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Ferretti JJ, Stevens DL, Fischetti VA, editors. Streptococcus pyogenes : Basic Biology to Clinical Manifestations [Internet]. Oklahoma City (OK): University of Oklahoma Health Sciences Center; 2016-.

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Streptococcus pyogenes : Basic Biology to Clinical Manifestations [Internet].

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Impetigo, Erysipelas and Cellulitis

, PhD, MD and , PhD.

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Introduction

Streptococcus pyogenes (group A Streptococcus) is one of the most important bacterial causes of skin and soft tissue infections (SSTIs) worldwide. In addition, no other pathogen causes as many diverse clinical entities as S. pyogenes. Specifically, this organism causes infections in the superficial keratin layer (impetigo), the superficial epidermis (erysipelas), the subcutaneous tissue (cellulitis), the fascia (necrotizing fasciitis), or muscle (myositis and myonecrosis). It is also the etiologic agent of scarlet fever and Streptococcal Toxic Shock Syndrome (StrepTSS). Impetigo is a non-life-threatening infection, but can result in post-streptococcal acute glomerulonephritis (AGN). Cellulitis and erysipelas can be mild or moderately severe, while necrotizing fasciitis, myonecrosis and StrepTSS are life-threatening. This chapter focuses on the clinical and epidemiological features of these infections, as well as treatment options, and includes a discussion of bacterial pathogenesis.

Anatomical Relationship of Skin and Skin Structure Infections with S. pyogenes

An understanding of the anatomy of the skin layers is crucial for the clinician to establish a correct diagnosis of streptococcal skin and soft tissue infections. Figure 1 illustrates the relationship between different anatomical structures and the types of S. pyogenes infections that affect specific layers of the skin and deeper tissues (from (Stevens, 2015)). Note that impetigo involves the outer keratin layer of the skin, which results in crusty lesions, whereas erysipelas affects the superficial epidermis, which results in well-demarcated borders of infection and a brilliant red skin color. Cellulitis occurs in the deeper subcutaneous tissues and has a pinkish hue with less defined edges. Necrotizing fasciitis caused by S. pyogenes has been defined by surgeons as an infection that involves the superficial or deep fascia, in association with destruction of tissue. In reality, necrotizing fasciitis in its later stages involves all layers of the skin and muscle as well. Muscle infection by S. pyogenes can take on two forms, myositis or myonecrosis. Myositis is not usually associated with necrosis and is most commonly caused by Staphylococcus aureus. Myonecrosis due to S. pyogenes is an aggressive, often life-threatening infection that can develop in any open wound or by hematogenous seeding of muscle that has been injured by a simple strain or other type of non-penetrating trauma (such as a contusion). The latter infection has been called cryptogenic or spontaneous myonecrosis and is associated with mortality as high as 80%. Note the intimate relationship of blood supply to the muscle layer. As myonecrosis progresses, the blood supply becomes compromised, resulting in the appearance of purple violaceous bullae, hemorrhage into the skin and rapid progression of tissue destruction. See the chapter on invasive S. pyogenes infections for further discussion of the pathogenesis of necrotizing fasciitis and myonecrosis.

Figure 1. . Anatomical relationship between skin and skin structures and different S.

Figure 1.

Anatomical relationship between skin and skin structures and different S. pyogenes infections. From Harrison’s Principals of Internal Medicine, 19th edition, and used with permission (Stevens, 2015).

Figure 2 shows a treatment algorithm prepared for the 2014 Infectious Diseases Society of America Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections (SSTI) (Stevens, et al., 2014). Purulent soft tissue infections are most commonly caused by staphylococcal species, whereas group A streptococcal cellulitis, erysipelas, necrotizing fasciitis, and myonecrosis are non-purulent. Once the clinician has made this distinction, the next decision is to determine whether the patient’s signs, symptoms, and laboratory tests indicate mild, moderate, or severe infection. Appropriate diagnostic and therapeutic approaches are then provided for each category.

Figure 2. . Algorithm for the Management of Skin and Soft Tissue Infections.

Figure 2.

Algorithm for the Management of Skin and Soft Tissue Infections. From Clinical Infectious Diseases, 2014, and used with permission (Stevens, et al., 2014).

Streptococcal pyoderma

Pyoderma, impetigo, and impetigo contagiosa are terms used synonymously to describe discrete purulent lesions that are primary infections of the skin and that are extremely prevalent in many parts of the world. In the great majority of cases, pyoderma is caused by β-hemolytic streptococci, Staphylococcus aureus, or both.

Epidemiology

The number of existing cases of streptococcal pyoderma in children less than 15 years of age is estimated to be 111 million (Carapetis, Steer, Mulholland, & Weber, 2005). Notably, this figure excludes cases in adults and those in adults and children in developed countries. The incidence of this disease is markedly influenced by several factors, the most important of which appear to be climate and hygiene—both of which parallel global socio-economic inequities between developed countries (northern latitudes, temperate climates) and developing countries (equatorial latitudes, tropical/sub-tropical climates). Thus, the greatest global burden of this infection is found in economically disadvantaged children in tropical or subtropical climates, though it is also prevalent in northern climates during the summer months (Ferrieri, Dajani, Wannamaker, & Chapman, 1972). The peak incidence of impetigo is in children aged 2 to 5 years, but may also occur among older children and adults whose recreational activities or occupation results in cutaneous cuts or abrasions (Adams, 2002; Fehrs, et al., 1987; Wasserzug, et al., 2009). There is no particular gender predilection, and all races appear to be susceptible.

Meticulous prospective studies of streptococcal impetigo have demonstrated that the responsible microorganisms initially colonize the unbroken skin (Ferrieri, Dajani, Wannamaker, & Chapman, 1972), an observation that probably explains the influence of personal hygiene on the incidence of disease. Development of skin colonization with a given streptococcal strain precedes the development of impetiginous lesions by an average interval of 10 days. The mechanism of production of skin lesions is unproven, but it is most likely caused by intradermal inoculation of surface organisms by abrasions, minor trauma, or insect bites. Frequently, there is a transfer of the streptococcal strains from the skin and/or pyoderma lesions to the upper respiratory tract. The interval between colonization of the skin and colonization of the nose and/or throat averages 2 to 3 weeks.

Scabies is also highly prevalent in socially disadvantaged communities, such as indigenous populations and in developing countries. Its association with group A streptococcal pyoderma is well established, and treatment of scabies clearly decreases the prevalence of subsequent bacterial infection. However, such infestations may do more than simply provide a portal of bacterial entry into the skin. A recent molecular study by Mika and colleagues demonstrated that the intestinal compounds excreted from the scabies mite have potent complement-inhibitory functions that promote the growth of group A streptococcus, even in the presence of type-specific antibodies (Mika, et al., 2012). These findings provide the first molecular mechanism to account for the well-recognized association between scabies and streptococcal pyoderma and suggest new targets for intervention.

Bacteriology and Immunology

Streptococci isolated from pyodermal lesions are primarily group A, but occasionally other serogroups are responsible, such as C and G. S. pyogenes strains that cause impetigo differ in several respects from those usually associated with tonsillitis and pharyngitis. Skin strains belong to different M serotypes and to different emm genotype patterns than the classic throat strains (reviewed in (Bessen, 2009)). For example, among the 3 main emm pattern genotypes, (namely, AC, D and E), the emm pattern AC group has a strong predilection to cause infection of the throat, and emm pattern D strains have a strong tendency to cause impetigo (Bessen, 2009). In contrast, the pattern E strains are designated generalists that readily cause infections at both tissue sites (Anthony, Kaplan, Wannamaker, & Chapman, 1976). Thus, S. pyogenes strains can be divided into 3 clinically and ecologically relevant groups, based on their emm pattern genotype. Aside from differences in emm, throat and skin strains can also be differentiated by other genetic markers (Fiorentino, Beall, Mshar, & Bessen, 1997) and functional traits, including differences in their binding avidity for keratinocytes. Because most skin strains have been identified more recently, they tend to be comprised of the higher numbered M types. The classic skin strain associated with impetigo and post-streptococcal AGN is the M-49 strain, which was isolated in Red Lake, Minnesota.

Clinical manifestations and diagnosis

The lesion of streptococcal pyoderma begins as a papule that rapidly evolves into a vesicle, surrounded by an area of erythema. The vesicular lesions are evanescent and rarely clinically recognized; they give rise to pustules that gradually enlarge and then break down over a period of 4 to 6 days to form characteristic thick crusts. The lesions heal slowly and leave depigmented areas. A deeply ulcerated form of impetigo is known as ecthyma.

Streptococcal impetigo occurs on exposed areas of the body, most frequently on the lower extremities or face. The lesions remain well localized, but frequently appear in multiples. Although regional lymphadenitis may occur, systemic symptoms are not ordinarily present.

In the past, the lesions previously described could be confidently diagnosed as streptococcal. This was the predominant form of impetigo, which could be distinguished from bullous impetigo caused by phage group II S. aureus. Although bullous impetigo remains almost exclusively caused by staphylococcus, the bacteriology of non-bullous impetigo has changed (Barnett & Frieden, 1992). S. aureus, either alone or in combination with S. pyogenes, is now the predominant causative agent (Gonzalez, et al., 1989). Almost all such staphylococci are penicillinase producers. Therefore, treatment with penicillin, which had previously been highly effective against non-bullous impetigo, even when both streptococci and staphylococci were isolated from the lesions, now frequently fails (Demidovich, Wittler, Ruff, Bass, & Browning, 1990).

Assays of anti-streptolysin O (ASO) antibodies are of no value in the diagnosis and management of impetigo, because the ASO response is weak in patients with streptococcal impetigo (Kaplan, Anthony, Chapman, Ayoub, & Wannamaker, 1970; Bisno, Nelson, Waytz, & Brunt, 1973), presumably because the activity of streptolysin O is inhibited by skin lipids (cholesterol) (Kaplan & Wannamaker, 1976). In contrast, anti–DNase B levels are elevated (Kaplan, Anthony, Chapman, Ayoub, & Wannamaker, 1970; Bisno, Nelson, Waytz, & Brunt, 1973) and thus provide helpful supporting evidence of recent streptococcal infection in patients who are suspected of having post-streptococcal glomerulonephritis.

Treatment and prevention

Because of the current frequency of isolation of S. aureus from non-bullous impetigo lesions and concomitant reports of penicillin failures (Demidovich, Wittler, Ruff, Bass, & Browning, 1990; Dagan & Bar-David, 1989; Barton & Friedman, 1987), penicillinase-resistant penicillins or first-generation cephalosporins are preferred (Demidovich, Wittler, Ruff, Bass, & Browning, 1990). Erythromycin has long been a mainstay of pyoderma therapy, but its use is contraindicated in areas in which erythromycin-resistant strains of S. aureus or, more recently, S. pyogenes are prevalent. Topical therapy with mupirocin is equivalent to oral systemic antimicrobial agents (Barton, Friedman, Sharkey, Schneller, & Swierkosz, 1989; Britton, Fajardo, & Krafte-Jacobs, 1990), and may be used when lesions are limited in number. However, it is expensive, and some strains of staphylococci may be resistant (Yun, et al., 2003). Retapamulin, a novel pleuromutilin antibacterial, has recently been approved by the FDA for treatment of bullous and non-bullous impetigo caused by S. pyogenes and methicillin-susceptible strains of S. aureus in children 9 months of age or older (Yang & Keam, 2008). In vitro data have suggested that it may be more effective than mupirocin against methicillin-resistant Staphylococcus aureus (MRSA).

Improved living conditions, improved personal hygiene and topical treatment of impetiginous lesions can prevent the spread of impetigo to susceptible individuals. In addition, a recent molecular study provided evidence that scabies mite proteins act as complement inhibitors and enhance S. pyogenes growth in whole blood assays, presumably by the inhibition of host innate immunity. Based on this groundwork data, we hypothesize that the complement-inhibitory functions of excreted gut molecules promote the growth of bacterial pathogens in the microenvironment of the epidermal burrows.

Complications

Suppurative complications are uncommon, but cutaneous infections with nephritogenic strains of S. pyogenes predispose patients to post-streptococcal AGN in many areas of the world. As yet, there are no conclusive data to indicate that treatment of an individual case of pyoderma prevents the subsequent occurrence of nephritis in these patients. Such therapy is nevertheless important as an epidemiologic measure in eradicating nephritogenic strains from the environment. For as-yet unexplained reasons, rheumatic fever has never been shown to occur after streptococcal pyoderma.

Erysipelas

Streptococci were first demonstrated in cases of erysipelas and wound infections by Billroth in 1874 and in the blood of a patient with puerperal sepsis by Pasteur in 1879. In 1883, Fehleisen showed that hemolytic streptococci fulfilled Koch’s postulates when he isolated chain-forming organisms in pure culture from erysipelas lesions and then demonstrated that these organisms could induce typical erysipelas in humans. Rosenbach applied the designation Streptococcus pyogenes to these organisms in 1884. In 1938, Lancefield gave them the distinction of group A streptococcus.

Erysipelas is a superficial cutaneous process that is usually restricted to the dermis, but with prominent lymphatic involvement. It is distinguished clinically from other forms of cutaneous infection by three features: the lesions are raised above the level of the surrounding skin, there is a clear line of demarcation between involved and uninvolved tissue, and the lesions are a brilliant salmon-red color. This disorder is more common in infants, young children, and older adults, and is almost always caused by β-hemolytic streptococci. In most cases, the infecting agent is S. pyogenes, but similar lesions can be caused by groups C or G streptococci. Rarely, group B streptococci or S. aureus may be the culprits. In older reports, erysipelas was described as characteristically involving the butterfly area of the face, but at present, the lower extremities are more frequently involved. In patients with facial erysipelas, there is frequently a history of preceding streptococcal sore throat, although the exact mode of spread to the skin is unknown. When erysipelas involves the extremities, breaks in the cutaneous barrier serve as portals of entry; these include surgical incisions, trauma or abrasions, dermatologic diseases (such as psoriasis), or local fungal infections.

The cutaneous lesion begins as a localized area of erythema and swelling and then spreads rapidly with advancing red margins, which are raised and well demarcated from adjacent normal tissue. There is marked edema, often with bleb formation, and in facial erysipelas, the eyes are frequently swollen shut. The lesion may demonstrate central resolution while continuing to extend on the periphery. The cutaneous inflammation is accompanied by chills, fever, and toxicity.

The differential diagnosis is limited. Early on, the lesions of facial herpes zoster, contact dermatitis, or giant urticaria may be confused with erysipelas. Lesions that resemble erysipelas may occur in patients with familial Mediterranean fever. Cutaneous lesions similar in appearance to those of erysipelas may occur on the hands of patients who sustain cuts or abrasions while handling fish or meats. This entity, which is known as erysipeloid of Rosenbach and caused by Erysipelothrix rhusiopathiae, is usually unaccompanied by fever or systemic symptoms.

With early diagnosis and treatment, the prognosis is excellent. Rarely, however, the process may spread to deeper levels of the skin and soft tissues. Penicillin, either parenterally or orally, depending on clinical severity, is the treatment of choice. If a staphylococcal infection is suspected, a penicillinase-resistant semisynthetic penicillin or cephalosporin should be selected. In a randomized, prospective multicenter trial (Bernard, et al., 1992), roxithromycin, a macrolide antimicrobial, was equivalent to penicillin. However, increased levels of macrolide resistance among S. pyogenes have been detected in certain areas of the United States (Martin, Green, Barbadora, & Wald, 2002; York, Gibbs, Perdreau-Remington, & Brooks, 1999).

Streptococcal cellulitis

Streptococcal cellulitis, an acute spreading inflammation of the skin and subcutaneous tissues, usually results from infection of burns, wounds, or surgical incisions, but may also follow mild trauma. Clinical findings include local pain, tenderness, swelling, and erythema. The process may rapidly extend to involve large areas of skin. Systemic manifestations include fever, chills, and malaise, and there may be associated lymphangitis, bacteremia, or both. In contrast to erysipelas, the lesion is not raised, the demarcation between involved and uninvolved skin is indistinct, and lesions are more pink than salmon-red in color. Often, however, the clinical differentiation between these entities is not clear-cut.

Two predisposing causes of streptococcal cellulitis deserve special mention. One is the parenteral injection of illicit drugs (Lentnek, Giger, & O'Rourke, 1990; Barg, Kish, Kauffman, & Supena, 1985). These cases are often associated with bacteremia and deep tissue infections, such as septic thrombophlebitis, suppurative arthritis, osteomyelitis, and occasionally infective endocarditis. Second, patients who have impaired lymphatic drainage from upper or lower extremities are prone to recurrent episodes of streptococcal cellulitis. Examples include individuals with filariasis and women who have undergone radical mastectomy with axillary node dissection (Simon & Cody, 1992). It is speculated that repetitive infection further damages local lymphatics and worsens lymphatic stasis (de Godoy, de Godoy, Valente, Camacho, & Paiva, 2000).

Recurrent episodes of severe cellulitis have also been reported in certain patients who have undergone coronary artery bypass grafting (Baddour & Bisno, 1982). The lesion invariably occurs in the extremity from which the saphenous vein was removed, and at times, may exhibit features of erysipelas. Patients with tinea pedis of the venectomy limb appear to be particularly at risk (Baddour & Bisno, 1984; Semel & Goldin, 1996). As with other forms of cellulitis, pathogenic bacteria are difficult to recover during these episodes, but the appearance of the lesions and the response to penicillin therapy suggest a streptococcal cause. The few β-hemolytic streptococci that have been recovered and characterized often belong to serogroups other than group A (Baddour & Bisno, 1985).

Disruption of the cutaneous barrier (leg ulcers, wounds, dermatophytosis) is a risk factor for the development of cutaneous streptococcal infection (Dupuy, et al., 1999). There is suggestive evidence that local dermatophyte infection (such as athlete’s foot) may serve as a reservoir for β-hemolytic streptococci that initiate episodes of erysipelas or cellulitis of the lower extremities (Semel & Goldin, 1996; Roldan, Mata-Essayag, & Hartung, 2000). Thus, care should be taken to eradicate such fungal infections in patients who experience recurrent bouts of erysipelas or cellulitis. Another potential reservoir is anal streptococcal colonization (Eriksson B. K., 1999). Other risk factors include venous insufficiency, edema, and obesity (Dupuy, et al., 1999). An increased risk of recurrent cellulitis has been associated with a lack of foot hygiene, and has also been reported in homeless persons (Lewis, Peter, Gómez-Marín, & Bisno, 2006).

Cellulitis may be caused by infection with a variety of bacterial pathogens, but most cases are caused by S. pyogenes (or, occasionally, streptococci of groups B, C, or G) or by S. aureus. S. aureus infection of the skin is usually associated with a pyogenic, fluctuant focus with surrounding erythema and has been referred to as “purulent cellulitis;” however, a better term would be purulent skin and soft tissue infection with surrounding erythema. In these cases, the erythema is entirely due to the host response to the purulent focus. The reddened skin is not itself infected, since simple drainage and no antibiotics are usually enough to resolve the infection. In the absence of positive blood cultures, which are present in only 5% of cases of non-purulent cellulitis, a specific microbiologic diagnosis is often not possible. Aspirate or biopsy samples from sites of active cellulitis are helpful when positive on smear or culture, but unfortunately, such specimens are usually negative in adult patients (Hook, et al., 1986; Howe, Eduardo Fajardo, & Orcutt, 1987; Newell & Norden, 1988).

Treatment

In some cases, it may be difficult to differentiate streptococcal from staphylococcal skin and soft tissue infection on initial presentation. In this case, a semi-synthetic penicillinase-resistant penicillin should be used. In penicillin-allergic patients, a first-generation cephalosporin may be used if the hypersensitivity is not of the immediate type. Clindamycin, linezolid, or vancomycin may be used in patients who manifest anaphylactic hypersensitivity to β-lactam antibiotics, and these agents should be administered later if there is reason to suspect infection with MRSA strains. Patients with milder cases of streptococcal cellulitis may be switched to oral medications after an initial favorable response to parenteral therapy.

The role of continuous antimicrobial prophylaxis (Wang, et al., 1997; Sjöblom, Eriksson, Jorup-Rönström, Karkkonen, & Lindqvist, 1993; Kremer, Zuckerman, Avraham, & Raz, 1991) in patients prone to frequent recurrences remains unsettled. At present, such prophylaxis seems justified only for patients with very frequent or severe episodes, and an optimal regimen has not been established.

Other Streptococcal Infections with Skin Manifestations

Suppurative soft-tissue complications following streptococcal pharyngitis

Inflammation in the facial area induced by acute streptococcal infection may affect structures that are directly contiguous to the pharynx or that drain that site. Such relatively rare complications include peritonsillar cellulitis, peritonsillar abscess, retropharyngeal abscess, and suppurative cervical lymphadenitis, as well as mastoiditis, acute sinusitis, and otitis media (Dajani, Taubert, Ferrieri, Peter, & Shulman, 1995). However, peritonsillar or retropharyngeal abscesses, frequently contain a variety of other oral flora, including anaerobes, with or without S. pyogenes. S. pyogenes are responsible for only a small minority of cases of otitis media or sinusitis.

Scarlet fever

Scarlet fever results from infection with a streptococcal strain that elaborates streptococcal pyrogenic exotoxins (erythrogenic toxins). Although this disease is usually associated with pharyngeal infections, it may follow streptococcal infections at other sites, such as wound infections or puerperal sepsis. The clinical syndrome is similar in most respects to that associated with non-toxigenic strains, except for the characteristic scarlatina-type rash. The latter must be differentiated from those of viral exanthems, drug eruptions, staphylococcal toxic shock syndrome, and Kawasaki disease.

The rash usually appears on the second day of clinical illness as a diffuse red blush, with many points of deeper red that blanch on pressure. It is often first noted over the upper part of the chest, and then spreads to the remainder of the trunk, neck, and extremities. The palms, soles, and usually the face are spared. Skin folds in the neck, axillae, groin, elbows, and knees appear as lines of deeper red (Pastia’s lines). There are scattered petechiae, and the Rumpel-Leeds test of capillary fragility is positive. Occlusion of sweat glands imparts a sandpaper texture to the skin—a particularly helpful finding in dark-skinned patients.

The face appears flushed, except for marked circumoral pallor. In addition to findings of exudative pharyngitis and tonsillitis, patients display an exanthem that is characterized by small, red, hemorrhagic spots on the hard and soft palates. The tongue is initially covered with a yellowish-white coating, through which may be seen the red papillae (white strawberry tongue). Later, the coating disappears, and the tongue is beefy red in appearance (red strawberry tongue). The skin rash fades over the course of one week and is followed by extensive desquamation that lasts for several weeks. A modest eosinophilia may be present early in the course of the illness.

Severe forms of scarlet fever, associated with either local or hematogenous spread of the organism (septic scarlet fever) or with profound toxemia (toxic scarlet fever), are characterized by a high fever and marked systemic toxicity. The course may be complicated by arthritis, jaundice, and, very rarely, hydrops of the gallbladder. Such severe forms of the disease are infrequent in the antibiotic era. However, in the late 1800s, scarlet fever was associated with mortalities of 20% in Chicago, New York and Scandinavia. During the American Civil War, epidemics of surgical scarlet fever, also called “hospital gangrene,” developed among soldiers after amputation for wounds. Recently, an epidemic of 900 cases of scarlet fever occurred in China in 2011 between January and July that was associated with emm-12 strains of S. pyogenes (Luk, et al., 2012).

Lymphangitis

Lymphangitis may accompany cellulitis or may occur after clinically minor or inapparent skin infection. Lymphangitis is readily recognized by the presence of red, tender, linear streaks directed toward enlarged, tender, regional lymph nodes. It is accompanied by systemic symptoms, such as chills, fever, malaise, and headache.

Puerperal sepsis and infection of the genitalia

Puerperal sepsis follows abortion or natural childbirth when streptococci that colonize the vaginal vault or are transmitted from medical personnel invade the endometrium and surrounding structures, lymphatics, and bloodstream. The resulting endometritis and septicemia may be complicated by pelvic cellulitis, septic pelvic thrombophlebitis, peritonitis, or pelvic abscess. This disease was associated with high mortality in the pre-antibiotic era. Vaginal wall tears during delivery or episiotomy sites can also be infected with S. pyogenes and can cause cellulitis of the perineum or necrotizing fasciitis. Clostridial species can also cause necrotizing infection under these conditions, but can be distinguished from S. pyogenes, because the latter does not produce gas.

S. pyogenes perianal cellulitis and vulvo-vaginitis are symptomatic but benign disorders that primarily affect children (Petersen, Kaltoft, Misfeldt, Schumacher, & Schønheyder, 2003; Mogielnicki, Schwartzman, & Elliott, 2000). Asymptomatic carriage of S. pyogenes in the vagina, anus, scalp or, rarely, the upper respiratory tract of adults has, however, been the source of some outbreaks of nosocomial streptococcal infection (Mastro, et al., 1990).

Streptococcal Virulence Factors Associated with SSTI

Adhesins

A number of somatic streptococcal components play critical roles in the first step of colonization, namely, adherence to the surface of human epithelial cells. At least 17 adhesin candidates have been described (Courtney, Hasty, & Dale, 2002; Hasty, Itzhak, Courtney, & Doyle, 1992), but the most extensively studied have been lipoteichoic acid (LTA), M protein, and fibronectin-binding proteins. Through hydrophobic interactions, LTA serves as a “first-step” adhesin, which brings the organisms into close contact with host cells and then allows other adhesins to promote high-affinity binding (Hasty, Itzhak, Courtney, & Doyle, 1992). Although M protein does not appear to promote adhesion to human buccal or tonsillar epithelial cells (Ofek, Beachey, Jefferson, & Campbell, 1975; Caparon, Stephens, Olsén, & Scott, 1991), it does mediate the adherence to skin keratinocytes via the attachment of the C repeat region to keratinocyte membrane cofactor CD46 (Okada, Pentland, Falk, & Caparon, 1994; Okada, Liszewski, Atkinson, & Caparon, 1995). S. pyogenes surface proteins that bind fibronectin have been studied extensively and are important in adherence to both throat and skin. These include protein F1 (PrtF1) (Hanski & Caparon, 1992), also known as SfbI (streptococcal fibronectin-binding protein I) (Talay, Valentin-Weigand, Jerlström, Timmis, & Chhatwal, 1992); and related proteins known as SbfII (Kreikemeyer, Talay, & Chhatwal, 1995), FBP54 (Courtney, Dale, & Hasty, 1996), protein F2 (Jaffe, Natanson-Yaron, Caparon, & Hanski, 1996), and PFBB (Rocha & Fischetti, 1999).

Moreover, the expression of these adhesins has been reported to be environmentally regulated (Gibson, et al., 1995). Expression of protein F1 is enhanced in an O2-rich environment, whereas that of M protein is greater at higher partial pressures of CO2 (Caparon, Geist, Perez-Casal, & Scott, 1992). Thus, teleologically, it might be postulated that the organism displays protein F1 on its surface when it seeks to adhere to the cutaneous surface, but expresses M protein in the deeper tissues, where it is more likely to encounter phagocytic cells.

Exotoxins

During the course of growth either in vitro or in vivo, S. pyogenes elaborates numerous extracellular products, only a limited number of which have been well characterized. Two distinct hemolysins have been described. The first is streptolysin O (SLO)—a member of the cholesterol-binding family of cytolysins (reviewed in (Alouf & Geoffroy, 1999)). Like several of its family members, SLO derives its name from its oxygen lability. It is reversibly inhibited by oxygen and irreversibly inhibited by cholesterol. In addition to its ability to lyse erythrocytes, it is toxic to a variety of cells and membrane-bound cell fractions, including leukocytes, platelets, endothelial cells, dermal fibroblasts, lysosomes, and isolated mammalian and amphibian cardiomyocytes. SLO is produced by virtually all strains of S. pyogenes (as well as many group C and G streptococci) and is antigenic. Measurement of anti-SLO (ASO) antibodies in human sera is useful as an indicator of recent streptococcal infection, but is of less value in patients with impetigo.

Other S. pyogenes extracellular products may facilitate the liquefaction of pus and the spreading of streptococci through tissue planes characteristic of streptococcal cellulitis and necrotizing fasciitis. These include: (1) four antigenically distinct deoxyribonucleic acid-degrading enzymes (DNases A, B, C, and D); (2) hyaluronidase, which degrades hyaluronic acid found in the ground substance of connective tissue; (3) streptokinase, which promotes the dissolution of clots by catalyzing the conversion of plasminogen to plasmin; (4) streptococcal pyrogenic exotoxin B (SpeB), which is a potent protease; and (5) C5a peptidase, which specifically cleaves the human chemotaxin C5a at the PMNL binding site (Ji, McLandsborough, Kondagunta, & Cleary, 1996; Wexler, Chenoweth, & Cleary, 1985). SpeB also cleaves IgG bound to S. pyogenes, thus interfering with ingestion and killing by phagocytes (Eriksson & Norgren, 2003).

Several members of the streptococcal pyrogenic exotoxin (Spe) family have been associated with StrepTSS, necrotizing fasciitis, and other severe S. pyogenes infections. This family of superantigens includes the bacteriophage-encoded SpeA and SpeC (historically known as the scarlatina toxins), as well as the cysteine protease SpeB and several of the more recently identified pyrogenic exotoxins, such as mitogenic factor (MF and SpeF), and streptococcal superantigen (SSA), as reviewed in (Bisno, Brito, & Collins, 2003). Superantigens are potent immunostimulators that cause the clonal proliferation of T cells and watershed production of pro-inflammatory cytokines that mediate tissue destruction, shock, and organ failure.

Genetic Control of Virulence Factors

Control of virulence factor gene expression over time and under diverse environmental conditions depends on multiple complex and interrelated genetic systems (reviewed in (Bisno, Brito, & Collins, 2003). Of the known transcriptional regulators in S. pyogenes, the most intensively studied include Mga (multiple virulence gene regulator of group A streptococcus) (McIver, 2009), Mry (M protein RNA yield) (Perez-Casal, Caparon, & Scott, 1991), and a two-component regulatory system known as CsrRS (capsule synthesis regulator, Response and Sensor components) (Levin & Wessels, 1998) or, alternatively, as CovRS (control of virulence genes) (Federle, McIver, & Scott, 1999), which represses the synthesis of the hyaluronic acid capsule and several exotoxins. The regulator of proteinase B (RopB) has also been shown to have multiple polymorphisms that control the virulence of S. pyogenes (Carroll, et al., 2011).

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