Group A Streptococcus

Etiology

Group A streptococci are gram-positive, coccoid-shaped bacteria that tend to grow in chains. They are broadly classified by their hemolytic activity on mammalian (typically sheep) red blood cells. The zone of complete hemolysis that surrounds colonies grown on blood agar distinguishes β-hemolytic (complete hemolysis) from α-hemolytic (green or partial hemolysis) and γ (nonhemolytic) species. The β-hemolytic streptococci can be divided into groups by a group-specific polysaccharide ( Lancefield C carbohydrate ) located in the bacterial cell wall. More than 20 serologic groups are identified, designated by the letters A through V. Serologic grouping by the Lancefield method is precise, but group A organisms can be identified more readily by any of a number of latex agglutination, coagglutination, molecular assays or enzyme immunoassays. Group A strains can also be distinguished from other groups by differences in sensitivity to bacitracin. A disk containing 0.04 unit of bacitracin inhibits the growth of most group A strains, whereas other groups are generally resistant to this antibiotic. This method is approximately 95% accurate. GAS can be subdivided into >220 serotypes on the basis of the M protein antigen, which is located on the cell surface and in fimbriae that project from the outer surface of the cell. Currently, a molecular approach to M-typing GAS isolates using the polymerase chain reaction (PCR) is based on sequencing the terminal portion of the emm gene of GAS that encodes the M protein. More than 220 distinct M types have been identified using emm typing, with excellent correlation between known serotypes and emm types. The emm types can be grouped into emm clusters that share structural and binding properties. Immunity is largely based on type-specific opsonic anti-M antibody.

M/ emm typing is valuable for epidemiologic studies; specific GAS diseases tend to be associated with certain M types. Types 1, 12, 28, 4, 3, and 2 (in that order) are the most common causes of uncomplicated streptococcal pharyngitis in the United States. M types usually associated with pharyngitis rarely cause skin infections, and the M types associated with skin infections rarely cause pharyngitis. A few pharyngeal strains (e.g., M type 12) are associated with glomerulonephritis, but many more skin strains (e.g., M types 49, 55, 57, and 60) are considered nephritogenic. Several pharyngeal serotypes (e.g., M types 1, 3, 5, 6, 18, and 29), but no skin strains, are associated with acute rheumatic fever in North America. Rheumatogenic potential is not solely dependent on serotype but is likely a characteristic of specific strains within several serotypes.

Epidemiology

Humans are the natural reservoir for GAS. These bacteria are highly communicable and can cause disease in normal individuals of all ages who do not have type-specific immunity against the particular serotype involved. Disease in neonates is uncommon in developed countries, probably because of maternally acquired antibody. The incidence of pharyngeal infections is highest in children 5-15 yr of age, especially in young school-age children. These infections are most common in the northern regions of the United States, especially during winter and early spring. Children with untreated acute pharyngitis spread GAS by airborne salivary droplets and nasal discharge. Transmission is favored by close proximity; therefore schools, military barracks, and homes are important environments for spread. The incubation period for pharyngitis is usually 2-5 days. GAS has the potential to be an important upper respiratory tract pathogen and to produce outbreaks of disease in the daycare setting. Foods contaminated by GAS occasionally cause explosive outbreaks of pharyngotonsillitis. Children are usually no longer infectious within 24 hr of starting appropriate antibiotic therapy. Chronic pharyngeal carriers of GAS rarely transmit this organism to others.

Streptococcal pyoderma (impetigo, pyoderma) occurs most frequently during the summer in temperate climates, or year-round in warmer climates, when the skin is exposed and abrasions and insect bites are more likely to occur (see Chapter 685 ). Colonization of healthy skin by GAS usually precedes the development of impetigo. Because GAS cannot penetrate intact skin, impetigo and other skin infections usually occur at the site of open lesions (insect bites, traumatic wounds, burns). Although impetigo serotypes may colonize the throat, spread is usually from skin to skin, not via the respiratory tract. Fingernails and the perianal region can harbor GAS and play a role in disseminating impetigo. Multiple cases of impetigo in the same family are common. Both impetigo and pharyngitis are more likely to occur among children living in crowded homes and in poor hygienic circumstances.

The incidence of severe invasive GAS infections, including bacteremia, streptococcal toxic shock syndrome, and necrotizing fasciitis, has increased in recent decades. The incidence appears to be highest in very young and elderly persons. Before the routine use of varicella vaccine, varicella was the most commonly identified risk factor for invasive GAS infection in children. Other risk factors include diabetes mellitus, HIV infection, intravenous drug use, and chronic pulmonary or chronic cardiac disease. The portal of entry is unknown in almost 50% of cases of severe invasive GAS infection; in most cases it is believed to be skin or less often mucous membranes. Severe invasive disease rarely follows clinically apparent GAS pharyngitis.

Pathogenesis

Virulence of GAS depends primarily on the M protein, and strains rich in M protein resist phagocytosis in fresh human blood, whereas M-negative strains do not. M protein stimulates the production of protective opsonophagocytic antibodies that are type specific, protecting against infection with a homologous M type but much less so against other M types. Therefore, multiple GAS infections attributable to various M types are common during childhood and adolescence. By adult life, individuals are probably immune to many of the common M types in the environment.

GAS produces a large variety of extracellular enzymes and toxins, including erythrogenic toxins, known as streptococcal pyrogenic exotoxins . Streptococcal pyrogenic exotoxins A, C, and SSA, alone or in combination, are responsible for the rash of scarlet fever and are elaborated by streptococci that contain a particular bacteriophage. These exotoxins stimulate the formation of specific antitoxin antibodies that provide immunity against the scarlatiniform rash but not against other streptococcal infections. GAS can produce up to 12 different pyrogenic exotoxins, and repeat attacks of scarlet fever are possible. Mutations in genes that are promoters of several virulence genes, including pyrogenic exotoxins, as well as several newly discovered exotoxins, appear to be involved in the pathogenesis of invasive GAS disease, including the streptococcal toxic shock syndrome.

The importance of other streptococcal toxins and enzymes in human disease is not yet established. Many of these extracellular substances are antigenic and stimulate antibody production after an infection. However, these antibodies do not confer immunity. Their measurement is useful for establishing evidence of a recent streptococcal infection to aid in the diagnosis of postinfectious illnesses. Tests for antibodies against streptolysin O (anti–streptolysin O) and DNase B (anti–DNase B) are the most frequently used antibody determinations. Because the immune response to extracellular antigens varies among individuals as well as with the site of infection, it is sometimes necessary to measure other streptococcal antibodies.

Clinical Manifestations

The most common infections caused by GAS involve the respiratory tract and the skin and soft tissues.

Scarlet Fever

Scarlet fever is GAS pharyngitis associated with a characteristic rash, which is caused by an infection with pyrogenic exotoxin (erythrogenic toxin)–producing GAS in individuals who do not have antitoxin antibodies. It is now encountered less often and is less virulent than in the past, but the incidence is cyclic, depending on the prevalence of toxin-producing strains and the immune status of the population. The modes of transmission, age distribution, and other epidemiologic features are otherwise similar to those for GAS pharyngitis.

The rash appears within 24-48 hr after onset of symptoms, although it may appear with the first signs of illness ( Fig. 210.1A ). It often begins around the neck and spreads over the trunk and extremities. The rash is a diffuse, finely papular, erythematous eruption producing bright-red discoloration of the skin, which blanches on pressure. It is often accentuated in the creases of the elbows, axillae, and groin (Pastia lines). The skin has a goose-pimple appearance and feels rough. The cheeks are often erythematous with pallor around the mouth. After 3-4 days, the rash begins to fade and is followed by desquamation , initially on the face, progressing downward, and often resembling a mild sunburn. Occasionally, sheetlike desquamation may occur around the free margins of the fingernails, the palms, and the soles. Examination of the pharynx of a patient with scarlet fever reveals essentially the same findings as with GAS pharyngitis. In addition, the tongue is usually coated and the papillae are swollen ( Fig. 210.1B ). After desquamation, the reddened papillae are prominent, giving the tongue a strawberry appearance ( Fig. 210.1C ).

Typical scarlet fever is not difficult to diagnose; the milder form with equivocal pharyngeal findings can be confused with viral exanthems, Kawasaki disease, and drug eruptions. Staphylococcal infections are occasionally associated with a scarlatiniform rash. A history of recent exposure to a GAS infection is helpful. Identification of GAS in the pharynx confirms the diagnosis.

Diagnosis

When deciding whether to perform a diagnostic test on a patient presenting with acute pharyngitis, the clinical and epidemiologic findings should be considered. A history of close contact with a well-documented case of GAS pharyngitis is helpful, as is an awareness of a high prevalence of GAS infections in the community. The signs and symptoms of streptococcal and nonstreptococcal pharyngitis overlap too broadly to allow the requisite diagnostic precision on clinical grounds alone. The clinical diagnosis of GAS pharyngitis cannot be made with reasonable accuracy even by the most experienced physicians, and laboratory confirmation is required, except for patients with overt viral signs and symptoms (e.g., rhinorrhea, cough, mouth ulcers, hoarseness), who generally do not need a diagnostic test performed.

Culture of a throat swab on a sheep blood agar plate is effective for documenting the presence of GAS and for confirming the clinical diagnosis of acute GAS pharyngitis. When performed correctly, a single throat swab has a sensitivity of 90–95% for detecting the presence of GAS in the pharynx.

The significant disadvantage of culturing a throat swab on a blood agar plate is the delay (overnight or longer) in obtaining the culture result. Streptococcal rapid antigen detection tests are available for the identification of GAS directly from throat swabs. Their advantage over culture is the speed in providing results, often <10-15 min. Rapid identification and treatment of patients with streptococcal pharyngitis can reduce the risk for spread of GAS, allowing the patient to return to school or work sooner, and can reduce the acute morbidity of this illness.

Almost all currently available rapid antigen detection tests have excellent specificity of >95% compared with blood agar plate cultures. False-positive test results are quite unusual, and therefore therapeutic decisions can be made with confidence on the basis of a positive test result. Unfortunately, the sensitivity of most of these tests is 80–90%, sometimes lower, when compared with blood agar plate culture. Therefore, a negative rapid test does not completely exclude the presence of GAS, and a confirmatory throat culture should be performed in children and adolescents, but not necessarily in adults, who are at exceptionally low risk for developing acute rheumatic fever. Definitive studies are not available to determine whether some rapid antigen detection tests are significantly more sensitive than others, or whether any of these tests is sensitive enough to be used routinely in children and adolescents without throat culture confirmation of negative test results. Some experts believe that physicians who use a rapid antigen detection test without culture backup should compare the results with that specific test to those of throat cultures to confirm adequate sensitivity in their practice.

Some microbiology laboratories have replaced culture methods with rapid and very sensitive and specific GAS molecular assays. These molecular assays include PCR methods and nucleic acid amplification tests using isothermal loop amplification. The isothermal loop amplification methods have been reported to have sensitivity up to 100% and specificity >96% compared to culture or PCR. This very high sensitivity may lead to higher numbers of positive results, which in turn may contribute to identification of more patients with asymptomatic GAS colonization and unnecessary antibiotic therapy. However, the benefit of faster results, sometimes <10 min, ensures more expedited initiation of appropriate antibiotic therapy for patients with GAS pharyngitis.

GAS infection can also be diagnosed retrospectively on the basis of an elevated or increasing streptococcal antibody titer. The anti–streptolysin O assay is the streptococcal antibody test most often used. Because streptolysin O also is produced by groups C G streptococci, the test is not specific for group A infection. The anti–streptolysin O response can be feeble after streptococcal skin infection. In contrast, the anti–DNase B responses are generally present after either skin or throat infections. A significant antibody increase is usually defined as an increase in titer of 2 or more dilution increments (≥4-fold rise) between the acute-phase and convalescent-phase specimens, regardless of the actual height of the antibody titer. Physicians frequently misinterpret streptococcal antibody titers because of a failure to appreciate that the normal levels of these antibodies are substantially higher among school-age children than adults. Both the traditional anti–streptolysin O and the anti–DNase B tests are neutralization assays. Newer tests use latex agglutination or nephelometric assays. Unfortunately, these newer tests often have not been well standardized against the traditional neutralization assays. Physicians should be aware of these potential problems when interpreting the results of streptococcal serologic testing.

A commercially available slide agglutination test for the detection of antibodies to several streptococcal antigens is the Streptozyme test (Wampole Laboratories, Stamford, CT). This test is much less well standardized and less reproducible than other antibody tests, and it should not be used as a test for evidence of a preceding GAS infection.

Treatment

Antibiotic therapy for patients with GAS pharyngitis can prevent acute rheumatic fever (RF), shorten the clinical course of the illness, reduce transmission of the infection to others, and prevent suppurative complications. For the patient with classic scarlet fever, antibiotic therapy should be started immediately, but for the majority of patients, who present with much less distinctive findings, treatment should be withheld until there is laboratory confirmation, by throat culture, molecular assay, or rapid antigen detection test. Rapid antigen detection tests, because of their high degree of specificity, allow initiation of antibiotic therapy immediately for the patient with a positive test result.

GAS is exquisitely sensitive to penicillin and cephalosporins , and resistant strains have never been encountered. Penicillin or amoxicillin is therefore the drug of choice (except in patients who are allergic to penicillins) for pharyngeal infections as well as for suppurative complications. Oral penicillin V (250 mg/dose 2 or 3 times daily [bid-tid] for children weighing ≤60 lb and 500 mg/dose bid-tid for children >60 lb) is recommended but must be taken for a full 10 days , even though there is symptomatic improvement within 3-4 days. Penicillin V (phenoxymethylpenicillin) is preferred over penicillin G, because it may be given without regard to mealtime. The major concern with all forms of oral therapy is the risk that the drug will be discontinued before the 10-day course has been completed. Therefore, when oral treatment is prescribed, the necessity of completing a full course of therapy must be emphasized. If the parents seem unlikely to comply with oral therapy because of family disorganization, difficulties in comprehension, or other reasons, parenteral therapy with a single intramuscular (IM) injection of benzathine penicillin G (600,000 IU for children weighing ≤60 lb and 1.2 million IU for children >60 lb) is the most efficacious and often the most practical method of treatment. Disadvantages include soreness around the site of injection, which may last for several days, and potential for injection into nerves or blood vessels if not administered correctly. The local reaction is diminished when benzathine penicillin G is combined in a single injection with procaine penicillin G, although it is necessary to ensure that an adequate dose of benzathine penicillin G is administered.

In several comparative clinical trials, once-daily amoxicillin (50 mg/kg, maximum: 1,000 mg) for 10 days has been demonstrated to be effective in treating GAS pharyngitis. This somewhat broader-spectrum agent has the advantage of once-daily dosing, which may enhance adherence. In addition, amoxicillin is relatively inexpensive and is considerably more palatable than penicillin V suspension.

A 10-day course of a narrow-spectrum oral cephalosporin is recommended for most penicillin-allergic individuals. It has been suggested that a 10-day course with an oral cephalosporin is superior to 10 days of oral penicillin in eradicating GAS from the pharynx. Analysis of these data suggests that the difference in eradication is mainly the result of a higher rate of eradication of carriers included unintentionally in these clinical trials. Some penicillin-allergic persons (up to 10%) are also allergic to cephalosporins, and these agents should be avoided in patients with immediate (anaphylactic-type) hypersensitivity to penicillin. Most oral broad-spectrum cephalosporins are considerably more expensive than penicillin or amoxicillin and are more likely to select for antibiotic-resistant flora.

Oral clindamycin is an appropriate agent for treating penicillin-allergic patients, and resistance to clindamycin among GAS isolates in the United States is currently only approximately 1%. An oral macrolide (erythromycin or clarithromycin) or azalide (azithromycin) is also an appropriate agent for patients allergic to penicillins. Ten days of therapy is indicated except for azithromycin, which is given at 12 mg/kg once daily for 5 days. Erythromycin is associated with substantially higher rates of gastrointestinal side effects than the other agents. In recent years, macrolide resistance rates among pharyngeal isolates of GAS in most areas of the United States have been approximately 5–8%. Sulfonamides and the tetracyclines are not recommended for treatment of GAS pharyngitis. However, studies showed that trimethoprim-sulfamethoxazole (TMP-SMX) is highly active in vitro against GAS and was comparable to IM penicillin for impetigo from GAS in clinical trials.

Most oral antibiotics must be administered for the conventional 10 days to achieve maximal pharyngeal eradication rates of GAS and prevention of RF, but certain newer agents are reported to achieve comparable bacteriologic and clinical cure rates when given for ≤5 days. However, definitive results from comprehensive studies are not available to allow full evaluation of these proposed shorter courses of oral antibiotic therapy, which therefore cannot be recommended at this time. In addition, these antibiotics have a much broader spectrum than penicillin and are generally more expensive, even when administered for short courses.

The majority of patients with GAS pharyngitis respond clinically to antimicrobial therapy, and GAS is eradicated from the pharynx. Posttreatment throat cultures are indicated only in the relatively few patients who remain symptomatic, whose symptoms recur, or who have had RF or rheumatic heart disease and are therefore at unusually high risk for recurrence.

Antibiotic therapy for a patient with nonbullous impetigo can prevent local extension of the lesions, spread to distant infectious foci, and transmission of the infection to others. However, the ability of antibiotic therapy to prevent poststreptococcal glomerulonephritis has not been definitively demonstrated. Patients with a few superficial, isolated lesions and no systemic signs can be treated with topical antibiotics. Mupirocin is a safe and effective agent that has become the topical treatment of choice. If there are widespread lesions or systemic signs, oral therapy with coverage for both GAS and S. aureus is needed . With the rapid emergence of methicillin-resistant S. aureus in many communities, one should consider using clindamycin alone or a combination of TMP-SMX and amoxicillin as first-line therapy. Oral cefuroxime is an effective treatment of perianal streptococcal disease.

Theoretical considerations and experimental data suggest that intravenous clindamycin is a more effective agent for the treatment of severe, invasive GAS infections than IV penicillin. However, because approximately 1% of GAS isolates in the United States are resistant to clindamycin, clindamycin initially should be used in combination with penicillin for these infections until susceptibility to clindamycin has been established. If necrotizing fasciitis is suspected, immediate surgical exploration or biopsy is required to identify a deep soft-tissue infection that should be debrided immediately. Patients with streptococcal TSS require rapid and aggressive fluid replacement, management of respiratory or cardiac failure, if present, and anticipatory management of multiorgan system failure. Limited data suggest that intravenous immune globulin (IVIG) is effective as adjunctive therapy in the management of streptococcal TSS.