Most clinical isolates of streptococci that contain the group A antigen are S. pyogenes. It is a prototypical human pathogen. It is used here to illustrate general characteristics of streptococci and specific characteristics of the species. S. pyogenes is the main human pathogen associated with local or systemic invasion and poststreptococcal immunologic disorders. S. pyogenes typically produces large (1 cm in diameter) zones of β-hemolysis around colonies greater than 0.5 mm in diameter. They are PYR-positive (hydrolysis of l-pyrrolidony l-β-naphthylamide) and usually are susceptible to bacitracin.

Morphology and Identification

A. Typical Organisms

 Individual cocci are spherical or ovoid and are arranged in chains (Figure 1). The cocci divide in a plane perpendicular to the long axis of the chain. The members of the chain often have a striking diplococcal appearance, and rodlike forms are occasionally seen. The lengths of the chains vary widely and are conditioned by environmental factors. Streptococci are Gram-positive; however, as a culture ages and the bacteria die, they lose their Gram positivity and can appear to be Gram-negative; for some streptococci, this can occur after overnight incubation.

Fig1. Streptococci grown in blood culture showing Gram-positive cocci in chains. Original magnification × 1000.

Most group A strains produce capsules composed of hyaluronic acid. The capsules are most notice able in very young cultures. They impede phagocytosis. The hyaluronic acid capsule likely plays a greater role in virulence than is generally appreciated and together with M protein was believed to be an important factor in the resurgence of rheumatic fever (RF) in the United States in the 1980s and 1990s. The capsule binds to hyaluronic-acid-binding protein, CD44, present on human epithelial cells. Binding induces disruption of intercellular junctions allowing microorganisms to remain extracellular as they penetrate the epithelium. Capsules of other streptococci (eg, S. agalactiae and S. pneumoniae) are different. The S. pyogenes cell wall contains proteins (M, T, R antigens), carbohydrates (group specific), and peptidoglycans. Hairlike pili project through the capsule of group A streptococci. The pili consist partly of M protein and are covered with lipoteichoic acid. The latter is important in the attachment of streptococci to epithelial cells.

B. Culture

 Most streptococci grow in solid media as discoid colonies, usually 1–2 mm in diameter. S. pyogenes is β-hemolytic (Figure 2); other species have variable hemolytic characteristics.

Fig2. Group A β-hemolytic streptococci (S. pyogenes) after growth overnight on a 10-cm plate with 5% sheep blood agar. The small (0.5–1 mm diameter) white colonies are surrounded by diffuse zones of β-hemolysis 7–10 mm in diameter. (Courtesy of H Reyes.)

C. Growth Characteristics

 Energy is obtained principally from the utilization of glucose with lactic acid as the end product. Growth of streptococci tends to be poor on solid media or in broth unless enriched with blood or tissue fluids. Nutritive requirements vary widely among different species. The human pathogens are most exacting, requiring a variety of growth factors. Growth and hemolysis are aided by incubation in 10% CO₂ . Most pathogenic hemolytic streptococci grow best at 37°C. Most streptococci are facultative anaerobes and grow under aerobic and anaerobic conditions.

D. Variation

 Variants of the same Streptococcus strain may show different colony forms. This is particularly marked among S. pyogenes strains, giving rise to either matte or glossy colonies. Matte colonies consist of organisms that produce much M protein and generally are virulent. The S. pyogenes in glossy colonies tend to produce little M protein and are often not virulent.

Antigenic Structure

 A. M Protein

 This substance is a major virulence factor of S. pyogenes. M protein is a filamentous structure anchored to the cell mem brane that penetrates and projects from the streptococcal cell wall. When M protein is present, the streptococci are virulent, and in the absence of M type-specific antibodies, they are able to resist phagocytosis by polymorphonuclear leukocytes by inhibiting activation of the alternate complement pathway. S. pyogenes that lack M protein are not virulent. Immunity to infection with group A streptococci is related to the presence of type-specific antibodies to M protein. Because there are more than 150 types of M protein, a person can have repeated infections with S. pyogenes of different M types. Both groups C and G streptococci have genes homologous to the genes for M protein of group A, and M proteins similar to those of group A have been found on groups C and G streptococci.

The M protein molecule has a rodlike coiled structure that separates functional domains. The structure allows for a large number of sequence changes while maintaining function, and the M protein immunodeterminants, therefore, can readily change. There are two major structural classes of M protein, classes I and II.

It appears that M protein and perhaps other streptococcal cell wall antigens have an important role in the pathogenesis of rheumatic fever. Purified streptococcal cell wall membranes induce antibodies that react with human cardiac sarcolemma; the characteristics of the cross-reactive antigens are not clear. A component of the cell wall of selected M types induces antibodies that react with cardiac muscle tissue. Conserved antigenic domains on the class I M protein cross react with human cardiac muscle, and the class I M protein may be a virulence determinant for rheumatic fever.

Toxins and Enzymes

 More than 20 extracellular products that are antigenic are elaborated by S. pyogenes, including the following.

A. Streptokinase (Fibrinolysin)

Streptokinase is produced by many strains of group A β-hemolytic streptococci. It transforms the plasminogen of human plasma into plasmin, an active proteolytic enzyme that digests fibrin and other proteins, allowing the bacteria to escape from blood clots. This process of digestion may be interfered with by nonspecific serum inhibitors and by a specific antibody, antistreptokinase. Streptokinase has been given intravenously for treatment of pulmonary emboli, coronary artery, and venous thromboses.

B. Deoxyribonucleases

 Streptococcal deoxyribonucleases A, B, C, and D degrade DNA (DNases) and similar to streptokinase facilitate the spread of streptococci in tissue by liquefying pus. The enzymatic activity can be measured by the decrease in viscosity of known DNA solutions. Purulent exudates owe their viscosity largely to deoxyribonucleoprotein. Mixtures of streptokinase and DNases are used in “enzymatic debridement.” They help to liquefy exudates and facilitate removal of pus and necrotic tissue; antimicrobial drugs thus gain better access, and infected surfaces recover more quickly. An antibody to DNAse develops after streptococcal infections (normal limit, 100 units), especially after skin infections.

C. Hyaluronidase

 Hyaluronidase splits hyaluronic acid, an important com ponent of the ground substance of connective tissue. Thus, hyaluronidase aids in spreading infecting microorganisms (spreading factor). Hyaluronidases are antigenic and specific for each bacterial or tissue source. After infection with hyaluronidase-producing organisms, specific antibodies are found in the serum.

D. Pyrogenic Exotoxins (Erythrogenic Toxin)

Pyrogenic exotoxins are elaborated by S. pyogenes. There are three antigenically distinct streptococcal pyrogenic exotoxins (Spe): A, B, and C. SpeA has been most widely studied. It is produced by group A streptococci that carry a lysogenic phage. The streptococcal pyrogenic exotoxins have been associated with streptococcal toxic shock syndrome and scarlet fever. Most strains of group A streptococci isolated from patients with streptococcal toxic shock syndrome either produce Spe A or have the gene that codes for it; in contrast, only about 15% of group A streptococci isolated from other patients have the gene. Spe C, also encoded by a phage, may contribute to the syndrome. Spe B, a potent protease, interferes with phagocytosis. The group A streptococci associated with toxic shock syndrome are primarily of M protein types 1 and 3.

The pyrogenic exotoxins act as superantigens, which stimulate T cells by binding to the class II major histocompatibility complex in the V_β region of the T-cell receptor. The activated T cells release cytokines that mediate shock and tis sue injury. The mechanisms of action appear to be similar to those caused by staphylococcal toxic shock syndrome toxin-1 and the staphylococcal enterotoxins.

E. Hemolysins

The β-hemolytic group A S. pyogenes elaborates two hemolysins (streptolysins) that not only lyse the membranes of erythrocytes but also damage a variety of other cell types. Streptolysin O is a protein (molecular weight [MW], 60,000) that is hemolytically active in the reduced state (available SH groups) but rapidly inactivated in the presence of oxygen. Streptolysin O is responsible for some of the hemolysis seen when growth occurs in cuts made deep into the medium in blood agar plates. It combines quantitatively with anti streptolysin O (ASO), an antibody that appears in humans after infection with any streptococci that produce streptolysin O. This antibody blocks hemolysis by streptolysin O. This phenomenon forms the basis of a quantitative test for the antibody. An ASO serum titer in excess of 160–200 units is considered abnormally high and suggests either recent infection with S. pyogenes or persistently high antibody levels caused by an exaggerated immune response to an earlier exposure in a hypersensitive person. Streptolysin S is the agent responsible for the hemolytic zones around streptococcal colonies growing on the surface of blood agar plates. It is elaborated in the presence of serum—hence the name streptolysin S. It is not antigenic. Most isolates of S. pyogenes produce both of these hemolysins. Up to 10% produce only one.

Pathogenesis and Clinical Findings

 A variety of distinct disease processes are associated with S. pyogenes infections. The infections can be divided into several categories.

A. Diseases Attributable to Invasion by S. pyogenes, β-Hemolytic Group A Streptococci

 The portal of entry determines the principal clinical picture. In each case, however, there is a diffuse and rapidly spreading infection that involves the tissues and extends along lymphatic pathways with only minimal local suppuration. From the lymphatics, the infection can extend to the bloodstream.

1. Erysipelas—If the portal of entry is the skin, erysipelas results. Lesions are raised and characteristically red. There is massive brawny edema and a rapidly advancing, sharply demarcated margin of infection.

2. Cellulitis—Streptococcal cellulitis is an acute, rapidly spreading infection of the skin and subcutaneous tissues. It follows infection associated with mild trauma, burns, wounds, or surgical incisions. Pain, tenderness, swelling, and erythema occur. Cellulitis is differentiated from erysipelas by two clinical findings: In cellulitis, the lesion is not raised, and the line between the involved and uninvolved tissue is indistinct.

3. Necrotizing fasciitis (streptococcal gangrene)—There is extensive and very rapidly spreading necrosis of the skin, tissues, and fascia. Bacteria other than S. pyogenes can also cause necrotizing fasciitis. The group A streptococci that cause necrotizing fasciitis have sometimes been termed flesh-eating bacteria.

 4. Puerperal fever—If the streptococci enter the uterus after delivery, puerperal fever develops, which is essentially a septicemia originating in the infected wound (endometritis).

5. Bacteremia or sepsis—Infection of traumatic or surgical wounds with streptococci results in bacteremia, which can rapidly be fatal. S. pyogenes bacteremia can also occur with skin infections, such as cellulitis and rarely pharyngitis.

B. Diseases Attributable to Local Infection with S. pyogenes and Their By-products

1. Streptococcal sore throat—The most common infection caused by β-hemolytic S. pyogenes is streptococcal sore throat or pharyngitis. S. pyogenes adheres to the pharyngeal epithelium by means of lipoteichoic acid-covered sur face pili and by means of hyaluronic acid in encapsulated strains. The glycoprotein fibronectin (MW, 440,000) on epithelial cells probably serves as lipoteichoic acid ligand. In infants and small children, the sore throat occurs as a subacute nasopharyngitis with a thin serous discharge and little fever but with a tendency of the infection to extend to the middle ear and the mastoid. The cervical lymph nodes are usually enlarged. The illness may persist for weeks. In older children and adults, the disease is more acute and is characterized by intense nasopharyngitis, tonsillitis, and intense redness and edema of the mucous membranes, with purulent exudate; enlarged, tender cervical lymph nodes; and (usually) a high fever. Twenty percent of infections are asymptomatic. A similar clinical picture can occur with infectious mononucleosis, diphtheria, gonococcal infection, and adenovirus infection.

S. pyogenes infection of the upper respiratory tract does not usually involve the lungs. Pneumonia, when it does occur, is rapidly progressive and severe and is most commonly a sequela to viral infections, such as influenza or measles, which seem to greatly enhance the predisposition to bacterial superinfection with this and other pathogens, such as S. pneumoniae.

2. Streptococcal pyoderma—Local infection of superficial layers of skin, especially in children, is called impetigo. It consists of superficial vesicles that break down and eroded areas whose denuded surface is covered with pus and later is encrusted. It spreads by continuity and is highly communicable, especially in hot, humid climates. More wide spread infection occurs in eczematous or wounded skin or in burns and may progress to cellulitis. Group A streptococcal skin infections are often attributable to M types 49, 57, and 59–61 and may precede glomerulonephritis (GN) but do not lead to rheumatic fever.

A clinically identical infection can be caused by Staphylococcus aureus and sometimes both S. pyogenes and S. aureus are present.

C. Invasive Group A Streptococcal Infections, Streptococcal Toxic Shock Syndrome, and Scarlet Fever

 Fulminant, invasive S. pyogenes infections with streptococcal toxic shock syndrome are characterized by shock, bacteremia, respiratory failure, and multiorgan failure. Death occurs in about 30% of patients. The infections tend to occur after minor trauma in otherwise healthy persons with several presentations of soft tissue infection. These include necrotizing fasciitis, myositis, and infections at other soft tissue sites; bacteremia occurs frequently. In some patients, particularly those infected with group A streptococci of M types 1 or 3, the disease presents with focal soft tissue infection accompanied by fever and rapidly progressive shock with multi organ failure. Erythema and desquamation may occur. The S. pyogenes of the M types 1 and 3 (and types 12 and 28) that make pyrogenic exotoxin A or B are associated with the severe infections.

Pyrogenic exotoxins A–C also cause scarlet fever in association with S. pyogenes pharyngitis or with skin or soft tissue infection. The pharyngitis may be severe. The rash appears on the trunk after 24 hours of illness and spreads to involve the extremities. Streptococcal toxic shock syndrome and scarlet fever are clinically overlapping diseases.

D. Poststreptococcal Diseases (Rheumatic Fever, Glomerulonephritis)

After an acute S. pyogenes infection, there is a latent period of 1–4 weeks (mean 7 days), after which nephritis or rheumatic fever occasionally develops. The latent period suggests that these poststreptococcal diseases are not attributable to the direct effect of disseminated bacteria but instead represent a hypersensitivity response. Nephritis is more commonly preceded by infection of the skin; rheumatic fever is more commonly preceded by infection of the respiratory tract.

1. Acute glomerulonephritis—This sometimes develops 1–5 weeks (mean 7 days) after S. pyogenes skin infection (pyoderma, impetigo) or pharyngitis. Some strains are particularly nephritogenic, principally with M types 2, 42, 49, 56, 57, and 60 (skin). Other nephritogenic M types associated with throat infections and glomerulonephritis are 1, 4, 12, and 25. After random streptococcal skin infections, the incidence of nephritis is less than 0.5%.

Glomerulonephritis may be initiated by antigen— antibody complexes on the glomerular basement mem brane. The most important antigens are thought to be SpeB and a nephritis-associated plasmin receptor. In acute nephritis, the patient has blood and protein in the urine, edema, high blood pressure, and urea nitrogen retention; serum complement levels are also low. A few patients die, some develop chronic glomerulonephritis with ultimate kidney failure, and the majority recovers completely.

2. Rheumatic fever—This is the most serious sequela of S. pyogenes because it results in damage to heart muscle and valves. Certain strains of group A streptococci contain cell membrane antigens that cross-react with human heart tissue antigens. Sera from patients with rheumatic fever contain antibodies to these antigens.

The onset of acute rheumatic fever (ARF) is often pre ceded by S. pyogenes pharyngitis 1–5 weeks (mean 19 days) earlier, although the infection may be mild and may not be detected. In general, however, patients with more severe streptococcal sore throats have a greater chance of developing rheumatic fever. Rheumatic fever is not associated with cutaneous streptococcal infections. In the 1950s, untreated streptococcal infections were followed by rheumatic fever in up to 3% of military personnel and 0.3% of civilian children. In the 1980s through 2000 a resurgence of ARF occurred in the United States. M types 1, 3, 5, 6, and 18 were most frequently involved. Since that time, the incidence has once again declined. Rheumatic fever occurs up to 100 times more frequently in tropical countries and is the most important cause of heart disease in young people in developing countries.

Typical symptoms and signs of rheumatic fever include fever, malaise, a migratory nonsuppurative polyarthritis, and evidence of inflammation of all parts of the heart (endocardium, myocardium, and pericardium). The cardi tis characteristically leads to thickened and deformed valves and to small perivascular granulomas in the myocardium (Aschoff bodies) that are finally replaced by scar tissue. Patients may develop severe and progressive congestive heart failure. Sydenham’s chorea is another manifestation of ARF and is characterized by involuntary, uncoordinated movements and associated muscle weakness. It has been hypothesized that other types of neurobehavioral conditions may also follow streptococcal infections. These are referred to as PANDAS—post-streptococcal autoimmune, neuropsychiatric disorders associated with streptococci. More research is required to definitely establish a link to S. pyogenes infections.

Erythrocyte sedimentation rates, serum transaminase levels, electrocardiograms, and other tests are used to estimate rheumatic activity.

Whereas rheumatic fever has a marked tendency to be reactivated by recurrent streptococcal infections, nephritis does not. The first attack of rheumatic fever usually produces only slight cardiac damage, which, however, increases with each subsequent attack. It is therefore important to protect such patients from recurrent S. pyogenes infections by pro phylactic penicillin administration.

Diagnostic Laboratory Tests

 A. Specimens

Specimens to be obtained depend on the nature of the streptococcal infection. A throat swab, pus, cerebrospinal fluid or other sterile body fluid, or blood is obtained for culture. Serum is obtained for antibody determinations.

B. Smears

Smears from pus often show single cocci or pairs rather than definite chains. Cocci are sometimes Gram-negative because the organisms are no longer viable and have lost their ability to retain the blue dye (crystal violet) and be Gram-positive. If smears of pus show streptococci but cultures fail to grow, anaerobic organisms must be suspected. Smears of throat swabs are rarely contributory because viridans streptococci are always present and have the same appearance as group A streptococci on stained smears.

C. Culture

Specimens suspected of containing streptococci are cultured on blood agar plates. If anaerobes are suspected, suitable anaerobic media must also be inoculated. Incubation in 10% CO2 often speeds hemolysis. Slicing the inoculum into the blood agar has a similar effect because oxygen does not readily diffuse through the medium to the deeply embedded organ isms, and it is oxygen that inactivates streptolysin O.

Blood cultures will grow hemolytic group A streptococci (eg, in sepsis) within hours or a few days. Certain α-hemolytic streptococci and enterococci may grow slowly, so blood cultures in cases of suspected endocarditis may not turn positive for a few days.

The degree and kind of hemolysis (and colonial appearance) may help place an organism in a definite group. S. pyogenes can be identified by rapid tests specific for the presence of the group A-specific antigen and by the PYR test. Streptococci belonging to group A may be presumptively identified by inhibition of growth by bacitracin, but this should be used only when more definitive tests are not available.

D. Antigen Detection Tests

 Several commercial kits are available for rapid detection of group A streptococcal antigen from throat swabs. These kits use enzymatic or chemical methods to extract the anti gen from the swab, then use enzyme immunoassay (EIA) or agglutination tests to demonstrate the presence of the antigen. The tests can be completed in minutes to hours after the specimen is obtained. They are 60–90% sensitive, depending on the prevalence of the disease in the population, and 98–99% specific compared with culture methods. More sensitive assays that use DNA probes or nucleic acid amplification techniques are now available and are beginning to replace the earlier anti gen detection tests, although they remain more costly.

E. Serologic Tests

A rise in the titer of antibodies to many group A streptococ cal antigens can be estimated. Such antibodies include ASO, particularly in respiratory disease; anti-DNase B and anti hyaluronidase, particularly in skin infections; antistreptoki nase; anti-M type-specific antibodies; and others. Of these, the anti-ASO titer is most widely used.

Immunity

 Resistance against streptococcal diseases is M type specific. Thus, a host who has recovered from infection by one group A streptococcal M type is relatively immune to reinfection by the same type but fully susceptible to infection by another M type. Anti-M type-specific antibodies can be demonstrated in a test that exploits the fact that streptococci are rapidly killed after phagocytosis. M protein interferes with phagocytosis, but in the presence of type-specific antibody to M protein, streptococci are killed by human leukocytes.

Antibody to streptolysin O develops after infection; it blocks hemolysis by streptolysin O but does not indicate immunity. High titers (>250 units) indicate recent or repeated infections and are found more often in rheumatic individuals than in those with uncomplicated streptococcal infections.

Treatment

 All S. pyogenes are uniformly susceptible to penicillin G. Macrolides, such as erythromycin and clindamycin, have often been recommended for penicillin-allergic patients and for patients with necrotizing fasciitis. However, resistance to macrolide antibiotics has been increasing in Europe and in the United States. Some are resistant to tetracyclines. Antimicrobial drugs have no effect on established glomerulonephritis and rheumatic fever. In acute streptococcal infections, however, every effort must be made to rapidly eradicate streptococci from the patient, eliminate the antigenic stimulus (before day 8), and thus prevent poststreptococcal disease. Doses of penicillin or erythromycin that result in effective tissue levels for 10 days usually accomplish this. Antimicrobial drugs are also very useful in preventing reinfection with β-hemolytic group A streptococci in patients with rheumatic fever.

Epidemiology, Prevention, and Control

 Although humans can be asymptomatic nasopharyngeal or perineal carriers of S. pyogenes, the organism should be considered significant if it is detected by culture or other means. The ultimate source of group A streptococci is a person harboring these organisms. The individual may have a clinical or subclinical infection or may be a carrier distributing streptococci directly to other persons via droplets from the respiratory tract or skin. The nasal discharges of a person harboring S. pyogenes are the most dangerous source for spread of these organisms.

Many other streptococci (eg, viridans streptococci and enterococci) are members of the normal microbiota of the human body. They produce disease only when established in parts of the body where they do not normally occur (eg, heart valves). To prevent such accidents, particularly in the course of surgical procedures on the respiratory, gastrointestinal, and urinary tracts that result in temporary bacteremia, antimicrobial agents are often administered prophylactically to persons with known heart valve deformity and to those with prosthetic valves or joints. Guidelines published by the American Heart Association and other professional societies have clarified some of these recommendations (see Wilson et al, 2007).

1. Detection and early antimicrobial therapy of respiratory and skin infections with group A streptococci. Prompt eradication of streptococci from early infections can effectively prevent the development of poststreptococcal disease. This requires maintenance of adequate penicillin levels in tissues for 10 days (eg, benzathine penicillin G given once intramuscularly). Erythromycin is an alternative drug, although many S. pyogenes are now resistant.

2. Antistreptococcal chemoprophylaxis in persons who have suffered an attack of rheumatic fever. This involves giving one injection of benzathine penicillin G intramuscularly every 3–4 weeks or daily oral penicillin or oral sulfonamide. The first attack of rheumatic fever infrequently causes major heart damage; however, such persons are particularly susceptible to reinfections with streptococci that precipitate relapses of rheumatic activity and give rise to cardiac damage. Chemoprophylaxis in such individuals, especially children, must be continued for years. Chemo prophylaxis is not used in glomerulonephritis because of the small number of nephritogenic types of streptococci. An exception may be family groups with a high rate of poststreptococcal nephritis.

3. Eradication of S. pyogenes from carriers. This is especially important when carriers are in areas such as obstetric delivery rooms, operating rooms, classrooms, or nurseries. Unfortunately, it is often difficult to eradicate β-hemolytic streptococci from permanent carriers, and individuals may occasionally have to be shifted away from “sensitive” areas for some time.

اخر الاخبار

اخبار العتبة العباسية المقدسة

فرقة العباس تنظم مجلس عزائها السنوي بذكرى شهادة النبي (صلى الله عليه وآله) في النجف

قسم الشؤون الفكرية وجامعة الكوفة يعقدان شراكة علمية لتدريب الطلبة على صيانة المخطوطات وحفظها

بالتزامن مع ذكرى شهادته.. قسم الشؤون الفكرية يصدر كتابًا عن النبي الأعظم (صلى الله عليه وآله)

بالصور.. جموع المؤمنين تحيي ذكرى شهادة الرسول الأكرم عند مرقد الإمام علي (صلوات الله عليهما)

المزيد

الآخبار الصحية

لون أسنانك يتحدث عن صحتك.. إليك ما يقول

عادة يومية بسيطة تخفض الكوليسترول وتحمي القلب

الزنجبيل.. دواء سحري لحماية القلب

المشروبات شديدة السخونة.. "خطر خفي" يهدد صحتك

المزيد

الآخبار التكنلوجية

كيف يمكن لعادات القيادة السيئة أن تؤثر على قيمة سيارتك

في طوفان الذكاء الاصطناعي.. نصائح لحجز "تذكرة النجاة"

هكذا يسرق "قراصنة الذكاء الاصطناعي" المليارات بطرق بسيطة

فيديو لانفجار كرة نارية في سماء اليابان.. ما تفسير ذلك؟

المزيد

مواضيع ذات صلة

Treatment of Staphylococci

Enzymes and Toxins of Staphylococci

Rocky Mountain Spotted Fever

Human Ehrlichiosis

Antimicrobial Susceptibility Testing and Therapy of Neisseria and Moraxella catarrhalis

Laboratory Diagnosis of Neisseria and Moraxella catarrhalis

Spirillum Minus

Streptobacillus moniliformis

Myositis and Myonecrosis

Necrotizing Fasciitis

Cellulitis

Laboratory Diagnosis of Francisella