Keywords
tonsillitis - penicillin - cephalosporins - clindamycin - streptococcus pyogenes
Introduction
The frequently reported inability of penicillin to eradicate of Group A β-hemolytic
streptococci (GABHS) from patients with pharyngo-tonsillitis (PT) despite its excellent
in vitro efficacy is of concern.[1] Although about half of the patients who harbor GABHS following therapy may be carriers,
the rest may still show signs of infection and represent true clinical failure. Studies
have shown that the recommended doses of either oral penicillin V or intramuscular
(IM) penicillin failed to eradicate GABHS in acute-onset pharyngitis in 35% patients
treated with oral penicillin V and 37% of those treated with IM penicillin.[1]
Penicillin failure in eradicating GABHS tonsillitis has several explanations ([Table 1]). These include noncompliance with 10-day course of therapy, carrier state, reinfection
from another person or object,[2] penicillin tolerance,[3] and the poor penetration of penicillin into the tonsillar tissues as well as into
the tonsillar epithelial cells which allows intracellular GABHS to survive.[4]
[5] Some postulate that bacterial interactions between GABHS and members of the pharyngotonsillar
bacterial flora can explain these failures. These include the protection of GABHS
by the enzyme β-lactamase that is produced by β-lactamase-producing bacteria (BLPB),
which colonize the pharynx and tonsils.[6] Other mechanisms are the coaggregation between Moraxella catarrhalis and GABHS, which can enhance the colonization by GABHS,[7] and the absence of competitive and interfering normal flora bacteria which makes
it easier for GABHS to colonize and invade the pharyngo-tonsillar area.[8] Repeated penicillin administration can induce many of these changes. It can result
in a shift in the oral microflora with selection of β-lactamase-producing strains
of S. aureus, Haemophilus spp., Moraxella catarrhalis, Fusobacterium spp., pigmented Prevotella and Porphyromonas spp., and Bacteroides spp.[9]
Table 1
Causes for penicillin failure in the treatment of GABHS pharyngo-tonsillitis
|
• Bacterial Interactions
|
|
– The presence of β-lactamase–producing bacteria that “protect” GABHS from penicillin
|
|
– Coaggregation between GABHS and M. catarrhalis
|
|
– Absence of members of the oral bacterial flora capable of interfering with the
growth of GABHS (through production of bacteriocins and/or competition on nutrients)
|
|
• Poor penetration of penicillin into the tonsillar cells and tonsillar surface fluid
(allowing intracellular survival of GABHS)
|
|
• Internalization of GABHS (survives within epithelial cells escaping eradication
by penicillin)
|
|
• Resistance (i.e., erythromycin) or tolerance (i.e., penicillin) to the antibiotic
used
|
|
• Inappropriate dose, duration of therapy, or choice of antibiotic
|
|
• Poor compliance
• Reacquisition of GABHS from a contact or an object (i.e., toothbrush or dental braces)
|
|
• Carrier state, not disease
|
This review describes the causes and treatments of penicillin failure in the eradication
of GABHS PT.
Review of Literature and Discussion
Review of Literature and Discussion
Materials and Methods
I conducted a literature search of the Cochrane Library, EMBASE, TRIP, and MEDLINE
databases from their inception (1993 for the Cochrane Library, 1980 for EMBASE, 1997
for TRIP, and 1966 for MEDLINE) through June 25, 2015. The search terms used were:
pharyngitis, sore throat, tonsillitis, pharyngotonsillitis, Streptococcus pyogenes,
Group A β-hemolytic Streptococcus pyogenes, and streptococcal pharyngitis. Searches
were limited to type of article or document (practice guideline or guideline) with
no language restrictions or language limits.
I closely evaluated results of these searches, and excluded articles and documents
that were not pertinent or were redundant. This review was focused on causes of penicillin
failure and treatment of GABHS tonsillitis.
Clinical failure of antimicrobial therapy is defined as continuation of clinical symptoms
and findings beyond five days. Bacteriological failure of antimicrobial therapy is
defined as detection of GABHS by culture or detection of bacterial antigen in the
tonsils through rapid method of identification beyond five days.
Causes of Penicillin failure in Eradicating GABHS PT
Causes of Penicillin failure in Eradicating GABHS PT
Intracellular Survival of GABHS due to the Inadequate Penetration of Penicillin into
the Tonsils
In vitro and in vivo studies have demonstrated that GABHS strains can survive within
the tonsillar epithelial cells and become “internalized.”[4] An internalization-associated gene, prtF1/sfbI, has been found more in patients
with eradication failure of GABHS than in patients with successful eradication.[5] One study found intracellular GABHS and intracellular Staphylococcus aureus in 3 (10%) and 13 (45%) of 29 recurrently infected tonsils, respectively.[10] Since penicillin penetrate mammalian cells poorly, intracellular survival of GABHS
possibly enables the pathogens to survive despite treatment with this antibiotic.[11]
The intracellular niche may therefore shield GABHS strains from penicillin that does
not reach high intracellular concentration. This hypothesis is supported by studies
that illustrate the ability of GABHS strains to survive for 4–7 days within cultured
epithelial cells.[12] Thus, internalization and intracellular survival of GABHS represent a novel explanation
for its ability to survive penicillin therapy.
Using an epithelial cell culture model, Marouni et al[12] compared the survival of GABHS strains recovered from patients who failed penicillin
therapy to those isolated from individuals who responded to penicillin. Strains recovered
from patients who were “eradication failure” showed significantly increased intracellular
survival, compared with the “eradication success” strains. These results illustrated
how the intracellular reservoir of GABHS may play a role in the etiology of eradication
failure using penicillin.
Kaplan et al[1] examined the viability of intracellular GABHS in a human laryngeal epithelial cell
line (HEp-2epithelial cell) after exposure to several antibiotics (penicillin V, erythromycin,
azithromycin, cephalothin, and clindamycin) that are frequently used for GABHS PT
therapy. They employed three techniques to evaluate the antibiotic killing of ingested
GABHS: 1) electron microscopy examination of ultrathin sections of internalized GABHS;
2) qualitative determination of intra–epithelial cell antibiotic; and 3) special stain
evaluation of intracellular GABHS viability within antibiotic-treated epithelial cells.
GABHS survived intracellularly despite exposure of the organism-infected epithelial
cells to penicillin. In contrast, cephalothin and clindamycin were more effective
than penicillin in killing ingested GABHS. However, the macrolides (erythromycin and
azithromycin), known to accumulate to high levels within cells, were more effective
than cephalothin and clindamycin in killing ingested GABHS. Even though the study
was not done in tonsillar cells, these findings suggest that GABHS carrier state may
result from its intra-cellular survival, and penicillin's failure to kill the internalized
bacteria.
Penicillin's failure to eradicate GABHS from pharyngo-tonsillar tissue may be the
result of its inability to eradicate intracellular GABHS as well as its failure in
maintaining sufficient concentration within the tonsillar fluid.
The inflammatory stage of GABHS PT can determine the concentration of penicillin in
tonsillar surface fluid. Stjernquist-Desatnik et al[11] investigated the concentration of penicillin in serum, as well as its penetration
to tonsillar surface fluid and saliva. Despite the high serum penicillin concentrations
(mean, 2.04 µg/mL), they detected no penetration to tonsillar surface fluid or to
saliva in the nine healthy subjects that were studied. Of the nine patients with acute
GABHS PT, eight manifested high concentrations of penicillin in tonsillar surface
fluid (mean, 0.34 µg/mL) on the first day of treatment, but only two individuals had
penicillin detected in their saliva. On the tenth day of treatment, penicillin was
present in the tonsillar surface fluid of only one patient and was not present in
the saliva of any patient. Orrling et al[13] demonstrated that cephalosporin (loracarbef) and clindamycin maintained higher concentration
in tonsillar surface fluid for a longer duration than penicillin.
A delicate microbial balance occurs in the oropharynx, which includes the pharyngo-tonsillar
area, between potential pathogens (e.g., GABHS, Haemophilus spp, Moraxella spp, and Streptococcus pneumoniae) and the normal oropharyngeal bacterial flora.[14]
Bacterial Interference
Prevention of upper respiratory tract bacterial infections is partially due to bacterial
interference.[14] The normal oropharyngeal flora employs several mechanisms that interfere with colonization
and subsequent infection by potential pathogens. These include competition for nutrients
and the production of antibiotic-like substances that are called “bacteriocins,” which
kill other bacteria.[14]
[15] The oropharyngeal flora of over 85% of otitis media-, sinusitis-, or tonsillitis-prone
children contains organisms that are capable of interfering with the in vitro growth
of potential bacterial pathogens. In contrast, only 25% to 30% of children who suffer
from recurrent upper respiratory tract bacterial infections harbor such interfering
bacteria.[14]
[15]
Only a third of individuals who suffer from recurrent GABHS PT are colonized by organisms
capable of interfering with GABHS.[14] In contrast, 85% of individuals who are GABHS PT-free harbor those protective organisms.
The predominant aerobic protective organisms are gamma- and α-hemolytic streptococci
(AHS), and the main anaerobic bacteria are Peptostreptococcus spp. and Prevotella spp. These bacteria play a homeostatic role by colonizing the pharyngo-tonsillar
area in large enough numbers to prevent colonization and subsequent infection by GABHS.
A series of studies performed in Göteborg, Sweden, attempted to prevent relapsing
GABHS PT through the use of therapeutic colonization of the nasopharynx with interfering
AHS.[16]
[17]
[18] These studies illustrated the efficacy of this approach in reducing the bacteriological
and clinical recurrence rate of GABHS PT in the AHS-treated children as compared with
placebo treated ones. However, the therapeutic use of AHS as a probiotic agent is
not yet accepted as a treatment modality and is at present only experimental.
Even though therapeutic reconstitution of the interfering flora may be helpful, preservation
of the normal interfering flora is even more desirable. Since administration of antimicrobials
can affect the composition of the nasopharyngeal flora, including the reduction of
interfering bacteria, judicious use of antimicrobials is essential in the preservation
of the normal interfering flora.[19] Oropharyngeal flora microorganisms with interfering capabilities are generally susceptible
to amoxicillin, and include aerobic- and anaerobic-streptococci, as well as penicillin-susceptible
Prevotella spp. Amoxicillin-clavulanate is also effective against potentially interfering β-lactamase-producing
Gram-negative bacilli (i.e., Prevotella spp.). In contrast, these microorganisms are relatively resistant to the extended
spectrum and second- and third-generation cephalosporins.[20] Treatment with antibiotics effective against interfering organisms can lead to their
elimination from the flora.
Brook and Gober[19] compared the effects of amoxicillin-clavulanate and cefdinir on the nasopharyngeal
flora in children with acute otitis media. While both antimicrobials are effective
against potential pathogens (S. pneumoniae, H. influenzae, and M. catarrhalis), they have selective activity against members of the normal nasopharyngeal flora.
Upon conclusion of amoxicillin-clavulanate treatment, the oral flora was more depleted
of aerobic and anaerobic organisms with interfering capability than was observed after
cefdinir therapy. The differences between the two treatment groups persisted for at
least two months and correlated with more rapid reacquisition of potential bacterial
pathogens that occurred in those treated with amoxicillin-clavulanate.
The above study[19] illustrates a potential beneficial effect of utilizing a narrow-spectrum antimicrobial
that selectively spares interfering organisms while eliminating pathogenic organisms.
The advantage of such treatment is the prevention of reacquisition of pathogenic bacteria
in the oropharynx. In contrast, administration of a broad-spectrum antimicrobial is
associated with prolonged absence of interfering organisms, and a rapid recolonization
of the oropharynx with potential pathogens.
Beta-Lactamase-Producing Bacteria
Treatment with penicillin has resulted in a shift in the oral microbial flora over
time by selecting for β-lactamase-producing strains of Haemophilus spp, Staphylococcus aureus (including methicillin resistant S. aureus or MRSA), M. catarrhalis, and anaerobic Gram-negative bacilli (e.g., pigmented Prevotella, Porphyromonas) and Fusobacterium spp.[9] These organisms are typically recovered from those who were recently treated with
β-lactam antibiotics.[6]
[9]
The inactivation of penicillin by BLPB, protects GABHS and allows it to survive.[6] Therapy with β-lactam antibiotics can select for BLPB that in the oropharyngeal
flora,[9] and is especially common following repeated courses of β-lactam antibiotics administered
therapeutically or prophylactically.[21] Antibiotic-treated individuals can also be a source for spread BLPB to other individuals.[22]
An association has been found in GABHS PT therapy between the failure of patients
to respond to penicillin and the pre-existence of BLPB in the oropharynx.[23] Over three fourths of tonsils removed as a result of recurrent tonsillitis harbor
BLPB ([Table 2]).[24]
[25]
[26]
[27]
[28]
[29] Free β-lactamase enzyme was detected in the core of most of the excised tonsils
that harbored BLPB.[30] Antibiotics that are effective against GABHS and are also resistant to the enzyme
β-lactamase achieve higher success rates in eradication of acute and recurrent GABHS
PT. These antibiotics included cephalosporins, clindamycin, lincomycin, macrolides,
and amoxicillin-clavulanate.[31]
[32]
[33]
[34]
[35]
[36]
Table 2
Prevalence of beta-lactamase–producing bacteria in excised tonsils
|
Investigators (country, year)
|
No. of Patients
|
% β lactamase producing bacteria
|
|
Brook et al[24] (USA, 1981)
|
50
|
74
|
|
Reilly et al[25] (UK, 1981)
|
41
|
78
|
|
Tuner and Nord[26] (Sweden, 1982)
|
167
|
73
|
|
Chagollan et al[27] (Mexico, 1984)
|
10
|
80
|
|
Kielmovitch et al[28] (USA, 1989)
|
25
|
100
|
|
Brook et al[29] (USA, 1995)
|
50
|
94
|
A correlation was noted between the rate of recovery of BLPB in healthy children and
the rate of amoxicillin failure to eradicate GABHS. Brook and Gober obtained pharyngo-tonsillar
cultures from 228 children with GABHS PT, treated with amoxicillin for 10 days, and
663 healthy children.[37] Amoxicillin failed to eradicate GABHS from 48 of the 228 (21%) children. Amoxicillin
failure rate varied from month to month; it was generally higher between October and
May (22–32%); and low between June and September (8% to 12%). They recovered BLPB
from 226 of 663 (34%) healthy children. The rate of recovery of BLPB in healthy children
also varied; it was also generally high between October and May (40–52%) and lowest
between June and September (10–12%). Prior to their treatment, the researchers recovered
BLPB from 26 of the 48 (54%) children who eventually failed amoxicillin therapy, and
from 28 of the 180 (16%) who did not fail (p < 0.001). A high failure rate of penicillin in eradication of GABHS in PT can therefore
serve as sensitive indicator for a high prevalence rate of BLPB in the community.
A study of 44 children who had undergone elective tonsillectomy reported the isolation
of MRSA in the cores of in 7 (16%) of the surgically excised tonsils.[38] Since most of the MRSA (5 of 7) were also β-lactamase producers, their presence
could potentially interfere with the eradication of GABHS by penicillin. MRSA that
is also able to produce β-lactamase can survive treatment with β-lactam antibiotics
and continue to “shield” GABHS from penicillin through the production of the enzyme
β-lactamase. Most of the S. aureus isolated from the tonsillar cores of the patients in the study (19 of 26 or 73%)
were, however, β-lactamase producers and not MRSA. These organisms are susceptible
to β-lactamase-resistant penicillin as well as most cephalosporins.
Coexistence of Both Bacterial Interference and β-Lactamase-Producing Bacteria
Studies have found coexistence of BLPB presence with the absence of interfering organisms
in children who failed penicillin therapy of acute GABHS PT[15] or became carriers of GABHS.[39]
Brook and Gober[15] determined the association among bacterial interference and β-lactamase production
and penicillin failure in treating streptococcal PT. They evaluated 52 children who
had GABHS PT and were treated for 10 days with penicillin. Based on eradication of
GABHS, 38 of the patients were in the classification bacteriologic “cure”; and 14
were in the classification bacteriologic “failure” after therapy.
In the cured group, before therapy the authors recovered AHS inhibiting their own
GABHS in the cultures of 14 children (37%), and detected BLPB in the cultures of two
children (5%). After therapy, they recovered inhibiting AHS in 31 cultures (82%),
and detected BLPB in five cultures (13%). In contrast, in the failure group, before
therapy AHS were isolated in one culture (7%) and BLPB were recovered from nine cultures
(64%). After therapy, AHS were recovered in four cultures (29%), and BLPB was recovered
in 13 cultures (93%). These data show that the absence of interfering AHS and the
presence of BLPB is associated with penicillin failure in the treatment of GABHS PT.
Brook and Gober[39] compared the frequency of recovery of aerobic and anaerobic organisms with interfering
capability against GABHS and BLPB from the tonsils of GABHS carriers and non-carriers.
The authors evaluated the presence of aerobic and anaerobic bacteria capable of such
interference in vitro in cultures obtained from the tonsils of 20 healthy children
who were non-GABHS carriers and 20 who were GABHS carriers. They also assessed 20
children who were asymptomatic after completing a course of penicillin for acute GABHS
PT and were non-GABHS carriers and 20 who were GABHS carriers. In healthy children,
32 interfering isolates were recovered from 16 non-GABHS carriers (1.6 per child)
and 13 were isolated from 7 GABHS carriers (0.65 per child) (p < 0.001).
In children who had suffered acute GABHS PT, they recovered 26 interfering organisms
from 15 non-GABHS carriers and isolated 8 from 5 GABHS carriers.[39] Among the healthy children, they recovered 13 BLPB from 5 non-GABHS carriers and
isolated 13 from 6 GABHS carriers. In children who had suffered acute GABHS PT, they
recovered 14 BLPB from 5 (25%) non-GABHS carriers and isolated 32 from 17 (85%) GABHS
carriers (p < 0.05). This study demonstrated that there was a higher rate of recovery of aerobic
and anaerobic organisms capable of interfering with GABHS in non-GABHS carriers than
in GABHS carriers. This was observed in all GABHS non-carriers and included healthy
children, as well as those recently treated for symptomatic GABHS PT with penicillin
that failed to eradicate GABHS. A higher rate of recovery of BLPB was observed only
in GABHS carriers who were treated with penicillin for GABHS PT.
The presence of bacterial biofilm in tonsillitis may also play a role in bacterial
interactions that take place in the tonsils. The milieu of a biofilm can trap microorganisms
in close proximity to each other, thus enabling bacterial interactions.[40]
Coaggregation between M. Catarrhalis and GABHS
Several studies suggest that tonsillar colonization by GABHS and other aerobic and
anaerobic bacteria can contribute to the inflammatory process and the ultimate failure
of penicillin treatment.[41] The existence of mutual symbiotic enhancement between GABHS and other aerobic and
anaerobic bacteria was illustrated in vitro and in an animal model.[42] Such a synergistic relationship may also occur in patients with PT. An example of
such synergy is the ability of M. catarrhalis to increase GABHS adherence to human epithelial cells through species-specific coaggregation.[7]
Brook and Gober[43] investigated whether the isolation of M. catarrhalis, H. influenzae, S. aureus, and S. pneumoniae is associated with the recovery of GABHS. Among 548 children with acute PT, GABHS
was isolated from 112 (20.4%) children. Of the 114 H. influenzae isolates, 32 isolates were associated with GABHS and 82 isolates were recovered without
GABHS (p < 0.05). Of the 69 M. catarrhalis isolates, 25 isolates were associated with GABHS and 44 isolates were recovered without
GABHS (p < 0.05). In contrast, there was no association between the isolation of GABHS and
S. aureus or S. pneumoniae. One hundred four isolates of GABHS were recovered from 548 healthy children. Of the
69 M. catarrhalis isolates, 24 isolates were associated with GABHS (23% of all patients with GABHS)
and 80 isolates were recovered without GABHS (10%) (p < 0.05). There was no association between the isolation of GABHS and the presence
of H. influenzae, S. aureus, or S. pneumoniae among healthy children. This study illustrates an association between the isolation
of GABHS and H. influenzae and M. catarrhalis from patients with PT, and between GABHS and M. catarrhalis from healthy children.
The increased recovery of H. influenzae (in PT only) and M. catarrhalis in association with GABHS may be due to a synergy between these organisms.[7]
[43] The ability of H. influenzae and M. catarrhalis to produce the enzyme β-lactamase, which can inactivate the penicillin in the tonsillar
tissues,[7] may protect these organisms, as well as GABHS from eradication, and contribute to
the failure of penicillin treatment.
An indirect support for the clinical importance of the synergistic relationship between
GABHS and H. influenzae and M. catarrhalis is the better clinical efficacy in eradicating GABHS, as compared with penicillin,
of antimicrobials active against these organisms. These antimicrobials include the
second, extended-spectrum, and third-generation cephalosporins[44]
[45] as well as amoxicillin-clavulanate.[33]
[34] The superior efficacy of these antimicrobials compared with penicillin may be due
to their activity against GABHS as well as β-lactamase producing H. influenzae and M. catarrhalis.
Susceptibility of GABHS to Penicillin
Antimicrobial resistance of GABHS to penicillin has rarely been an issue in the management
of PT. A clinical isolate of GABHS was never found to be resistant to penicillin.
Despite the extensive use of penicillin in the past half century, no resistance has
emerged in the treatment of GABHS infections.[46]
[47]
Sporadic reports correlated in vitro penicillin tolerance (i.e., significantly decreased
bactericidal effect of penicillin) with GABHS eradication failure. However, conflicting
findings have been reported by various investigators[3]
[48] and there is no common consensus about the role of tolerance in penicillin failure.
Treatment of acute and recurrent GABHS PT
Treatment of acute and recurrent GABHS PT
Acute Pharyngo-Tonsillitis
Patients with acute streptococcal pharyngitis should receive therapy with an antimicrobial
agent in a dose and for a duration that is likely to eradicate the infecting organism
from the pharynx. Despite its relatively high clinical and bacteriological failure
rate to other antimicrobials, penicillin is still used for the treatment of acute
GABHS PT,[49]
[50] mostly because of its long track record and low cost. Many antibiotics are available
for the treatment of PT caused by GABHS. Most oral antimicrobials should be administered
for 10 days to achieve the best eradication rates of GABHS; however, there have been
reports of newer agents achieving comparable rates of bacteriologic and clinical cure
of GABHS PT when administered for less than five days. These include azithromycin,[51] Clarithromycin,[52] cefuroxime,[53] cefixime,[54] ceftibuten,[55] cefdinir,[56] and cefpodoxime.[57]
The recommended treatment for GABHS infection is penicillin administered for 10 days.[49]
[50] Oral penicillin-VK is used more often than intramuscular benzathine penicillin-G.
However, IM penicillin can be given as initial therapy in those who cannot tolerate
oral medication or to ensure compliance. An alternative medication is amoxicillin,
which is as active against GABHS, but its absorption is more reliable, blood levels
are higher, plasma half-life is longer, and protein binding is lower, giving it theoretical
advantages. Furthermore, oral amoxicillin has better compliance (better taste). In
comparative clinical trials, once-daily amoxicillin (50 mg/kg, to a maximum of 1000
mg) for 10 days has been shown to be effective for GABHS pharyngitis.[58] Amoxicillin should not be used, however, in patients suspected of infectious mononucleosis,
where it can produce a skin rash.
Treatment of GABHS PT with a single daily dose of penicillin has been unsuccessful.[59] Once-daily azithromycin[60] and once-daily regimens of several cephalosporins (e.g., cefadroxil,[61] cefixime,[62] ceftibuten,[63] cefpodoxime,[64] cefprozil,[65] and cefdinir[66]), were effective in eradicating GABHS PT. However, only azithromycin, cefadroxil,
cefixime, and cefdinir are FDA-approved as once-daily therapies for GABHS PT in children.
There are, however, individuals for whom more effective antimicrobials should be considered.
Individual medical, economic, and social issues should be taken into consideration
before selecting an antimicrobial for the treatment of GABHS PT. The existence of
a high probability for the presence of BLPB in the pharyngo-tonsillar area, the absence
of interfering organisms, the recent failure of penicillin therapy, or a history of
relapsing GABHS PT should be considered.
Macrolides are an alternative to penicillin. However, the increased use of macrolides
has been associated with increased GABHS resistance to these agents - up to 60% in
Italy, Finland, Japan, Spain, and Turkey.[67] Of particular concern is the recent increase of such resistance in the United States,[68]
[69] reaching 48% in specific populations.[68] Therefore, it is advisable to avoid the routine administration of macrolides for
GABHS PT and to save these antimicrobials for patients who are Type I penicillin-allergic.
When treating acute GABHS PT, amoxicillin-clavulanate was not superior to penicillin.[70] Furthermore, the use of this agent at the earlier stages of the infection can reduce
the number of the aerobic- and anaerobic-interfering organisms, which may be counterproductive.[71]
The high failure rates in the treatment of GABHS PT by penicillin and amoxicillin
may be due to their inability to eradicate BLPB (bacteria) and their ability to eradicate
the beneficial interfering bacteria. In contrast to cephalosporins, especially those
that are β-lactamase stable, are effective in the treatment of individuals who are
likely to fail penicillin therapy as well as those with recurring infection. The efficacy
of cephalosporins is explained by their ability to eradicate aerobic BLPB, preserve
aerobic and anaerobic interfering organisms, and eliminate GABHS ([Tables 3] and [4]).
Table 3
Antibacterial activity of penicillin compared with cephalosporins in the management
of acute GABHS tonsillitis
|
Antimicrobial Activity
|
Penicillin
|
Cephalosporins
|
|
Aerobic betalactamase–producing bacteria
|
No
|
Yes
|
|
Interfering organisms
|
Yes
|
No
|
|
GABHS
|
Yes
|
Yes
|
Table 4
Antibacterial activity of cephalosporins against aerobic Beta-Lactamase–Producing
Bacteria (BLPB)
|
BLPB
|
First generation
(cephalothin)
|
Second generation
(cefuroxime)
|
Extended spectrum
(cefdinir, cefpodoxime)
|
Third generation
(cefixime, ceftibuten)
|
|
S. aureus
|
Yes
|
Yes
|
Yes
|
No
|
|
H. influenzae
|
No
|
Yes
|
Yes
|
Yes
|
|
M. catarrhalis
|
No
|
Yes
|
Yes
|
Yes
|
When making a choice to select broader spectrum antimicrobial, it is important to
consider the potential of selection of resistant organisms.
Several antimicrobials are not recommended for treatment of GABHS PT. Tetracyclines
should not be used as resistance in GABHS patients is common.[72] Sulfonamides and trimethoprim-sulfamethoxazole resistance is also prevalent and
these agents often fail to eradicate GABHS from patients with acute PT.[3] Older fluoroquinolones (e.g., ciprofloxacin) have limited antibacterial activity
against GABHS and are not recommended for the treatment of GABHS PT.[49] The newer fluoroquinolones (e.g., levofloxacin and moxifloxacin) are effective in
vitro against GABHS; however, they are expensive and possess a broad spectrum of activity.
They are therefore not recommended for routine treatment of GASBHS PT.[49]
Penicillin allergic patients can be treated with cephalosporins, macrolides, or clindamycin.
It is important to note that some penicillin-allergic individuals (up to 10%) are
also allergic to cephalosporins, which should not be used in patients with immediate
(anaphylactic-type) hypersensitivity to penicillin.[73] Clindamycin resistance among GABHS isolates in the United States is ∼1%, and this
is a reasonable agent for treating penicillin-allergic patients.[69]
Because of the general increase in rates of bacterial resistance to antimicrobials,
antibiotic therapy should be administered only for proven episodes of GABHS PT.[49]
[50]
The length of therapy of acute tonsillitis with medication other than penicillin has
not been determined by large comparative controlled studies. However, certain new
agents have been administered in shorter courses of 5 or more days. Early initiation
of antimicrobial therapy results in faster resolution of signs and symptoms. However,
spontaneous disappearance of fever and other symptoms generally occurs within 3 to
4 days, even without antimicrobials. Furthermore, acute rheumatic fever can be prevented
even when therapy is postponed up to 9 days.
Prevention of recurrent tonsillitis due to GABHS by prophylactic administration of
daily oral or monthly benzathine penicillin should be attempted in patients who suffered
from rheumatic fever. American Heart Committee guidelines on the prevention of rheumatic
fever[74] should be followed, and if any family members are carrying GABHS, the disease should
be eradicated and the carrier state monitored.
Recurrent Pharyngo-Tonsillitis
Penicillin failure in treatment of recurrent and chronic tonsillitis is even higher
than the failure of therapy of acute infection. Several clinical studies demonstrated
the superiority of lincomycin, clindamycin, and amoxicillin-clavulanic acid over penicillin
in the treatment of recurrent PT.[32]
[33]
[34]
[57]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
[84]
[85] Only one of these studies showed reduction in the need for tonsillectomies following
treatment with clindamycin ([Table 5]).[32] These antimicrobial agents are effective against aerobic, as well as anaerobic BLPB
and GABHS, in eradicating recurrent tonsillar infection. However, no studies have
shown them to be superior to penicillin in treatment of acute tonsillitis.
Table 5
Studies of therapy of acute and recurrent group A streptococcal pharyngitis
|
|
Failure rate
|
|
No. of Patients
|
Penicillin
|
Other drugs
|
|
ACUTE
|
|
Breese et al[75]
[76]
|
262
|
29%
|
Lincomycin
|
13%
|
|
Randolph & DeHaan[77]
|
525
|
14%
|
Lincomycin
|
8%
|
|
Howie & Ploussard[57]
|
156
|
40%
|
Lincomycin
|
13%
|
|
Randolph et al[78]
|
128
|
21%
|
Clindamycin
|
7%
|
|
Stillerman et al[80]
|
103
|
18%
|
Clindamycin
|
10%
|
|
Chaudhary et al[81]
|
99
|
28%
|
Penicillin & rifampin
|
0%
|
|
Massell (prophylaxis)[82]
|
202
|
25%
|
Clindamycin
|
12%
|
|
Casey et al[85]
|
4278
|
Pen 16%
Amox 14%
|
Cephalosporin (1st)
Cephalosporin (2nd)
Cephalosporin (3rd)
|
14%
9%
7%
|
|
RECURRENT
|
|
Brook and Hirokawa[32]
|
30
|
87%
|
Erythromycin
|
60%
|
|
|
|
Clindamycin
|
7%
|
|
Tanz et al (carriers)[83]
|
48
|
45%
|
Clindamycin
|
8%
|
|
Brook[33]
|
40
|
30%
|
Amoxicillin & clavulanate
|
0%
|
|
Smith et al[84]
|
74
|
83%
|
Dicloxacillin
|
50%
|
|
Orrling et al[85]
|
48
|
64%
|
Clindamycin
|
0%
|
|
* with rifampin
|
Abbreviations: Amox, amoxicillin; Pen, peniciliin.
A study[86] of 774 patients with acute recurrent GABHS PT that compared oral clindamycin 300mg
BID and oral amoxicillin-clavulanate 1 g BID achieved comparable rates of bacteriologic
eradication at 12 days and 3 months and comparable clinical cure rates at three months.
Patients who received clindamycin had significantly greater clinical cure rates at
12 days (92.6% versus 85.2%).
Other drugs that may also be effective in the therapy of recurrent or chronic tonsillitis
are penicillin plus rifampin and a macrolide (e.g., erythromycin) plus metronidazole
([Table 6]). Referral of a patient for tonsillectomy should be considered only after these
medical therapeutic modalities have failed.
Table 6
Oral antimicrobials in treatment of GABHS tonsillitis
|
Acute
|
Recurrent/Chronic
|
Carrier State
|
|
Penicillin (amoxicillin)
|
Clindamycin, amoxicillin-clavulanate
|
Clindamycin
|
|
Cephalosporins[b]
|
Metronidazole plus macrolide
|
Penicillin plus rifampin
|
|
Clindamycin
|
Penicillin plus rifampin
|
–
|
|
Amoxicillin-clavulanate
|
–
|
–
|
|
Macrolides[a]
|
–
|
–
|
a GABHS may be resistant.
b All generations.
Amoxicillin-clavulanate and clindamycin, which are also active against the anaerobic
component (including the anaerobic BLPB) of the oropharyngeal flora, are appropriate
for the treatment of patients with chronic tonsillitis and in those with recurrent
PT who had failed treatment and are considered for elective tonsillectomy. Clindamycin
has also been found to be effective in eradicating the GABHS carrier state.[87] This may be due to its ability to eradicate the BLPB present[39] in these children as well as penetrate into the tonsillar cells.[1]
The Carrier State
Antimicrobial therapy is not indicated for most individuals who are chronic streptococcal
carriers. However, some circumstances justify the eradication of the organism. These
include: (1) during an outbreak of acute rheumatic fever, acute post-streptococcal
glomerulonephritis, or invasive GABHS infection in the community; (2) during an outbreak
of GABHS PT in a closed community; (3) in those with a personal or family history
of acute rheumatic fever; (4) in families with excessive anxiety about GABHS infections;
or (5) when GABHS carriage is considered as an indication for tonsillectomy.
Several antimicrobials have been found to be more effective than penicillin or amoxicillin
in eliminating chronic streptococcal carriage. These include clindamycin[87] and the combination of penicillin (IM or PO) and rifampin.[83]
Final Comment
There have been 13 national guidelines published regarding GABHS PT management since
1999.[49]
[50]
[74]
[88]
[89]
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97] These include six from European countries (France, United Kingdom, Finland, Holland,
Scotland, and Belgium), six from the United States, and one from Canada. Recommendations
differ substantially with regard to the use of a rapid antigen diagnostic test or
throat culture and the indications for antibiotic treatment. The North American, Finnish,
and French guidelines recommend performing one timely microbiologic investigation
in suspected cases, and prescribing antibiotics in confirmed cases to prevent suppurative
complications and acute rheumatic fever. According to the remaining European guidelines,
however, acute sore throat is considered a benign, self-limiting disease. Microbiologic
tests are not routinely recommended by these latter guidelines, and antibiotic treatment
is reserved for well-selected cases. Without microbiological testing, bacteriological
failure of therapy cannot be detected.
Penicillin remains the antibiotic of choice recommended by all national guidelines,[49]
[50]
[74]
[88]
[89]
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97] although other antibiotics are more effective in the bacteriological eradication
and clinical cure of acute and recurrent GABHS PT.[33]
[34]
[35]
[36] Macrolides and cephalosporins are more effective clinically and bacteriologically
than penicillin in acute GABHS PT,[44]
[45] while lincomycin, clindamycin, and amoxicillin-clavulanate are more effective in
relapsing GABHS PT.[32]
[33]
[34]
[57]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
[84]
[85]
The goal of the treatment of PT in individuals who failed penicillin therapy is also
to eradicate the BLPB that protect GABHS from penicillin, while preserving whatever
“protective” interfering organisms (i.e., AHS) that may be present in the pharyngo-tonsillar
area.
Cephalosporins have been successful in eradicating GABHS better, and in some instances
even faster than penicillin.[44]
[45] Thirty-five randomized studies showed that all classes of cephalosporins have a
higher success rate in eradicating GABHS than penicillin (a third of the failure rate
of penicillin,[44]
[45] and 12 studies illustrated equal or better success rate in 5 to 7 days of therapy,
compared with 10 days of penicillin.[73] The frequency of symptomatic relapses of GABHS PT following all generations of cephalosporins
was significantly lower compared with penicilin[98] ([Table 5]). The explanation for the superiority of cephalosporins over penicillin is that
even though they are as efficacious in vitro as penicillin in eradicating GABHS, penicillin
also eliminates the aerobic- and anaerobic-interfering bacteria. Penicillin use may
therefore deprive the patient of the potential beneficial effects of interfering organisms,
which can decrease colonization with GABHS. In contrast, cephalosporins are less inhibitory
of aerobic- and anaerobic-interfering organisms; thus, they are more likely to survive
the antimicrobial therapy.[42] The higher the generation of the cephalosporins, the less effective they are against
both aerobic- and anaerobic-interfering organisms ([Tables 5] and [6]).
Cephalosporins lesser efficacy against interfering bacteria accounts for their potential
advantage. The administration of a cephalosporin has therefore a selective effect:
eradicating GABHS while preserving both aerobic- and anaerobic-interfering organisms
([Tables 3] and [4]). The sparing effects of the cephalosporins persisted for at least two months after
their administration.[20]
Cephalosporins are generally resistant to β-lactamase and are not hydrolyzed by extracellular
β-lactamases produced by BLPB. However, cephalosporinś antibacterial efficacy against
BLPB is generation-dependent ([Table 3]). First generation cephalosporins (e.g., cephalexin, cefadroxil) are effective only
against S. aureus; second generation (cefuroxime acetil) and extended-spectrum third generation (cefdinir
and cefpodoxime axetil) cephalosporins are effective against S. aureus, Haemophilus spp., and Moraxella spp.; and third generation (e.g., cefixime, ceftibuten) cephalosporins are only effective
against Haemophilus spp. and Moraxella spp.[99]
The selective activity of cephalosporins has been demonstrated in an animal model
study of mixed infection,[21] as well as in patients treated with an extended-spectrum cephalosporin prior to
elective tonsillectomy.[100] Brook and Foote[100] compared two treatment modes of recurrent GABHS tonsillitis: one with penicillin
and the other with an extended-spectrum cephalosporin (cefdinir). Both antimicrobials
were given for 10 days prior to elective tonsillectomy to children who suffered from
recurrent GABHS tonsillitis and were scheduled for surgery. Of the two, cefdinir was
more effective in eradicating GABHS, reducing the number of BLPB, and preserving AHS
capable of inhibiting GABHS. These results illustrate the ability of an oral extended-spectrum
cephalosporin, in comparison to penicillin, to eradicate GABHS as well as BLPB, while
preserving the interfering AHS.
The data presented suggest that consideration should be given to utilization of antimicrobials
other than penicillin for the treatment of GABHS PT, especially in clinical settings
where penicillin failure had occurred or is high. Further studies are warranted to
demonstrate if this approach would reduce the need for tonsillectomies.
The author does not have a financial relationship with any organization.
