J Infect Chemother (2013) 19:1219

DOI 10.1007/s10156-012-0444-1

ORIGINAL ARTICLE

Comparison of clinical efcacy 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 efcacy of 3-day treatment with a com-
bined clavulanate/amoxicillin preparation (Clavamox com-
bination dry syrup for pediatric cases) and 10-day
treatment with amoxicillin against pediatric pharyngolar-
yngitis and tonsillitis caused by Group A b-hemolytic
Streptococcus was compared. Among the patients included
in the efcacy evaluation (54 from the clavulanate/amox-
icillin 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 ef-
cacy 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
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
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/amoxi-
cillin 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 efcacy
Group A b-hemolytic Streptococcus

Short-term therapy
Introduction
Group A b-hemolytic Streptococcus (Group A Streptococ-
cus) is a major pathogen for pediatric pharyngolaryngitis and
tonsillitis. Penicillin is a rst-line treatment for these con-
ditions [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 guard-
ians, and possible reduction in compliance with dosing
instructions. A basic rule of antimicrobial drug treatment is
short-term treatment at sufciently high dose levels. Short-
term 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 com-
bined clavulanate/amoxicillin preparation (hereafter, CVA/

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AMPC) clinically available in Japan as the only penicillin-
based preparation enabling high-dose amoxicillin (AMPC)
treatment with a standard dosing method. Beginning in
November 2009, a multicenter study involving seven med-
ical 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 nal 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 diag-
nosis kit between November 2009 and May 2011.
Study design
The study was designed as an active drug-controlled, open-
label, multicenter study. Patients who tested positive on the
instantaneous Group A Streptococcus infection diagnosis
kit during the rst study visit, and who (or whose guardian)
gave informed consent to participate in the study, were
enrolled. Case registration was carried out as central reg-
istration at the Data Center (ARO Ofce, Department of
Clinical Studies, Chiba University Hospital). The subjects
were divided into the following two groups by simple
randomization. Samples were not stratied:
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. Obser-
vation of symptoms and bacteriological tests were con-
ducted, 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, uri-
nalysis (to check for acute glomerulonephritis), laboratory
testing, efcacy evaluation, investigation of adverse events,
investigation of diarrhea status, and evaluation of compli-
ance with dosing instructions.
Body temperature, diarrhea status, and compliance with
dosing instructions were investigated by using the patient
diary.
During the rst visit and a follow-up visit, a sample (i.e.,
throat swab) was collected for bacteriological testing,
including isolation, identication, and quantication of
Group A Streptococcus and other bacteria (Streptococcus
pneumoniae, Haemophilus inuenzae, Moraxella catarrh-
alis, Neisseria spp., a-hemolytic Streptococcus). The min-
imum 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 efcacy
Clinical efcacy 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 efcacy was rated on a four-category scale
(markedly effective, effective, slightly effective, or inef-
fective) 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, lab-
oratory 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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Results CVA/AMPC group and 12 patients in the AMPC group

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

Table 1 Background variables

Variable Combined clavulanate/ AMPC group
amoxicillin preparation
(CVA/AMPC) group
Number of cases (%) Number of cases (%)
Total 54 (100) 43 (100)

Gender
Male 25 (46.3) 22 (51.2)
Female 29 (53.7) 21 (48.8)
Age (years)
13 10 (18.5) 8 (18.6)
46 28 (51.9) 23 (53.5)
C7 16 (29.6) 12 (27.9)
Range/mean 213/5.6 19/5.3
Hospitalization status
Inpatient 0 (0) 0 (0)
Outpatient 54 (100) 43 (100)
Diagnosis
Pharyngitis 45 (83.3) 37 (86.0)
Laryngitis 4 (7.4) 1 (2.3)
Tonsillitis 4 (7.4) 3 (7.0)
Unknown 1 2
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)
Pretreatment severity
Mild 53 (98.1) 42 (97.7)
Moderate 1 (1.9) 1 (2.3)
Severe 0 (0) 0 (0)
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
Absent 10 (18.5) 14 (32.6)
Present 44 (81.5) 29 (67.4)
Concomitant therapy
There was no intergroup Absent 51 (94.4) 40 (93.0)
difference in any background Present 3 (5.6) 3 (7.0)
variable

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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 medi-
cine in the prescribed days in both groups.
Table 2 Clinical efcacy
Judgment CVA/ AMPC
AMPC group
group
Number of Number of
cases (%) cases (%)
Total 54 42
Efcacy (on treatment completion/discontinuation)
The data on clinical efcacy for the patients included in
efcacy 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 efcacy rate (percentage of markedly
effective cases) being 92.6 % and the clinical response
rate (percentage of effective cases ? markedly effec-
tive 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 efcacy rate being
88.1 % and the clinical response rate being 92.9 %. There
was no signicant difference between the two groups in
terms of the clinical efcacy 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
Chi-
completion/discontinuation. During the visit made 12
square weeks after treatment completion, fever ([37.5 C) was
test 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 efcacy.

Markedly effective 50 (92.6) 37 (88.1) Bacteriological efcacy (after treatment completion)

Effective 3 (5.6) 2 (4.8)
Slightly effective 1 (1.94) 2 (4.8) Data on bacteriological efcacy for the patients included in
Ineffective 0 (0) 1 (2.4) the evaluation (52 cases from the CVA/AMPC group and
Markedly effective 50 (92.6) 37 (88.1) NS 41 cases from the AMPC group) are given in Table 3. The
Markedly 53 (98.1) 39 (92.9) NS Group A Streptococcus eradication rate was signicantly
effective ? effective higher in the AMPC group (85.4 %, 35/41) than in the
There was no intergroup difference in the percentage of markedly CVA/AMPC group (65.4 %, 34/52) (p \ 0.05, chi-square
effective cases or the percentage of effective cases test).

Number of cases

Time Total Number of cases

0 5 10 15 20 25 30 35 40 45 50 55

Pre-treatment 54 21 9 17 7

CVA/AMPC Group Upon completion/discontinuation 54 53 1

After end of treatment 34 33 1

Pre-treatment 42 19 8 11 4 <37.5
37.5 to <38
AMPC Group Upon completion/discontinuation 41 40 1 38 to <39
After end of treatment 24 22 1 11 39

Fig. 1 Time-course of body temperature. In most patients from the treatment. During the visit at 12 weeks after the end of treatment,
CVA/AMPC group and the AMPC group, body temperature fever ([37.5 C) was noted in only 1 patient from the CVA/AMPC
decreased to less than 37.5 C by completion/discontinuation of group and 2 patients from the AMPC group

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Table 3 Bacteriological efcacy (Group A hemolytic Streptococcus) There was no sign of abnormality or of acute glomerulo-
Judgment CVA/AMPC AMPC group Chi-square
nephritis in any patient.
group test
Number of Number of Adverse reactions
cases (%) cases (%)

Total 52 41 The status of diarrhea, known as the most frequent adverse

Eradicated 34 (65.4) 35 (85.4) p \ 0.05 reaction to penicillin, was evaluated by using the patient
Detected 18 (34.6) 6 (14.6) diary. The patient diary could be obtained from 47 patients
in the CVA/AMPC group and 39 patients in the AMPC
The Group A hemolytic Streptococcus eradication rate following
group. Of these patients, 22 patients (46.8 %) from the
treatment was signicantly higher in the AMPC group than in the
CVA/AMPC group CVA/AMPC group and 5 patients (12.8 %) from the
AMPC group developed diarrhea during the treatment
period. The incidence of diarrhea was signicantly higher
Table 4 Bacteriological test (oral indigenous ora) in the CVA/AMPC group than in the AMPC group (p \
Judgment CVA/AMPC AMPC group Chi-square 0.01, chi-square test). In both groups, diarrhea developed
group test about once or twice in many patients. In all patients fol-
Number of Number of
cases (%) cases (%)
lowed up after the onset of diarrhea, diarrhea resolved
during continued treatment or after the completion of
Streptococcus pneumoniae treatment.
Eradicated 50 (96.2) 35 (85.4) p = 0.065 Urticaria and eruption (one case each) were noted in the
Detected 2 (3.8) 6 (14.6) CVA/AMPC group, and upper airway inammation (one
Haemophilus inuenzae case) was seen in the AMPC group. None of these adverse
Eradicated 40 (76.9) 30 (73.2) p [ 0.1 reactions was severe. Discontinuation of test drug treat-
Detected 12 (23.1) 11 (26. 8) ment because of an adverse reaction occurred in one patient
Moraxella catarrhalis (urticaria) from the CVA/AMPC group and one patient
Eradicated 51 (98.1) 39 (95.1) p [ 0.1 (diarrhea) from the AMPC group.
Detected 1 (1.9) 2 (4.8)
Neisseria Drug susceptibility
Eradicated 21 (40.4) 9 (22.0) p = 0.059
Detected 31 (59.6) 32 (78.0) The data on susceptibility of the 111 strains of Group A
a-Hemolytic Streptococcus Streptococcus (isolated before and after the start of treat-
Eradicated 13 (25.0) 13 (31.7) p [ 0.1 ment) to each antimicrobial drug are given in Table 5. The
Detected 39 (75.0) 28 (68.3) MIC of both CVA/AMPC and AMPC against each strain of
the bacterium was B0.06 lg/ml, indicating that all strains
The posttreatment eradication rate for Streptococcus pneumoniae and
Neisseria tended to be higher in the CVA/AMPC group than in the
were susceptible to both drugs. The susceptibility of
AMPC group, although none of these differences was signicant. S. pneumoniae and H. inuenzae did not differ markedly
There was no intergroup difference in the eradication rate for Hae- between CVA/AMPC and AMPC. The susceptibility of
mophilus inuenzae, Moraxella catarrhalis, or a-hemolytic Strep- M. catarrhalis was high to CVA/AMPC but it was low to
tococcus
AMPC.

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 signicant. There was no difference between
the two groups in terms of the eradication rate for H. in-
uenzae, 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.
Discussion
Ten-day treatment with penicillin is now a standard therapy
for pharyngitis and tonsillitis caused by Group A Strepto-
coccus. 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

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Table 5 Drug susceptibility

Minimum inhibitory concentration (MIC) (lg/ml) MIC range MIC50 MIC90
B0.06 0.12 0.25 0.5 1 2 4 8 16 16

Group A hemolytic Streptococcus (111 strains)

AMPC/CVA 111 B0.06 B0.06 B0.06
(14:1)
AMPC 111 B0.06 B0.06 B0.06
CFPN 111a B0.12 B0.12 B0.12
CDTR 111a B0.12 B0.12 B0.12
TBPM 110 1 B0.06 to B0.06 B0.06
0.12
CAM 35 1 2 4 1 63 5 B0.06 to\16 8 8
AZM 19 17 1 1 4 62 7b B0.06 to \8 8 8
TFLX 21 80 7 2 1 B0.06 to 2 0.12 0.12
MIC (lg/ml) MIC range MIC50 MIC90
B0.06 0.12 0.25 0.5 1 2 4 8 16

Haemophilus inuenzae (56 strains)

AMPC/CVA (14:1) 1 9 12 6 4 9 11 4b 0.12 to [8 1 8
AMPC 1 7 12 2 5 5 11 13b 0 12 to [8 4 [8
CFPN 28a 1 1 13 6 5 2b B0.12 to [8 B0.12 4
CAM 1 1 1 12 40 1 0.2516 8 8
TFLX 56 B0.06 B0.06 B0.06

MIC (lg/ml) MIC range MIC50 MIC90

B0.06 0.12 0.25 0.5 1 2 4 8 16 [16

Streptococcus pneumoniae (19 strains)

AMPC/CVA(14:1) 8 1 1 5 1 3 B0.06 to 2 0.25 2
AMPC 8 1 1 5 1 3 B0.06 to 2 0.25 2
CFPN 5 a
1 11 2 B0.12 to 1 0.5 1
CAM 3 1 4 2 1 1 7 B0.06 to [16 8 8
TFLX 1 18 B0.06 0.12 0.12

MIC (lg/ml) MIC range MIC50 MIC90

\0.06 0.12 0.25 0.5 1 2 4 8 16

Moraxella catarrhalis (5 strains)

AMPC/CVA (14:1) 1 3 1 B0.06 to 0.25
AMPC 1 2 1 1b 2 to [8
CFPN 1a 1 3 B0.12 to 0.5
CAM 1 4 B0.06 to 0.12
TFLX 5 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 inuenzae and Streptococcus pneumoniae. Susceptibility of
Moraxella catarrhalis to CVA/AMPC was high and that to AMPC was low
a
B0.12
b
[8

caused to the patient receiving the medication, and less pharyngotonsillitis, the American Academy of Pediatrics
priority is attached to short-term therapy, which tends to recommends a single intramuscular injection of penicillin
require higher cost. On the other hand, for the treatment of 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 efcacy 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 rst-line treatment for pharyngitis and ton-
sillitis caused by Group A Streptococcus. If the usefulness
of short-term penicillin treatment can be sufciently
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 prepara-
tion 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 ef-
cacy does not attenuate even in cases where b-lactamase-
producing bacteria (e.g., M. catarrhalis, Staphylococcus
aureus, and anaerobes) coexist as indigenous ora or
pathogenic organisms in the upper airway.
In the present study, the efcacy of treatment did not
differ signicantly between the CVA/AMPC group (clini-
cal efcacy rate, 92.6 %; clinical response rate, 98.1 %)
and the AMPC group (clinical efcacy rate, 88.1 %; clin-
ical response rate, 92.9 %). In the CVA/AMPC group, only
one patient developed fever ([37.5 C) during the follow-
up period, and urinalysis revealed no abnormality in any
patient. These results suggest that 3-day treatment with
CVA/AMPC can provide clinical efcacy comparable to
10-day treatment with AMPC.
In a specic 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 sufcient
clinical efcacy.
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 approxi-
mately 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 adminis-
tered orally in past studies. The total number of doses
during the 3-day CVA/AMPC treatment was 6, which was
one-fth 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 signicantly
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 efcacy against hemolytic streptococcal infec-
tion [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 erad-
ication and redetection after eradication. Group A hemo-
lytic streptococcal infection is an epidemic disease. During
disease prevalence, the disease can spread among schools,
and redetection among groups can take place after eradi-
cation 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 hemo-
lytic Streptococcus-induced pharyngitis in Chiba Prefec-
ture in 2010 [11]) and the pathogen eradication rate in the
present study, we noted a tendency for pathogen eradica-
tion 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 ora, 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 investi-
gators reported that the change in oral indigenous ora 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 signicantly
higher following CVA/AMPC treatment [12]. In the pres-
ent study, there was no signicant difference between the
CVA/AMPC group and the AMPC group in terms of the
eradication rate for S. pneumoniae, H. inuenzae, M. ca-
tarrhalis, 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 signi-
cantly 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 prepa-
ration 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 rheu-
matic fever has been decreasing sharply, and there has also
been an apparent decrease in the incidence of acute glo-
merulonephritis [13]. The importance of preventing severe
courses of pharyngolaryngitis and tonsillitis and of pro-
tecting 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 nancial aid from Glaxo-
SmithKline K.K.
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