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Streptocococcus pyogenes
Donald E. Low | January 19th, 2019

OVERVIEW: What every clinician needs to know.

Pathogen name and classification.

Streptococcus pyogenes is a Gram-positive bacterium (Figure 1) that causes several diseases in

humans, including pharyngitis, skin infections, acute rheumatic fever, scarlet fever,
poststreptococcal glomerulonephritis, a toxic shock–like syndrome, and necrotizing fasciitis.

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Figure 1.

GAS is a Gram-positive that occurs in chains or in pairs of cells.

The naming and classification of streptococci is cumbersome and confusing. Streptococci can be
characterized in the laboratory by the type of hemolytic reaction displayed on the blood agar on
which they are grown; complete (β), incomplete (α), or no (γ) hemolysis. S. pyogenes causes β
hemolysis (Figure 2). Hemolytic streptococci from humans can be classified into Lancefield groups
A, B, C, F, G, and L on the basis of carbohydrate antigens of the cell wall. S. pyogenes contains the
Lancefield group A antigen on their cell surface and is therefore commonly referred to as group A
streptococci (GAS). The GAS cell surface M proteins contain antigenic targets of the major
serological typing scheme (Figure 3).

Figure 2.

Beta hemolysis.

Figure 3.

The coiled-coil dimeric nature of M protein and its relationship to the bacterial cell surface is
shown. The N-terminal region of the M protein, distal to the cell surface, varies among different M
types, thereby providing the molecular basis of Dr. Lancefield’s method of serotyping GAS. In
contrast, the C-terminal region of M protein, commencing at the pepsin susceptible site, is more
conserved.

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M typing

The GAS cell surface M proteins that form short hair-like fibrils of approximately 60nm, contain the
antigenic targets of the major serological typing scheme (
Figure 3). Determinants of serotype lie at the distal fibril tips (amino termini). Over the past decade,
serological typing has been largely replaced by nucleotide sequence typing, based on sequence
identity within the 5’ end of the emmgene encoding the type-specific determinants. To date, over
200 emmtypes have been identified.

What is the best treatment?

Penicillin still remains the treatment of choice for infections due to GAS. For mild to moderate
infections including pharyngitis and skin and soft tissue infections, oral penicillin V at a dose of
500mg two to three times a day for 10 days is recommended. A first-generation cephalosporin is
an acceptable alternative unless there is a history of immediate hypersensitivity to a β-lactam
antibiotic. Macrolides (erythromycin, clarithromycin and azithromycin) and lincosamides
(clindamycin) are commonly used first-line drugs against GAS infections in patients with beta-
lactam allergies.

Alternative antimicrobials for treatment include:

Fluoroquinolones: The most optimal fluoroquinolones are those with enhanced gram-positive
activity including levofloxacin and moxifloxacin. Levofloxacin or moxifloxacin parenterally or orally
at doses of 500mg and 400mg, respectively, once a day for 5 to 10 days depending on the severity
of illness. The prevalence of GAS clinical isolates with reduced susceptibility to fluoroquinolones
are less than 1% in North America, but as high as 10% in some parts of Europe. Reduced
susceptibility to fluoroquinolones is mediated by point mutations in the quinolone resistance
determining region of the parC gene, whereas high-level resistance has been associated with
mutations in the quinolone resistance determining region of both parC and gyrA genes.

Tetracyclines: Tetracycline can be administered orally or parenterally at doses of 250–500mg four

times a day, and doxycycline can be administered orally or parenterally at a dose of 100mg twice a
day, both for 5 to 10 days depending on the severity of illness. Organisms susceptible to
tetracycline can also be considered susceptible to doxycycline. In GAS, the prevalence of
resistance varies from 1 to 10% in North America and is typically conferred by ribosome protection
genes such astet(M) and tet(O). Since tetracycline resistance genes can reside on mobile genetic
elements that carry macrolide resistance genes, the co-occurrence of resistance to both classes
of drugs often occurs.

Linezolid: Linezolid can be administered orally or parenterally at doses of 600mg twice a day for 5
to 10 days depending on the severity of illness. Resistance rates are less than 1%.

Vancomycin: Vancomycin can be administered parenterally at a dose of 30mg/kg/day twice a day

until step down to another oral agent is clinically indicated.

Despite years of widespread use there is no evidence of resistance or even a decrease in

susceptibility to penicillin. A high prevalence of macrolide resistance among GAS has been
recognized in Europe and Asia for many years. Resistance rates to the macrolide antibiotics in
North America has been generally reported to be less than 10%, however there may be regional
variation where the prevalence of macrolide resistance might be higher or lower than the
national average. Resistance rates to clindamycin remain less than 1% .

The presence of resistance can be reliably detected by routine disk diffusion, microbroth dilution
or Etest. Susceptibility testing is not required for the beta-lactam antibiotics, since resistance has
not been reported. Testing of erythromycin predicts susceptibility or resistance to azithromycin
and clarithromycin. Testing for a phenotypic marker that might predict the development of
clindamycin resistance while on clindamycin therapy requires the use of a modified disk diffusion
test: the D-zone test (Figure 4).

Figure 4.

The D-zone test is performed by placing clindamycin (2 µg) and erythromycin disks (15 µg) at an
edge-to-edge distance of 15 to 26 mm and looking for flattening of the clindamycin zone nearest
the erythromycin disk. A positive D-zone test suggests the presence of an erm gene that could
result in constitutive clindamycin resistance and clinical failure.

Testing of tetracycline predicts susceptibility of doxycycline.

Treatment of group A streptococcal tonsillopharyngitis.

GAS tonsillopharyngitis is the most frequent and important cause of bacterial pharyngitis in
children and adults. The various treatment regimens have been primarily designed to prevent
acute rheumatic fever by eradicating GAS from the pharynx. As a result, duration of therapy should
extend beyond the resolution of the patients’ symptoms. In regions of the world where rheumatic
fever is rare or non-existent, the need for antimicrobial treatment is a moot point as this is, in most
cases, a self-limited disease with antimicrobials only shortening the signs and symptoms by less
than 24 hours.

The oral antibiotics of choice are penicillin V and amoxicillin for an entire 10-day period. The
Cochrane Database of Systematic Reviews has reviewed duration of therapy and different
antibiotic treatments for GAS pharyngitis. They concluded that three to six days of oral antibiotics
had comparable efficacy compared to the standard duration of 10-day oral penicillin in treating
children with acute GAS pharyngitis. However, they commented that in areas where the
prevalence of rheumatic heart disease is still high, these results must be interpreted with caution.
They found that the evidence was insufficient for clinically meaningful differences between
antibiotics for GAS tonsillopharyngitis. Limited evidence in adults suggested cephalosporins were
more effective than penicillin for relapse.

Based on these results and considering the low cost and absence of resistance, penicillin can still
be recommended as first choice. Still the best evidence for prevention of acute rheumatic fever is
benzathine penicillin 1.2 million units intramuscularly as a single dose, thereby obviating concerns
about patient adherence. Oral regimens are shown below in Table I.

Table I.

Antimicrobial Dose(mg) Frequency (times/day) Duration (days)

Penicillin V 500 Three 10 days

Amoxicillin 500 Twice 10 days

Amoxicillin 1,000 Once 10 days

Cephalexin 500 Twice 10 days

Clarithromycin 250 Twice 10 days

Azithromycin 500 Once 5 days

Clindamycin 300 Three 10 days

Mechanisms of resistance to the MLSB antibiotics

Resistance to the MLSB(M; macrolides including erythromycin, clarithromycin, and azithromycin:

Lincosamides including clindamycin: streptogramin B) antibiotics is predominantly mediated by
two distinct mechanisms; efflux and target site modification. The first, or ‘M-phenotype’, elicits low
level protection against erythromycin, clarithromycin and azithromycin, but not clindamycin, and is
mediated by a drug efflux pump, encoded by mefA.

The second mechanism is a result of target site modification and generally consists in post-
transcriptional methylation of an adenine residue in 23S rRNA caused byerm gene-encoded
methylases, and is associated with either constitutive (cMLS phenotype) or inducible (iMLS
phenotype) resistance to the macrolides and clindamycin antibiotics. While cMLS isolates are
rather homogeneous in susceptibility patterns and their methylase gene is normallyerm(B), iMLS
isolates are more heterogeneous and their methylase gene is either erm(B) or an erm(A) subclass,
commonly referred to as erm(TR). These resistance mechanisms elicit high-level resistance against
macrolides, lincosamides and streptogramin B, hence designated the MLSBphenotype. Resistance
due to iMLS is typically more common than the cMLS phenotype. Regional variations in the relative
prevalence of the two resistance mechanism have been observed. In North America, greater than
90% of the macrolide-resistant isolates express the M phenotype.

Induction of clindamycin resistance in erythromycin-resistant isolates of group A streptococci

The resistance phenotypes conferred by iMLS are characterized by dissociated resistance to

MLSBantibiotics because of differences in the inducing capacity of the antibiotics. The strains are
resistant to the macrolides, which are inducers. By contrast, clindamycin which is not an inducer,
remains active. Inducible clindamycin resistance can be detected by disk diffusion using the D-
zone test. The D-zone test is performed by placing clindamycin and erythromycin disks at an edge-
to-edge distance of 15 to 26mm and looking for flattening of the clindamycin zone nearest the
erythromycin disk. A positive D-zone test suggests the presence of an ermgene that could result in
constitutive clindamycin resistance and clinical failure (Figure 4).

Constitutive mutants can be selected in vitro at frequencies of 10-7colony forming units in the
presence of clindamycin. Bacterial inocula exceeding 10-7colony forming units can be found in
lower respiratory tract infections. The risk to patients is illustrated by reports of selection of
constitutive mutants during the course of clindamycin therapy administered to patients with
severe infections due to inducibly erythromycin-resistant S. aureus.

How do patients contract this infection, and how do I prevent spread to other patients?

Epidemiology

Pharyngitis and impetigo can be associated with crowding, which often is present in
socioeconomically disadvantaged populations. The close contact that occurs in schools, child care
centers, and military installations facilitates transmission. Pharyngitis usually results from contact
with a person who has GAS pharyngitis. Transmission of GAS infection, including in school
outbreaks of pharyngitis, almost always follows contact with respiratory tract secretions.
Foodborne outbreaks of pharyngitis have occurred, but are uncommon.

Infections due to GAS occur at all times of the year but there are important variations in the time of
occurrence of specific clinical syndromes. GAS pharyngitis and invasive infections are more
common during late autumn, winter, and spring in temperate climates, presumably because of
close person-to-person contact in schools and predisposing viral infections. For example both
influenza A and B can be complicated by GAS infection. On the other hand, impetigo is more
common in tropical climates and warm seasons, presumably because of antecedent insect bites
and other minor skin trauma.

Environmental factors that predispose to GAS infections are inadequate hygiene and
overcrowding. Most, but not all, populations with high pyoderma prevalence also have been found
to have high prevalence rates of scabies. Although children had the highest prevalence of
pyoderma and scabies, these diseases were also common in adults in many studies.

GAS is a human-specific pathogen that is highly prevalent throughout the world, but especially in
developing countries with poverty, overcrowding and inadequate hygiene practices.

Although the incidence of GAS infections is staying the same, the incidence of more severe GAS
infections has been noted to be increasing in developing countries since the 1980s.

Infection control issues

Hospital outbreaks have involved large numbers of patients and health care workers, and have
continued for as long as 3 years. The current Centers for Disease Control and Prevention
recommendations for preventing nosocomial outbreaks exist only for postpartum and postsurgical
settings. However, nonobstetric, nonsurgical infections have been found to contribute to many, if
not most, outbreaks and the case-fatality rate is higher in patients with these types of infections,
supporting the view that the potential for transmission should be recognized for all types of
hospital-acquired GAS infections, and case finding should not be limited to a single type of
infection or patient population.

GAS can be transmitted by direct or indirect contact and/or by droplets. Rarely, it can be
transmitted from the environment. In addition to standard precautions, droplet precautions are
recommended for persons with GAS pneumonia or severe soft tissue infections until 24 hours after
initiation of appropriate antimicrobial therapy. For burns with secondary GAS infection and
extensive or draining cutaneous infections that cannot be covered or contained adequately by
dressings, contact precautions should be used for at least 24 hours after the start of appropriate
therapy.

Health care workers may be the source of transmission to secondary nosocomial cases. Those
epidemiologically linked to a case should have specimens from the anus, skin lesions, throat, and
vagina for culture. Those positive should be treated with antibiotics in order to eradicate the GAS.

Practices to prevent hospital transmission of GAS should include isolation of patients admitted to
the intensive care unit with necrotizing fasciitis, investigation after a single nosocomial case and
emphasis on identifying and treating health care worker carriers on surgical and obstetric services
and patient reservoirs on other wards. Transmission of GAS is disproportionately high from patients
with community-acquired necrotizing fasciitis who are admitted to the intensive care unit,
therefore supporting the use of droplet and contact precautions for all patients admitted with
necrotizing fasciitis until GAS has been ruled out as a cause, or until 24 hours after initiation of
effective antimicrobial therapy.

Although research towards an effective vaccine for the prevention of GAS diseases has been
conducted for over 70 years, a commercial vaccine is not yet available.

It is not uncommon for persons to be asymptomatic carriers of GAS. Surveillance cultures have
shown that up to 20% of individuals in certain populations may have asymptomatic pharyngeal
colonization with GAS. Antimicrobial therapy is not indicated for most GAS pharyngeal carriers.

There are only a few indications for the use of antimicrobial prophylaxis to prevent colonization and
subsequent infection. Two groups of persons that may warrant chemoprophylaxis are those with
contact with a person with invasive GAS infections and new military recruits.

Management of health care workers colonized with group A streptococci

Because most health care workers (HCW) associated with a given outbreak will not be colonized,
HCWs may return to work pending culture results. However, colonized HCWs should be suspended
from patient care for the first 24 hours that they receive chemoprophylaxis, and HCW strains
should be compared with patient strains by use of the same typing method(s). If an HCW is
epidemiologically linked to the case patients and the strain the HCW is carrying is the same as the
strains isolated from patients, follow-up cultures should be done for the HCW 7–10 days after the
completion of therapy.

Treatment of asymptomatic group A streptococcal colonized health care workers

Treatment options for asymptomatic colonized HCWs include: benzathine penicillin G (1200000U
intramuscularly one dose) plus rifampin (300mg twice daily for 4 days), clindamycin (300mg orally
three times a day for 10 days) or azithromycin (500mg orally daily for five days). Any of these
regimens is appropriate for nonpregnant HCWs who are not allergic to penicillin and for their
colonized household contacts. Clindamycin or azithromycin is recommended for HCWs and
colonized household contacts who are allergic to penicillin. Rectal carriage of GAS is difficult to
eradicate with penicillin-based regimens.

Oral therapy with vancomycin in combination with rifampin has been recommended in such
cases, however no controlled trials have been done to support this recommendation. Given the
well-documented effects of clindamycin on bowel flora, oral clindamycin is recommended for the
treatment of HCWs who have rectal carriage of GAS and their household contacts. If azithromycin
or clindamycin is used, susceptibility testing of the HCW strain of GAS against macrolides and
clindamycin should be performed.

Management of asymptomatice group A streptococci carriers

Antimicrobial therapy is not indicated for most GAS pharyngeal carriers. Exceptions include the
following: (1) an outbreak of acute rheumatic fever or poststreptococcal glomerulonephritis occurs;
(2) an outbreak of GAS pharyngitis in a closed or semi-closed community occurs; (3) a family history
of acute rheumatic fever exists; or (4) multiple episodes of documented symptomatic GAS
pharyngitis continue to occur within a family during a period of many weeks despite appropriate
therapy.

Chemoprophylaxis of military recruits

Military recruits are at particularly high risk for streptococcal infection. Factors that might
contribute to increased susceptibility in this population include the rapid gathering of persons
from across the country into crowded living and working quarters, which exposes nonimmune
persons to several pathogens, and the physical and psychological stress of training. Primary and
secondary penicillin chemoprophylaxis for GAS infections are effective in military recruit
populations and have been used intermittently since 1951.

Primary prophylaxis is administered to all recruits shortly after their arrival at a training facility to
prevent the introduction of GAS into this population, and secondary (i.e., mass) prophylaxis is
provided concurrently to all recruits in a given facility to interrupt established disease transmission.
Penicillin G benzathine, because of its ease of administration and assured compliance, has been
one of the drugs of choice for preventing GAS infection in such high-risk populations. Oral
erythromycin or azithromycin prophylaxis is used to prevent infection among recruits who are
allergic to penicillin.

Indications for chemoprophylaxis for close contacts of a person with invasive group A streptococcal infection

Although the risk of subsequent invasive GAS disease among household contacts of persons with
invasive GAS infections is higher than the risk among the general population, subsequent invasive
GAS infections among household contacts are rare. Given the infrequency of these infections and
the lack of a clearly effective chemoprophylactic regimen, testing for GAS colonization or for
routine administration of chemoprophylaxis to all household contacts of persons with invasive GAS
disease is not recommended by the Centers for Disease Control and Prevention unless the person
is at an increased risk of sporadic disease or mortality due to GAS, i.e. person is over the age of 65.

The Public Health Agency of Canada recommends that close contacts of a confirmed severe case
should be offered chemoprophylaxis. Both organizations recommend that close contacts should
be alerted to signs and symptoms of invasive GAS disease and be advised to seek medical
attention immediately should they develop febrile illness or any other clinical manifestations of
GAS infection within 30 days of diagnosis in the index case.

The waxing and waning of group A streptococcal disease

In the 19th century, GAS infections were associated with severe and frequent epidemics of invasive
and often fatal illnesses, including a pandemic of scarlet fever in the United States and Great
Britain. Invasive GAS infections with severe manifestations continued through the 1920s. The
severity of these illnesses then declined notably until the early 1980s, when a significant
simultaneous recrudescence of the severe and fatal forms of invasive GAS infections occurred in
different parts of the world. The current upsurge of invasive infections in developed countries is
predominantly linked to the spread of a clonal hypervirulent population of M1T1 serotype strains.
This phenomenon is certainly not unique to the M1T1 strain, but is also seen in the M3 and M18
strain, which co-emerged with the M1T1 clonal strain in the 1980s.

Prior to 2004, M59 had been rarely recognized in Canada, and remains uncommon in other parts
of the world. However, Canadian surveillance documented an epidemic of a clonal strain of M59.
From January 2006 through to December 2009, 13.0% of invasive GAS cases were identified as M59
in the western provinces. The predominant clinical presentation was bacteremia, followed by
cellulitis. Risk factors were alcohol abuse, homelessness, hepatitis C virus infection, and illicit drug
use.

Although the waxing and waning of clones of GAS causing disease have been well-recognized
events in the past, the reasons for these have never been well defined. It has been suggested that
the emergence of a new clone may evolve slowly through the accumulation of point mutations or
by acquisition of new genetic material through horizontal gene-transfer events. A decrease in the
prevalence of a particular clone may be the result of a decrease in virulence, an increase in host
defense (herd immunity), and/ or serotype replacement by a more “fit” clone.

What host factors protect against this infection?

The GAS cell surface bears M proteins that form short hair-like fibrils. Antibody directed to the M
protein mediates opsonophagocytosis of the organism, and provides protective immunity. Type-
specific immunity against GAS depends on antibodies toward the hypervariable amino-terminal
part of M proteins, but repeated infections can also yield protective antibodies directed to
conserved epitopes of the M protein. Individuals with low levels of protective anti-streptococcal
antibodies in their plasma are at risk of developing invasive GAS infection. However, once the
bacteria invade a normally sterile site, the severity of the invasive infection is unrelated to the levels
of these antibodies. Severity is rather related to the organism’s virulence factors, the presence or
absence of antibodies to them, and how the host responds.

The interplay of host/pathogen factors and severity of disease

Depending on complex host-pathogen interactions, invasive GAS infections can cause severe
shock, multiple organ failure or nonsevere systemic disease such as mild bacteremia and cellulitis.
Likewise, invasive infections of soft tissues can be severe (e.g. necrotizing fasciitis) or nonsevere (e.g.