Streptococcus pyogenes (Group A β-hemolytic Streptococcus)

Chief, Infectious Diseases Section, Veterans Affairs Medical Center, Boise, ID and

Dennis L. Stevens, Ph.D., M.D., Infectious Diseases Section, Veterans Affairs Medical Center, 500 West Fort St. (Bldg 45), Boise, ID 83702;

This material is based upon work supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs.

Streptococcus pyogenes, or Group A streptococcus (GAS), is a facultative, Gram-positive coccus which grows in chains and causes numerous infections in humans including pharyngitis, tonsillitis, scarlet fever, cellulitis, erysipelas, rheumatic fever, post-streptococcal glomerulonephritis, necrotizing fasciitis, myonecrosis and lymphangitis. The only known reservoirs for GAS in nature are the skin and mucous membranes of the human host. The clinical diseases produced by GAS have been well described, however, the pathogenic mechanisms underlying them are poorly understood, largely because each is the culmination of highly complex interactions between the human host defense mechanisms and specific virulence factors of the streptococcus.

Group A streptococci require complex media containing blood products, grow best in an environment of 10% carbon dioxide and produce pinpoint colonies on blood agar plates which are surrounded by a zone of complete (beta) hemolysis. The exhaustive work of Rebecca Lancefield established the classification of streptococci into types A through O based upon acid extractable carbohydrate antigens of cell wall material (51). In addition, GAS have also been subdivided based upon the surface expression of M and T antigens. Sub-typing strains of GAS has proven invaluable for epidemiological studies, in much the same way that phage typing has been useful to define the epidemiology of Staphylococcus aureus. High resolution genotyping provides a more specific determination of relatedness among strains isolated from outbreaks of GAS infections (65). Finally rapid, sequencing of the gene encoding M-protein is providing a rapid definitive way of comparing M-typeable and M-non-typeable strains (5,27).

Group A β-hemolytic streptococcus (GABHS, Streptococcus pyogenes) is a common cause of a wide variety of infections in infants, children, and adults. Group A streptococcal infections have long been associated with serious morbidity and mortality, but toward the middle of the 20th century, a marked decline in the incidence and severity of such infections occurred. However, over the past 15 years, there has been a resurgence in the incidence of severe invasive group A streptococcal infections (77,87). These include necrotizing fasciitis, myositis, toxic shock syndrome, and streptococcal bacteremia. In addition, since the early 1980s, an increase in reports of individual cases of acute rheumatic fever (ARF) have been described in Utah and in some military posts (6,43).

While group A streptococcal infections have not been reportable diseases for several decades, the true incidences of ARF, streptococcal pharyngitis, scarlet fever and invasive infections are unknown. However, there is a general consensus that the number and severity of both suppurative and non-suppurative complications of group A streptococcal infection have increased. This resurgence has been partly attributed to a change in the epidemiology of group A streptococcus as well as a change in the virulence of the organism (81). Some have suggested that changes in the susceptibility of group A streptococci to commonly used antibiotics may have contributed as well (57,75). The increased number and severity of group A streptococcal infections present special challenges to both the general practitioner and the infectious disease specialist, and the treatment of group A streptococcal infections has taken on greater importance.

Scarlet Fever: Scarlet fever has its highest prevalence in children 4 - 8 years of age and is very uncommon in adults. The primary infection most commonly associated with scarlet fever is pharyngitis, though soft tissue infection at a surgical site has been described (surgical scarlet fever).

Acute Rheumatic Fever: Large epidemics of scarlet fever have been reported in the literature since the 12 and 13th centuries in association with childbed fever, non-pasteurized milk, surgical wards, schools, day care centers and certainly among family members. The transmission in non-hospitalized patients is usually via the oral route from droplets from primary cases or from ingestion of milk contaminated with toxin producing strains of GAS. Reductions in incidence and mortality rates of ARF in the United States had begun prior to the discovery of penicillin, primarily because of improved housing, sanitation, and delivery of health care. The recent increase in incidence of ARF in the United States has occurred primarily in children of middle class families (89). However, the use of penicillin in the treatment of GAS pharyngitis dramatically reduced the incidence of ARF. Mucoid colonies of group A streptococci have been associated with cases of rheumatic fever in North America but not in developing countries. Five serotypes have predominated: M-1, M-3, M-18, M-5, and M-6. Types M- 5 and M-18 have been reported as most consistently mucoid (77,87,89).

Streptococcal Toxic Shock Syndrome (StrepTSS): Several population-based studies of StrepTSS have documented the annual incidence of 1-5 cases per 100,000 population (74) with most cases being sporadic in nature, however, larger epidemics of invasive Group A streptococcal infections have also been described in some settings. In 1994, an epidemic of related invasive infections occurred in Wannamingo, Minnesota (16) with an annualized prevalence of 24 cases per 100,000 population. In Missoula, Montana in 1999, the incidence of invasive infections reached 30 cases per 100,000 population. In addition to community-based infections, invasive Group A streptococcal infections have also been described in hospitals, convalescent centers and among hospital employees and family contacts of patients with invasive infections (11,25,31). Some of these studies have documented the same M-type and identical RFLP patterns in strains from primary and index cases (11,25,31,44). In addition, carriage of Group A streptococcus by healthcare personnel has been associated with the spread of life threatening Group A streptococcal infections in the obstetrics/gynecology and ear-nose-throat wards of American hospitals (1). Such infections have also originated in outpatient surgical settings and within the home environment.

It has been estimated that the risk of secondary cases may be approximately 200 times greater than the risk among the general population (23) There is ample data from studies conducted over several decades that Group A streptococcus is quickly and efficiently transmitted from index cases to susceptible individuals and that transmission may result in colonization, pharyngitis, scarlet fever, rheumatic fever or invasive Group A streptococcal infections. The risk for secondary cases is likely related to close or intimate contact and crowding as well as host factors such as 1. active viral infections such as varicella or influenza; 2. recent surgical wounds and childbirth (author's unpublished observations); 3. absence of type specific opsonic antibody against the Group A streptococcus causing the index case; and 4. absence of neutralizing antibody against pyrogenic exotoxin A or B (59).

The portals of entry for streptococci are the vagina, pharynx, mucosa and skin in 50% of cases (87). Interestingly, a specific portal cannot be defined in the remaining 50% (87). Rarely, patients with symptomatic pharyngitis develop StrepTSS. Surgical procedures such as suction lipectomy, hysterectomy, vaginal delivery, bunionectomy and bone pinning provide a portal of entry in some cases. Numerous cases have developed within 24 - 72 hours of minor non-penetrating trauma resulting in hematoma, deep bruise to the calf or even following muscle strain (87). Virus infections such as varicella and influenza have provided portals in other cases (87). In some cases the use of non-steroidal anti-inflammatory agents may have either masked the presenting symptoms or predisposed to more severe streptococcal infection and shock (87). Most cases of StrepTSS occur sporadically, though outbreaks of severe Group A streptococcal infections have been described in closed environments such as nursing homes (2,42), and hospital environments (25,31).

Each type of streptococcal infection presents with its own unique set of clinical manifestations. Thus, each type of infections will be described below in the section on specific antimicrobial treatment.

The diagnosis of GAS infection may be suspected on clinical grounds, but rests on the demonstration of the organism in samples of pharyngeal exudates, blood, tissue, or body fluids using criteria described under Microbiology above. Rapid strep tests have proven useful for the office diagnosis of streptococcal pharyngitis, though the specificity and sensitivity vary widely (reviewed in (76)). A negative rapid strep test should be followed with a pharyngeal culture. An antecedent streptococcal infection may be diagnosed by a 4-fold increase in antibody against streptolysin O (ASO), hyaluronidase, or DNAse B (56).

Anti-Phagocytic Properties: M-protein contributes to invasiveness through its ability to impede phagocytosis of streptococci by human polymorphonuclear leukocytes (PMNL) (52). Conversely, type specific antibody against the M-protein enhances phagocytosis (52). Following infection with a particular M-type, specific antibody confers resistance to challenge with viable GAS of that M-type (52). Recently, Boyle has shown that GAS protease cleaves the terminal portion of the M-protein, rendering the organism more susceptible to phagocytosis by normal serum but more resistant to phagocytosis in the presence of type specific antibody (72). While M types 1 and 3 strains have accounted for the vast majority of strains isolated from cases of StrepTSS, many other M types, including some non-typeable strains, have also been isolated from such cases. M types 1 and 3 are also commonly isolated from asymptomatic carriers, and patients with pharyngitis or mild scarlet fever (45,48).

Mechanisms of Fever Induction: Pyrogenic exotoxins induce fever in humans and animals and also participate in shock by lowering the threshold to exogenous endotoxin (77). Streptococcal pyrogenic exotoxin A (SPEA) and SPEB induce human mononuclear cells to synthesize not only tumor necrosis factor- α (TNFα) (28) but also interleukin-1β (IL-1β) (38) and interleukin-6 (IL-6) (38,62,68) suggesting that TNF could mediate the fever, shock and organ failure observed in patients with StrepTSS (87). Pyrogenic exotoxin C has been associated with mild cases of scarlet fever in the United States (author's observations) and in England (41). The roles of two newly described pyrogenic exotoxins, SSA (60) and MF (67), in the pathogenesis of Strep TSS have not been elucidated.

Cytokine Induction: There is strong evidence suggesting that SPEA, SPEB and SPEC, as well as a number of staphylococcal toxins (TSST-1, and staphylococcal enterotoxins A, B, and C) act as superantigens and stimulate T cell responses through their ability to bind to both the Class II MHC complex of antigen presenting cells and the V_β region of the T cell receptor (61). The net effect is induction of T cell proliferation (via an IL-2 mechanism) with concomitant production of cytokines (e.g., IL-1, TNFα, TNFβ, IL-6, IFNγ) that mediate shock and tissue injury. Recently, Hackett and Stevens demonstrated that SPEA induced both TNFα and TNFβ from mixed cultures of monocytes and lymphocytes (39), supporting the role of lymphokines (TNFβ) in shock associated with strains producing SPEA. Kotb (49) has shown that a digest of M-protein type 6 can also stimulate T cell responses by this mechanism. Interestingly, quantitation of such Vβ T-cell subsets in patients with acute StrepTSS demonstrated deletion rather than expansion, suggesting that perhaps the life-span of the expanded subset was shortened by a process of apoptosis (91). In addition, the subsets deleted were not specific for SPEA, SPEB, SPEC, or MF suggesting that perhaps an as yet undefined superantigen may play a role in StrepTSS (91).

Cytokine production by less exotic mechanisms may also contribute to the genesis of shock and organ failure. Peptidoglycan, lipoteichoic acid (84) and killed organisms (37,63) are capable of inducing TNFα production by mononuclear cells in vitro (40,63,77). Exotoxins such as SLO are also potent inducers of TNFα and IL-1β. SPEB, a proteinase precursor, has the ability to cleave pre-IL-1β to release preformed IL-1β (46). Finally, SLO and SPEA together have additive effects in the induction of IL-1β by human mononuclear cells (39). Whatever the mechanisms, induction of cytokines in vivo is likely the cause of shock and SLO, SPEA, SPEB, SPEC as well as cell wall components, etc., are potent inducers of TNF and IL-1 (11). Finally, a cysteine protease formed from cleavage of SPEB may play an important role in pathogenesis by the release of bradykinin from endogenous kininogen and by activating metalloproteases involved in coagulation (10).

The mere presence of virulence factors, such as M-protein or pyrogenic exotoxins, may be less important in Strep TSS than the dynamics of their production in vivo. For example, Chaussee et al (11) have demonstrated that among strains from patients with necrotizing fasciitis and StrepTSS, 40% and 75% produced SPEA or SPEB, respectively. In addition, the quantity of SPEA but not SPEB was higher for strains from Strep TSS patients compared to non invasive cases (11). Recently, Cleary has proposed a regulon in GAS that controls the expression of a group of virulence genes coding for virulence factors such as M-protein and C5-peptidase (14). Using DNA fingerprinting, differences were shown in M-1 strains isolated from patients with invasive disease compared to M-1 strains from patients with non-invasive GAS infections (15). Such strains of GAS could acquire genetic information coding for SPEA via specific bacteriophage. Multi-locus enzyme electrophoresis demonstrates two patterns that correspond to M-1 and M-3 type organisms which produce pyrogenic exotoxin A, a finding that fits epidemiologic studies implicating these strains in invasive GAS infections (64) in the United States.

Pathogenic Mechanisms in Acute Rheumatic Fever: The pathogenesis of acute rheumatic fever involves an intimate interplay between streptococcal virulence factors and the susceptible host. That T cells play an integral role was demonstrated by obtaining T-cell clones from valvular tissue of patients with rheumatic fever and then showing that these clones were responsive to specific epitopes of type 5 M-protein (35). That B-lymphocytes play an important role is suggested by the demonstration that antibodies raised against particular M-protein digests cross react with cardiac tissue including myosin and endothelium (71). Interestingly anti-myosin antibodies also react strongly to cardiac endothelium (36). Thus, as antibody against M-protein develops in a patient with antecedent Group A streptococcal pharyngitis, antibody could fix complement, thereby damaging and activating the endothelium yielding cytokines and chemokines which attract and activate T-lymphocytes. Thus, molecular mimicry between specific epitopes on M-protein and cardiac tissue results in damage to endothelium on the heart valve mediated by specific B and T-lymphocytes.

Post Streptococcal Glomerulonephritis: It is clear that only certain strains of streptococci are capable of causing post-streptococcal glomerulonephritis. The best hypothesis at the present time is that proteins with unique antigenic determinants produced only by Anephritogenic strains, intercalate into the lipid bilayer of the glomerular basement membrane during the course of pharyngitis or impetigo. Recent studies suggest that streptokinase, which has certain lipophilic regions may be the streptococcal virulence factor responsible. Once streptokinase is membrane bound, complement is activated directly. Further glomerulus-bound streptokinase interacts with circulating anti-streptococcal antibodies, resulting in further complement fixation and glomerular damage (66).

Susceptibilities for commonly used antibiotics in the treatment of GAS are presented in Table 1. Susceptibilities from Coonan and Kaplan's study were obtained from 282 pharyngeal isolates along with 43 isolates from severe or invasive group A streptococcal disease (18).

No in vitro susceptibility testing has been undertaken to investigate whether combinations of antibiotic may exert an additive, synergistic or antagonistic effect against GAS.

Despite possible changes in virulence, group A streptococci have universally remained susceptible to penicillin since its introduction. This is of considerable interest, since other streptococci have developed multiple antibiotic resistance, and higher concentrations of penicillin are currently required to inhibit pneumococcus. Penicillin is still considered first-line therapy in the treatment of most GAS infections despite a recognized increase in microbiologic failure rates. Erythromycin has been the antibiotic of choice in the penicillin-allergic child for most GAS infections, yet impressive emergence of resistance has been documented on three continents during the last 30 years (57,58,75). Thus, antibiotic treatment of GAS infections in general will likely become much more complex.

GAS Pharyngitis: GAS infections of the pharynx are the most common bacterial infections of childhood. Treatment of GAS pharyngitis is primarily aimed at preventing non-suppurative (in particular, rheumatic fever) and suppurative complications. The drug of choice remains penicillin VK, 25 to 50 mg/kg/day in 4 divided doses for children, or 250 to 500 mg per dose, 4 times/day for adults. However, a study conducted by Gerber et al. demonstrated that twice-a-day dosing of penicillin was as effective as three-times-a-day dosing (34). Treatment with penicillin should be continued for 10 days since shorter courses of penicillin have shown decreased efficacy. A clinical response is generally obtained within 24 h of beginning therapy, and most children have a negative throat culture by 48 h and can return to school at that time. Persistence of symptoms beyond this period suggests development of a suppurative complication of GAS, a lack of compliance, or the presence of another underlying disease.

A single injection of 1.2 million units of penicillin G benzathine given intramuscularly is as effective as enteral penicillin (4) and was the long-time gold standard in treatment of GAS pharyngitis. It can provide bactericidal levels against GAS for as long as 28 days. Children who weigh less than 140 pounds (64 kg) should receive an intramuscular injection composed of 900,000 units of benzathine penicillin G and 300,000 units of procaine penicillin G.

Penicillin's efficacy in preventing rheumatic fever is well established, and is related to the eradication of the organism from the pharynx. This efficacy, however, is dependent upon prolonged, rather than high-dose, therapy. Penicillin has been shown effective when therapy is started within 9 days of onset of symptoms of GAS pharyngitis (90). Other desirable features of penicillin include lower cost, lower side effects, and a narrow antimicrobial spectrum. There has been no documentation of resistance in GAS to penicillin; the minimal bactericidal concentration of penicillin G for GAS has remained 0.005 μg/mL (reviewed in 76). Erythromycin remains the first alternate choice in patients who are allergic to penicillin. Erythromycin estolate (20 - 40 mg/ kg/day) or erythromycin ethylsuccinate (40 mg/kg/day) given enterally in 2 to 4 divided doses has been shown as effective as penicillin in treatment of pharyngitis. However, documented reports of erythromycin-resistant GAS have occurred in Finland, Japan, and, most recently, in the United States (57,58,75,92). In 1970, resistance to erythromycin in Japan had increased to 70% of all isolates, corresponding to a marked increase in macrolide use during that time (30). Use of macrolides since then has declined, and a marked decrease in rates of erythromycin resistance has followed (30). Resistance rates fell to 46% in 1981 and are currently at 3% (1989) (30). In Finland, erythromycin resistance reached 25% and was highest among strains isolated from soft tissue infections (75).

The newest macrolides, azithromycin and clarithromycin, have been shown highly effective in the treatment of GAS pharyngitis. They provide easier dosing schedules and thus improve patient compliance. Azithromycin has been shown to be efficacious in the treatment of GAS pharyngitis when given for only 3 - 5 days. For example, a recent study comparing azithromycin (20 mg/kg, once daily for 3 days) with penicillin V (125-200 mg four times daily for 10 days) showed significantly higher bacteriologic eradication rates and lower pathogen recurrence in the azithromycin group (69): 100% of the azithromycin group had a satisfactory clinical response, defined as cure or improvement, compared with 97% in the penicillin group; 5% of the azithromycin group relapsed, compared with 2% in the penicillin group (69). However, azithromycin-resistant GAS have been reported in the United States (19), and treatment failure of azithromycin was documented in the United States recently among children harboring GAS with high level azithromycin resistance (57). The ability of macrolides to prevent episodes of rheumatic fever has not been studied.

Amoxicillin has been shown to be effective in eradicating GAS, is more palatable, and provides easier dosing than penicillin. Oral cephalosporins have been extensively studied in the treatment of GAS pharyngitis and are highly effective. In fact, some studies have suggested greater efficacy with cephalosporins than with penicillin, possibly because of their resistance to β-lactamase producing organisms in the pharynx (70); other studies have not supported this (76). Cephalexin can be given at 30 mg/day, in four divided doses for 10 days; cefadroxil, 30 mg/kg/day, in two divided doses forns10 days; cefaclor, 30 mg/kg/day in three divided doses for 10 days; cefuroxime axetil, 15 mg/kg/day in two divided doses for 10 days; cefoxitin, 80 to 160 mg/kg/day or 4 to12 g/day in four divided doses for 10 days; and cefixime, 8 mg/kg/day, once a day for 10 days (76). Cefaclor has been associated with a higher incidence of serum sickness than most other antibiotics. In addition, cephalosporins as a class are more expensive than penicillin, are associated with greater side effects in general, and have a broader spectrum of activity.

In many areas, tetracycline resistance occurs in a high percentage of strains of GAS and thus, this drug is not recommended for treatment of pharyngitis. Sulfonamides, including trimethoprim-sulfamethoxazole, are ineffective in the treatment of GAS pharyngitis, though sulfadiazine has proven useful for prophylaxis in acute rheumatic fever (8,47).

Treatment failures in GAS pharyngitis are of major concern in the prevention of rheumatic fever. Studies have reported failure rates as high as 30%, including studies of penicillin G given one time intramuscularly (76). Noncompliance is thought to play a major role with oral treatments but does not account for all failures, however, it is unlikely that bacteriologic failures in the treatment of GAS are due solely to β-lactamase-flora colonizing a patient's pharynx (76).

Some investigators have postulated that early treatment of GAS, within 48 h of symptoms, impairs the patient=s immune response by altering the course of the illness. In fact, studies have shown that delaying therapy for 3 to 5 days resulted in an increase in anti-streptolysin O antibodies but did not affect development of type-specific antibodies (32). Antibodies such as anti-streptolysin O, unlike type-specific antibodies, do not confer immunity on the host. At present, it is unclear if delaying therapy for 2 to 3 days in patients with GAS pharyngitis results in a significantly greater antibody rise. Since adequate antimicrobial therapy prevents development of suppurative and non-suppurative complications of GAS, most authors do not recommend delaying therapy.

Some bacteriologic and clinical failures may also represent infection with a tolerant strain or acquisition of a new strain of GAS. In addition, GAS carriers with an intercurrent viral pharyngitis may be mistakenly diagnosed as patients with acute GAS pharyngitis and thus considered treatment failures, since penicillin is ineffective in eradication of the GAS carrier state (76).

Clindamycin has been extremely effective in the treatment of GAS. It is unaffected by the activity of β-lactamases, but is more expensive than penicillin and has been associated with development of pseudomembranous colitis in some patients.

In patients with recurring episodes of GAS pharyngitis or persistent, culture-positive, clinical GAS pharyngitis, it is often necessary to change antibiotic therapy. Usually, a 10 day course of amoxicillin/clavulanate, clindamycin, or an oral cephalosporin eradicates the GAS. Therapies shown to be effective in eliminating the carrier state include clindamycin (20 mg/kg/day in 3 divided doses over 10 days), amoxicillin/clavulanate given for 10 days, oral rifampin (20 mg/kg every 24 h for 4 doses) started during the last 4 days of a 10 day course of oral penicillin (88), and a combination of penicillin plus rifampin (oral rifampin 10 mg/kg every 12 h for 8 doses, with one dose of intramuscular benzathine penicillin G) (88). In addition, topical application of α-streptococci may eliminate the carrier state (73).

Tonsillectomy may help reduce the number of acute infections in children with GAS pharyngitis (see below section VI AAdjunctive Therapy@).

Scarlet Fever: Scarlet fever is characterized by high fever, circumoral pallor and a diffuse erythematous rash over the neck, trunk, face and limbs. There is a sandpaper consistency to the rash which blanches with pressure. A white coating over the tongue resolves quickly leaving a strawberry appearance to the tongue owing to the swollen papillae.

The treatment of scarlet fever is the same as that for GAS pharyngitis as the disease usually results from infection of the pharynx with a streptococcal strain that elaborates one of the streptococcal pyrogenic exotoxin (8). Scarlet fever can also result from GAS infections at other sites, such as the skin (8). Patients in modern times resolve the illness in 5-7 days and by 10-14 days there may be impressive desquamation of the skin particularly over the hands and feet.

Soft-Tissue Infections Due to GAS: The second most common clinical manifestation of GAS is a localized, relatively benign, infection of the skin. Recent reports have documented increased frequency and severity of invasive group A streptococcal infections of the skin and soft tissues, associated with group A streptococcal serotypes M-1 and M-3 (7). This is of considerable interest because these serotypes are more often associated with episodes of pharyngitis. Strains of group A streptococci that cause skin infections normally differ from those that cause pharyngitis and can be identified by their M serotypes. The most common streptococcal M serotypes that cause pharyngitis (types 1, 3, 5, 6, 12, 18, 19, 24 and others), including M-1 and M-3, have rarely been identified in skin lesions (8). In contrast, "skin strains" have been found to colonize the pharynx but are rarely associated with acute episodes of pharyngitis (8).

GAS Pyoderma (Streptococcal Impetigo, Impetigo Contagiosum, Ecthyma): Pyoderma is a term for a localized purulent infection of the skin and is used synonymously with streptococcal impetigo and impetigo contagiosa. Pyoderma is most common in children aged 2 to 5 years and occurs most commonly among economically disadvantaged children in tropical or subtropical climates but can occur in northern climates during the summer months. It normally results from direct inoculation of the skin surface with GAS following minor trauma, abrasions, or insect bites. Often S. aureus can be isolated in addition to S. pyogenes from skin lesions of patients with pyoderma. Penicillin was effective treatment in the past but is now often associated with treatment failures. First line therapy includes dicloxacillin, cephalexin, or cefadroxil. Erythromycin is an alternative for penicillin-allergic patients but must be used with caution in regions where erythromycin-resistant strains of S. pyogenes and S. aureus are known. Therapy is continued for 10 days. Mupirocin ointment (applied to skin lesions 3 times daily for 10 days) has achieved cure rates comparable to those with enteral therapy but is more expensive. While rheumatic fever is not an associated complication of pyoderma, skin infections caused by nephritogenic strains of group A streptococci are the major antecedent of post-streptococcal glomerulonephritis (reviewed in (7)).

Erysipelas: Erysipelas is an acute inflammation of the skin with involvement of cutaneous lymphatic vessels. It is most commonly found in infants and adults over 30 years of age. Historically, erysipelas most commonly involved the face. However, recent reports document up to 85% of infections involving the legs and feet (7). It is often preceded by a sore throat and commonly occurs at the site of a wound or surgical incision, especially when involving the trunk or extremities. The lesions are associated with fever and toxicity and are noted to spread outward. The rash itself is a scarlet-red or salmon color with well-defined borders. Blood cultures are positive in 5% of patients (7). Facial erysipelas may spontaneously resolve in 4 to 10 days (7). The mainstay of treatment remains penicillin (7). Superficial infections may be treated orally for 10 days, while more aggressive infections require parenteral therapy. Typical antimicrobial regimens include clindamycin, nafcillin, or a third generation cephalosporin.

Cellulitis: Streptococcal cellulitis is an acute inflammation of the skin and subcutaneous tissues resulting from infection of burns, wounds, or surgical sites or following minor trauma. Symptoms include fever and toxicity and may be associated with lymphangitis or bacteremia. Cellulitis can be differentiated from erysipelas by noting that the skin lesion of cellulitis is not raised and the demarcation between involved and uninvolved skin is indistinct. Therapy should consist of a semisynthetic, penicillinase-resistant penicillin, since it is often difficult to differentiate streptococcal from staphylococcal cellulitis (7). In patients who are penicillin allergic, a first generation cephalosporin may be used. Therapy can be given orally, unless there is evidence of lymphangitic spread. If lymphangitis is noted, parenterally administered antimicrobials should be used until there is marked clinical improvement. Oral antimicrobials can then be used to complete 10 days of therapy.

Necrotizing Fasciitis (Streptococcal Gangrene): GAS necrotizing fasciitis is a rapidly progressing infection of the deep subcutaneous tissues and fascia with extensive and rapidly spreading necrosis. Infections often spare the skin, but 50% of patients may have associated myonecrosis. Necrotizing fasciitis is often associated with severe systemic involvement and an associated high mortality rate (7,80,87). As in other invasive streptococcal and staphylococcal skin infections, the site of inoculation is usually at area of minor trauma or the skin lesions of varicella. Like streptococcal bacteremia, there is a clear association between varicella and necrotizing fasciitis. Varicella is characterized by full-thickness dermal lesions that may induce selective immunosuppression to GAS, though this has not been substantiated (7). Necrotizing fasciitis caused by mixed infections, involving both aerobic and anaerobic Gram negative bacteria, is more likely to occur in the abdominal wall, following abdominal surgery or in diabetic patients.

Early and aggressive surgical debridement of the site of infection as well as appropriate antimicrobial therapy is required. Due to the "inoculum effect," penicillin may be less effective in the treatment of necrotizing fasciitis (83). Appropriate antibiotics include nafcillin and clindamycin (7,83).

Myositis/Myonecrosis: Myositis is a purulent infection of the muscles, normally occurring in the tropics and caused by S. aureus. Infections of the muscles are rarely caused by group A streptococcus but can occur. Infections occur following mild trauma, in toxic shock, and spontaneously. It is often difficult to differentiate streptococcal myonecrosis from necrotizing fasciitis, as the clinical features overlap, and the two entities often occur together. Fatality rates have been reported to be as high as 80 and 100% (78,80). Therapy includes extensive debridement of the infected muscle and parenterally administered antimicrobials. Penicillin has poor efficacy in the treatment of GAS myonecrosis, and aggressive surgical debridement remains the most important factor in treatment (83). The failure of penicillin is attributed to decreased expression of penicillin-binding proteins during the stationary growth phase and the slow growth of group A streptococcus. This is known as the Eagle effect and has been described elsewhere (83). Clindamycin, erythromycin, and ceftriaxone have been more effective than penicillin in experimental models (83).

Lymphangitis: Lymphangitis may occur in association with cellulitis or after a clinically minor skin infection. When group A streptococcus is implicated as the etiologic agent, therapy consists of parenterally administered penicillin. When the cause of the infection is in doubt, nafcillin can be used to provide coverage for S. aureus. Patients allergic to penicillin can be treated with a first generation cephalosporin, clindamycin, or vancomycin (8).

Puerperal Sepsis: Puerperal sepsis occurs during pregnancy or during an abortion, when group A streptococcus colonizing the patient invades the endometrium and surrounding structures as well as the lymphatics and bloodstream. Endometritis and septicemia result and can be complicated by pelvic cellulitis, thrombophlebitis, peritonitis, or pelvic abscess. Therapy consists of aggressive surgical exploration and parenterally administered penicillin or clindamycin (see section on myositis/myonecrosis). Patients allergic to penicillin can be treated with a first generation cephalosporin, clindamycin, or vancomycin (8).

Vulvovaginitis: Group A streptococcus is a common cause of vulvovaginitis in the prepubertal female. Symptoms include a serous vaginal discharge, erythema of the vulvar area, and intense pruritus. Therapy consists of orally administered penicillin for 10 days. Patients allergic to penicillin can be treated with erythromycin.

Proctitis: Perianal cellulitis (proctitis or asymptomatic anal infection) has been associated with several reported outbreaks of hospital-acquired streptococcal infection. Because it is difficult to differentiate streptococcal cellulitis from staphylococcal cellulitis, it is advisable to use a first generation cephalosporin, such cephalexin, for therapy. Therapy should be given enterally for 10 days.

Funisitis and Omphalitis: Omphalitis is an infection of the umbilical cord and surrounding tissues. Etiologic agents include group A streptococcus, S. aureus, group B streptococcus, and Gram negative enteric organisms. Combination therapy is normally provided while culture results are pending and consists of a semisynthetic penicillin, such as oxacillin and gentamicin. Patients allergic to penicillin can be treated with a first generation cephalosporin.

StrepTSS usually occurs secondary to soft tissue infections, particularly as a secondary infection of varicella lesions or as a complication of necrotizing fasciitis, myositis, pneumonia, or post-partum infection. M-type l GAS has been the predominant serotype associated with StrepTSS, but types 3, 12, and 28 have been implicated as well (7,80,87). Recent interest in the pathophysiology of this disorder has focused on the role of streptococcal pyrogenic exotoxins (SPEs), extracellular products of group A streptococci that mediate not only scarlatiniform-like rashes but also multi-organ damage and shock. These toxins were rarely associated with GAS strains in the United States until the recent increase in the number of cases of StrepTSS (7,87).

SPEA is the most common exotoxin found in the United States and has been shown to be both a superantigen and a potent inducer of tumor necrosis factor (7). SPEB has also been implicated but more commonly occurs in episodes of StrepTSS in European countries (7,80,87). Recently, nicotine adenine glycohydrolase (NADase) has been linked with the resurgence of severe invasive group A streptococcal infections (86).

The patient with StrepTSS requires intensive management of hemodynamic abnormalities and vital functions. Patients with a soft tissue focus of infection may require surgical intervention. Broad spectrum antibiotic coverage should be instituted until the presence of group A streptococcus has been confirmed. Therapy may then consist of parenterally administered clindamycin. In StrepTSS, tissue destruction continues despite high concentrations of penicillin. Penicillin is known to be relatively ineffective in the treatment of soft tissue infections with a high concentration of organisms (the Eagle effect) (83,85). This is thought to be due to the slow rate of replication of group A streptococci, decreased expression of penicillin-binding proteins, and the fact that penicillin acts by interfering with cell wall synthesis (83,85). Clindamycin inhibits protein synthesis, decreases the production of M proteins and toxins, and is unaffected by slow growing toxin-producing streptococci (83,85). A study by Brook et al. showed that by the 4th day of therapy, the frequency of capsular expression by GAS was significantly lower in patients treated with clindamycin than in patients treated with penicillin (9). A mouse model of a soft tissue infection with GAS showed clindamycin to be more effective than penicillin (83). Erythromycin and ceftriaxone may also be more effective than penicillin in such cases.

Accompanying the increase in number and severity of invasive group A streptococcal infections is an increase in the incidence of group A streptococcal bacteremia. There have been a number of cases associated with intravenous drug abuse as well as nosocomial outbreaks in nursing homes. Intravenous drug use has become the leading cause of GAS bacteremia in individuals between the ages of 14 and 40 years (78). Bacteremia usually follows a cutaneous focus of infection but may follow an upper respiratory infection. In addition, the number of children with varicella who develop GAS bacteremia has increased (26). Doctor et al. reported an increased incidence of GAS bacteremia in patients with varicella from 7% to 50% at their institution (26). GAS bacteremia in varicella is thought to occur secondary to a superinfected cutaneous lesion. Serotypes M1 and M3 have been most commonly isolated in patients with GAS bacteremia. Serotypes M1, M3, and M18 are more invasive and are associated with higher morbidity and mortality rates than M4 and M12, which are generally considered less virulent. M type 1 strains produce pyrogenic exotoxins A and B, and the latter toxin also has associated proteinase activity (7). Therapy for GAS bacteremia consists of parenterally administered penicillin. Patients allergic to penicillin can be treated with clindamycin, vancomycin, or a first generation cephalosporin.

Pneumonia secondary to group A streptococcus is frequently associated with preceding or concurrent viral infections such as measles, varicella, or influenza. Since the mid 1980s, the number of reports describing this association has increased. Up to 30% of patients with GAS pneumonia have a history of group A streptococcal upper respiratory tract infection (8). Empyema develops in 40% of patients, and bacteremia in 15%. Other complications include mediastinitis, pericarditis, pneumothorax, and bronchiectasis. Therapy consists of surgical drainage of an empyema and parenteral penicillin. Adequate drainage of pleural infection may be difficult and frequently requires prolonged chest tube drainage, thoracoscopy or pleural surgery.

Peritonsillar Abscess (AQuinsy@): Peritonsillar abscess results from direct extension of group A streptococcus from an acute pharyngitis. However, a peritonsillar abscess may yield mixed flora as well. Needle aspiration or surgical drainage of the abscess as well as antimicrobials are usually required. Indications for needle aspiration include severe pain and trismus, difficulty swallowing, and poor response to antimicrobials alone. Patients can be treated orally for 10 days with either a first generation cephalosporin such as cephalexin, clindamycin, or amoxicillin-clavulanic acid, if they appear nontoxic and can maintain adequate hydration. Some patients may require initial treatment with a parenteral antibiotic and be discharged to home on oral antibiotics to complete a 10 day course. Tonsillectomy at the time of surgical incision and drainage can provide improved drainage, prevent recurrences, and permit earlier discharge. Patients with a known allergy to cephalosporins can be treated with clindamycin.

Peritonsillar Cellulitis: Occasionally, peritonsillar cellulitis occurs without development of a localized abscess. Like peritonsillar abscesses, peritonsillar cellulitis results from direct extension of an acute tonsillopharyngitis and may result solely from group A streptococcus but can include mixed oral flora as well. Patients with mild symptoms who can maintain adequate hydration can be treated orally with a first or second generation cephalosporin such as cephalexin or cefazolin. Patients with a known allergy to cephalosporins can be treated with clindamycin. Patients with severe trismus or inadequate hydration can be treated parenterally with clindamycin or a first generation cephalosporin such as cefazolin. Duration of therapy is generally 10 days. Tonsillectomy can ensure complete recovery and prevent recurrences.

Retropharyngeal Abscess: Retropharyngeal abscess also occurs from direct extension of an acute pharyngitis. Causative organisms include both aerobes and anaerobes. Therapy consists of parenterally administered antimicrobials such as a first generation cephalosporin or clindamycin. Patients who do not respond to antimicrobial therapy or who have impaired respiratory function may require surgical incision and drainage under general anesthesia. Duration of therapy should be 10 days.

Otitis Media and Sinusitis: Otitis media and sinusitis due to group A streptococcus normally are secondary to direct extension from a streptococcal infection occurring in the upper respiratory tract. Appropriate therapy for both is amoxicillin. With persistent infection, an appropriate alternative would be amoxicillin/clavulanate. In patients allergic to amoxicillin, erythromycin or clindamycin is an acceptable alternative. Oral cephalosporins can be effective as well in patients who have not had immediate hypersensitivity reactions to penicillin.

Uvulitis: Uvulitis can occur alone or in association with acute pharyngitis or epiglottitis (50). Long known to be primarily a complication of H. influenzae type b infection, recent immunization strategies have greatly decreased its incidence. However, uvulitis can occur secondary to group A streptococcus, usually as a complication of an acute pharyngitis (50). Parenteral therapy should be used, directed against both group A streptococcus and H. influenzae, i.e., cefuroxime. Patients can be discharged on an oral antibiotic to complete a 10 day course of therapy.

Cervical Lymphadenitis: Cervical lymphadenitis secondary to group A streptococcus infection can result from direct extension from an acute pharyngitis or direct inoculation. Since the etiologic agent is not always known, therapy is initially directed against the most common organisms, which include S. aureus and S. pyogenes. Therefore, a first generation cephalosporin, such as cephalexin, or a β-lactamase-resistant penicillin should be given enterally for 10 days. If the infection persists or the patient develops signs of systemic toxicity, parenteral antibiotics should generally be used. First generation cephalosporins such as cefazolin, nafcillin, or clindamycin are also appropriate choices.

Meningitis and Brain Abscess: Meningitis and brain abscesses are rare complications of group A streptococcus that can occur either from direct extension of acute pharyngitis or sinusitis or from bacteremic spread. Penicillin is still the drug of choice for treatment of known group A streptococcal meningitis or brain abscess (12). Antimicrobial therapy should be given parenterally for 10 to 14 days (12). Patients allergic to penicillin can be treated with a third generation cephalosporin such as ceftriaxone or cefotaxime (12).

Arthritis: Post-streptococcal reactive arthritis (PSRA) is a recognized complication of group A streptococcal infections. Antibiotic therapy aimed at the underlying focus of infection is generally all that is required. However, anti-inflammatory drugs may aid patient comfort. Of concern, is the risk that a subset of patients with PSRA may develop rheumatic heart disease. In fact, the risk of ARF in children with PRSA is ~1% (24). This has led some to suggest that patients with PSRA, like patients who have had ARF, may require antimicrobial prophylaxis to prevent the occurrence of rheumatic heart disease (20). It has been recommended that these patients receive prophylaxis for 1 year, and then if no evidence of rheumatic heart disease develops, prophylaxis could be discontinued (20).

Septic arthritis secondary to group A streptococcal infection can result from direct inoculation or bacteremic spread. Therapy consists of parenteral antibiotics given for 10 to 14 days. Choices include a third generation cephalosporin, such as ceftriaxone and cefotaxime, or beta lactams such as nafcillin or penicillin. In addition, surgical drainage of purulent material from the joint space is required.

Endocarditis: Endocarditis due to group A streptococcus was relatively common during the preantibiotic era. However, it is now rarely seen. Therapy aimed at the most common organisms in endocarditis also provides coverage for group A streptococcus and should be continued for 4 to 6 weeks. Patients with known GAS endocarditis have been treated successfully with 6 weeks of parenterally administered penicillin (53).

Osteomyelitis: Like septic arthritis, osteomyelitis secondary to group A streptococcal infection is known, but rare. Therapy consists of appropriate antimicrobials given parenterally to control the infection. If group A streptococcus has been identified as the etiologic agent, penicillin can be used. Patients allergic to penicillin can be treated with clindamycin, vancomycin, or cefazolin.

Liver Abscess: Liver abscesses secondary to group A streptococcal infection generally result from hematogenous spread. Therapy consists of long term parenterally administered penicillin and surgical drainage. Initially, until an etiologic agent has been determined, a combination of a penicillinase-resistant penicillin, such as nafcillin, and an aminoglycoside should be used. Treatment should consist of 2 to 4 weeks of parenterally administered antibiotics followed by oral antibiotics to complete a 4 week course. Patients allergic to penicillin can be treated with clindamycin, vancomycin, or an appropriate first generation cephalosporin.

Acute Rheumatic Fever: Treatment of patients with acute rheumatic fever is generally directed toward decreasing acute inflammation, decreasing fever and toxicity, controlling cardiac failure, preventing episodes of recurrent ARF after significant streptococcal upper respiratory tract infections, and preventing rheumatic heart disease. The mainstays of treatment are salicylates and corticosteroids. Neither of these agents prevents or modifies the development of rheumatic heart disease. Patients clinically diagnosed with ARF who have not received antimicrobial therapy for a recent episode of GAS pharyngitis should receive a 10 day course of penicillin.

Primary prevention of ARF depends on accurate diagnosis of an antecedent streptococcal infection as well as adequate therapy. Penicillin given orally for 10 days or intramuscularly one time will prevent rheumatic fever. Erythromycin is considered the drug of choice f the treatment of GAS pharyngitis in penicillin-allergic patients, but it has not been shown to prevent ARF (17). Approximately one third of patients who develop ARF have streptococcal infections that are either subclinical or too mild to be brought to medical attention; as a result, they receive no antibiotic therapy for the infection. Recent reports have suggested that up to 75% of patients with ARF either had no history of a preceding streptococcal infection or had an infection that was so mild they did not seek medical attention. In contrast, in the past, preceding streptococcal infections were noted to be severe (55). Of even more concern are reports of patients who develop ARF despite receiving adequate therapy for GAS pharyngitis (21). Possible explanations for this include poor patient compliance with antibiotic therapy, a shorter latency period, documented streptococcal infections were not the cause of the resultant episodes of ARF, or currently recommended therapies for GAS pharyngitis have become inadequate for prevention of ARF (15). The last is of greatest concern.

Only one series of studies has ever documented prevention of ARF following antimicrobial therapy for GAS pharyngitis. These studies were conducted during the 1940s on army recruits at Fort Warren, Wyoming. Penicillin G suspended in oil, administered parenterally in a placebo-controlled study, decreased the incidence of ARF (90). Following these studies, researchers compared orally administered penicillin with parenterally administered penicillin and found equivalent bacteriologic effects. It was then assumed that bacterial eradication from the pharynx was the necessary step in prevention of ARF. As a result, penicillins as a class were assumed to be efficacious in preventing ARF. This has never been studied. No study has investigated the efficacy of other antibiotics in prevention of ARF.

Patients who develop ARF require continuous prophylaxis to prevent intercurrent and recurrent streptococcal infections and recurrent episodes of ARF. The preferred regimen consists of penicillin G benzathine, 1.2 million units given intramuscularly every 4 weeks (17). The recurrence rate of ARF with this regimen was reported to be 0.4 cases per 100 patient years of observation (8). Alternative therapies include oral sulfadiazine (1 g/day for persons over 60 lb and 0.5 g/day for those weighing less than 60 lb) or penicillin V (250 mg, twice a day). Both of these regimens are considered less effective than penicillin G benzathine. This is thought to be due to lack of patient compliance with an oral regimen. Patients who are allergic to penicillin can be treated with erythromycin stearate (250 mg, twice a day) (8).

Considerable debate has arisen over the optimal duration of prophylaxis. Some investigators previously recommended lifelong prophylaxis. However, the risk of recurrence of ARF decreases with patient age and the number of years since the last attack and increases with the presence of rheumatic heart disease or previous recurrences. The physician must take into account all factors when deciding when to discontinue prophylaxis. In general, it is recommended that prophylaxis continue until patients are in their early twenties and at least 5 years have passed since the most recent episode of ARF. In 1995, the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, the American Heart Association, released a special statement on the treatment of GAS pharyngitis and prevention of rheumatic fever. The committee recommended that patients who had rheumatic fever without rheumatic carditis should receive prophylaxis until the age of 21 or until at least 5 years had passed since their last attack. Patients who had rheumatic fever with carditis but no valvular disease should receive prophylaxis until adulthood and until at least 10 years had passed since their last attack of ARF. Patients with valvular disease should receive prophylaxis until age 40 and until at least 10 years had passed since their last attack (20).

Patients with residual rheumatic valvular disease must receive antibiotic prophylaxis whenever they undergo a surgical or dental procedure that may potentially evoke bacteremia. This is done to prevent the occurrence of bacterial endocarditis. Antimicrobial regimens recommended for the prevention of bacterial endocarditis are entirely distinct from regimens used in the prevention of ARF (14). Currently, investigators are attempting to develop a polyvalent M-protein vaccine for the prevention of streptococcal infection and ARF.

Acute Glomerulonephritis: Unlike rheumatic fever, post-streptococcal acute glomerulonephritis (AGN) has shown no increase in incidence. Indeed, nephritogenic strains (particularly serotype M type 12) have decreased in prevalence (54). Treatment strategies in the approach to post-streptococcal acute glomerulonephritis are directed toward management of acute problems. All patients should be treated with penicillin to eradicate the nephritogenic strain regardless of culture results of group A streptococci or immunologic tests. Paralleling the recent changes in the pathogenesis of ARF, a substantial number of patients who develop post-streptococcal AGN do not have a history of a preceding pharyngitis or soft tissue infection. Penicillin-allergic patients can be treated with erythromycin in doses adequate for treatment of streptococcal pharyngitis. It is generally recommended that family members be cultured for group A streptococcus. Family members with positive cultures should be treated appropriately. Treatment of patients with post-streptococcal AGN or of family contacts is for epidemiologic purposes only. Therapy will not alter pre-existent post-streptococcal AGN or prevent the disease in patients who are in the latent period. Some data suggest that antibiotic therapy may have a small effect on prevention of post-streptococcal AGN, but this has not been substantiated. However, antibiotic therapy is effective in epidemiologic efforts at eradicating nephritogenic strains of group A streptococcus. In high risk settings during an acute epidemic of AGN, universal penicillin prophylaxis can be considered. Recurrent episodes of AGN are rare, and continuous anti-streptococcal prophylaxis is generally not recommended. Long-term prognosis is generally thought to be excellent, but some studies found that up to 20% of patients develop urinary abnormalities (13).

In general, combination antimicrobial therapy offers no added benefit in the treatment of known GAS infections. Antimicrobial agents possess sufficient activity in vitro to GAS and, when initiated promptly, are effective in the treatment of such infections. However, in clinical situations in which GAS is suspected but has not been identified (e.g., necrotizing fasciitis and TSS) antimicrobial therapy should be initiated with combinations effective against all possible pathogens.

Invasive Streptococcal Infections: For necrotizing streptococcal infections, early and aggressive surgical debridement of the site of infection as well as appropriate antimicrobial therapy is required. The patient with StrepTSS also requires intensive management of hemodynamic abnormalities and vital functions. Some investigators have suggested use of hyperbaric oxygen therapy (HBO) in treatment of necrotizing fasciitis (reviewed in (7)), however, HBO therapy is not without risks, and its use has not been well studied.

Other proposed therapeutic interventions include the use of intravenous immunoglobulin (IVIG) and monoclonal antibodies. It is thought that IVIG may act by binding and inactivating toxins (3); however, use of IVIG in the treatment of StrepTSS has not been thoroughly evaluated. Investigators are studying the use of monoclonal antibodies against specific group A streptococcal toxins and the neutralization of circulating cytokines in managing invasive streptococcal disease caused by toxin-producing strains.

It was recently suggested that the use of nonsteroidal antiinflammatory drugs (NSAIDS) in the treatment of fever in patients with GAS infections may predispose the patient to a more severe invasive infection. NSAIDs may inhibit neutrophil function and enhance cytokine production (79). In addition, their use may mask some of the early signs and symptoms of invasive GAS infections and has been associated with episodes of necrotizing fasciitis and toxic shock syndrome in patients with varicella (79).

Pharyngitis: Tonsillectomy may help reduce the number of acute infections in children with recurrent GAS pharyngitis and is generally recommended for children who have 6 to 7 documented GAS infections in a given year or 3 to 4 infections in each of 2 years (8). It may also be desirable as a method to eliminate the carrier state in a select group of patients such as those with a family history of rheumatic fever.

Other alternative therapies that have been suggested to reduce the incidence of treatment failures in GAS pharyngitis include using α-streptococci to replace normal pharyngeal flora, delaying treatment of GAS pharyngitis 48 h to promote the host's immune system (discussed above), and using topical antibiotics. The latter has not been well studied.

Elimination of α-streptococci from the pharynx after therapy for acute GAS pharyngitis has been proposed as a possible explanation for treatment failures, development of the carrier phenomenon, and frequent recurrences (76). α-Streptococci interfere strongly against GAS (73). α-Streptococci share pharyngeal epithelial receptor sites in the posterior pharynx with GAS, and elimination of α-streptococci may provide more attachment sites for GAS (33). Roos et al. looked at 31 patients with recurrent GAS pharyngitis who were given antibiotics for 10 days and then had the oropharynx sprayed with α-streptococci (73). None of the patients treated with α-streptococci had a recurrence of GAS pharyngitis over a period of 3 months, while the control group had an 8% recurrence rate (73).

Acute Rheumatic Fever: Salicylates and steroids are very effective in suppressing the acute manifestations of rheumatic fever, but neither has been shown to proven chronic valvular rheumatic heart disease (55). Patients with definite clinical evidence of arthritis should receive aspirin starting at a total dose of 100 mg/kg/day in divided doses for the first two weeks, then reduced to 75 mg/kg/day for the next 2 - 4 weeks until all laboratory manifestations of inflammatory disease are resolved (55). Corticosteroid therapy is only for patients with significant carditis, especially cardiomegaly or congestive heart failure. Prednisone is the drug of choice, starting at 2 mg/kg/day in divided doses not to exceed a total dose of 80 mg/day (55). After 2 - 3 weeks, a slow taper may begin, decreasing the daily dose at the rate of 5 mg every 2 - 3 days. When tapering is started, aspirin at 75 mg/kg/day should be added and continued for 6 weeks after prednisone is stopped (55).

The problem of bacteriologic and clinical failures in the treatment of GAS pharyngitis has led some investigators to suggest that all patients should receive a test of cure at the end of treatment. The patient who is symptomatic and culture positive at the end of treatment for acute pharyngitis may represent either failed treatment or acquisition of a new strain of GAS and should receive further treatment. Clearly, patients with previous rheumatic fever who have symptoms of strep throat should be re-cultured at the end of treatment.

Development of an effective group A streptococcal vaccine continues to be of interest; currently, none are commercially available. Researchers have looked at the conserved region of the M protein since this region is shared by all serotypes of GAS and because long-term exposure to group A streptococci results in acquired immunity (29). A vaccine incorporating the conserved region of the M protein of group A streptococcus may stimulate a rapid rise in protective antibodies, but may also stimulate development of cross-reactive antibodies that recognize heart tissue. Because of these potential safety issues, recent efforts have been directed at developing a vaccine against certain epitopes of the M protein that do not cross-react with myocardial tissue, providing a safer vaccine for immunizations (22). This strategy is not without its problems. To provide immunity against the 150 or so known M-types of GAS, the vaccine would need to be polyvalent. Further, the vaccine composition would likely need to be changed periodically to reflect those M-types prevalent in the population.

Group A streptococci are highly contagious and epidemics of pharyngitis, impetigo, scarlet fever, rheumatic fever, post-streptococcal glomerulonephritis, bacteremia, puerperal sepsis, streptococcal toxic shock syndrome and necrotizing fasciitis have been described (reviewed in (82)). The acquisition of GAS in the family environment poses problems for individuals in that environment who may have previously acquired rheumatic fever. This issue is discussed in section III.B. above on treatment issues in rheumatic fever. In the hospital environment, group A streptococcus can spread rapidly to patients with surgical wounds, burns or chicken pox or post-partum patients. Strict adherence to infection control measures is crucial. Because there are over 150 different M-types of GAS this means that nosocomial isolates should be saved for subsequent epidemiologic comparisons should additional cases be identified. Performing M-typing or comparing RFLP patterns is extremely important to determine if these cases originated from a common source such as an employee who is a carrier of GAS. Strict isolation procedures should be employed in patients who are admitted to hospitals with GAS infections. Close contacts of primary cases of severe invasive GAS infections are at greater risk than the general population for development of colonization or superficial infection. The risk for invasive infection is less, but still higher than the general population. The clinician managing such cases should consider the risk and safety of these contacts and may wish to prescribe penicillin V K or, in penicillin allergic patients, clindamycin. In a situation such as military barracks, benzathine penicillin administered intramuscularly on a monthly basis has been very useful to prevent streptococcal pharyngitis and rheumatic fever.

Group A streptococcus has the unique ability to cause both acute purulent infections and nonpurulent complications that develop days after an initial infection. With a recognized increase in incidence and severity of invasive group A streptococcal infections and changes in the epidemiology of ARF, treatment of group A streptococcal infections has taken on even greater importance. While penicillin remains the mainstay of treatment, its use has recently been brought into question. New antibiotics and new strategies for treatment are being evaluated, and a vaccine effective against group A streptococcus is being developed. Once thought to have been relegated to simple sore throats, group A streptococcus has returned to the forefront of infectious diseases.

Table 1. In Vitro Susceptibilities of Streptococcus pyogenes to Common Antibiotics

Antibiotic	MIC₅₀ (μg/mL)	MIC₉₀ (μg/mL)	Range (μg/mL)	Reference
Penicillin	0.006	0.012	0.003 - 0.024	13
Oxacillin	0.06	0.06	≤0.03 - 0.25	64
Erythromycin	0.016	0.031	0.0078 - 8.0	13
Azithromycin	0.016	0.031	0.0078 - 4.0	13
Clarithromycin	0.0078	0.016	0.0039 - 4.0	13
Cephalothin	0.1	0.1	0.0125 - 0.2	13
Cefoxitin	1	1	1 - 4	64
Cefixime	0.25	0.5	0.078 - 0.5	13
Cefuroxime	≤0.03	≤0.03	≤0.03	64
Cefotaxime	≤0.03	≤0.03	≤0.03	64
Ceftriaxone	≤0.03	≤0.03	≤0.03 - 0.125	64
Vancomycin	0.25	0.5	0.25 - 0.5	5, 64
Clindamycin	0.125	0.125	0.06 - 0.125	64
Rifampin	0.5	0.5	≤0.03 - 0.5	64
Ciprofloxacin	0.256	0.5	0.016 - 2.0	13
Tetracycline	0.25	2	0.0039 - 8.0	13
Cotrimoxazole	≥64	≥64	≥64	64
Chloramphenicol	4	4	2 - 8	64

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