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Infeksi Strepto
Infection with Streptococcus pyogenes, a beta-hemolytic bacterium that belongs to Lancefield
serogroup A, also known as the group A streptococci (GAS), causes a wide variety of diseases in
humans. A ubiquitous organism, S pyogenes is the most common bacterial cause of acute
pharyngitis, accounting for 15-30% of cases in children and 5-10% of cases in adults. [1] During the
winter and spring in temperate climates, up to 20% of asymptomatic school-aged children may be
group A streptococcus carriers. (See Pathophysiology, Etiology, and Epidemiology.) [2, 3]
An understanding of the diverse nature of infectious disease complications attributable to this
organism is an important cornerstone of pediatric medicine. In addition to infections of the upper
respiratory tract and the skin, S pyogenes can cause a wide variety of invasive systemic infections.
Along with Staphylococcus aureus, group A streptococcus is one of the most common pathogens
responsible for cellulitis . Infection with this pathogen is also causally linked to 2 potentially serious
nonsuppurative complications: acute rheumatic fever (ARF) and acute glomerulonephritis. In addition,
infection with S pyogenes has reemerged as an important cause of toxic shock syndrome (TSS) and
of life-threatening skin and soft-tissue infections, especially necrotizingfasciitis

Lancefield classification scheme

As originally described by Lancefield, beta-hemolytic streptococci can be divided into many groups
based on the antigenic differences in group-specific polysaccharides located in the bacterial cell wall.
More than 20 serologic groups have been identified and designated by letters (eg, A, B, C). Of the
nongroup A streptococci, group B is the most important human pathogen (the most common cause
of neonatal sepsis and bacteremia), although other groups (particularly group G) have occasionally
been implicated as causes of pharyngitis. (See Pathophysiology.)

The emm classification scheme

The traditional Lancefield classification system, which is based on serotyping, has been replaced
by emm typing, which has been used to characterize and measure the genetic diversity among
isolates of S pyogenes. This system is based on a sequence at the 5' end of a locus (emm) that is
present in all isolates. The targeted region of emm displays the highest level of sequence
polymorphism known for an S pyogenes gene; more than 150 emm types have been described to
date.[4] The emm gene encodes the M protein.
There are 4 major subfamilies of emm genes, which are defined by sequence differences within the 3'
end, encoding the peptidoglycan-spanning domain. The chromosomal arrangement of emm subfamily
genes reveals 5 major emmpatterns, designated as emm patterns A through E. An example of the
usefulness of emm typing is described by McGregor et al.[5]

Identification of GAS
Although serologic grouping by the Lancefield method is the criterion standard for differentiation of
pathogenic streptococcal species, group A organisms can be identified more cost effectively by
numerous latex agglutination, coagglutination, or enzyme immunoassay procedures. (See Workup.)
Group A strains can also be distinguished from other groups by their sensitivity to bacitracin. A disc
that contains 0.04U of bacitracin inhibits the growth of more than 95% of group A strains, whereas 8090% of nongroup A strains are resistant to this antibiotic. The bacitracin disc test is simple to perform
and interpret in an office-based laboratory and is sufficiently accurate for presumptive identification of
Presumptive identification of a strain as a group A streptococcus can also be made on the basis of
production of the enzyme L-pyrrolidonyl-beta-naphthylamide (PYRase). Among the beta-hemolytic
streptococci isolated from throat culture, only group A isolates produce PYRase, which can be
identified on the basis of the characteristic color change (red) after inoculation of a disk on an agar
plate followed by overnight incubation.
When cultured on blood agar plates, the production of a characteristic zone of complete hemolysis
(beta hemolysis) is another important clue to the classification of S pyogenes (see the image below).

(For example, Streptococcus pneumoniae generates a zone of only partial hemolysis [alpha

Streptococcus group A infections. Beta hemolysis is demonstrated on blood

agar media.

Spectrum of diseases caused by group A streptococcal infections

In the preantibiotic era, streptococci frequently caused significant morbidity and were associated with
significant mortality rates. However, in the postantibiotic period, diseases due to streptococcal
infections are well-controlled and uncommonly cause death. GAS can cause a diverse variety of
suppurative diseases and nonsuppurative postinfectious sequelae. (See Pathophysiology, Etiology,
Prognosis, and Treatment.)
The suppurative spectrum of GAS diseases includes the following:

Pharyngitis - With or without tonsillopharyngeal cellulitis or abscess

Impetigo - Purulent, honey-colored, crusted skin lesions
Necrotizing fasciitis
Streptococcal bacteremia
Otitis media
Meningitis or brain abscess (a rare complication resulting from direct extension of an ear or
sinus infection or from hematogenous spread)
The nonsuppurative sequelae of GAS infections include the following:

ARF - Defined by Jones criteria

Rheumatic heart disease - Chronic valvular damage, predominantly the mitral valve
Acute glomerulonephritis
A superantigen-mediated immune response may result in the development of scarlet fever or
streptococcal TSS. Scarlet fever is characterized by an upper-body rash, generally following
Streptococcal TSS is characterized by systemic shock with multiorgan failure, with manifestations that
include respiratory failure, acute renal failure, hepatic failure, neurologic symptoms, hematologic
abnormalities, and skin findings, among others. This is predominantly associated with M types 1 and 3
that produce pyrogenic exotoxin A, exotoxin B, or both

Streptococci are a large group of gram-positive, nonmotile, nonspore-forming cocci about 0.5-1.2m
in size. They often grow in pairs or chains and are negative for oxidase and catalase.
S pyogenes tends to colonize the upper respiratory tract and is highly virulent as it overcomes the
host defense system. The most common forms of S pyogenesdisease include respiratory and skin
infections, with different strains usually responsible for each form.
The cell wall of S pyogenes is very complex and chemically diverse. The antigenic components of the
cell are the virulence factors. The extracellular components responsible for the disease process

include invasins and exotoxins. The outermost capsule is composed of hyaluronic acid, which has a
chemical structure resembling host connective tissue, allowing the bacterium to escape recognition by
the host as an offending agent. Thus, the bacterium escapes phagocytosis by neutrophils or
macrophages, allowing it to colonize. Lipoteichoic acid and M proteins located on the cell membrane
traverse through the cell wall and project outside the capsule.

Epithelial cell invasion

A characteristic of S pyogenes is the organisms ability to invade epithelial cells. Failure of penicillin to
eradicate S pyogenes from the throats of patients, especially those who are carriers of S
pyogenes, has been increasingly reported. The results of one study strongly suggested that if the
carrier state results from intraepithelial cell streptococci survival, the failure of penicillin to kill
ingested S pyogenes may be related to a lack of effective penicillin entry into epithelial cells. [7] These
observations may have clinical implications for understanding carriers and managing S
pyogenes infection.

Bacterial virulence factors

The cell wall antigens include capsular polysaccharide (C-substance), peptidoglycan and lipoteichoic
acid (LTA), R and T proteins, and various surface proteins, including M protein, fimbrial proteins,
fibronectin-binding proteins (eg, protein F), and cell-bound streptokinase.
The C-substance is composed of a branched polymer of L-rhamnose and N -acetyl-D-glucosamine. It
may have a role in increased invasive capacity. The R and T proteins are used as epidemiologic
markers and have no known role in virulence.[8]
Another virulence factor, C5A peptidase, destroys the chemotactic signals by cleaving the
complement component of C5A.
M protein, the major virulence factor, is a macromolecule incorporated in fimbriae present on the cell
membrane projecting on the bacterial cell wall. It is the primary cause of antigenic shift and antigenic
drift among GAS.
M protein binds the host fibrinogen and blocks the binding of complement to the underlying
peptidoglycan. This allows survival of the organism by inhibiting phagocytosis. Strains that contain an
abundance of M protein resist phagocytosis, multiply rapidly in human tissues, and initiate the disease
process. After an acute infection, type-specific antibodies develop against M protein activity in some
However, although such antibodies protect against infection by a homologous M protein type, they
confer no immunity against other M types. This observation is one of the factors representing a major
theoretical obstacle to the S pyogenesvaccine design, because more than 80 M serotypes have been
described to date.
Community-based outbreaks of particular streptococcal diseases tend to be associated with certain M
types; therefore, M serotyping has been very valuable for epidemiologic studies.

Bacterial adherence factors

At least 11 different surface components of GAS have been suggested to play a role in adhesion. In
1997, Hasty and Courtney proposed that GAS express different arrays of adhesins in various
environmental niches. Based on their review, M protein mediates adhesion to HEp-2 cells, but not to
buccal cells, in humans, whereas FBP54 mediates adhesion to buccal cells, but not to HEp-2 cells.
Protein F mediates adhesion to Langerhans cells, but not to keratinocytes.
One of the theories proposed with regard to the process of adhesion is a 2-step model. The initial step
in overcoming the electrostatic repulsion of the bacteria from the host is mediated by LTA, which
provides weak, reversible adhesion. The second step takes the form of firm, irreversible adhesion
mediated by tissue-specific M protein, protein F, or FBP54, among others. Once adherence has
occurred, the streptococci resist phagocytosis, proliferate, and begin to invade the local tissues. [11]
GAS show enormous and evolving molecular diversity, driven by horizontal transmission among
various strains. This is also true when they are compared with other streptococci. Acquisition of

prophages accounts for much of the diversity, conferring not only virulence via phage-associated
virulence factors but also increased bacterial survival against host defenses.

Extracellular products and toxins

Various extracellular growth products and toxins produced by GAS are responsible for host cell
damage and inflammatory response.
S pyogenes elaborates 2 distinct hemolysins. These proteins are responsible for the zone of
hemolysis observed on blood agar plates and are also important in the pathogenesis of tissue
damage in the infected host. Streptolysin O is toxic to a wide variety of cell types, including
myocardium, and is highly immunogenic. The determination of the antibody responses to this protein
(antistreptolysin O [ASO] titer) is often useful in the serodiagnosis of recent infection.
Streptolysin S is another virulence factor capable of damaging polymorphonuclear leukocytes and
subcellular organelles. However, in contrast to streptolysin O, it does not appear to be immunogenic.
Pyrogenic exotoxins
The family of streptococcal pyrogenic exotoxins (SPEs) includes SPEs A, B, C, and F. These toxins
are responsible for the rash of scarlet fever. Other pathogenic effects caused by these substances
include pyrogenicity, cytotoxicity, and enhancement of susceptibility to endotoxin. SPE B is a
precursor of a cysteine protease, another determinant of virulence. [12]
Group A streptococcal isolates associated with streptococcal TSS encode certain SPEs (ie, A, C, F)
capable of functioning as superantigens. These antigens induce a marked febrile response, induce
proliferation of T lymphocytes, and induce synthesis and release of multiple cytokines, including tumor
necrosis factor, interleukin-1 beta, and interleukin-6. This activity is attributed to the ability of the
superantigen to simultaneously bind to the V-beta region of the T-cell receptor and to class II major
histocompatibility antigens of antigen-presenting mononuclear cells, resulting in widespread,
nonspecific T-cell proliferation and increased production of interleukin-2.
Four antigenically distinct nucleases (A, B, C, D) assist in the liquefaction of pus and help to generate
substrate for growth.
Other products
Other extracellular products include NADase (leukotoxic), hyaluronidase (which digests host
connective tissue, hyaluronic acid, and the organism's own capsule), streptokinases (proteolytic), and
streptodornase A-D (deoxyribonuclease activity). [13]
Proteinase, amylase, and esterase are additional streptococcal virulence factors, although the role of
these proteins in pathogenesis is not fully understood.

Suppurative disease spectrum

Streptococcal pharyngitis
S pyogenes causes up to 15-30% of cases of acute pharyngitis. [14] Frank disease occurs based on the
degree of bacterial virulence after colonization of the upper respiratory tract. Accurate diagnosis is
essential for appropriate antibiotic selection.
Pyoderma is the most common form of skin infection caused by GAS . 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.

Streptococcal pyoderma may occur in children belonging to certain population groups and in
overcrowded institutions. The modes of transmission are direct contact, environmental contamination,
and houseflies. The strains of streptococci that cause pyoderma differ from those that cause
exudative tonsillitis.
The bacterial toxins cause proteolysis of epidermal and subepidermal layers, allowing the bacteria to
spread quickly along the skin layers and thereby cause blisters or purulent lesions. The other common
cause of impetigo isStaphylococcus aureus.
Invasive GAS can cause pulmonary infection, often with rapid progression to necrotizing pneumonia.
Necrotizing fasciitis
Necrotizing fasciitis is caused by bacterial invasion into the subcutaneous tissue, with subsequent
spread through superficial and deep fascial planes. The spread of GAS is aided by bacterial toxins
and enzymes (eg, lipase, hyaluronidase, collagenase, streptokinase), interactions among organisms
(synergistic infections), local tissue factors (eg, decreased blood and oxygen supply), and general
host factors (eg, immunocompromised state, chronic illness, surgery).
As the infection spreads deep along the fascial planes, vascular occlusion, tissue ischemia, and
necrosis occur.[15] Although GAS is often isolated in cases of necrotizing fasciitis, this disease state is
frequently polymicrobial.
Otitis media and sinusitis
These are common suppurative complications of streptococcal tonsillopharyngitis. They are caused
by the spread of organisms via the eustachian tube (otitis media) or by direct spread to the sinuses

Nonsuppurative disease spectrum

Acute rheumatic fever
ARF is a delayed, nonsuppurative sequela of GAS tonsillopharyngitis. Following the pharyngitis, a
latent period of 2-3 weeks passes before the signs or symptoms of ARF appear. The disease presents
with various clinical manifestations, including arthritis, carditis, chorea, subcutaneous nodules, and
erythema marginatum.
Rheumatic fever may be the result of host genetic predisposition. The disease gene may be
transmitted either in an autosomal-dominant fashion or in an autosomal-recessive fashion, with limited
penetrance. However, the disease gene has not yet been identified.
Considerable evidence supports the link between group A streptococcal infections of the upper
respiratory tract and ARF, although only certain M-group serotypes (ie, 1, 3, 5, 6, 18, 24) are
associated with this complication. Very mucoid strains, particularly strains of M type 18, have
appeared in numerous communities prior to the appearance of rheumatic fever. Rheumatic fever is
most frequently observed in children aged 5-15 years (the age group most susceptible to GAS
The attack rate following upper respiratory tract infection is approximately 3% for individuals with
untreated or inadequately treated infection. The latent period between the GAS infection and the
onset of rheumatic fever varies from 2-4 weeks. In contrast to poststreptococcal glomerulonephritis
(PSGN), which may follow either pharyngitis or streptococcal pyoderma, rheumatic fever can occur
only after an infection of the upper respiratory tract.
Despite the depth of knowledge that has been accumulated about the molecular microbiology
of Streptococcus pyogenes, the pathogenesis of ARF remains unknown. A direct effect of a
streptococcal extracellular toxin, in particular streptolysin O, may be responsible for the pathogenesis
of ARF, according to some hypotheses. Observations that streptolysin O is cardiotoxic in animal
models support this hypothesis, but linking this toxicity to the valvular damage observed in ARF has
been difficult.

A more popular hypothesis is that an abnormal host immune response to some component of the
group A Streptococcus is responsible. The M protein of GAS shares certain amino acid sequences
with some human tissues, and this has been proposed as a source of cross-reactivity between the
organism and human host that could lead to an immunopathologic immune response. Also, antigenic
similarity between the group-specific polysaccharide of S pyogenes and glycoproteins found in human
and bovine cardiac valves has been recognized, and patients with ARF have prolonged persistence of
these antibodies compared with controls with uncomplicated pharyngitis. Other GAS antigens appear
to cross-react with cardiac sarcolemma membranes.[16]
During the course of the host's immune response to the GAS, the host's antigens may, as a result of
this molecular mimicry, be mistaken as foreign; this leads to an inflammatory cascade with resultant
tissue damage. In patients with ARF with Sydenham chorea, common antibodies to antigens found in
the S pyogenes cell membrane and the caudate nucleus of the brain are present, further supporting
the concept of an aberrant autoimmune response in the development of ARF.
Interest in whether such autoimmune responses play a role in the pathogenesis of the syndrome
known as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections
(PANDAS) has been considerable, although further work is necessary to establish the link between
streptococcal infections and these syndromes.
Poststreptococcal glomerulonephritis
Glomerulonephritis can follow group A streptococcal infections of either the pharynx or the skin, and
incidence varies with the prevalence of so-called nephritogenic strains of group A streptococci in the
community. Type 12 is the most frequent M serotype that causes PSGN after pharyngitis, and M type
49 is the serotype most commonly related to pyoderma-associated nephritis. The latent period
between GAS infection and the onset of glomerulonephritis varies from 1-2 weeks.
Pathogenesis appears to be immunologically mediated. Immunoglobulins, complement components,
and antigens that react with streptococcal antisera are present in the glomerulus early in the course of
the disease, and antibodies elicited by nephritogenic streptococci are postulated to react with renal
tissue in such a way as to promote glomerular injury. In contrast to acute rheumatic fever, recurrences
of PSGN are rare. Diagnosis of PSGN is based on clinical history, physical examination findings, and
confirmatory evidence of recent streptococcal infection.
Toxic shock syndrome
Severe GAS infections associated with shock and organ failure have been reported with increasing
frequency, predominantly in North America and Europe.
Considerable overlap occurs between streptococcal TSS and streptococcal necrotizing fasciitis,
insofar as most cases occur in association with soft-tissue infections. However, streptococcal TSS
may also occur in association with other focal streptococcal infections, including pharyngeal infection.
The pathogenesis of streptococcal TSS appears to be related in part to the ability of certain (ie, A, C,
F) streptococcal pyogenic exotoxins (SPEs) to function as superantigens.
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.
Scarlet fever has apparently become less common and 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.

Central nervous system diseases

The primary evidence for poststreptococcal autoimmune central nervous system (CNS) disease is
provided by studies of Sydenham chorea, the neurologic manifestation of rheumatic fever. Reports of

obsessive-compulsive disorder (OCD), tic disorders, and other neuropsychiatric symptoms occurring
in association with group A beta-hemolytic streptococcal infections suggest that various CNS
sequelae may be triggered by poststreptococcal autoimmunity

S pyogenes is highly communicable and can cause disease in healthy people of all ages who do not
have type-specific immunity against the specific serotype responsible for infection. The streptococcus
can be present on healthy skin for at least a week before lesions appear.
S pyogenes is primarily spread through person-to-person transmission, although foodborne and
waterborne outbreaks have been documented. Neither spread of organisms by fomites nor
transmission from animals (eg, family pets) appears to play a significant role in contagion.
Respiratory droplet spread is the major route for transmission of strains associated with upper
respiratory tract infection, although skin-to-skin spread is known to occur with strains associated with
streptococcal pyoderma. Impetigo serotypes may colonize the throat.
Children with untreated acute infections spread organisms by airborne salivary droplet and nasal
discharge. The incubation period for pharyngitis is 2-5 days. Children are usually not infectious within
24 hours after appropriate antibiotic therapy has been started, an observation that has important
implications for return to the daycare or school environment.
Individuals who are streptococcal carriers (chronic asymptomatic pharyngeal and nasopharyngeal
colonization) are not usually at risk of spreading disease to others because of the generally small
reservoir of often-avirulent organisms.
Fingernails and the perianal region can harbor streptococci and can play a role in disseminating
Multiple streptococcal infections in the same family are common. Impetigo and pharyngitis are more
likely to occur among children living in crowded homes and in suboptimal hygienic conditions.

Acute proliferative PSGN carries a good prognosis, as more than 95% of patients recover
spontaneously within 3-4 weeks with no long-term sequelae. With appropriate treatment, pharyngitis
and skin infections also have a good prognosis.
As reported by the CDC in April 2008, invasive GAS infections carry an overall mortality rate of 1015%, with streptococcal TSS and necrotizing fasciitis carrying fatality rates of over 35% and
approximately 25%, respectively.

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. [23]
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
Streptococcal TSS may cause organ system failure (including renal impairment in approximately 80%
of patients, and hepatic dysfunction in 65% of patients), while necrotizing fasciitis may result in
Puerperal sepsis follows abortion or delivery when streptococci that colonize the genital tract invade
the endometrium and enter the bloodstream. Pelvic cellulitis,septic pelvic thrombophlebitis, pelvic
abscess, and septicemia can occur. Peripartum genital tract infections with group B streptococci are
relatively more common, but fatal peripartum GAS infections have been reported. [25]

Empyema develops in 30-40% of pneumonia cases. Other complications of pneumonia include

mediastinitis, pericarditis, pneumothorax, and bronchiectasis.
The nonsuppurative complications of GAS tonsillopharyngitis include ARF, rheumatic heart disease,
and acute glomerulonephritis.
Group A streptococci (GAS) can cause various diseases, including strep throat, skin and soft-tissue
infections (eg, pyoderma, erysipelas, cellulitis, necrotizing fasciitis, myositis, osteomyelitis,
pneumonia, abscess), severe systemic disease, and long-term nonsuppurative complications (eg,
rheumatic fever, acute glomerulonephritis).

Head and neck infections

Streptococcal pharyngitis is strongly suggested by the presence of fever; tonsillar exudate; tender,
enlarged, anterior cervical lymph nodes; and absence of cough (Centor criteria). [14] Strep throat has an
incubation period of 2-4 days and is characterized by sudden onset of sore throat, cervical
lymphadenopathy, malaise, fever, and headache. Younger patients may also develop nausea,
vomiting, and abdominal pain. Acute sinusitis manifests as persistent coryza, postnasal drip,
headache, and fever.
The most important historic information to obtain in the evaluation of a sore throat is whether other
symptoms of upper respiratory tract infection are present or not. 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 that they vary widely
depending on patient age, severity of the infection, and 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
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.

Approach Considerations
Depending on disease manifestations, cultures of pharyngeal secretions, blood, cerebrospinal fluid,
joint aspirate, leading edge aspirate of cellulitis, skin biopsy specimen, epiglottic secretions,
bronchoalveolar lavage fluid, thoracocentesis fluid, or abscess fluid may be sources for locating the
organism. In cases of suspected necrotizing fasciitis, a frozen section biopsy obtained in the operating
room may be of great value in confirming the diagnosis and may aid in defining how much surgical
dbridement of devitalized tissue is necessary.
Serologic assays (antistreptococcal antibodies) are a potentially useful adjunct for diagnosis. Other
ancillary laboratory testseg, complete blood count (CBC), white blood cell (WBC) count, erythrocyte
sedimentation rate, and C-reactive proteinmay also be useful, depending on the manifestations of
disease under consideration.
Other tests, depending on disease syndrome, can be very diverse in nature. For example, a
histopathologic analysis of skin biopsy specimens, which may need to be analyzed intraoperatively, is
warranted in cases of suspected necrotizing fasciitis. Calculation of creatinine clearance may be
valuable in assessing the extent of renal dysfunction for nephritis.

Throat culture
Because pharyngitis and tonsillitis may result from various infectious etiologies other than S
pyogenes infection, the diagnosis should be confirmed. Throat culture remains the criterion standard
diagnostic test for streptococcal pharyngitis.
If performed correctly, culture of a single throat swab on a blood agar plate yields a sensitivity of 9095% for the detection of group A streptococci (GAS) in the pharynx. [2, 28]
Although some throat culture results are false-positive (eg, they do not reflect acute infection but,
rather, symptomatic carriage), all patients with positive culture results are treated with antibiotics.

Culture technique
GAS grow readily on routine media, but they can be isolated more easily using selective media that
inhibit the growth of normal pharyngeal flora. Most laboratories inoculate throat swabs on 5% sheep
blood agar containing trimethoprim-sulfamethoxazole. A bacitracin disk that contains 0.04U of
bacitracin is also placed at the initial inoculation of the swab.
After overnight incubation at a temperature of 35-37C, beta-hemolytic colonies that grow despite
inhibition of the antibiotic disk are presumed to be composed of GAS.
Cultures that are negative for GAS after 24 hours are held for another overnight incubation and

Blood culture, ASO titer, sputum culture, and tissue culture

These studies should be performed in patients with systemic infections. In patients with acute
pharyngitis, group A beta-hemolytic streptococcal infection should be ruled out. With appropriate
antibiotic treatment, the duration of illness is decreased, suppurative complications are prevented,
infectivity is decreased, and serious nonsuppurative sequelae (eg, ARF, PSGN) can be prevented.
Interestingly, delaying antimicrobial therapy for a short period does not diminish its efficacy in
preventing rheumatic fever.
Elevated streptococcal antibody titers in the setting of hypocomplementemic nephritis are essentially
diagnostic of PSGN.
With rare exceptions, neither posttreatment throat cultures in asymptomatic patients nor routine
cultures in asymptomatic family contacts are necessary.

Rapid antigen detection test

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 GAS 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

Therapy for streptococcal pharyngitis is aimed primarily at preventing nonsuppurative and suppurative
complications and decreasing infectivity. A 10-day course of penicillin V 250 mg twice daily in children
and 500 mg twice daily or 250 mg 4 times daily in adults is very effective. A single intramuscular
injection of 1.2 million units of penicillin G benzathine can be administered in patients who weigh more
than 27 kg; 600,000 units is used in patients who weigh less than 27 kg. Amoxicillin is equally
effective and may be better tolerated in children.

Timing of treatment
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 starting treatment of GAS sore throat as long as
9 days after the 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, but early treatment 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.
Antibiotic considerations
In patients who are allergic to penicillin, erythromycin or the newer macrolides (eg, azithromycin,
clarithromycin) appear to be effective. Oral cephalosporins are also highly effective in the treatment of
streptococcal pharyngitis. Although eradication rates associated with cephalosporins may be superior
to those achieved with penicillin, the latter is the recommended drug of choice by
the Association and the Infectious Diseases Society of America.[2]
A meta-analysis comparing bacterial and clinical cure rates in patients with GAS tonsillopharyngitis
found that short-course cephalosporin treatment was superior to 10 days of penicillin for bacterial cure
rate, that short-course penicillin therapy was inferior to 10 days of penicillin, and that clinical cure
rates were similar to bacterial cure rates.[31]
Treatment failure
Treatment failures are uncommon but may occur. If symptoms recur, the throat should be recultured
and another course of treatment should be prescribed, preferably with an oral cephalosporin. An
asymptomatic carrier state, as evidenced by positive throat culture results obtained on a weekly basis,
is not treated with antibiotics.
The most common reason for oral antibiotic failure for streptococcal pharyngitis is noncompliance.
Use of the drug is often discontinued before the 10-day course is completed, because individuals
usually appear to have recovered in 3-4 days. When oral treatment is prescribed, the necessity of
completing a full course of therapy must be emphasized.
Even in compliant patients, reports suggest that penicillin fails to eradicate S pyogenes in about 15%
of treated patients. Many theories have been proposed to explain these apparent penicillin failures.
The presence of beta-lactamaseproducing 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 in which streptococcal
pharyngitis has not been defined rigorously enough, and some of the studies' patients may, in fact, be
streptococcal carriers who had viral pharyngitis at the onset of these trials.
Strains of GAS resistant to macrolides have been highly prevalent in some areas of the world and
have resulted in treatment failures. The ISDA 2012 guidelines state macrolide resistance rates among
pharyngeal isolates in most areas of theStates have been around 5-8%.[2]

Streptococcal pyoderma is treated with oral antibiotics (eg, penicillin or erythromycin) for 10 days.
However, because concomitant Staphylococcus aureusinfection may occur, therapy with cephalexin
or cefaclor is suggested. Treatment of pyoderma may not prevent nephritis if the patient is infected
with a nephritogenic strain.

Toxic shock syndrome

IV polyspecific immunoglobulin G (IVIG) has been reported to be efficacious as an adjunctive therapy

in patients with GAS TSS.

Necrotizing fasciitis
Treatment of necrotizing fasciitis consists of antibiotic therapy, supportive therapy for associated
shock, and prompt surgical intervention.
Early and extensive surgical intervention is currently advocated for necrotizing fasciitis. However, a
medical regimen, which includes IVIG, may allow an initial nonoperative or minimally invasive
management approach, thus limiting the need for extensive dbridement and amputation. [32]
GAS remain susceptible to beta-lactam antibiotics. Clinical failures of penicillin therapy for
streptococcal infections may occur. The failure rates in patients with invasive infections are higher
because of the larger number of organisms.
Clindamycin may be more effective in invasive infections. Unlike with penicillin, the efficacy of
clindamycin is unaffected by the size of the inoculum and the stage of bacterial growth. In addition,
clindamycin inhibits the production of toxin by streptococci.

Prospects for streptococcal vaccines

Apart from rheumatic fever prophylaxis and the prevention of intrafamily spread, few strategies are
available to prevent streptococcal infection.[33]
A streptococcal vaccine could be a promising tool for disease prevention, but an effective vaccine
would have to provide protection from multiple serotypes. Furthermore, theoretical concern that
vaccine-induced antibodies could injure host tissue and precipitate rheumatic fever is recognized.
Multivalent vaccines that contain multiple M-protein peptide epitopes have been engineered and show
efficacy in animal models but have not yet entered clinical trials. [34] However, several vaccine
candidates against GAS infection are in varying stages of preclinical and clinical development, and
the hope is that one of these vaccines will reach licensure within the next decade. [35] Only the
multivalent N-terminal vaccine has entered clinical trials over the last 30 years.
Natural penicillins have good activity against S pyogenes. Various forms of natural penicillins are used
for various diseases caused by GAS. The recommendation forS pyogenes pharyngitis in adults is a
single intramuscular (IM) dose of benzathine penicillin G 1.2 million units or penicillin V 500 mg PO
BID for 10 days. For S pyogenes necrotizing fasciitis in adults, IV penicillin G (up to 24 million units
daily in divided doses q4-6h) is recommended.
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Penicillin VK
Penicillin VK is a drug of choice for GAS pharyngitis. It inhibits the biosynthesis of cell-wall
mucopeptides. This agent elicits bactericidal effects against sensitive organisms when adequate
concentrations are reached and is most effective during the stage of active multiplication.
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Amoxicillin (Moxatag)
Amoxicillin is a drug of choice for GAS pharyngitis. It is a derivative of ampicillin and has a similar
antibacterial spectrum. With a bactericidal action comparable to penicillin, amoxicillin acts on
susceptible bacteria during the multiplication stage by inhibiting cell-wall mucopeptide biosynthesis. It
has superior bioavailability and stability to gastric acid and has a broader spectrum of activity than
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Penicillin G benzathine (Bicillin LA)

Penicillin G benzathine interferes with the synthesis of cell wall mucopeptides during active
multiplication, which results in bactericidal activity. If noncompliance with oral therapy seems likely,
parenteral therapy is indicated.

The formulation is painful when administered intramuscularly, 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 900,000U of penicillin G benzathine and 300,000 U of penicillin G procaine is
satisfactory for most children.
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Erythromycin (E.E.S., Ery-Tab, EryPed, Erythrocin)

Erythromycin inhibits bacterial growth, possibly by blocking the dissociation of peptidyl tRNA from
ribosomes, causing RNA-dependent protein synthesis to arrest. This agent is used for the treatment
of staphylococcal and streptococcal infections.
In children, age, weight, and the severity of infection determine proper dosage. When twice-daily
dosing is desired, the half-total daily dose may be taken every 12 hours. For more severe infections,
double the dose.
Oral erythromycin is an acceptable alternative for patients who are allergic to penicillin or
cephalosporin antibiotics and is effective in the treatment of streptococcal pharyngitis. Erythromycin
estolate and erythromycin ethylsuccinate are each effective. Note local antibiotic resistant rates,
however, because up to 5% of isolates of S pyogenes may be erythromycin resistant.
Erythromycin is associated with substantially higher rates of GI side effects compared with other
macrolides. Strains of GAS resistant to macrolides have been highly prevalent in some areas of the
world and have resulted in treatment failures.
The ISDA 2012 guidelines state macrolide resistance rates among pharyngeal isolates in most areas
of the States have been around 5-8%.
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Clarithromycin (Biaxin)
Clarithromycin inhibits bacterial growth, possibly by binding to 50S ribosomal unit, causing RNAdependent protein synthesis to arrest. It has a similar susceptibility profile to erythromycin, but
clarithromycin has fewer adverse effects.
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Azithromycin (Zithromax, Zmax)

Azithromycin has a similar susceptibility profile to erythromycin, but it has fewer adverse effects. This
agent treats mild to moderate microbial infections. Binds to the 50S ribosomal subunit where it blocks
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Cephalexin (Keflex)
Cephalexin, a first-generation cephalosporin, arrests bacterial growth by inhibiting bacterial cell wall
synthesis. It has bactericidal activity against rapidly growing organisms. The drug's primary activity is
against skin flora; cephalexin is used for skin infections and for prophylaxis in minor procedures. Oral
cephalosporins are effective in the treatment of streptococcal pharyngitis.
Short-course regimens of oral 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.
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Cefadroxil is a first-generation semi-synthetic cephalosporin that arrests bacterial growth by inhibiting
bacterial cell wall synthesis. It may be considered for GAS pharyngitis in patients allergic to penicillin
(without immediate-type hypersensitivity).
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Clindamycin (Cleocin)
Clindamycin is a lincosamide for the treatment of serious skin and soft-tissue staphylococcal
infections. It is also effective against aerobic and anaerobic streptococci (except enterococci).
Clindamycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl transfer ribonucleic
acid (tRNA) from ribosomes, causing RNA-dependent protein synthesis to arrest. Patients with
invasive GAS infections (eg, necrotizing fasciitis, TSS, sepsis) should be treated with IV penicillin in
combination with clindamycin. Because the pathophysiology of invasive GAS infection is largely toxin
mediated, the use of a 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 byEagle in 1952, appears to occur because of
the high inoculum of organisms encountered in overwhelming infections (eg, necrotizing fasciitis,
myositis, sepsis).
Large concentrations of organisms lead to the 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 GAS 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, dbridement,
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, situations in which 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
year) may benefit from tonsillectomy.
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Vancomycin acts by inhibiting proper cell wall synthesis in gram-positive bacteria. It is indicated for the
treatment of serious infections caused by beta-lactamresistant organisms and in patients who have
serious allergies to beta-lactam antimicrobials.
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Oritavancin (Orbactiv)
Oritavancin is lipoglycopeptide antibiotic that inhibits cell wall biosynthesis and disrupts bacterial
membrane integrity that leads to cell death. It is indicated for treatment of acute bacterial skin and skin
structure infections caused by gram-positive bacteria including S aureus (including methicillinsusceptible S aureusand MRSA), S pyogenes, S agalactiae, S dysgalactiae, S anginosus group (S
anginosus, S intermedius, S constellatus) and E faecalis (vancomycin-susceptible isolates only).
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Dalbavancin (Dalvance)
Dalbavancin is lipoglycopeptide antibiotic that prevents cross-linking by interfering with cell wall
synthesis. It is bactericidal in vitro against Staphylococcus aureusand Streptococcus pyogenes at
concentrations observed in humans at recommended doses. It is indicated for treatment of acute
bacterial skin and skin structure infections caused by Gram-positive bacteria
including Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant S
aureus[MRSA]), S pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group
(including S anginosus, S intermedius, S constellatus).
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Tedizolid (Sivextro)
Tedizolid is an oxazolidinone antibiotic indicated for skin and skin structure infections caused by
susceptible isolates of Gram-positive bacteria includingStaphylococcus aureus (including methicillinresistant [MRSA] and methicillin-susceptible [MSSA] isolates), Streptococcus pyogenes, S agalactiae,
S anginosus Group (including S anginosus, S intermedius, and S constellatus), andEnterococcus
faecalis. Its action is mediated by binding to the 50S subunit of the bacterial ribosome resulting in
inhibition of protein synthesis.