Infectious Diseases

Streptocococcus pyogenes

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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.

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.

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.

Antimicrobials for the treatment of GAS tonsillopharyngitis.
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. cellulitis or erysipelas). Whereas host genetic susceptibility plays a key role in modulating disease manifestation, variations in bacterial virulence properties contribute to infection severity.

What are the clinical manifestations of infection with this organism?

  • Pharyngitis:GAS is a major cause of pharyngitis and remains the only agent of this syndrome requiring etiologic diagnosis and treatment. The burden and economic costs of GAS pharyngitis are great. It has been estimated that in the United States alone more than seven million cases of acute pharyngitis are diagnosed by pediatricians annually. On clinical grounds, streptococcal pharyngitis is strongly suggested by the presence of fever, tonsillar exudate, tender enlarged anterior cervical lymph nodes and absence of cough ( Figure 4).

  • Otitis media and rhinosinusitis:GAS is isolated from 2%–5% of cultures of middle ear fluid specimens obtained from children with acute otitis media: the fourth most predominant pathogen causing pediatric acute otitis media, after Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.

  • Pneumonia and empyema:In the pre-antibiotic era, GAS was the etiologic agent in 3% to 5% of cases of community-acquired pneumonia, occurring most commonly after outbreaks of viral illness, such as influenza or measles. Local complications such as empyema were common, and the reported case fatality rate was as high as 50%. Since the 1940s, the incidence of GAS pneumonia declined dramatically. However, the occurrence of pneumonia has increased with the resurgence of invasive GAS disease since the 1980s, with 10% of patients with invasive GAS disease presenting with pneumonia. Small outbreaks of GAS pneumonia have been described in chronic care facilities and within families, as well as sporadic cases occurring in the community. GAS pneumonia now occurs with a frequency similar to that of other causes, such as Staphylococcus aureus or Klebsiella pneumoniae.

  • Genitourinary tract infections and maternal sepsis:GAS is an uncommon cause of urinary tract infections. Although GAS is an uncommon cause of peripartum infection, it is an important cause of puerperal (maternal) sepsis. Sepsis was the most frequent underlying cause of maternal mortality in the 19th century, responsible for 50% of all cases. Cesarean section is a risk factor for serious puerperal infection. Prophylactic antibiotics in women undergoing caesarean section (both elective and emergency) have substantially reduced the incidence of febrile morbidity, wound infection, endometritis and serious maternal infectious complications.

  • Scarlet fever:Scarlet fever is a diffuse erythematous eruption that generally occurs in association with pharyngitis. Development of the scarlet fever rash requires prior exposure to GASand occurs as a result of delayed-type skin reactivity to pyrogenic exotoxin (erythrogenic toxin, usually types A, B or C) produced by the organism. The rash of scarlet fever is a diffuse erythema that blanches with pressure, with numerous small (1-2mm) papular elevations, giving a "sandpaper" quality to the skin. It usually starts on the head and neck and is accompanied by circumoral pallor and a strawberry tongue. Subsequently the rash expands rapidly to cover the trunk followed by the extremities and ultimately desquamates; the palms and soles are usually spared. The rash is most marked in the skin folds of the inguinal, axillary, antecubital, abdominal areas, and about pressure points. It often exhibits a linear petechial character in the antecubital fossae and axillary folds, known as Pastia's lines.

  • Erysipelas:Erysipelas is an acute, superficial, non-necrotizing dermal/hypodermal infection that is mainly caused by streptococci. The definitive diagnosis is based on clinical findings that usually include a sharply demarcated shiny erythematosus plaque associated with pain, swelling and fever. Erysipelas affects predominantly adult patients in the sixth or seventh decade and is located on the lower limb in more than 80% of cases. A female predominance exists, except in young patients. Risk factors include disruption of the cutaneous barrier (leg ulcer, wound, fissured toe-web intertrigo, and pressure ulcer), lymphedema, chronic edema, or local surgical operations (lymph node dissection, saphenectomy). Toe-web intertrigo appears to be a major portal of entry whether due or not due to dermatophyte infection.

    Erysipelas is less commonly caused group B, C or G streptococci and rarely by staphylococci. Bulla formation is considered as a relatively severe but frequent local complication of the disease. Although most cases of erysipelas are caused by β-hemolytic streptococci, many other bacteria can produce non-necrotizing cellulitis, which can often occur in particular circumstances, e.g.Pasteurella multocida following cat or dog bites, Aeromonas hydrophila following immersion in fresh water,Vibrio species after saltwater exposure, orHaemophilus influenzae in periorbital cellulitis in children. Recurrence is the main complication of erysipelas; it occurs in about 20% of cases. Measures to reduce recurrences of erysipelas include treatment of any predisposing factor such as toe-web intertrigo or wound, or reducing any underlying edema. If frequent infections occur despite such measures, prophylactic antibiotics may be warranted.

  • Impetigo:Impetigo is a highly contagious infection of the superficial epidermis that most often affects children two to five years of age, although it can occur in any age group. Impetigo is classified as bullous or non-bullous impetigo. Bullous impetigo simply means that the skin eruption is characterized by bullae (blisters). Non-bullous impetigo is the most common form of impetigo. The infection usually heals without scarring, even without treatment. S. aureus is the most important causative organism, especially in bullous impetigo. GAS causes fewer cases, either alone or in combination with S. aureus and is more often found in non-bullous impetigo. The diagnosis usually is made clinically and can be confirmed by Gram stain and culture, although this is not usually necessary. Culture may be useful to identify patients with nephritogenic strains of GAS during outbreaks of poststreptococcal glomerulonephritis. Impetigo usually is transmitted through direct contact. Patients can further spread the infection to themselves or others after excoriating an infected area. Infections often spread rapidly through schools and day care centers. There is good evidence that the topical antibiotics, mupirocin and fusidic acid, are equal to or possibly more effective than oral antibiotic treatment. Based on the available evidence on efficacy, no clear preference can be given for β-lactamase resistant narrow-spectrum penicillins such as cloxacillin, dicloxacillin and flucloxacillin, a broad spectrum penicillin, such as amoxicillin plus clavulanic acid, cephalosporins, and macrolides. Oral antibiotics may have a role for more serious and extensive forms of impetigo. Penicillin is not as effective as most other antibiotics.

  • Cellulitis:Bacterial cellulitis refers to a diffuse, spreading skin infection. Associated regional lymphadenopathy and lymphatic streaking are variable, and local complications (abscesses, necrosis) are more frequent than in erysipelas. Petechiae and ecchymoses with frequent bullae may develop in inflamed skin resulting in hemorrhagic cellulitis. Cellulitis usually refers to a more deeply situated skin infection than erysipelas which is considered to be a more superficial. However, the distinction between these entities is not clear cut, and the two conditions share the typical clinical features including sudden onset, usually with a high fever, and the tendency to recur. GAS has been considered to be the main causative agent of cellulitis, although group B, C and G streptococcus and S. aureus can also be a cause. The predominant infection site for cellulitis is on the lower extremities. Lymphedema and disruption of the cutaneous barrier, which serves as a site of entry for the pathogens, are risk factors for infections. Twenty percent to 30% of patients have a recurrence during a 3-year follow-up period. Results of patient blood cultures are usually positive for β-hemolytic streptococci in less than 5% of cases.

  • Necrotizing fasciitis/myonecrosis:Necrotizing fasciitis is a rapidly progressive, highly destructive bacterial infection involving the skin, subcutaneous and deep soft tissue, and muscle (Figure 6) (Figure 7). Necrotizing fasciitis is historically divided into 2 types. Type I results from mixed infection with anaerobic species in combination with facultatively anaerobic organisms such as streptococci (non-group A), enterococci, and Gram-negative rods, whereas type II involves GAS either alone or in mixed infections.Early diagnosis is difficult as there is no single clinical laboratory test, imaging technique, or pathognomonic physical exam finding available. Patients with GAS necrotizing fasciitis commonly present with nonspecific symptoms such as fever, exquisitely tender skin lesions, vomiting, diarrhea, and toxemia.

    It is noteworthy that a substantial number of invasive streptococca infections have no known portal of entry. Transient bacteremia originating from the oropharynx has been suggested as the source in such cases. Anecdotal reports have suggested an association between the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the progression or development of GAS necrotizing infection, although this has not been found in prospective studies.

    In a matter of hours to days, the infection can progress from an apparently non-descript pain or benign appearing skin lesion, to a highly lethal disease. Of patients with necrotizing fasciitis, more than half have concomitant myonecrosis. Not infrequently, the patient will have sought medical care prior to the diagnosis being made. One of the clinical clues early in the course of the disease is pain out of proportion to the history or physical findings.

Figure 7.

40-year-old previously healthy man who had nicked his finger with his childs skate 6 days previously. He had sought medical care two days earlier for flu like symptoms and severe axillary pain.

  • Invasive GAS disease:Invasive disease is defined as the isolation of GAS from an otherwise sterile site. A prospective population-based surveillance for invasive GAS infections in Ontario from 1991 to 1995 identified 323 patients with invasive GAS disease corresponding to an annual incidence of 1.4/100000 population. The most common clinical presentations were soft-tissue infection (48%), bacteremia with no septic focus (14%), and pneumonia (11%). The clinical spectrum of disease may vary from mild to severe, resulting in streptococcal toxic shock.

Risk factors for cellulitis

Streptococcal cellulitis tends to develop at anatomic sites in which normal lymphatic drainage has been disrupted such as sites of prior cellulitis, the arm ipsilateral to a mastectomy and axillary lymph node dissection, a lower extremity previously involved in deep venous thrombosis, or chronic lymphedema, or the leg from which a saphenous vein has been harvested for coronary artery bypass grafting. The organism may enter via a dermal breach some distance from the eventual site of clinical cellulitis. For example, some patients with recurrent leg cellulitis following saphenous vein removal stop having recurrent episodes only after treatment of tinea pedis on the affected extremity. Fissures in the skin presumably serve as a portal of entry for streptococci, which then produce infection more proximally in the leg at the site of previous injury.

Streptococcal cellulitis may also involve recent surgical wounds. GAS is among the few bacterial pathogens that typically produce signs of wound infection and surrounding cellulitis within the first 24 hours after surgery. These wound infections are usually associated with a thin exudate and may spread rapidly, either as cellulitis in the skin and subcutaneous tissue, or as a deeper tissue infection. Streptococcal wound infection or localized cellulitis may also be associated with lymphangitis, manifested by red streaks extending proximally along superficial lymphatics from the infection site.

Varicella is a risk factor for invasive GAS disease in all age groups, but in children it is the most important risk factor for the acquisition of invasive GAS infection.

Controversies in management of severe group A streptococcal disease

Clindamycin is recommended for the treatment of streptococcal toxic shock syndrome (STTS) and necrotizing fasciitis. The rationale for clindamycin is based on in vitro studies demonstrating both toxin suppression and modulation of cytokine (i.e., TNF) production, on animal studies demonstrating superior efficacy versus that of penicillin, and on 2 observational studies demonstrating greater efficacy for clindamycin than for β-lactam antibiotics.

Prompt and aggressive exploration of suspected deep-seated GAS infections is currently advocated in order to determine the presence or absence of necrotizing fasciitis. Despite only anecdotal evidence, the current medical literature as well as standard surgical and medical reference textbooks advocates an early and aggressive surgical approach for patients with suspected or proven necrotizing fasciitis. A delay of surgery in a patient with streptococcal toxic shock and necrotizing fasciitis may increase their morbidity and mortality; in patients with streptococcal toxic shock syndrome (STSS) the mortality ranges from 30% to 80%, whereas in patients with necrotizing fasciitis without STSS the mortality is below 5%. Delaying surgery may decrease morbidity by allowing the development of a line of demarcation separating necrotic from vital tissue, thereby limiting the extent of tissue resection. It may also decrease mortality by allowing the patient to stabilize hemodynamically prior to surgery.

Early versus late surgical debridement has been a matter of debate also in acute necrotizing pancreatitis, where a common therapeutic approach in the past was early surgical intervention and debridement. However, it was subsequently found that early surgical intervention in severe necrotizing pancreatitis was in fact deleterious, resulting in mortality rates exceeding 50%, whereas delayed surgical debridement along with close supportive care in an intensive care unit improved the clinical outcome. Thus, the concept that the existence of infected tissue in the acute stages of pancreatitis worsens the outcome may not be true, and in fact the more crucial process may be the inflammatory response that results. However, any necrotic tissue should eventually be removed, but if the use of an immunomodulating agent such as intravenous polyspecific immunoglobulin G (IVIG) that neutralizes the toxins and the pathological levels of pro-inflammatory cytokines allows for the tissue debridement to be performed at a later stage, this may be beneficial for the patient (Figure 8).

Figure 8.

This women had STSS and widespread evidence of severe soft tissue disease, with the presence of bullae. The original surgical plan was to debride all involved tissue, however because of being unstable it was decided to wait and observe. She was treated with IVIG. Over next 72 hours patient stabilized and lesions regressed. No surgical debridement was carried out.

IVIG has been recommended by some authors for the management of patients with STSS. These studies include 1 observational cohort study based on Canadian patients identified through active surveillance of invasive GAS infections PUBMED:10825042, and 1 European multicenter placebo-controlled trial PUBMED:12884156. The mechanistic actions of IVIG in this setting are believed to include inhibition of the superantigen activity through neutralizing antibodies, opsonization through M-specific antibodies, and a general anti-inflammatory effect.

What common complications are associated with infection with this pathogen?

  • Pharyngitis: Although the major consequence of GAS pharyngitis, acute rheumatic fever (ARF), is much less common now than in the past, it is still a considerable problem in the developing world. The World Health Organization (WHO) estimates that there are about half a million cases of ARF. Suppurative complications such as peritonsillar and retropharyngeal abscesses are rare and their frequency reduced with antibiotic therapy.

  • Otitis media and rhinosinusitis:One of the more striking findings is the association of GAS acute otitis media (AOM) with increased risk of development of mastoiditis. Although the risk is small (<1%), it is much greater than with AOM due to S. pneumoniae, H. influenzaeor M. catarrhalis.

  • Pneumonia:A Canadian population-based surveillance program of invasive GAS disease confirmed that GAS pneumonia is a severe illness of sudden onset frequently associated with local and systemic complications, particularly empyema (19%), toxic shock (32%), and death (38%).

  • Invasive GAS infections:Streptococcal toxic-shock syndrome (STSS) is a rare but important complication of invasive GAS infection with a mortality rate of 30% to 80%. STSS is defined as hypotension accompanied by multiple organ failure, indicated by 2 of the following signs: renal impairment, coagulopathy, liver involvement, adult respiratory distress syndrome, a generalized rash, and soft tissue necrosis.

How should I identify the organism?

Rapid tests

Several rapid diagnostic tests for GAS pharyngitis are available. Most are based on nitrous acid extraction of group A carbohydrate antigen from organisms obtained by throat swab. The specificities of these tests generally are high, but the reported sensitivities vary considerably. As with throat cultures, the sensitivity of these tests is highly dependent on the quality of the throat swab specimen, the experience of the person performing the test, and the rigor of the culture standard used for comparison. Therefore, when a patient suspected of having GAS pharyngitis has a negative rapid streptococcal test, a throat culture should be obtained to ensure that the patient does not have GAS infection.

Because of the high specificity of these rapid tests, a positive test result generally does not require throat culture confirmation. Rapid diagnostic tests using techniques such as optical immunoassay and chemiluminescent DNA probes have been developed. These tests may be as sensitive as standard throat cultures on sheep blood agar. Some experts believe that the optical immunoassay is sufficiently sensitive to be used without throat culture back-up.

Serology

Serologic studies targeting nonspecific streptococcal extracellular products, such as streptolysin O and DNase B, may be useful in differentiating the carrier state of GAS from acute infection or providing evidence of past infection. It is inadequate to use a single serologic result to try to predict the presences of acute infection versus chronic carriage of an organism. One has to look at acute and convalescent responses to determine whether there is a new exposure to a particular pathogen. A single elevated antibody titer may simply reflect antibody persistence from an infection that occurred months earlier. Using both streptolysin O and DNase B will increase the probability of accurately diagnosing a true GAS infection. Serologic studies performed on at least 2 occasions, 2–4 weeks apart, can perhaps separate the patient with acute GAS pharyngitis from the chronic carrier of this pathogen.

Culture

GAS can be readily cultured from samples taken from other wise sterile sites including blood and cerebrospinal fluid. Culture on sheep blood agar can confirm GAS infection, and latex agglutination, fluorescent antibody, coagglutination, or precipitation techniques performed on colonies growing on an agar plate can differentiate GAS from other β-hemolytic streptococci. Bacitracin-susceptibility disks (containing 0.04 units of bacitracin) allow presumptive identification of GAS but are a less accurate method of diagnosis. Quantitation of GAS from the throat swab culture cannot be used to differentiate carriage from infection, because sparse growth may be associated with true infection. A negative throat culture permits the physician to withhold antibiotic therapy from the large majority of patients with sore throats.The use of PCR to diagnose the presence of GAS from sterile sites has not had enough of an impact on patient management to warrant its adoption in routine or reference laboratories.

How does this organism cause disease?

Although the factors behind the global resurgence of GAS since the 1980s remain unknown, a critical observation is the global rise in abundance and mortality associated with emm1 genotype strains that express the M1 protein. Each epidemic of GAS that has occurred was caused by a shift in GAS population dynamics resulting in the emergence of a new subpopulation within a previously immune community. This may explain the traditional 4–7 yearly cycle of GAS epidemics. The current emm1 GAS epidemic has persisted for over 25 years. A key feature of the M1 clone is its ability to switch rapidly to a hypervirulent phenotype during infection as a result of the CovR/S two component system: a global regulator of virulence gene expression in GAS that regulates about 15% of the genes, either directly or indirectly. GAS possesses a variety of virulence factors, vital in enabling the establishment of infection in the host.

M protein

The major surface protein of GAS is M protein (Figure 3), which occurs in more than 100 antigenically distinct types and is the basis for the serotyping of strains with specific antisera. The M protein molecules are fibrillar structures anchored in the cell wall of the organism that extend as hair-like projections away from the cell surface. The amino acid sequence of the distal or amino-terminal portion of the M protein molecule is quite variable, accounting for the antigenic variation of the different M types, while more proximal regions of the protein are relatively conserved. A newer technique for assignment of M type to GAS isolates uses the polymerase chain reaction to amplify the variable region of the M protein gene.

The presence of M protein on a GAS isolate correlates with its capacity to resist phagocytic killing in fresh human blood. This phenomenon appears to be due, at least in part, to the binding of plasma fibrinogen to M protein molecules on the streptococcal surface, which interferes with complement activation and deposition of opsonic complement fragments on the bacterial cell. This resistance to phagocytosis may be overcome by M protein–specific antibodies; thus individuals with antibodies to a given M type acquired as a result of prior infection are protected against subsequent infection with organisms of the same M type but not against that with different M types.

Hyaluronic acid

GAS also elaborates, to varying degrees, a polysaccharide capsule composed of hyaluronic acid. The production of large amounts of capsule by certain strains lends a characteristic mucoid appearance to the colonies. The capsular polysaccharide plays an important role in protecting GAS from ingestion and killing by phagocytes. In contrast to M protein, the hyaluronic acid capsule is a weak immunogen, and antibodies to hyaluronate have not been shown to be important in protective immunity. The presumed explanation is the apparent structural identity between streptococcal hyaluronic acid and the hyaluronic acid of mammalian connective tissues. The capsular polysaccharide may also play a role in GAS colonization of the pharynx by binding to CD44, a hyaluronic acid–binding protein expressed on human pharyngeal epithelial cells.

Extracellular toxins

GAS produces a large number of extracellular products that may be important in local and systemic toxicity and in the spread of infection through tissues. These products include streptolysins S and O, toxins that damage cell membranes and account for the hemolysis produced by the organisms streptokinase, DNases, protease, and superantigens.

Streptococcal toxic shock syndrome

GAS possess a large battery of virulence factors that engage a wide variety of host defenses, the streptococcal superantigens play a pivotal role in triggering potent inflammatory responses which, if not regulated, can set off host-mediated pathogenesis that, in genetically susceptible individuals, can cause streptococcal toxic shock with multiorgan dysfunction, vascular collapse, and death (Figure 9). The magnitude of inflammatory responses triggered by the same superantigens in different patients can vary drastically, and there is a direct correlation between the levels of inflammatory cytokine responses and the severity of GAS sepsis. This finding suggests that host factors play a crucial role in dictating disease severity and outcomes.

Figure 9.

Superantigens bind directly to class II major histocompatibility complexes of antigen-presenting cells outside the conventional antigen-binding grove. This complex recognizes only the Vβ element of the T cell receptor. Thus any T cell with the appropriate Vβ element can be stimulated, whereas normally, antigen specificity is also required in binding.

Necrotizing fasciitis

Necrotizing fasciitis may affect any anatomic site, but the lower and upper extremities are most commonly involved. The infection begins locally, often at the site of an antecedent trauma or as the result of hematogenous seeding of deep soft tissue from a distant site such as the pharynx. Once at the site of infection, SpeB, an extracellular cysteine proteasea and a well-known virulence factor for severe invasive episodes of GAS infection, is thought to be crucial for necrotizing fasciitis pathogenesis. Consistent with this, SpeB is abundantly present in necrotic human tissue.

Key virulence factors

Superantigens interact with antigen-presenting cells and T cells to induce T cell proliferation and massive cytokine production, which leads to fever, rash, capillary leak, and subsequent hypotension - the major symptoms of toxic shock syndrome. GAS produces numerous superantigens, including streptococcal pyrogenic exotoxin (SPE, scarlet fever toxin) serotypes A, C, G–M, streptococcal superantigen (SSA), and streptococcal mitogenic exotoxin Z (Figure 9).

SpeB is a secreted cysteine protease which is known to cleave numerous host proteins including components of the extracellular matrix, cytokine precursors, immunoglobulins, and antimicrobial peptides, which could interfere with host immune functions. However, SpeB has also been shown to cleave a range of GAS proteins such as the fibrinogen-binding M1 protein, various superantigens, the secreted plasminogen activator streptokinase as well as the DNase Sda1, and thus possibly interfere with the proven virulence functions of these bacterial factors.

Figure 5.

A throat score for use in both children and adults with sore throat.

Figure 6.

An 80 year old women who presented with two day history of flu like symptoms and pain in here left arm.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Kaul, R. "Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome: a comparative observational study". Clin Infect Dis. vol. 28. 1999. pp. 800.

(The authors gleaned from a population-based study in Ontario, Canada of invasive group A streptococcal disease, the possible benefit of the use of immune serum globulin [IVIG] for treatment of streptococcal toxic shock. They found evidence, although anecdotal, that the use of IVIG reduced morbidity and mortality.)

Norrby-Teglund, A. "Successful management of severe group A streptococcal soft tissue infections using an aggressive medical regimen including intravenous polyspecific immunoglobulin together with a conservative surgical approach". Scand J Infect Dis. vol. 37. 2005. pp. 166.

(This study provides anecdotal evidence to support a more conservative medical approach to the management of patients with severe GAS that may delay the need for surgery to later date when patient more stable and the need and/or extent of surgery is better defined)

Aziz, RK, Kotb, M. "Rise and persistence of global M1T1 clone of Streptococcus pyogenes". Emerg Infect Dis. vol. 14. 2008 Oct. pp. 1511-7.

(There is compelling evidence in the literature that a clone of MITI, has been responsible for the resurgence of severe group A streptococcal disease. This provides a important summary of the epidemiology and pathogenesis of this clone.)

Daneman, N. "Surveillance for hospital outbreaks of invasive group A streptococcal infections in Ontario, Canada, 1992 to 2000". Ann Intern Med. vol. 147. 2007 Aug 21. pp. 234-41.

(The experience in Toronto suggested that to prevent hospital transmission of group A streptococci practices 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.)

Tyrrell, GJ. "Epidemic of group A streptococcus M/emm59 causing invasive disease in Canada". Clin Infect Dis. vol. 51. 2010 Dec 1. pp. 1290-7.

(This M type strain of GAS had only rarely been seen in North America, but from January 2006 through December 2009, 13.0% all invasive GAS cases reported to the National Centre for Streptococcus were identified as M59 and were found in a select population of disadvantaged persons in western Canada. Although it has waned during the last few years, it has emerged in parts of the USA for the first time.)

McIsaac, WJ. "Empirical validation of guidelines for the management of pharyngitis in children and adults". JAMA. vol. 291. 2004 Apr 7. pp. 1587-95.

(A practical validated office/urgent care setting approach to the management of patients with sore throats. It provides a validated score that can be used in an outpatient setting to determine which patient needs antibiotic therapy and/or testing.)

Muller, MP. "Clinical and epidemiologic features of group A streptococcal pneumonia in Ontario, Canada". Arch Intern Med.. vol. 163. 2003 Feb 24. pp. 467-72.

(Group A streptococcal pneumonia is a common form of invasive GAS disease but remains an uncommon cause of community-acquired pneumonia. Progression is rapid despite appropriate therapy.)

Davies, HD. "Invasive group A streptococcal infections in Ontario, Canada". N Engl J Med.. vol. 335. 1996 Aug 22. pp. 547-54.

(A citation classic that reports a the clinical features of invasive GAS disease gleaned from a population-based surveillance study over a two year period in Ontario)
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