aeromonas infection is suspected, the patient should additionally be prescribed doxycycline or a related tetracycline.3 Fluoroquinolones are highly effective against Aeromonas species.1
Fluid Resuscitation and Correction of Electrolyte and Acid Base Abnormalities: Since the intravascular volume is always depleted in patients with NSTIs as a result of fluid shifts caused by the body’s response to the infection, it is usually necessary to take measures to restore this volume.3 A normal volume ensures effective tissue and organ perfusion, preventing organ system failure if the infection progresses and avoiding hypotension during surgery. Crystallized fluids are first-line treatment, particularly lactated Ringer’s solution, which corrects acidemia.3 Colloid solutions are suitable for malnourished patients and those with liver disease or poor response to large volumes of crystalloid.3 Anemic patients may be given a blood transfusion. The electrolyte disturbances commonly seen in NSTI patients include hyponatremia corrected with lactated Ringer’s solution or 0.9% normal saline; hypocalcemia corrected with calcium gluconate; and hyperglycemia corrected with insulin.3
Operative Debridement: Early and complete debridement of the infected area reduces the rate of mortality.3,5,8,21 A radical excision of all devitalized tissue is performed through a generous incision until healthy bleeding tissue is encountered; serial debridements are generally spaced 12 to 36 hours apart.1 Amputation of the affected limbs is reserved for situations where debridement is not viable.3
Support of Failing Organ Systems: Patients who are hypotensive even after fluid resuscitation should be given vasopressors and monitored closely in the ICU.3
IV Immunoglobulin (IVIG): This is a concentrated pooled product that primarily contains IgG isotypes derived from multiple human donors.1 While its use is controversial, IVIG has an anti-inflammatory effect and contains broad-spectrum antibodies that enhance bacterial opsonization, neutralize virulence factors and toxins, and inhibit super-antigen-elicited T-cell activation.3
Hyperbaric Oxygen (HBO) Therapy: This type of therapy can be used as an adjunct to surgical intervention and antibiotics in the treatment of NSTI.1 It ameliorates tissue hypoxia that is induced by microcirculatory thrombosis.22 HBO therapy has been shown to improve wound healing and therefore reduce the number of debridements and amputations required.22
Maintenance: Nutritional support can be initiated once infection and sepsis response are controlled.3
Relatively uncommon, NSTIs threaten the patient’s life and limbs. A rapid diagnosis and management are major determinants of the outcome. Aggressive empiric anti-microbial therapy and early surgical debridement form the cornerstone of management. Adjunctive therapies utilized in modern medicine include IVIG and HBO. Despite advances in the medical field, mortality rates of NSTI patients remain high, and there is a need for prompt diagnosis and therapy.
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