Streptococcus pyogenes and Streptococcal Disease

INTRODUCTION

Streptococcus pyogenes (Group A streptococcus) is a Gram-positive, nonmotile, nonsporeforming

coccus that occurs in chains or in pairs of cells. Individual cells are round-to-ovoid cocci, 0.6-1.0
micrometer in diameter (Figure 1). Streptococci divide in one plane and thus occur in pairs or (especially
in liquid media or clinical material) in chains of varying lengths. The metabolism of S. pyogenes is
fermentative; the organism is a catalase-negative aerotolerant anaerobe (facultative anaerobe), and
requires enriched medium containing blood in order to grow. Group A streptococci typically have a
capsule composed of hyaluronic acid and exhibit beta (clear) hemolysis on blood agar.

Figure 1. Streptococcus pyogenes. Left. Gram stain of Streptococcus pyogenes in a clinical specimen.
Right. Colonies of Streptococcus pyogenes on blood agar exhibiting beta (clear) hemolysis.

Streptococcus pyogenes is one of the most frequent pathogens of humans. It is estimated that between
5-15% of normal individuals harbor the bacterium, usually in the respiratory tract, without signs of
disease. As normal flora, S. pyogenes can infect when defenses are compromised or when the organisms
are able to penetrate the constitutive defenses. When the bacteria are introduced or transmitted to
vulnerable tissues, a variety of types of suppurative infectionscan occur.

In the last century, infections by S. pyogenes claimed many lives especially since the organism was the
most important cause of puerperal fever (sepsis after childbirth). Scarlet fever was formerly a severe
complication of streptococcal infection, but now, because of antibiotic therapy, it is little more than
streptococcalpharyngitis accompanied by rash. Similarly, erysipelas (a form of cellulitis accompanied by
fever and systemic toxicity) is less common today. However, there has been a recent increase in variety,
severity and sequelae ofStreptococcus pyogenes infections, and a resurgence of severe invasive
infections, prompting descriptions of "flesh eating bacteria" in the news media. A complete explanation
for the decline and resurgence is not known. Today, the pathogen is of major concern because of the
occasional cases of rapidly progressive disease and because of the small risk of serious sequelae in
untreated infections. These diseases remain a major worldwide health concern, and effort is being
directed toward clarifying the risk and mechanisms of these sequelae and identifying rheumatogenic
and nephritogenic strains of streptococci.
Acute Streptococcus pyogenes infections may present as pharyngitis (strep throat), scarlet
fever (rash), impetigo (infection of the superficial layers of the skin) or cellulitis (infection of the deep
layers of the skin). Invasive, toxigenic infections can result in necrotizing
fasciitis, myositis and streptococcal toxic shock syndrome. Patients may also develop immune-
mediated post-streptococcal sequelae, such as acute rheumatic fever and acuteglomerulonephritis,
following acute infections caused by Streptococcus pyogenes.

Streptococcus pyogenes produces a wide array of virulence factors and a very large number of diseases.
Virulence factors of Group A streptococci include: (1) M protein, fibronectin-binding protein (Protein F)
and lipoteichoic acid for adherence; (2) hyaluronic acid capsule as an immunological disguise and to
inhibit phagocytosis; M-protein to inhibit phagocytosis (3) invasins such
asstreptokinase, streptodornase (DNase B), hyaluronidase, and streptolysins; (4) exotoxins, such
as pyrogenic (erythrogenic) toxin which causes the rash ofscarlet fever and systemic toxic shock
syndrome.

CLASSIFICATION OF STREPTOCOCCI

Hemolysis on blood agar

The type of hemolytic reaction displayed on blood agar has long been used to classify the
streptococci. Beta -hemolysis is associated with complete lysis of red cells surrounding the colony,
whereas alpha-hemolysis is a partial or "green" hemolysis associated with reduction of red cell
hemoglobin. Nonhemolytic colonies have been termed gamma-hemolytic. Hemolysis is affected by the
species and age of red cells, as well as by other properties of the base medium. Group A streptococci
are nearly always beta-hemolytic; related Group B can manifest alpha, beta or gamma hemolysis. Most
strains of S. pneumoniae are alpha-hemolytic but can cause ß-hemolysis during anaerobic incubation.
Most of the oral streptococci and enterococci are non hemolytic. The property of hemolysis is not very
reliable for the absolute identification of streptococci, but it is widely used in rapid screens for
identification of S. pyogenes and S. pneumoniae.

Antigenic types

The cell surface structure of Group A streptococci is among the most studied of any bacteria (Figure 2).
The cell wall is composed of repeating units of N-acetylglucosamine and N-acetylmuramic acid, the
standard peptidoglycan. Historically, the definitive identification of streptococci has rested on the
serologic reactivity of "cell wall" polysaccharide antigens as originally described by Rebecca
Lancefield. Eighteen group-specific antigens (Lancefield groups) were established. The Group A
polysaccharide is a polymer of N-acetylglucosamine and rhamnose. Some group antigens are shared by
more than one species. This polysaccharide is also called the C substance or group carbohydrate
antigen.
Pathogenesis

Streptococcus pyogenes owes its major success as a pathogen to its ability to colonize and rapidly
multiply and spread in its host while evading phagocytosis and confusing the immune system.

Acute diseases associated with Streptococcus pyogenes occur chiefly in therespiratory

tract, bloodstream, or the skin. Streptococcal disease is most often a respiratory infection (pharyngitis
or tonsillitis) or a skin infection (pyoderma). Some strains of streptococci show a predilection for the
respiratory tract; others, for the skin. Generally, streptococcal isolates from the pharynx and respiratory
tract do not cause skin infections. Figure 3 describes the pathogenesis of S. pyogenes infections.

S. pyogenes is the leading cause of uncomplicated bacterial pharyngitis andtonsillitis commonly

referred to a strep throat. Other respiratory infections include sinusitis, otitis, and pneumonia.
Infections of the skin can be superficial (impetigo) or deep (cellulitis). Invasive streptococci cause joint
or bone infections, destructive wound infections (necrotizing fasciitis)
and myositis, meningitis andendocarditis. Two post streptococcal sequelae, rheumatic
fever andglomerulonephritis, may follow streptococcal disease, and occur in 1-3% of untreated
infections. These conditions and their pathology are not attributable to dissemination of bacteria, but to
aberrent immunological reactions to Group A streptococcal antigens. Scarlet fever and streptococcal
toxic shock syndromeare systemic responses to circulating bacterial toxins.

The cell surface of Streptococcus pyogenes accounts for many of the bacterium's determinants of
virulence, especially those concerned with colonization and evasion of phagocytosis and the host
immune responses. The surface of Streptococcus pyogenes is incredibly complex and chemically-diverse.
Antigenic components include capsular polysaccharide (C-substance), cell
wall peptidoglycan and lipoteichoic acid (LTA), and a variety of surface proteins, including M
protein, fimbrial proteins, fibronectin-binding proteins, (e.g. Protein F) and cell-bound streptokinase.

The cytoplasmic membrane of S. pyogenes contains some antigens similar to those of human cardiac,
skeletal, and smooth muscle, heart valve fibroblasts, and neuronal tissues, resulting in molecular
mimicry and a tolerant or suppressed immune response by the host.

The cell envelope of a Group A streptococcus is illustrated in Figure 2. The complexity of the surface can
be seen in several of the electron micrographs of the bacterium that accompany this article.
Figure 2. Cell surface structure of Streptococcus pyogenes and secreted products involved in virulence.

In Group A streptococci, the R and T proteins are used as epidemiologic markers and have no known
role in virulence. The group carbohydrate antigen (composed of N-acetylglucosamine and rhamnose)
has been thought to have no role in virulence, but emerging strains with increased invasive capacity
produce a very mucoid colony, suggesting a role of the capsule in virulence.

The M proteins are clearly virulence factors associated with both colonization and resistance to
phagocytosis. More than 50 types of S. pyogenes M proteins have been identified on the basis of
antigenic specificity, and it is the M protein that is the major cause of antigenic shift and antigenic drift
in the Group A streptococci. The M protein (found in fimbriae) also binds fibrinogen from serum and
blocks the binding of complement to the underlying peptidoglycan. This allows survival of the organism
by inhibiting phagocytosis.

The streptococcal M protein, as well as peptidoglycan, N-acetylglucosamine, and group-specific

carbohydrate, contain antigenic epitopes that mimic those of mammalian muscle and connective tissue.
As mentioned above, the cell surface of recently emerging strains of streptococci is distinctly mucoid
(indicating that they are highly encapsulated). These strains are also rich in surface M protein. The M
proteins of certain M-types are considered rheumatogenic since they contain antigenic epitopes related
to heart muscle, and they therefore may lead to autoimmune rheumatic carditis (rheumatic fever)
following an acute infection.
The Hyaluronic Acid Capsule

The capsule of S. pyogenes is non antigenic since it is composed of hyaluronic acid, which is chemically
similar to that of host connective tissue. This allows the bacterium to hide its own antigens and to go
unrecognized as antigenic by its host. The Hyaluronic acid capsule also prevents opsonized phagocytosis
by neutrophils or mancrophages.

Adhesins

Colonization of tissues by S. pyogenes is thought to result from a failure in the constitutive defenses
(normal flora and other nonspecific defense mechanisms) which allows establishment of the bacterium
at a portal of entry (often the upper respiratory tract or the skin) where the organism multiplies and
causes an inflammatory purulent lesion.

It is now realized that S. pyogenes (like many other bacterial pathogens) produces multiple adhesins
with varied specificities. There is evidence thatStreptococcus pyogenes utilizes lipoteichoic acids
(LTA), M protein, and multiple fibronectin-binding proteins in its repertoire of adhesins. LTA is
anchored to proteins on the bacterial surface, including the M protein. Both the M proteins and
lipoteichoic acid are supported externally to the cell wall on fimbriae and appear to mediate bacterial
adherence to host epithelial cells. The fibronectin-binding protein, Protein F, has also been shown to
mediate streptococcal adherence to the amino terminus of fibronectin on mucosal surfaces.

Identification of Streptococcuspyogenes adhesins has long been a subject of conflict and debate. Most of
the debate was between proponents of the LTA model and those of the M protein model. In 1972,
Gibbons and his colleagues proposed that attachment of streptococci to the oral mucosa of mice is
dependent on M protein. However, Olfek and Beachey argued that lipoteichoic acid (LTA), rather than M
protein, was responsible for streptococcal adherence to buccal epithelial cells. In 1996, Hasty and
Courtney proposed a two-step model of attachment that involved both M protein and teichoic acids.
They suggested that LTA loosely tethers streptococci to epithelial cells, and then M protein and/or other
fibronectin (Fn)-binding proteins secure a firmer, irreversible association. The first streptococcal
fibronectin-binding protein (Sfb) was demonstrated in 1992. Shortly thereafter, protein F was
discovered. Most recently (1998), the M1 and M3 proteins were shown to bind fibronectin.

Extracellular products: invasins and exotoxins

Colonization of the upper respiratory tract and acute pharyngitis may spread to other portions of the
upper or lower respiratory tracts resulting in infections of the middle ear (otitis media), sinuses
(sinusitis), or lungs (pneumonia). In addition, meningitis can occur by direct extension of infection from
the middle ear or sinuses to the meninges or by way of bloodstream invasion from the pulmonary focus.
Bacteremia can also result in infection of bones (osteomyelitis) or joints (arthritis). During these aspects
of acute disease the streptococci bring into play a variety of secretory proteins that mediate their
invasion.
For the most part, streptococcal invasins and protein toxins interact with mammalian blood and tissue
components in ways that kill host cells and provoke a damaging inflammatory response. The soluble
extracellular growth products and toxins of Streptococcus pyogenes (see Figure 2, above), have been
studied intensely. Streptolysin S is an oxygen-stable leukocidin; Streptolysin O is an oxygen-labile
leukocidin. NADase is also leukotoxic. Hyaluronidase (the original "spreading factor") can digest host
connective tissue hyaluronic acid, as well as the organism's own capsule. Streptokinases participate in
fibrin lysis.Streptodornases A-D possess deoxyribonuclease activity; Streptodornases B and D possess
ribonuclease activity as well. Protease activity similar to that inStaphylococcus aureus has been shown in
strains causing soft tissue necrosis or toxic shock syndrome. This large repertoire of products is
important in the pathogenesis of S. pyogenes infections. Even so, antibodies to these products are
relatively insignificant in protection of the host.

The streptococcal invasins act in a variety of ways summarized in Table 1 at the end of this article.
Streptococcal invasins lyse eukaryotic cells, including red blood cells and phagocytes; they lyse other
host macromolecules, including enzymes and informational molecules; they allow the bacteria to spread
among tissues by dissolving host fibrin and intercellular ground substances.

Pyrogenic Exotoxins

Three streptococcal pyrogenic exotoxins (SPE), formerly known asErythrogenic toxin, are recognized:
types A, B, C. These toxins act assuperantigens by a mechanism similar to those described for
staphylococci. As antigens, they do not requiring processing by antigen presenting cells. Rather, they
stimulate T cells by binding class II MHC molecules directly and nonspecifically. With superantigens
about 20% of T cells may be stimulated (vs 1/10,000 T cells stimulated by conventional antigens)
resulting in massive detrimental cytokine release. SPE A and SPE C are encoded by lysogenic phages; the
gene for SPE B is located on the bacterial chromosome.

The erythrogenic toxin is so-named for its association with scarlet fever which occurs when the toxin is
disseminated in the blood. Re-emergence in the late 1980's of exotoxin-producing strains of S.
pyogenes has been associated with atoxic shock-like syndrome similar in pathogenesis and
manifestation to staphylococcal toxic shock syndrome, and with other forms of invasive disease
associated with severe tissue destruction. The latter condition is termednecrotizing fasciitis. Outbreaks
of sepsis, toxic shock and necrotizing fasciitis have been reported at increasing frequency. The
destructive nature of wound infections prompted the popular press to refer to S. pyogenes as "flesh-
eating bacteria" and "skin-eating streptococci". The increase in invasive streptococcal disease was
associated with emergence of a highly virulent serotype M1 which is disseminated world-wide. The M1
strain produces the erythrogenic toxin (Spe A), thought to be responsible for toxic shock, and the
enzyme cysteine protease which is involved in tissue destruction. Because clusters of toxic shock were
also associated with other serotypes, particularly M3 strains, it is believed that unidentified host factors
may also have played an important role in the resurgence of these dangerous infections.
FIGURE 3. Pathogenesis of Streptococcus pyogenes infections. Adapted from Baron's Medical
Microbiology Chapter 13, Streptococcus by Maria Jevitz Patterson.

Post streptococcal sequelae

Infection with Streptococcus pyogenes can give rise to serious nonsuppurative sequelae:
acute rheumatic fever and acute glomerulonephritis. These pathological events begin 1-3 weeks after
an acute streptococcal illness, a latent period consistent with an immune-mediated etiology. Whether
all S. pyogenesstrains are rheumatogenic is controversial; however, clearly not all strains are
nephritogenic.

Acute rheumatic fever is a sequel only of pharyngeal infections, but acuteglomerulonephritis can follow
infections of the pharynx or the skin. Although there is no adequate explanation for the precise
pathogenesis of acute rheumatic fever, an abnormal or enhanced immune response seems essential.
Also, persistence of the organism on pharyngeal tissues (i.e., the tonsils) is associated with an increased
likelihood of rheumatic fever. Acute rheumatic fever can result in permanent damage to the heart
valves. Less than 1% of sporadic streptococcal pharyngitis infections result in acute rheumatic fever;
however, recurrences are common, and life-long antibiotic prophylaxis is recommended following a
single case.
The occurrence of cross-reactive antigens in S. pyogenes and heart tissues possibly explains the
autoimmune responses that develop following some infections. The antibody mediated immune (AMI)
response (i.e., level of serum antibody) is higher in patients with rheumatic fever than in patients with
uncomplicated pharyngitis. In addition, cell-mediated immunity (CMI) seems to play a role in the
pathology of acute rheumatic fever.

Acute glomerulonephritis results from deposition of antigen-antibody-complement complexes on the

basement membrane of kidney glomeruli. The antigen may be streptococcal in origin or it may be a host
tissue species with antigenic determinants similar to those of streptococcal antigen (cross-reactive
epitopes for endocardium, sarcolemma, vascular smooth muscle). The incidence of acute
glomerulonephritis in the United States is variable, perhaps due to cycling of nephritogenic strains, but it
appears to be decreasing. Recurrences are uncommon, and prophylaxis following an initial attack is
unnecessary.

Host defenses

S. pyogenes is usually an exogenous secondary invader, following viral disease or disturbances in the
normal bacterial flora. In the normal human the skin is an effective barrier against invasive streptococci,
and nonspecific defense mechanisms prevent the bacteria from penetrating beyond the superficial
epithelium of the upper respiratory tract. These mechanisms include mucociliary movement, coughing,
sneezing and epiglottal reflexes.

The host phagocytic system is a second line of defense against streptococcal invasion. Organisms can be
opsonized by activation of the classical or alternate complement pathway and by anti-streptococcal
antibodies in the serum. S. pyogenes is rapidly killed following phagocytosis enhanced by specific
antibody. The bacteria do not produce catalase or significant amounts of superoxide dismutase to
inactivate the oxygen metabolites (hydrogen peroxide, superoxide) produced by the oxygen-dependent
mechanisms of the phagocyte. Therefore, they are quickly killed after engulfment by phagocytes. The
streptococcal defense must be one to stay out of phagocytes.

In immune individuals, IgG antibodies reactive with M protein promote phagocytosis which results in
killing of the organism. This is the major mechanism by which AMI is able to terminate Group A
streptococcal infections.M protein vaccines are a major candidate for use against rheumatic fever, but
certain M protein types cross-react antigenically with the heart and themselves may be responsible for
rheumatic carditis. This risk of autoimmunity has prevented the use of Group A streptococcal vaccines.
However, since the cross-reactive epitopes of the M-protein are now known, it appears that limited
anti-streptococcal vaccines are on the horizon.
FIGURE 4. Phagocytosis of Streptococcus pyogenes by a macrophage.CELLS alive!

The hyaluronic acid capsule allows the organism to evade opsonization. The capsule is also an antigenic
disguise that hides bacterial antigens and is non antigenic to the host. Actually, the hyaluronic acid outer
surface of S. pyogenesis weakly antigenic, but it does not result in stimulation of protective immunity.
The only protective immunity that results from infection by Group A streptococcus comes from the
development of type-specific antibody to the M protein of the fimbriae, which protrude from the cell
wall through the capsular structure. This antibody, which follows respiratory and skin infections, is
persistent. Presumably, protective levels of specific IgA is produced in the respiratory secretions while
protective levels of IgG are formed in the serum. Sometimes, intervention of an infection with effective
antibiotic treatment precludes the development of this persistent antibody. This accounts, in part, for
recurring infections in an individual by the same streptococcal strain. Antibody to the erythrogenic toxin
involved in scarlet fever is also long lasting.

Treatment and prevention

Penicillin is still uniformly effective in treatment of Group A streptococcal disease. It is important to

identify and treat Group A streptococcal infections in order to prevent sequelae. No effective vaccine
has been produced, but specific M-protein vaccines are being tested.

Table 1. Summary of virulence determinants of Streptococcus pyogenes

Adherence (colonization) surface macromolecules

M protein

Lipoteichoic acid (LTA)

Protein F and Sfb (fibronectin-binding proteins)

Enhancement of spread in tissues

Hyaluronidase hydrolyses hyaluronic acid, part of the ground substance in host tissues.

Proteases

Streptokinase lyses fibrin

Evasion of phagocytosis
Capsule: hyaluronic acid is produced.

C5a peptidase: C5a enhances chemotaxis of phagocytes .

M protein is a fibrillar surface protein. Its distal end bears a negative charge that interferes with
phagocytosis. It also blocks complement deposition on the cell surface. Mutations during the course of
infection alter the structure of M proteins, rendering some antibodies ineffective. Strains that persist in
carriers frequently exhibit altered M proteins.

Leukocidins, including streptolysin S and streptolysin O, are proteins secreted by the streptococci to kill
phagocytes (and probably to release nutrients for their growth)

Defense against host immune responses

Antigenic disguise and tolerance provided by hyaluronic acid capsule

Antigenic variation. Antibody against M protein (antigen) is the only effective protective antibody, but
there are more than 50 different M types, and subsequent infections may occur with a different M
serotype.

Production of toxins and other systemic effects

Toxic shock: Exotoxin is superantigen that binds directly to MHC II (without being processed) and binds
abnormally to the T cell receptor of many (up to 20% of) T cells. Exaggerated production of cytokines
causes the signs of shock: fever, rash, low blood pressure. aberrant interaction between toxin,
macrophage, and T cells.

Induction of circulating, cross-reactive antibodies

Some of the antibodies produced during infection by certain strains of streptococci cross-react with
certain host tissues. These antibodies can indirectly damage host tissues, even after the organisms have
been cleared, and cause autoimmune complications.

Table 2. Summary of diseases caused by Streptococcus pyogenes

Suppurative conditions (active infections associated with pus) occur in the throat, skin, and
systemically.

Throat
Streptococcal pharyngitis is acquired by inhaling aerosols emitted by infected individuals. The symptoms
reflect the inflammatory events at the site of infection. A few (1-3%) people develop rheumatic fever
weeks after the infection has cleared.

Skin
Impetigo involves the infection of epidermal layers of skin. Pre-pubertal children are the most
susceptible. Cellulitis occurs when the infection spreads subcutaneous tissues. Erysipelas is the infection
of the dermis. About 5% of patients will develop more disseminated disease. Necrotizing fasciitis
involves infection of the fascia and may proceed rapidly to underlying muscle.

Systemic
Scarlet fever is caused by production of erythrogenic toxin by a few strains of the organism.

Toxic shock is caused by a few strains that produce a toxic shock-like toxin.

Non-suppurative Sequelae
Some of the antibodies produced during the above infections cross-react with certain host tissues.
These can indirectly damage host tissues, even after the organisms have beencleared, and cause non
suppurative complications.

Rheumatic fever. M protein cross reacts with sarcolemma. Antibodies cross-react with heart tissue, fix
complement, and cause damage.

Glomerulonephritis. Antigen-antibody complexes may be deposited in kidney, fix complement, and

damage glomeruli. Only a few M-types are nephritogenic.

http://textbookofbacteriology.net/streptococcus.html
ABSTRACT

Streptococcus pyogenes can cause a variety of diseases in immunocompetent individuals, from

pharyngotonsillitis to life-threatening invasive diseases, such as streptococcal toxic shock syndrome, and
rapidly progressing deep-tissue infections, such as necrotizing fasciitis. Necrotizing fasciitis is often seen
in combination with streptococcal toxic shock syndrome, which further increases morbidity and
mortality. We review here the hostpathogen interactions in the tissue milieu and discuss the use of
intravenous immunoglobulin as potential adjunctive therapy in these life-threatening infections.

Since the late 1980s, a resurgence of severe invasive infections due toStreptococcus pyogenes (also
known as group A streptococci) has been reported world wide [1, 2]. The 2 most severe invasive
manifestations are streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis, both of which are
associated with high morbidity and mortality (Figure 1). A prospective population-based surveillance for
invasive S. pyogenesinfections in Ontario, Canada, during 1991–1995 identified 323 patients,
corresponding to an annual incidence of 1.4 cases per 100,000 population [3]. The most common clinical
presentations were soft-tissue infection (48% of cases), bacteremia with no septic focus (14%), and
pneumonia (11%). Necrotizing fasciitis occurred in 6% of patients, and STSS occurred in 13%. The
mortality rate was 15% overall and was 81% among those with STSS (P < .001). Seventy-seven patients
met clinical and/or histopathological criteria for necrotizing fasciitis; of these patients, 47% (36) also
presented with STSS [4]. Among these patients, the overall case fatality rate was 34% (26 of 77); patients
who met the criteria for STSS had a mortality of 67% (24 of 36), compared with 4.9% (2 of 41) among
those who did not have STSS.

Figure 1

Patients with group A streptococcal toxic shock syndrome and necrotizing fasciitis. A, An 85-year-old
woman admitted to the hospital with a 2-day history of diarrhea, confusion, and the rapid onset of
swelling, pain, and discoloration of the right arm. There was a history of blunt trauma to the arm 1 day
before the onset of the patient's symptoms. The patient had type II diabetes. B, A 38-year-old man 12 h
after admission from the emergency department, where he had presented with a complaint of left-sided
chest pain thought to be possibly due to a pulmonary embolism. The patient's history was unremarkable
except for an uncomplicated laceration of the patient's left second finger 6 days before admission while
lacing up his son's skates. During the subsequent 6 days, the patient developed worsening symptoms of
fever, malaise, and left-sided chest and arm pain.
S. Pyogenes: Colonization to Rapidly Progressive Soft-Tissue Infections

The throat and skin of the human host are the principal reservoirs for S. pyogenes. The M proteins of
group A streptococci form elongated structures on the bacterial surface and provide the basis of widely
used epidemiological typing schemes that employ serological methods (M type) or nucleotide sequence
analysis of the M protein gene (emm type). Although >150 distinct emm and emm-like genes are now
recognized, their evolutionary history can be traced to 4 major phylogenetic lineages, designated as
subfamilies [5, 6]. The content and relative chromosomal arrangements of the 4 emm subfamily genes
are found to exist in only 5 basic patterns, A-E. The emm pattern A-C isolates are found to be
disproportionately associated with the nasopharynx, whereas emm pattern D strains are most often
isolated from skin and impetigo lesions [7]. Organisms of a third pattern group, emm pattern E, are
found at both tissue sites.

Epidemiologic studies have revealed that certain disease manifestations are commonly associated with
particular M types, such as M1 and M3 types, which are associated with the severe invasive
manifestations STSS and necrotizing fasciitis [1, 2]. Although studies have shown that this tissue
preference or disease manifestation may be linked to particular pathogenic traits of the strains, the
associations are far from exclusive, which likely reflects the fact that the outcome of infection depends
not only on bacterial factors but also on host factors [8].

It is noteworthy that a substantial number of invasive streptococcal infections have no known portal of
entry [9, 10]. Transient bacteremia originating from the oropharynx has been suggested as the source in
such cases. S. pyogenes cause a variety of skin and soft-tissue infections, including frequent and less
complicated manifestations of impetigo, erysipelas, and mild cellulitis and rare but life-threatening
infections of deep tissue or muscle (eg, necrotizing fasciitis and myositis). Several studies have reported
that patients with necrotizing fasciitis and myositis often have a history of recent blunt trauma [4, 10]. A
casecontrol study confirmed that patients with necrotizing fasciitis were 6 times more likely than control
subjects to have had a recent blunt trauma [11]. A potential mechanism underlying the association of
blunt trauma and severe streptococcal tissue infection was provided by Bryant et al [12], who reported
that skeletal muscle injury resulted in increased cellular vimentin expression, which enhanced binding
of S. pyogenes to skeletal muscle cells.

Massive Bacterial Load and Intracellular Persistence at the Infected Tissue Site

S. pyogenes is readily cultured from tissue samples from patients with necrotizing fasciitis, myositis, or
severe cellulitis, in contrast to erysipelas biopsy specimens, from which streptococci only rarely can be
cultured [13]. A similar association between severity of tissue infection and bacterial load was
demonstrated by Thulin et al [14], who analyzed snap-frozen tissue biopsy specimens collected from
patients with necrotizing fasciitis or severe cellulitis caused by S. pyogenes of varying serotypes. Bacteria
were detected in all biopsy specimens, even those collected from distal areas, and the bacterial load was
positively correlated to severity of tissue infection. Strikingly, biopsy specimens obtained as late as 20
days after diagnosis of infection and initiation of intravenous antibiotics still contained bacteria [14].
Bacterial viability assessment confirmed the presence of viable bacteria in the biopsy specimens, despite
the fact that the patients had been receiving intravenous antibiotics, many of them for a prolonged
time. The bacteria were tested and were found to be susceptible to the antibiotics used (in most cases,
penicillin and clindamycin). S. pyogenes remain exclusively susceptible to β-lactam agents, but in severe
invasive infections, a combination therapy with clindamycin is recommended, because the efficacy of
clindamycin is unaffected by bacterial growth phase and also has inhibitory actions on protein synthesis,
including the important superantigens [15]. The streptococcal tissue infections are commonly associated
with poor tissue perfusion as a result of microvascular thrombosis [16], and it has been questioned
whether the antibiotic concentration at the tissue site is sufficient. Culture of a tissue biopsy on a blood
agar plate revealed a clear inhibitory zone around the biopsy specimen, and bacteria only grew at a
distance from the biopsy specimen (Figure 2A) [14]. Hence, the biopsy contained toxic substances, which
were likely antibiotics and/or other bacteriostatic substances, such as host antimicrobial peptides
(discussed below in Host Antimicrobial Peptides and Bacterial Counter Strategies). However, despite the
presence of these toxic substances within the biopsy specimen, the bacteria still resisted killing.

Figure 2

Persistence of Streptococcus pyogenes during severe infections. A, Blood agar culture of a tissue biopsy
specimen obtained on day 7 after onset of necrotizing fasciitis caused by S. pyogenes. The arrow
indicates the inhibitory zone where the tissue biopsy specimen was initially placed. B, Viable S.
pyogenes intracellularly (green)within a human macrophage (cellular nuclei is shown in red).

Subsequent studies provided an explanation to this persistence, because viable S. pyogenes was found
intracellularly in host cells at the local site of tissue infection during the acute phase of infection (Figure
2B) [14]. The ability of S. pyogenes to invade and persist in human cells has previously been reported in
epithelial cells [17, 18] and in neutrophils [19, 20]. In the tissue biopsy specimens, the main host cells
were phagocytic cells and were predominantly macrophages [14]. In vitro cultures confirmed that S.
pyogenes could survive intracellularly in macrophages for an extended period of time, and once the
antibiotic was removed, a striking extracellular bacterial growth could be observed [14]. Antibiotic
eradication failure as the result of an intracellular streptococcal reservoir has previously been reported
for recurrent tonsillitis cases [21, 22]. The results emphasize that alternate approaches to antimicrobial
therapy may be required to improve the morbidity and mortality associated with severeS.
pyogenes soft-tissue infections.
Streptococcal Factors Present at the Infected Tissue Site: The Streptococcal Cysteine Protease

S. pyogenes express an array of virulence factors that are crucial for adherence, colonization,
dissemination of infection, and immune evasion [23, 24]. The expression and function of many virulence
factors may differ depending on the site of infection and the infection stages. One such factor is the
cysteine protease SpeB, which is highly expressed at the tissue site of infection in patients with
necrotizing fasciitis [14, 25], whereas it is downregulated in blood [26]. SpeB has been recognized as a
critical factor in promoting tissue site of infection at the skin [27], and genetic inactivation results in
significantly reduced skin and soft-tissue injury in experimental models [28, 29]. There is also
epidemiologic data linking a single nucleotide mutation in the mtsR gene with a decreased prevalence of
necrotizing fasciitis cases [30]. A subsequent study proposed that this is likely attributable to a
dysregulated multiple gene virulence axis, which in turn leads to reduced enzymatic activity of SpeB and,
thus, attenuated virulence at the tissue site [31]. SpeB is a protease with numerous substrates, including
many physiologically important human proteins, as well as its own virulence factors [32]. It was
proposed that SpeB-mediated degradation of virulence factors and host proteins, such as extracellular
matrix proteins, LL-37, and immunoglobulins, are required during the initial stages of infection, whereas,
at later points and during systemic infection, down-regulation of SpeB occurs to ensure that the bacteria
are equipped with the essential virulence factors required to survive in a hostile hyperinflammatory
environment [26, 33]. Another way of regulating the proteolytic activity of SpeB is to retain human
proteinase inhibitors, in particular α2-macroglobulin, at the bacterial surface through binding to the
streptococcal surface protein G—related α2-M-binding protein (GRAB) [34]. Once secreted, SpeB
becomes trapped in the GRAB/a2-macroglobulin cage, where it remains proteolytically active only
against factors small enough to penetrate the cage [35]. Patient tissue biopsy data support that this
regulation occurs in vivo and contributes to bacterial resistance towards antimicrobial peptides,
discussed below [25].

Superantigens and Inflammatory Responses in the Tissue

Similar to the link between proinflammatory cytokine responses in circulation and the severity of
invasive streptococcal infections [8, 36], a significant correlation between in vivo inflammatory
responses at the infected tissue site and the severity of streptococcal tissue infection was demonstrated
[37]. Increasing levels of interleukin (IL) 1 and significantly higher frequencies of Th1 cytokines (eg,
tumor necrosis factor [TNF] β- and interferon [IFN] γ—producing cells) were associated with more-
severe tissue infection. Detection of streptococcal superantigens in these tissue biopsy specimens,
together with a typical superantigen cytokine response, provided strong support for the direct action of
superantigens at the tissue site [37]. The high prevalence of TNF-β- or IFN-γ—producing cells in the
tissue was an interesting finding, because several studies have failed to detect significant numbers of
these cells in the peripheral circulation of patients with invasive S. pyogenes infection [37–39].
Assessment of homing receptor expression on cells in patient tissue biopsy specimens revealed a strong
correlation between the magnitude of Th1 cytokines and certain homing receptors, in particular CCR5,
CD44, and cutaneous lymphocyte antigen [37]. Taken together with previous reports on superantigens
and these particular homing receptors [40–44], this suggested that superantigen-mediated activation of
peripheral T cells may induce up-regulation of skin-homing receptors and thereby promote the
migration of activated T cells to the skin and, subsequently, exacerbated inflammation at the local site of
infection.

Neutrophils at the Tissue Site of Infection

Infiltration of polymorphonuclear cells in superficial fascia and dermis was one of the histopathological
criteria for diagnosis of necrotizing fasciitis proposed in 1984 by Stamenkovic and Lew [45]. This was also
evident in the patient tissue material described above, in which neutrophils represented one of the
dominant cell populations and the degree of infiltration correlated significantly with bacterial load [14].
However, there have also been several elegant studies that describe a paucity of neutrophil influx at the
tissue site of streptococcal infection resulting from degradation of IL-8 by a streptococcal trypsinlike
protease, SpyCEP/ScpC [46–48]. The reports also demonstrated a dramatic effect of SpyCEP/ScpC,
because proteasedeficient strains were attenuated in virulence when tested inmurine experimental
models. The fact that heavy infiltration is detected in patient biopsy specimens suggests that the murine
models fail to mimic the complexity of the clinical setting, in which there is a plethora of chemotactic
signals that may mask an effect of SpyCEP/ScpC.

In fact, the concept of neutrophil activation and degranulation as important contributors to disease
pathology in invasive group A streptococcal infections has recently been emphasized [49–52]. The
classical streptococcal virulence factor M-protein has been implicated as a major trigger of these
responses through its ability to form complexes with fibrinogen [49]. The complexes bind to β2-integrins
on the neutrophil surface, resulting in activation and release of massive amounts of the granule protein,
which is directly responsible for induction of vascular leakage and acute lung damage [49, 51, 52].
Soluble M1-protein and M1-protein/fibrinogen complexes have been demonstrated in patient biopsy
specimens, which underline the potential pathophysiological significance of these complexes generated
during infection [49, 51]. This is further substantiated by the presence of neutrophil proteins at the
infected tissue site, including heparin-binding protein, IL-8, resistin, and LL-37, all of which are likely to
contribute to the hyperinflammatory state that characterizes these infections [25, 49–52].

Host Antimicrobial Peptides and Bacterial Counter Strategies

Other important host factors are the antimicrobial peptides that are essential components of the first
line of defence against pathogens [53]. The cathelicidin LL-37 was shown to provide protection against
murine necrotic skin infections caused by S. pyogenes [54]. However, several pathogenic bacteria
secrete factors that can degrade and inactivate antimicrobial peptides, such as the streptococcal
cysteine protease SpeB [35, 55], and the streptococcal inhibitor of complement [56].
Analyses of patient tissue biopsy specimens revealed that the active LL-37 peptide was present in all
infected biopsy specimens, and its expression was positively correlated with bacterial load [25].
Although an up-regulation of LL-37 is expected in response to streptococcal infection [54,57], such a
positive correlation to bacterial load, together with the fact that there are viable bacteria in the tissue
during a prolonged time, strongly implied that LL-37 in the infected tissue did not efficiently contribute
to bacterial killing. Further studies revealed that this lack of antimicrobial activity was likely attributable
to SpeB inactivation of LL-37 at the bacterial surface [25], according to the model proposed by Nyberg et
al [35]. In this model, SpeB is entrapped by the a2-macroglobulin-GRAB complex, thereby achieving an
accumulation of SpeB around the bacteria, where the biological significance of an inactivation of LL-37
will be the greatest.

It is becoming increasingly evident that many of the antimicrobial peptides act not only as antimicrobial
agents, but also as significant mediators of other biological effects, including immunomodulatory and
chemotactic activities [53]. Considering the hyperinflammatory state of these severe tissue infections,
such effects would likely exacerbate the pathological responses and worsen the disease progression. In
addition, a potential effect on bacterial virulence was suggested by Gryllos et al [58], who reported that
subinhibitory concentrations of LL-37 resulted in enhanced expression of several streptococcal virulence
factors, including capsule, SpyCEP/ScpC, and IdeS.

Intravenous Polyspecific Immunoglobulin (IVIG) as Adjunctive Therapy for Severe S.

Pyogenes Infection

The finding that lack of protective antibodies against streptococcal M-protein and superantigens
correlated with risk to develop invasive streptocococcal diseases [59–61] highlighted the importance of
antibodies in protection against these infections and suggested that IVIG might be a potential adjunctive
therapy. IVIG exhibits high polyspecificity generated by antibodies pooled from several thousands of
donors and has been shown to contain broad-spectrum antibodies against streptococcal superantigens
and M-proteins [62–65]. In addition, IVIG has a general anti-inflammatory effect that is attributable, in
large part, to Fc-receptor mediated mechanisms [66, 67].

The documentation of clinical efficacy of IVIG in STSS includes several case reports, as well as 2
observational cohort studies, 1 case-control study, and 1 multicenter placebo-controlled trial [68]. The
case-control study was designed to evaluate the efficacy of IVIG therapy in patients with STSS and
included 21 case patients that were treated with IVIG during 1994–1995 and 32 nontreated control
subjects identified through active surveillance of invasive S. pyogenes infections during 1992–1995 [69].
Multivariate analysis revealed that IVIG therapy and a lower acute physiology and chronic health
evaluation (APACHE) II score was significantly associated with survival. Although the results of this study
demonstrated a significant benefit of IVIG, the study had 2 confounding factors—the use of historical
control subjects and differences in antibiotic therapy—that could potentially affect the mortality rate.
To further document the safety and efficacy of this adjunctive therapy, a multicenter placebo-controlled
trial of IVIG in STSS was initiated in Europe [70]. The trial was prematurely terminated because of a low
incidence of disease in the participating countries and, consequently, a slow patient recruitment. Results
were obtained from 21 enrolled patients (10 IVIG recipients and 11 placebo recipients). The primary end
point was mortality at 28 days, and a 3.6-fold higher mortality rate was found in the placebo group. This
trend to improved survival was strengthened by the significant improvement in organ function revealed
by the reduction in the sepsis-related organ failure assessment score after treatment, which was evident
in the IVIG group but not in the placebo group. Furthermore, a significant increase in plasma-
neutralizing activity against superantigens expressed by autologous isolates was noted in the IVIG group
after treatment.

In an observational case study involving patients with severe S. pyogenessoft-tissue infections [71], the
use of an aggressive medical regimen that included high-dose IVIG together with a conservative surgical
approach was studied. The report describes 7 patients with severe soft-tissue infection caused by S.
pyogenes who did not undergo surgery or for whom only limited exploration was performed. Six of the
patients had STSS, and they all received effective antimicrobial therapy and high-dose IVIG. Impressively,
all patients survived. One of the main mechanisms of action of IVIG in STSS is neutralization of bacterial
virulence factors, in particular superantigens, as well as a general anti-inflammatory effect. Tissue biopsy
specimens collected from the same surgical site at different time points after IVIG administration were
available from 1 patient. Analyses of bacterial load, superantigens, and inflammatory cytokines in the
biopsy specimens revealed dramatic improvement in all markers at the later time point (Figure 3). This
observational study, although limited in numbers, suggests that an initial conservative surgical approach
combined with the use of immune modulators, such as IVIG, may reduce the morbidity associated with
extensive surgical exploration in hemodynamically unstable patients without increasing mortality.

Figure 3

Bacterial factors and inflammatory responses in same site tissue biopsy specimens after administration
of intravenous immunoglobulin (IVIG). Photographs illustrate the extent of tissue infection at hospital
admission and after 66 h in a patient with necrotizing fasciitis. Tissue biopsy specimens taken from the
same surgical site at 18 and 66 h, respectively, after IVIG therapy were immunostained for specific
factors as indicated in the figure. The stains were quantified by acquired computerized image analysis,
and image analysis data are indicated in each image. ctr, control; IFN, interferon; IL, interleukin; S.
pyogenes, Streptococcus pyogenes. Used with permission from Norrby-Teglund et al [71].
CONCLUSIONS

S. pyogenes is an important human pathogen by virtue of its many immunomodulatory properties.

Analyses of host-microbe interactions at the tissue site of infection have provided in vivo evidence for
many of the immune evasion strategies previously described in vitro (Figure 4). The studies have
revealed that severe soft-tissue infections are characterized by massive bacterial load; the presence of
important streptococcal virulence factors, including soluble M1-protein, the cysteine protease SpeB, and
superantigens; DNAses; and heavy infiltration of inflammatory cells and inflammatory mediators.
Important bacterial resistance mechanisms at the tissue site include exploitation of human phagocytic
cells as host cells, thereby allowing persistence intracellularly, as well as protection against antimicrobial
peptides by SpeB retained at the bacterial surface through GRAB-α2-macroglobulin complexes. It is clear
that the pathogenesis of severe streptococcal tissue infections is multifactorial in nature. This
complexity is important to consider in the design of novel therapeutic strategies, in which IVIG
represents an immunomodulatory therapy that should be evaluated further.

Figure 4

Host-microbe interactions at the tissue site of infection during severe deep-tissue infections caused
byStreptococcus pyogenes. S. pyogenes have evolved several immune evasion mechanisms that
contribute to the massive bacterial persistence that characterizes deep-tissue infections. Such
mechanisms include (1) proteolytic degradation of host immune effector molecules, including LL-37 and
immunoglobulins; (2) intracellular persistence within phagocytic cells; (3) protection against
antimicrobial peptides by SpeB entrapped in protein G—related α2-M-binding protein (GRAB)/α2-
macroglobulin (α2m) complexes on the bacterial surface; and (4) degradation of neutrophil extracellular
traps (NETs) by bacterial DNases. Dissemination of infection and tissue injury are contributed by
proteolytic events, such as SpeB-mediated degradation of extracellular matrix (ECM) proteins, as well as
induction of excessive inflammatory responses mediated largely by superantigens (Sag) and soluble M1
protein (sM1) that activate T cells, antigen presenting cells (APC), and neutrophils. This activation results
in release of heparin-binding protein (HBP), an inducer of vascular leakage and shock, as well as release
of pathologic levels of proinflammatory cytokines. IL, interleukin.

http://cid.oxfordjournals.org/content/51/1/58.full
Streptococcus pyogenes, other Streptococci, and Enterococcus

Clinical Manifestations

Acute Streptococcus pyogenes infections may take the form of pharyngitis, scarlet fever (rash), impetigo,
cellulitis, or erysipelas. Invasive infections can result in necrotizing fasciitis, myositis and streptococcal
toxic shock syndrome. Patients may also develop immune-mediated sequelae such as acute rheumatic
fever and acute glomerulonephritis. S agalactiae may cause meningitis, neonatal sepsis, and pneumonia
in neonates; adults may experience vaginitis, puerperal fever, urinary tract infection, skin infection, and
endocarditis. Viridans streptococci can cause endocarditis, and Enterococcus is associated with urinary
tract and biliary tract infections. Anaerobic streptococci participate in mixed infections of the abdomen,
pelvis, brain, and lungs.

Structure

Streptococci are Gram-positive, nonmotile, nonsporeforming, catalase-negative cocci that occur in pairs
or chains. Older cultures may lose their Gram-positive character. Most streptococci are facultative
anaerobes, and some are obligate (strict) anaerobes. Most require enriched media (blood agar). Group A
streptococci have a hyaluronic acid capsule.

Classification and Antigenic Types

Streptococci are classified on the basis of colony morphology, hemolysis, biochemical reactions, and
(most definitively) serologic specificity. They are divided into three groups by the type of hemolysis on
blood agar: β-hemolytic (clear, complete lysis of red cells), α hemolytic (incomplete, green hemolysis),
and γ hemolytic (no hemolysis). Serologic grouping is based on antigenic differences in cell wall
carbohydrates (groups A to V), in cell wall pili-associated protein, and in the polysaccharide capsule in
group B streptococci.

Pathogenesis

Streptococci are members of the normal flora. Virulence factors of group A streptococci include (1) M
protein and lipoteichoic acid for attachment; (2) a hyaluronic acid capsule that inhibits phagocytosis; (3)
other extracellular products, such as pyrogenic (erythrogenic) toxin, which causes the rash of scarlet
fever; and (4) streptokinase, streptodornase (DNase B), and streptolysins. Some strains are
nephritogenic. Immune-mediated sequelae do not reflect dissemination of bacteria. Nongroup A strains
have no defined virulence factors.

Host Defenses

Antibody to M protein gives type-specific immunity to group A streptococci. Antibody to erythrogenic

toxin prevents the rash of scarlet fever. Immune mechanisms are important in the pathogenesis of acute
rheumatic fever. Maternal IgG protects the neonate against group B streptococci.

Epidemiology
Group A β-hemolytic streptococci are spread by respiratory secretions and fomites. The incidence of
both respiratory and skin infections peaks in childhood. Infection can be transmitted by asymptomatic
carriers. Acute rheumatic fever was previously common among the poor; susceptibility may be partly
genetic. Group B streptococci are common in the normal vaginal flora and occasionally cause invasive
neonatal infection.

Diagnosis

Diagnosis is based on cultures from clinical specimens. Serologic methods can detect group A or B
antigen; definitive antigen identification is by the precipitin test. Bacitracin sensitivity presumptively
differentiates group A from other β-hemolytic streptococci (B, C, G); group B streptococci typically show
hippurate hydrolysis; group D is differentiated from other viridans streptococci by bile solubility and
optochin sensitivity. Acute glomerulonephritis and acute rheumatic fever are identified by anti-
streptococcal antibody titers. In addition, acute rheumatic fever is diagnosed by clinical criteria.

Control

Prompt penicillin treatment of streptococcal pharyngitis reduces the antigenic stimulus and therefore
prevents glomerulonephritis and acute rheumatic fever. Vancomycin resistance among the enterococci
is an emerging microbial threat. Vaccines are under development.

http://www.ncbi.nlm.nih.gov/books/NBK7611/
SECTION I - INFECTIOUS AGENT

Name: Streptococcus pyogenes

Synonym or cross reference: Group A (β-hemolytic) streptocci (GAS), streptococcal sore throat, strep
throat, pharyngitis, scarlet fever, impetigo, erysipelas, puerperal fever, necrotizing fasciitis, toxic shock
syndrome, septicaemia, acute rheumatic fever, acute post-streptococcal glomerulonephritis, gas
gangrene

Characteristics: Streptococcus pyogenes is an aerobic, gram-positive extracellular bacterium (1, 2). It is

made up of non-motile, non-sporing cocci that are less then 2 µm in length and that form chains and
large colonies greater then 0.5 mm in size (3, 4). It has a β-hemolytic growth pattern on blood agar and
there are over 60 different strains of the bacterium (5, 6)

SECTION II – HAZARD IDENTIFICATION

Pathogenicity/toxicity: This bacterium is responsible for a wide array of infections(7, 8). It can cause
streptococcal sore throat which is characterized by fever, enlarged tonsils, tonsillar exudate, sensitive
cervical lymph nodes and malaise (6, 9). If untreated, strep throat can last 7-10 days (9). Scarlet fever (pink-
red rash and fever) as well as impetigo (infection of the superficial layers of skin) and pneumonia are
also caused by this bacterium (3, 6, 7, 10). Septicaemia, otitis media, mastitis, sepsis, cellulitis, erysipelas,
myositis, osteomyelitis, septic arthritis, meningitis, endocarditis, pericarditis, and neonatal infections are
all less common infections due to S. pyogenes (3, 6, 7). Streptococcal toxic shock syndrome, acute
rheumatic fever (joint inflammation, carditis and CNS complications), post-streptococcal
glomerulonephritis (inflammation, hematuriia, fever, edema, hypertension, urinary sediment
abnormalties and severe kidney pain) and necrotizing fasciitis (rapid and progressive infection of
subcutaneous tissue, massive systematic inflammation, hemorrhagic bullae, crepitus and tissue
destruction) are some of the more serious complications involving S. pyogenes infections (1, 6-8). There
are at least 517,000 deaths globally each year due to severe S. pyogenes infections and rheumatic fever
disease alone causes 233,000 deaths (8). 1,800 invasive S. pyogenes disease-related deaths are reported
in the USA yearly, necrotizing fasciitis kills about 30% of patients and streptococcal toxic shock
syndrome has a mortality rate of 30-70% (3, 11, 12).

Epidemiology: Different clinical manifestations of this bacterium are more common in different parts of
the world. Streptococccal pharyngitits is predominant in temperate areas and peaks in late winter and
early spring (5, 9). There are 616 million cases of pharyngitis caused by S. pyogenes world-wide each
year (5, 8). 15-20% of school-aged children hasS. pyogenes in its carrier form in their throats and are more
at risk of having the disease(5, 9). Impetigo is more common with children in warm humid climates and
there are 111 million reported cases world-wide each year (5). There are 115.6 million cases of rheumatic
heart disease yearly and at least 18.1 million cases of invasive infections, predominantly in older
populations (3, 8). Post-streptococcal glomerulonephritis is seasonal and is more common in children,
young adults and males (1). Crowding and poor hygiene increase the chance of an outbreak of GAS
infections (1).
Host range: S. pyogenes is an exclusively human pathogen (5, 7).

Infectious dose: Unknown.

Mode of transmission: Transmission via respiratory droplets, hand contact with nasal discharge and skin
contact with impetigo lesions are the most important modes of transmission (5, 9, 13). The pathogen can
be found in its carrier state in the anus, vagina, skin and pharynx and contact with these surfaces can
spread the infection (5, 14, 15) The bacterium can be spread to cattle and then back to humans through raw
milk as well as through contaminated food sources (salads, milk, eggs); however, cattle do not contract
the disease (16-18). Necrotizing fasciitis is usually because of contamination of skin lesions or wounds with
the infectious agent (12).

Incubation period: The incubation period is usually 1-3 days (9).

Communicability: If untreated, patients with streptococcal pharyngitis are infective during the acute
phase of the illness, usually 7-10 days, and for one week afterwards; however, if antibiotics are used, the
infective period is reduced to 24 hours (9). The bacterium can remain in the body in its carrier state
without causing illness in the host for weeks or months and is transmissible in this state (5).

SECTION III - DISSEMINATION

Reservoir: Humans are primary reservoir for this bacterium (5, 7), although cattle can also act as a
reservoir (16-18).

Zoonosis: Cows infected by humans are intermediate hosts and can pass the bacterium in their milk,
which, if consumed unpasteurized, can infect other humans (16).

Vectors: None.

SECTION IV – STABILITY AND VIABILITY

Drug susceptibility: S. pyogenes infections are susceptible to a variety of drugs: β-lactams such as
penicillin, as well as erythromycin, clindamycin, imipenem, rifampin, vanomycin, macrolides and
lincomycin; however, certain strains of the bacterium have been found to resistant to macrolides,
lincomycin, chloramphenicol, tetracyclines and cotrimoxazole (5, 7, 19, 20).

Susceptibility to disinfectants: This bacteria is susceptible to 1% sodium hypochlorite, 4% formaldehyde,

2% glutaraldehyde, 70% ethanol, 70% propanol, 2% peracetic acid, 3-6% hydrogen peroxide and 0,16%
iodine (2).

Physical inactivation: Bacteria are susceptible to moist heat (121 ºC for at least 15 minutes) and dry
heat (170 ºC for at least 1 hour) (21).

Survival outside host: The bacterium can survive on a dry surface for 3 days to 6.5 months (22). It has
been found to survive in ice cream (18 days), raw and pasteurized milk at 15-37 ºC (96 hrs), room
temperature butter (48 hrs), and neutralized butter (12-17 days) (17). GAS has been found to last several
days in cold salads at room temperature(18).

SECTION V – FIRST AID / MEDICAL

Surveillance: Monitor for symptoms. Confirm infection by bacteriological and serological testing, latex
bead agglutination, fluorescent antibody staining or ELISA (6).

Note: All diagnostic methods are not necessarily available in all countries.

First aid/treatment: Appropriate antibiotic treatment is necessary for a S. pyogenesinfection. Penicillin

is used for respiratory tract infections (pharyngitis) and macrolides or lincosamides are used if there are
allergies (5, 6). Clindamycin may be used in cases of necrotizing fasciitis and surgical debridement of the
affected area is necessary (2, 5).

Immunization: None (6).

Prophylaxis: Administering penicillin to carriers has been shown to reduce the number of people
infected during an outbreak of streptococcal sore throat (18).

SECTION VI - LABORATORY HAZARDS

Laboratory-acquired infections: 78 laboratory-acquired infections by streptococcal agents have been

reported as of 1983 (2).

Sources/specimens: Respiratory specimens, skin lesions, blood, sputum and wound exudates contain
the infectious agent (5, 13, 23).

Primary hazards: Inhalation of infectious aerosols and contamination of mucocutaneous lesions are the
primary hazards associated with working with this pathogen (1, 2, 10)

Special hazards: None

SECTION VII – EXPOSURE CONTROLS / PERSONAL PROTECTION

Risk group classification: Risk group 2 (24).

Containment requirements: Containment Level 2 facilities, equipment, and operational practices for
work involving infectious or potentially infectious material, animals, or cultures.

Protective clothing: Lab coat. Gloves when direct skin contact with infected materials or animals is
unavoidable. Eye protection must be used where there is a known or potential risk of exposure to
splashes (25).

Other precautions: All procedures that may produce aerosols, or involve high concentrations or large
volumes should be conducted in a biological safety cabinet (BSC)(25). The use of needles, syringes and
other sharp objects should be strictly limited. Additional precautions should be considered with work
involving animals or large scale activities (25).

SECTION VIII - HANDLING AND STORAGE

Spills: Allow aerosols to settle and, wearing protective clothing, gently cover spill with paper towels and
apply appropriate disinfectant, starting at the perimeter and working towards the centre. Allow
sufficient contact time before clean up (25).

Disposal: Decontaminate all wastes before disposal by incineration, chemical disinfection or steam
sterilization (25).

Storage: The infectious agent should be stored in a sealed and identified container (25).

http://www.phac-aspc.gc.ca/lab-bio/res/psds-ftss/strep-pyogenes-eng.php
GENERAL DESCRIPTION

Microbiology

Streptococcus pyogenes, or Group A streptococcus (GAS), is a facultative, Gram-positive coccus

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

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

Epidemiology

Group A β-hemolytic streptococcus (GABHS, Streptococcus pyogenes) is a common cause of a

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

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

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

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

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

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

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

Clinical Manifestations

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

Laboratory Diagnosis

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

Pathogenesis

Anti-Phagocytic Properties: M-protein contributes to invasiveness through its ability to impede

phagocytosis of streptococci by human polymorphonuclear leukocytes (PMNL) (52). Conversely, type
specific antibody against the M-protein enhances phagocytosis (52). Following infection with a particular
M-type, specific antibody confers resistance to challenge with viable GAS of that M-type (52). Recently,
Boyle has shown that GAS protease cleaves the terminal portion of the M-protein, rendering the
organism more susceptible to phagocytosis by normal serum but more resistant to phagocytosis in the
presence of type specific antibody (72). While M types 1 and 3 strains have accounted for the vast
majority of strains isolated from cases of StrepTSS, many other M types, including some non-typeable
strains, have also been isolated from such cases. M types 1 and 3 are also commonly isolated from
asymptomatic carriers, and patients with pharyngitis or mild scarlet fever (45,48).
Mechanisms of Fever Induction: Pyrogenic exotoxins induce fever in humans and animals and also
participate in shock by lowering the threshold to exogenous endotoxin (77). Streptococcal pyrogenic
exotoxin A (SPEA) and SPEB induce human mononuclear cells to synthesize not only tumor necrosis
factor- α (TNFα) (28) but also interleukin-1β (IL-1β) (38) and interleukin-6 (IL-6) (38,62,68) suggesting
that TNF could mediate the fever, shock and organ failure observed in patients with StrepTSS (87).
Pyrogenic exotoxin C has been associated with mild cases of scarlet fever in the United States (author's
observations) and in England (41). The roles of two newly described pyrogenic exotoxins, SSA (60) and
MF (67), in the pathogenesis of Strep TSS have not been elucidated.

Streptococcal Toxic Shock Syndrome

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

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

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

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

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

SUSCEPTIBILITY IN VITRO AND IN VIVO

Single Drug Susceptibility

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

Combination Drug Susceptibility

No in vitro susceptibility testing has been undertaken to investigate whether combinations of

antibiotic may exert an additive, synergistic or antagonistic effect against GAS.
Antimicrobial Therapy

GENERAL

Despite possible changes in virulence, group A streptococci have universally remained

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

Special Infections

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

A single injection of 1.2 million units of penicillin G benzathine given intramuscularly is as

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

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

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

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

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

Treatment failures in GAS pharyngitis are of major concern in the prevention of rheumatic
fever. Studies have reported failure rates as high as 30%, including studies of penicillin G given one time
intramuscularly (76). Noncompliance is thought to play a major role with oral treatments but does not
account for all failures, however, it is unlikely that bacteriologic failures in the treatment of GAS are due
solely to β-lactamase-flora colonizing a patient's pharynx (76).
 Some investigators have postulated that early treatment of GAS, within 48 h of symptoms,
impairs the patient=s immune response by altering the course of the illness. In fact, studies have shown
that delaying therapy for 3 to 5 days resulted in an increase in anti-streptolysin O antibodies but did not
affect development of type-specific antibodies (32). Antibodies such as anti-streptolysin O, unlike type-
specific antibodies, do not confer immunity on the host. At present, it is unclear if delaying therapy for 2
to 3 days in patients with GAS pharyngitis results in a significantly greater antibody rise. Since adequate
antimicrobial therapy prevents development of suppurative and non-suppurative complications of GAS,
most authors do not recommend delaying therapy.

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

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

In patients with recurring episodes of GAS pharyngitis or persistent, culture-positive, clinical

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

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

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

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

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

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

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

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

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

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

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

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

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

Vulvovaginitis: Group A streptococcus is a common cause of vulvovaginitis in the prepubertal female.

Symptoms include a serous vaginal discharge, erythema of the vulvar area, and intense pruritus.
Therapy consists of orally administered penicillin for 10 days. Patients allergic to penicillin can be treated
with erythromycin.

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

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

Group A Streptococcal Toxic Shock Syndrome (StrepTSS)

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

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

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

Bacteremia

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

Pneumonia

Pneumonia secondary to group A streptococcus is frequently associated with preceding or

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

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

Peritonsillar Cellulitis: Occasionally, peritonsillar cellulitis occurs without development of a localized

abscess. Like peritonsillar abscesses, peritonsillar cellulitis results from direct extension of an acute
tonsillopharyngitis and may result solely from group A streptococcus but can include mixed oral flora as
well. Patients with mild symptoms who can maintain adequate hydration can be treated orally with a
first or second generation cephalosporin such as cephalexin or cefazolin. Patients with a known allergy
to cephalosporins can be treated with clindamycin. Patients with severe trismus or inadequate
hydration can be treated parenterally with clindamycin or a first generation cephalosporin such as
cefazolin. Duration of therapy is generally 10 days. Tonsillectomy can ensure complete recovery and
prevent recurrences.

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

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

Uvulitis: Uvulitis can occur alone or in association with acute pharyngitis or epiglottitis (50). Long known
to be primarily a complication of H. influenzae type b infection, recent immunization strategies have
greatly decreased its incidence. However, uvulitis can occur secondary to group A streptococcus, usually
as a complication of an acute pharyngitis (50). Parenteral therapy should be used, directed against both
group A streptococcus and H. influenzae, i.e., cefuroxime. Patients can be discharged on an oral
antibiotic to complete a 10 day course of therapy.
Cervical Lymphadenitis: Cervical lymphadenitis secondary to group A streptococcus infection can result
from direct extension from an acute pharyngitis or direct inoculation. Since the etiologic agent is not
always known, therapy is initially directed against the most common organisms, which include S.
aureus and S. pyogenes. Therefore, a first generation cephalosporin, such as cephalexin, or a β-
lactamase-resistant penicillin should be given enterally for 10 days. If the infection persists or the
patient develops signs of systemic toxicity, parenteral antibiotics should generally be used. First
generation cephalosporins such as cefazolin, nafcillin, or clindamycin are also appropriate choices.

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

Arthritis: Post-streptococcal reactive arthritis (PSRA) is a recognized complication of group A

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

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

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

Osteomyelitis: Like septic arthritis, osteomyelitis secondary to group A streptococcal infection is

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

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

Non-Suppurative Complications

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

Primary prevention of ARF depends on accurate diagnosis of an antecedent streptococcal

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

Only one series of studies has ever documented prevention of ARF following antimicrobial
therapy for GAS pharyngitis. These studies were conducted during the 1940s on army recruits at Fort
Warren, Wyoming. Penicillin G suspended in oil, administered parenterally in a placebo-controlled
study, decreased the incidence of ARF (90). Following these studies, researchers compared orally
administered penicillin with parenterally administered penicillin and found equivalent bacteriologic
effects. It was then assumed that bacterial eradication from the pharynx was the necessary step in
prevention of ARF. As a result, penicillins as a class were assumed to be efficacious in preventing ARF.
This has never been studied. No study has investigated the efficacy of other antibiotics in prevention of
ARF.
 Patients who develop ARF require continuous prophylaxis to prevent intercurrent and recurrent
streptococcal infections and recurrent episodes of ARF. The preferred regimen consists of penicillin G
benzathine, 1.2 million units given intramuscularly every 4 weeks (17). The recurrence rate of ARF with
this regimen was reported to be 0.4 cases per 100 patient years of observation (8). Alternative therapies
include oral sulfadiazine (1 g/day for persons over 60 lb and 0.5 g/day for those weighing less than 60 lb)
or penicillin V (250 mg, twice a day). Both of these regimens are considered less effective than penicillin
G benzathine. This is thought to be due to lack of patient compliance with an oral regimen. Patients who
are allergic to penicillin can be treated with erythromycin stearate (250 mg, twice a day) (8).

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

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

Acute Glomerulonephritis: Unlike rheumatic fever, post-streptococcal acute glomerulonephritis (AGN)

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

Combination Therapy

In general, combination antimicrobial therapy offers no added benefit in the treatment of

known GAS infections. Antimicrobial agents possess sufficient activity in vitro to GAS and, when initiated
promptly, are effective in the treatment of such infections. However, in clinical situations in which GAS is
suspected but has not been identified (e.g., necrotizing fasciitis and TSS) antimicrobial therapy should be
initiated with combinations effective against all possible pathogens.

ADJUNCTIVE THERAPY

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

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

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

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

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

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

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

ENDPOINTS FOR MONITORING THERAPY

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

VACCINES

Development of an effective group A streptococcal vaccine continues to be of interest;

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

PREVENTION OR INFECTION CONTROL MEASURES

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

CONTROVERSIES, CAVEATS, OR COMMENTS

Group A streptococcus has the unique ability to cause both acute purulent infections and
nonpurulent complications that develop days after an initial infection. With a recognized increase in
incidence and severity of invasive group A streptococcal infections and changes in the epidemiology of
ARF, treatment of group A streptococcal infections has taken on even greater importance. While
penicillin remains the mainstay of treatment, its use has recently been brought into question. New
antibiotics and new strategies for treatment are being evaluated, and a vaccine effective against group A
streptococcus is being developed. Once thought to have been relegated to simple sore throats, group A
streptococcus has returned to the forefront of infectious diseases.
Table 1. In Vitro Susceptibilities of Streptococcus pyogenes to Common Antibiotics

MIC50 MIC90 Range

Antibiotic (μg/mL) (μg/mL) (μg/mL) Reference

Penicillin 0.006 0.012 0.003 - 0.024 13

Oxacillin 0.06 0.06 ≤0.03 - 0.25 64

Erythromycin 0.016 0.031 0.0078 - 8.0 13

Azithromycin 0.016 0.031 0.0078 - 4.0 13

Clarithromycin 0.0078 0.016 0.0039 - 4.0 13

Cephalothin 0.1 0.1 0.0125 - 0.2 13

Cefoxitin 1 1 1- 4 64

Cefixime 0.25 0.5 0.078 - 0.5 13

Cefuroxime ≤0.03 ≤0.03 ≤0.03 64

Cefotaxime ≤0.03 ≤0.03 ≤0.03 64

Ceftriaxone ≤0.03 ≤0.03 ≤0.03 - 0.125 64

Vancomycin 0.25 0.5 0.25 - 0.5 5, 64

Clindamycin 0.125 0.125 0.06 - 0.125 64

Rifampin 0.5 0.5 ≤0.03 - 0.5 64

Ciprofloxacin 0.256 0.5 0.016 - 2.0 13

Tetracycline 0.25 2 0.0039 - 8.0 13

Cotrimoxazole ≥64 ≥64 ≥64 64

Chloramphenicol 4 4 2-8 64

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