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. 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. 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 GAS. 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. GAS 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 M protein. More than 150 such serotypes and more than 220 genotypes are currently recognized. 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. Various vaccine strategies have targeted multiple individual M proteins with some success. Recently, however, convalescent serum samples from patients with skin and soft tissue infection demonstrated cross-reactive immune responses that align with M-protein clusters, suggesting that fewer individual M-types may be required for an effective vaccine against GAS.

The M protein itself is a filamentous macromolecule that exists as a stable dimer with an α-helical coiled coil structure. 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 GAS, whereas the more distal portion contains type-specific epitopes. This configuration localizes the type-specific moiety on the tips of fibrils protruding from the cell surface ( Fig. 197.1 ). In the nonimmune host, M protein exerts its antiphagocytic effect by inhibiting activation of the alternative complement pathway on the cell surface. 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) and fibrinogen. 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. M proteins analogous to those of GAS are present in many strains of groups C and G 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 immunoglobulin (Ig)G or IgA at the non–antigen-binding site and appear to be cooperative with M protein in antiphagocytic effect. 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 antiopsonic surface proteins continue to be described. For example, Mac, a secreted group A streptococcal protein with homology to a human β ₂ -integrin, binds to CD16 on the surface of human PMNs and inhibits phagocytosis and bacterial killing. An additional surface protein, streptococcal heme-associated protein (Shp), has been found in M1 strains of GAS and likely has a role in transport of iron intracellularly. Antibody against Shp has been found in convalescent sera and has opsonic capability. 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 GAS 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. Strains of a minority of the currently identified M types elaborate this antigen. 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. 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. Of interest, 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.

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, 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. Although M protein does not appear to promote adhesion to human buccal or tonsillar epithelial cells, it does mediate adherence to skin keratinocytes via the attachment of the C repeat region to keratinocyte membrane cofactor CD46. 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), also known as SfbI (streptococcal fibronectin-binding protein I), and related proteins known as SbfII, FBP54, protein F2, and PFBB.

Moreover, the expression of these adhesins has been reported to be environmentally regulated. 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. 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, GAS elaborates numerous extracellular products, only a limited number of which have been well characterized. Two distinct hemolysins are recognized. SLO 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, in high concentrations it is toxic to a variety of cells and cell fractions, including PMNs, platelets, endothelial cells, lysosomes, and isolated mammalian cardiomyocytes. In subcytotoxic doses SLO stimulates hyperresponsiveness in these same cell types, including enhanced neutrophil degranulation, increased platelet activation and adhesion, induced synthesis of lipid mediators by endothelial cells and spontaneous, nonpaced and hyperaugmented contractions in cardiomyocytes. SLO is produced by almost all strains of S. pyogenes , as well as many group C and G organisms, and is antigenic. Measurement of ASO antibodies in human sera is useful as an indicator of recent streptococcal infection.

Streptolysin S (SLS) 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. SLS is nonantigenic, or at least no antibody to it has been detected that neutralizes its hemolytic activity. Like SLO, SLS can damage the membranes of PMNs, platelets, and subcellular organelles. Unlike SLO, 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 SLS, whereas SLO 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.

Recently emerged, globally disseminated strains of hypervirulent GAS have been associated with production of nicotine adenine dinucleotidase (NADase), whereas older strains had the gene for this toxin but did not produce a functional enzyme. Recent isolates have mutations in the SLO/NADase coregulator that result in enhanced coproduction of both virulence factors. It has been demonstrated that the binding of NADase to SLO stabilizes both toxins and enhances group A streptococcal virulence.

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 chemotaxis factor C5a at the PMN binding site. SpeB also cleaves IgG bound to GAS, thus interfering with ingestion and killing by phagocytes. The streptococcal pyrogenic exotoxins are a family of bacterial superantigens believed to be associated with strep TSS, necrotizing fasciitis, and other severe infections. This family includes the bacteriophage-encoded SpeA 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. SSA and SpeC have been implicated in a recent upsurge of scarlet fever in China. SpeB has also been implicated as a causative antigen in poststreptococcal glomerulonephritis, having been found in glomerular membranes in such patients. Despite its many functions and its widespread distribution among clinical isolates of GAS the role of SpeB in pathogenesis remains controversial. One view is that SpeB is a key contributor to pathogenesis; alternatively, GAS may be under in vivo pressure to downregulate this toxin.

Superantigens are potent immunostimulators able to bind simultaneously to the class II major histocompatibility complex (MHC) and specific V-β regions of the T-cell receptor. 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 “Streptococcal Toxic Shock Syndrome.”

Emerging concepts regarding the molecular biology of streptococcal virulence, colonization, and tissue invasion have been reviewed. 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 Mga (multiple gene regulator) or Mry (regulator of M-protein expression) and a two-component regulatory system known as CsrRS (capsule synthesis regulator) or, alternatively, CovRS (control of virulence genes), which represses the synthesis of the capsule and several exotoxins. The regulator of proteinase B (RopB) has been shown to have various polymorphisms that regulate the virulence of S. pyogenes.

Epidemiology

Streptococcal sore throat is among the most common bacterial infections of childhood. It is estimated that more than 600 million cases of streptococcal pharyngitis occur annually worldwide. GAS are responsible for the great majority of such infections, but strains of other serogroups, especially groups C and G, are occasionally involved. The disease occurs primarily among children 5 to 15 years of age, with the peak incidence occurring during the first few years of school. All age groups are susceptible, however, and severe epidemics are common in military training facilities. There is no gender predilection. The disease is ordinarily spread by direct person-to-person contact, most likely via droplets of saliva or nasal secretions. Crowding such as occurs in schools or barracks favors interpersonal spread of the organism ( Fig. 197.2 ) and may also enhance its virulence by processes of natural selection analogous to those that occur during mouse passage in the laboratory. The effect of crowding in facilitating transmission may account in part for the increased incidence of streptococcal pharyngitis in northern latitudes during the colder months of the year. Explosive foodborne or waterborne outbreaks are also well documented. Contamination of dust, clothing, blankets, or other fomites does not appear to play a significant role in contagion.

GAS frequently colonize the throats of asymptomatic persons. Pharyngeal carriage rates among normal schoolchildren vary with geographic location and season of the year. Carriage rates as high as 15% to 20% have been noted in several studies. The carriage rate among adults is considerably lower.

Studies of experimentally induced human infections and of transmission in military barracks have shed considerable light on the variables involved in interpersonal spread. During the acute phase of tonsillopharyngeal infection, M-typeable GAS are frequently present in large numbers in the nose and throat. In untreated infections organisms may persist for many weeks, although the signs and symptoms of illness abate within a few days. During convalescence the organisms decrease in numbers and tend to disappear from the anterior nares sooner than from the throat. In addition, the M-protein content and virulence of persisting organisms gradually decline. The result of these qualitative and quantitative changes is that convalescent carriers are much less likely to transmit the organism to close contacts than acutely infected persons.

In patients who do not receive effective antibiotic therapy for acute streptococcal pharyngitis, type-specific antibodies are frequently detectable in the serum between 4 and 8 weeks after the infection. These opsonic antibodies protect against subsequent infection with organisms of the same M type, but the person remains susceptible to infection by heterologous types. Prompt and effective antibiotic therapy may ablate the type-specific immune response.

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. 197.3 ); 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 (WBC) count usually exceeding 12,000/mm, with increased numbers of PMNs. The test for C-reactive protein is usually positive.

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. 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.

Diagnosis

Pharyngitis and tonsillitis may be caused by infectious agents other than S. pyogenes. Among these are streptococci of groups C and G. Corynebacterium diphtheriae, the other major bacterial pathogen associated with exudative pharyngitis, is now extremely rare in the United States 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. A. 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. 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 229B ). The oropharyngeal form of tularemia is characterized by severe sore throat, exudative and ulcerative tonsillopharyngitis, and cervical adenopathy (see Chapter 227 ).

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, influenza, and parainfluenza viruses may also simulate streptococcal pharyngitis, as may initially the acute retroviral syndrome in human immunodeficiency virus (HIV) infection. Pharyngitis associated with the acute retroviral syndrome is, however, not exudative. Even when careful microbiologic techniques are used to detect bacteria, mycoplasmas, and viruses, no causative agent can be detected in a substantial proportion of all cases of acute sore throat. 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 GAS. 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-age 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 (≈85%) with the presence of positive throat cultures for GAS. 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. 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 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 coworkers, 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 GAS. A subsequent cost-effectiveness analysis and two prospective clinical studies 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. It is important to realize that the most common age group of streptococcal pharyngitis is in the 5- to 15-year-old group. This is of particular concern because annually 73% of the 6.7 million adults who visit primary care providers in the United Sates with the complaint of sore throat receive a prescription for antibiotics.

Thus, for adults and children, expert panels of the Infectious Diseases Society of America, American Heart Association (AHA), and American Academy of Pediatrics (AAP) recommend that the presence of GAS in the pharynx should be documented by a throat culture or rapid antigen detection test (RADT). 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

Update: Short Course Treatment for Pharyngitis

Update: Probiotics for Recurrent Pharyngitis

Antimicrobial therapy is indicated for children and adults with symptomatic pharyngitis (see Centor criteria earlier) 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.

Treatment of group A streptococcal sore throat as long as 9 days after onset is still effective for the prevention of rheumatic fever. Thus, if the patient is seen early in the course of the 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 may result in faster resolution of the signs and symptoms in children and adults, 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. 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 197.1 ). 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 197.1 , 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 in children. An oral time-release formulation of amoxicillin has recently been approved by the US 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.

A variable percentage of patients continue to harbor GAS of the originating serotype in their pharynx after completion of a course of oral penicillin. Such bacteriologic treatment failures are sometimes associated with symptomatic relapse. Unless such children have symptomatic sore throat as clinically defined earlier, they should not be re-treated unless there is a history of rheumatic fever. 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.

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. However, these analyses have been strongly challenged on methodologic grounds. This is related to high efficacy in treatment in patients with no prior antibiotic treatment and in vitro data that has never identified penicillin resistance in GAS. In penicillin-allergic patients, macrolide (erythromycin or clarithromycin) or azalide (azithromycin) antimicrobial agents, clindamycin, or first-generation cephalosporins are the agents of choice. The latter should be avoided in those with immediate (type I) penicillin hypersensitivity (see Table 197.1 ). 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 (see section on invasive infection later, where resistance to these agents is high in China) and reports of increased rates of macrolide resistance in certain localized areas of the United States, three multistate surveillance studies conducted during 2002 and 2003 detected overall macrolide resistance rates of 3.8%, 5.2%, and 6.8%, respectively. 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, cefixime, ceftibuten, cefdinir, cefpodoxime, and cefditoren, are effective in eradication of GAS from the pharynx when administered for 5 days, although not all of these are approved by the FDA for a 5-day course of therapy for acute streptococcal pharyngitis 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, and azithromycin. Because of its long intracellular half-life and slow release from tissue sites, a 5-day course of azithromycin is approved by the AHA for use in penicillin-allergic patients. As noted, promiscuous use of macrolides has been associated with development of resistance by GAS.

Because tetracycline-resistant GAS are prevalent in many areas, this drug is not recommended. Sulfonamides, which are effective for the secondary prophylaxis of rheumatic fever (see Chapter 198 ), 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., reisolation of the original infecting streptococcal serotype shortly after completion of a full course of antibiotic therapy), causes of posttreatment 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 an asymptomatic postconvalescent 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 advised 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 US cities during the 1980s, the approach to streptococcal infection must be particularly rigorous, and serious consideration should be given to routine performance of posttreatment cultures. If reculture is undertaken in patients with a history of rheumatic fever, re-treatment with an oral cephalosporin might be considered in view of the slightly increased eradication rates observed with these agents; this may be due to β-lactamase production by the oral microbiota.

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 asymptomatic postconvalescent streptococcal carriers 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, amoxicillin-clavulanate, or azithromycin may be efficacious. Any of these antibiotic treatments can have adverse events, such as Clostridioides difficile (formerly 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. The advisability of culture and/or prophylaxis of household contacts of patients with invasive group A streptococcal infection is discussed later.

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. Tonsillectomy should be considered only for the most severely affected patients.