Group A Beta-hemolytic Streptococcal Infections Michael E. Pichichero, MD*

IMPORTANT POINTS

1. Group A streptococci cause about 15% of acute sore throats in children.

2. Group A streptococcal infection cannot be diagnosed reliably on clinical grounds; a rapid strep test or throat culture is

needed.

3. Although penicillixi G therapy for 10 days remains the gold standard, treatment of streptococcal pharyngitis for 5 days

with several kinds of cephalosporins or azithromycin is effective and has the advantage of greater compliance.

4. Recent cases of rheumatic fever in children often have occurred ¡u middle-income, suburban families.

5. Streptococcal toxic shock syndrome generally has skin and soft tissues as portals of entry, especially when secondary

infection is concurrent with varicella.

Group A beta-hemolytic streptococci (GABHS) are gram-positive bacteria that grow in culture as pairs or chains of variable

length. On sheep blood agar they appear as transparent to opaque round, small colonies surrounded by a zone of complete

hemolysis (beta) of red cells. The beta-hemolytic streptococci include the pathogens of Lancefield groups A. C, and G. In

contrast, viridans streptococci produce partial (alpha) or no (gamma) hemolysis. Group D streptococci produce variable

hemolysis, and S pneumoniae (pneumococcus) produce alpha-hemolysis.

Biologic products elaborated by GABHS are important determinants of virulence. Antibody responses to these antigens

sometimes are used to identify these bacteria as the cause of an infection. In addition to hemolysins (including streptolysins

O and S), GABHS may elaborate streptokinase, streptodornase bacteriocins, deoxyribonuclease, exotoxins, hyaluronidase,

nicotinamide adenine dinucleotidase, and proteinase.

Types of Group A

Streptococcal Infections

UPPER RESPIRATORY

TRACT INFECTIONS

GABHS causes many types of infection in children (Table 1). Tonsillopharyngitis is by far the most common manifestation

in the pediatric population; it will be discussed at length later in this review. Most cases of bacterial otitis media and

sinusitis are caused by S pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis; GABHS accounts for 5% to

10% of cases and, therefore, must be considered as a possible pathogen in these conditions. The history of acute otitis media

generally includes acute ear pain, often associated with fever, diminished hearing, and cough. Pneumatic otoscopy should

be employed on physical examination. The findings of a red, bulging tympanic membrane and purulent material in the

middle ear space are seen more frequently with pneumococcal or GABHS Otitis media. Otitis media caused by H influenzae

and M catarrhalis is more likely to produce a thickened-appearing tympanic membrane That has less erythema and a

grayish exudate in the middle ear space. However these distinctions on clinical examination are far from universal and

cannot be relied upon to direct therapy.

LOWER RESPIRATORY TRACT INFECTIONS

GABHS can cause lobar pneumonia. Affected children generally have high fevers and appear quite toxic. Empyema occurs

more commonly than with pneumococcal pneumonia which is a more common bacteria] cause of lobar pneumonia.

SKIN INFECTIONS

The most common skin and soft tissue infection caused by GABHS is impetigo. Typically, a small pustule develops at the

site of a previous injury, such as a scratch. abrasion or insect bite, then ruptures spontaneously and develops a thin, honey-

colored scab. Multiple sites of involvement result from scratching. The individual lesions are very superficial and involve

the outermost layers of the epidermis. The streptococci causing impetigo or pyoderma may be found in the nose at throat,

but this infection usually occurs after the skin infection has been established. Impetigo generally occurs during summer

months.

Erysipelas is a superficial cellulitis characterized by a raised irregular, advancing border. Systemic symptoms include

fever, vomiting, and irritability. GABHS may be the only causative organism or may be present with Staphylococcus

aureus, as in other forms of cellulitis. There are no clinical features unique to skin and soft-tissue infections caused by

GABHS as compared with those caused by S aureus; this, both organisms should be considered.

CARDIOVASCULAR, MUSCULOSKELETAL, AND LYMPHATIC LNFECTIONS

GABHS accounts for a small percentage of cases of endocarditis (more commonly due to viridans streptococci and group D

streptococci) myocarditis and pericarditis (more commonly due to viruses), and phlebitis (more commonly due to S aureus).

GABHS is the second most common bacteria] cause of musculoskeletal infections and lymphadenitis following S aureus.

Necrotizing fasciitis is discussed later as a GABHS complication. Genera]ly when GABHS is the cause of cardiovascular,

musculo-skeletal, or lymphatic infections illness progresses rapidly and is marked by high fever and systemic toxicity.

BACTEREMIA AND MENINGITIS

The blood stream or meninges rarely are invaded following infection of the upper respiratory tract or skin with GABHS. An

increased incidence of invasive streptococcal infection is observed in certain vulnerable host conditions (eg, post-

splenectomy, sickle cell disease, varicella, or immunodeficiency). Signs and symptoms of streptococcal bacteremia and/or

meningitis do not differ notably from these infections caused by other bacteria, which are more common pathogens.

Tonsillopharyngitis

EPIDEMIOLOGY

GXBHS throat infections produce a self-limited, localized inflammation of the tonsillopharynx that generally lasts 3 to 5

days. Antibiotic treatment if prompt and appropriate shortens the duration of symptoms and the period of contagion and

reduces the occurrence of localized spread and suppurative complications. A major objective of antibiotic therapy is to

prevent rheumatic fever and possibly reduce the incidence of poststreptococcal glometrulonephritis.

Humans are the natural reservoir for GABHS, and infections are spread person to person. The nasopharynx and

oropharynx are the primary carriage sites for this organism; the skin and anus also are potential sites. Direct contact with

infected nasopharyngeal or oropharyngeal mucosa and with contaminated objects such as toothbrushes is of less

importance. Rarely, food is a vehicle for the spread of GABHS.

Spread of GABHS requires a susceptible host and is facilitated by close contact. Infection rarely is acquired in infancy,

probably because of maternal immunity conferred transplacentally. Infection is uncommon in those younger than 2 years of

age, possibly due to decreased attachment of GABHS

to nasopharyngeal and oropharyngeal epithelial cells.

When infection occurs in toddlers, it most often

involves the nasopharynx or skin (impetigo). Close

contact with a large number of individuals who

potential]y are infected with GABHS, as occurs in

child care and grade school, results in more frequent

spread of illness. Adolescents usually have had contact

with the organism over time, which provides

immunity, thereby rendering GABHS infections less

common in this population. The frequency of isolation

of GABHS and other tonsillopharyngeal pathogens in

children and adolescents is shown in Table 2.

DIFFERENTIAL DIAGNOSIS

The largest proportion (15% to 40%) of children and

young adults (30% to 60%) who have tonsillopharyngitis have viral infections. About 8% to 40% of children and 5% to 9%

of adolescents who have sore throat, fever, and tonsillopharyngeal inflammation have GABHS infection. Other bacteria

infrequently cause throat infection. The differential diagnosis of GAB HS tonsillopharyngitis, particularly among

adolescents, should include infection caused by group C and G Streptococcus sp and Neisseria gonorrhoeae. Anaerobes

may be involved in deep-seated infections such as peritonsillar or retropharyngeal abscesses, but there is no evidence that

surface colonization with these organisms causes symptomatic tonsillopharyngitis.

Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR agent), and Arcanobacieriwn haemolyticum are occasional

causative agents of symptomatic tonsillopharyngitis[ Corynebacterium diphtheriae remains a cause of tonsillopharyngitis in

developing countries. Sore throats often are “idiopathic” in etiology. It is not clear whether these cases of tonsillopharyngitis

actually are caused by viruses that at present cannot be identified or whether they are dime to other factors such as postnasal

drip or allergy.

CLINICAL MANIFESTATIONS

GABHS tonsillopharyngitis cannot be diagnosed on clinical grounds in most patients. The patient who has a classic

GABHS throat infection exhibits fever, tonsillopharyngeal erythema and exudate, swollen and tender anterior cervical

adenopathy, absence of rhinorrhea and cough, and an elevated white blood cell count during mid-winter to early spring

(Table 3). When this constellation of symptoms is present, the likelihood of GABHS infection approaches 60% to 70% in

children and 20% to 30% in adolescents.

Symptoms of groups C and G streptococcal pharyngitis are similar to those of GABHS. Adolescents and young adults

are particularly susceptible to groups C and G streptococcal pharyngitis. The symptoms may not be as severe as those asso-

ciated with GABHS infection, but all may be present.

After screening more than 20,000 children who had cute respiratory illnesses associated with sore throat. Breese derived

a nine-factor scoring system for diagnosing GABHS tonsillopharyngitis. Children who had fewer than 25 points in the

Breese scoring system had a 6% probability of having GABHS tonsillopharyngitis; this represented 20% of the children

from whom throat cultures were obtained. Children who scored 26 to 31 points had a probability of approximately 40% and

represented 36% of the study population. Children who had 32 to 38 points had a probability of 84% and represented 44%

of the study population. The Breese scoring system requires a white blood cell count from every patient; eliminating this

finding invalidates the applicability of the scoring.

The accuracy of probability estimates for diagnosing GABHS tonsillopharyngitis made by experienced physicians has

been assessed in a university health service among an adolescent population. When two general internists, three pediatri-

cians, and five family physicians predicted the culture outcome on clinical grounds for 308 patients who had sore throat, the

probability of positive GABHS culture was overestimated for 81% of patients. Only 15 cultures (4.9%) were positive for

GABHS. Over diagnosis almost always led to the decision to treat with antibiotics.

Based on these carefully conducted studies, it would appear that the clinical diagnosis of GABHS throat infections is

unreliable in most patients. A subset of children (approximately 20%) and adolescents (approximately 67%) will present

with sore throat and few other symptoms or signs of GABHS tonsillopharyngitis; they require neither a diagnostic test

(culture or rapid antigen detection) nor treatment. The sore throat is pan of a viral upper respiratory tract infection. These

individuals can be distinguished clinically from other patients by an accompanying rhinorrhea, cough, hoarseness, and often

an absence of fever, tonsillopharyngeal erythema or exudate, and cervical lymphadenitis.

LABORATORY TESTING

Throat Culture

Breese and Disney were the first to report the use of throat cultures plated un sheep

blood agar in an office in 1954. The use of a throat culture to confirm the presence of

GABHS has become a common pediatric practice: by the early 1980s, the Centers for

Disease Control and Prevention estimated that 28 to 36 million throat cultures were

performed annually in the United States. Ibis simple laboratory test is valuable in

avoiding unnecessary antibiotic therapy and in identifying patients who require

treatment.

False-positive Throat Cultures

False-positive GABHS throat cultures usually occur through misidentification of

beta-hemolytic streptococci belonging to Lancefield groups B, C, F, or G, or betahemolytic S aureus. The bacitracin

sensitivity test can differentiate GABHS from non-GABHS betahemolytic strains; 95% to 100% of GABHS demonstrate

a zone of growth inhibition around a disk containing 0.04 units of bacitracin compared with 83% to 97% of non-GABHS

that do nut. If there are sufficient numbers of bacteria in the area of the disk, the test can be interpreted adequately on a

primary blood agar plate.

False-negative Throat Cultures

Explanations fur false-negative throat cultures include: 1) faulty culture technique, 2) surreptitious antibiotic use, and 3)

faulty bacteriologic methods. The optimal site fur throat culture is the surface of the tonsil. The tongue, hard palate, teeth,

and buccal mucosa are not satisfactory. It is difficult to isolate GABHS after one or two doses of antibiotic have been

administered, and occult antibiotic use may be a significant cause of false-negative throat cultures. Patients frequently do

not take the full amount of prescribed antibiotic, and leftover drug is saved for the next occurrence of similar symptoms.

In a hospital emergency department study, 10% of patients who forthrightly denied antibiotic use on direct questioning by

a physician had evidence of antibiotics detected in their urine.

Quality assurance methods should be incorporated into laboratory routines and now are mandated by CLIA

regulations. A known isolate of GABHS should be inoculated daily onto a plate and incubated concurrently as a positive

control with other throat swab cultures obtained from patients suspected of having GABHS infection. Duplicate throat

swabs should be processed in a reference laboratory (hospital) periodically to corroborate office laboratory results.

Rapid GABHS Antigen

Detection Tests

GABHS antigen detection tests can be performed quickly in a physician’s office or clinic at a cost that is comparable to a

10-day prescription of penicillin. These tests rely un extraction of carbohydrate antigen of GABHS followed by detection

with an antibody-tagged reagent that produces a clumping effect or color change after interaction. If properly performed,

the sensitivity (average, 76% to 87%) and specificity (ayera2e, 90% to 96%) of rapid antigen detection testing can

approach that of throat cultures (Table 4).

One recommended strategy for use of the rapid GABHS antigen test is to deem a positive result as reliable, with treatment

rendered as appropriate. In contrast, a negative rapid antigen detection test result suggests no need for treatment, but

consideration of sending a throat swab for confirmatory culture to avoid missing an infection that might require therapy.

It should be recognized that this strategy could result in over treatment of about one third of patients who have positive

tests , given the positive predictive value of the test because GABHS prevalence is about 15% in the winter respiratory

infection season. Moreover, confirmatory cultures in those who have negative results to rapid tests will be positive in only

1.5% to 3.4% of patients if the prevalence of GABHS is 8% to 15%, respectively. The test is most effective when iris

performed in immediate proximity to where patients are seen and the charge to patients should be modest so as not to dis-

courage its use. Such availability allows the integration of rapid GABHS antigen detection testing into clinical decision-

making, despite the busy flow of patients in all types of settings. Rapid GABHS antigen testing does not require the

expertise of a certified microbiologist or laboratory technician; it can be performed by any properly trained physician; nurse,

or allied health professional. It is essential that those performing the tests review the package insert carefully to comply

fully with the instructions. Shortcuts and lack of attention to detail reduce the sensitivity and specificity of these tests

ANTIBIOTIC SUSCEPTIBILITY GABHS are highly susceptible o penicillins and cephalosporins. In vivo activity of these

drugs is influenced significantly by the level of antibiotic achieved at the site of infection. Antibiotics may have variable

rates of absorption, absorption can be influenced by food, or their action may be compromised by enzymatic breakdown or

other microbial resistance mechanisms. GABHS usually are susceptible to erythromycin, clarithromycin, azithrornycin,

Lincomycin, and clindamycin. However, GABHS resistance to the macrolides occurs and may develop in a community or

country as a consequence of antibiotic pressure from their extensive use. Cross-resistance among macrolides is observed.

The minimal inhibitory concentration (MIC) of the aminoglycosides. sulfonamides, chloramphenicol, and tetracycline

against most GABHS strains is consistent with the clinical observation that these agents are of limited value in the treatment

of such infections. Sulfadiazine is acceptable for secondary prophylaxis in rheumatic fever. This reflects the difference

between antibiotic efficacy when bacterial colonization first begins (prophylactic drugs might be effective) versus when

active infection is established (agents effective in treatment are required).

ANTIBIOTIC TOLERANCE

GABHS tolerance to penicillin has been studied extensively in the laboratory and clinically over the past decade. A ratio of

the MIC to the minimum bactericidal concentration (MBC) of 32-fold or greater defines a tolerant strain, which is inhibited

but non killed by penicillin. Whereas a clear correlation between antibiotic tolerance and clinical treatment failures has been

demonstrated for S aureus, there is no such correlation for GABHS. Clinical observations of tolerant GABHS strains have

involved outbreaks in which penicillin-tolerant strains resulted in penicillin treatment failures and penicillin-tolerant and

susceptible strains were associated with equivalent penicillin treatment failure rates.

TISSUE AND BLOOD LEVELS

For beta-lactam antibiotics (penicillin and the cephalosporins), the time during which the antibiotic is above the MIC is

much more important than the height of the peak antibiotic concentration in producing efficacy; this is termed “time--

dependent” as compared with “concentration-dependent” antibiotic killing. Increasing blood levels of beta-lactam

antibiotics by administering probenecid concurrently or adding procaine penicillin to benzathine penicillin does non

produce better bacteriologic efficacy Once a concentration of a betalactam antibiotic has been reached that ensures activity

at the bacterial cell wall, increased drug concentrations do not eradicate GABHS more effectively.

Beta-lactam antibiotics work against actively growing bacteria. After initial bactericidal activity, there is a time span of

treatment before active bacterial growth resumes during which the antibiotic -is non essential. Ibis makes intermittent oral

therapy feasible as an alternative to the continuous levels of antibiotics achieved with injectable benzathine penicillin G.

DURATION OF THERAPY

injections of benzathine penicillin provide bactericidal levels against GABHS for 21 no 28 days. The addition of procaine

alleviates some of the discomfort associated with benzathine injections and may influence the initial clinical response

favorably GABHS is eradicated through the sustained levels of penicillin achieved with the benzathine formulation. Ten

days of penicillin treatment is required no achieve a maximum bacteriologic cure rate in GABHS tonsillopharyngitis: 5 no 7

days therapy with injectable or oral penicillin does not produce maximal GABHS eradication.

Because compliance with 10 days of therapy often can be problematic, a shorter course of

Therapy is attractive. A regimen of 4 to 5 days of therapy with several cephalosporins-cefadroxil, cefuroxime axetil,

cefpodoxime proxetil and cefdinir has been shown to produce a bacteriologic eradication rate similar or superior to that

achieved with 10 days of oral penicillin V. Cefpodoxime proxetil has been approved by the United States Food and Drug

Administration as a 5-day therapy for throat infections caused by GABHS. Azithromycin may be administered for 5 days no

treat GABHS because it persists in tonsillopharyngeal tissues form approximately 10 days after discontinuation of the drug

(total of 15 days therapy). If bacteriologic eradication is the primary measure of effective GABHS treatment, as the only

corollary for the prevention of acute rheumatic fever, then superior bacteriologic eradication with a short course of

cephalosporin or azithromycin therapy with which patients comply may prove to be a significant advance.

SYMPTOMATIC RESPONSE TO ANTIBIOTIC THERAPY

The primary reason that patients seek antibiotic therapy for sore throat is to quell symptoms and shorten the clinical course

of illness. For many years it was thought that antibiotics only minimally ameliorated the symptoms of GABHS

tonsillopharyngitis. In the 1980s this tenet was refuted by several double-blind evaluations that showed greater clinical

improvement in patients receiving penicillin compared with those receiving a placebo. One study showed that penicillin

relieves symptoms of GABHS tonsillopharyngitis faster and more effectively than acetaminophen.

Although antibiotics do alleviate symptoms of GABHS tonsillopharyngitis, nearly all patients will improve spontaneously,

even without treatment. The natural course of GABHS tonsillopharyngitis is a rapid onset of symptoms and signs of

infection followed by spontaneous resolution within 2 to 5 days. Thus, patients who seek care after they have had a sore

throat for more than 1 week usually do non have GABHS tonsillopharyngitis. It is non the spontaneous resolution of

symptoms, but the persistence of the organism in the tonsillopharynx that sets the stage for ongoing contagion and the risk

of acute rheumatic fever (ARF). Even though the patient feels better, persistence of the organism elicits an ongoing immune

response. If the strain is rheumatogenic and the host genetically predisposed, then ARF may follow.

If the patient has GABHS tons tonsillopharyngitis, clinical improvement should occur promptly following the start of

antibiotic therapy; failure no improve usually indicates that GABHS is non the cause of the tonsillopharyngeal infection.

GABHS is either non present or it is present bun the patient is only a carrier. The symptom-relieving effects of therapy are

most marked if treatment is instituted early in the course of illness. If therapy is started after the first 24 no 48 hours of

illness, symptoms and signs of GABHS tonsillopharyngitis may non disappear significantly more rapidly than with no

treatment.

Prompt treatment is non vital to preventing rheumatic fever. A study of military recruits in the 1950s documented that ARE

can be prevented even if treatment is delayed for 9 days after onset of symptoms of GAIBHS tonsillopharyngitis. Thus,

even after the acute symptoms of GABHS tonsillopharyngitis have subsided. ARF can be prevented. This observation is in

contrast to results with sulfadiazine treatment, which favorably influences acute symptoms when administered early in the

course of illness but does non eradicate GABHS from the respiratory tract and does non prevent ARE.

CONTAGION

The transmission rate of GABHS is approximately 35% within a family or school if the patient 15 untreated. Appropriate,

effective antibiotic treatment prevents transmission no others who are susceptible. Penicillin renders an infected individual

minimally contagious to others in approximately 24 hours. The duration of contagion when alternative antibiotics are used

has non been studied systematically. If penicillin is discontinued after 3 days of therapy, there is a 50% likelihood that the

patient will relapse with a positive GABHS infection (which may be asymptomanic). If the penicillin is stopped after 6 no 7

days of treatment, the likelihood of GABHS recurring is approximately 34%. Untreated, the spontaneous rate of

disappearance

of GABHS from the throat (by host immunity) is 50% within 1 month of acute infection.

PREVENTION OF RHEUMATIC FEVER

The efficacy of penicillin for the primary prevention of ARF was established in the early 1950s. In these seminal studies,

military recruits who had GABHS tonsillopharyngitis were given injectable penicillin G mixed in peanut Oil or sesame oil

and 2% aluminum monostearate. Injection schedules that provided at least 9 to 11 days of effective penicillin therapy

optimized GABHS eradication and the primary prevention of ARE.

BENZATHINE PENICILLIN G

A preparation of injectable penicillin was developed that combined the long-acting effect of benzathine with procaine

penicillin, a drug that diminishes pain at the injection site. A combination of 900,000 U of benzathine penicillin G plus

300,000 U of procaine penicillin is the preferred product for most school-age children.

ORAL PENICILLIN V

Following the determination that GABHS eradication by penicillin prevented ARE, acceptable treatment of GABHS

tonsillopharyngitis was evaluated on the basis of bacteriologic eradication. It often is forgotten or widely unknown that oral

penicillin never was shown in a prospective controlled trial no prevent ARF. The logical presumption applied no treatment

of GABHS tonsillopharyngitis has been no equate bacteriologic elimination of the pathogen from the tonsillopharynx with

likely prevention of ARF. The low incidence of ARF among patients given oral penicillin appears no validate this

hypothesis.

Various dosing regimens of oral penicillin G and V have been assessed. A daily dose of 500 no 1.000 mg of penicillin V is

preferable. Lower doses are associated with lower eradication rates, and higher doses are non beneficial. Twice-daily dosing

with oral penicillin y may be adequate therapy for GABHS tonsillopharyngitis, but once-daily treatment is not.

AMOXICILLIN, AMOXICILLIN/

CLAVULANATE, NAFCILLIN,

CLOXACILLIN, AND

DICLOXACLLLIN

Orally administered ampicillin and amoxicillin are equivalent but not superior to penicillin in eradicating GABHS from the

tonsillopharynx. Amoxicillin is more effective than penicillin against the common pathogens than cause otitis media, which

occurs concurrently with GABHS tonsillopharyngitis in up no 15% of pediatric patients. Children younger than 4 years of

age have a higher incidence of concurrent otitis media when they contract GABHS tonsillopharyngitis. Two-other features

of amoxicillin therapy may be important: 1) it tastes better than oral penicillin in suspension formulation, which can

enhance compliance for children, and 2) a recent study showed that a 6-day regimen of amoxicillin was equivalent no 10

days of penicillin therapy in eradicating GABHS from the throat.

In most comparative studies of the treatment of GABHS tonsillopharyngitis, amoxicillin/clavulanate exhibited superior

bacteriologic eradication oven penicillin. Amoxicillin is bactericidal against GABHS and clavulanate is a potent inhibitor of

bena-lactamase. Thus, amoxicillin clavulanate would be effective if copathogens were colonizing the tonsillopharynx

(discussed below). Cloxacillin and dicloxacillin are adequate therapy for GABHS eradication, bun oral nafcillin is non.

ERYTHROMYCIN, CLARITHROMYCIN, AND AZITHROMYCIN

For patients allergic to penicillin, a macrolide antibiotic (eg, erythromycin) is the suggested antibiotic for GABHS

tonsillopharyngitis. Erythtomycin estolate and ethylsuccinate have been shown consistently no compare more favorably

with oral penicillin in bacteriologic eradication than erythromycin base or stearate. Dosing frequency studies with various

erythromycin preparations have shown that administration two, three, or four times daily produces equivalent bacteriologic

eradication rates.

Clarithtromycin has eradicated GABHS causing tonsillopharyngitis at a rate similar or superior no penicillin. Azithromycin

has been evaluated for treatment of GABHS tonsillopharyngitis in 3- and 5-day regimens. The 5-day course of treatment

proved as effective or more effective than penicillin in eliminating GABHS from the throat. -A 3-day treatment course with

azithtomycin for GABHS tonsillopharyngitis has been approved by regulatory agencies outside the United States, but two

recent studies suggest that 3 days is inadequate for optimal efficacy. The regimen for azithtomycin in the treatment of

GABHS tonsillopharyngitis in the United States is 10 no 12 mg/kg per day for 5 days, which differs from the dosing

recommended for acute otitis media. The 5-day dosing regimen usually requires the purchase of two bottles of medication,

which increases the cost. Both azinhtomycin and clarithtomycin produce fewer gastrointestinal side effects than does

erythromycin.

CLINDAMYCIN, LINCOMYCIN, AND RIFAMPIN

Clindamycin and lincomycin have been evaluated as primary treatment for GABHS tonsillopharyngitis. Clindamycin is

effective in eliminating carriage of GABHS, but its routine use is non advocated for GABHS tonsillopharyngitis because of

conicern for infrequent but significant side effects, including pseudo membranous colitis. Rifampin has been studied in

combination with oral penicillin as a potential antibiotic for eradicating carriage of GABHS, and successful results have

been observed.

CEPHALOSPORINS

Oral cephalosporins have been studied as alternative antibiotics for the treatment of GABHS tonsillopharyngitis since 1969.

Consistently superior bacteriologic eradication rates, and in many cases clinical cure rates, have been observed with the

cephalosporins compared with penicillin. In 1991, a meta-analysis was published comparing the bacteriologic and clinical

cure rates achieved with various cephalosponins and various penicillin preparations. Nineteen studies of adequate study

design and implementation were analyzed. The mean bacteriologic failure rare under these ideal study conditions was

significantly higher in patients treated with penicillin (16%) than in those treated with cephalosporins (8%, P <0.001). The

mean clinical failure rate also was evaluated by meta analysis and documented as 11% with various penicillin formulations

and 5% with the cephalosporins (P <0.001). Although the methodology of this meta-analysis has been questioned and the

Red Book states that additional studies are warranted, numerous subsequent large prospective, double-blind, randomized

initials comparing first-, second-, and third generation cephalosporins have confirmed the meta-analysis results. The

superiority of cephalosporins in GABHS eradication form the throat now appears no be established. The current debate

focuses on their cost effectiveness compared with penicillin or amoxicillin given the magnitude of the difference in the

anticipated efficacy rates. There also is concern about possible widespread empiric use of these valuable, broader spectrum

agents for all sore throats rather than only for laboratory-confirmed GABHS cases.

CHANGES IN PENICILLIN TREATMENT SUCCESS

Penicillin treatment failure rates raiigingftoms%to35%for GABHS tonsillopharyngitis have been reported in various studies

oven the past 30 years; an increase in such failures has been noted in the past decade. This increase could be reflected in a

rise in the incidence of ARF, which has non been observed consistently. However, declining efficacy of penicillin (and

other antibiotics) may not necessary manifest as an increased incidence in ARE because treatment failure must occur in the

presence of a rheumatogenic GABHS strain and as yet undetermined specific host susceptibility factors.

Recent descriptions of GABHS toxic shock syndrome and GABHS mediated necrotizing fasciitis have raised concerns that

a resurgence of virulent GABHS infections may be occurring. Penicillin treatment failure has been noted among patients

expeniencing severe GABHS infections. Although the site of infection usually is cutaneous for these severe infections, the

tonsillopharynx has been the source in some cases. These penicillin failures may be due to the “Eagle” effect in which

virulent, toxin-producing strains of GABHS divide rapidly, reach a stationary phase of growth (perhaps as a consequence of

diminished nutrients in the immediate environment of the infection), and resist the bactericidal activity of penicillin and

other beta-lactams while in this phase. Antibiotics that inhibit bacterial protein synthesis, such as clindamycin have proven

useful in eradicating such GABHS strains.

Explanations for Antibiotic Failure

DEFICIENCIES IN ANTIBIOTIC FORMULATIONS

The quality of benzathine penicillin G may not be uniform among various manufacturers un various- countries. Benzanhine

penicillin G preparations that produce lower, variable, and a shorter duration of adequate levels have been described

COMPLIANCE

For optimal absorption, oral penicillin V should be administered 1hour before or 2 hours after meals. Recommended thrice

daily dosing of penicillin that must be administered away from meal time can prescnn a formidable bamer no compliance.

Reducing the number of times a day that a patient must take any medication and making it possible no take doses with

meals will improve patient compliance. Three nines daily dosing typically is associated with a 30% no 50% compliance rate

compared with 70% no 90% compliance with once or twice daily dosing schedules. Intramuscular benzanhine penicillin

injections obviate issues of compliance.

Good-tasting suspension formulations of oral antibiotics can enhance compliance among children. In contrast, a marginal

or poor taste may lead to the child refusing, spitting out, or vomiting the drug. Penicillin V suspension does not have a good

taste, but most children find the taste of amoxicillin quite pleasant. Perhaps this is why amoxicillin is prescribed for

tonsillopharyngitis more frequently by physicians in the United States that is penicillin. Taste comparisons of antibiotic

suspensions have found several cephalosporins to taste best.

Patients’ perceptions of antimicrobial side effects strongly influence compliance. All of the antibiotics commonly employed

no treat GABHS tonsillopharyngitis are notable for their low incidence of adverse effects. Rash and gastrointestinal upset

occur in 1% 10 2% of patients who receive the penicillins and cephalosporins, Macrolides, particularly erythromycin, more

frequently produce gastrointestinal upset. Amoxicillin/clavulanate is associated with a higher incidence of diarrhea than

other agents.

REPEATED EXPOSURE

Crowded living conditions encourage the transmission of GABHS within the family, an work, at school, or in child care

settings. A recurrence of GABHS tonsillopharyngitis after treatment that involves the same serotype may be associated with

milder symptoms. These individuals are contagious no others in their environment and are susceptible no rheumatic fever.

EARLY TREATMET SUPPRESSES IMMUNITY

Prompt initiation of antibiotic treatment with the onset of acute symptoms may suppress the increases in antistreptolysin O

(ASO) and antiDNase B antibody that typically follow GABHS infections. Antibody suppression has been associated with

relapse and recurrence of GABHS tonsillopharyngitis. Although delaying treatment probably is not necessary in most cases,

it may be useful for patients who have frequent recurrent, mild-to-moderate infections. Delaying treatment for 2 or 3 days

(maximum of 9 days from onset of symptoms) may allow the patient’s natural immunity to develop without risk of

rheumatic fever. Such a strategy should not be considered if the patient is toxic or severely in or if highly virulent or

rheumatogenic strains are circulating in a community.

COPATHOGENS

The presence of co-colonizing bacteria in the throat, termed copathogens, that elaborate beta-lactamase in the

tonsillopharynx has been proposed as a possible mechanism by which penicillin is inactivated in vivo prior to bactericidal

action on GABHS. S. aureus, H influenza, M catarrhalis and beta-lactamase-producing anaerobic species are common flora

in the tonsillopharynx. The prevalence of these beta-lactamase-producing bacteria may increase as a consequence of

penicillin treatment of patients who have GABHS tonsillopharyngitis. This recent penicillin threatening may predispose

some patients to harbor higher numbers o beta-lactamase-producin copathogens, which in turn may lead to increased rates

of penicillin treatment failure.

Indirect evidence suggests that when copathogens are present in the tonsillopharynx, use of antibiotics that are effective

despite the presence of beta-lactamase may enhance bacteriologic and clinical success, but this is not a universal finding. It

is not necessary to eradicate the copathogens that produce betalactamase. Rather, the antibiotic employed must remain

active despite the presence of beta -lactamase in vivo.

STREPTOCOCCAL CARIUAGE

GABHS carriage is likely when GABHS is documented in the throat but the patient shows neither symptoms of

tonsillopharyngitis nor a demonstrable rise in streptococcal antibody titers. This operational definition is complicated by

early initiation of antibiotic therapy that may prevent an antibody response following GABHS infection. The absence of an

antibody response, therefore, does not rule out a bona fide GABHS infection if treatment has been rendered. Also, patients

experiencing a relapse with the same strain of GAB 1-LS (a homologous serotype) soon after a primary infection often have

milder symptoms of GABHS infection. These symptoms may be recalled only on direct questioning. Such patients have

been shown to demonstrate a rise in antibody, which identifies them as susceptible to ARF.

Whether treated or untreated symptoms of acute GABHS infection eventually resolve, but carriage of the bacteria may

persist. In the early stages of this carrier state, patients are contagious to others. After 1 to 2 months, the carrier state is

associated with diminished numbers of GABHS organisms in the tonsillopharynx, reduced bacterial virulence, and less

transmissibility to others. The presence of GABHS on throat culture or as detected through rapid diagnostic testing does not

distinguish between the patient who has bona fide GABHS tonsillopharyngitis and is at risk for ARF and the patient who

has an acute viral sore throat and is only a GABHS carrier. Asymptomatic GABHS carriage may persist despite intensive

antibiotic treatment and may account for apparent penicillin failures because eradication of the GABHS carrier state

generally cannot be achieved with penicillin.

Disadvantages and Advantages of Penicillin Alternatives

Penicillin (not amoxicillin) currently is recommended as first-line therapy for GABHS infections by the American Academy

of Pediatrics Red Book Committee and the American Heart Association. Erythromycin is recommended as the alternative in

those allergic to penicillin. Increase use of empiric broad-spectrum antibiotic therapy for treatment of sore throat with newer

macrolides, cephalosporins or amoxicillin/clavulanate has the potential for exacerbating the escalating problem of antibiotic

resistance among respiratory pathogens.

Alternatives to penicillin for the treatment of GABHS tonsillopharyngitis are five to ten times more expensive, ranging from

approximately $30 to $60 for a l0-day treatment course. The differing bacteriologic cure rates of antibiotic therapy must be

viewed in light of the different antibiotic costs. If enhanced bacteriologic eradication can be achieved with a more expensive

agent and the enhanced eradication results in a reduction in illness burden, recurrence rates, physician visits. laboratory

tests, morbidity and/or mortality (direct costs). and loss of school for children and work for parents (indirect costs), then the

difference in antibiotic cost may be small compared with the overall cost of failed therapy. For example, in the subset of

patients who have recently experienced a penicillin treatment failure for GABHS tonsillopharyngitis, a cost-effectiveness

analysis has shown that follow-up treatment with cefadroxil is less costly than re-treatment with penicillin. In that study,

antibiotic acquisition costs represented about 5% (for penicillin) to 15% (for cefadroxil) of the total cost of treatment, with

the remainder attributable to direct and indirect costs. Cephalosporins appeared more cost-effective because the higher cure

rate resulted in lower overall costs.

Complications

RHEUMATIC FEVER

Rheumatic fever is a

nonsuppurative sequela of

infections with GABHS. There has

been a steady and dramatic decline

in its incidence in the United States

since the beginning of this century.

The decrease in incidence occurred

before the antibiotic era and, thus,

has been attributed largely to

improving socioeconomic

conditions and better access to

medical care. A shift from rheu-

matogenic to nonrheumatogenic

strains circulating in the United

States also may be a major con-

tributing factor.

Focal outbreaks of rheumatic fever occurred in the United States during the time span of 1984 through 1989 in Salt Lake

City, Utah; Columbus and Akron, Ohio; Pittsburgh, Pennsylvania; Nashville and Memphis, Tennessee; and among military

recruits in training centers in California and Missouri. Epidemiologic features of these outbreaks are presented in Table 6. A

particularly striking feature of these episodes was their occurrence in predominantly middle-income families as opposed to

patients in urban, lower socioeconomic environments. The major manifestations of ARF are carditis, arthritis, chorea,

erythema marginatum, and subcutaneous nodules. Minor manifestations include arthralgia, fever, laboratory documentation

of GABHS infection, elevated erythrocyte sedimentation rate or C-reactive protein levels, and prolonged P-R interval on

electrocardiography.

STREPTOCOCCAL TOXIC SHOCK SYNDROME

Since the mid-l980s there has been a resurgence of severe and even fatal acute GABHS infections. A toxic shock syndrome

has been described in association with soft tissue infections that resembles staphylococcal toxic shock syndrome. The

clinical characteristics included profound hypotension, shock, and multiorgan system failure (Table 7). An increased

prevalence of virulent toxin-producing GABHS serotypes, along with diminished host immunity because of the low

prevalence of these serotypes in preceding years, seems to have contributed to this increase in severe GABHS infections.

Pre-existing varicella infections have been noted in 40% to 50% of case reports of severe, invasive GABHS disease in

children. Notable laboratory features of the streptococcal toxic shock syndrome include a depression of the white blood cell

count, with a preponderance of immature granulocytes. Thrombocytopenia, hypocalcemia, and hypoalbuminemia also are

observed frequently. Patients suspected of experiencing streptococcal toxic shock syndrome should have serum creatinine

and creatinine kinase blood levels measured; elevations in these laboratory parameters have been noted frequently with this

condition due to associated necrotizing fasciitis.

POSTSTREPTOCOCCAL

GLOMERULONEPHRITIS

Poststreptococcal g1om~rulonephritis is the

most common form of glomerulonephritis in

children; it is primarily a disease of preschool

and school-age children. It follows either an

upper respiratory tract or skin infection due to

GABHS, but it is far more common after an

infection of the throat. Just as there are apparent

rheumatogenic strain, so too are there

nephritogenic strains of streptococci. The

principal clinical findings of poststreptococcal

glomerulonephritis are hematuria and edema

Depression of the total hemolytic complement

activity and C3 are seen in virtually all children during the initial phase of this nonsuppurative streptococcal complication.

Treatment is symptomatic and the prognosis is favorable.

Prevention

The development of a vaccine for the prevention of GABHS infection has been pursued for several decades. An

unsuccessful vaccine derived from streptococcal proteins produced cross-reactive antibodies in vaccines that resulted in

rheumatic carditis and glomerulonephritis and showed progress in vaccine development. Currently, efforts are focused on

identifying peptides within the streptococcal protein that are conserved among the strains, do not produce antibodies cross-

reactive with human heart or kidney tissue, are immunogenic and are protective. Other vaccine antigens also are under

study.