# Comparative Study of 5-Day and 10-Day Cefditoren Pivoxil Treatments for Recurrent Group Aβ-Hemolytic Streptococcus pharyngitis in Children

Authors: Hideaki Kikuta; Mutsuo Shibata; Shuji Nakata; Tatsuru Yamanaka; Hiroshi Sakata; Kouji Akizawa; Kunihiko Kobayashi
Journal: International Journal of Pediatrics
 (2009)

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## Abstract

Efficacy of short-course therapy with cephalosporins for treatment of group Aβ-hemolytic streptococcus (GABHS) pharyngitis is still controversial. Subjects were 226 children with a history of at least one episode of GABHS pharyngitis. Recurrence within the follow-up period (3 weeks after initiation of therapy) occurred in 7 of the 77 children in the 5-day treatment group and in 1 of the 149 children in the 10-day treatment group; the incidence of recurrence being significantly higher in the 5-day treatment group. Bacteriologic treatment failure (GABHS isolation without overt pharyngitis) at follow-up culture was observed in 7 of the 77 children in the 5-day treatment group and 17 of the 149 children in the 10-day treatment group. There was no statistical difference between the two groups. A 5-day course of oral cephalosporins is not always recommended for treatment of GABHS pharyngitis in children who have repeated episodes of pharyngitis.


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## Body

## 1. Introduction

Group Aβ-hemolytic streptococci (GABHS, also
referred to as Streptococcus pyogenes)
are the most common bacterial cause of acute pharyngitis, accounting for
approximately 15 to 30% of cases in children and 5 to 10% of cases in adults [1–3].
The objectives of treatment for GABHS pharyngitis are prevention of rheumatic
fever, prevention of suppurative complications, reduction in transmission of
GABHS, and shortening of the clinical course. Although the standard oral
recommended therapy for GABHS pharyngitis has long been penicillin V for 10
days, there has been no change in the susceptibility of GABHS for over 50 years
[1–4]. However, recurrent GABHS infections occurred more frequently in the
1990s than the 1970s, and treatment failure rates as high as 10 to 30% have
been reported [5, 6]. Reasons for failure of the standard therapy include an
increase in β-lactamase-producing pharyngeal pathogens that inactivate
penicillin, poor compliance, intracellular location of GABHS, eradication of
protective pharyngeal α-streptococci, and increased exposure in crowded
day-care centers and schools [7–9].The increase in failure rate of the standard 10-day
course of therapy with penicillin has heightened interest in alternative
treatments for this infection. Cephalosporins have been used successfully for
treatment of this infection since the 1970s [10, 11]. A meta-analysis showed
that 10-day cephalosporin treatment was superior in eradication of GABHS and in
clinical response [12]. Recent studies on the efficacy of a short-course
treatment (5 days) with cephalosporins compared with that of 10-day penicillin
V treatment have shown that the shorter cephalosporin treatments were
equivalent or superior in eradication of GABHS and in clinical response [13].
However, there are several controversial issues regarding the increase in
recurrent GABHS pharyngitis since the 1990s, reasons for failure of the
standard penicillin therapy and evaluation of alternative cephalosporin
treatments for GABHS pharyngitis [14–16]. The
purpose of this study was to determine the efficacy of a 5-day course of oral
cephalosporin compared with that of a 10-day course of oral cephalosporin for
recurrent GABHS pharyngitis in children.


## 2. Materials and Methods

### 2.1. Subjects

In a prospective, multicenter surveillance
study, a total of 299 children with a history of at least 1 episode of GABHS
pharyngitis were enrolled at private offices of 41 practicing pediatricians and
hospitals of 23 practicing pediatricians between May 2006 and August 2007 in Hokkaido,
the northernmost island of Japan. A total of 73 children were excluded after
enrollment because of incomplete follow-up(n=61), inappropriate enrollment
(n=11), and noncompliance (n=1). The number of eligible patients for the study
was 226. The 226
children (138 males and 88 females; 2 to 14 years old; mean age: 6.8 years; SD:
2.0 years) were diagnosed as having GABHS pharingitis by both clinical findings
and a positive reaction in pharyngeal swab specimens using commercially
available rapid antigen detection tests (RADTs) for GABHS (Immunocard ST Strep
A, TFB, INC., Tokyo; Dipstick Eiken Strept A, Eiken Chemical Co., Ltd., Tokyo;
Quickview Strep A, Wako Pure Chemical Industries, Ltd., Osaka). The clinical
findings included presence of oropharyngeal erythema or tonsillar exudate,
fever, cervical lymphadenitis, and sore throat. Patients with signs and
symptoms suggestive of viral infection (rhinorrhea, cough, conjunctivitis) were
excluded. Follow-up visit and follow-up culture were scheduled 3 weeks after
the initiation of therapy. The culture samples were obtained by rubbing over
the posterior portion of the pharynx and both tonsils with a sterile,
rayon-tipped swab. All pharyngeal
swab specimens were collected after obtaining informed
consent from the patients or children’s parents. The swabs were placed in an aerobic transport
system and then transported to our laboratory. The children with subsequent
GABHS pharyngitis within the follow-up period were also diagnosed by both
clinical findings and results of RADTs. The
226 patients were treated with cefditoren pivoxil (9 mg/kg; maximum dose of 300 mg/day, 3 times a day) for 5 days (77 patients) or for 10 days (149 patients).
Since each pediatrician arbitrarily decided the period of antibiotic treatment,
there was no complete randomization of the patients.


### 2.2. Definition

Clinical response to
treatment was defined here as recurrence (clinical treatment failure;
clinically and RADT-confirmed GABHS pharyngitis within the follow-up period,
irrespective of T serotype) and as clinical cure (clinical treatment success;
no clinical findings of GABHS pharyngitis within the follow-up period).
Bacteriologic response to treatment was defined here as eradication
(bacteriologic treatment success; no GABHS isolation at follow-up visit) and as
noneradication (bacteriologic treatment failure; GABHS isolation without overt
pharyngitis at follow-up visit, irrespective of T serotype). Treatment success
was, therefore, defined as bacteriologic treatment success with no recurrence,
and treatment failure was defined as either clinical or bacteriologic treatment
failure.


### 2.3. Serotyping

Serotyping was examined for T types by the
agglutination method using Group A streptococcus hemolyticus T typing
immunoserum “SEIKEN” (Denka Seiken Co.,
Ltd., Tokyo).


### 2.4. Statistical Analysis

Quantitative variables were
compared using Welch’st-test, and qualitative variables were compared
using the chi-square test with Fisher's exact test. For all statistical
comparisons, P<.05 was considered to be significant.


## 2.1. Subjects

In a prospective, multicenter surveillance
study, a total of 299 children with a history of at least 1 episode of GABHS
pharyngitis were enrolled at private offices of 41 practicing pediatricians and
hospitals of 23 practicing pediatricians between May 2006 and August 2007 in Hokkaido,
the northernmost island of Japan. A total of 73 children were excluded after
enrollment because of incomplete follow-up(n=61), inappropriate enrollment
(n=11), and noncompliance (n=1). The number of eligible patients for the study
was 226. The 226
children (138 males and 88 females; 2 to 14 years old; mean age: 6.8 years; SD:
2.0 years) were diagnosed as having GABHS pharingitis by both clinical findings
and a positive reaction in pharyngeal swab specimens using commercially
available rapid antigen detection tests (RADTs) for GABHS (Immunocard ST Strep
A, TFB, INC., Tokyo; Dipstick Eiken Strept A, Eiken Chemical Co., Ltd., Tokyo;
Quickview Strep A, Wako Pure Chemical Industries, Ltd., Osaka). The clinical
findings included presence of oropharyngeal erythema or tonsillar exudate,
fever, cervical lymphadenitis, and sore throat. Patients with signs and
symptoms suggestive of viral infection (rhinorrhea, cough, conjunctivitis) were
excluded. Follow-up visit and follow-up culture were scheduled 3 weeks after
the initiation of therapy. The culture samples were obtained by rubbing over
the posterior portion of the pharynx and both tonsils with a sterile,
rayon-tipped swab. All pharyngeal
swab specimens were collected after obtaining informed
consent from the patients or children’s parents. The swabs were placed in an aerobic transport
system and then transported to our laboratory. The children with subsequent
GABHS pharyngitis within the follow-up period were also diagnosed by both
clinical findings and results of RADTs. The
226 patients were treated with cefditoren pivoxil (9 mg/kg; maximum dose of 300 mg/day, 3 times a day) for 5 days (77 patients) or for 10 days (149 patients).
Since each pediatrician arbitrarily decided the period of antibiotic treatment,
there was no complete randomization of the patients.


## 2.2. Definition

Clinical response to
treatment was defined here as recurrence (clinical treatment failure;
clinically and RADT-confirmed GABHS pharyngitis within the follow-up period,
irrespective of T serotype) and as clinical cure (clinical treatment success;
no clinical findings of GABHS pharyngitis within the follow-up period).
Bacteriologic response to treatment was defined here as eradication
(bacteriologic treatment success; no GABHS isolation at follow-up visit) and as
noneradication (bacteriologic treatment failure; GABHS isolation without overt
pharyngitis at follow-up visit, irrespective of T serotype). Treatment success
was, therefore, defined as bacteriologic treatment success with no recurrence,
and treatment failure was defined as either clinical or bacteriologic treatment
failure.


## 2.3. Serotyping

Serotyping was examined for T types by the
agglutination method using Group A streptococcus hemolyticus T typing
immunoserum “SEIKEN” (Denka Seiken Co.,
Ltd., Tokyo).


## 2.4. Statistical Analysis

Quantitative variables were
compared using Welch’st-test, and qualitative variables were compared
using the chi-square test with Fisher's exact test. For all statistical
comparisons, P<.05 was considered to be significant.


## 3. Results and Discussion

### 3.1. Results

The
characteristics of children with repeated GABHA pharyngitis are shown in Table1. The mean number of episodes of repeated GABHS pharyngitis including the
present episode was 2.79 (range: 2–12; SD: 1.35). Of the 226 patients, 182
(80.5%) patients had a history of at least 2 episodes of repeated GABHS
pharyngitis. The mean interval between preceding and present episodes was 10.48
months (range: 0.4–79 months; SD:
13.85). Of the 226 patients, 98 (43.3%) patients had preceding GABHS
pharyngitis within 3 months before the present GABHS pharyngitis. The mean
length of follow-up excluding recurrence cases (definition of recurrence case
given below) was 22.20 days (range: 14–35 days; SD: 2.98
days). Of the 226 patients, 218 (96.4%) patients were followed up for 14–28 days after the
initiation of therapy. The characteristics of children treated for 5 days and
10 days are shown in Table 1. The ratios of males to females were 1:0.67 in the
5-day treatment group and  1:0.62 in the 10-day treatment group. Mean ages were
6.70 years (range: 3–12 years; SD:
1.93 years) in the 5-day treatment group and 6.80 years (range: 2–14 years; SD:
2.10 years) in the 10-day treatment group. Mean numbers of episodes of repeated
GABHS pharyngitis were 2.75 (range: 2–12; SD: 1.54) in
the 5-day treatment group and 2.81 (range: 2–8; SD: 1.24) in
the 10-day treatment group. Mean intervals between preceding and present
episodes were 12.95 months (range: 0.5–79 months; SD:
17.30 months) in the 5-day treatment group and 9.20 months (range: 0.4–55 months; SD:
11.47 months) in the 10-day treatment group. Mean lengths of follow-up
excluding recurrence cases were 22.57 days (range: 14–32 days; SD: 3.03
days) in the 5-day treatment group and 22.02 days (range: 15–35 days; SD: 2.94
days) in the 10-day treatment group. There were no significant differences
between the two treatment groups in the distribution of age, gender, number of
episodes of repeated GABHS pharyngitis, interval between preceding and present
episodes, and length of follow-up.Table 1
Characteristics of children with repeated GABHA pharyngitis.
CharacteristicsTotal5-day treatment group10-day treatment groupP  valueNumber of cases22677149Male:Female138:8846:3192:57.775Age (years) (mean±SD)6.77±2.046.70±1.936.80±2.10.728Frequency of episodes (times) (mean±SD)2.79±1.352.75±1.542.81±1.24.768Interval between preceding and present episodes
(months) (mean±SD)10.48±13.812.95±17.309.20±11.47.089Length of follow-up (days) (mean±SD)22.20±2.9822.57±3.0322.02±2.94.203The
clinical and bacteriological results are shown in Table2. Recurrence (clinical
treatment failure) occurred in 7 (9.1%) of the 77 children in the 5-day
treatment group and in 1 (0.7%) of the 149 children in the 10-day treatment
group. The 5-day treatment group showed a significantly higher incidence of
recurrent GABHS pharyngitis than that in the 10-day treatment group (P=.003).
The eight patients with recurrent GABHS phayryngitis included 5 males and 3
females with a mean age of 6.36 years (range: 5–8 years; SD: 0.91
years). The mean interval from onset of the index infection to onset of
subsequent recurrent GABHS pharyngitis was 11.3 days after the initiation of
therapy (range: 6–22 days; SD: 4.94
days). The mean number of episodes of repeated GABHS pharyngitis was 2.88
(range: 2–6; SD: 1.36). The
mean interval between preceding and present episodes was 10.81 months (range:
0.5–24 months; SD:
8.268 months). There was no recognizable risk factor of recurrent GABHS
pharyngitis in the patients, probably due to the limited number of recurrent
cases. Bacteriologic treatment failure at the follow-up visit was observed in 7
(9.1%) of the 77 children in 5-day treatment group and in 17 (11.4%) of the 149
children in the 10-day treatment group. There was no significant difference
between the two treatment groups (P=.655). The treatment failure rates
were 18.2% in the 5-day group and 12.1% in the 10-day group. This difference
was also not statistically significant (P=.231). No poststreptococcal
sequelae were noted in this study.Table 2
Clinical and bacteriological results.
ResultsTotal5-day treatment group10-day treatment groupP  valueRecurrence (clinical treatment failure)8/2267/771/149.003Bacteriologic treatment failure
(noneradication)24/2267/7717/149.655Treatment failure32/22614/7718/149.231The
characteristics of children in the treatment success group (bacteriologic
treatment success with no recurrence) and treatment failure group (either
clinical or bacteriologic treatment failure) are shown in Table3. Ratios of
males to females were 1:0.73 in the treatment success group (194 children) and
1:0.23 in the treatment failure group (32 children). Treatment failure rates
were significantly affected by gender (P=.011). Mean ages were 6.86
years (range: 2–14 years; SD:
2.12 years) in the treatment success group and 6.24 years (range: 3–9 years; SD: 1.39
years) in the treatment failure group (P=.036). Treatment failure was
observed more frequently in the 86 children aged 6 to 7 years (in 22 of the 86
children, treatment failure rate of 25.6%) than in the 66 children aged 2 to 5
years (in 6 of the 66 children, treatment failure rate of 9.1%; P<.001)
and in the 74 children aged 8 to 14 years (in 4 of the 74 children, treatment
failure rate of 5.4%; P<.001). The mean number of episodes of
repeated GABHS pharyngitis in the treatment success group was 2.77 (range: 2–6; SD: 1.36) and
that in the treatment failure group was 2.91 (range: 2–12; SD: 1.26),
the difference between the groups not being statistically significant (P=.586).
The mean intervals between preceding and present episodes were 11.04 months
(range: 0.5–79 months; SD:
14.57 months) in the treatment success group and 7.05 months (range: 0.4–27 months; SD:
7.31 months) in the treatment failure group. Although the difference between
the intervals in the two groups was statistically significant (P=.019),
the interval responsible for treatment failure could not be statistically
determined.Table 3
Characteristics of children with treatment success and treatment failure.
CharacteristicsTreatment success groupTreatment failure groupP  valueNumber of cases19432Male:Female112:8226:6.011Age (years) (mean±SD)6.86±2.126.24±1.39.036Frequency of episodes (times) (mean±SD)2.77±1.362.91±1.26.586Interval between preceding and present
episodes (months) (mean±SD)11.04±14.577.05±7.31.018All
corresponding strains isolated from the 24 children with positive follow-up
cultures both at pre- and posttreatments had the same serotype. Six different T
types were identified, of which T12 was the most common serotype. In the 8
children with recurrence within the follow-up period, only 4 corresponding
strains isolated at pretreatment and at recurrence were available for
characterization by serotyping. GABHS with different serotype was identified in
one child in the 5-day treatment group but not in other children.


### 3.2. Discussion

Recurrence of GABHS pharyngitis frequently occurs in
children after treatment. Approximately 10 to 20% of children have recurrent
infection within 1 year of an index infection [5, 11, 17]. Possible explanations
for the recurrence are 1) reinfection: new infection with GABHS, and 2)
relapse: recurrence of originally persisted GABHS. Although serotyping of GABHS
isolates helps to make the distinction, it may be difficult to distinguish
between reinfection and relapse. Holm et al. reported that 10-day cephalosporin
treatment in children with recurrent GABHS pharyngitis resulted in
bacteriologic and clinical cure rates higher than those of 10-day penicillin
treatment [18].In this study, the recurrence
rate within 3 weeks after the initiation of therapy was significantly higher in
the 5-day treatment group than in the 10-day treatment group. However, the
difference between the two treatment groups in rate of bacteriologic treatment
failure at the follow-up visit was not statistically significant. All
corresponding strains isolated at pre- and posttreatments in the 24 patients
with bacteriologic treatment failure had the same serotype, indicating that the
treatment failure might be relapse. Only one of the corresponding isolates in 4
children with recurrence had different serotypes, indicating that the treatment
failure in this case was reinfection. Test-of-cure timing, follow-up visit in
this study, is important in the interpretation of treatment failure rate. It
has been suggested that the test-of-cure evaluation should optimally be done
within 3 to 14 days after completion of therapy [12]. Although we were not able
to rule out the possibility of reinfection with a new strain, the fact that 96%
of corresponding isolates during 3-week period had the same serotype in this
study suggested that most of the treatment failure cases within 3 weeks were
caused by relapse. Age of 6 to 7 years for boys and short interval between
preceding and present episodes were associated with a significantly higher risk
of treatment failure including recurrence and bacteriologic treatment failure.
The frequency of episodes of recurrent GABHS pharyngitis had no effect on
treatment failure.In comparative GABHS
pharyngitis antibiotic trials, it is difficult to distinguish between a GABHS
carrier with an intercurrent viral infection and a patient with acute GABHS
pharyngitis. Penicillin is not so effective in eradication of GABHS in
carriers, whereas cephalosporins are effective [18]. The incidence of GABHS
carriers is approximately 5 to 20% [19]. In our study, GAS carriers, if any,
would have been equally distributed in the two treatment groups. Furthermore,
to reduce the risk of enrolling GABHS carriers with concurrent viral
pharyngitis, we excluded patients with symptoms such as rhinorrhea, cough, and
conjunctivitis.The results of a previous meta-analysis indicated that
5-day or 10-day administration cephalosporins were superior to 10-day
administration penicillin for treatment of GABHS pharyngitis although the
results are controversial [14–16]. There was no significant difference between treatment
failures at the follow-up visit in the cephalosporin treatment groups in our
study. However, subsequent GABHS pharyngitis within the follow-up period
occurred more frequently in the 5-day treatment group than in the 10-day
treatment group.


## 3.1. Results

The
characteristics of children with repeated GABHA pharyngitis are shown in Table1. The mean number of episodes of repeated GABHS pharyngitis including the
present episode was 2.79 (range: 2–12; SD: 1.35). Of the 226 patients, 182
(80.5%) patients had a history of at least 2 episodes of repeated GABHS
pharyngitis. The mean interval between preceding and present episodes was 10.48
months (range: 0.4–79 months; SD:
13.85). Of the 226 patients, 98 (43.3%) patients had preceding GABHS
pharyngitis within 3 months before the present GABHS pharyngitis. The mean
length of follow-up excluding recurrence cases (definition of recurrence case
given below) was 22.20 days (range: 14–35 days; SD: 2.98
days). Of the 226 patients, 218 (96.4%) patients were followed up for 14–28 days after the
initiation of therapy. The characteristics of children treated for 5 days and
10 days are shown in Table 1. The ratios of males to females were 1:0.67 in the
5-day treatment group and  1:0.62 in the 10-day treatment group. Mean ages were
6.70 years (range: 3–12 years; SD:
1.93 years) in the 5-day treatment group and 6.80 years (range: 2–14 years; SD:
2.10 years) in the 10-day treatment group. Mean numbers of episodes of repeated
GABHS pharyngitis were 2.75 (range: 2–12; SD: 1.54) in
the 5-day treatment group and 2.81 (range: 2–8; SD: 1.24) in
the 10-day treatment group. Mean intervals between preceding and present
episodes were 12.95 months (range: 0.5–79 months; SD:
17.30 months) in the 5-day treatment group and 9.20 months (range: 0.4–55 months; SD:
11.47 months) in the 10-day treatment group. Mean lengths of follow-up
excluding recurrence cases were 22.57 days (range: 14–32 days; SD: 3.03
days) in the 5-day treatment group and 22.02 days (range: 15–35 days; SD: 2.94
days) in the 10-day treatment group. There were no significant differences
between the two treatment groups in the distribution of age, gender, number of
episodes of repeated GABHS pharyngitis, interval between preceding and present
episodes, and length of follow-up.Table 1
Characteristics of children with repeated GABHA pharyngitis.
CharacteristicsTotal5-day treatment group10-day treatment groupP  valueNumber of cases22677149Male:Female138:8846:3192:57.775Age (years) (mean±SD)6.77±2.046.70±1.936.80±2.10.728Frequency of episodes (times) (mean±SD)2.79±1.352.75±1.542.81±1.24.768Interval between preceding and present episodes
(months) (mean±SD)10.48±13.812.95±17.309.20±11.47.089Length of follow-up (days) (mean±SD)22.20±2.9822.57±3.0322.02±2.94.203The
clinical and bacteriological results are shown in Table2. Recurrence (clinical
treatment failure) occurred in 7 (9.1%) of the 77 children in the 5-day
treatment group and in 1 (0.7%) of the 149 children in the 10-day treatment
group. The 5-day treatment group showed a significantly higher incidence of
recurrent GABHS pharyngitis than that in the 10-day treatment group (P=.003).
The eight patients with recurrent GABHS phayryngitis included 5 males and 3
females with a mean age of 6.36 years (range: 5–8 years; SD: 0.91
years). The mean interval from onset of the index infection to onset of
subsequent recurrent GABHS pharyngitis was 11.3 days after the initiation of
therapy (range: 6–22 days; SD: 4.94
days). The mean number of episodes of repeated GABHS pharyngitis was 2.88
(range: 2–6; SD: 1.36). The
mean interval between preceding and present episodes was 10.81 months (range:
0.5–24 months; SD:
8.268 months). There was no recognizable risk factor of recurrent GABHS
pharyngitis in the patients, probably due to the limited number of recurrent
cases. Bacteriologic treatment failure at the follow-up visit was observed in 7
(9.1%) of the 77 children in 5-day treatment group and in 17 (11.4%) of the 149
children in the 10-day treatment group. There was no significant difference
between the two treatment groups (P=.655). The treatment failure rates
were 18.2% in the 5-day group and 12.1% in the 10-day group. This difference
was also not statistically significant (P=.231). No poststreptococcal
sequelae were noted in this study.Table 2
Clinical and bacteriological results.
ResultsTotal5-day treatment group10-day treatment groupP  valueRecurrence (clinical treatment failure)8/2267/771/149.003Bacteriologic treatment failure
(noneradication)24/2267/7717/149.655Treatment failure32/22614/7718/149.231The
characteristics of children in the treatment success group (bacteriologic
treatment success with no recurrence) and treatment failure group (either
clinical or bacteriologic treatment failure) are shown in Table3. Ratios of
males to females were 1:0.73 in the treatment success group (194 children) and
1:0.23 in the treatment failure group (32 children). Treatment failure rates
were significantly affected by gender (P=.011). Mean ages were 6.86
years (range: 2–14 years; SD:
2.12 years) in the treatment success group and 6.24 years (range: 3–9 years; SD: 1.39
years) in the treatment failure group (P=.036). Treatment failure was
observed more frequently in the 86 children aged 6 to 7 years (in 22 of the 86
children, treatment failure rate of 25.6%) than in the 66 children aged 2 to 5
years (in 6 of the 66 children, treatment failure rate of 9.1%; P<.001)
and in the 74 children aged 8 to 14 years (in 4 of the 74 children, treatment
failure rate of 5.4%; P<.001). The mean number of episodes of
repeated GABHS pharyngitis in the treatment success group was 2.77 (range: 2–6; SD: 1.36) and
that in the treatment failure group was 2.91 (range: 2–12; SD: 1.26),
the difference between the groups not being statistically significant (P=.586).
The mean intervals between preceding and present episodes were 11.04 months
(range: 0.5–79 months; SD:
14.57 months) in the treatment success group and 7.05 months (range: 0.4–27 months; SD:
7.31 months) in the treatment failure group. Although the difference between
the intervals in the two groups was statistically significant (P=.019),
the interval responsible for treatment failure could not be statistically
determined.Table 3
Characteristics of children with treatment success and treatment failure.
CharacteristicsTreatment success groupTreatment failure groupP  valueNumber of cases19432Male:Female112:8226:6.011Age (years) (mean±SD)6.86±2.126.24±1.39.036Frequency of episodes (times) (mean±SD)2.77±1.362.91±1.26.586Interval between preceding and present
episodes (months) (mean±SD)11.04±14.577.05±7.31.018All
corresponding strains isolated from the 24 children with positive follow-up
cultures both at pre- and posttreatments had the same serotype. Six different T
types were identified, of which T12 was the most common serotype. In the 8
children with recurrence within the follow-up period, only 4 corresponding
strains isolated at pretreatment and at recurrence were available for
characterization by serotyping. GABHS with different serotype was identified in
one child in the 5-day treatment group but not in other children.


## 3.2. Discussion

Recurrence of GABHS pharyngitis frequently occurs in
children after treatment. Approximately 10 to 20% of children have recurrent
infection within 1 year of an index infection [5, 11, 17]. Possible explanations
for the recurrence are 1) reinfection: new infection with GABHS, and 2)
relapse: recurrence of originally persisted GABHS. Although serotyping of GABHS
isolates helps to make the distinction, it may be difficult to distinguish
between reinfection and relapse. Holm et al. reported that 10-day cephalosporin
treatment in children with recurrent GABHS pharyngitis resulted in
bacteriologic and clinical cure rates higher than those of 10-day penicillin
treatment [18].In this study, the recurrence
rate within 3 weeks after the initiation of therapy was significantly higher in
the 5-day treatment group than in the 10-day treatment group. However, the
difference between the two treatment groups in rate of bacteriologic treatment
failure at the follow-up visit was not statistically significant. All
corresponding strains isolated at pre- and posttreatments in the 24 patients
with bacteriologic treatment failure had the same serotype, indicating that the
treatment failure might be relapse. Only one of the corresponding isolates in 4
children with recurrence had different serotypes, indicating that the treatment
failure in this case was reinfection. Test-of-cure timing, follow-up visit in
this study, is important in the interpretation of treatment failure rate. It
has been suggested that the test-of-cure evaluation should optimally be done
within 3 to 14 days after completion of therapy [12]. Although we were not able
to rule out the possibility of reinfection with a new strain, the fact that 96%
of corresponding isolates during 3-week period had the same serotype in this
study suggested that most of the treatment failure cases within 3 weeks were
caused by relapse. Age of 6 to 7 years for boys and short interval between
preceding and present episodes were associated with a significantly higher risk
of treatment failure including recurrence and bacteriologic treatment failure.
The frequency of episodes of recurrent GABHS pharyngitis had no effect on
treatment failure.In comparative GABHS
pharyngitis antibiotic trials, it is difficult to distinguish between a GABHS
carrier with an intercurrent viral infection and a patient with acute GABHS
pharyngitis. Penicillin is not so effective in eradication of GABHS in
carriers, whereas cephalosporins are effective [18]. The incidence of GABHS
carriers is approximately 5 to 20% [19]. In our study, GAS carriers, if any,
would have been equally distributed in the two treatment groups. Furthermore,
to reduce the risk of enrolling GABHS carriers with concurrent viral
pharyngitis, we excluded patients with symptoms such as rhinorrhea, cough, and
conjunctivitis.The results of a previous meta-analysis indicated that
5-day or 10-day administration cephalosporins were superior to 10-day
administration penicillin for treatment of GABHS pharyngitis although the
results are controversial [14–16]. There was no significant difference between treatment
failures at the follow-up visit in the cephalosporin treatment groups in our
study. However, subsequent GABHS pharyngitis within the follow-up period
occurred more frequently in the 5-day treatment group than in the 10-day
treatment group.


## 4. Conclusion

A 5-day course of oral cephalosporins is not always
recommended for treatment of recurrent GABHS pharyngitis in children,
especially for 6- to 7-year-old boys and for children with a short interval
between preceding and present episodes. Sincethis study has a limitation because of its
nonrandomized design, further studies are necessary to determine how best to reduce
treatment failure for recurrent GABHS pharyngitis in children.



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*Source: 863608-2009-03-05.xml*