J Infect Chemother (2013) 19:1219

DOI 10.1007/s10156-012-0444-1

ORIGINAL ARTICLE

Comparison of clinical efficacy between 3-day combined

clavulanate/amoxicillin preparation treatment and 10-day
amoxicillin treatment in children with pharyngolaryngitis
or tonsillitis
Haruo Kuroki Naruhiko Ishiwada
Nobue Inoue Nobuyasu Ishikawa
Hiroshi Suzuki Kyoko Himi Tomomichi Kurosaki
Received: 25 April 2012 / Accepted: 27 May 2012 / Published online: 4 July 2012
 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2012

Abstract The efficacy of 3-day treatment with a combined clavulanate/amoxicillin preparation (Clavamox combination dry syrup for pediatric cases) and 10-day
treatment with amoxicillin against pediatric pharyngolaryngitis and tonsillitis caused by Group A b-hemolytic
Streptococcus was compared. Among the patients included
in the efficacy evaluation (54 from the clavulanate/amoxicillin group and 43 from the amoxicillin group), the
clinical response rate on completion of treatment was
98.1 % in the clavulanate/amoxicillin group and 92.9 % in
the amoxicillin group, thus supporting the equivalent efficacy of these two therapies. The Group A b-hemolytic
Streptococcus eradication rate at approximately 12 weeks
after completion/discontinuation of treatment was 65.4 %
in the clavulanate/amoxicillin group and 85.4 % in the

amoxicillin group. Even in cases from which the pathogen

continued to be isolated, relapse/recurrence of clinical
symptoms was seldom seen. Urinalysis, conducted to
assess the presence or absence of acute glomerulonephritis,
revealed no abnormality in any patient. These results
suggest that 3-day treatment with this clavulanate/amoxicillin preparation is expected to provide a valid means of
treating pediatric pharyngolaryngitis and tonsillitis caused
by Group A b-hemolytic Streptococcus.
Keywords Amoxicillin
Clavulanate/amoxicillin

Clinical efficacy
Group A b-hemolytic Streptococcus

Short-term therapy

Introduction
H. Kuroki (&)
Sotobo Childrens Clinic, 1880-4 Izumi Misaki-machi,
Isumi, Chiba, Japan
e-mail: kuroki-haruo@krc.biglobe.ne.jp
N. Ishiwada
Division of Control and Treatment of Infectious Diseases,
Chiba University, Chiba, Japan
N. Inoue
Yamanouchi Hospital, Mobara, Japan
N. Ishikawa
Chiba Aoba Municipal Hospital, Chiba, Japan
H. Suzuki
Chiba Rosai Hospital, Chiba, Japan
K. Himi
Sanmu Medical Center, Sanbu, Japan
T. Kurosaki
Kurosaki Childrens Clinic, Chiba, Japan

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Group A b-hemolytic Streptococcus (Group A Streptococcus) is a major pathogen for pediatric pharyngolaryngitis and
tonsillitis. Penicillin is a first-line treatment for these conditions [1], and when used, it is recommended to continue
penicillin treatment for 10 days to prevent rheumatic fever,
which can develop after Group A Streptococcus infection.
However, treatment for such a long period involves risks,
including high stress on both the patient and his/her guardians, and possible reduction in compliance with dosing
instructions. A basic rule of antimicrobial drug treatment is
short-term treatment at sufficiently high dose levels. Shortterm treatment with penicillin for Group A Streptococcus
infection is expected to augment bactericidal activity and to
improve compliance with dosing instructions. We should
positively consider this alternative approach to treatment,
and it is desirable to clinically evaluate its feasibility.
Clavamox combination dry syrup for pediatric is a combined clavulanate/amoxicillin preparation (hereafter, CVA/

J Infect Chemother (2013) 19:1219

AMPC) clinically available in Japan as the only penicillinbased preparation enabling high-dose amoxicillin (AMPC)
treatment with a standard dosing method. Beginning in
November 2009, a multicenter study involving seven medical facilities in Chiba Prefecture was carried out to evaluate
the non-inferiority of 3-day treatment with CVA/AMPC
compared to 10-day treatment with AMPC (30 mg/kg/day)
recommended in the Japanese guidelines. We previously
reported the interim results of the study on the basis of the
data collected by November 2010 [2]. This article presents
the final results of this study and also includes data on
additional cases and the results of bacteriological evaluation.

Patients and methods

Patients
The study included children with pharyngolaryngitis or
tonsillitis, aged less than 15 years, who tested positive on
the instantaneous Group A Streptococcus infection diagnosis kit between November 2009 and May 2011.
Study design
The study was designed as an active drug-controlled, openlabel, multicenter study. Patients who tested positive on the
instantaneous Group A Streptococcus infection diagnosis
kit during the first study visit, and who (or whose guardian)
gave informed consent to participate in the study, were
enrolled. Case registration was carried out as central registration at the Data Center (ARO Office, Department of
Clinical Studies, Chiba University Hospital). The subjects
were divided into the following two groups by simple
randomization. Samples were not stratified:

CVA/AMPC group: 3-day treatment with a combined

CVA/AMPC preparation (Clavamox combination dry
syrup for pediatric) at a dose level of 96.4 mg/kg/day
(CVA 6.4 mg/kg/day, AMPC 90 mg/kg/day) in two divided
doses
AMPC group: 10-day treatment with AMPC (e.g.,
Widecillin, Sawacillin) at a dose level of 30 mg/kg/day
in three divided doses

Each patient was followed for approximately 12 weeks

after completion or discontinuation of treatment. Observation of symptoms and bacteriological tests were conducted, and urinalysis was carried out to check for
complications (i.e., acute glomerulonephritis). All patients
and their guardians provided written informed consent or
assent to participate in the study. The study was approved
by the Institutional Review Board of Chiba University
School of Medicine.

13

Investigation/test/evaluation
The study included investigation of background variables
[gender, age, diagnosis, hospitalization status (inpatient/
outpatient), pretreatment severity, time of onset, presence/
absence of underlying disease, name of underlying disease,
and noteworthy physical/allergic disposition], investigation
of the treatment provided (concomitant drugs, concomitant
therapies, and use of intestinal medicines), investigation of
clinical course (body weight), bacteriological testing, urinalysis (to check for acute glomerulonephritis), laboratory
testing, efficacy evaluation, investigation of adverse events,
investigation of diarrhea status, and evaluation of compliance with dosing instructions.
Body temperature, diarrhea status, and compliance with
dosing instructions were investigated by using the patient
diary.
During the first visit and a follow-up visit, a sample (i.e.,
throat swab) was collected for bacteriological testing,
including isolation, identification, and quantification of
Group A Streptococcus and other bacteria (Streptococcus
pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Neisseria spp., a-hemolytic Streptococcus). The minimum inhibitory concentration (MIC) of each antimicrobial
drug (eight drugs) against each isolated strain was measured
using the Clinical and Laboratory Standards Institute
(CLSI) microdilution method [3]. We did not examine
carriers of the organisms in siblings and families of patients.
Clinical efficacy
Clinical efficacy was the primary endpoint of this study.
Disease severity was rated on a three-category scale (mild,
moderate, or severe) using the Criteria for Judgment in
Clinical Studies of Antimicrobial Drugs in the Field of
Pediatrics [4].
Clinical efficacy was rated on a four-category scale
(markedly effective, effective, slightly effective, or ineffective) using the Criteria for Judgment in Clinical Studies
of Antimicrobial Drugs in the Field of Pediatrics [4].
Safety
The onset of any adverse event (i.e., disease, symptom, laboratory abnormality) during test drug treatment was entered
into the survey form, and the severity and association with the
drug were evaluated. The status of diarrhea was evaluated
using the diary that was kept by the guardian for each child.
Statistical analysis
The difference in incidence between the two groups was
statistically tested using the chi-square test.

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J Infect Chemother (2013) 19:1219

Results
Background variables
A total of 119 patients were randomly assigned to CVA/
AMPC group or AMPC group.Of these, 10 patients in the
Table 1 Background variables

Variable

Total

CVA/AMPC group and 12 patients in the AMPC group

were excluded because of lack of follow-up.
Data on background variables for the patients included
in the evaluation (54 cases from the CVA/AMPC group
and 43 cases from the AMPC group) are given in Table 1.
The age of the patients ranged from 2 to 13 years (mean,

Combined clavulanate/
amoxicillin preparation
(CVA/AMPC) group
Number of cases (%)
54 (100)

AMPC group

Number of cases (%)

43 (100)

Gender
Male

25 (46.3)

22 (51.2)

Female

29 (53.7)

21 (48.8)

13

10 (18.5)

8 (18.6)

46
C7

28 (51.9)
16 (29.6)

23 (53.5)
12 (27.9)

Range/mean

213/5.6

19/5.3

Age (years)

Hospitalization status
Inpatient

0 (0)

0 (0)

Outpatient

54 (100)

43 (100)

Pharyngitis

45 (83.3)

37 (86.0)

Laryngitis

4 (7.4)

1 (2.3)

Tonsillitis

4 (7.4)

3 (7.0)

Unknown

Diagnosis

Time of symptom onset (days before consultation)

03

48 (88.9)

36 (83.7)

47

5 (9.3)

5 (11.6)

C8

1 (1.8)

2 (4.7)

Mild
Moderate

53 (98.1)
1 (1.9)

42 (97.7)
1 (2.3)

Severe

0 (0)

0 (0)

Pretreatment severity

Underlying disease
Absent

36 (66.7)

30 (69.8)

Present

18 (33.3)

13 (30.2)

Noteworthy physical/allergic predisposition

Absent

54 (100)

41 (95.3)

Present

0 (0)

2 (4.7)

Concomitant drug
Absent

4 (7.4)

3 (7.0)

Present

50 (92.6)

40 (93.0)

Concomitant use of intestinal medicine

There was no intergroup

difference in any background
variable

123

Absent

10 (18.5)

14 (32.6)

Present

44 (81.5)

29 (67.4)

51 (94.4)

40 (93.0)

3 (5.6)

3 (7.0)

Concomitant therapy
Absent
Present

J Infect Chemother (2013) 19:1219

15

5.6 years) in the 3-day CVA/AMPC treatment group and

from 1 to 9 years (mean, 5.3 years) in the 10-day AMPC
treatment group. All subjects were outpatients. In both
groups, the diagnosis was pharyngitis in more than 80 % of
all patients, and pretreatment severity was mild in most
cases. The percentage of patients having at least one
underlying disease was 33.3 % (18 cases) in the CVA/
AMPC group (including 10 cases of bronchial asthma and
9 cases of allergic rhinitis) and 30.2 % (18 cases) in the
AMPC group (including bronchial asthma in 9 cases,
allergic rhinitis in 6 cases, and food allergy in 2 cases). The
percentage of patients using at least 1 concomitant drug
was 92.6 % in the CVA/AMPC group and 93.0 % in the
AMPC group, and the percentage of patients using at least
one concomitant intestinal drug was 81.5 % in the CVA/
AMPC group and 67.4 % in the AMPC group. In regard to
drug compliance, more than 80 % of patients took medicine in the prescribed days in both groups.

Table 2 Clinical efficacy

Judgment

AMPC
group

Total

CVA/
AMPC
group
Number of
cases (%)
54

Markedly effective

50 (92.6)

37 (88.1)

3 (5.6)

2 (4.8)

Effective

Chisquare
test

Number of
cases (%)
42

Slightly effective

1 (1.94)

2 (4.8)

Ineffective

0 (0)

1 (2.4)

Efficacy (on treatment completion/discontinuation)

The data on clinical efficacy for the patients included in
efficacy evaluation (54 cases from the CVA/AMPC group
and 42 cases from the AMPC group) are given in Table 2.
In the CVA/AMPC group (n = 54), the drug was rated as
markedly effective in 50 cases and effective in 3 cases,
with the clinical efficacy rate (percentage of markedly
effective cases) being 92.6 % and the clinical response
rate (percentage of effective cases ? markedly effective cases) being 98.1 %. In the AMPC group (n = 42),
the drug was rated as markedly effective in 37 cases and
effective in 2 cases, with the clinical efficacy rate being
88.1 % and the clinical response rate being 92.9 %. There
was no significant difference between the two groups in
terms of the clinical efficacy or response rates (chi-square
test).
The time-course of body temperature from the pre- to
posttreatment period is graphically represented in Fig. 1. In
both groups, body temperature in most patients had
decreased to less than 37.5 C by the time of treatment
completion/discontinuation. During the visit made 12
weeks after treatment completion, fever ([37.5 C) was
noted in one patient from the CVA/AMPC group and two
patients from the AMPC group. There was no relationship
between time of onset and clinical efficacy.
Bacteriological efficacy (after treatment completion)

Markedly effective

50 (92.6)

37 (88.1)

NS

Markedly
effective ? effective

53 (98.1)

39 (92.9)

NS

There was no intergroup difference in the percentage of markedly

effective cases or the percentage of effective cases

Data on bacteriological efficacy for the patients included in

the evaluation (52 cases from the CVA/AMPC group and
41 cases from the AMPC group) are given in Table 3. The
Group A Streptococcus eradication rate was significantly
higher in the AMPC group (85.4 %, 35/41) than in the
CVA/AMPC group (65.4 %, 34/52) (p \ 0.05, chi-square
test).
Number of cases

Time

Total Number of cases

0

CVA/AMPC Group

AMPC Group

Pre-treatment

54

Upon completion/discontinuation

54

After end of treatment

34

Pre-treatment

42

Upon completion/discontinuation

41

After end of treatment

24

Fig. 1 Time-course of body temperature. In most patients from the

CVA/AMPC group and the AMPC group, body temperature
decreased to less than 37.5 C by completion/discontinuation of

10

15

20

25

30

21

35

40

45

17

1
1

33
8
40
22

55

53

19

50

11

4
1

1 11

<37.5
37.5 to <38
38 to <39
39

treatment. During the visit at 12 weeks after the end of treatment,

fever ([37.5 C) was noted in only 1 patient from the CVA/AMPC
group and 2 patients from the AMPC group

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J Infect Chemother (2013) 19:1219

Table 3 Bacteriological efficacy (Group A hemolytic Streptococcus)

Judgment

Total

CVA/AMPC
group
Number of
cases (%)
52

AMPC group

Chi-square
test

Adverse reactions

Number of
cases (%)
41

Eradicated

34 (65.4)

35 (85.4)

Detected

18 (34.6)

6 (14.6)

p \ 0.05

The Group A hemolytic Streptococcus eradication rate following

treatment was significantly higher in the AMPC group than in the
CVA/AMPC group

Table 4 Bacteriological test (oral indigenous flora)

Judgment

CVA/AMPC
group
Number of
cases (%)

AMPC group

Chi-square
test

Number of
cases (%)

Streptococcus pneumoniae
Eradicated

50 (96.2)

35 (85.4)

Detected

2 (3.8)

6 (14.6)

p = 0.065

Haemophilus influenzae
Eradicated

40 (76.9)

30 (73.2)

Detected

12 (23.1)

11 (26. 8)

p [ 0.1

Moraxella catarrhalis
Eradicated

51 (98.1)

39 (95.1)

Detected

1 (1.9)

2 (4.8)

p [ 0.1

Eradicated

21 (40.4)

9 (22.0)

Detected

31 (59.6)

32 (78.0)

p = 0.059

a-Hemolytic Streptococcus
13 (25.0)
39 (75.0)

13 (31.7)
28 (68.3)

p [ 0.1

The posttreatment eradication rate for Streptococcus pneumoniae and

Neisseria tended to be higher in the CVA/AMPC group than in the
AMPC group, although none of these differences was significant.
There was no intergroup difference in the eradication rate for Haemophilus influenzae, Moraxella catarrhalis, or a-hemolytic Streptococcus

The eradication rate for S. pneumoniae and for Neisseria

tended to be higher in the CVA/AMPC group than in the
AMPC group, although none of these differences were
statistically significant. There was no difference between
the two groups in terms of the eradication rate for H. influenzae, M. catarrhalis, or a-hemolytic Streptococcus
(Table 4).
Urinalysis
Urinalysis was carried out for 52 patients from the CVA/
AMPC group and 42 patients from the AMPC group about
12 weeks after treatment completion or discontinuation.

123

The status of diarrhea, known as the most frequent adverse

reaction to penicillin, was evaluated by using the patient
diary. The patient diary could be obtained from 47 patients
in the CVA/AMPC group and 39 patients in the AMPC
group. Of these patients, 22 patients (46.8 %) from the
CVA/AMPC group and 5 patients (12.8 %) from the
AMPC group developed diarrhea during the treatment
period. The incidence of diarrhea was significantly higher
in the CVA/AMPC group than in the AMPC group (p \
0.01, chi-square test). In both groups, diarrhea developed
about once or twice in many patients. In all patients followed up after the onset of diarrhea, diarrhea resolved
during continued treatment or after the completion of
treatment.
Urticaria and eruption (one case each) were noted in the
CVA/AMPC group, and upper airway inflammation (one
case) was seen in the AMPC group. None of these adverse
reactions was severe. Discontinuation of test drug treatment because of an adverse reaction occurred in one patient
(urticaria) from the CVA/AMPC group and one patient
(diarrhea) from the AMPC group.
Drug susceptibility

Neisseria

Eradicated
Detected

There was no sign of abnormality or of acute glomerulonephritis in any patient.

The data on susceptibility of the 111 strains of Group A

Streptococcus (isolated before and after the start of treatment) to each antimicrobial drug are given in Table 5. The
MIC of both CVA/AMPC and AMPC against each strain of
the bacterium was B0.06 lg/ml, indicating that all strains
were susceptible to both drugs. The susceptibility of
S. pneumoniae and H. influenzae did not differ markedly
between CVA/AMPC and AMPC. The susceptibility of
M. catarrhalis was high to CVA/AMPC but it was low to
AMPC.

Discussion
Ten-day treatment with penicillin is now a standard therapy
for pharyngitis and tonsillitis caused by Group A Streptococcus. This therapy is recommended in the guidelines
prepared by the Infectious Diseases Society of America
(IDSA) [5], and it is also referred to in the Japanese
Guidelines on Management of Pediatric Respiratory
Diseases 2007 (hereafter the Japanese guidelines) [1].
However, the basic view on treatment of these diseases
differs between the United States (USA) and Japan. In the
USA, emphasis tends to be on cost rather than the stress

J Infect Chemother (2013) 19:1219

17

Table 5 Drug susceptibility

Minimum inhibitory concentration (MIC) (lg/ml)
B0.06

0.12

0.25

0.5

16

MIC range

MIC50

MIC90

B0.06

B0.06

B0.06

16

Group A hemolytic Streptococcus (111 strains)

AMPC/CVA
(14:1)

111

AMPC

111

B0.06

B0.06

B0.06

CFPN

111a

B0.12

B0.12

B0.12

CDTR

111a

B0.12

B0.12

B0.12

B0.06 to
0.12

B0.06

B0.06

B0.06 to\16

B0.06 to \8

B0.06 to 2

0.12

0.12

TBPM

110

CAM

35

AZM

19

17

TFLX

21

80

4
1

63

62

5
7b

MIC (lg/ml)
B0.06

MIC range

MIC50

MIC90

0.12

0.25

0.5

16

AMPC/CVA (14:1)

12

11

4b

0.12 to [8

AMPC

12

11

13b

0 12 to [8

[8

CFPN

28a

13

2b

B0.12 to [8

B0.12

12

0.2516

B0.06

B0.06

B0.06

Haemophilus influenzae (56 strains)

CAM
TFLX

40

56
MIC (lg/ml)
B0.06

0.12

0.25

0.5

16

MIC range

MIC50

MIC90

[16

Streptococcus pneumoniae (19 strains)

AMPC/CVA(14:1)

B0.06 to 2

0.25

AMPC

B0.06 to 2

0.25

CFPN

CAM

TFLX

18

11

MIC (lg/ml)
\0.06

B0.12 to 1

0.5

B0.06 to [16

B0.06

0.12

0.12

MIC range

0.12

0.25

0.5

16

1b

MIC50

MIC90

Moraxella catarrhalis (5 strains)

AMPC/CVA (14:1)

B0.06 to 0.25

AMPC
CFPN
CAM

TFLX

1a
4

2 to [8
B0.12 to 0.5
B0.06 to 0.12
B0.06

Data on susceptibility of bacteria (isolated before and after treatment) to each drug are presented. The MIC of both CVA/AMPC and AMPC was
B0.06 lg/ml for all 111 strains of Group A hemolytic Streptococcus. Thus, all strains of this bacterium were susceptible to both drugs. There was
little difference between the two drugs in the susceptibility of Haemophilus influenzae and Streptococcus pneumoniae. Susceptibility of
Moraxella catarrhalis to CVA/AMPC was high and that to AMPC was low
a

B0.12

[8

caused to the patient receiving the medication, and less

priority is attached to short-term therapy, which tends to
require higher cost. On the other hand, for the treatment of

pharyngotonsillitis, the American Academy of Pediatrics

recommends a single intramuscular injection of penicillin
G as the shortest treatment method [6]. In Japan, a greater

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concern is placed on the stress caused to the patient by the

medication.
Studies on short-term therapy for this type of disease
have been carried out, primarily on the cefem family of
drugs. Clinical studies on 5-day treatment with cefcapene
pivoxil (CFPN-PI) and cefditoren pivoxil (CDTR-PI)
demonstrated that the efficacy of 5-day treatment with
these drugs did not differ from that of 10-day AMPC
treatment [7, 8]. However, such evaluation has not been
widely accepted. The Japanese guidelines still recommend
penicillin as a first-line treatment for pharyngitis and tonsillitis caused by Group A Streptococcus. If the usefulness
of short-term penicillin treatment can be sufficiently
endorsed, this therapy may be widely accepted as a less
stressful method of treatment for patients with such a
disease.
In the present study, a combined CVA/AMPC preparation was selected as the test drug for short-term treatment.
In Japan, the combined CVA/AMPC (1:14) preparation is
the only AMPC-based preparation enabling high-dose
treatment with the conventional dosing method. With this
preparation, AMPC can be administered at a dose level of
90 mg/kg/day using the conventional dosing method. As
this preparation contains a b-lactamase inhibitor, its efficacy does not attenuate even in cases where b-lactamaseproducing bacteria (e.g., M. catarrhalis, Staphylococcus
aureus, and anaerobes) coexist as indigenous flora or
pathogenic organisms in the upper airway.
In the present study, the efficacy of treatment did not
differ significantly between the CVA/AMPC group (clinical efficacy rate, 92.6 %; clinical response rate, 98.1 %)
and the AMPC group (clinical efficacy rate, 88.1 %; clinical response rate, 92.9 %). In the CVA/AMPC group, only
one patient developed fever ([37.5 C) during the followup period, and urinalysis revealed no abnormality in any
patient. These results suggest that 3-day treatment with
CVA/AMPC can provide clinical efficacy comparable to
10-day treatment with AMPC.
In a specific postmarketing survey on the CVA/AMPC
preparation in children with respiratory infection [9], the
response rate was high (97.1 % for pharyngitis, 96.6 % for
laryngitis, and 97.0 % for tonsillitis), and the response rate
was 100 % for patients from whom Group A hemolytic
Streptococcus (Streptococcus pyogenes) had been isolated.
The MIC against Streptococcus pyogenes (30 clinically
isolated strains), which were evaluated at the same time,
was B0.06 lg/ml for all strains, suggesting sufficient
clinical efficacy.
In the present study, the treatment period for the CVA/
AMPC group was 3 days, making the total amount of
AMPC administered to the CVA/AMPC group approximately equal to that administered to the AMPC group,
because the daily AMPC dose level in the CVA/AMPC

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J Infect Chemother (2013) 19:1219

group was three times as high as in the AMPC group. This

treatment period for the CVA/AMPC group is shorter than
the treatment period for any other b-lactam drug administered orally in past studies. The total number of doses
during the 3-day CVA/AMPC treatment was 6, which was
one-fifth the total number of doses (30 doses) during the
10-day AMPC treatment; this suggests that short-term
therapy is a valuable means of reducing the stress on
patients receiving medication. On the other hand, in Japan
the medicine expense for 10-day AMPC treatment can be
managed with about 2550 % compared with that of 3-day
treatment with CVA/AMPC.
In posttreatment bacteriological testing, the percentage
of Group A Streptococcus-negative cases was significantly
lower in the CVA/AMPC group (65.4 %, 34/52) than in the
AMPC group (85.4 %, 35/41). According to recent clinical
reports on efficacy against hemolytic streptococcal infection [1, 2], the pathogen eradication rate was 91.7100 %
after 10-day AMPC treatment. Thus, the eradication rate in
both groups of the present study was lower than previously
reported rates.
Factors possibly responsible for positive hemolytic
Streptococcus bacteriological tests include failure in eradication and redetection after eradication. Group A hemolytic streptococcal infection is an epidemic disease. During
disease prevalence, the disease can spread among schools,
and redetection among groups can take place after eradication of the pathogen [10]. In analysis of the relationship
between the number of reports from sentinel clinics and
hospitals (results of the sentinel survey on Group A hemolytic Streptococcus-induced pharyngitis in Chiba Prefecture in 2010 [11]) and the pathogen eradication rate in the
present study, we noted a tendency for pathogen eradication to become lower as the number of reported cases
increased; the eradication rate was 85 % during weeks
2945, when the number of reported cases from sentinels
was less than 1.5, whereas the eradication rate was 73 %
during weeks 128, when the number of reported cases was
more than 1.5.
The frequency of redetection seems to also be affected
by the length of time from the end of treatment to the
bacteriological test. In the present study, a high incidence
of redetection was probably associated with the longer
period until the bacteriological test was conducted (10.5
days in the CVA/AMPC group and 9.4 days in the AMPC
group), as compared to the period in many past studies.
However, because only a very small number of patients in
both groups had fever when undergoing repeat pharyngeal
sample culture, redetection seldom caused a clinical issue.
CVA/AMPC treatment has strong activity not only on
the pathogen but also on the indigenous oral flora, because
the daily AMPC dosage in the CVA/AMPC treatment
group was three times as high as that in the AMPC group

J Infect Chemother (2013) 19:1219

and because CVA/AMPC treatment exerts antibacterial

activity on b-lactamase-producing bacteria. Some investigators reported that the change in oral indigenous flora was
greater following CVA/AMPC treatment than following
treatment with cefdinir (one of the cefem antimicrobial
agents), and that the recolonization rate of pathogenic
bacteria, which can induce infection, was significantly
higher following CVA/AMPC treatment [12]. In the present study, there was no significant difference between the
CVA/AMPC group and the AMPC group in terms of the
eradication rate for S. pneumoniae, H. influenzae, M. catarrhalis, Neisseria spp., or a-hemolytic Streptococcus.
Diarrhea is a problematic adverse reaction to penicillin,
and its frequency tends to increase with increasing dose. In
the present study, the incidence of diarrhea was significantly higher in the CVA/AMPC group (46.8 %, 22/47)
than in the AMPC group (12.8 %, 5/39). However, no
patient in the CVA/AMPC group discontinued treatment
because of an adverse reaction, and diarrhea did not affect
CVA/AMPC treatment. Because the CVA/AMPC preparation contains a large amount of AMPC, the onset of
diarrhea is inevitable to some extent. However, it seems
highly probable that the onset of severe diarrhea, which can
affect treatment, can be avoided if appropriate prophylactic
measures (e.g., prior advice to patients and concomitant use
of intestinal medicine) are taken. As demonstrated in the
present study, diarrhea usually subsides rapidly after the
responsible drug is discontinued, so the risk for persistent
diarrhea seems to be low following 3-day treatment. When
contending with Group A Streptococcus infection, a 10-day
treatment has been recommended for the prevention of
rheumatic fever, which is serious complications of this
infection. In developed countries, the incidence of rheumatic fever has been decreasing sharply, and there has also
been an apparent decrease in the incidence of acute glomerulonephritis [13]. The importance of preventing severe
courses of pharyngolaryngitis and tonsillitis and of protecting the patient and his/her guardian from excessive
stress by means of treatment of the clinical symptoms of
these diseases by short-term treatment is apparent.
As described here, 3-day treatment with CVA/AMPC
(96.4 mg/day) is a promising alternative for treatment of
pharyngolaryngitis and tonsillitis caused by Group A
hemolytic Streptococcus.
Acknowledgments The authors are indebted to Dr. Noriko Tateno
and Dr. Hiroaki Ito (Sotobo Childrens Clinic) for providing valuable

19
clinical data. The lead author received financial aid from GlaxoSmithKline K.K.

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