Invited Review
The Group A Streptococcal Carrier State
Reviewed: Still an Enigma
Gregory P. DeMuri and Ellen R. Wald
University of Wisconsin School of Medicine and Public Health, Madison
Corresponding Author: Gregory P. DeMuri, MD, Department of Pediatrics, 600 Highland Ave, H6/570 Madison, WI 53792-4108.
E-mail: [email protected].
Received August 15, 2013; accepted March 19, 2014; electronically published April 30, 2014.
Despite the common nature of group A streptococcal (GAS) infections, the carrier state of this organism is not
well understood. In this article, we review the historical and recent research on the definition, epidemiology, and
pathogenesis of the GAS carrier state. In addition, we outline trials of antimicrobial agents in the eradication of
the carrier state and discuss indications for providing treatment to patients in the clinical setting.
Key words.
carrier state; group A Streptococcus; pharyngitis; Streptococcus pyogenes.
Pharyngitis is one of the most common reasons for which
children and young adults seek medical care, and the
group A streptococcus (GAS) is the most frequent cause of
bacterial pharyngitis in these age groups [1]. Group A streptococcus is also responsible for invasive disease and nonsuppurative sequelae such as acute rheumatic fever and
glomerulonephritis. Despite the common nature of GAS infections, the carrier state is not well understood and has been
referred to as an “enigma” by some experts [2]. Identification
and management of GAS carriers often causes frustration for
the clinician, the patient, parents, and researchers.
The GAS carrier was first described in the pre-antibiotic
era during outbreaks of GAS disease. It was observed that
many individuals during an outbreak harbored GAS in
their pharynx but did not have any clinical symptoms
[3]. These individuals did not suffer from the nonsuppurative complications of GAS infection and tended to carry
GAS in the throat for a prolonged period. Children who
are carriers of GAS must be distinguished from those
with asymptomatic or subclinical infection. Although this
latter group of children does not have overt clinical symptoms of GAS pharyngitis, they transiently acquire a pharyngeal infection and may be at risk for nonsuppurative sequelae
(Figure 1) [2]. In fact, 66% to as many as 75% of individuals
who are diagnosed with acute rheumatic fever do not recall a
pharyngeal infection in the preceding 3 months [4, 5].
The Definition of the Carrier State
Despite over 70 years of observation and research, an exact
definition of the GAS carrier remains elusive. Historically,
carriers were defined as patients who were asymptomatic
but had a positive throat culture. However, this definition
excludes children with symptomatic pharyngitis from a
viral infection who have a positive throat culture for
GAS. Another definition found in the literature is an individual who has a positive throat culture for GAS but does
not develop an antibody to the extracellular antigens
(antistreptolysin-O [ASO], anti-deoxyribonuclease B, antihyaluronidase) or M proteins elaborated by the organism.
However, a study by Gerber et al [6] casts doubt as
to the validity of this definition. In their study, children
who presented with symptoms of pharyngitis were divided
into 3 groups: those with negative throat cultures, those
with positive throat cultures and negative serology, and
those with positive throat cultures and positive serology.
As expected, it was observed that children with negative
throat cultures did not respond to antibiotics.
However, both children with and without serologic responses reacted similarly to antibiotic therapy, suggesting
that some children without a serological response were in
fact actively infected. In another study, over 50% of children who presented with signs and symptoms of pharyngitis and a positive pharyngeal culture for GAS did not
develop a detectable antibody response to the extracellular
proteins elaborated by GAS [7]. These studies suggest that
early treatment aborts the development of antibody to the
extracellular antigens in many children. In addition, using
serology to distinguish carriers from acutely infected children with GAS also presents practical challenges because
Journal of the Pediatric Infectious Diseases Society, Vol. 3, No. 4, pp. 336–42, 2014. DOI:10.1093/jpids/piu030
© The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society.
All rights reserved. For Permissions, please e-mail: [email protected].
The Group A Streptococcal Carrier State Reviewed
Figure 1. Outcome of GAS infection (derived from Kaplan [2]). *Subclinical infection may result in nonsuppurative complications. #Atypical symptoms may resemble the
common cold [13]. +Typical symptoms are sore throat, headache, and fever.
serologic responses do not occur until several weeks after
the clinical presentation. Accordingly, they cannot be helpful at the time of the acute visit.
Another way to identify streptococcal carriers is to evaluate children for microbiologic failure after treatment with
an appropriate antimicrobial agent. In a study of an outbreak of GAS in a closed community in the 1970s,
Gastanaduy et al, performed throat cultures and serology
on over 300 individuals [8]. Nearly 20% of 132 patients
who were treated with either oral penicillin or intramuscular benzathine penicillin continued to harbor the same
strain of GAS in their throats after a course of treatment.
In addition, nearly half of the children who experienced
a microbiological treatment failure continued to have a
positive throat culture with an identical strain after a second, and 42% were positive after a third course of penicillin. Furthermore, among the patients who failed treatment,
only 8% had overt symptoms of pharyngitis. This observation and the fact that the few patients who were true treatment failures did have a serologic response suggest that the
majority of patients, who are adherent to an appropriate
antimicrobial regimen and nonetheless experience microbiologic failure, are in fact GAS carriers [9].
In the clinical setting, the carrier state is usually suspected in the child with closely spaced symptomatic recurrences
of GAS pharyngitis. The most practical method of identifying carriers is to perform a test of cure shortly after an
effective course of therapy has been delivered. The asymptomatic child with a positive throat culture for GAS under
these conditions is very likely to be a carrier. Before identifying a child as a carrier by this method, the clinician
should be confident that treatment failure is not due to
nonadherence to therapy.
Epidemiology of the Carrier State
There has been much interest in defining the rate of carriage of GAS in the throats of ill and healthy children.
However, the rates of carriage of GAS vary greatly depending on the population studied and how carriers are defined.
For instance, in an office-based setting, throat cultures were
obtained from well children ages 2–16 years, children with
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sore throat, and children recently treated with penicillin for
a positive throat culture [10]. As expected, well children
had the lowest rate of positive throat cultures (2.5%).
Children presenting with sore throat and those recently
treated with penicillin were positive 4.4% and 11.3% of
the time, respectively.
Studies that determine the efficacy of antimicrobial
agents give us another estimate of carrier rates. Because
carriers may be defined as treatment failures, the percentage of children who harbor GAS after treatment will
provide an estimation of the carrier rate. In these studies,
5%–25% of children are carriers [11, 12].
School-based studies provide yet another perspective on
carriage. A recent 4-year longitudinal study of children in
an elementary school setting provided useful insights into
the carrier state [13]. Throat cultures were performed on
the children twice a month and during every respiratory illness. At any given time, the mean prevalence of carriers was
approximately 16%, and over 40% of children were classified as carriers at least once during the 4-year study period.
Over half of the carriers switched emm types during the
study period, and most of the acquisitions of these new
emm types were not associated with any clinical symptoms.
Children in this study carried GAS for an average of 10.8
weeks, with a maximum duration of carriage of 127 weeks.
Recently, a meta-analysis of studies reporting GAS infection and carrier rates in the past 35 years was performed
[14]. The analysis included clinic and emergency department sites from around the world in both symptomatic
and asymptomatic patients. In children who had clinical
symptoms of pharyngitis, the prevalence of GAS detected
in the throat was 37%. In children who lacked clinical
symptoms, GAS was detected 12% of the time. In both
groups, children who were younger than 5 years had
lower rates of GAS detection.
Overall, asymptomatic carriage of GAS is common, especially among school-aged children. The rate of carriage
depends highly on the methods of the study, particularly
how carriers are defined. In surveys of asymptomatic children, the rate is approximately 2%–5%, whereas in children who experience microbiological treatment failure,
the rate is 5%–25%. Lastly, in school surveys, the carriage
rates are between 8% and 40%.
Pathogenesis of the Carrier State
Several theories have been proposed to explain the
pathogenesis of the carrier state in children exposed
to GAS (Table 1). The first theory is that some of the normal bacterial flora of the pharynx and tonsils produce
β-lactamase that shields GAS from the effects of penicillins.
This theory has been based on studies that have detected
Table 1. Proposed Pathogenetic Mechanisms for Carriage
of GAS
Effects of the pharyngeal microbiome
(a) β-lactamase-producing flora
(b) Absence of inhibitory flora
Internalization of GAS into epithelial cells
Production of biofilms
Development of antimicrobial tolerance
Abbreviation: GAS, group A streptococcal.
β-lactamase-producing bacteria and detectable levels of
β-lactamase in the pharynx and tonsillar tissues of
patients with GAS. Bacteria such as Bacteroides species,
Staphylococcus aureus, Moraxella, and Haemophilus have
been associated with GAS treatment failures and carriers in
some studies. In addition, several studies have shown that antimicrobials directed at β-lactamase-producing organisms
have higher GAS eradication rates than penicillin [15–20].
However, this theory has been controversial and conflicting
results are reported in other investigations that have found no
association between the presence of β-lactamase-producing
organisms and penicillin treatment failure nor higher eradication rates with β-lactamase-stable antimicrobials [21–24].
Other authors have suggested that certain bacteria have
an inhibitory effect on the establishment of GAS colonization in the pharynx [25]. Brook at al demonstrated a higher
rate of recovery of α-hemolytic streptococci, non-hemolytic
streptococci, and Prevotella and Peptostreptococcus species from the tonsillar surfaces of children who were not
GAS carriers than in those who were asymptomatic carriers
[17]. This hypothesis is supported by studies of the use of
probiotics such as Lactobacillus and α-streptococci to prevent colonization of GAS in vitro and in vivo [26–33].
However, it is noteworthy that these latter studies were
done in the context of children with apparent recurrent
pharyngitis.
Other theories have proposed that GAS are capable of
evading treatment and establishing residence in the pharynx secondary to their ability to become internalized in
epithelial cells. In in vitro models of infection, it has been
demonstrated that GAS are internalized into epithelial cells
and survive intracellularly despite exposure to penicillin.
Strains that have been associated with persistence in patients after antibiotic therapy are more likely to be sequestered intracellularly [34, 35]. Additional evidence for this
hypothesis comes from biopsies of tonsils of asymptomatic
carriers from whom over 70% of tonsils have GAS detected
intracellularly [36, 37].
Another potential explanation for treatment failure and
thus persistence of GAS in the pharynx is the ability of
many strains of GAS to produce biofilms in vitro. This
The Group A Streptococcal Carrier State Reviewed
process permits the organism to survive antibiotic concentrations greater than 10 times the minimal inhibitory concentration of the organism. Furthermore, the formation of
biofilms seems to be related to the ability of GAS to internalize into epithelial cells (as noted above), which also
allows the organism to evade antibiotic treatment [38–40].
Lastly, lack of response to penicillin in carriers has been
hypothesized to be the phenomenon of tolerance, in which
bacteria survive despite levels of antibiotic above their minimal inhibitory concentration. Early studies suggested that
most strains of GAS isolated from patients who failed penicillin exhibited tolerance in vitro [41–43]. However, there
has been disagreement in the literature as to a uniform
method of detecting tolerance, and subsequent studies
have failed to verify the role of tolerance in treatment failure and the carrier state [20, 44–47].
Importance of the Carrier State
When considering the implications of the carrier state, several important questions arise. Does being a carrier convey
a risk for nonsuppurative complications such as acute
rheumatic fever or post-streptococcal glomerulonephritis?
Do carriers serve as a source of transmission of GAS to others in the community? Does pharyngeal carriage of GAS
place the carrier at risk for severe invasive disease? How
does the carrier state confuse the diagnosis of pharyngitis
in the acute care setting?
It has long been recognized that GAS carriers have little
or no risk for acute rheumatic fever. These observations
were first made in 1935 and were based mainly on antibody titers to ASO [48]. It was observed that patients
who had had acute rheumatic fever had significant rises
in ASO titers, whereas those patients who had GAS isolated from the pharynx but did not develop rheumatic fever
did not. Since carriers have been defined historically as
not developing an antibody response to ASO, it has been
concluded that they are not at risk for acute rheumatic
fever. The second observation in carriers comes from studies on the latent period between isolation of GAS from
the throat and the development of symptoms. In a group
of Air Force recruits, it was observed that the majority
(92%) of individuals who developed acute rheumatic
fever did so within 1 month of acquiring GAS in the pharynx [49]. Because carriers would theoretically harbor GAS
for a much longer period of time, it was then surmised that
carriers would be at little risk for acute rheumatic fever.
One observational study suggests that carriers also have a
low risk of glomerulonephritis [50].
The carrier of GAS has been considered to be ineffective
as a transmitter of infection. This belief was derived in part
from a study of outbreaks of GAS in institutionalized children in the 1930s and 1940s [51]. In this study of 4 major
outbreaks, it was determined that the source of GAS was
not from known carriers in the institution but rather
from serotypes recently introduced to the population.
Several minor outbreaks, with less than 10% of children
becoming infected, were secondary to strains known to
be harbored by carriers. This discovery led investigators
to conclude that although infection from carriers can
occur, it is substantially less likely than transmission
from a child with active infection. Also, in a study of military recruits, Wannamaker [52] observed the risk of transmission from military recruits following new acquisition of
GAS in the pharynx. Those recruits who carried GAS for
more than 2 weeks were much less likely to transmit the
organisms to others. Most importantly, children who are
carriers are asymptomatic with regard to respiratory symptoms (cough or coryza) for the majority of time that they
are carriers, which dramatically reduces the likelihood of
spread of GAS to the environment. When a carrier does
develop respiratory symptoms secondary to a communityacquired virus, transmission is more likely.
The role of carriers in invasive disease is not entirely
clear. Although GAS may be found in the pharynx of patients with invasive infection at the time of presentation, it
is usually not possible to determine whether the patient was
a carrier before infection or was more recently colonized or
infected. However, a common model for respiratory pathogens that cause systemic disease is that if invasive disease
is going to occur, it does so within days of acquisition [53].
GAS carriage is commonly found among close contacts of
patients with invasive infections. In a study of 17 patients
with invasive infection, GAS was detected in the pharynx
of 27% of close contacts of the index patient [54]. In a
case-control study of children with invasive GAS disease,
(1) invasive disease was associated with the presence of
other children in the home and (2) in another outbreak setting
there was an increase in carriage rates of the invasive GAS
strain among school-aged children in the community [55,
56]. It is most likely that the carriers served as a reservoir of
infection for the patient with invasive disease [54, 56].
Perhaps the most significant impact of the carrier state is
the confusion it may cause in the evaluation of the patient
with symptoms of acute pharyngitis. This confusion arises
when the carrier acquires a respiratory virus and presents
with sore throat. An important strategy to minimize this
issue is for the practitioner to avoid testing children with
prominent nasal symptoms and cough for GAS infection.
However, some community-acquired viruses target the
pharynx. When the clinician performs a rapid antigen
detection test or throat culture, it will be positive because
the patient is a carrier and yet a virus is the actual cause
of the pharyngitis. The positive test will be interpreted as
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an acute streptococcal infection, and an antibiotic will be
prescribed unnecessarily. In the clinical setting, there is
no practical way to differentiate the carrier from the person
with acute infection. Assuming there are 10 million cases of
streptococcal pharyngitis per year in the United States, and
the carrier rate is 15%, 1.5 million of these patients will be
carriers who do not require treatment [57–59]. This unintended overuse of antimicrobials may have a significant
public health impact because it may promote the development of antibiotic resistance, result in adverse events, and
add to healthcare costs.
Although several antimicrobial regimens are variably effective in eradicating GAS carriage, the question remains as
to the benefit of treatment to the patient. If there is no risk
of nonsuppurative sequelae and the risk of transmission to
others is low, it would appear that there may be little to
gain by treating carriers. Published guidelines, based on expert opinion, generally recommend against identifying and
treating carriers except for the following special situations:
(1) a local outbreak of acute rheumatic fever, invasive GAS
disease, or poststreptococcal glomerulonephritis; (2) an
outbreak of GAS pharyngitis in a closed or semiclosed
community; (3) family or personal history of acute rheumatic fever; (4) multiple episodes of GAS pharyngitis occurring in a family for many weeks despite appropriate
treatment; and (5) when tonsillectomy is being considered
only because of GAS carriage [9, 65].
One important reason to consider eradication of carriage is to avoid confusion when the patient presents with
subsequent episodes of symptomatic pharyngitis. This situation may be particularly important in the patient who
presents with apparent, closely spaced, recurrent episodes
of GAS pharyngitis early in the respiratory season. If the
etiology of the carrier’s symptoms is a viral infection,
then the patient will continue to receive unnecessary treatment because a rapid antigen detection test or throat culture will likely be positive repeatedly.
Furthermore, because carriers are not precluded from acquiring new emm types while they are carriers, they may
indeed be at risk of acute rheumatic fever if a new acquisition occurs. Thus, carriers should be tested and treated as if
they have new GAS infection when they have symptomatic
episodes of pharyngitis, especially without viral symptoms,
and a test is positive for GAS.
Finally, repeated episodes of pharyngitis accompanied
by a positive test for GAS may cause much consternation
among parents and patients. The patient may have missed
Treatment of the Carrier State: Evidence and Controversies
Two important questions arise when a GAS carrier has
been identified. (1) Does treatment eradicate carriage?
(2) Is eradication of benefit to the patient or to the population? Six trials of treatment of the carrier state have been
reported in the medical literature (Table 2) [20, 60–64]. In
reviewing these trials, it is important to consider how the
carrier state is defined and under what circumstances the
study was done. Azithromycin (12 mg/kg per day for 5
days) was studied in an uncontrolled trial in school children who were contacts of a case of invasive GAS disease;
the overall eradication rate was 91% [61]. Tanz et al [62]
found an eradication rate of 92% with oral clindamycin
(10 days) vs 55% with benzathine penicillin in carriers defined as children who experienced microbiologic failure
after penicillin treatment. It is important to note that
both of these studies were performed over 10 years ago,
and recent investigations have shown a rising rate of resistance of GAS to the macrolides and clindamycin. In the
setting of a community outbreak, amoxicillin-clavulanate
(10 days) and dicloxacillin (10 days) had a 91% and 50%
eradication rate, respectively [20, 60]. Finally, rifampin (4
days) in combination with penicillin demonstrated a rate
of eradication of 55%–100% [62–64].
Table 2. Studies of the Treatment of GAS Carriers
Study
Carrier Definition
Morita et al [60]
Asymptomatic
School
contacts
Treatment failures Outpatient clinics
and ED
Treatment failures Community
outbreak
Treatment failures Community
outbreak
Serological
Outpatient clinics
Treatment failures Outpatient clinics
and ED
Tanz et al [61]
Smith et al [20]
Kaplan et al [59]
Chaudhary et al [63]
Tanz et al [62]
Study Setting
Control Drug
Eradication
Rate (%)
Study Drug
Eradication
Rate (%)
None
-
Azithromycin
91
Benzathine
penicillin + rifampin
Penicillin V
55
Clindamycin
92
17
Dicloxacillin
50
Penicillin V
29
Amoxicillin-clavulanate
91
Penicillin V
Benzathine penicillin*
71
30
Penicillin + rifampin
Benzathine
penicillin + rifampin
Abbreviations: ED, emergency department; GAS, group A streptococcal.
*A group that received no treatment had a 23% eradication rate in this study.
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89
The Group A Streptococcal Carrier State Reviewed
significant time in school or childcare, the parent may have
missed work, and invasive procedures such as tonsillectomy may be requested by parents or primary care providers.
An attempt at eradicating carriage may provide reassurance in this scenario.
CONCLUSIONS
Despite decades of research, the GAS carrier state remains
poorly understood. A working definition used in some clinical trials and practical to clinicians is the patient who harbors GAS in the pharynx after adherence to an appropriate
antibiotic for an episode of pharyngitis presumed to be
caused by GAS. Streptococcal carriers are common in
school-age populations, representing 10%–15% of children in most surveys. Carriers have little risk for nonsuppurative complications of GAS and though they may
possibly transmit the organism to others, the degree of
communicability is less than from acutely infected individuals. Most children who are carriers do not require treatment, but an attempt at eradication of the carrier state
may be of benefit in select children.
Acknowledgments
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest.
References
1. Bisno AL. Acute pharyngitis. N Engl J Med 2001; 344:205–11.
2. Kaplan EL. The group A streptococcal upper respiratory tract carrier state: an enigma. J Pediatr 1980; 97:337–45.
3. Hartley G, Enders JF, Mueller JH, Schoenbach EB. Absence of
clinical disease in spite of a high incidence of carriers of group a
hemolytic streptococci of a single type; failure of tyrothricin to
influence the carrier rate. J Clin Invest 1945; 24:92–6.
4. Veasy LG, Wiedmeier SE, Orsmond GS, et al. Resurgence of acute
rheumatic fever in the intermountain area of the United States.
N Engl J Med 1987; 316:421–7.
5. Wald ER, Dashefsky B, Feidt C, et al. Acute rheumatic fever in
western Pennsylvania and the tristate area. Pediatrics 1987; 80:
371–4.
6. Gerber MA, Randolph MF, Mayo DR. The group A streptococcal
carrier state. A reexamination. Am J Dis Child 1988; 142:562–5.
7. Kaplan EL, Top FH Jr, Dudding BA, Wannamaker LW.
Diagnosis of streptococcal pharyngitis: differentiation of active
infection from the carrier state in the symptomatic child.
J Infect Dis 1971; 123:490–501.
8. Gastanaduy AS, Kaplan EL, Huwe BB, et al. Failure of penicillin
to eradicate group A streptococci during an outbreak of pharyngitis. Lancet 1980; 2:498–502.
9. Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal
pharyngitis: 2012 update by the Infectious Diseases Society of
America. Clin Infect Dis 2012; 55:1279–82.
10. Pichichero ME, Marsocci SM, Murphy ML, et al. Incidence of
streptococcal carriers in private pediatric practice. Arch Pediatr
Adolesc Med 1999; 153:624–8.
11. Kaplan EL, Johnson DR. Unexplained reduced microbiological
efficacy of intramuscular benzathine penicillin G and of oral penicillin V in eradication of group a streptococci from children with
acute pharyngitis. Pediatrics 2001; 108:1180–6.
12. Casey JR, Kahn R, Gmoser D, et al. Frequency of symptomatic
relapses of group A beta-hemolytic streptococcal tonsillopharyngitis in children from 4 pediatric practices following penicillin,
amoxicillin, and cephalosporin antibiotic treatment. Clin Pediatr
(Phila) 2008; 47:549–54.
13. Martin JM, Green M, Barbadora KA, Wald ER. Group A streptococci among school-aged children: clinical characteristics and
the carrier state. Pediatrics 2004; 114:1212–9.
14. Shaikh N, Leonard E, Martin JM. Prevalence of streptococcal
pharyngitis and streptococcal carriage in children: a metaanalysis. Pediatrics 2010; 126:e557–64.
15. Brook I. The role of beta-lactamase-producing bacteria in the persistence of streptococcal tonsillar infection. Rev Infect Dis 1984;
6:601–7.
16. Brook I. Failure of penicillin to eradicate group A beta-hemolytic
streptococci tonsillitis: causes and management. J Otolaryngol
2001; 30:324–9.
17. Brook I, Gober AE. Recovery of interfering and beta-lactamaseproducing bacteria from group A beta-haemolytic streptococci carriers and non-carriers. J Med Microbiol 2006; 55:1741–4.
18. Brook I, Leyva F. The treatment of the carrier state of group A
beta-hemolytic streptococci with clindamycin. Chemotherapy
1981; 27:360–7.
19. Pichichero ME, Casey JR. Systematic review of factors contributing to penicillin treatment failure in Streptococcus pyogenes pharyngitis. Otolaryngol Head Neck Surg 2007; 137:851–7.
20. Smith TD, Huskins WC, Kim KS, Kaplan EL. Efficacy of
beta-lactamase-resistant penicillin and influence of penicillin
tolerance in eradicating streptococci from the pharynx after failure of penicillin therapy for group A streptococcal pharyngitis.
J Pediatr 1987; 110:777–82.
21. Gerber MA, Tanz RR, Kabat W, et al. Potential mechanisms for
failure to eradicate group A streptococci from the pharynx.
Pediatrics 1999; 104:911–7.
22. Quie PG, Pierce HC, Wannamaker LW. Influence of penicillinaseproducing staphylococci on the eradication of group A streptococci from the upper respiratory tract by penicillin treatment.
Pediatrics 1966; 37:467–76.
23. Tanz RR, Shulman ST, Sroka PA, et al. Lack of influence of
beta-lactamase-producing flora on recovery of group A streptococci after treatment of acute pharyngitis. J Pediatr 1990; 117:
859–63.
24. van Driel ML, De Sutter AI, Keber N, et al. Different antibiotic
treatments for group A streptococcal pharyngitis. Cochrane database of systematic reviews (Online). 2013; 4:CD004406.
25. Crowe CC, Sanders WE Jr, Longley S. Bacterial interference. II.
Role of the normal throat flora in prevention of colonization by
group A streptococcus. J Infect Dis 1973; 128:527–32.
26. Falck G, Grahn-Hakansson E, Holm SE, et al. Tolerance and efficacy of interfering alpha-streptococci in recurrence of streptococcal pharyngotonsillitis: a placebo-controlled study. Acta
Otolaryngol 1999; 119:944–8.
27. Guglielmetti S, Taverniti V, Minuzzo M, et al. A dairy bacterium
displays in vitro probiotic properties for the pharyngeal mucosa
by antagonizing group A streptococci and modulating the immune response. Infect Immun 2010; 78:4734–43.
28. Lilja H, Grahn E, Holm SE, Roos K. Alpha-streptococci-inhibiting
beta-streptococci group A in treatment of recurrent streptococcal
tonsillitis. Adv Otorhinolaryngol 1992; 47:168–71.
29. Roos K, Grahn E, Holm SE, et al. Interfering alpha-streptococci
as a protection against recurrent streptococcal tonsillitis in children. Int J Pediatr Otorhinolaryngol 1993; 25:141–8.
341
342
DeMuri and Wald
30. Roos K, Grahn E, Lind L, Holm S. Treatment of recurrent streptococcal tonsillitis by recolonization with alpha-streptococci. Eur
J Clin Microbiol Infect Dis 1989; 8:318–9.
31. Roos K, Hakansson EG, Holm S. Effect of recolonisation with
“interfering” alpha streptococci on recurrences of acute and
secretory otitis media in children: randomised placebo controlled
trial. BMJ 2001; 322:210–2.
32. Roos K, Holm SE, Grahn E, Lind L. Alpha-streptococci as supplementary treatment of recurrent streptococcal tonsillitis: a randomized placebo-controlled study. Scand J Infect Dis 1993; 25:31–5.
33. Roos K, Holm SE, Grahn-Hakansson E, Lagergren L. Recolonization with selected alpha-streptococci for prophylaxis of
recurrent streptococcal pharyngotonsillitis–a randomized placebocontrolled multicentre study. Scand J Infect Dis 1996; 28:459–62.
34. Kaplan EL, Chhatwal GS, Rohde M. Reduced ability of penicillin to
eradicate ingested group A streptococci from epithelial cells: clinical
and pathogenetic implications. Clin Infect Dis 2006; 43:1398–406.
35. Marouni MJ, Barzilai A, Keller N, et al. Intracellular survival of
persistent group A streptococci in cultured epithelial cells. Int J
Med Microbiol 2004; 294:27–33.
36. Osterlund A, Engstrand L. An intracellular sanctuary for
Streptococcus pyogenes in human tonsillar epithelium–studies
of asymptomatic carriers and in vitro cultured biopsies. Acta
Otolaryngol 1997; 117:883–8.
37. Osterlund A, Popa R, Nikkila T, et al. Intracellular reservoir of
Streptococcus pyogenes in vivo: a possible explanation for recurrent pharyngotonsillitis. Laryngoscope 1997; 107:640–7.
38. Ogawa T, Terao Y, Okuni H, et al. Biofilm formation or internalization into epithelial cells enable Streptococcus pyogenes to
evade antibiotic eradication in patients with pharyngitis.
Microb Pathog 2011; 51:58–68.
39. Conley J, Olson ME, Cook LS, et al. Biofilm formation by group a
streptococci: is there a relationship with treatment failure? J Clin
Microbiol 2003; 41:4043–8.
40. Baldassarri L, Creti R, Recchia S, et al. Therapeutic failures of antibiotics used to treat macrolide-susceptible Streptococcus pyogenes infections may be due to biofilm formation. J Clin
Microbiol 2006; 44:2721–7.
41. Dagan R, Ferne M. Association of penicillin-tolerant streptococci
with epidemics of streptococcal pharyngitis in closed communities. Eur J Clin Microbiol Infect Dis 1989; 8:629–31.
42. Grahn E, Holm SE, Roos K. Penicillin tolerance in betastreptococci isolated from patients with tonsillitis. Scand J
Infect Dis 1987; 19:421–6.
43. Kim KS, Kaplan EL. Association of penicillin tolerance with failure to eradicate group A streptococci from patients with pharyngitis. J Pediatr 1985; 107:681–4.
44. Orrling A, Stjernquist-Desatnik A, Schalen C, Kamme C.
Treatment failure in streptococcal pharyngotonsillitis. An attempt to identify penicillin tolerant Streptococcus pyogenes.
Scand J Infect Dis 1996; 28:143–7.
45. Steininger C, Allerberger F, Gnaiger E. Clinical significance of inhibition kinetics for Streptococcus pyogenes in response to penicillin. J Antimicrob Chemother 2002; 50:517–23.
46. Stjernquist-Desatnik A, Orrling A, Schalen C, Kamme C. Penicillin
tolerance in group A streptococci and treatment failure in streptococcal tonsillitis. Acta Otolaryngol Suppl 1992; 492:68–71.
47. van Asselt GJ, Mouton RP, van Boven CP. Penicillin tolerance
and treatment failure in group A streptococcal pharyngotonsillitis. Eur J Clin Microbiol Infect Dis 1996; 15:107–15.
48. Coburn AF, Pauli RH. Studies on the immune response of the rheumatic subject and its relationship to activity of the rheumatic
process. VI. The significance of the rise of antistreptolysin level in
the development of rheumatic activity. J Clin Invest 1935; 14:
769–81.
49. Rammelkamp CH, Jr., Stolzer BL. The latent period before
the onset of acute rheumatic fever. Yale J Biol Med 1961; 34:
386–98.
50. Dunlap MB, Bergin JW. Subsequent health of former carriers of
hemolytic streptococci. N Y State J Med 1973; 73:1875–80.
51. Kuttner AG, Krumwiede E. Observations on the epidemiology
of streptococcal pharyngitis and the relation of streptococcal carriers to the occurrence of outbreaks. J Clin Invest 1944; 23:
139–50.
52. Wannamaker LW. The epidemiology of streptococcal infections.
In: McCarty M, ed. Streptococcal Infections. New York:
Columbia University Press; 1954: pp 157–75.
53. Edwards EA, Devine LF, Sengbusch GH, Ward HW. Immunological
investigations of meningococcal disease. III. Brevity of group C acquisition prior to disease occurrence. Scand J Infect Dis 1977; 9:105–10.
54. Weiss K, Laverdiere M, Lovgren M, et al. Group A Streptococcus
carriage among close contacts of patients with invasive infections.
Am J Epidemiol 1999; 149:863–8.
55. Factor SH, Levine OS, Harrison LH, et al. Risk factors for pediatric invasive group A streptococcal disease. Emerg Infect Dis
2005; 11:1062–6.
56. Cockerill FR 3rd, MacDonald KL, Thompson RL, et al. An outbreak of invasive group A streptococcal disease associated with
high carriage rates of the invasive clone among school-aged children. JAMA 1997; 277:38–43.
57. Musser JM, Shelburne SA 3rd. A decade of molecular pathogenomic analysis of group A Streptococcus. J Clin Invest 2009;
119:2455–63.
58. Pichichero ME. Group A beta-hemolytic streptococcal infections.
Pediatr Rev 1998; 19:291–302.
59. Centers for Disease Control and Prevention. Group A Streptococcal
(GAS) Disease. Available at: http://www.cdc.gov/ncidod/dbmd/
diseaseinfo/groupastreptococcal_t.htm. Accessed 2 January 2014.
60. Kaplan EL, Johnson DR. Eradication of group A streptococci from
the upper respiratory tract by amoxicillin with clavulanate after
oral penicillin V treatment failure. J Pediatr 1988; 113:400–3.
61. Morita JY, Kahn E, Thompson T, et al. Impact of azithromycin
on oropharyngeal carriage of group A Streptococcus and nasopharyngeal carriage of macrolide-resistant Streptococcus pneumoniae. Pediatr Infect Dis J 2000; 19:41–6.
62. Tanz RR, Poncher JR, Corydon KE, et al. Clindamycin treatment
of chronic pharyngeal carriage of group A streptococci. J Pediatr
1991; 119:123–8.
63. Tanz RR, Shulman ST, Barthel MJ, et al. Penicillin plus rifampin
eradicates pharyngeal carriage of group A streptococci. J Pediatr
1985; 106:876–80.
64. Chaudhary S, Bilinsky SA, Hennessy JL, et al. Penicillin V and rifampin for the treatment of group A streptococcal pharyngitis: a
randomized trial of 10 days penicillin vs 10 days penicillin with
rifampin during the final 4 days of therapy. J Pediatr 1985;
106:481–6.
65. Committee on Infectious Diseases, A.A.o.P. Group A
Streptococcal Infections. In: Pickering LK, ed. Red Book: 2012
Report of the Committee on Infectious Diseases. Elk Grove, IL:
American Academy of Pediatrics; 2012; pp. 668–80.