Streptococcus pyogenes

Somatic Constituents

The organism is enveloped in a hyaluronic acid capsule that serves as an accessory virulence factor in retarding phagocytosis by polymorphonuclear neutrophils (PMNs) and macrophages of the host.^6,7 Streptococcal strains vary greatly in their degree of encapsulation, and those with the most exuberant capsule production have a mucoid appearance when cultivated on blood agar plates. In certain heavily encapsulated group A streptococcal strains, the capsule may take precedence over M protein in mediating resistance to phagocytosis.⁷ Group A streptococcal capsular hyaluronate is chemically similar to that found in human connective tissue. For this reason, it is a poor immunogen, and antibodies to group A streptococcal hyaluronic acid have not been demonstrated in humans.

The cell wall is a complex structure containing many different antigenic substances. The group-specific carbohydrate of group A strains is a dimer of rhamnose and N-acetylglucosamine in a ratio of approximately 2 : 1. The mucopeptide (peptidoglycan) layer provides rigidity to the cell wall; it is composed of polymers of repeating subunits of N-acetylglucosamine and N-acetylmuramic acid connected by amino acid side chains.

M protein is the major somatic virulence factor of group A streptococci. Strains rich in this protein are resistant to phagocytosis by PMNs, multiply rapidly in fresh human blood, and are capable of initiating disease. Strains that do not express M protein are avirulent.⁸ Group A streptococcus may be divided into serotypes on the basis of antigenic differences in M protein molecules and more recently into genotypes on the basis of nucleotide differences in the emm gene encoding the molecule. More than 150 such serotypes and/or genotypes are currently recognized.⁹ Acquired human immunity to streptococcal infection is based on the development of opsonic antibodies directed against the antiphagocytic moiety of M protein. Such immunity is type specific and quite durable, lasting for many years and perhaps indefinitely.

M protein is a filamentous macromolecule that exists as a stable dimer with an α-helical coiled coil structure.¹⁰ The molecule, which is anchored to the cell membrane, traverses and penetrates the cell wall. The more proximal portion of the molecule contains epitopes widely conserved among group A streptococci, whereas the more distal portion contains type-specific epitopes.¹¹ This configuration localizes the type-specific moiety on the tips of fibrils protruding from the cell surface (Fig. 199-1). In the nonimmune host, M protein exerts its antiphagocytic effect by inhibiting activation of the alternate complement pathway on the cell surface.^12,13 Such inhibition appears to be mediated by the binding to the M protein molecule of host proteins, among which are complement control proteins (factor H, a factor H–like protein, and human C4b-binding protein)^14-16 and fibrinogen.^17-19 The antiphagocytic effect is nullified in the presence of adequate concentrations of type-specific antibody. There is evidence that immunity caused by opsonic anti–M-type antibody may be strain and not type specific.^20,21M proteins analogous to those of group A streptococcus are present in many strains of groups C²² and G²³ streptococci.

Additional surface proteins related to M protein have now been identified. Although their structure is overall similar to that of M protein, they differ in the types of repeats and in their ability to interact with different human proteins. Genes encoding these proteins (e.g., enn, mrp, fcrA, arp, protH) have been designated as members of the emm gene superfamily. A number of the M-like proteins bind IgG or IgA at the non–antigen-binding site and appear to be cooperative with M protein in antiphagocytic effect.^24,25 Indeed, a notable function of the M protein family is its ability to bind to a wide range of host proteins, including, among others, albumin, fibrinogen, and plasminogen. Still other anti-opsonic surface proteins continue to be described.²⁶ For example, Mac, a secreted group A streptococcal protein with homology to a human β₂-integrin, binds to CD16 on the surface of human PMNs and inhibits phagocytosis and bacterial killing.²⁷ An additional surface protein, streptococcal heme-associated protein (Shp), has been found in M1 strains of group A streptococci, which likely has a role in transport of iron intracellularly. Antibody against Shp has been found in convalescent sera and has opsonic capability.²⁸ These observations underscore the extreme virtuosity with which the bacterium develops multiple mechanisms to evade phagocytic killing.

A protein antigen very closely associated with the M protein molecule of group A streptococci is the so-called serum opacity factor (OF). This factor is an α-lipoproteinase that is detected by its ability to opacify horse serum and that also has fibronectin-binding properties.²⁹ Strains of a minority of the currently identified M types elaborate this antigen.³⁰ OF itself is antigenic and type-specific—that is, its ability to opacify serum can be specifically inhibited by antiserum raised against homologous but not heterologous M types. Type-specific and non–type-specific immune responses to streptococcal M protein are generally weaker after pharyngeal infection with OF-positive than with OF-negative types.³¹ The former importance of this substance as an ancillary typing system for strains that could not be M serotyped has been obviated by the advent of emm genotyping. Interestingly, antibody against OF has opsonic activity and has been shown to synergize with anti–M protein antibody in protecting mice against challenge with OF-positive strains.³²

A number of somatic streptococcal constituents play critical roles in the first step of colonization, namely, adherence to the surface of human epithelial cells. At least 17 adhesin candidates have been described,³³ but the most extensively studied have been lipoteichoic acid (LTA), M protein, and fibronectin-binding proteins. Through hydrophobic interactions, LTA serves as a “first-step” adhesin, bringing the organisms into close contact with host cells and then allowing other adhesins to promote high-affinity binding.³⁴ Although M protein does not appear to promote adhesion to human buccal or tonsillar epithelial cells,^35,36 it does mediate adherence to skin keratinocytes via the attachment of the C repeat region to keratinocyte membrane cofactor CD46.^37,38 Group A streptococcal surface proteins that bind fibronectin have been studied extensively and are important in adherence to both throat and skin. These include protein F1 (PrtF1),³⁹ also known as SfbI (streptococcal fibronectin-binding protein I),⁴⁰ and related proteins known as SbfII,⁴¹ FBP54,⁴² protein F2,⁴³ and PFBB.⁴⁴

Moreover, the expression of these adhesins has been reported to be environmentally regulated.⁴⁵ Expression of protein F1 is enhanced in an oxygen-rich environment, whereas that of M protein is greater at higher partial pressures of carbon dioxide.⁴⁶ Thus, teleologically, it might be postulated that the organism displays protein F1 on its surface when it seeks to adhere to the cutaneous surface but expresses M protein in the deeper tissues, where it is more likely to encounter phagocytic cells.

Extracellular Products

During the course of growth in vitro or in vivo, group A streptococcus elaborates numerous extracellular products, only a limited number of which have been well characterized. Two distinct hemolysins have been elaborated. Streptolysin O derives its name from its oxygen lability. It is reversibly inhibited by oxygen and irreversibly inhibited by cholesterol. In addition to its effect on erythrocytes, it is toxic to a variety of cells and cell fractions, including PMNs, platelets, tissue culture cells, lysosomes, and isolated mammalian and amphibian hearts. Streptolysin O is produced by almost all strains of S. pyogenes (as well as many group C and G organisms) and is antigenic. Measurement of anti–streptolysin O antibodies in human sera is useful as an indicator of recent streptococcal infection.

Streptolysin S is a hemolysin produced by streptococci growing in the presence of serum (hence the “S”) or in the presence of a variety of other substances such as serum albumin, α-lipoprotein, ribonucleic acid, or detergents such as Tween. Streptolysin S is nonantigenic, or at least no antibody to it has been detected that neutralizes its hemolytic activity. Streptolysin S shares with streptolysin O the capacity to damage the membranes of PMNs, platelets, and subcellular organelles. Unlike streptolysin O, it is not inactivated by oxygen, but it is thermolabile. Most strains of S. pyogenes produce both hemolysins. Hemolysis on the surface of blood agar plates is primarily caused by streptolysin S, whereas streptolysin O exerts its hemolytic effect best in subsurface colonies, in pour plates, or in anaerobic cultures. An occasional strain may produce only one of the two hemolysins. Rarely, strains are encountered that lack both hemolysins.

Several extracellular products may theoretically serve to facilitate the liquefaction of pus and the spreading of streptococci through tissue planes characteristic of streptococcal cellulitis and necrotizing fasciitis. These include the following: (1) four antigenically distinct enzymes that participate in the degradation of deoxyribonucleic acid (DNases A, B, C, and D); (2) hyaluronidase, which enzymatically degrades hyaluronic acid found in the ground substance of connective tissue; (3) streptokinase, which promotes the dissolution of clots by catalyzing the conversion of plasminogen to plasmin; (4) streptococcal pyrogenic exotoxin B (SpeB), which is a potent protease; and (5) C5a peptidase, which specifically cleaves the human chemotaxin C5a at the PMN binding site.^47,48 SpeB also cleaves IgG bound to group A streptococcus, thus interfering with ingestion and killing by phagocytes.⁴⁹

The streptococcal pyrogenic exotoxins are a family of bacterial superantigens believed to be associated with streptococcal toxic shock syndrome (strep TSS), necrotizing fasciitis, and other severe infections. This family includes the bacteriophage-encoded SpeA⁵⁰ and SpeC, historically known as the scarlatinal toxins because of their association with scarlet fever, as well as the cysteine protease SpeB; a number of additional pyrogenic exotoxins (e.g., mitogenic factor [MF, SpeF], and streptococcal superantigen [SSA]) have more recently been identified.⁵¹

Superantigens are potent immunostimulators able to bind simultaneously to the major histocompatibility complex (MHC) class II molecule and specific V-β regions of the T-cell receptor.⁵² This binding results in clonal proliferation of these T cells. Superantigen activation of T cells leads to increased secretion of proinflammatory cytokines produced by both antigen presenting cells and T lymphocytes. This issue is discussed in more detail later in the section on pathogenesis of streptococcal toxic shock syndrome.

Emerging concepts regarding the molecular biology of streptococcal virulence, colonization, and tissue invasion have been reviewed.^51,53 Control of the expression of the heretofore-mentioned virulence factors over time and under diverse environmental circumstances depends on a complex system of genetic modulation. Of the known transcriptional regulators in S. pyogenes, the two most intensively studied are Mga⁵⁴ (multiple gene regulator) or Mry (regulator of M protein expression) and a two-component regulatory system known as CsrRS⁵⁵ (capsule synthesis regulator) or, alternatively, CovRS⁵⁶ (control of virulence genes), which represses the synthesis of the capsule and several exotoxins.⁵⁷ The regulator of proteinase B (RopB) has been shown to have various polymorphisms that regulate the virulence of S. pyogenes.⁵⁸

Clinical Manifestations

The usual incubation period of streptococcal pharyngitis is 2 to 4 days. The onset of illness is heralded by the rather abrupt onset of sore throat accompanied by malaise, feverishness, and headache. Nausea, vomiting, and abdominal pain are common in children. Prominent physical findings include redness, edema, and lymphoid hyperplasia of the posterior portion of the pharynx; enlarged, hyperemic tonsils; patchy discrete tonsillopharyngeal exudates (Fig. 199-3); enlarged, tender lymph nodes at the angles of the mandibles; and a temperature of 38.3° C (101° F) or higher. In the absence of these symptoms and signs, simple coryza, hoarseness, cough, or conjunctivitis does not suggest the presence of streptococcal infection. Laboratory findings include a positive throat culture for β-hemolytic streptococci and a total white blood cell count usually exceeding 12,000/mm³, with increased numbers of PMNs. The test for C-reactive protein is usually positive.⁶⁰

Not all patients with streptococcal pharyngitis have the full-blown syndrome just described. Endemically occurring infections in open populations manifest a wide spectrum of clinical severity. For example, only approximately 50% of such patients with sore throats and positive throat cultures have tonsillar or pharyngeal exudates. Patients who have undergone tonsillectomy tend to experience a milder clinical syndrome. In infants, the response to streptococcal infection is much less sharply focalized to the lymphoid tissue of the faucial and posterior pharyngeal area. Rhinorrhea, suppurative complications, low-grade fever, and a more protracted course tend to characterize infections at this age. Exudative pharyngitis in children younger than 3 years is rarely streptococcal in cause.

In the absence of suppurative complications, the disease is self-limited. Fever abates within 3 to 5 days. Almost all acute signs and symptoms subside within 1 week, although several additional weeks may be required for tonsils and lymph nodes to return to their usual size. Penicillin shortens the period of fever, toxicity, and infectivity.^61-63 Given the rather brief time course of untreated disease, however, such shortening of the clinical syndrome may not be striking unless therapy is initiated within the first 24 hours of illness. Antibiotic treatment shortens the clinical symptoms by 24 hours, and the main reason for treatment is the prevention of rheumatic fever.⁶⁴

Diagnosis

Pharyngitis and tonsillitis may be caused by infectious agents other than S. pyogenes.^59,68 Among these are streptococci of groups C^69,70 and G.^71-73 Corynebacterium diphtheriae, the other major bacterial pathogen associated with exudative pharyngitis, is now extremely rare in the United States⁷⁴ and, when it occurs in the classic form, is differentiated by the appearance of the diphtheritic membrane, respiratory embarrassment, severe systemic toxicity, and myocardial and neurologic manifestations. Other bacterial agents such as Neisseria gonorrhoeae and perhaps Neisseria meningitidis occasionally cause pharyngitis, as does Mycoplasma pneumoniae.

Pharyngitis due to Arcanobacterium (formerly Corynebacterium) hemolyticum, although rare, may closely mimic that caused by S. pyogenes.^75,76 Arcanobacterium hemolyticum affects primarily teenagers and young adults, and the patients may exhibit both an exudative pharyngitis and a scarlatiniform rash. The organism is more readily identified on rabbit or human blood agar than on sheep blood agar. Another rare cause of acute pharyngitis is Yersinia enterocolitica.⁷⁷ Patients infected with this organism may appear quite ill and may or may not have associated enteric symptoms. When Y. enterocolitica pharyngitis is associated with disseminated yersiniosis, the mortality rate may be appreciable. Diagnosis depends on clinical clues because the organism is unlikely to be detected on routine throat cultures and antistreptococcal therapy is unavailing (see Chapter 231). The oropharyngeal form of tularemia is characterized by severe sore throat, exudative and ulcerative tonsillopharyngitis, and cervical adenopathy (see Chapter 229).

Acute pharyngitis is more frequently caused by viruses than by bacteria. Infectious mononucleosis and adenovirus infections frequently give rise to exudative pharyngitis and thus may closely mimic streptococcal sore throat. Herpes simplex viruses 1 and 2,^78-80 influenza,⁸¹ and parainfluenza viruses may also simulate streptococcal pharyngitis, as may initially the acute retroviral syndrome in human immunodeficiency virus infection. Pharyngitis associated with the acute retroviral syndrome is, however, not exudative.⁸² Even when careful microbiologic techniques are used to detect bacteria, mycoplasma, and viruses, no causative agent can be detected in a substantial proportion of all cases of acute sore throat.⁸³ A more complete discussion of the differential diagnosis of acute pharyngitis may be found in Chapter 59.

Approximately one fourth to one third of all children complaining of sore throat have a positive throat culture for group A streptococci. Of these, about half can be demonstrated to have immunologically significant infection, as judged by a significant rise in serum titer of one or more antistreptococcal antibodies. Many of the remainder are likely to be asymptomatic carriers, because the average carriage rate among school-aged children in temperate climates during the winter months may approximate 15% to 20%. Such asymptomatic carriers are at no risk for developing suppurative and nonsuppurative com­plications and do not require antibiotic therapy. Although acutely infected individuals tend to have more strongly positive throat cultures, this distinction cannot be made with confidence in patients whose signs and symptoms are compatible with those of streptococcal pharyngitis.

Numerous studies have tested the precision with which physicians may differentiate between streptococcal and nonstreptococcal sore throat by clinical criteria alone. In the presence of a classic scarlatinal rash or during a documented epidemic of streptococcal infections, such differentiation is usually easy. On the other hand, in the case of endemically occurring infections, the problem is much more complex. Certain clinical findings, particularly fever, sore throat, tonsillopharyngeal exudate, and tender, enlarged lymph nodes at the angles of the jaws, have a statistically significant correlation (approximately 85%) with the presence of positive throat cultures for group A streptococci.⁸⁴ Such findings are not diagnostic, however. Although only approximately 50% of patients with immunologically proven streptococcal sore throat have tonsillar exudate, a substantial proportion of cases of exudative pharyngitis are nonstreptococcal in cause.

It is possible to identify individual patients in which “strep throat” can be effectively excluded on a combination of epidemiologic (see earlier) and clinical grounds. For example, symptoms of the common cold are not caused by S. pyogenes. Similarly, the presence of hoarseness and conjunctivitis and the absence of fever or pharyngeal erythema make streptococcal pharyngitis very unlikely. A number of investigators have developed clinical algorithms in children and adults to assist in determining the likelihood that a particular patient has group A streptococcal pharyngitis.^84-90 These algorithms are useful and accurate in identifying patients whose risk for streptococcal infection is so low as to obviate the need for further microbiologic testing. Otherwise, such testing should be performed.

One published practice guideline^91,92 has suggested that in adults with features strongly suggestive of streptococcal pharyngitis, empirical antimicrobial therapy without microbiologic confirmation is an acceptable alternative. That guideline uses an algorithm, developed by Centor and co-workers,⁹⁰ using four clinical criteria—presence of tonsillar exudates, presence of swollen tender anterior cervical nodes (i.e., cervical lymphadenitis), lack of cough, and history of fever—that have been reported to be independently associated with the likelihood of a positive throat culture for group A streptococci.⁹³ A subsequent cost-effectiveness analysis⁹⁴ and two prospective clinical studies^95,96 have concluded that such empirical therapy is neither the most effective nor least expensive strategy for diagnosis of “strep throat” in adults. Furthermore, empirical therapy in adults leads to considerable overuse of antibiotics.⁹⁷ It is important to realize that the most common age group of streptococcal pharyngitis is in the 5- to 15-year age group. This is of particular concern in view of the fact that 73% of the 6.7 million adults visiting primary care providers annually in the United Sates with the complaint of sore throat receive a prescription for antibiotics.⁹⁸

Thus, for adults and children, expert panels of the Infectious Diseases Society of America,⁶⁴ American Heart Association,⁹⁹ and American Academy of Pediatrics¹⁰⁰ recommend that the presence of group A streptococci in the pharynx should be documented by a throat culture or rapid antigen detection test (RADT).^63,99,100 It should be noted that a positive test does not discriminate between active streptococcal infection versus colonization and a concomitant viral infection. Clinical criteria for streptococcal pharyngitis should be present before antibiotic treatment is considered.

Therapy

Antimicrobial therapy is indicated for individuals with symptomatic pharyngitis after the presence of the organism in the throat is confirmed by culture or RADT. The goals of antimicrobial therapy are (1) prevention of acute rheumatic fever, (2) prevention of suppurative complications, (3) improvement in clinical symptoms and signs, and (4) rapid decrease in infectivity so as to reduce transmission of group A β-hemolytic streptococci to family members, classmates, and other close contacts and to allow the rapid resumption of usual activities. There is no firm evidence that poststreptococcal acute glomerulonephritis is preventable by treatment of the antecedent streptococcal infection.¹¹²

Treatment of group A streptococcal sore throat as long as 9 days after onset is still effective for the prevention of rheumatic fever.¹¹³ Thus, if the patient is seen early in the course of his illness, the delay in initiation of therapy occasioned by obtaining a positive throat culture is not ordinarily a matter of concern in this regard. As noted, patients with signs and symptoms of acute pharyngitis and a positive rapid test (properly performed and interpreted) for group A carbohydrate antigen should receive appropriate antimicrobial therapy.

In the minority of patients who are severely ill or toxic at presentation and in whom there is clinical and epidemiologic evidence resulting in a high index of suspicion, oral antimicrobial therapy can be initiated while awaiting the results of the throat culture (either as a primary diagnostic tool or in confirmation of a negative RADT). If oral therapy is prescribed, a positive throat culture serves as a guide to the necessity of completion of a full antimicrobial course or, alternatively, of recalling the patient for an injection of penicillin G benzathine. Early initiation of antimicrobial therapy results in faster resolution of the signs and symptoms,^61-63 but group A streptococcal pharyngitis is usually a self-limited disease; fever and constitutional symptoms are markedly diminished within 3 or 4 days of onset, even without antimicrobial therapy.¹¹⁴ Thus, antimicrobial therapy initiated within the first 48 hours of onset hastens symptomatic improvement by only 1 to 2 days.

The drug of choice in the treatment of streptococcal infection is penicillin, because of its efficacy in the prevention of rheumatic fever, safety, narrow spectrum, and low cost (Table 199-1).^63,99,100 Prevention of acute rheumatic fever is believed to require eradication of the infecting streptococcus from the pharynx, an effect that depends on prolonged rather than high-dose penicillin therapy. This objective may be accomplished by the administration of a single injection of 1.2 million units of penicillin G benzathine. For children weighing 60 pounds (27 kg) or less, the dose is reduced to 600,000 units. Most physicians in the United States, however, elect to administer oral therapy. In this case, penicillin V, in one of the regimens listed in Table 199-1, must be continued for a full 10 days, Amoxicillin is often prescribed in preference to penicillin V in children requiring liquid medication because of poor palatability of oral suspensions of penicillin V. Once-daily amoxicillin therapy is effective for the treatment of group A streptococcal pharyngitis^115-117 in children. An oral time-release formulation of amoxicillin has recently been approved by the U.S. Food and Drug Administration (FDA) for once-daily treatment of group A streptococcal pharyngitis in adolescents and adults. Because of its convenience, low cost, and relatively narrow spectrum, once-daily amoxicillin is an acceptable alternative regimen for the treatment of group A β-hemolytic streptococcal pharyngitis.⁹⁹

A variable percentage of patients continue to harbor group A streptococci of the originating serotype in their pharynx after com­pletion of a course of oral penicillin.¹¹⁸ Such bacteriologic treatment failures are sometimes associated with symptomatic relapse. Because penicillin is ineffective in eradicating asymptomatic streptococcal pharyngeal carriage, apparent treatment failures may actually represent persistence of such carriage in patients with superimposed viral pharyngitis.¹¹⁹

Oral cephalosporins are highly effective in the treatment of streptococcal pharyngitis, and meta-analyses have suggested that streptococcal eradication rates and clinical cure rates attained with these agents are slightly higher in children and adults than those achieved with penicillin.^118,120,121 These analyses have, however, been strongly challenged on methodologic grounds.^122,123 It does appear that cephalosporins are more effective than penicillin in eradicating asymptomatic group A streptococcal carriage. Penicillin remains the recommended drug of choice.^63,99,100 In penicillin-allergic patients, macrolide (erythromycin or clarithromycin) or azalide (azithromycin) antimicrobial agents, clindamycin, or first-generation cephalosporins are the agents of choice.⁶³ The latter should be avoided in those with immediate (type I) penicillin hypersensitivity (see Table 199-1). Cephalosporins should not be administered to patients with a history of immediate (anaphylactic-type) hypersensitivity to penicillin. The physician should bear in mind the possibility of an increased risk for allergic reactions to cephalosporins when treating penicillin-allergic patients.

Erythromycin is less expensive than clarithromycin or azithromycin but may be associated with more gastrointestinal side effects. Although there have been reports of relatively high levels of resistance to macrolide antimicrobial agents from several countries,^124-126 as well as isolated reports of increased rates of macrolide resistance in certain localized areas of the United States,^127,128 such resistance does not appear to be widespread in this country at present. Three multistate surveillance studies conducted during 2002 and 2003 detected overall macrolide resistance rates of 3.8%,¹²⁹ 5.2%,¹³⁰ and 6.8%.¹³¹ However, given the increasing use of azalides for upper and lower respiratory tract infections, the situation may change. Physicians should therefore be cognizant of local patterns of antimicrobial resistance. In areas in which macrolide resistance is known to be prevalent, antimicrobial susceptibility testing should be performed if these agents are used to treat group A streptococcal infections. Furthermore, continued surveillance of national trends in macrolide susceptibility is warranted.

There has been considerable recent interest in abbreviated courses of antimicrobial therapy. It has been reported that second- and third-generation cephalosporins such as cefuroxime,^132,133 cefixime,¹³⁴ ceftibuten,¹³⁵ cefdinir,¹³⁶ cefpodoxime,¹³⁷ and cefditoren¹³⁸ are effective in eradication of group A streptococci from the pharynx when administered for 5 days, although not all of these are approved for a 5-day course of therapy for acute streptococcal pharyngitis by the FDA at the time of this writing. Although such shortened courses might theoretically enhance patient compliance, the potential ecologic effects of using these broad-spectrum agents to treat such a common bacterial infection are of great concern. This is particularly true should these agents be used as first-line therapy for “strep throat.” Moreover, even when administered for short courses, they are considerably more expensive than penicillin. Clearly, penicillin treatment is also associated with potential adverse effects.

Similar favorable results of short-course therapy have also been reported for the newer macrolides or azalides, clarithromycin,¹³⁹ and azithromycin.^140-143 Because of its long intracellular half-life and slow release from tissue sites, a 5-day course of azithromycin is approved by the American Heart Association⁹⁹ for use in penicillin-allergic patients. As noted, promiscuous use of macrolides has been associated with development of resistance by group A streptococci.^124,125

Because tetracycline-resistant group A streptococci are prevalent in many areas, this drug is not recommended. Sulfonamides, which are effective for the secondary prophylaxis of rheumatic fever (see Chapter 200), are ineffective for the eradication of pharyngeal organisms or the prevention of rheumatic fever when used as therapy for acute pharyngeal infections.

Patients with more severe suppurative infections, such as those involving the mastoid or ethmoid, may require higher doses of penicillin or other β-lactam antibiotics administered parenterally. When streptococcal upper respiratory tract infection is complicated by the development of abscesses associated with suppurative cervical adenitis or in the peritonsillar or retropharyngeal soft tissues, aspiration or incision and drainage is usually required.

Because prevention of rheumatic fever appears to require eradication of the streptococcal organism from the pharynx, treatment failures are of concern. In addition to true treatment failure (i.e., re-isolation of the original infecting streptococcal serotype shortly after completion of a full course of antibiotic therapy), causes of post-treatment culture positivity include failure of compliance with oral medication schedules and reinfection with the same or different streptococcal types in the home or school environment. Apparent failure may also occur when the patient is in reality a streptococcal carrier suffering from an acute viral pharyngitis. In everyday practice, it is often impossible to differentiate among these alternatives.

Nevertheless, routine reculture of the throat after a course of antistreptococcal therapy in an asymptomatic patient is not advised⁶³ because the cost-benefit ratio of such cultures continues to decline in parallel with the incidence of acute rheumatic fever in developed countries. Such cultures should be undertaken in high-risk circumstances (e.g., if the patient or a family member has a history of rheumatic fever) or when symptoms compatible with streptococcal infection persist or recur. When an increased incidence of acute rheumatic fever is detected in a community, as happened in a number of U.S. cities during the 1980s, the approach to streptococcal infection must be particularly rigorous, and serious consideration should be given to routine performance of post-treatment cultures. If reculture is undertaken, only a single re-treatment course is warranted for patients who still harbor group A streptococci. Re-treatment with an oral cephalosporin might be considered in view of the slightly increased eradication rates observed with these agents.

The presence of persistently but weakly positive throat cultures after repeated courses of antibiotic therapy in an otherwise asymptomatic patient is not a cause for alarm. Such persons are streptococcal carriers¹¹⁹ who are neither at risk for developing rheumatic fever nor likely to spread their infection to others. Their most frequent problem is anxiety produced by multiple medical consultations associated with the streptococcal colonization. In the event in which, for medical or psychological reasons, eradication of chronic streptococcal carriage becomes highly desirable, clindamycin,¹⁴⁴ amoxicillin-clavulanate,¹⁴⁵ or azithromycin may be efficacious.^63,146 Any of these antibiotic treatments can have adverse events such as Clostridium difficile colitis.

Streptococcal acquisition rates of 25% or higher have been recorded in family contacts. Certainly, family contacts with symptoms of upper respiratory tract infection should be cultured and treated appropriately if positive. Asymptomatic family contacts should also be cultured in high-risk circumstances, such as a family member who has had rheumatic fever or known cases of rheumatic fever or poststreptococcal glomerulonephritis occurring in the general area. In situations of lesser risk, routine culture of asymptomatic family contacts is not recommended.^63,99 The advisability of culture and/or prophylaxis of household contacts of patients with invasive group A streptococcal infection is discussed later.¹⁴⁶

There is no firm evidence to suggest that tonsillectomy reduces the incidence of rheumatic fever, either in healthy persons or in persons who have had rheumatic fever and faithfully maintained continuous antibiotic prophylaxis. In certain patients with recurrent bouts of tonsillopharyngitis, however, tonsillectomy may decrease the frequency of incapacitating acute infections.^147,148 Tonsillectomy should be considered only for the most severely affected patients.¹⁴⁹

Epidemiology

Pyoderma occurs most frequently in economically disadvantaged children dwelling in tropical or subtropical climates. It is also prevalent in northern climates during the summer.¹⁵⁰ The peak incidence of impetigo is in children aged 2 to 5 years. This disorder also occurs among older children and adults whose recreational activities or occupation results in cutaneous cuts or abrasions.^151-153 There is no gender predilection, and all races appear to be susceptible. The prevalence of streptococcal pyoderma is markedly influenced by several factors, the most important of which appear to be climate and level of hygiene.

Meticulous prospective studies of streptococcal impetigo have demonstrated that the responsible microorganisms initially colonize the unbroken skin,¹⁵⁰ an observation that probably explains the influence of personal hygiene on disease incidence. Development of skin colonization with a given streptococcal strain precedes the development of impetiginous lesions by an average interval of 10 days. The mechanism of production of skin lesions is unproved, but it is most likely caused by intradermal inoculation of surface organisms by abrasions, minor trauma, or insect bites. Frequently, there is a transfer of the streptococcal strains from the skin and/or pyoderma lesions to the upper respiratory tract. The interval between colonization of the skin and colonization of nose or throat or both averages 2 to 3 weeks.

Bacteriology and Immunology

Streptococci isolated from pyodermal lesions are primarily group A, but occasionally representatives of other serogroups such as C and G are responsible. Group A streptococci that cause impetigo differ in several respects from those usually associated with tonsillitis and pharyngitis. Skin strains belong to different M serotypes or genotypes from the classic throat strains; because most have been identified more recently, they tend to comprise the higher numbered M types. Throat and skin strains can also be differentiated by genetic markers.¹⁵⁴ A relatively small number of serotypes seem capable of regularly initiating both pharyngitis and pyoderma.¹⁵⁵

Assays of streptococcal antibodies are of no value in the diagnosis and management of impetigo, but they provide helpful supporting evidence of recent streptococcal infection in patients suspected of having poststreptococcal glomerulonephritis. The anti–streptolysin O response is weak in patients with streptococcal impetigo,^156,157 presumably because the activity of streptolysin O response is inhibited by skin lipids (cholesterol),¹⁵⁸ whereas anti–DNase B levels are elevated.^156,157

Clinical Manifestations

The lesion of streptococcal pyoderma begins as a papule that rapidly evolves into a vesicle surrounded by an area of erythema. The vesicular lesions are evanescent and rarely recognized clinically; they give rise to pustules that gradually enlarge and then break down over a period of 4 to 6 days to form characteristic thick crusts (Fig. 199-4). The lesions heal slowly and leave depigmented areas. A deeply ulcerated form of impetigo is known as ecthyma.

Streptococcal impetigo occurs on exposed areas of the body, most frequently on the lower extremities or face. The lesions remain well localized but are frequently multiple. Although regional lymphadenitis may occur, systemic symptoms are not ordinarily present.

In the past, the lesions just described could be rather confidently diagnosed as streptococcal. This was the predominant form of impetigo and could be distinguished from bullous impetigo caused by phage group II S. aureus. Although bullous impetigo remains almost exclusively staphylococcal in cause, the bacteriology of nonbullous impetigo has changed.¹⁵⁹ S. aureus, either alone or in combination with S. pyogenes, is now the predominant causative agent.^160-162 Almost all such staphylococci are penicillinase producers. Therefore, treatment with penicillin, which in the past had been highly effective against nonbullous impetigo, even when both streptococci and staphylococci were isolated from the lesions, now frequently fails.¹⁶¹

Complications

Suppurative complications are uncommon. For as yet unexplained reasons, rheumatic fever has never been shown to occur after streptococcal pyoderma. On the other hand, cutaneous infections with nephritogenic strains of group A streptococci are the major antecedent of poststreptococcal glomerulonephritis in many areas of the world. There are as yet no conclusive data to indicate that treatment of an individual case of pyoderma prevents the subsequent occurrence of nephritis in these patients. Such therapy is nevertheless important as an epidemiologic measure in eradicating nephritogenic strains from the environment.

Erysipelas

Erysipelas is a superficial cutaneous process, usually restricted to the dermis but with prominent lymphatic involvement. It is distinguished clinically from other forms of cutaneous infection by three features: the lesions are raised above the level of the surrounding skin, there is a clear line of demarcation between involved and uninvolved tissue, and the lesions are a brilliant salmon red. This disorder is more common in infants, young children, and older adults. It is almost always caused by β-hemolytic streptococci. In most cases the infecting agent is the group A streptococci, but similar lesions can be caused by streptococci of group C or G. Rarely, group B streptococci or S. aureus may be the culprit. In older reports, erysipelas was described as characteristically involving the butterfly area of the face (Fig. 199-5), but at present the lower extremities are more frequently involved (Fig. 199-6). In patients with facial erysipelas, there is frequently a history of preceding streptococcal sore throat, although the exact mode of spread to the skin is unknown. When erysipelas involves the extremities, breaks in the cutaneous barrier serve as portals of entry; these include surgical incisions, trauma or abrasions, dermatologic diseases such as psoriasis, or local fungal infections.

The cutaneous lesion begins as a localized area of erythema and swelling and then spreads rapidly with advancing red margins, which are raised and well demarcated from adjacent normal tissue. There is marked edema, often with bleb formation, and in facial erysipelas the eyes are frequently swollen shut. The lesion may demonstrate central resolution while continuing to extend on the periphery. The cutaneous inflammation is accompanied by chills, fever, and toxicity.

The differential diagnosis is limited. Early on, the lesions of facial herpes zoster, contact dermatitis, or giant urticaria may be confused with erysipelas. Lesions resembling erysipelas may occur in patients with familial Mediterranean fever. Cutaneous lesions similar in appearance to those of erysipelas may occur on the hands of patients who sustain cuts or abrasions while handling fish or meats. This entity, known as erysipeloid of Rosenbach and caused by Erysipelothrix rhusiopathiae, is usually unaccompanied by fever or systemic symptoms.

With early diagnosis and treatment, the prognosis is excellent. Rarely, however, the process may spread to deeper levels of the skin and soft tissues. Penicillin, either parenterally or orally, depending on clinical severity, is the treatment of choice. If staphylococcal infection is suspected, a penicillinase-resistant semisynthetic penicillin or cephalosporin should be selected. In a randomized, prospective multicenter trial,¹⁷⁸ roxithromycin, a macrolide antimicrobial agent, was equivalent to penicillin. Increased levels of macrolide resistance among group A streptococci, however, have been detected in certain areas of the United States.^127,128

Streptococcal Cellulitis

Streptococcal cellulitis, an acute spreading inflammation of the skin and subcutaneous tissues, results from infection of burns, wounds, or surgical incisions but may also follow mild trauma. Clinical findings include local pain, tenderness, swelling, and erythema. The process may extend rapidly to involve large areas of skin. Systemic manifestations include fever, chills, and malaise, and there may be associated lymphangitis, bacteremia, or both. In contrast to erysipelas, the lesion is not raised, the demarcation between involved and uninvolved skin is indistinct, and lesions are more pink than salmon red. Often, however, the clinical differentiation between these entities is not clear cut.

Two predisposing causes of streptococcal cellulitis deserve special mention. One is the parenteral injection of illicit drugs.^179-181 These cases are often associated with bacteremia and deep tissue infections such as septic thrombophlebitis, suppurative arthritis, osteomyelitis, and, occasionally, infective endocarditis. Second, patients who have impaired lymphatic drainage from upper or lower extremities are prone to recurrent episodes of streptococcal cellulitis. Examples include individuals with filariasis and women who have undergone radical mastectomy with axillary node dissection.¹⁸² It is speculated that repetitive infection further damages local lymphatics and worsens lymphatic stasis.¹⁸³

Recurrent episodes of severe cellulitis have also been reported in certain patients who have undergone coronary artery bypass grafting.¹⁸⁴ The lesion invariably occurs in the extremity from which the saphenous vein was removed, and at times it may exhibit features of erysipelas (see Fig. 199-6). Patients with tinea pedis of the venectomy limb appear to be particularly at risk.^185-187 As with other forms of cellulitis, pathogenic bacteria are difficult to recover during these episodes. The appearance of the lesions and the response to penicillin therapy suggest, however, a streptococcal cause. The few β-hemolytic streptococci that have been recovered and characterized often belong to serogroups other than A.¹⁸⁸

Disruption of the cutaneous barrier (leg ulcers, wounds, dermatophytosis) is a risk factor for the development of cutaneous streptococcal infection.¹⁸⁹ There is suggestive evidence that local dermatophyte infection (i.e., athlete's foot) may serve as a reservoir for β-hemolytic streptococci that initiate episodes of erysipelas or cellulitis of the lower extremities.^185,190 Thus, care should be taken to eradicate such fungal infections in patients who experience recurrent bouts of erysipelas or cellulitis. Another potential reservoir is anal streptococcal colonization.¹⁹¹ Other risk factors include venous insufficiency, edema, and obesity.¹⁸⁹ Not surprisingly, an increased risk for recurrent cellulitis has also been reported in homeless persons.¹⁹²

Cellulitis may be caused by infection with a variety of bacterial pathogens (see Chapter 95), but most cases are caused by S. pyogenes (or, occasionally, streptococci of groups B, C, or G) or by S. aureus. S. aureus infection of the skin is usually associated with a pyogenic, fluctuant focus with surrounding erythema and is referred to as “purulent cellulitis.” In the absence of positive blood cultures, which are present in only 5% of cases of nonpurulent cellulitis, a specific microbiologic diagnosis is often not possible. Aspirate or biopsy samples from sites of active cellulitis are helpful when positive on smear or culture, but unfortunately such specimens are usually negative in adult patients.^193-195

It is often impossible to differentiate streptococcal from staphy­lococcal cellulitis on initial presentation confidently. In this case a semi-synthetic penicillinase-resistant penicillin should be used. In penicillin-allergic patients, a first-generation cephalosporin may be used if the hypersensitivity is not of the immediate type. Clindamycin or vancomycin may be used in patients who manifest anaphylactic hypersensitivity to β-lactam antibiotics, and the latter should be administered if there is reason to suspect infection with methicillin-resistant S. aureus. Patients with milder cases of streptococcal cellulitis may be switched to oral medications after an initial favorable response to parenteral therapy.

The role of continuous antimicrobial prophylaxis^196-198 in patients prone to frequent recurrences remains unsettled. At present, such prophylaxis seems justified only for patients with very frequent or severe episodes, and the optimal regimen has not been established.

Necrotizing Fasciitis (Streptococcal Gangrene)

Necrotizing fasciitis is an infection of the deeper subcutaneous tissues and fascia, characterized by extensive and rapidly spreading necrosis and by gangrene of the skin and underlying structures. As detailed in Chapter 95, this entity may arise in several distinct epidemiologic settings, may be caused by multiple aerobic and anaerobic microorganisms, and may vary in clinical manifestations. The present discussion is limited to necrotizing fasciitis caused by group A streptococci¹⁹⁹ and described by Meleney²⁰⁰ in 1924 as hemolytic streptococcal gangrene. Characteristically, streptococcal gangrene begins at a site of trivial or even inapparent trauma or in an operative incision. The initial lesion may appear only as an area of mild erythema but over the next 24 to 72 hours undergoes a rapid evolution. The inflammation becomes more pronounced and extensive, the skin becomes dusky and then purplish, and bullae containing yellow or hemorrhagic fluid appear. Bacteremia is frequently present, and metastatic abscesses may occur. By the fourth to fifth day, frank gangrenous changes are evident in the affected skin,²⁰¹ followed by extensive sloughing. The process may march inexorably over large areas of the body unless measures are taken to contain it. The patient with streptococcal gangrene appears perilously ill, with high fever and extreme prostration. Mortality rates are high, even with appropriate treatment.²⁰¹ Fournier's gangrene, a form of necrotizing fasciitis involving the male genital area, may rarely be caused by group A streptococci.

The course of necrotizing fasciitis today appears to be much more fulminant than that described by Meleney. Specifically, ecchymoses and bullae may appear within 2 to 3 days and associated myonecrosis is more common. In addition, the mortality rate in 1924 was 20%, whereas mortality rates of 20% to 70% have been reported in the current era. This difference is even more remarkable because anti­biotics, intravenous fluids, ventilators, and dialysis were not available in 1924.

Myositis and Myonecrosis

Most cases of purulent muscle infection occur in the tropics, and S. aureus is the predominant causative agent. Myositis caused by group A streptococci has been rare but occurs in many patients with necrotizing fasciitis and strep TSS. Most of these cases occur after blunt nonpenetrating trauma or occur spontaneously. Most likely, bacteria are translocated to the deep tissue hematogenously from the throat. Systemic toxicity is common, and mortality as high as 80% has been reported.²⁰⁵ Destruction of tissue is poorly understood, but infection and inflammation within the confined muscle compartment space may result in pressures exceeding arterial pressure, necessitating emergent fasciotomy and débridement (Fig. 199-7). There is much overlap in the clinical features of necrotizing fasciitis and myonecrosis,^201,205 and the differentiation must be made by surgical inspection or biopsy.

Streptococcal Toxic Shock Syndrome

Strep TSS is defined as described in Table 199-2 but, simply put, it is any streptococcal infection associated with the sudden onset of shock and organ failure. Such cases were first described in the mid to late 1980s, and reports of strep TSS have subsequently emanated from North America, Europe, Australia, and Asia.^{172,177,178,206-213,214} Most cases have occurred sporadically. The highest incidence of invasive streptococcal disease occurred in a small Minnesota community, where 26 cases/100,000 population were recorded.²¹³ In addition, outbreaks of invasive group A streptococcal infections have occurred in closed environments such as nursing homes^215-219 and hospitals.²²⁰ Secondary cases of strep TSS are unusual, but transmission to family members^220,221 or health care workers^220,222 has been well documented by demonstrating identical pulsed-field gel electrophoresis patterns from cross-infecting strains. Although many of the studies cited earlier described strep TSS in adults, several reports have documented that this disorder also occurs in children.^{207,212,213,223,224} Thus, persons of all ages can be afflicted and, although some have underlying medical conditions such as diabetes and alcoholism,^{207,209,225-229} many have no predisposing medical condition and are not immunocompromised. This contrasts sharply to reviews of group A streptococcal bacteremia from several decades ago^225-227 that found the disease to occur primarily among the very young, the very old, or patients with predisposing conditions such as cancer, renal failure, leukemia, severe burns, or iatrogenic immunosuppression.

The portals of entry for streptococci are the vagina, pharynx, mucosa, and skin in 50% of cases.¹⁷⁶ Surgical procedures such as suction lipectomy, hysterectomy, vaginal delivery, bunionectomy, reduction mammoplasty, hernia repair, bone pinning, and vasectomy have provided portals in other cases (Table 199-3). Rarely, infection occurs secondary to streptococcal pharyngitis.^230-232 Virus infections such as varicella and influenza have provided portals of entry in other cases.^176,212,230

Additional factors that increase the risk for invasive group A streptococcal infection, including bacteremia, strep TSS, and necrotizing fasciitis, are listed in Table 199-3. Three studies have demonstrated that a high or increasing prevalence of M-1 or M-3 strains among throat isolates may signal an increased incidence of strep TSS in a community.^212,228,233 NSAIDs taken for problems such as muscle strain, trauma, or postpartum pain may mask the early signs and symptoms of streptococcal infection or possibly predispose to more severe infection, such as necrotizing fasciitis or strep TSS.^176,234,235

Prompt and aggressive surgical exploration and débridement of suspected deep-seated streptococcal infection are mandatory. It is as important to establish the cause of the infection as it is to determine the extent of necrosis. CT and MRI are helpful to locate the primary site of infection, but because the group A streptococci do not form gas or frank abscess, radiologic interpretations are frequently not definitive. Such findings in a patient with extreme pain and fever or who is toxic should prompt surgical consultation. Once necrosis is established, extensive débridement is necessary, because shock and organ failure continue to progress if devitalized tissue remains. Although necrosis of the fascia may be present, it is important to know that necrosis of muscle, skin, and subcutaneous tissue also is commonly present.

Prophylaxis and Risk for Secondary Cases of Streptococcal Toxic Shock Syndrome

Strep TSS is most commonly community acquired and sporadic, yet clusters of invasive cases have been described in nursing homes,^215-219 families,^220,221 and hospital workers.^222,291 In San Francisco, 23 hospital workers became colonized or infected with group A streptococci as a result of contact from a single case of strep TSS.²⁹¹ This example, as well as many historical studies in schools, military posts, and nursing homes, shows that group A streptococci are highly contagious. Luckily, mere contact or colonization is usually not sufficient to cause a secondary case of invasive group A streptococcal infection. Epidemiologic studies by the Centers for Disease Control and Prevention found one secondary case of invasive infection among more than 1,500 contacts.¹⁴⁶ This would extrapolate to 66/100,000 population/year for secondary cases.²⁹² As noted, the current incidence of primary cases of invasive group A streptococcal infections in the United States is 3.5/100,000 population/year. Thus, the risk to contacts is roughly 20 times greater than that for the general population but is still very low. Given the relative infrequency of these infections and the lack of a clearly effective chemoprophylactic regimen, routine screening for and prophylaxis against streptococcal infection are not recommended for household contacts of index patients. In deciding who should receive prophylaxis, the clinician needs to factor in the duration of contact, intimacy of contact, and underlying host factors of individual contacts. Specifically, contacts with open wounds, recent surgery, recent childbirth, concurrent viral infections such as varicella or influenza, or immunodeficiency diseases should receive prophylaxis. In a multicenter study of adults aged 18 to 45 years, human immunodeficiency virus infection and injecting drug use were independently associated with an increased risk for invasive group A streptococcal disease. In those aged 45 years of age or older, diabetes, cardiac disease, cancer, and corticosteroid use were significant risk factors.²⁹³ Moreover, adults 65 years or older are at increased risk for mortality should they contract invasive disease. Thus, it may be prudent to initiate prophylaxis in households with older adults or those with the just-mentioned risk factors.

Lacking firm data on which to base antimicrobial prophylaxis, it seems reasonable to choose those agents that have achieved highest rates of pharyngeal eradication in asymptomatic individuals; among these are clindamycin and azithromycin. Specific regimens have been published elsewhere.¹⁴⁶