Streptococcus Group A Infections
Zartash Zafar Khan, MD, Fellow in Infectious Diseases, University of Oklahoma Health Science Center
Michelle R Salvaggio, MD, Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine; Medical Director of Infectious Diseases Institute, University of Oklahoma Health Sciences Center; Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital; Godfrey Harding, MD, FRCP(C), Program Director of Medical Microbiology, Professor, Department of Medicine, Section of Infectious Diseases and Microbiology, St Boniface Hospital, University of Manitoba, Canada
Updated: Sep 23, 2009
Introduction
Background
Streptococcus pyogenes is beta-hemolytic bacterium that belongs to Lancefield serogroup A, also known as group A streptococci (GAS). GAS, a ubiquitous organism, causes a wide variety of diseases in humans and is the most common bacterial cause of acute pharyngitis, accounting for 15%-30% of cases in children and 5%-10% of cases in adults.1 During the winter and spring in temperate climates, up to 20% of asymptomatic school-aged children may be GAS carriers.2
GAS usually causes pharyngitis or impetigo but, in rare cases, can also cause invasive diseases such as cellulitis, bacteremia, necrotizing fasciitis, and toxic shock syndrome (TSS). Along with Staphylococcus aureus, GAS is one of the most common pathogens responsible for cellulitis .
Historical perspectives
S pyogenes was first described by Billroth in 1874 in patients with wound infections. In 1883, Fehleisen isolated chain-forming organisms in pure culture from perierysipelas lesions. Rosebach named the organism S pyogenes in 1884. Studies by Schottmueller in 1903 and J.H. Brown in 1919 led to knowledge of different patterns of hemolysis described as alpha, beta, and gamma hemolysis.
A later development in this field was the Lancefield classification of beta-hemolytic streptococci by serotyping based on M-protein precipitin reactions. Lancefield established the critical role of M protein in disease causation. In the early 1900s, Dochez, George, and Dick identified hemolytic streptococcal infection as the cause of scarlet fever. The epidemiological studies of the mid 1900s helped establish the link between GAS infection and acute rheumatic fever (ARF) and acute glomerulonephritis.3
The traditional Lancefield M-protein classification system, which is based on serotyping, has been replaced by emm typing. This gene-typing system is based on sequence analysis of the emm gene, which encodes the cell surface M protein. Approximately 200 emm types have been identified by the Centers for Disease Control and Prevention (CDC) thus far.
Spectrum of diseases due to group A streptococcal infections
In the preantibiotic era, streptococci frequently caused significant morbidity and were associated with significant mortality rates. However, in the postantibiotic period, diseases due to streptococcal infections are well-controlled and uncommonly cause death. GAS can cause a diverse variety of both suppurative diseases and nonsuppurative postinfectious sequelae.
The suppurative spectrum of GAS diseases includes the following:
Pharyngitis with or without tonsillopharyngeal cellulitis or abscess
Impetigo (purulent honey-colored crusted skin lesions)
Pneumonia
Necrotizing fasciitis
Streptococcal bacteremia
Osteomyelitis
Otitis media
Sinusitis
Meningitis or brain abscess (a rare complication resulting from direct extension of an ear or sinus infection or from bacteremic spread)
The nonsuppurative sequelae of GAS infections include the following:
Acute rheumatic fever (ARF; defined by Jones criteria)
Rheumatic heart disease (chronic valvular damage, predominantly mitral valve)
Acute glomerulonephritis
Superantigen-mediated immune response may result in the following entities:
Streptococcal TSS (STSS): This is characterized by systemic shock with multiorgan failure, with manifestations of respiratory failure, acute renal failure, hepatic failure, neurological symptoms, hematological abnormalities, and skin findings, among others. This is predominantly associated with M types 1 and 3 that produce pyrogenic exotoxin A, exotoxin B, or both.4
Scarlet fever: This is characterized by upper-body rash, generally following pharyngitis.
Pathophysiology
Streptococci are a large group of gram-positive, nonmotile, non?spore-forming cocci about 0.5-1.2 ?m in size. They often grow in pairs or chains and are oxidase- and catalase-negative.
S pyogenes tends to colonize the upper respiratory tract and is highly virulent as it overcomes the host defense system. The most common forms of S pyogenes disease include respiratory and skin infections, with different strains usually responsible for each form.
The cell wall of S pyogenes is very complex and chemically diverse. The antigenic components of the cell are the virulence factors. The extracellular components responsible for the disease process include invasins and exotoxins. The outermost capsule is composed of hyaluronic acid, which has a chemical structure resembling host connective tissue, allowing the bacterium to escape recognition by the host as an offending agent. Thus, the bacterium escapes phagocytosis by neutrophils or macrophages, allowing it to colonize. Lipoteichoic acid and M proteins located on the cell membrane traverse through the cell wall and project outside the capsule.
Bacterial virulence factors
The cell wall antigens include capsular polysaccharide (C-substance), peptidoglycan and lipoteichoic acid (LTA), R and T proteins, and various surface proteins, including M protein, fimbrial proteins, fibronectin-binding proteins (eg, protein F), and cell-bound streptokinase.
The C-substance is composed of a branched polymer of L-rhamnose and N -acetyl-D-glucosamine. It may have a role in increased invasive capacity. The R and T proteins are used as epidemiologic markers and have no known role in virulence.
M protein, the major virulence factor, is a macromolecule incorporated in fimbriae present on the cell membrane projecting on the bacterial cell wall. More than 50 types of S pyogenes M proteins have been identified based on antigenic specificity, and the M protein is the major cause of antigenic shift and antigenic drift among GAS.5 The M protein binds the host fibrinogen and blocks the binding of complement to the underlying peptidoglycan. This allows survival of the organism by inhibiting phagocytosis. Strains that contain an abundance of M protein resist phagocytosis, multiply rapidly in human tissues, and initiate disease process. After an acute infection, type-specific antibodies develop against M protein activity in some cases.
In addition to M protein, S pyogenes possesses additional virulence factors, such as C5A peptidase, which destroys the chemotactic signals by cleaving the complement component of C5A.
Streptococcus group A infections. M protein.
Bacterial adherence factors
At least 11 different surface components of GAS have been suggested to play a role in adhesion. In 1997, Hasty and Courtney proposed that GAS express different arrays of adhesins in various environmental niches. Based on their review, M protein mediates adhesion to HEp-2 cells in humans, but not buccal cells, whereas FBP54 mediates adhesion to buccal cells, but not to HEp-2 cells. Protein F mediates adhesion to Langerhans cells, but not keratinocytes.
The most recent theory proposed in the process of adhesion is a two-step model. The initial step of overcoming the electrostatic repulsion of the bacteria from the host is mediated by LTA rendering weak reversible adhesion. The second step is firm irreversible adhesion mediated by tissue-specific M protein, protein F, or FBP54, among others. Once adherence has occurred, the streptococci resist phagocytosis, proliferate, and begin to invade the local tissues.6 GAS show enormous and evolving molecular diversity, driven by horizontal transmission among various strains. This is also true when compared with other streptococci. Acquisition of prophages accounts for much of the diversity, conferring not only virulence via phage-associated virulence factors but also increased bacterial survival against host defenses.
Extracellular products and toxins
Various extracellular growth products and toxins produced by GAS are responsible for host cell damage and inflammatory response. Streptolysin S, a 28 residue peptide, is an oxygen-stable leukocidin toxic to polymorphonuclear leukocytes, RBCs, and platelets. Streptolysin S is responsible for RBC lysis observed on sheep blood agar. Streptolysin O is an oxygen-labile leukocidin that is toxic to neutrophils and induces a brisk antibody response. Measurement of antistreptolysin O (ASO) antibody titer in humans is used as an indicator of recent streptococcal infection. Other extracellular products include NADase (leukotoxic), hyaluronidase (which digests host connective tissue, hyaluronic acid, and the organism's own capsule), streptokinases (proteolytic), and streptodornase A-D (deoxyribonuclease activity).7
Pyrogenic exotoxins
GAS produce 3 different types of exotoxins (A, B, C).5 These toxins act as superantigens and are responsible for inciting systemic immune response and acute disease caused by the sudden and massive release of T-cell cytokines into the blood stream. The superantigens bypass processing by antigen presenting cells and cause T-cell activation by binding class II MHC molecules directly and nonspecifically.
The streptococcal pyrogenic exotoxins (SPEs) are responsible for causing scarlet fever, pyrogenicity, and STSS. The mechanism is similar to that of staphylococcal TSS.8
Nucleases
Four antigenically distinct nucleases (A, B, C, D) assist in the liquefaction of pus and help to generate substrate for growth.
Other enzymes
In addition, streptococci produce proteinase, nicotinamide adenine dinucleotidase, adenosine triphosphatase, neuraminidase, lipoproteinase, and cardiohepatic toxin.
Suppurative Disease Spectrum
Streptococcal pharyngitis
S pyogenes causes up to 15%-30% of cases of acute pharyngitis.9 Frank disease occurs based on degree of bacterial virulence after colonization of the upper respiratory tract. Accurate diagnosis is essential for appropriate antibiotic selection.
Impetigo
The bacterial toxins cause proteolysis of epidermal and subepidermal layers, allowing the bacteria to spread quickly along the skin layers, thereby causing blisters or purulent lesions. The other common cause of impetigo is S aureus.
Pneumonia
Invasive GAS can cause pulmonary infection, often with rapid progression to necrotizing pneumonia.
Necrotizing fasciitis
Necrotizing fasciitis is caused by bacterial invasion into the subcutaneous tissue, with subsequent spread through superficial and deep fascial planes. The spread of organisms is aided by bacterial toxins and enzymes (eg, lipase, hyaluronidase, collagenase, streptokinase), interactions among organisms (synergistic infections), local tissue factors (eg, decreased blood and oxygen supply), and general host factors (eg, immunocompromised state, chronic illness, surgery). As the infection spreads deep along the fascial planes, vascular occlusion, tissue ischemia, and necrosis occur.10 Although GAS is often isolated in cases of necrotizing fasciitis, this disease state is frequently polymicrobial.
Otitis media and sinusitis
These are common suppurative complications of streptococcal tonsillopharyngitis. They are caused by spread of organisms via the eustachian tube (otitis media) and direct spread to sinuses (sinusitis).
Nonsuppurative Complications
Acute rheumatic fever
Certain M types are considered rheumatogenic, as they contain antigenic epitopes related to heart muscle, and therefore may lead to autoimmune rheumatic carditis (rheumatic fever) following acute infection. CD4+ T cells are probably the ultimate effectors of chronic valve lesions in rheumatic heart disease. T cells can recognize streptococcal M5 protein peptides and produce various inflammatory cytokines (eg, tumor necrosis factor [TNF]?alpha, interferon [IFN]?gamma, interleukin [IL]?10, IL-4), which could be responsible for progressive fibrotic valvular lesions. Cardiac myosin has been defined as a putative autoantigen recognized by autoantibodies in patients with rheumatic fever. Cross-reactivity between cardiac myosin and group A beta-hemolytic streptococcal M protein has been adequately demonstrated and may contribute to pathogenesis.11
Poststreptococcal glomerulonephritis
Poststreptococcal glomerulonephritis (PSGN) is caused by infection with specific nephritogenic strains of GAS (types 12 and 49) and may occur in sporadic cases or during an epidemic. PSGN results from deposition of antigen-antibody-complement complexes on the basement membrane of renal glomeruli. Subepithelial deposits of immunoglobulin can be observed with immunofluorescent staining.
Streptococcal toxic shock syndrome
Severe GAS infections associated with shock and organ failure have been reported with increasing frequency, predominantly in North America and Europe. STSS is a severe systemic immune response mediated by superantigens, as described above (see Pyrogenic exotoxins).
Central Nervous System Diseases
The primary evidence for poststreptococcal autoimmune CNS disease is provided by studies of Sydenham chorea, the neurologic manifestation of rheumatic fever. Reports of obsessive-compulsive disorder (OCD), tic disorders, and other neuropsychiatric symptoms that occur in association with group A beta-hemolytic streptococcal infections suggest that various CNS sequelae may be triggered by poststreptococcal autoimmunity.12
Frequency
United States
According to a CDC report dated April 3, 2008, approximately 9,000-11,500 cases of invasive GAS disease (3.2-3.9 per 100,000 population) occur each year in the United States. STSS and necrotizing fasciitis each accounted for approximately 6%-7% of cases. More than 10 million noninvasive GAS infections (primarily throat and superficial skin infections) occur annually.13
International
The resurgence of GAS as a cause of serious human infections in the United States, Europe, and elsewhere in the 1980s and into the 1990s was thoroughly documented and has heightened public awareness about this organism. Disease resurgence coupled with the lack of a licensed GAS vaccine and ongoing concern about acquisition of penicillin resistance remain a major concern.
In Denmark, the incidence of rheumatic fever decreased from 250 cases per 100,000 population to 100 cases per 100,000 population from 1862-1962. By 1980, the incidence ranged from 0.23-1.88 cases per 100,000 population.
The incidence of PSGN ranges from 9.5-28.5 new cases per 100,000 individuals per year. PSGN accounted for 2.6% to 3.7% of all primary glomerulopathies from 1987-1992, but only 9 cases were reported between 1992 and 1994. In China and Singapore, the incidence of PSGN has decreased in the past 40 years. In Chile, the disease has virtually disappeared since 1999, and, in Maracaibo, Venezuela, the incidence of sporadic PSGN decreased from 90-110 cases per year from 1980-1985 to 15 cases per year from 2001-2005. In Guadalajara, Mexico, the combined data from two hospitals showed a reduction in cases of PSGN from 27 in 1992 to only 6 in 2003.14
The Strep-EURO program, which analyzed data gathered in 11 participating countries, reported the epidemiology of severe S pyogenes disease in Europe during the 2000s. A crude rate of 2.46 cases per 100,000 population was reported in Finland, 2.58 in Denmark, 3.1 in Sweden, and 3.31 in the United Kingdom. In contrast, the rates of reports in the more central and southern countries, the Czech Republic, Romania, Cyprus, and Italy, were substantially lower (0.3-1.5 per 100,000 population), attributed to poor diagnostic microbiological investigative methods in these countries.
Mortality/Morbidity
As reported by the CDC in April 2008, invasive GAS infections carry a mortality rate of 10%-15%, with STSS and necrotizing fasciitis carrying fatality rates of over 35% and approximately 25%, respectively. STSS may also result in organ system failure, while necrotizing fasciitis may result in amputation.13
Race
GAS infections have no racial predilection.
Sex
GAS infections have no sexual predilection, although rheumatic mitral stenosis is more common in females.
Age
Strep throat is more common in school-aged children and teens.
PSGN is more common in persons older than 60 years and in children younger than 15 years.
ARF is commonly seen in young adults or children aged 4-9 years.
Clinical
History
Group A streptococci (GAS) can cause various diseases, including strep throat, skin and soft-tissue infections (eg, pyoderma, erysipelas, cellulitis, necrotizing fasciitis, myositis, osteomyelitis, pneumonia, abscess), severe systemic disease, and long-term nonsuppurative complications (eg, rheumatic fever, acute glomerulonephritis).
Head and neck infections
Streptococcal pharyngitis is strongly suggested by the presence of fever, tonsillar exudate, tender enlarged anterior cervical lymph nodes, and absence of cough (Centor criteria).9 Strep throat has an incubation period of 2-4 days and is characterized by sudden onset of sore throat, cervical lymphadenopathy, malaise, fever, and headache. Younger patients may also develop nausea, vomiting, and abdominal pain.
Acute sinusitis manifests as persistent coryza, postnasal drip, headache, and fever.
Skin and soft-tissue infections
Scarlet fever results from pyrogenic exotoxin released by GAS and is characterized by scarlatiniform rash that blanches with pressure. The rash usually appears on the second day of illness and fades within a week, followed by extensive desquamation that lasts for several weeks.
Erysipelas is an acute infection of the skin. In the past, the face was the most commonly involved site of infection; however, it now accounts for 20% or less of cases. Lower extremities are commonly affected. The symptoms of erysipelas include erythematous, warm, painful skin lesions with raised borders, commonly associated with fever. With appropriate antibiotics, the lesions resolve in days to weeks, with possible peeling. The condition usually occurs in children or elderly people.
Streptococcus group A infections. Erysipelas is a group A streptococcal infection of skin and subcutaneous tissue.
Cellulitis is characterized by inflammation of the skin and subcutaneous tissues and is associated with local pain, tenderness, swelling, and erythema. Patients also develop fever, chills, and malaise and may become bacteremic. Intravenous drug abuse, abnormal lymphatic drainage, and breaks in skin integrity (eg, dry cracked skin, tenia pedis) predispose to streptococcal cellulitis.
Erythema secondary to group A streptococcal cellulitis.
Impetigo and pyoderma, also called impetigo or impetigo contagiosa, are outbreaks of streptococcal pyoderma that may occur in children of certain population groups and in overcrowded institutions. The mode of spread is via direct contact, environmental contamination, and houseflies. The strains of streptococci that cause pyoderma differ from those that cause exudative tonsillitis.
Necrotizing fasciitis is a rapidly invasive GAS infection that may arise following minor trauma or from hematogenous spread of GAS from the throat to a site of blunt trauma or muscle strain. Unexplained and rapidly progressing pain may be the first indication of necrotizing fasciitis. Pain may be disproportional to the physical findings. Erythema may be diffused or localized or may be absent. Fever, malaise, myalgias, diarrhea, and anorexia may also be present. Hypotension may develop initially or over time. Surgical exploration is critical for establishing the diagnosis and directing management.
Bacteremia
The risk factors for GAS bacteremia vary with age. Among children younger than 2 years, risk factors include burns, varicella virus infection, malignant neoplasm, and immunosuppression. Among individuals aged 40-60 years, the risk factors for GAS bacteremia include burns, cuts, surgical incisions, childbirth, intravenous drug abuse, and nonpenetrating trauma. Predisposing factors for GAS bacteremia in elderly people include diabetes mellitus, peripheral vascular disease, malignancy, and corticosteroid use.
GAS bacteremia usually results from invasive GAS infection. TSS is characterized by early onset of shock and multiorgan failure. Blood cultures results are positive in approximately 60% of STSS cases. These patients usually develop renal failure, acute respiratory distress syndrome, hepatic dysfunction, hematological abnormalities, confusion, skin lesions, and diffuse capillary leak syndrome.
Acute rheumatic fever
The Jones criteria are used to diagnose rheumatic fever. The 5 major criteria include carditis, polyarthritis, chorea, erythema marginatum, and subcutaneous nodules. The minor criteria include fever, arthralgia, elevated erythrocyte sedimentation rate or C-reactive protein level, and prolonged PR interval on ECG. The presence of two major manifestations or of one major and two minor manifestations, supported by evidence of a preceding GAS infection by positive throat swab or culture results or high serum ASO titers, strongly suggests acute rheumatic fever (ARF).
Following the initial pharyngitis, a latent period of 2-3 weeks occurs before the first signs or symptoms of ARF appear.
Rheumatic heart disease is a sequela of ARF that manifests as valvular heart disease 10-20 years after the causative episode of ARF.
Poststreptococcal glomerulonephritis: This manifestation occurs rapidly within days after streptococcal pharyngitis and is characterized by acute renal failure with hematuria and nephrotic-range proteinuria.
Physical
Physical findings of pharyngitis include erythema, edema, and swelling of the pharynx. The tonsils are enlarged, and a grayish-white exudate may be present. Submandibular and periauricular lymph nodes are usually enlarged and tender to palpation. Patients with pharyngitis may develop chills and fever. Scarlet fever, characterized by diffuse erythematous eruption, fever, sore throat, and a bright red tongue, can accompany pharyngitis in patients who have had prior exposure to the organism. The rash of scarlet fever requires the presence of pyrogenic exotoxin and delayed type skin reactivity to streptococcal toxins.
Streptococcus group A infections. White strawberry tongue observed in streptococcal pharyngitis. Image courtesy of J. Bashera, eMedicine, Inc.
Pyoderma begins as a small papule and evolves into a vesicle surrounded by erythema. The vesicle turns into a pustule and then breaks down over 4-6 days to form a thick crust. Patients usually do not have systemic symptoms.
Local signs of skin erythema, warmth, tenderness and swelling are usually associated with cellulitis and erysipelas. Rash with honey-colored crust is observed with impetigo.
In patients with pneumonia, crackles may be found on physical examination. In patients with empyema or pleural effusion, decreased breath sounds and dullness on percussion are observed.
Necrotizing fascitis is an extensive and rapidly spreading infection of the subcutaneous tissue and fascia accompanied by necrosis and gangrene of the skin and underlying structures. Initially, the involved area appears erythematous but progresses rapidly within 24-48 hours, becoming purplish and then often evolving into blisters or bullae that contain hemorrhagic fluid. Frank gangrene and extensive tissue necrosis follows.
Streptococcus group A infections. Necrotizing fasciitis rapidly progresses from erythema to bullae formation and necrosis of skin and subcutaneous tissue.
Streptococcus group A infections. Necrotizing fasciitis of the left hand in a patient who had severe pain in the affected area.
Streptococcus group A infections. Patient who had had necrotizing fasciitis of the left hand and severe pain in the affected area (from Image 8). This photo was taken at a later date, and the wound is healing. The patient required skin grafting.
Signs of sepsis (eg, fever, tachycardia, tachypnea, hypotension) may be present in invasive infections.
Differential Diagnoses
Acute Rheumatic Fever Pharyngitis, Bacterial
Cellulitis Pharyngitis, Viral
Endometritis Rheumatic Fever
Glomerulonephritis, Acute Toxic Shock Syndrome
Glomerulonephritis, Poststreptococcal
HIV Disease
Infectious Mononucleosis
Other Problems to Be Considered
Nonstreptococcal infections should be ruled out.
Workup
Laboratory Studies
Throat culture
Because pharyngitis and tonsillitis may result from various infectious etiologies other than S pyogenes infection, confirm the diagnosis before initiating treatment.
Throat culture remains the criterion standard diagnostic test for streptococcal pharyngitis.
If performed correctly, culture of a single throat swab on a blood agar plate yields a sensitivity of 90%?95% for the detection of group A streptococci (GAS) in the pharynx.2
Some throat culture results are false-positive (eg, not reflecting acute infection but, rather, symptomatic carriage), although all patients with positive culture results are treated with antibiotics.
Culture technique
GAS grow readily on routine media, but GAS can be isolated more easily using selective media that inhibit the growth of normal pharyngeal flora.
Most laboratories inoculate throat swabs on 5% sheep blood agar containing trimethoprim-sulfamethoxazole.
A bacitracin disk that contains 0.04 U of bacitracin is also placed at the initial inoculation of the swab.
After overnight incubation at a temperature of 35-37?C, beta-hemolytic colonies that grow despite inhibition of the antibiotic disk are presumed to be GAS.
Cultures that are negative for GAS after 24 hours are held for another overnight incubation and reexamined.
Rapid antigen detection test
This test can be completed within minutes.
A carbohydrate antigen is detected directly from throat swabs.
Presently, the test uses enzyme immunoassay, optical immunoassay, or chemiluminescent DNA probes.
These tests yield high specificity (>95%) and sensitivity (80%?90%). Therefore, a negative antigen detection test result should prompt submission of a throat swab for culture.2
Blood culture, ASO titer, sputum culture, and tissue culture: These studies should be performed in patients with systemic infections.
In patients with acute pharyngitis, group A beta-hemolytic streptococcal infection should be ruled out. With appropriate antibiotic treatment, the duration of illness is decreased, suppurative complications are prevented, infectivity is decreased, and serious nonsuppurative sequelae (eg, acute rheumatic fever [ARF], poststreptococcal glomerulonephritis [PSGN]) can be prevented. Interestingly, delaying antimicrobial therapy for a short period does not diminish its efficacy in preventing rheumatic fever.15 With rare exceptions, neither posttreatment throat cultures in asymptomatic patients nor routine cultures in asymptomatic family contacts are necessary.16
Imaging Studies
CT scanning and MRI are helpful in the diagnosis of cellulitis, myositis, abscess, and necrotizing fasciitis.
Chest radiography and CT scanning of the thorax can aid in the diagnosis of pneumonia.
Procedures
Surgical debridement is used to manage extensive necrotizing fasciitis.
Abscesses, if present, are incised and drained.
Intubation is used in patients with airway compromise or acute respiratory distress syndrome associated with TSS or necrotizing pneumonia.
A central venous catheter or a wide-bore peripheral line may be needed immediately for fluid resuscitation in patients with shock.
Histologic Findings
Gram stain of tissue shows gram-positive cocci in chains or clusters. Tissue removed for diagnostic or therapeutic measures may show inflammation with polymorph neutrophil infiltration, cytotoxic effects, and/or extensive necrosis. In case of PSGN, immune complex deposition is observed on glomerular basement membrane.
Group A Streptococcus on Gram stain of blood isolated from a patient who developed toxic shock syndrome.
Treatment
Medical Care
Therapy for streptococcal pharyngitis is primarily aimed at preventing nonsuppurative and suppurative complications and decreasing infectivity. A 10-day course of penicillin V 250 mg bid in children and 500 mg bid or 250 mg qid in adults is very effective. A single intramuscular injection of 1.2 million U of penicillin G benzathine can be administered in patients who weigh more than 27 kg; 600,000 U is used in patients who weigh less than 27 kg. Amoxicillin is equally effective and may be better tolerated in children.
A meta-analysis compared bacterial and clinical cure rates in patients with group A streptococcal (GAS) tonsillopharyngitis treated with oral beta-lactam or macrolide antibiotics for 4-5 days versus 10-days. Twenty-two trials that involved 7470 patients were included in 4 separate analyses. Short-course cephalosporin treatment was superior to 10 days of penicillin for bacterial cure rate, short-course penicillin therapy was inferior to 10 days of penicillin, and clinical cure rates were similar to bacteriologic cure rates.17
In patients who are allergic to penicillin, erythromycin or the newer macrolides (eg, azithromycin, clarithromycin) appear to be effective. Oral cephalosporins are also highly effective in the treatment of streptococcal pharyngitis. Although eradication rates conferred by cephalosporins may be superior to those achieved with penicillin, the latter is the recommended drug of choice by the American Heart Association and the Infectious Diseases Society of America.2
Treatment failures are uncommon but may occur. If symptoms recur, the throat should be recultured and another course of treatment should be prescribed, preferably with an oral cephalosporin. An asymptomatic carrier state, as evidenced by positive throat culture results obtained on a weekly basis, is not treated with antibiotics.
Streptococcal pyoderma is treated with oral antibiotics (eg, penicillin or erythromycin) for 10 days. However, because concomitant S aureus infection may occur, therapy with cloxacillin, cephalexin, or cefaclor is suggested. Treatment of pyoderma may not prevent nephritis if the patient is infected with a nephritogenic strain.
Treatment of necrotizing fasciitis consists of antibiotic therapy, supportive therapy for associated shock, and prompt surgical intervention. GAS remain susceptible to beta-lactam antibiotics; clinical failures of penicillin therapy for streptococcal infections may occur. The failure rates in patients with invasive infections are higher because of the larger number of organisms. Clindamycin may be more effective in invasive infections. Unlike with penicillin, the efficacy of clindamycin is unaffected by the size of the inoculum and the stage of bacterial growth. In addition, clindamycin inhibits the production of toxin by streptococci.
Intravenous polyspecific immunoglobulin G (IVIG) has been reported to be efficacious as adjunctive therapy in patients with GAS TSS. GAS can also cause necrotizing fasciitis, for which early and extensive surgical intervention is currently advocated. A medical regimen including IVIG may allow an initial nonoperative or minimally invasive management approach, thus limiting the need for extensive debridement and amputation.18
Surgical Care
Consultation with a surgeon should be obtained early to assess the need for debridement in patients with necrotizing fasciitis.
Consultations
Complicated pharyngeal infections with peripharyngeal extension, abscess, or Ludwig angina should be evaluated by an ENT specialist.
Consultation with a surgeon should be obtained in cases of necrotizing fasciitis.
Consultation with an infectious diseases specialist should be considered.
Medication
To date, S pyogenes has remained universally susceptible to the first-line treatment of choice, penicillin. European surveillance in Italy identified that 32% of group A streptococcal (GAS) isolates exhibited resistance to macrolides. France has reported a steady escalation of erythromycin resistance, reaching 23% to date. Portugal identified 11% of GAS isolates as resistant to macrolides. Resistance in other European countries during the 1990s fell between 1% and 7%.19
Invasive GAS isolates were tested for fluoroquinolone susceptibility from 1992-1993 and in 2003 in Ontario, Canada. All isolates were susceptible to levofloxacin. Two of 153 (1.3%) in 1992-1993 and 7 of 160 (4.4%) in 2003 had a levofloxacin minimal inhibitory concentration (MIC) of 2 ?g/mL; all 9 had parC mutations, and 8 were serotype M6.
Between October 2003 and September 2006, 482 GAS strains were collected from 45 medical institutions in various parts of Japan. Susceptibility of GAS strains to 8 beta-lactam agents was excellent, with MICs of 0.0005?0.063 ?g/mL?1. Macrolide-resistant strains accounted for 16.2% of all strains. Although no strains with high resistance to levofloxacin were found, strains with an MIC of 2?4 ?g/mL?1 (17.4%) with intermediate susceptibility were observed.20
In 2006, of 50 GAS isolates examined with antibiotic susceptibility tests, 100% were found to be susceptible to penicillin, ampicillin, cefotaxime, cefazolin, and vancomycin. Eight isolates (16%) exhibited some level of antibiotic resistance. Six were resistant to erythromycin alone, and two were resistant to erythromycin and clindamycin (the first clindamycin-resistant isolates reported since 1999).21
Antibiotics
Therapy should cover all likely pathogens in the context of clinical settings. Antibiotic selection should be guided by blood culture sensitivity, whenever feasible.
Natural penicillins have good activity against S pyogenes. Various forms of natural penicillins are used for various diseases caused by GAS. The recommendation for S pyogenes pharyngitis in adults is a single IM dose of benzathine penicillin G 1.2 million U or penicillin V 500 mg qid PO for 10 days. For S pyogenes necrotizing fasciitis in adults, IV penicillin G (up to 24 million U/d in divided doses q4-6h) is recommended.
Clindamycin (Cleocin)
Lincosamide with activity against anaerobic organisms (resistance being seen with Bacteroides fragilis) and most gram-positive cocci (except enterococci and hospital-acquired MRSA). It is bacteriostatic and acts by binding to 23S portion of 50S ribosome and inhibiting elongation of peptide chain by inhibiting transpeptidase reaction.
Dosing
Adult
600 mg IV q8h or 300-450 mg PO q6h
Pediatric
25-40 mg/kg/d IV divided tid/qid
Interactions
Increases duration of neuromuscular blockage induced by tubocurarine and pancuronium; erythromycin may antagonize effects (in vitro); antidiarrheals (kaolin-pectin) may delay absorption, while loperamide may increase risk of diarrhea and Clostridium difficile ?associated colitis
Contraindications
Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis
Penicillin G (Pfizerpen)
Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.
Dosing
Adult
2-4 million U IV q4h
Pediatric
150,000 U/kg/d IV divided q4h
Interactions
Probenecid increases serum concentration of PCN; coadministration of tetracyclines can decrease effects
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in impaired renal function; rare side effects include hemolytic anemia, thrombocytopenia, leucopenia, interstitial nephritis, hepatitis; in very rare cases, seizures may occur with higher doses in patients with renal failure
Vancomycin (Lyphocin, Vancocin, Vancoled)
Vancomycin acts by inhibiting proper cell wall synthesis in gram-positive bacteria. Indicated for treatment of serious infections caused by beta-lactam?resistant organisms and in patients who have serious allergies to beta-lactam antimicrobials.
Dosing
Adult
15 mg/kg IV q12h (dose based on actual body weight); consider 22.5 mg/kg q12h for CNS infections
Pediatric
40 mg/kg/d IV divided tid/qid for 7-10 d
Interactions
Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; when taken concurrently with aminoglycosides, risk of nephrotoxicity may increase; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in renal failure; side effects may include thrombocytopenia, neutropenia, eosinophilia, and ototoxicity; red man syndrome is caused by rapid IV infusion (characterized by flushing and pruritus with or without hypotension) and can be avoided by slow infusion (over >1 h)
Telavancin (Vibativ)
Lipoglycopeptide antibiotic that is a synthetic derivative of vancomycin. Inhibits bacterial cell wall synthesis by interfering with polymerization and cross-linking of peptidoglycan. Unlike vancomycin, telavancin also depolarizes the bacterial cell membrane and disrupts its functional integrity. Indicated for complicated skin and skin structure infections caused by susceptible gram-positive bacteria, including Staphylococcus aureus (both methicillin-resistant and methicillin-susceptible strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, and Enterococcus faecalis (vancomycin-susceptible isolates only).
Dosing
Adult
10 mg/kg IV q24h for 7-14 d; infuse over 1 h
CrCl 30-50 mL/min: 7.5 mg/kg/d
CrCl 10-29 mL/min: 10 mg/kg q48h
Pediatric
Not established
Interactions
Data limited; coadministration with other drugs that prolong QTc interval (eg, phenothiazine, TCAs, macrolide antibiotics, class I and III antiarrhythmic agents) may increase risk for life-threatening arrhythmias
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects include taste disturbance, nausea, vomiting, and foamy urine; new-onset or worsening renal impairment has been reported (monitor renal function); efficacy decreased with moderate-to-severe baseline renal impairment (ie, CrCl <50 mL/min); administer over at least 1 h to minimize infusion-related adverse reactions; Clostridium difficile ?associated diarrhea may occur; may prolong QTc interval; interferes with coagulation test results, including PT, INR, and aPTT, but does not interfere with coagulation
Penicillin VK (Beepen-VK, Betapen-VK, Pen-Vee K, Robicillin VK, V-Cillin K, Veetids)
Inhibits cell wall biosynthesis.
Dosing
Adult
500 mg PO bid, tid, or qid for 10 d
Pediatric
250 mg PO bid or tid for 10 d
Interactions
Tetracyclines decrease the therapeutic effect of PCN; probenecid increases serum PCN level; PCN may increase serum methotrexate level
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution with renal impairment; high level of PCN may cause seizure; monitor for neutropenia, hemolytic anemia, and interstitial nephritis
Follow-up
Further Outpatient Care
Routine throat culture is unnecessary in asymptomatic patients who have completed a course of antibiotic therapy, except in special circumstances. Symptoms that persist after a treatment course may have several explanations.
Persistent carriage in the face of intercurrent viral infection
Noncompliance with the prescribed antimicrobial regimen
A new group A streptococci (GAS) infection acquired from family, the classroom, or community contacts
A recurrent episode of pharyngitis caused by the original infecting strain of GAS (ie, treatment failure)
Streptococcus carriers are unlikely to spread the organism to their close contacts and are at very low risk, if any, for developing suppurative complications or nonsuppurative complications (eg, acute rheumatic fever [ARF]). Continuous antimicrobial prophylaxis is not recommended except to prevent the recurrence of rheumatic fever in patients who have experienced a previous episode of rheumatic fever.
Follow-up culture of throat swabs is not routinely indicated in asymptomatic patients who have received a complete course of therapy for GAS pharyngitis (A-II), except in those with a history of rheumatic fever. Follow-up throat culture should also be considered in patients who develop acute pharyngitis during outbreaks of ARF or acute poststreptococcal glomerulonephritis (PSGN), during outbreaks of GAS pharyngitis in closed or partially closed communities, and when "ping-pong" spread of GAS infection has been occurring within a family (B-III).2
Deterrence/Prevention
Uncertainty remains about the risk of secondary cases of invasive GAS disease developing among close contacts of an index case of GAS infection. The currently available evidence does not justify routine chemoprophylaxis in close contacts. All household contacts of a patient with invasive GAS disease should be informed of the clinical manifestations of invasive disease and counseled to seek immediate medical attention upon development of such symptoms.
Complications
Potential complications of GAS tonsillopharyngitis include peritonsillar abscess, otitis media, and sinusitis. Inferior intrathoracic spread may lead to necrotizing mediastinitis.22 Contiguous intracranial invasion may result in fatal meningitis.23
Necrotizing fasciitis carries high morbidity and mortality rates and can result in TSS with multiorgan failure.
Puerperal sepsis follows abortion or delivery when streptococci that colonize the genital tract invade the endometrium and enters the blood stream. Pelvic cellulitis, septic pelvic thrombophlebitis, pelvic abscess, and septicemia can occur. Peripartum genital tract infections with group B streptococci are relatively more common, but fatal peripartum GAS infections have been reported.24
Empyema develops in 30%-40% of pneumonia cases. Other complications of pneumonia include mediastinitis, pericarditis, pneumothorax, and bronchiectasis.
The nonsuppurative complications of GAS tonsillopharyngitis include ARF, rheumatic heart disease, and acute glomerulonephritis.
Prognosis
Acute proliferative PSGN carries a good prognosis, as more than 95% of patients recover spontaneously within 3-4 weeks with no long-term sequelae.
With appropriate treatment, pharyngitis and skin infections carry a good prognosis.
Invasive GAS disease carries an overall mortality rate of 10%-15%. TSS and necrotizing fasciitis carry higher morbidity and mortality rates.
Patient Education
For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center; Women's Health Center; and Ear, Nose, and Throat Center. Also, see eMedicine's patient education articles Sore Throat, Toxic Shock Syndrome, and Strep Throat.
Miscellaneous
Medicolegal Pitfalls
The index of suspicion for GAS infection should be very high in cases of acute pharyngitis and skin infections including impetigo, cellulitis, erysipelas, wound infection, and gangrene.
GAS infection can result in two nonsuppurative sequelae, acute rheumatic fever (ARF) and acute poststreptococcal glomerulonephritis (PSGN).
GAS are important organisms that cause necrotizing fasciitis and STSS. Both of these conditions are associated with high mortality rates unless treated promptly and aggressively.
Special Concerns
Acute rheumatic fever
General description: ARF is a delayed nonsuppurative sequela of GAS tonsillopharyngitis. Following the pharyngitis, a latent period of 2-3 weeks passes before the signs or symptoms of ARF appear. The disease presents with various clinical manifestations, including arthritis, carditis, chorea, subcutaneous nodules, and erythema marginatum.
Epidemiology: A streptococcal strain capable of causing bacterial pharyngitis is capable of causing rheumatic fever, although some exceptions have been noted.
Pathogenesis: The pathogenic mechanisms that lead to the development of ARF remain incompletely understood. It is clearly associated with streptococcal pharyngitis, but genetic susceptibility may exist. The evidence is insufficient that toxins
produced by the streptococci are important in
pathogenesis.
http://emedicine.medscape.com/article/228936-print
Genetic susceptibility: Rheumatic fever might be the result of host genetic predisposition. The disease gene may be transmitted either in an autosomal-dominant fashion or in an autosomal-recessive fashion, with limited penetrance. The disease gene has not yet been identified.
Zartash Zafar Khan, MD, Fellow in Infectious Diseases, University of Oklahoma Health Science Center
Michelle R Salvaggio, MD, Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine; Medical Director of Infectious Diseases Institute, University of Oklahoma Health Sciences Center; Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital; Godfrey Harding, MD, FRCP(C), Program Director of Medical Microbiology, Professor, Department of Medicine, Section of Infectious Diseases and Microbiology, St Boniface Hospital, University of Manitoba, Canada
Updated: Sep 23, 2009
Introduction
Background
Streptococcus pyogenes is beta-hemolytic bacterium that belongs to Lancefield serogroup A, also known as group A streptococci (GAS). GAS, a ubiquitous organism, causes a wide variety of diseases in humans and is the most common bacterial cause of acute pharyngitis, accounting for 15%-30% of cases in children and 5%-10% of cases in adults.1 During the winter and spring in temperate climates, up to 20% of asymptomatic school-aged children may be GAS carriers.2
GAS usually causes pharyngitis or impetigo but, in rare cases, can also cause invasive diseases such as cellulitis, bacteremia, necrotizing fasciitis, and toxic shock syndrome (TSS). Along with Staphylococcus aureus, GAS is one of the most common pathogens responsible for cellulitis .
Historical perspectives
S pyogenes was first described by Billroth in 1874 in patients with wound infections. In 1883, Fehleisen isolated chain-forming organisms in pure culture from perierysipelas lesions. Rosebach named the organism S pyogenes in 1884. Studies by Schottmueller in 1903 and J.H. Brown in 1919 led to knowledge of different patterns of hemolysis described as alpha, beta, and gamma hemolysis.
A later development in this field was the Lancefield classification of beta-hemolytic streptococci by serotyping based on M-protein precipitin reactions. Lancefield established the critical role of M protein in disease causation. In the early 1900s, Dochez, George, and Dick identified hemolytic streptococcal infection as the cause of scarlet fever. The epidemiological studies of the mid 1900s helped establish the link between GAS infection and acute rheumatic fever (ARF) and acute glomerulonephritis.3
The traditional Lancefield M-protein classification system, which is based on serotyping, has been replaced by emm typing. This gene-typing system is based on sequence analysis of the emm gene, which encodes the cell surface M protein. Approximately 200 emm types have been identified by the Centers for Disease Control and Prevention (CDC) thus far.
Spectrum of diseases due to group A streptococcal infections
In the preantibiotic era, streptococci frequently caused significant morbidity and were associated with significant mortality rates. However, in the postantibiotic period, diseases due to streptococcal infections are well-controlled and uncommonly cause death. GAS can cause a diverse variety of both suppurative diseases and nonsuppurative postinfectious sequelae.
The suppurative spectrum of GAS diseases includes the following:
Pharyngitis with or without tonsillopharyngeal cellulitis or abscess
Impetigo (purulent honey-colored crusted skin lesions)
Pneumonia
Necrotizing fasciitis
Streptococcal bacteremia
Osteomyelitis
Otitis media
Sinusitis
Meningitis or brain abscess (a rare complication resulting from direct extension of an ear or sinus infection or from bacteremic spread)
The nonsuppurative sequelae of GAS infections include the following:
Acute rheumatic fever (ARF; defined by Jones criteria)
Rheumatic heart disease (chronic valvular damage, predominantly mitral valve)
Acute glomerulonephritis
Superantigen-mediated immune response may result in the following entities:
Streptococcal TSS (STSS): This is characterized by systemic shock with multiorgan failure, with manifestations of respiratory failure, acute renal failure, hepatic failure, neurological symptoms, hematological abnormalities, and skin findings, among others. This is predominantly associated with M types 1 and 3 that produce pyrogenic exotoxin A, exotoxin B, or both.4
Scarlet fever: This is characterized by upper-body rash, generally following pharyngitis.
Pathophysiology
Streptococci are a large group of gram-positive, nonmotile, non?spore-forming cocci about 0.5-1.2 ?m in size. They often grow in pairs or chains and are oxidase- and catalase-negative.
S pyogenes tends to colonize the upper respiratory tract and is highly virulent as it overcomes the host defense system. The most common forms of S pyogenes disease include respiratory and skin infections, with different strains usually responsible for each form.
The cell wall of S pyogenes is very complex and chemically diverse. The antigenic components of the cell are the virulence factors. The extracellular components responsible for the disease process include invasins and exotoxins. The outermost capsule is composed of hyaluronic acid, which has a chemical structure resembling host connective tissue, allowing the bacterium to escape recognition by the host as an offending agent. Thus, the bacterium escapes phagocytosis by neutrophils or macrophages, allowing it to colonize. Lipoteichoic acid and M proteins located on the cell membrane traverse through the cell wall and project outside the capsule.
Bacterial virulence factors
The cell wall antigens include capsular polysaccharide (C-substance), peptidoglycan and lipoteichoic acid (LTA), R and T proteins, and various surface proteins, including M protein, fimbrial proteins, fibronectin-binding proteins (eg, protein F), and cell-bound streptokinase.
The C-substance is composed of a branched polymer of L-rhamnose and N -acetyl-D-glucosamine. It may have a role in increased invasive capacity. The R and T proteins are used as epidemiologic markers and have no known role in virulence.
M protein, the major virulence factor, is a macromolecule incorporated in fimbriae present on the cell membrane projecting on the bacterial cell wall. More than 50 types of S pyogenes M proteins have been identified based on antigenic specificity, and the M protein is the major cause of antigenic shift and antigenic drift among GAS.5 The M protein binds the host fibrinogen and blocks the binding of complement to the underlying peptidoglycan. This allows survival of the organism by inhibiting phagocytosis. Strains that contain an abundance of M protein resist phagocytosis, multiply rapidly in human tissues, and initiate disease process. After an acute infection, type-specific antibodies develop against M protein activity in some cases.
In addition to M protein, S pyogenes possesses additional virulence factors, such as C5A peptidase, which destroys the chemotactic signals by cleaving the complement component of C5A.
Streptococcus group A infections. M protein.
Bacterial adherence factors
At least 11 different surface components of GAS have been suggested to play a role in adhesion. In 1997, Hasty and Courtney proposed that GAS express different arrays of adhesins in various environmental niches. Based on their review, M protein mediates adhesion to HEp-2 cells in humans, but not buccal cells, whereas FBP54 mediates adhesion to buccal cells, but not to HEp-2 cells. Protein F mediates adhesion to Langerhans cells, but not keratinocytes.
The most recent theory proposed in the process of adhesion is a two-step model. The initial step of overcoming the electrostatic repulsion of the bacteria from the host is mediated by LTA rendering weak reversible adhesion. The second step is firm irreversible adhesion mediated by tissue-specific M protein, protein F, or FBP54, among others. Once adherence has occurred, the streptococci resist phagocytosis, proliferate, and begin to invade the local tissues.6 GAS show enormous and evolving molecular diversity, driven by horizontal transmission among various strains. This is also true when compared with other streptococci. Acquisition of prophages accounts for much of the diversity, conferring not only virulence via phage-associated virulence factors but also increased bacterial survival against host defenses.
Extracellular products and toxins
Various extracellular growth products and toxins produced by GAS are responsible for host cell damage and inflammatory response. Streptolysin S, a 28 residue peptide, is an oxygen-stable leukocidin toxic to polymorphonuclear leukocytes, RBCs, and platelets. Streptolysin S is responsible for RBC lysis observed on sheep blood agar. Streptolysin O is an oxygen-labile leukocidin that is toxic to neutrophils and induces a brisk antibody response. Measurement of antistreptolysin O (ASO) antibody titer in humans is used as an indicator of recent streptococcal infection. Other extracellular products include NADase (leukotoxic), hyaluronidase (which digests host connective tissue, hyaluronic acid, and the organism's own capsule), streptokinases (proteolytic), and streptodornase A-D (deoxyribonuclease activity).7
Pyrogenic exotoxins
GAS produce 3 different types of exotoxins (A, B, C).5 These toxins act as superantigens and are responsible for inciting systemic immune response and acute disease caused by the sudden and massive release of T-cell cytokines into the blood stream. The superantigens bypass processing by antigen presenting cells and cause T-cell activation by binding class II MHC molecules directly and nonspecifically.
The streptococcal pyrogenic exotoxins (SPEs) are responsible for causing scarlet fever, pyrogenicity, and STSS. The mechanism is similar to that of staphylococcal TSS.8
Nucleases
Four antigenically distinct nucleases (A, B, C, D) assist in the liquefaction of pus and help to generate substrate for growth.
Other enzymes
In addition, streptococci produce proteinase, nicotinamide adenine dinucleotidase, adenosine triphosphatase, neuraminidase, lipoproteinase, and cardiohepatic toxin.
Suppurative Disease Spectrum
Streptococcal pharyngitis
S pyogenes causes up to 15%-30% of cases of acute pharyngitis.9 Frank disease occurs based on degree of bacterial virulence after colonization of the upper respiratory tract. Accurate diagnosis is essential for appropriate antibiotic selection.
Impetigo
The bacterial toxins cause proteolysis of epidermal and subepidermal layers, allowing the bacteria to spread quickly along the skin layers, thereby causing blisters or purulent lesions. The other common cause of impetigo is S aureus.
Pneumonia
Invasive GAS can cause pulmonary infection, often with rapid progression to necrotizing pneumonia.
Necrotizing fasciitis
Necrotizing fasciitis is caused by bacterial invasion into the subcutaneous tissue, with subsequent spread through superficial and deep fascial planes. The spread of organisms is aided by bacterial toxins and enzymes (eg, lipase, hyaluronidase, collagenase, streptokinase), interactions among organisms (synergistic infections), local tissue factors (eg, decreased blood and oxygen supply), and general host factors (eg, immunocompromised state, chronic illness, surgery). As the infection spreads deep along the fascial planes, vascular occlusion, tissue ischemia, and necrosis occur.10 Although GAS is often isolated in cases of necrotizing fasciitis, this disease state is frequently polymicrobial.
Otitis media and sinusitis
These are common suppurative complications of streptococcal tonsillopharyngitis. They are caused by spread of organisms via the eustachian tube (otitis media) and direct spread to sinuses (sinusitis).
Nonsuppurative Complications
Acute rheumatic fever
Certain M types are considered rheumatogenic, as they contain antigenic epitopes related to heart muscle, and therefore may lead to autoimmune rheumatic carditis (rheumatic fever) following acute infection. CD4+ T cells are probably the ultimate effectors of chronic valve lesions in rheumatic heart disease. T cells can recognize streptococcal M5 protein peptides and produce various inflammatory cytokines (eg, tumor necrosis factor [TNF]?alpha, interferon [IFN]?gamma, interleukin [IL]?10, IL-4), which could be responsible for progressive fibrotic valvular lesions. Cardiac myosin has been defined as a putative autoantigen recognized by autoantibodies in patients with rheumatic fever. Cross-reactivity between cardiac myosin and group A beta-hemolytic streptococcal M protein has been adequately demonstrated and may contribute to pathogenesis.11
Poststreptococcal glomerulonephritis
Poststreptococcal glomerulonephritis (PSGN) is caused by infection with specific nephritogenic strains of GAS (types 12 and 49) and may occur in sporadic cases or during an epidemic. PSGN results from deposition of antigen-antibody-complement complexes on the basement membrane of renal glomeruli. Subepithelial deposits of immunoglobulin can be observed with immunofluorescent staining.
Streptococcal toxic shock syndrome
Severe GAS infections associated with shock and organ failure have been reported with increasing frequency, predominantly in North America and Europe. STSS is a severe systemic immune response mediated by superantigens, as described above (see Pyrogenic exotoxins).
Central Nervous System Diseases
The primary evidence for poststreptococcal autoimmune CNS disease is provided by studies of Sydenham chorea, the neurologic manifestation of rheumatic fever. Reports of obsessive-compulsive disorder (OCD), tic disorders, and other neuropsychiatric symptoms that occur in association with group A beta-hemolytic streptococcal infections suggest that various CNS sequelae may be triggered by poststreptococcal autoimmunity.12
Frequency
United States
According to a CDC report dated April 3, 2008, approximately 9,000-11,500 cases of invasive GAS disease (3.2-3.9 per 100,000 population) occur each year in the United States. STSS and necrotizing fasciitis each accounted for approximately 6%-7% of cases. More than 10 million noninvasive GAS infections (primarily throat and superficial skin infections) occur annually.13
International
The resurgence of GAS as a cause of serious human infections in the United States, Europe, and elsewhere in the 1980s and into the 1990s was thoroughly documented and has heightened public awareness about this organism. Disease resurgence coupled with the lack of a licensed GAS vaccine and ongoing concern about acquisition of penicillin resistance remain a major concern.
In Denmark, the incidence of rheumatic fever decreased from 250 cases per 100,000 population to 100 cases per 100,000 population from 1862-1962. By 1980, the incidence ranged from 0.23-1.88 cases per 100,000 population.
The incidence of PSGN ranges from 9.5-28.5 new cases per 100,000 individuals per year. PSGN accounted for 2.6% to 3.7% of all primary glomerulopathies from 1987-1992, but only 9 cases were reported between 1992 and 1994. In China and Singapore, the incidence of PSGN has decreased in the past 40 years. In Chile, the disease has virtually disappeared since 1999, and, in Maracaibo, Venezuela, the incidence of sporadic PSGN decreased from 90-110 cases per year from 1980-1985 to 15 cases per year from 2001-2005. In Guadalajara, Mexico, the combined data from two hospitals showed a reduction in cases of PSGN from 27 in 1992 to only 6 in 2003.14
The Strep-EURO program, which analyzed data gathered in 11 participating countries, reported the epidemiology of severe S pyogenes disease in Europe during the 2000s. A crude rate of 2.46 cases per 100,000 population was reported in Finland, 2.58 in Denmark, 3.1 in Sweden, and 3.31 in the United Kingdom. In contrast, the rates of reports in the more central and southern countries, the Czech Republic, Romania, Cyprus, and Italy, were substantially lower (0.3-1.5 per 100,000 population), attributed to poor diagnostic microbiological investigative methods in these countries.
Mortality/Morbidity
As reported by the CDC in April 2008, invasive GAS infections carry a mortality rate of 10%-15%, with STSS and necrotizing fasciitis carrying fatality rates of over 35% and approximately 25%, respectively. STSS may also result in organ system failure, while necrotizing fasciitis may result in amputation.13
Race
GAS infections have no racial predilection.
Sex
GAS infections have no sexual predilection, although rheumatic mitral stenosis is more common in females.
Age
Strep throat is more common in school-aged children and teens.
PSGN is more common in persons older than 60 years and in children younger than 15 years.
ARF is commonly seen in young adults or children aged 4-9 years.
Clinical
History
Group A streptococci (GAS) can cause various diseases, including strep throat, skin and soft-tissue infections (eg, pyoderma, erysipelas, cellulitis, necrotizing fasciitis, myositis, osteomyelitis, pneumonia, abscess), severe systemic disease, and long-term nonsuppurative complications (eg, rheumatic fever, acute glomerulonephritis).
Head and neck infections
Streptococcal pharyngitis is strongly suggested by the presence of fever, tonsillar exudate, tender enlarged anterior cervical lymph nodes, and absence of cough (Centor criteria).9 Strep throat has an incubation period of 2-4 days and is characterized by sudden onset of sore throat, cervical lymphadenopathy, malaise, fever, and headache. Younger patients may also develop nausea, vomiting, and abdominal pain.
Acute sinusitis manifests as persistent coryza, postnasal drip, headache, and fever.
Skin and soft-tissue infections
Scarlet fever results from pyrogenic exotoxin released by GAS and is characterized by scarlatiniform rash that blanches with pressure. The rash usually appears on the second day of illness and fades within a week, followed by extensive desquamation that lasts for several weeks.
Erysipelas is an acute infection of the skin. In the past, the face was the most commonly involved site of infection; however, it now accounts for 20% or less of cases. Lower extremities are commonly affected. The symptoms of erysipelas include erythematous, warm, painful skin lesions with raised borders, commonly associated with fever. With appropriate antibiotics, the lesions resolve in days to weeks, with possible peeling. The condition usually occurs in children or elderly people.
Streptococcus group A infections. Erysipelas is a group A streptococcal infection of skin and subcutaneous tissue.
Cellulitis is characterized by inflammation of the skin and subcutaneous tissues and is associated with local pain, tenderness, swelling, and erythema. Patients also develop fever, chills, and malaise and may become bacteremic. Intravenous drug abuse, abnormal lymphatic drainage, and breaks in skin integrity (eg, dry cracked skin, tenia pedis) predispose to streptococcal cellulitis.
Erythema secondary to group A streptococcal cellulitis.
Impetigo and pyoderma, also called impetigo or impetigo contagiosa, are outbreaks of streptococcal pyoderma that may occur in children of certain population groups and in overcrowded institutions. The mode of spread is via direct contact, environmental contamination, and houseflies. The strains of streptococci that cause pyoderma differ from those that cause exudative tonsillitis.
Necrotizing fasciitis is a rapidly invasive GAS infection that may arise following minor trauma or from hematogenous spread of GAS from the throat to a site of blunt trauma or muscle strain. Unexplained and rapidly progressing pain may be the first indication of necrotizing fasciitis. Pain may be disproportional to the physical findings. Erythema may be diffused or localized or may be absent. Fever, malaise, myalgias, diarrhea, and anorexia may also be present. Hypotension may develop initially or over time. Surgical exploration is critical for establishing the diagnosis and directing management.
Bacteremia
The risk factors for GAS bacteremia vary with age. Among children younger than 2 years, risk factors include burns, varicella virus infection, malignant neoplasm, and immunosuppression. Among individuals aged 40-60 years, the risk factors for GAS bacteremia include burns, cuts, surgical incisions, childbirth, intravenous drug abuse, and nonpenetrating trauma. Predisposing factors for GAS bacteremia in elderly people include diabetes mellitus, peripheral vascular disease, malignancy, and corticosteroid use.
GAS bacteremia usually results from invasive GAS infection. TSS is characterized by early onset of shock and multiorgan failure. Blood cultures results are positive in approximately 60% of STSS cases. These patients usually develop renal failure, acute respiratory distress syndrome, hepatic dysfunction, hematological abnormalities, confusion, skin lesions, and diffuse capillary leak syndrome.
Acute rheumatic fever
The Jones criteria are used to diagnose rheumatic fever. The 5 major criteria include carditis, polyarthritis, chorea, erythema marginatum, and subcutaneous nodules. The minor criteria include fever, arthralgia, elevated erythrocyte sedimentation rate or C-reactive protein level, and prolonged PR interval on ECG. The presence of two major manifestations or of one major and two minor manifestations, supported by evidence of a preceding GAS infection by positive throat swab or culture results or high serum ASO titers, strongly suggests acute rheumatic fever (ARF).
Following the initial pharyngitis, a latent period of 2-3 weeks occurs before the first signs or symptoms of ARF appear.
Rheumatic heart disease is a sequela of ARF that manifests as valvular heart disease 10-20 years after the causative episode of ARF.
Poststreptococcal glomerulonephritis: This manifestation occurs rapidly within days after streptococcal pharyngitis and is characterized by acute renal failure with hematuria and nephrotic-range proteinuria.
Physical
Physical findings of pharyngitis include erythema, edema, and swelling of the pharynx. The tonsils are enlarged, and a grayish-white exudate may be present. Submandibular and periauricular lymph nodes are usually enlarged and tender to palpation. Patients with pharyngitis may develop chills and fever. Scarlet fever, characterized by diffuse erythematous eruption, fever, sore throat, and a bright red tongue, can accompany pharyngitis in patients who have had prior exposure to the organism. The rash of scarlet fever requires the presence of pyrogenic exotoxin and delayed type skin reactivity to streptococcal toxins.
Streptococcus group A infections. White strawberry tongue observed in streptococcal pharyngitis. Image courtesy of J. Bashera, eMedicine, Inc.
Pyoderma begins as a small papule and evolves into a vesicle surrounded by erythema. The vesicle turns into a pustule and then breaks down over 4-6 days to form a thick crust. Patients usually do not have systemic symptoms.
Local signs of skin erythema, warmth, tenderness and swelling are usually associated with cellulitis and erysipelas. Rash with honey-colored crust is observed with impetigo.
In patients with pneumonia, crackles may be found on physical examination. In patients with empyema or pleural effusion, decreased breath sounds and dullness on percussion are observed.
Necrotizing fascitis is an extensive and rapidly spreading infection of the subcutaneous tissue and fascia accompanied by necrosis and gangrene of the skin and underlying structures. Initially, the involved area appears erythematous but progresses rapidly within 24-48 hours, becoming purplish and then often evolving into blisters or bullae that contain hemorrhagic fluid. Frank gangrene and extensive tissue necrosis follows.
Streptococcus group A infections. Necrotizing fasciitis rapidly progresses from erythema to bullae formation and necrosis of skin and subcutaneous tissue.
Streptococcus group A infections. Necrotizing fasciitis of the left hand in a patient who had severe pain in the affected area.
Streptococcus group A infections. Patient who had had necrotizing fasciitis of the left hand and severe pain in the affected area (from Image 8). This photo was taken at a later date, and the wound is healing. The patient required skin grafting.
Signs of sepsis (eg, fever, tachycardia, tachypnea, hypotension) may be present in invasive infections.
Differential Diagnoses
Acute Rheumatic Fever Pharyngitis, Bacterial
Cellulitis Pharyngitis, Viral
Endometritis Rheumatic Fever
Glomerulonephritis, Acute Toxic Shock Syndrome
Glomerulonephritis, Poststreptococcal
HIV Disease
Infectious Mononucleosis
Other Problems to Be Considered
Nonstreptococcal infections should be ruled out.
Workup
Laboratory Studies
Throat culture
Because pharyngitis and tonsillitis may result from various infectious etiologies other than S pyogenes infection, confirm the diagnosis before initiating treatment.
Throat culture remains the criterion standard diagnostic test for streptococcal pharyngitis.
If performed correctly, culture of a single throat swab on a blood agar plate yields a sensitivity of 90%?95% for the detection of group A streptococci (GAS) in the pharynx.2
Some throat culture results are false-positive (eg, not reflecting acute infection but, rather, symptomatic carriage), although all patients with positive culture results are treated with antibiotics.
Culture technique
GAS grow readily on routine media, but GAS can be isolated more easily using selective media that inhibit the growth of normal pharyngeal flora.
Most laboratories inoculate throat swabs on 5% sheep blood agar containing trimethoprim-sulfamethoxazole.
A bacitracin disk that contains 0.04 U of bacitracin is also placed at the initial inoculation of the swab.
After overnight incubation at a temperature of 35-37?C, beta-hemolytic colonies that grow despite inhibition of the antibiotic disk are presumed to be GAS.
Cultures that are negative for GAS after 24 hours are held for another overnight incubation and reexamined.
Rapid antigen detection test
This test can be completed within minutes.
A carbohydrate antigen is detected directly from throat swabs.
Presently, the test uses enzyme immunoassay, optical immunoassay, or chemiluminescent DNA probes.
These tests yield high specificity (>95%) and sensitivity (80%?90%). Therefore, a negative antigen detection test result should prompt submission of a throat swab for culture.2
Blood culture, ASO titer, sputum culture, and tissue culture: These studies should be performed in patients with systemic infections.
In patients with acute pharyngitis, group A beta-hemolytic streptococcal infection should be ruled out. With appropriate antibiotic treatment, the duration of illness is decreased, suppurative complications are prevented, infectivity is decreased, and serious nonsuppurative sequelae (eg, acute rheumatic fever [ARF], poststreptococcal glomerulonephritis [PSGN]) can be prevented. Interestingly, delaying antimicrobial therapy for a short period does not diminish its efficacy in preventing rheumatic fever.15 With rare exceptions, neither posttreatment throat cultures in asymptomatic patients nor routine cultures in asymptomatic family contacts are necessary.16
Imaging Studies
CT scanning and MRI are helpful in the diagnosis of cellulitis, myositis, abscess, and necrotizing fasciitis.
Chest radiography and CT scanning of the thorax can aid in the diagnosis of pneumonia.
Procedures
Surgical debridement is used to manage extensive necrotizing fasciitis.
Abscesses, if present, are incised and drained.
Intubation is used in patients with airway compromise or acute respiratory distress syndrome associated with TSS or necrotizing pneumonia.
A central venous catheter or a wide-bore peripheral line may be needed immediately for fluid resuscitation in patients with shock.
Histologic Findings
Gram stain of tissue shows gram-positive cocci in chains or clusters. Tissue removed for diagnostic or therapeutic measures may show inflammation with polymorph neutrophil infiltration, cytotoxic effects, and/or extensive necrosis. In case of PSGN, immune complex deposition is observed on glomerular basement membrane.
Group A Streptococcus on Gram stain of blood isolated from a patient who developed toxic shock syndrome.
Treatment
Medical Care
Therapy for streptococcal pharyngitis is primarily aimed at preventing nonsuppurative and suppurative complications and decreasing infectivity. A 10-day course of penicillin V 250 mg bid in children and 500 mg bid or 250 mg qid in adults is very effective. A single intramuscular injection of 1.2 million U of penicillin G benzathine can be administered in patients who weigh more than 27 kg; 600,000 U is used in patients who weigh less than 27 kg. Amoxicillin is equally effective and may be better tolerated in children.
A meta-analysis compared bacterial and clinical cure rates in patients with group A streptococcal (GAS) tonsillopharyngitis treated with oral beta-lactam or macrolide antibiotics for 4-5 days versus 10-days. Twenty-two trials that involved 7470 patients were included in 4 separate analyses. Short-course cephalosporin treatment was superior to 10 days of penicillin for bacterial cure rate, short-course penicillin therapy was inferior to 10 days of penicillin, and clinical cure rates were similar to bacteriologic cure rates.17
In patients who are allergic to penicillin, erythromycin or the newer macrolides (eg, azithromycin, clarithromycin) appear to be effective. Oral cephalosporins are also highly effective in the treatment of streptococcal pharyngitis. Although eradication rates conferred by cephalosporins may be superior to those achieved with penicillin, the latter is the recommended drug of choice by the American Heart Association and the Infectious Diseases Society of America.2
Treatment failures are uncommon but may occur. If symptoms recur, the throat should be recultured and another course of treatment should be prescribed, preferably with an oral cephalosporin. An asymptomatic carrier state, as evidenced by positive throat culture results obtained on a weekly basis, is not treated with antibiotics.
Streptococcal pyoderma is treated with oral antibiotics (eg, penicillin or erythromycin) for 10 days. However, because concomitant S aureus infection may occur, therapy with cloxacillin, cephalexin, or cefaclor is suggested. Treatment of pyoderma may not prevent nephritis if the patient is infected with a nephritogenic strain.
Treatment of necrotizing fasciitis consists of antibiotic therapy, supportive therapy for associated shock, and prompt surgical intervention. GAS remain susceptible to beta-lactam antibiotics; clinical failures of penicillin therapy for streptococcal infections may occur. The failure rates in patients with invasive infections are higher because of the larger number of organisms. Clindamycin may be more effective in invasive infections. Unlike with penicillin, the efficacy of clindamycin is unaffected by the size of the inoculum and the stage of bacterial growth. In addition, clindamycin inhibits the production of toxin by streptococci.
Intravenous polyspecific immunoglobulin G (IVIG) has been reported to be efficacious as adjunctive therapy in patients with GAS TSS. GAS can also cause necrotizing fasciitis, for which early and extensive surgical intervention is currently advocated. A medical regimen including IVIG may allow an initial nonoperative or minimally invasive management approach, thus limiting the need for extensive debridement and amputation.18
Surgical Care
Consultation with a surgeon should be obtained early to assess the need for debridement in patients with necrotizing fasciitis.
Consultations
Complicated pharyngeal infections with peripharyngeal extension, abscess, or Ludwig angina should be evaluated by an ENT specialist.
Consultation with a surgeon should be obtained in cases of necrotizing fasciitis.
Consultation with an infectious diseases specialist should be considered.
Medication
To date, S pyogenes has remained universally susceptible to the first-line treatment of choice, penicillin. European surveillance in Italy identified that 32% of group A streptococcal (GAS) isolates exhibited resistance to macrolides. France has reported a steady escalation of erythromycin resistance, reaching 23% to date. Portugal identified 11% of GAS isolates as resistant to macrolides. Resistance in other European countries during the 1990s fell between 1% and 7%.19
Invasive GAS isolates were tested for fluoroquinolone susceptibility from 1992-1993 and in 2003 in Ontario, Canada. All isolates were susceptible to levofloxacin. Two of 153 (1.3%) in 1992-1993 and 7 of 160 (4.4%) in 2003 had a levofloxacin minimal inhibitory concentration (MIC) of 2 ?g/mL; all 9 had parC mutations, and 8 were serotype M6.
Between October 2003 and September 2006, 482 GAS strains were collected from 45 medical institutions in various parts of Japan. Susceptibility of GAS strains to 8 beta-lactam agents was excellent, with MICs of 0.0005?0.063 ?g/mL?1. Macrolide-resistant strains accounted for 16.2% of all strains. Although no strains with high resistance to levofloxacin were found, strains with an MIC of 2?4 ?g/mL?1 (17.4%) with intermediate susceptibility were observed.20
In 2006, of 50 GAS isolates examined with antibiotic susceptibility tests, 100% were found to be susceptible to penicillin, ampicillin, cefotaxime, cefazolin, and vancomycin. Eight isolates (16%) exhibited some level of antibiotic resistance. Six were resistant to erythromycin alone, and two were resistant to erythromycin and clindamycin (the first clindamycin-resistant isolates reported since 1999).21
Antibiotics
Therapy should cover all likely pathogens in the context of clinical settings. Antibiotic selection should be guided by blood culture sensitivity, whenever feasible.
Natural penicillins have good activity against S pyogenes. Various forms of natural penicillins are used for various diseases caused by GAS. The recommendation for S pyogenes pharyngitis in adults is a single IM dose of benzathine penicillin G 1.2 million U or penicillin V 500 mg qid PO for 10 days. For S pyogenes necrotizing fasciitis in adults, IV penicillin G (up to 24 million U/d in divided doses q4-6h) is recommended.
Clindamycin (Cleocin)
Lincosamide with activity against anaerobic organisms (resistance being seen with Bacteroides fragilis) and most gram-positive cocci (except enterococci and hospital-acquired MRSA). It is bacteriostatic and acts by binding to 23S portion of 50S ribosome and inhibiting elongation of peptide chain by inhibiting transpeptidase reaction.
Dosing
Adult
600 mg IV q8h or 300-450 mg PO q6h
Pediatric
25-40 mg/kg/d IV divided tid/qid
Interactions
Increases duration of neuromuscular blockage induced by tubocurarine and pancuronium; erythromycin may antagonize effects (in vitro); antidiarrheals (kaolin-pectin) may delay absorption, while loperamide may increase risk of diarrhea and Clostridium difficile ?associated colitis
Contraindications
Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis
Penicillin G (Pfizerpen)
Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.
Dosing
Adult
2-4 million U IV q4h
Pediatric
150,000 U/kg/d IV divided q4h
Interactions
Probenecid increases serum concentration of PCN; coadministration of tetracyclines can decrease effects
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in impaired renal function; rare side effects include hemolytic anemia, thrombocytopenia, leucopenia, interstitial nephritis, hepatitis; in very rare cases, seizures may occur with higher doses in patients with renal failure
Vancomycin (Lyphocin, Vancocin, Vancoled)
Vancomycin acts by inhibiting proper cell wall synthesis in gram-positive bacteria. Indicated for treatment of serious infections caused by beta-lactam?resistant organisms and in patients who have serious allergies to beta-lactam antimicrobials.
Dosing
Adult
15 mg/kg IV q12h (dose based on actual body weight); consider 22.5 mg/kg q12h for CNS infections
Pediatric
40 mg/kg/d IV divided tid/qid for 7-10 d
Interactions
Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; when taken concurrently with aminoglycosides, risk of nephrotoxicity may increase; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in renal failure; side effects may include thrombocytopenia, neutropenia, eosinophilia, and ototoxicity; red man syndrome is caused by rapid IV infusion (characterized by flushing and pruritus with or without hypotension) and can be avoided by slow infusion (over >1 h)
Telavancin (Vibativ)
Lipoglycopeptide antibiotic that is a synthetic derivative of vancomycin. Inhibits bacterial cell wall synthesis by interfering with polymerization and cross-linking of peptidoglycan. Unlike vancomycin, telavancin also depolarizes the bacterial cell membrane and disrupts its functional integrity. Indicated for complicated skin and skin structure infections caused by susceptible gram-positive bacteria, including Staphylococcus aureus (both methicillin-resistant and methicillin-susceptible strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, and Enterococcus faecalis (vancomycin-susceptible isolates only).
Dosing
Adult
10 mg/kg IV q24h for 7-14 d; infuse over 1 h
CrCl 30-50 mL/min: 7.5 mg/kg/d
CrCl 10-29 mL/min: 10 mg/kg q48h
Pediatric
Not established
Interactions
Data limited; coadministration with other drugs that prolong QTc interval (eg, phenothiazine, TCAs, macrolide antibiotics, class I and III antiarrhythmic agents) may increase risk for life-threatening arrhythmias
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects include taste disturbance, nausea, vomiting, and foamy urine; new-onset or worsening renal impairment has been reported (monitor renal function); efficacy decreased with moderate-to-severe baseline renal impairment (ie, CrCl <50 mL/min); administer over at least 1 h to minimize infusion-related adverse reactions; Clostridium difficile ?associated diarrhea may occur; may prolong QTc interval; interferes with coagulation test results, including PT, INR, and aPTT, but does not interfere with coagulation
Penicillin VK (Beepen-VK, Betapen-VK, Pen-Vee K, Robicillin VK, V-Cillin K, Veetids)
Inhibits cell wall biosynthesis.
Dosing
Adult
500 mg PO bid, tid, or qid for 10 d
Pediatric
250 mg PO bid or tid for 10 d
Interactions
Tetracyclines decrease the therapeutic effect of PCN; probenecid increases serum PCN level; PCN may increase serum methotrexate level
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution with renal impairment; high level of PCN may cause seizure; monitor for neutropenia, hemolytic anemia, and interstitial nephritis
Follow-up
Further Outpatient Care
Routine throat culture is unnecessary in asymptomatic patients who have completed a course of antibiotic therapy, except in special circumstances. Symptoms that persist after a treatment course may have several explanations.
Persistent carriage in the face of intercurrent viral infection
Noncompliance with the prescribed antimicrobial regimen
A new group A streptococci (GAS) infection acquired from family, the classroom, or community contacts
A recurrent episode of pharyngitis caused by the original infecting strain of GAS (ie, treatment failure)
Streptococcus carriers are unlikely to spread the organism to their close contacts and are at very low risk, if any, for developing suppurative complications or nonsuppurative complications (eg, acute rheumatic fever [ARF]). Continuous antimicrobial prophylaxis is not recommended except to prevent the recurrence of rheumatic fever in patients who have experienced a previous episode of rheumatic fever.
Follow-up culture of throat swabs is not routinely indicated in asymptomatic patients who have received a complete course of therapy for GAS pharyngitis (A-II), except in those with a history of rheumatic fever. Follow-up throat culture should also be considered in patients who develop acute pharyngitis during outbreaks of ARF or acute poststreptococcal glomerulonephritis (PSGN), during outbreaks of GAS pharyngitis in closed or partially closed communities, and when "ping-pong" spread of GAS infection has been occurring within a family (B-III).2
Deterrence/Prevention
Uncertainty remains about the risk of secondary cases of invasive GAS disease developing among close contacts of an index case of GAS infection. The currently available evidence does not justify routine chemoprophylaxis in close contacts. All household contacts of a patient with invasive GAS disease should be informed of the clinical manifestations of invasive disease and counseled to seek immediate medical attention upon development of such symptoms.
Complications
Potential complications of GAS tonsillopharyngitis include peritonsillar abscess, otitis media, and sinusitis. Inferior intrathoracic spread may lead to necrotizing mediastinitis.22 Contiguous intracranial invasion may result in fatal meningitis.23
Necrotizing fasciitis carries high morbidity and mortality rates and can result in TSS with multiorgan failure.
Puerperal sepsis follows abortion or delivery when streptococci that colonize the genital tract invade the endometrium and enters the blood stream. Pelvic cellulitis, septic pelvic thrombophlebitis, pelvic abscess, and septicemia can occur. Peripartum genital tract infections with group B streptococci are relatively more common, but fatal peripartum GAS infections have been reported.24
Empyema develops in 30%-40% of pneumonia cases. Other complications of pneumonia include mediastinitis, pericarditis, pneumothorax, and bronchiectasis.
The nonsuppurative complications of GAS tonsillopharyngitis include ARF, rheumatic heart disease, and acute glomerulonephritis.
Prognosis
Acute proliferative PSGN carries a good prognosis, as more than 95% of patients recover spontaneously within 3-4 weeks with no long-term sequelae.
With appropriate treatment, pharyngitis and skin infections carry a good prognosis.
Invasive GAS disease carries an overall mortality rate of 10%-15%. TSS and necrotizing fasciitis carry higher morbidity and mortality rates.
Patient Education
For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center; Women's Health Center; and Ear, Nose, and Throat Center. Also, see eMedicine's patient education articles Sore Throat, Toxic Shock Syndrome, and Strep Throat.
Miscellaneous
Medicolegal Pitfalls
The index of suspicion for GAS infection should be very high in cases of acute pharyngitis and skin infections including impetigo, cellulitis, erysipelas, wound infection, and gangrene.
GAS infection can result in two nonsuppurative sequelae, acute rheumatic fever (ARF) and acute poststreptococcal glomerulonephritis (PSGN).
GAS are important organisms that cause necrotizing fasciitis and STSS. Both of these conditions are associated with high mortality rates unless treated promptly and aggressively.
Special Concerns
Acute rheumatic fever
General description: ARF is a delayed nonsuppurative sequela of GAS tonsillopharyngitis. Following the pharyngitis, a latent period of 2-3 weeks passes before the signs or symptoms of ARF appear. The disease presents with various clinical manifestations, including arthritis, carditis, chorea, subcutaneous nodules, and erythema marginatum.
Epidemiology: A streptococcal strain capable of causing bacterial pharyngitis is capable of causing rheumatic fever, although some exceptions have been noted.
Pathogenesis: The pathogenic mechanisms that lead to the development of ARF remain incompletely understood. It is clearly associated with streptococcal pharyngitis, but genetic susceptibility may exist. The evidence is insufficient that toxins
produced by the streptococci are important in
pathogenesis.
http://emedicine.medscape.com/article/228936-print
Genetic susceptibility: Rheumatic fever might be the result of host genetic predisposition. The disease gene may be transmitted either in an autosomal-dominant fashion or in an autosomal-recessive fashion, with limited penetrance. The disease gene has not yet been identified.
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