INTRODUCTION — Group A streptococcal (GAS) tonsillopharyngitis presents with abrupt onset of sore throat, tonsillar exudate, tender cervical adenopathy, and fever, followed by spontaneous resolution within two to five days. Patients with sore throat lasting longer than one week usually do not have GAS tonsillopharyngitis.

Issues related to treatment and prevention of group A streptococcal tonsillopharyngitis will be reviewed here. A general approach to patients with pharyngitis and the factors responsible for antibiotic failure are discussed separately. (See "Evaluation of acute pharyngitis in adults" and "Approach to diagnosis of acute infectious pharyngitis in children and adolescents" and "Antibiotic failure in the treatment of streptococcal tonsillopharyngitis".)

GOALS OF THERAPY — Goals of antimicrobial therapy for eradication of GAS from the pharynx in the setting of acute streptococcal pharyngitis include:

• Reducing duration and severity of clinical signs and symptoms, including suppurative complications
• Reducing incidence of nonsuppurative complications (eg, acute rheumatic fever)
• Reducing transmission to close contacts by reducing infectivity

Considerations of treatment include ease of antibiotic administration and limited expense with as few adverse effects as possible [1-3].

Reducing clinical symptoms — Antibiotic therapy is most beneficial for hastening resolution of symptoms if instituted within the first two days of illness [4-8]. Antibiotic therapy is also beneficial for reducing suppurative complications such as peritonsillar abscess, cervical lymphadenitis, and mastoiditis. Additional issues related to antibiotic therapy for reducing clinical symptoms are discussed further below (see 'Timing of therapy' below.

Reducing nonsuppurative complications — Antibiotic therapy is primarily helpful for reducing the incidence of acute rheumatic fever as a nonsuppurative complication of GAS pharyngitis. The role of antibiotic therapy in decreasing the nonsuppurative complications of glomerulonephritis and PANDAS syndrome is not clear [9].

Acute rheumatic fever — Although symptoms of GAS pharyngitis resolve without antibiotic therapy, persistence of the organism in the upper respiratory tract elicits an immune response that can set the stage for subsequent risk of acute rheumatic fever (ARF) if the strain is rheumatogenic and the host is genetically predisposed. In some populations, group G and group C streptococci may also play a role in ARF pathogenesis [10,11]. (See "Epidemiology and pathogenesis of acute rheumatic fever" and "Clinical manifestations and diagnosis of acute rheumatic fever", section on 'Predisposing factors',The efficacy of penicillin for primary prevention of ARF was established in the early 1950s, when military recruits with GAS tonsillopharyngitis received injectable penicillin G mixed in peanut oil or sesame oil with 2 percent aluminum monostearate [12,13]. GAS eradication and ARF primary prevention were optimized with injection schedules that provided at least 9 to 11 days of penicillin.

Subsequently, evaluation of GAS tonsillopharyngitis therapies has been based upon GAS eradication from the upper respiratory tract; it is assumed that such eradication is an adequate surrogate marker for efficacy in primary prevention of rheumatic fever. Antibiotic therapy can be helpful for prevention of rheumatic fever if initiated up to nine days following onset of symptoms [12].

Glomerulonephritis — Children younger than seven years of age appear to be at greatest risk of poststreptococcal glomerulonephritis. Although antibiotic therapy has efficacy for primary prevention of acute rheumatic fever, the role of antibiotics in the setting of GAS tonsillopharyngitis for prevention of poststreptococcal glomerulonephritis is not certain. (See "Hematuria following an upper respiratory infection".)

PANDAS syndrome — Pediatric autoimmune neuropsychiatric disorder associated with group A streptococci (PANDAS) is discussed separately. It is not clear whether antibiotic therapy for GAS pharyngitis reduces the incidence of this syndrome. (See "Complications of streptococcal tonsillopharyngitis", section on 'PANDAS syndrome'.)

Reducing transmission — The rate of GAS transmission from an infectious case to close contacts (such as a family or school setting) is approximately 35 percent. Antibiotic treatment does have a role for preventing transmission of GAS; after 24 hours of treatment with penicillin, subsequent cultures are negative in about 80 percent of cases [14]. Data on the duration of contagion for alternative antibiotics are not available. In untreated patients, GAS is eliminated from the upper respiratory tract by host immune factors in 50 percent of cases at one month following acute infection [15].

Additional issues related to antibiotic therapy for reducing transmission are discussed further below (see 'Follow up' below.

TREATMENT — Antimicrobial therapy is warranted for patients with symptomatic pharyngitis if the presence of group A streptococci in the pharynx is confirmed by culture or rapid antigen detection testing (RADT). The approach to establishing the diagnosis of acute streptococcal pharyngitis is discussed in detail separately. (See "Evaluation of acute pharyngitis in adults", section on 'Diagnostic tests'.)

Antimicrobial therapy may also be administered to mitigate the clinical course of pharyngitis due to group C and group G streptococci. The approach to antibiotic selection is as outlined in the following sections. However, treatment need not continue for ten days since acute rheumatic fever is not a complication of infection due to these organisms; five days of treatment is sufficient [1,16,17]. (See "Group C and group G streptococcal infection".)

In general, antimicrobial therapy is of no proven benefit for treatment of pharyngitis due to bacteria other than streptococcus (with the exception of relatively rare infections caused by other bacterial pathogens such as Corynebacterium diphtheriae and Neisseria gonorrhoeae). Such therapy unnecessarily exposes patients to the expense and potential hazards of antimicrobial drugs, and contributes to the emergence of antibiotic resistant bacteria.

Timing of therapy — If clinical and/or epidemiologic factors point to a high index of suspicion for GAS pharyngitis while laboratory results are pending, it is appropriate to initiate empiric antimicrobial therapy. However, if laboratory testing does not confirm the diagnosis of GAS pharyngitis, antimicrobial therapy should be discontinued.

In the natural history of GAS pharyngitis, the incubation period is two to four days. Fever and constitutional symptoms usually resolve within three to four days, even in the absence of antimicrobial therapy [15]. Clinical improvement has been observed up to 48 hours sooner in patients receiving penicillin versus placebo within the first two days of illness [4-8].

There is some concern that early therapy may suppress host antibody response and thereby increase risk for recurrent pharyngitis. In a study of 142 children with presumed GAS pharyngitis, those treated with penicillin at the initial office visit had a higher incidence of recurrent infection than those for whom treatment was delayed at least 48 hours (recurrent infection occurred eight times more frequently) [5].

Nonetheless, delaying treatment is not warranted in most cases of GAS tonsillopharyngitis. It may be a useful strategy for patients who have frequent, recurrent, mild to moderate infections, to allow development of immunity to the infecting strain without increasing the risk of acute rheumatic fever. Antibiotic therapy delayed for up to nine days following onset of symptoms is still helpful for prevention of rheumatic fever (although may be less effective for prevention of suppurative complications) [12]. However, this approach should not be considered if the patient is severely ill or if highly virulent or rheumatogenic strains are actively circulating within a community. Patients are considered no longer contagious after 24 hours of antibiotic therapy [14].

Antibiotics — Antibiotic options for treatment of GAS pharyngitis include penicillin (and other related agents including ampicillin and amoxicillin), cephalosporins, macrolides, and clindamycin [18]. Sulfonamides and tetracyclines should NOT be used for treatment of GAS pharyngitis because of high rates of resistance to these agents and their frequent failure to eradicate even susceptible organisms from the pharynx.

Intramuscular penicillin is the only therapy that has been shown to prevent initial attacks of rheumatic fever in controlled studies [13,19]. These studies were performed with procaine penicillin G in oil containing aluminum monostearate; this preparation has since been supplanted by benzathine penicillin G. There are data suggesting that benzathine penicillin G is effective for primary prevention of rheumatic fever, although they are not definitive [20]. Other antimicrobials have been shown to effectively eradicate GAS from the upper respiratory tract, and it is assumed that such eradication is a surrogate for efficacy in primary prevention of rheumatic fever.

Resistance — Antimicrobial resistance has not been a significant issue in the treatment of GAS. No clinical isolate of GAS has demonstrated penicillin resistance, likely due to the organism's lack of altered penicillin-binding proteins and/or inefficient gene transfer mechanisms for resistance [21,22]. However, streptococcal strains tolerant to penicillin (eg, strains inhibited but not killed by penicillin in vitro, with ratio of MIC to the minimum bactericidal concentration of ≥32) have been described [23-27]. The clinical significance of such strains is not clear; they have been isolated in the setting of outbreaks in which penicillin treatment failure was observed, but there was no difference in failure rates among tolerant and susceptible strains. (See "Antibiotic failure in the treatment of streptococcal tonsillopharyngitis".)

There have been reports of relatively high levels of resistance to macrolide antibiotics in some regions; given the increasing use of macrolides for treatment of upper and lower respiratory tract infections, clinicians should be cognizant of local patterns of antimicrobial resistance [28-36].

Selection — Oral penicillin V is the agent of choice for treatment of GAS pharyngitis given its proven efficacy, safety, narrow spectrum and low cost [1,37-40]. The appropriate duration is 10 days of therapy; dosing is outlined in the Table (table 1). This approach is extrapolated from studies performed in the 1950s demonstrating that that treatment of streptococcal pharyngitis with intramuscular penicillin prevents acute rheumatic fever [13,19]. (See "Treatment and prevention of rheumatic fever".)

Amoxicillin is often used in place of oral penicillin in children, since the taste of the amoxicillin suspension is more palatable than that of penicillin. Some data suggest that oral amoxicillin may be marginally superior to penicillin, most likely due to better GI absorption [41,42]. In addition, amoxicillin has activity against the common pathogens that cause otitis media (which presents concurrently with GAS tonsillopharyngitis in up to 15 percent of children, particularly those under four years of age). Dosing is outlined in the table (table 1). (See "Acute otitis media in children: Treatment".)

Intramuscular benzathine penicillin G (single dose) may be administered to patients who cannot complete a 10 day course of oral therapy or to patients at enhanced risk for rheumatic fever (eg, those with history of previous rheumatic heart disease and/or living in crowded conditions). Injections of benzathine penicillin provide bactericidal levels against GAS for 21 to 28 days. The addition of procaine penicillin alleviates some of the discomfort associated with benzathine injections and may favorably influence the initial clinical response. The preferred product is the combination of 900,000 units of benzathine penicillin G plus 300,000 units of procaine penicillin.

Cephalosporins are acceptable alternatives in patients with recurrent GAS infection but are not recommended as first line therapy [43-50]. Cephalosporins have demonstrated better microbiologic and clinical cure rates than penicillin; these differences appear to be greater among children than adults, and some favor use of first generation cephalosporins as first line therapy in this group [51-53]. However, cephalosporins are more expensive than penicillin and may facilitate development of antibiotic resistance [44,45]. (See 'Recurrent infection' below.)

Antibiotic therapy directed against beta lactamase producing upper respiratory tract flora (such as amoxicillin-clavulanate) remains controversial and is not indicated in patients with acute pharyngitis [1,54,55].

For patients with beta-lactam hypersensitivity, cephalosporins (cefuroxime, cefpodoxime, cefdinir, and ceftriaxone) may be used, in the absence of history of life threatening allergic reaction [43,56-58]. Macrolides (clarithromycin, azithromycin or erythromycin) are an acceptable alternative for penicillin allergic patients, depending on local resistance patterns [28,31-36]. For the rare patient with an erythromycin-resistant strain of GAS who is unable to tolerate beta lactam agents, clindamycin is an appropriate choice.

Duration — In general, the conventional duration of oral antibiotic therapy to achieve maximal pharyngeal GAS eradication rates is 10 days, even though patients usually improve clinically within the first few days of treatment [59]. If penicillin is discontinued after three days of therapy, the probability of relapse is higher than if penicillin is discontinued after seven days of treatment (50 versus 34 percent, respectively) [13,15,19].

Five days of therapy with cefpodoxime, cefdinir, or azithromycin is an acceptable alternative approach, with rates of bacteriologic and clinical cure of streptococcal pharyngitis comparable to that of the conventional 10-day course of penicillin [33-37,60-72].

Attempts to treat GAS pharyngitis with a single daily dose of penicillin have been unsuccessful. Although some data suggest that once daily amoxicillin may be sufficient for treatment of GAS pharyngitis, others have shown that this approach is not adequate for effective eradication further investigation is needed [73-76]. Among the alternative agents, azithromycin and some cephalosporins (including cefixime, cefpodoxime, cefadroxil and cefdinir) may be effective for eradication of pharyngeal streptococci with once daily dosing [65,77-80].

Follow up — Patients with GAS pharyngitis should have improvement in clinical symptoms within three to four days of initiating antibiotic therapy. Failure to observe a clinical response to antibiotics should prompt diagnostic reconsideration or the possibility of a suppurative complication. If acute streptococcal pharyngitis was diagnosed by rapid testing, the result may represent a false-positive finding; if the diagnosis was made by culture, the patient may be a pharyngeal carrier whose symptoms are likely attributable to an alternate process (see 'Carriers' below.

In general, test of cure is not necessary for asymptomatic patients or their close contacts following completion of a course of antimicrobial therapy. The majority of patients with GAS remaining in their upper respiratory tracts after completing a course of antimicrobial therapy are streptococcus carriers [81,82].

However, follow-up test of cure is appropriate testing for asymptomatic index patients and their asymptomatic household contacts in the following circumstances:

• Individuals with history of rheumatic fever
• Individuals who develop acute pharyngitis during an outbreak of acute rheumatic fever or acute poststreptococcal glomerulonephritis [82].
• Spread of GAS among several family members

Asymptomatic patients and asymptomatic household contacts in the above circumstances with positive laboratory results should receive a standard course of antimicrobial therapy with one of the agents outlined above [83]. Repeat treatment should be administered with an agent with greater beta lactamase stability than the previous agent [54]. If a penicillin was used for initial therapy, repeat treatment with amoxicillin-clavulanate or a first generation cephalosporin may be used; if initial treatment was with a first generation cephalosporin, a second or third generation cephalosporin may be used. (See "Evaluation of acute pharyngitis in adults" and 'Antibiotics' above.)

Recurrent infection — In the setting of recurrent acute pharyngitis with positive repeat diagnostic testing, there are several possible explanations [81,83,84]:

• Persistence of streptococcus carriage in the setting of viral infection
• Nonadherence with the prescribed antimicrobial regimen
• New infection with GAS acquired from household or community contacts
• Treatment failure (eg, repeat episode of pharyngitis caused by the original infecting strain); treatment failure is rare.

In the setting of a second episode of acute pharyngitis with positive repeat diagnostic testing, a repeat course of treatment is appropriate (table 1). Repeat treatment should be administered with an agent with greater beta lactamase stability than the previous agent [54].

If adherence is uncertain, intramuscular benzathine penicillin G may be chosen as the second course of therapy. If a full course of penicillin was completed as initial therapy, a first generation cephalosporin (such as cephalexin, cefadroxil) may be used; if a first generation cephalosporin was used for initial therapy, a second or third generation cephalosporin (such as cefpodoxime, cefdinir) may be used. Alternative agents include amoxicillin-clavulanate or clindamycin.

It is not necessary to perform follow up testing after the second course of therapy unless the patient remains or becomes symptomatic, or unless special circumstances as outlined above are present. (See 'Antibiotics' above and 'Follow up' above.)

In the setting of multiple recurrent episodes, it may be difficult to distinguish true GAS pharyngitis from viral pharyngitis in the setting of streptococcal carriage. It is likely that most of these patients are carriers experiencing nonstreptococcal infections. This may be discernible by evaluating for the presence of GAS during asymptomatic intervals, and/or by typing streptococcal isolates obtained during distinct episodes (with the expertise of a specialized laboratory). In these circumstances, treatment with clindamycin or amoxicillin-clavulanate may be beneficial since these agents have demonstrated high eradication rates for pharyngeal streptococci (table 1) [54,85,86]. (See 'Carriers' below.)

For patients with as many as six GAS infections in a single year or three to four episodes in two consecutive years, tonsillectomy may be an appropriate therapeutic consideration [87,88]. This was illustrated in a randomized trial including 187 children with recurrent pharyngitis, of whom 95 were managed with tonsillectomy [87]. The incidence of pharyngitis during the first two years of follow-up was significantly lower among the tonsillectomy group.

Antibiotic failure in the treatment of streptococcal tonsillopharyngitis is discussed separately. (See "Antibiotic failure in the treatment of streptococcal tonsillopharyngitis".)

PREVENTION

Carriers — In general, GAS resides in the oropharynx of streptococcus carriers in the absence of host immunologic response to the organism [89]. In temperate climates during the winter and spring up to 20 percent of asymptomatic school-aged children may be carriers. About 25 percent of asymptomatic individuals in the households of index patients harbor GAS in their upper respiratory tracts [83]. Streptococcal carriage may persist for many months.

Carriers may demonstrate evidence of GAS in the upper respiratory tract during an episode of viral pharyngitis, suggesting acute streptococcal pharyngitis. In these circumstances, clinically distinguishing viral from streptococcal pharyngitis can be difficult. Useful clues may include patient age, season, local epidemiology, and the nature of presenting signs and symptoms. In addition, pharyngeal strep carriers tend to have very low ASO titers; they may be just above detectable. (See "Evaluation of acute pharyngitis in adults", section on 'Identifying GAS pharyngitis'.)

Streptococcus carriers are unlikely to spread the organism to close contacts and are at very low risk for developing suppurative complications or acute rheumatic fever [89]. Moreover, eradication of GAS from the upper respiratory tract of carriers is much more difficult than eradication of GAS from patient with acute infections [48,81,90]. In general, except for the circumstances described above, streptococcus carriers do not require antimicrobial therapy. (See 'Follow up' above.)

Prophylaxis — Continuous antimicrobial prophylaxis is only appropriate for prevention of recurrent rheumatic fever in patients who have experienced a previous episode of rheumatic fever. (See "Treatment and prevention of rheumatic fever", section on Antibiotic prophylaxis.)

Vaccination — There is no vaccine against GAS available for clinical use, although development of this preventive measure is under investigation [91,92]. An important area of uncertainty is whether vaccine-induced antibodies may cross-react with host tissue to produce nonsuppurative sequelae in the absence of clinical infection.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Sore throat in children" and "Patient information: Sore throat in adults".) We encourage you to print or e-mail these topic reviews, or to refer patients to our public web site, www.uptodate.com/patients, which includes these and other topics.

SUMMARY AND RECOMMENDATIONS

• Goals of antimicrobial therapy for eradication of group A streptococcus (GAS) from the pharynx in the setting of acute streptococcal pharyngitis include (see 'Goals of therapy' above:

• - Reducing duration and severity of clinical signs and symptoms, including suppurative complications
• - Reducing incidence of nonsuppurative complications (eg, acute rheumatic fever)
• - Reducing transmission to close contacts by reducing infectivity

• We recommend initiating treatment with antimicrobial therapy for patients with symptomatic pharyngitis if the presence of group A streptococci in the pharynx is confirmed by culture or rapid antigen detection testing (RADT) (Grade 1A). (See 'Treatment' above.)

• We suggest initiating treatment with antimicrobial therapy for patients whose clinical and/or epidemiologic factors point to a high index of suspicion for GAS pharyngitis while laboratory results are pending (Grade 2B). (See 'Treatment' above.)

• Oral penicillin V is the agent of choice for treatment of GAS pharyngitis in many clinical settings given its proven efficacy, safety, narrow spectrum and low cost. Amoxicillin is often used in place of oral penicillin in children, since the taste of the amoxicillin suspension is more palatable than that of penicillin (table 1). First generation cephalosporins are an acceptable alternative to penicillin and amoxicillin in the setting of treatment failure or beta-lactam hypersensitivity. (See 'Selection' above.)

• Although most patients improve clinically within the first few days of treatment, the conventional duration of oral antibiotic therapy is 10 days to achieve maximal pharyngeal GAS eradication rates. Intramuscular benzathine penicillin G may be administered to patients who cannot complete a 10 day course of oral therapy. (See 'Duration' above.)

• In general, test of cure is not necessary for asymptomatic patients or their close contacts following completion of a course of antimicrobial therapy, except in unique circumstances. (See 'Follow up' above.)

• We suggest a repeat course of treatment for patients with a repeat episode of acute pharyngitis and positive repeat diagnostic testing (Grade 2C). Patients warranting a repeat course of treatment may receive an agent with greater beta lactamase stability than the previous agent. (See 'Recurrent infection' above.)
• Patients who are long-term streptococcal carriers may develop multiple episodes of pharyngitis due to viral infection. In such cases, repeatedly positive cultures or rapid antigen tests for GAS may be misleading, and further treatment for streptococcal pharyngitis may not be warranted. Carriers are unlikely to spread the organism to close contacts and are at very low risk for developing suppurative complications or acute rheumatic fever. Moreover, eradication of GAS from the upper respiratory tract of carriers can be difficult and is not necessary. (See 'Carriers' above.)