Etiology and Management of
Acute and Recurrent Group
A Streptococcal Tonsillitis
Asher Barzilai, MD*, Dan Miron, MD, and Shlomo Sela, PhD
Address
*Pediatric Infectious Disease Unit, Chaim Sheba Medical Center,
Tel Hashomer, Israel.
E-mail: barzilaia@hotmail.com
Current Infectious Disease Reports 2001, 3:217223
Current Science Inc. ISSN 1523-3847
Copyright 2001 by Current Science Inc.
Tonsillitis is one of the most prevalent infections in children
and adolescents. The etiologic agents might be viral or
bacterial. About 30% of cases are reported to be of bacterial
origin, mainly due to group A Streptococcus (GAS). Although
in most instances GAS tonsillitis is a self-limited disease,
antibiotic treatment is recommended, mainly to prevent the
suppurative and nonsuppurative poststreptococcal sequelae
of acute rheumatic fever and to prevent glomerulonephritis.
In this paper we review the current knowledge of the etiology
of acute and recurrent GAS tonsillitis, with special emphasis
on a recent hypothesis regarding the etiology of bacterial
eradication failure. While penicillin V remains the drug of
choice for acute tonsillitis, other antibiotics are being
approved and recommended for particular indications in both
Europe and the United States.
Introduction
Streptococcus pyogenes, also known as group A Streptococcus
(GAS), is one of the most important human bacterial patho-
gens commonly causing throat and skin infections [1].
Tonsillitis caused by GAS is usually a self-limited illness
lasting 3 to 5 days [2]. However, antibiotic treatment is
desirable because it not only shortens and reduces the signs
and symptoms of GAS tonsillitis, but also reduces transmissi-
bility and prevents the development of nonsuppurative
sequelae [2,3]. In particular, antibiotic therapy is
important in the prevention of poststreptococcal rheumatic
fever and in the decreased incidence of glomerulonephritis,
as well as local suppurative complications [1,2,3].
Known for its efficacy against GAS and its good tolera-
bility, relatively low cost, narrow spectrum, and excellent
side-effect profile, penicillin V is the standard therapy for
tonsillitis caused by GAS [1,4]. Nonetheless, clinical and
microbiologic penicillin treatment sometimes fails. In fact,
rates of penicillin or other -lactam antibiotic failure as
high as 30% have been reported. Thus, debate over
whether penicillin is truly the best drug for treating GAS
tonsillitis has arisen in recent years [2,3,5,6,7]. We
discuss the etiology of acute and recurrent GAS tonsillitis,
emphasizing the recently emerged theory that might
explain failure of bacterial eradication. We also present our
approach for treating acute and recurrent tonsillitis.
Epidemiology
Acute tonsillitis is caused by viral and bacterial agents.
Bacterial sore throat accounts for only about 30% of cases,
of which GAS is the most common etiologic agent in child-
hood. GAS tonsillitis occurs most frequently in the late fall,
winter, and spring in temperate climates. Crowding in day
care centers, schools, and military installations facilitates
transmission. Food- and waterborne outbreaks of GAS
tonsillitis have also been documented [8]. The infection
can occur at all ages but is most common among children
and adolescents 5 to 15 years of age; it is rare in children
younger than 3 years of age. There is no sex predilection;
transmission of GAS throat infection almost always follows
close person-to-person contact via droplets of saliva or
nasal secretions. Communicability of patients with strepto-
coccal tonsillitis is highest during acute infection, and in
untreated individuals gradually decreases over a period of
several weeks. Patients are not contagious within 24 hours
of the initiation of appropriate antimicrobial therapy. The
bacteria may also colonize the throats without causing
infection. During the disease season, the asymptomatic
carriage rate in school children has been found to be 15%
to 20%, with a lower rate among adults [8].
Apparent Eradication Failure
Recurrent tonsillitis commonly occurs days to weeks after a
recent episode, although the presence of three or more epi-
sodes in a year is generally considered recurrent tonsillitis.
Diagnosis of recurrent tonsillitis is based on the return
of signs and symptoms of tonsillitis (pharyngotonsillitis)
with re-isolation of GAS from patient tonsils or pharynx.
Upon further examination, the isolated GAS strain might
218 Upper Respiratory, Head, and Neck Infections
be identical to the one isolated at a previous episode or
might be a newly infecting strain.
In a retrospective chart review study, Pichichero et al. [9]
reported a substantial increase in the rate of recurrent infec-
tions during the past three decades. They examined 2140 cases
of GAS infections from the years 1975 to 1996. Within 30
days after penicillin-amoxicillin treatment, infection recurred
in 9% of patients form 1975 to 1979, compared with an
infection recurrence rate of 22.4% from 1990 to 1994 and
25.9% from 1995 to 1996. A majority (53.4%) of the cases
were associated with symptoms and signs of GAS infection,
while 9.9% were asymptomatic and 36.7% could not be clas-
sified. Recurrences within 60 days have also increased signifi-
cantly. The authors concluded that recurrences within 30 days
occurred more often after therapy with penicillin than after
therapy with cephalosporins or macrolides. In addition,
recurrence was more frequent in children younger than 8
years of age than in adolescents [9]. Several theories have
been proposed as a cause of treatment failure. Below we will
discuss some of the causes for apparent failure.
GAS carriage
A common clinical situation involves a child or a young
adolescent who visits a physicians office for a relapse of
acute GAS tonsillitis. An unknown portion of these patients
might not have recurrent tonsillitis, but may actually be GAS
carriers having intercurrent viral tonsillitis [10]. A careful
examination of signs and symptoms from patients and
awareness of epidemiology data may aid in the differential
diagnosis [11,12]. Still, the standard throat culture will only
point out the presence of GAS; it will not determine the exact
genotype of the specific isolate. Thus, general practitioners
will not be able to conclude whether a repeated episode of
tonsillitis is caused by the original infecting strain or by
acquisition of a new strain, or whether it is merely an
intercurrent viral infection with GAS carriage.
In one study, 25% of patients with multiple episodes of
tonsillitis were suggested to be merely GAS carriers having
infection of viral origin [13]. In another study, a first-genera-
tion cephalosporin (cefadroxil) had the same efficacy as pen-
icillin V in bacterial eradication (94% and 93%, respectively)
among patients clinically classified as likely to have a bona
fide GAS infection. In contrast, in patients clinically classified
as likely to be streptococcal carriers, the efficacy was 92% for
cefadroxil and 72% for penicillin [14]. However, this study
did not report any serologic data to allow clear discrimina-
tion between children with acute GAS tonsillitis and chronic
GAS carriers with a viral infection. It may be possible,
although not practical in the routine setting, to distinguish
between a patient with acute GAS infection and a streptococ-
cal carrier by comparing the titers of antibody to GAS anti-
gens (usually antistreptolysin O) in acute and convalescent
serum specimens. A low antibody titer in two consecutive
specimens may suggest continuous carriage of GAS rather
than an acute GAS infection [11,12].
If the physician has chosen to treat the patient, the out-
come of therapy might also suggest the cause of the infec-
tion, ie, rapid resolution of symptoms indicates the
presence of a bacterial (possibly GAS) etiologic agent.
New GAS infection
An unknown portion of patients with recurrent GAS tonsil-
litis represent cases of successful antibiotic treatment, ie,
resolution of signs and symptoms and complete eradica-
tion of the original infecting strain. These patients might
have been reinfected with the same strain or a new one and
might consequently develop a mild or acute tonsillitis epi-
sode. The source of strain is generally a close contact of the
patient, such as a family member or a schoolmate. Because
it is unfeasible for the routine bacteriologic laboratory to
subtype GAS strains, the physician cannot determine
whether the etiologic source for recurrent infection repre-
sents a true eradication failure or reinfection.
True Eradication Failure
A repeating episode of GAS tonsillitis might be caused by a
true failure of the antibiotic to eradicate the original GAS
strain from the patients throat. In contrast to other bacte-
rial pathogens that can develop resistance to many antibi-
otics, no GAS strains with resistance to penicillin or any of
the cephalosporins have yet been found. In fact, a recent
study showed that the sensitivity of GAS strains to penicil-
lin has not changed in eight decades [15].
Numerous theories and mechanisms have been pro-
posed over the years to explain the perplexing phenome-
non of bacterial eradication failure after penicillin therapy.
Several comprehensive reviews summarize the proposed
explanations that have evolved over the past few decades
[2,16,17]. We briefly summarize the current knowledge
regarding the possible causes for eradication failure, and
present a new explanation that has emerged from our
recently accumulated knowledge of the capacity of GAS
strains to be internalized by epithelial cells.
Too-early antibiotic treatment
It has been proposed that a lack of protective, specific anti-
GAS (anti M-protein) antibodies might decrease treatment
success. This may be related to suppression of natural
immune response by too-early administration of antibio-
tics. Several studies have demonstrated an association
between eradication failure rate and the number of days of
illness before initiation of treatment [18,19]. Nevertheless,
other studies failed to support this theory [20].
Inappropriate treatment
Apparent eradication failure in some patients might be due
to the lack of sufficient antibiotic concentration at the site of
infection during the recommended treatment time [21]. Pos-
sible reasons are inappropriate dosage of antibiotic, short
duration of antibiotic therapy, and poor adherence. The
 Acute and Recurrent GAS Tonsillitis Barzilai et al.
effect of short treatment time on eradication failure was
demonstrated by Gerber et al. [22] who have compared 5
versus 10 days of penicillin V therapy (250 mg three times
daily) for streptococcal tonsillitis. Failure to eradicate the
original infecting strain was documented in 18% of patients
receiving the short therapy compared with 6% in patients
receiving the recommended 10 days of therapy [22].
Bacterial interference
A common explanation for recurrent infection is based on
the capacity of various members of the normal oropharyn-
geal flora to inhibit or interfere with GAS colonization. It has
been suggested that the normal oropharyngeal flora contains
numerous species of aerobic and anaerobic bacteria that may
interfere and compete with the growth of GAS [2327]. Con-
sequently, it was postulated that the eradication of the inter-
fering flora from a patients throat might facilitate
recolonization of GAS after therapy.
Brook and Gober [28] have recently demonstrated that
tonsils of children with a history of recurrent GAS infection
contain fewer aerobic and anaerobic bacteria with interfering
capability of GAS than tonsils from children without a
history of recurrent GAS infection. Several studies showed
the importance of bacterial interference as a source for bacte-
rial eradication failure [2931]. For example, 342 patients
with clinical signs of tonsillitis who carried GAS in their
throats were enrolled in a randomized, placebo-controlled,
multicenter study. All patients were treated with antibiotics,
and two thirds were also treated with -hemolytic strepto-
cocci, given as a spray for 10 days after antibiotic treatment.
The frequency of bacteriologic, verified clinical recurrence at
the follow-up visit on day 22 was 13% in the patients treated
with the -hemolytic streptococci and 15% in the placebo
group. However, at the last valid visit after 45 to 75 days, 19%
of patients in the first group and 30% of those in the placebo
group showed clinical recurrence (P = 0.037). In addition, at
the same visit, 5% of patients in the first group and 12% of
those in the placebo group were found to be asymptomatic
carriers [29]. However, the role of bacterial interference in
eradication failure has not always been established [14].
Production of -lactamases by
normal oropharyngeal flora
It has been suggested that various bacterial commensals
residing in the upper respiratory tract express -lactamases
that can inactivate penicillin and other -lactam antibiotics.
Several studies have demonstrated the ability of some aero-
bic and anaerobic bacteria to secrete -lactamases and have
shown a correlation between the number of -lactamase
producing species in the throats of patients before and after
therapy and the rate of GAS eradication failure [23,24,
32,33]. Studies suggested that both the presence of -lacta-
mase-producing bacteria and the lack of GAS-inhibiting
flora might be associated with increased rates of bacterial
eradication failure [23,24].
219
Although this so-called co-pathogenicity theory
gained much support, the results of other studies were
inconsistent, and a similar correlation has not always
been demonstrated [14,34].
It has been reported that certain cephalosporins are
somewhat superior to penicillin in preventing recurrence of
GAS infection. This might be explained, on the one hand,
by the broad-host spectrum of these antibiotics, resulting in
a more efficient eradication rate of the -lactamase-produc-
ing flora [1]. On the other hand, it might be explained by
the higher resistance of -hemolytic streptococci, and
perhaps other interfering bacteria, to these antibiotics [25].
Resistance to penicillin
It is intriguing that despite the extensive use of penicillin
and other -lactams in the past eight decades, no resistance
has emerged in the treatment of GAS infections [15].
Sporadic reports correlated in vitro penicillin tolerance (ie,
significantly decreased bactericidal effect of penicillin)
with GAS eradication failure. Nevertheless, conflicting
findings have been reported by various researchers [17,35],
and there is no common agreement regarding the role of
tolerance in penicillin failure.
Another explanation for ineffective bactericidal effect
of penicillin might be associated with the growth phase of
GAS. It has been proposed that GAS might survive in a
stationary-like phase, in which cell-wall synthesis is mini-
mal [36,37]. In accordance with this theory, researchers
showed that certain penicillin-binding proteins of GAS are
lost when the bacterium enters the stationary phase in
vitro [38]. If this is the case, it is not clear why certain
strains enter a stationary phase under similar conditions
whereas others do not.
Intracellular niche
In addition to the growth phasedependent resistance
mechanism discussed above, GAS may also hide in an anti-
biotic-protected niche. A wealth of published reports now
describe the capacity of various GAS strains to enter and sur-
vive within mammalian cells [3948]. Consequently,
researchers suggested that the ability of GAS to enter
epithelial and macrophage-like cells of the upper respiratory
tract enables the bacterium to survive in an environment that
is shielded from the bactericidal effect of penicillin, as well as
other -lactams, which cannot reach comparable intracellu-
lar concentrations [39,41,42,44,49]. Internalization was
found to be more efficient in GAS strains grown to stationary
phase than in logarithmic-phase bacteria [39]. Persisting
strains would probably grow in an environment that mimics
the stationary phase of growth.
It should be stressed that at this time, the biologic sig-
nificance of GAS internalization in the pathogenesis of
GAS infections is not obvious. GAS is still considered an
extracellular pathogen that causes a variety of infections by
adhering to certain tissues of the host and by secreting a
220 Upper Respiratory, Head, and Neck Infections
wide range of toxins and enzymes [50]. Internalization
may play a critical role in the bacterium's ability to enter
deep tissue of the host [39]. In contrast, other researchers
have argued that internalization is a host defense mecha-
nism that finally leads to bacterial eradication [51]. The lat-
ter group showed that highly mucoid invasive strains
internalized cultured keratinocytes less efficiently than
nonencapsulated strains [51]. Nevertheless, recent findings
have demonstrated not only that GAS could internalize
epithelial cells in tonsillar biopsy specimens [42], but also
that bacteria are found in vivo inside epithelial and mac-
rophage-like cells in tonsils of GAS carriers [43]. The dem-
onstration that some GAS strains may survive
intracellularly for several days [41] may support a biologic
role for internalization in the persistence of GAS during a
period of penicillin therapy.
The first genes to be implicated with high efficiency
internalization of various GAS strains were sfbI and prtF1,
which encode for a closely related fibronectin-binding pro-
tein [45,52]. In a recent study, we compared the prevalence
of the prtF1 gene in 13 GAS strains derived from asymp-
tomatic patients with eradication failure following antibi-
otic therapy versus the prevalence in 54 strains derived
from patients with successful bacterial eradication. We
found a strong correlation between the presence of prtF1
and GAS eradication failure [5]. Furthermore, strains of
the former group adhered to and entered into cultured res-
piratory epithelial cells significantly better than strains
derived from the latter group [53]. These results support
the hypothesis that efficient internalization is associated
with increased persistence of GAS in the oropharynx.
Therapy for Acute GAS Tonsillitis
Similar simple practice guidelines regarding therapy for
GAS tonsillitis were recently published by the American
Heart Association, the American Academy of Pediatrics Red
Book Committee, and the Infectious Diseases Society of
America [1,854] (Table 1).
These guidelines recommend that the therapy of choice
is penicillin V two or three times daily for 10 days (250 mg/
dose for children; 500 mg/dose for adolescents).
The attempts to reduce the frequency and duration of
penicillin administration for the treatment of GAS tonsil-
litis have been successful with regard to reduction of fre-
quency only. Adherence diminishes with schedules that
require frequent doses or longer durations of therapy
[55]. The twice-daily regimen has been shown to be as
effective as three- or four-times-daily regimens. Attempts
to reduce the length of penicillin treatment were unsuc-
cessful, both with 5- or 7-day penicillin treatment and the
standard 10-day course [55]. Although not used by many
pediatricians, intramuscular benzathine penicillin is an
excellent choice to ensure adherence when oral treatment
cannot be given [55].
Resistance of GAS to macrolides has been reported
from around the world and is closely related to the extent
of macrolides used (0% to 25% in Europe) [56]. Resistance
to erythromycin is mainly due to one of three mechanisms:
target modification (the most common), enzymatic inacti-
vation, and active efflux [56].
For penicillin-allergic patients, erythromycin estolate or
ethylsuccinate two to four times daily for 10 days is recom-
mended. Erythromycin estolate (20 to 40 mg/kg/d) and
erythromycin ethylsuccinate (40 mg/kg/d) are both effec-
tive when used twice daily [57].
Recent studies have shown that amoxicillin (50 mg/kg
or 750 mg) given once daily is as good as penicillin given
three or four times per day [58, 59]. Once-daily dosing of
amoxicillin has the advantage of increasing patient adher-
ence to medication. The use of amoxicillin once daily for
treating GAS tonsillitis is not approved by the Food and
Drug Administration (FDA).
It is unclear why some of the oral cephalosporins
h ave h i g h e r b a c t e r i o l o g i c e r a d i c a t i o n r a t e s t h a n
penicillin [2,60,61], although some theories have
been discussed above.
Four cephalosporins are currently approved for use
once-daily for 10 days as treatment of acute GAS tonsilli-
tis: cefadroxil (30 mg/kg, up to 1000 mg); cefixime (8 mg/
kg, up to 400 mg); cefdinir (14 mg/kg, up to 600 mg);
and ceftibuten (9 mg/kg, up to 400 mg). Two cepha-
losporinscefpodoxime (5 mg/kg per dose, twice daily)
and cefdinir (7 mg/kg per dose, up to 300 mg dose, twice
daily)are FDA approved for less than 10 days for
treatment for GAS tonsillitis [55].
Adam et al. [62] recently summarized a large study of
culture-proven tonsillitis, conducted by the German
Society for Pediatric Infectious Diseases, involving sev-
eral agents and including 1-year follow-up to establish
the effect on sequelae. A 5-day antibiotic regimen with
cefuroxime axetil did not cause more poststreptococcal
sequelae than did standard penicillin V treatment.
Cefuroxime axetil, 250 mg twice daily for 5 days, was
superior to oral penicillin V in eradication of GAS and in
overall clinical efficacy.
Azithromycin, a newer macrolide, has also been
approved for GAS tonsillitis therapy. In the United States,
the regimen for adults is 500 mg on day 1, followed by
250 mg on days 2 to 5; in children, the regimen is a daily
dose (10 to 12 mg/kg, up to 250 mg) on the first day
followed by 5 mg/kg/d for 4 more days. In Europe, the
dosages are 500 mg once daily for 3 days for adults and 10
mg/kg (up to 250 mg) for children.
Therapy for Repeated Episodes
of Acute GAS Tonsillitis
For a single recurrence of acute tonsillitis (documented
by throat culture or antigen detection test) that occurs
 Acute and Recurrent GAS Tonsillitis Barzilai et al. 221

Table 1. Recommended therapy for acute group A streptococcal tonsillitis

Agent Dose Mode Duration
Penicillin V Children: 250 mg bid or tid; adolescents or adults: Oral 10 days
250 mg tid or qid, 500 mg bid
Benzathine penicillin G 600,000 U for patients < 27 kg; 1,200,000 U for Intramuscular Once
patients > 27 kg
Controlled-release bicillin (900/300) 1,200,000 for adolescents and adults

For penicillin-allergic (immediate and not immediate type) patients

Erythromycin estolate 2040 mg/kg/d (maximum, 1 g/d) bid or tid Oral 10 days
Erythromycin ethyl succinate 40 mg/kg/d (maximum, 1 g/d) bid or tid

For penicillin-allergic patients (not immediate type)

First- or second-generation cephalosporin See text
Azithromycin In United States: for adolescents and adults, 500 mg Oral 5 days
on day 1, followed by 250 mg on days 25; for
children, 10 mg/kg on day 1, followed by 5 mg/kg on
days 25
In Europe: for adolescents and adults, 500 mg once Oral 3 days
daily; for children, 10 mg/kg (maximum, 250 mg)
bidtwice daily; qidfour times daily; tidthree times daily.

Table 2. Suggested therapy for multiple or recurrent episodes of group A streptococcal tonsillitis
Agent Dose Mode Duration
Clindamycin For children: 2030 mg/kg/d qid; for adults: 600 mg/d bid or tid Oral 10 days
Amoxicillin-clavulanate 40 mg/kg/d (maximum, 750 mg/d) tid Oral 10 days
Benzanthine penicillin G 600,000 U for patients < 27 kg; 1,200,000 U for patients > 27 kg Intramuscular Once
bidtwice daily; qidfour times daily; tidthree times daily.

shortly after completion of therapy, re-treatment with Conclusions and

agents listed in Table 1 is recommended. For most
asymptomatic patients who have received a complete
course of therapy, bacteriologic follow-up is not indi-
cated [1]. We recommend follow-up throat cultures for
asymptomatic patients in the following cases: 1) history
of rheumatic fever; 2) ping-pong spread of GAS that
has been occurring within a family; and 3) development
of acute tonsillitis during outbreaks of acute rheumatic
fever or poststreptococcal acute glomerulonephritis or
during outbreaks of GAS tonsillitis in closed or semi-
closed communities [1,63,64]. For patients with multi-
ple episodes of GAS tonsillitis over several months, the
treatment approach is less established. Clindamycin,
amoxicillin-clavulanate, and benzathine penicillin G
(Table 2), used in selected cases, have yielded high rates
of streptococcal eradication [1].
Continuous antibiotic treatment in these patients is
not recommended. Adenotonsillectomy or tonsillectomy
might be beneficial [65]. The number of episodes of GAS
necessary to predict benefit from this surgery has not been
established by the American Academy of Otolaryngology
and Head and Neck Surgery [66]. Four or more infections
of the tonsils per year, despite adequate medical therapy,
are sufficient indication for tonsillectomy [67].
Future Therapeutic Approaches
Research has shown that GAS internalization by epithelial cells
is mediated by fibronectin that bridges between bacterial
ligands and host cell receptors of the integrin family [6870].
A recent study has established that fibronectin also mediates
the entry of a GAS strain that lacks the fibronectin-binding
proteins F1 or SfbI. Of note, this occurred through binding of
the virulent factor M1-protein to fibronectin [70]. The appar-
ently common mechanism, involving GAS entry into
mammalian cells, led Cue et al. [70] to propose the use of a
low-molecular-weight nonpeptide integrin antagonist to
inhibit epithelial cell ingestion of GAS. The researchers found
that this substance, which specifically interacts with 5/1
integrin, significantly blocked fibronectin binding by primary
tonsillar epithelial and A549 cultured cells. Consequently, they
proposed that traditional antibiotic treatment, coupled with
integrin antagonist therapy, might prevent GAS internalization
and lead to more efficient eradication of the extracellular
pathogen [70]. It should be noted, however, that because inte-
grins are involved in many essential biologic activities, an anti-
integrin drug might have other adverse effects. Nonetheless,
such a novel approach targeted at the bacterial or host compo-
nents involved in internalization may lead to more effective
eradication of the GAS reservoir in the human respiratory tract.
222 Upper Respiratory, Head, and Neck Infections
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Papers of particular interest, published recently, have been
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Of importance
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prtF1 gene, encoding fibronectin-binding protein, which mediates
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