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Streptococcal Infection, Group A: Treatment & Medication

Author: Mark R Schleiss, MD, American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota School of Medicine
Contributor Information and Disclosures

Updated: May 2, 2008

Treatment

Medical Care

Streptococcal Pharyngitis

Acute pharyngitis represents one of the most common reasons children are seen by a pediatrician. Yet, despite the common nature of the problem, few subjects engender more controversy than that of the diagnostic and therapeutic approach to the child with a sore throat. Many questions provoke disagreement on this topic, but some of the major points debated among clinicians include the following:

• Which children should be tested for streptococcal pharyngitis?
• How should children be tested for streptococcal pharyngitis?
• What treatment approach should be used for suspected streptococcal pharyngitis?

In general, make decisions about laboratory testing and antibiotic therapy only after careful consideration of epidemiologic factors and clinical findings. The most important historic information in the evaluation of a sore throat is that of the presence or absence of other symptoms of upper respiratory tract infection. Children with streptococcal pharyngitis do not have cough, rhinorrhea, or symptoms of viral upper respiratory tract infection. Indeed, the diagnosis of streptococcal pharyngitis can effectively be ruled out on the basis of the clinical findings of marked coryza, hoarseness, cough, or conjunctivitis.

However, although these are important exclusionary criteria, the pediatrician must be aware that signs and symptoms of streptococcal pharyngitis may otherwise be nonspecific and widely vary depending on patient age, severity of the infection, or timing of the illness.

Relatively few localizing or constitutional symptoms may be present, such that the illness may be unrecognized (subclinical infection). Young infants do not present with classic pharyngitis. Streptococcal upper respiratory tract infections in infants and toddlers instead may be characterized by low-grade fever, anorexia, and a thick purulent nasal discharge (so-called "streptococcosis"). Conversely, some patients may be toxic, with high fever, malaise, headache, and severe pain upon swallowing.

Streptococcal toxic shock can be associated with pharyngitis; however, this is rare. Vomiting and abdominal pain may be prominent early symptoms simulating gastroenteritis or even acute appendicitis. Hence, streptococcal pharyngitis should be considered in a child with acute onset of abdominal pain. Because streptococcal pharyngitis is chiefly a disease of winter and spring and primarily affects children older than 3 years, fewer throat cultures should be completed in the summer and in children younger than 3 years.

Upon physical examination, children with classic group A streptococcal pharyngitis are more likely to demonstrate tonsillopharyngeal erythema, a red edematous uvula, palatal petechiae, and tender anterior cervical adenopathy than children with pharyngitis of other etiologies. Typically, tonsils are enlarged and erythematous with patchy exudate on the surface, although the presence of exudate is not pathognomonic for streptococcal pharyngitis and may be observed in the context of other bacterial and viral etiologies of pharyngitis, particularly Epstein-Barr virus.

The papillae of the tongue may be red and swollen (so-called strawberry tongue). Cutaneous petechiae are not uncommon, and a scarlatiniform rash may be present (see Scarlet Fever). When the characteristic rash of scarlet fever is present, a clinical diagnosis can be made with increased confidence. However, consistently making the diagnosis of streptococcal pharyngitis on clinical grounds alone is difficult.

Various clinical scoring systems has been devised to attempt to predict the results of subsequent throat cultures or antigen detection tests; however, at best, these scoring systems have no more than an 80% predictive value. Therefore, even the most experienced clinician should rely on bacteriologic confirmation of the diagnosis. Some clinicians express a reluctance to obtain diagnostic studies in children with sore throats, rationalizing this approach with the mistaken assumption that all febrile respiratory tract ailments require a course of antibiotic therapy. The ongoing crisis in antibiotic resistance and the urgent need to use a more judicious approach in antimicrobial prescribing practice should, hopefully, herald a return to appropriate diagnostic testing for group A streptococcal pharyngitis.

The appropriate bacteriologic confirmation of the tentative diagnosis of streptococcal pharyngitis is disputed. Fifteen years after their introduction into clinical practice, controversy persists regarding the relative merits of antigen detection systems for Streptococcus pyogenes compared with traditional throat culture. Despite technologic improvements in rapid streptococcal testing, the throat culture remains the criterion standard for the diagnosis of streptococcal pharyngitis.

If performed correctly, a throat swab cultured on a blood agar plate has a sensitivity rate of 90-95% in detecting the presence of S pyogenes in the pharynx. This sensitivity depends on properly obtaining the specimen. When possible, a specimen should be obtained from the surface of both tonsils and from the posterior pharyngeal wall. Other areas of the oropharynx are not acceptable; in the uncooperative child, study of a culture that was obtained from areas of the mouth that are clearly known to be inadequate for culturing is difficult to justify. The culture should be examined at 24 hours postinoculation and again at 48 hours postinoculation.

When considering the approach to bacteriologic diagnosis, emphasizing those patients who should not undergo throat culture is important. Cultures should not be obtained from children with nasal congestion, injected conjunctiva, and cough because these features indicate the presence of acute viral pharyngitis. A positive culture finding in this context only reflects chronic colonization (streptococcal carrier state). Although identifying and treating the streptococcal carrier may occasionally have merit, routinely obtaining cultures in children with symptoms suggestive of viral pharyngitis is not warranted and leads to unwarranted courses of antibiotic therapy.

Although a negative throat culture finding essentially rules out the diagnosis of streptococcal pharyngitis, a positive culture finding unfortunately cannot be used to differentiate between acute infection and asymptomatic carriage. Some studies have reported that the degree of positivity of the culture may, by quantifying the load of organisms, assist in making this differentiation. However, in practice, assuming that all positive results in appropriately cultured patients represent streptococcal infection and accepting that some degree of overtreatment is inevitable is probably best.

Sometimes families express concern regarding the delay of 24-48 hours that is required to obtain throat culture findings. Therefore, clinicians feel pressure to immediately initiate therapy, prior to obtaining the result of the culture. However, because treatment of group A streptococcal sore throat as long as 9 days after onset of symptoms still effectively prevents rheumatic fever, initiation of antibiotics is seldom of urgent importance. Early antibiotic therapy may have beneficial effects in relieving symptoms and allowing an earlier return to school or daycare; however, early antibiotic therapy may have disadvantages as well. Several controlled studies have shown that children receiving immediate antibiotic therapy are more likely to have symptomatic recurrences in the months following treatment than are children who delay the initiation of therapy by 48 hours.

When the diagnosis of streptococcal pharyngitis seems particularly likely based on examination findings or when social factors necessitate an immediate decision about antibiotic therapy, the use of rapid antigen detection tests capable within minutes of identifying group A streptococci directly from the throat swab is a reasonable option in most practice settings.

Most kits use antibodies for the detection of group A carbohydrate antigen. The indicator systems used are latex agglutination or enzyme immunoassay. Tests can be completed in a matter of minutes. Numerous studies have demonstrated that the currently available rapid streptococcal tests have a sensitivity of 70-90% compared with standard throat cultures. In contrast to their relatively low sensitivity, the specificity of these rapid tests has consistently been 90-100%. Therefore, if a rapid streptococcal test result is positive, a culture is not necessary, and appropriate antibiotic therapy can be immediately initiated. However, when a negative rapid test result is encountered, a standard throat culture should always be obtained.

Streptococcal Skin Infections

Superficial pyoderma is the most common form of skin infection caused by group A Streptococcus. Also referred to as streptococcal impetigo (or "impetigo contagiosa"), it occurs most commonly in tropical climates but can be highly prevalent in northern climates as well, particularly in the summer months. Risk factors that predispose to this infection include low socioeconomic status; low level of overall hygiene; and local injury to skin caused by insect bites, scabies, atopic dermatitis, and minor trauma. Colonization of unbroken skin precedes the development of pyoderma by approximately 10 days.

This form of streptococcal infection is usually painless, and the patient is usually afebrile. Streptococcal impetigo usually has the highest prevalence in young children (aged 2-5 y). Infection spreads readily to other individuals from the skin lesions, and multiple occurrences within families are common.

Streptococcal impetigo usually appears first as a discrete papulovesicular lesion surrounded by a localized area of redness. The vesicles rapidly become purulent and covered with a thick, confluent, honey-colored crust. The appearance of the lesions of streptococcal impetigo is in contrast to the classic bullous appearance of impetigo due to phage group II Staphylococcus aureus. However, recent evidence indicates that many cases of nonbullous impetigo are, in fact, mixed infections containing both S aureus and S pyogenes, and conclusions about etiology based on the clinical appearance of impetigo should be drawn with caution.

Lesions are most commonly encountered on the face and extremities. If untreated, streptococcal impetigo is a mild but chronic illness, often spreading to other parts of the body. Regional lymphadenitis is common. The M types that give rise to streptococcal tonsillitis (ie, types 1, 3, 5, 6, 12, 18, 19, and 24) are rarely found in streptococcal impetigo. One of the streptococcal pyoderma-associated strains, the M49 strain, is very strongly associated with PSGN.

Deeper soft tissue infections may occur following colonization of the skin with S pyogenes. A deeply ulcerated form of streptococcal impetigo, ecthyma, may complicate streptococcal impetigo. Ecthyma tends to be a more deep-seated and chronic form of streptococcal impetigo and is encountered mainly in the tropics.

Streptococcal cellulitis is an acute rapidly spreading infection of skin and subcutaneous tissue, which can follow burns, wounds, surgical incisions, varicella infection, and mild trauma. Pain, tenderness, swelling and erythema, and systemic toxicity are common, and patients may have associated bacteremia. Careful serial examination is crucial because cellulitis may progress to necrotizing fasciitis (see Media file 1).

Perianal cellulitis and vaginitis should be considered in children who report perineal discomfort or vaginal discharge. Today, erysipelas is a relatively rare acute streptococcal infection involving the deeper layers of the skin and the underlying connective tissue. Skin over the affected area tends to be swollen, red, and exquisitely tender in contrast to streptococcal impetigo, which is usually painless. Superficial blebs may be present. The most characteristic finding in erysipelas, the sharply defined and slightly elevated border, helps to differentiate this entity from cellulitis, which has an indistinct border.

At times, reddish streaks of lymphangeitis may project out from the margins of the lesion. Systemic toxicity is common. For both erysipelas and cellulitis, cultures obtained by leading edge needle aspirate of the inflamed area are warranted.

Scarlet Fever

When a fine, diffuse, erythematous rash is present in the setting of acute streptococcal pharyngitis, the illness is called scarlet fever. The rash of scarlet fever is caused by the pyrogenic exotoxins (ie, SPE A, B, C, and F). The rash highly depends on toxin expression; preexisting humoral immunity to the specific SPE toxin prevents the clinical manifestations of scarlet fever. Recently, scarlet fever is apparently less common and is less virulent than in past decades; however, incidence is cyclic, depending on the prevalence of toxin-producing strains and the immune status of the population. Modes of transmission, age distribution of cases, and other epidemiologic features are similar to those for streptococcal pharyngitis.

Scarlet fever rash usually appears within 24-48 hours after onset of symptoms, although it may appear with the first signs of illness. It is often initially noticed on the neck and upper chest as a diffuse, finely papular, erythematous eruption producing a bright red discoloration of the skin, which blanches on pressure. The texture is that of fine sandpaper.

The flexor skin creases, particularly in the antecubital fossae, may be unusually prominent (ie, Pastia lines). The area around the mouth is pale, creating the appearance of circumoral pallor. In severe cases, small vesicular lesions (ie, miliary sudamina) may appear on the abdomen, hands, and feet. Toward the end of the first week of illness, the rash begins to fade and is followed by a desquamation over the trunk, which progresses to the hands and feet. Typical scarlet fever is not generally difficult to diagnose, but it may be confused with roseola, Kawasaki syndrome, drug eruptions, and toxigenic S aureus infections.

A history of recent exposure to another individual (eg, classroom or household contact) with streptococcal infection is a helpful clue. Isolation of S pyogenes from the pharynx confirms the diagnosis in uncertain cases, and serologic evidence of recent group A streptococcal infection may be present (ASO or anti-DNAse B antibody response).

Other Miscellaneous Streptococcal Infections

Suppurative complications from the spread of streptococci to adjacent structures were very common in the preantibiotic era. Cervical adenitis, peritonsillar abscess, retropharyngeal abscess, otitis media, mastoiditis, and sinusitis still occur in children in whom the primary illness has gone unnoticed or in whom treatment of the pharyngitis has been inadequate because of noncompliance. S pyogenes is an occasional etiology of pneumonia and is an important etiology of parapneumonic effusion. Acute hematogenous osteomyelitis is an important complication of streptococcal infection. Isolated bacteremia, meningitis, and endocarditis are described but appear to be rare manifestations of acute infection.

Invasive Streptococcal Infections

Invasive infections with S pyogenes have been encountered with increased frequency in recent years. These may manifest as either necrotizing fasciitis or streptococcal TSS.

Necrotizing fasciitis

Necrotizing fasciitis caused by S pyogenes (so-called streptococcal gangrene) is an acute, rapidly progressive, severe, deep-seated infection of the subcutaneous tissue associated with extensive destruction of superficial and deep fascia. Diffuse erythematous swelling heralds the onset, with exquisite pain at the affected site. Indeed, severe excruciating pain that seems inconsistent with the observed clinical findings should strongly suggest the possibility of this diagnosis.

As the lesion progresses (approximately 48-72 h), the skin becomes bluish and dusky, and bullae containing yellow or hemorrhagic fluid appear. By the fourth to fifth day, frank gangrene is present, and extensive sloughing of skin occurs. Surgical debridement of necrotic tissue is a crucial adjunct to management. Differentiation between streptococcal cellulitis and necrotizing fasciitis can be difficult, and careful serial physical examination is crucial.

Consultation with a surgeon early in the course of infection is essential because debridement is often lifesaving. If diagnosis is not certain on clinical grounds, a biopsy with frozen section may be useful. Histopathology commonly reveals both microbial and neutrophilic infiltration of deep dermal and superficial fascial layers of skin, with resultant thrombosis, vasculitis, and necrosis.

Although any part of the body may be affected, streptococcal fasciitis usually begins on an extremity. It may begin at a site of trivial or inapparent trauma, or it may follow cuts, burns, penetrating injuries, or blunt trauma. A major risk factor for development of streptococcal necrotizing fasciitis is a history of recent varicella-zoster virus (VZV) infection (see Media file 1). The risk of varicella-associated necrotizing fasciitis should decrease with the implementation of routine childhood immunization against VZV.

Streptococcal TSS

Streptococcal TSS is characterized by hypotension and multiple-organ failure. Considerable overlap occurs with streptococcal necrotizing fasciitis, insofar as most cases occur in association with soft tissue infections; however, streptococcal TSS may occur in association with other focal streptococcal infections, including pharyngeal infection.

As noted above, the pathogenesis of streptococcal TSS appears to be related in part to the ability of certain SPEs (A, C, F) to function as superantigens. Multiple-organ system disease is common and manifests as renal impairment, occurring in approximately 80% of patients, and hepatic dysfunction, occurring in 65% of patients.

Criteria proposed by the Working Group on Severe Streptococcal Infections for the diagnosis of streptococcal toxic shock are outlined as follows:⁸

• Isolation of group A Streptococcus
  • From a sterile site
  • From a nonsterile body site
• Clinical signs of severity (Two or more of the following clinical and laboratory abnormalities are required.)
  • Renal impairment
  • Coagulopathy
  • Liver abnormalities
  • Acute respiratory distress
  • Extensive tissue necrosis (necrotizing fasciitis)
  • Erythematous rash
• Definite case - Isolation of group A Streptococcus from a sterile site plus compatible clinical signs
• Probable case - Isolation of group A Streptococcus from a nonsterile body site plus compatible clinical signs

Surgical Care

Necessary procedures for management of the diverse nature of group A streptococcal infections may include endotracheal intubation, thoracocentesis, lumbar puncture, abscess or skin aspirate, prompt surgical drainage, and even surgical debridement of devitalized tissue, fasciotomy, or amputation (see Medical Care). Some children with recurrent streptococcal pharyngitis (7 culture-proven episodes in the preceding year) may benefit from tonsillectomy.

Consultations

• Surgeon (for necrotizing fasciitis and bone and joint infections)
• Critical care specialist (for epiglottitis and TSS)
• Nephrologist (for PSGN)
• Neurologist (for chorea and PANDAS syndrome)
• Infectious diseases specialist (for assistance in differential diagnosis and broad management issues)
• Cardiologist (for carditis)
• Dermatologist (for skin conditions)
• Pathologist (for analysis of biopsies and other intraoperative specimens)

Medication

Treatment approaches for group A streptococcal infections vary depending on the clinical syndrome. Penicillin therapy, in general, remains the treatment of choice in most situations. Remarkably, no penicillin-resistant strains of S pyogenes have yet been encountered in clinical practice.⁹  Therefore, penicillin remains the drug of choice (except in individuals who are allergic to penicillin) for pharyngeal infections as well as for complicated or invasive infections. Approaches to antibiotic therapy of various streptococcal syndromes are considered below.

Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Penicillin VK ( Pfizerpen, Pen-Vee K, Beepen-VK)

Inhibits the biosynthesis of cell wall mucopeptide. Bactericidal against sensitive organisms when adequate concentrations are reached, and most effective during the stage of active multiplication. Inadequate concentrations may produce only bacteriostatic effects. For streptococcal pharyngitis, the PO antibiotic of choice is penicillin VK (phenoxymethyl penicillin). Penicillin VK is preferable to penicillin G because of its acid stability, allowing it to be dosed without regard to meals. The most common reason for penicillin failure is noncompliance. The drug is often discontinued before the 10-d course is completed because children usually appear to have recovered in 3-4 d. When PO treatment is prescribed, the necessity of completing a full course of therapy must be emphasized. Even in compliant patients, recent reports suggest penicillin fails to eradicate S pyogenes from about 15% of treated patients. Many theories have been proposed to explain these apparent penicillin failures.
The presence of beta-lactamase–producing normal flora (particularly organisms such as mouth anaerobes) is proposed as a potential mechanism by which penicillin may become inactivated. However, the clinical significance of this theory has never been conclusively demonstrated. Many of the failures of penicillin therapy are more likely to occur in studies where streptococcal pharyngitis has not been defined rigorously enough, and some of these patients may, in fact, be streptococcal carriers who had viral pharyngitis at study onset.

Penicillin G benzathine (Bicillin LA)

Interferes with synthesis of cell wall mucopeptides during active multiplication, which results in bactericidal activity. If noncompliance with PO therapy seems likely, parenteral therapy is indicated.
Formulation is painful when administered IM, and it is often combined with penicillin G procaine to minimize discomfort at the injection site. When this combination is used in a single injection, take care to ensure that an adequate amount of penicillin G benzathine is administered. The combination of 900,000 U of penicillin G benzathine and 300,000 U of penicillin G procaine is satisfactory for most children.

Erythromycin (EES, Ery-Tab, E-Mycin)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. For treatment of staphylococcal and streptococcal infections.
In children, age, weight, and severity of infection determine proper dosage. When bid dosing is desired, half-total daily dose may be taken q12h. For more severe infections, double the dose. PO erythromycin is an acceptable alternative for patients allergic to penicillin or cephalosporin antibiotics and is effective in the treatment of streptococcal pharyngitis. Erythromycin estolate and erythromycin ethylsuccinate are both effective, although note local antibiotic resistant rates because up to 5% of isolates of S pyogenes may be erythromycin resistant.

Clarithromycin (Biaxin)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Similar susceptibility profile to erythromycin but has fewer adverse effects.

Azithromycin (Zithromax)

Similar susceptibility profile to erythromycin, but has fewer adverse effects. Treats mild-to-moderate microbial infections.

Cephalexin (Keflex, Biocef)

First-generation cephalosporin arrests bacterial growth by inhibiting bacterial cell wall synthesis. Bactericidal activity against rapidly growing organisms. Primary activity against skin flora; used for skin infections or prophylaxis in minor procedures. PO cephalosporins are effective in the treatment of streptococcal pharyngitis.
Short-course regimens of PO cephalosporin therapy have been studied and offer obvious advantages from a compliance perspective. However, this must be balanced against the higher cost and unnecessarily broad spectrum of these agents.

Clindamycin (Cleocin)

Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Patients with invasive group A streptococcal infections (eg, necrotizing fasciitis, TSS, sepsis) should be treated with IV penicillin in combination with clindamycin. Because the pathophysiology of invasive group A streptococcal infection is largely toxin mediated, the use of protein synthesis inhibitor (eg, clindamycin) offers a theoretical advantage.
Furthermore, in vivo evidence of the lack of efficacy of penicillin in deep tissue infections has been observed in animal models. This effect, first described by Eagle in 1952, appears to occur because of high inoculum of organisms encountered in overwhelming infections (eg, necrotizing fasciitis, myositis, sepsis).
Large concentrations of organisms lead to rapid attainment of the stationary growth phase, which is associated with decreased expression of cell wall penicillin-binding proteins (PBPs), the molecular targets of penicillin. Decreased expression of PBPs in deep tissue infections with group A streptococci appears to render penicillin less effective. In contrast, clindamycin retains efficacy. Vigorous supportive care, including fluids, pressors, and mechanical ventilation, is also a critical aspect of management of invasive streptococcal skin and soft tissue infections. Prompt surgical drainage, debridement, fasciotomy, or amputation may be indicated.
Differentiating a streptococcal carrier with recurrent viral infection from a child with recurrent streptococcal pharyngitis may be difficult. Although most streptococcal carriers do not require medical intervention, situations arise in which eradication of the carrier state is desirable (eg, families in with an inordinate amount of anxiety about streptococci, families in which ping-pong spread has been occurring, when tonsillectomy is considered only because of chronic carriage). A course of clindamycin has been shown to be highly effective in eradicating the carrier state and should be tried in patients with recurrent or frequent episodes of culture-proven pharyngitis. Some children with recurrent streptococcal pharyngitis (7 culture-proven episodes in the preceding y) may benefit from tonsillectomy.

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