Nakao et al. BMC Pediatrics(2019) 19:205
https://doi.org/10.1186/s12887-019-1582-8

RESEARCH ARTICLE

Open AccessAmoxicillin effect on bacterial load ingroup A streptococcal pharyngitis:
comparison of single and multiple daily
dosage regimens
Akihiro Nakao1* , Ken Hisata1, Makoto Fujimori2, Nobuaki Matsunaga1, Mitsutaka Komatsu1 and Toshiaki Shimizu1

Abstract
Background: Culture tests have demonstrated that once-daily administration of amoxicillin may be effective in thetreatment of group A streptococcal (GAS) pharyngitis. However, culture methods do not allow accurate
assessments of bacterial load changes because of the suppressive effect of the antibiotic on bacterial growth. In
this study, we used real-time PCR to compare the effectiveness of once-daily and multiple-daily amoxicillin
treatment for pediatric patients with GAS pharyngitis.
Methods: The subjects were children (≧3 years of age) diagnosed with GAS pharyngitis. Amoxicillin was administered
at a dose of 40–50 mg/kg/day, divided into one (QD), two (BID), or three (TID) daily doses, for 10 days. Throat swabs
were collected before treatment (visit 1), 1 to 3 days after treatment (visit 2), and 9 to 11 days after treatment (visit 3),
and GAS copies were quantified by real-time PCR. The main compared parameters were the rate of negative PCR
results and the number of GAS determined by PCR in throat swabs between each regimen.
Results: Samples were collected from 34 patients (QD, 12; BID, 15; TID, 7) at visit 1, 32 patients (QD, 11; BID, 14; TID, 7)
at visit 2, and 25 patients (QD, 7; BID, 11; TID, 7) at visit 3. The rates of negative PCR result for QD, BID, and TID regimens
were 18.2, 0, and 14.3% at visit 2, and 85.7, 72.7, and 85.7% at visit 3, respectively. The median values of bacterial loadfor QD, BID, and TID groups at visit 1 were 1.4 × 106, 8.2 × 105, and 5.4 × 105 copies/μL. At visit 2, they comprised 3.8 ×103, 1.1 × 103, and 2.8 × 103 copies/μL, respectively, whereas at visit 3, GAS copies were mostly undetectable. There wasno statistical difference in the negative results and median value of GAS copies between regimens at any stage.
Conclusions: Our results obtained by a molecular biology approach indicated that the QD regimen was as effective in
eradicating GAS infection as BID or TID.
Trial registration: UMIN000036083 / March 12, 2019.
Keywords: Group a streptococcus, Streptococcus pyogenes, Amoxicillin, Pharyngitis, Bacterial load, Quantification

Background
Group A beta-hemolytic Streptococcus (GAS) causes awide variety of clinical conditions: upper respiratory tract
infections, skin and soft tissue infections, and toxic-shock
syndrome, as well as non-pyogenic secondary diseases,
such as acute glomerulonephritis and rheumatic fever [1].
The purpose of antibiotic therapy of GAS infection is to* Correspondence: aknakao@juntendo.ac.jp
1
Department of Pediatrics, Faculty of Medicine, Juntendo University, 2-1-1
Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Full list of author information is available at the end of the article

reduce acute phase symptoms and prevent pyogenic complications and rheumatic fever [2]. For this reason, rapid
antigen and culture tests are recommended for children
over the age of three, who are suspected to have a GAS infection [3]. If the pathogen is detected by these tests, thenan appropriate antibiotic treatment is necessary: the administration of penicillin class drugs is recommended according to the guidelines [3]. Since this treatment was first
introduced in 1950s, it has been used by many clinicians,
and its widespread application has contributed greatly tothe prevention of rheumatic fever [4].

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Nakao et al. BMC Pediatrics(2019) 19:205

Penicillin class drugs are commonly administered several times a day. However, the regimen of once-daily
amoxicillin in GAS pharyngitis has been studied for over
20 years as the efficacy of such treatment has been shown
to be equivalent to that of the multiple-daily regimen [5–9]. In these studies, the use of the single dose regimen has
been advocated on the basis of the clinical course after thetreatment, culture test results, and adverse events. It is
certainly very important to evaluate these parameters toassess the therapeutic effects. However, culture after treatment does not accurately report the presence of pathogens
because the suppressive effect of antibiotics influences its
robustness. In this situation, false-negative results may beobtained. Homme et al. reported that PCR is more sensitive than culture methods in comparing positive rates after
antibiotic treatment for GAS pharyngitis [10]. Thus, weanalyzed the presence of pathogens and quantitativechanges in bacterial load using a molecular method tocompare the effectiveness of the antibiotic regimens. The
evaluation of antibiotic therapy needs a more microbiologically precise method, although it is possible that GAS
copies detected after the treatment are from bacteria
already damaged by antibiotics.
In this study, we compared the effects of once-daily
and multiple-daily administrations of oral amoxicillin on
bacterial load in throat swabs collected in GAS pharyngitis cases by using real-time PCR at three different
points. This is the first report evaluating bacterial loads
from GAS lesion areas by genetic methods.

Methods
Study design and patients

The study subjects were children aged older than 3
years, who visited pediatric department at two medical
institutions in Japan between October 2015 and September 2016 and were suspected of having acute pharyngeal
tonsillitis due to a GAS infection. Clinical diagnoses
were made on the basis of reference symptoms, such as
fever, sore throat, malaise, and headache with acute onset, whereas the physical findings that suggested the infection included prominent pharyngeal redness, tonsil
swelling with exudate, and cervical lymphadenopathy[11]. The study subjects underwent rapid antigen testingwith ImunoAce StrepA (Tauns, Shizuoka, Japan), using athroat swab and isolation culture tests, in which GAS
was detected. Patients with a history of penicillin allergies or those who received antibacterial drugs within theprevious 4 weeks were excluded from this study. For all
subjects, amoxicillin was administered at a dose of 40 to
50 mg/kg/day with an upper limit of 1000 mg/day, divided into one (QD), two (BID), or three (TID) daily
doses, for 10 days. Patient families determined daily
times of antibiotic dose administration according to theirlifestyle. No antimicrobial agent other than amoxicillin

Page 2 of 6

was given to patients enrolled in this study. The main
outcomes were the negative rate and a number of GAS
copies determined by PCR in throat swabs collected
after the start of treatment. Differences in these parameters were compared between QD, BID, and TID regimens. The clinical course after the treatment was
examined during outpatient visits at later dates. All subjects were educated as to the symptoms of relapse andcomplications. They were also instructed to come for reexamination if any of these symptoms were suspected.
Sampling and detection of GAS

Throat swab samples were collected using FLOQ double
swabs (Copan, Brescia, Italy) at three time points: duringvisit 1 (before the start of the treatment), visit 2 (1 to 3
days after the treatment), and visit 3 (9 to 11 days after
the treatment). One swab sample was seeded on blood
agar medium and cultured at 36 °C for 24–48 h to checkfor the development of colonies exhibiting β hemolysis.
Then, the latex agglutination test (Strept LA, DENKA
SEIKEN Co., Ltd., Tokyo, Japan) was used to identify
GAS. The other swab was cryopreserved at − 80 °C until
DNA extraction.
DNA extraction and quantitative PCR

Bacterial load was calculated from the solution of throatswab samples. After stored throat swab samples weretreated with achromopeptidase, DNA was extractedusing a QIAamp DNA Mini Kit (QIAGEN, Hilden
Germany). Real-time PCR was performed using primers,a probe targeting spe B, as described in a previous report[12], and a TaqMan Fast Advanced Master Mix (Thermo
Fisher Scientific, MA, USA). As positive control, DNA
of Streptococcus pyogenes ATCC BAA-572 was used.
Plasmid DNA, in which a detection region was introduced by the TA cloning method, was used as standard
DNA. Correct targeting of the detection region to plasmid DNA was confirmed by sequencing using an Applied Biosystems 3130 Genetic Analyzer (Thermo Fisher
Scientific, MA, USA). In order to prepare a calibration
curve, the number of DNA copies per μL of standard
DNA solution was calculated in advance. The detection
limit of quantitative real-time PCR was defined as 102
copies per μL, corresponding to a threshold cycle valueof 35 on the calibration curve.
Data analysis

Analyses were conducted using Prism 8.1.1 (GraphPad
Software, Inc., San Diego, CA, USA). Patient population
demographics, clinical symptoms and signs, and the rateof negative PCR results between treatment groups werecompared by the Student’s unpaired t-test and Fisher’s
exact test. The Mann-Whitney U-test was used to compare the median of bacterial load between QD and BID

Nakao et al. BMC Pediatrics(2019) 19:205

Page 3 of 6

or TID, respectively. All statistical analyses were conducted with a significance level of α = 0.05 (P < 0.05).
Ethical approval

This study was approved by the Ethics Committee of theTokyo Metropolitan Health Public Corporation Toshima
Hospital. For all patients, written informed consent wasprovided by a parent and/or legal proxy.

Results
Fifty-one patients were suspected to have GAS pharyngitis clinically and were positive in the rapid antigen test.
In 12 of these patients, GAS was not detected using theculture test, whereas 5 other patients did not agree toparticipate in this study. Of the remaining 34 subjects inthis study, 12, 15, and 7 took amoxicillin using QD, BID,
and TID regimens. All patients confirmed that they hadtaken antibiotics according to the respective regimens at
visit 3. The QD group was older and comprised significantly more boys than the BID group (Table 1).
Specimens from all 34 patients were collected duringvisit 1. During visit 2 and 3, additional samples were collected from 32 and 25 patients, respectively. The results of
PCR and culture test are shown in Table 2. At visit 2, 95%
confidence intervals (CIs) of the negative PCR result rateusing PCR were 3.2 to 47.7, 0 to 21.5, and 0.7 to 51.3 for
QD, BID, and TID, respectively. At visit 3, the corresponding CIs were 48.7 to 99.3, 43.4 to 90.3, and 48.7 to 99.3.
When the culture test was used, only one patient was
positive at visit 2 and visit 3. All patients exhibited symptomatic improvement after antimicrobial treatment, withno recurrence or complications such as rheumatic fever,including patients positive for GAS at visit 3.
The Fisher’s exact test was used to compare the negative rate between QD and BID or TID, respectively. P
values were 0.18 and 1.00 at visit 2 between QD and
BID and QD and TID, whereas at visit 3, P value wasboth of these comparisons was 1.00.
The median values of bacterial load for QD, BID, andTID groups at visit 1 were 1.4 × 106, 8.2 × 105, and 5.4 ×
105 copies/μL and at visit 2 were 3.8 × 103, 1.1 × 103, and2.8 × 103 copies/μL, respectively, whereas at visit 3, GAS
copies were mostly undetectable (Table 3). The differences in the median values between QD and BID regimens, and between QD and TID were not statisticallysignificant at any stage of the experiment. The 95% CI
values for the median of GAS copies at visit 1 were
within a narrow range for all regimens. At visit 2, theinterquartile range values were also relatively close forall groups, but 95% CI values had a very wide range, andthe same tendency was observed at visit 3. GAS copies
in the two patients that were culture positive after treatment were 6.9 × 104 (TID group, visit 2) and 7.1 × 104
copies/μL (BID group, visit 3), respectively.
The Mann-Whitney U-test was used to compare
the median of bacterial load between QD and BID
or TID, respectively.

Discussion
In order to assess the effectiveness of the antimicrobial
therapy, it is very important to confirm the result of theculture test after the treatment. However, it is difficult toTable 1 Characteristics of patients included in the studyQDn = 12 (%)

BID
n = 15 (%)

P-valueTID
n = 7 (%)

P-value

Age, yearsa

7.3 ± 3.1

5.0 ± 1.4

0.02

7.7 ± 1.3

0.71

Male sex

12 (100)

10 (66.7)

0.047

6 (85.7)

0.37

12 (100)

14 (93.3)

1.00

7 (100)1.00

Symptoms
Feverb
Absence of cough9 (75.0)

13 (86.6)

0.63

4 (57.1)

0.62

Sore throat

7 (58.3)

9 (60.0)

1.00

6 (85.7)

0.33

Headache

6 (50.0)

5 (33.3)

0.45

3 (42.9)

1.00

Abdominal pain

0 (0)4 (26.7)

0.11

2 (28.6)

0.12

Nausea1 (8.3)3 (20.0)

0.61

1 (14.3)

1.00

Signs
Lymphadenopathy

9 (75.0)

12 (80.0)

1.00

6 (85.7)

1.00

Tonsillar swelling

8 (66.7)

13 (86.7)

0.36

4 (57.1)

1.00

Skin rash

2 (16.7)

3 (20.0)

1.00

0 (0)

0.51

Abbreviations: QD quaque die, BID bis in die, TID ter in die
The unpaired Student’s t-test was used to compare age, and the Fisher’s exact test was used to evaluate possible differences in the distribution of sex, symptoms,
and clinical signs between QD and BID or TID, respectivelya
Age is presented as the mean ± standard deviationb
Fever was defined as a temperature above 38 °C by axillary measurement

Nakao et al. BMC Pediatrics(2019) 19:205

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Table 2 PCR and culture tests of pharyngeal swabs
Visit 1 n = 34 Visit 2 n = 32 Visit 3 n = 25
qPCR

Negative (%) QD 0 / 12 (0)2 / 11 (18.2)

6 / 7 (85.7)

BID 0 / 15 (0)0 / 14 (0)8 / 11 (72.7)

TID 0 / 7 (0)1 / 7 (14.3)

6 / 7 (85.7)

Culture Negative (%) QD 0 / 12 (0)11 / 11 (100) 7 / 7 (100)BID 0 / 15 (0)14 / 14 (100) 10 / 11 (90.9)

TID 0 / 7 (0)6 / 7 (85.7)

7 / 7 (100)Abbreviations: QD quaque die, BID bis in die, TID ter in die, qPCR quantitative
polymerase chain reaction

capture subtle changes in bacterial load by using the culture method, so it is necessary to evaluate it by a moreaccurate approach. This study is the first report in whichchanges in bacterial load before and after treatment wereassessed using quantitative PCR.
Quantitative analysis of the samples collected before
the antibiotic therapy revealed slightly higher initial bacterial load in the QD group compared to the values in
BID and TID groups. We set the maximum dose for all
subjects at 1000 mg per day, but there are no data to
support the TID regimen with an upper limit of 1000 mg
per day, therefore the blood levels might end up lower
than the minimum inhibitory concentration (MIC) of
amoxicillin for GAS. Nevertheless, there were no significant differences in the rate of negative PCR results andquantitative parameters between QD, BID, and TID at
repeated visits after the antibiotic treatment. If we define
a non-inferiority margin as 10%, following previous reports [7, 8], the rate of negative PCR results in QD
group at visits 2 and 3 was within the upper 95% CI for

BID and TID. The outcome of eradication following QD
regimen was not inferior to that achieved after BID and
TID regimens, however it should be noted that the 95%
CI was very wide because of the small number of samples. For quantitative analysis, the bacterial load at visit
1 was similar among the groups, although significant differences were observed in the age and sex of the subjects. At visit 2, each regimen resulted in reduction toapproximately 1/100 or more compared to the medianvalues at visit 1. At visit 3, eradication of GAS was genetically confirmed in many cases. There were no significant differences between the results obtained after QD
and after the other two regimens, but the number ofsamples was insufficient to indicate non-inferiority of
the QD regimen.
Because the antibacterial effect of amoxicillin predominantly depends on the duration of its binding to the
penicillin-binding proteins and the resulting inhibitionof bacterial wall synthesis, it could be expected that administration of multiple doses would be more effective.
We believe there are two reasons why there was no significant difference in the PCR results between QD andother regimens. One is the pharmacokinetics of amoxicillin: its absorption into the bloodstream and distribution to the respiratory tract after oral administration arevery high [13, 14]. This is why amoxicillin is recommended as one of the most useful antimicrobial agentsfor respiratory infections, including GAS pharyngitis [15,16]. The second reason is high susceptibility of GAS
strains to amoxicillin. The MIC of penicillins for GAS isvery low, and there have been no reports of antimicrobial resistance of GAS strains to the drugs of this class

Table 3 Quantitative analysis of GAS strains
QD

BID

TID

n

12

15

7

median, copies /μL

1.4 × 106

8.2 × 105

5.4 × 105

[interquartile range][2.2 × 105–4.3 × 106]

Visit 1

95% confidence interval

56[2.4 × 105–1.6 × 106]5

6

[1.4 × 105–2.2 × 106]

2.2 × 10 , 4.3 × 10

2.4 × 10 , 1.6 × 10

1.0 × 105, 6.1 × 106

11

14

7

Visit 2n

3

3

2.8 × 103

median, copies /μL

3.8 × 10[interquartile range][2.7 × 10 –2.8 × 10 ][5.2 × 10 –4.8 × 10 ][1.8 × 102–6.9 × 104]

95% confidence interval

0.0, 1.2 × 105

4.9 × 102, 8.0 × 103

0.0, 1.3 × 105

1.1 × 10

2

4

2

3

Visit 3
n

7

11

7

median copies /μL

0

0

0

[interquartile range][0.0–0.0][0.0–1.2 × 102]

[0.0–0.0]

0.0, 1.7 × 104

0.0, 2.8 × 103

95% confidence interval

30.0, 9.0 × 10

Abbreviations: QD quaque die, BID bis in die, TID ter in die

Nakao et al. BMC Pediatrics(2019) 19:205[17, 18]. Because of these two factors, amoxicillin
achieves a high concentration in the pharyngeal lesion
site, which remains above the MIC for a sufficient periodof time even after QD regimen.
The guideline of the Infectious Diseases Society ofAmerica recommends a 10-days duration of treatment
with amoxicillin for GAS pharyngitis [3]. However, the efficacy of shorter therapy has been also reported [19, 20].
In our study, 30 patients out of 32 tested at visit 2 and 5
out of 25 at visit 3 were PCR positive for GAS, respectively, so there is a concern about how efficiently GAS
could be eradicated by a short treatment. It should be
noted that positive PCR result does not necessarily mean
treatment failure. More data should be accumulated before short regimen therapy may be recommended.
Although reducing the number of doses contributes toimproved patient adherence [21], we do not recommend
only QD regimen as the preferred and sufficient treatment for GAS pharyngitis. Designing dose regimens, including multiple administrations per day, which fit thepatient’s wishes and lifestyle is very important to improve adherence [22]. In addition, the burden associatedwith an increase in the dosage per time should be observed carefully in pediatric patients. Clinicians should
decide on the preferred number of dosages per day taking these factors into consideration.

Conclusion
By using real-time PCR, we compared bacterial loads insamples collected from colonized lesions in patients with
GAS pharyngitis following QD, BID, and TID amoxicillin
treatment regimens. Our results obtained by the molecular biology approach indicated that the QD regimen was
as effective in eradicating the infection as BID or TID regimens, although this may appear counterintuitive given the
dynamics of the antibacterial effect of amoxicillin.
Abbreviations
BID: Bis in die; CI: Confidence interval; GAS: Group A streptococcus;
MIC: Minimum inhibitory concentration; QD: Quaque die; TID: Ter in die
Acknowledgments
We wish to thank Yumiko Sakurai, Juntendo University, for technicalassistance.
Author’s contributions
AN designed the research and wrote the manuscript. AN and MF collected
the samples. AN and KH isolated GAS strains and quantified bacterial loads
in swabs. NM performed statistical analysis. MK and TS supervised the study,
provided suggestions for the experiments, and commented on the draft ofthe manuscript. All authors read and approved the manuscript.
Funding
This study was supported by the grant from the Tokyo Metropolitan HealthPublic Corporation by Toshima Hospital Research Projects. The funders had
no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.

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Availability of data and materials
The datasets obtained during the current study are available from thecorresponding author on a reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of the Tokyo Metropolitan
Health Public Corporation Toshima Hospital. Written informed consent was
obtained from a parent or legal proxy of all patients before their enrolment
in this study.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
Department of Pediatrics, Faculty of Medicine, Juntendo University, 2-1-1
Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. 2Fujimori Children’s Clinic, 1499-1
Amadocho, Hanamigawa-ku, Chiba-shi, Chiba 262-0043, Japan.
1

Received: 20 February 2019 Accepted: 11 June 2019

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