Title: Improvement in the appropriate antimicrobial usage for treating pediatric

acute otitis media in Japan: A descriptive study using nation-wide electronic

medical record data

Bibliography: Kono, M., Sugita, G., Itahashi, K., Sasagawa, Y., Iwama, Y.,
Hiraoka, S., Ohtani, M., & Hotomi, M. (2021). Improvement in the appropriate
antimicrobial usage for treating pediatric acute otitis media in Japan: A
descriptive study using nation-wide electronic medical record data. Journal of
Infection and Chemotherapy, 27(10), 1413–1422.
https://doi.org/10.1016/j.jiac.2021.05.013

Summary:

Otitis media is an inflammation of the middle ear, which is discerned as one

of the most common infancy and childhood diseases worldwide that causes
morbidity to children. Moreover, sixty-two percent of children may experience
acute otitis media at least once by one(1) year of age, and seventeen percent
will have it at least three times, and eighty-three will have it at least once by
three(3) years of age. This disease can be the agent of hearing loss, delay
speech or voice acquisition, and development of cognitive function. With that,
evidence-based guidelines arise and have been advocated by a lot of countries.

Due to the potential adverse effects of the disease, antimicrobials are

essential to combat its effects; however, frequent usage of antibiotics could
develop drug resistance in causative pathogens. Aside from that, it could result
in vomiting, rashes, diarrhea, which signifies that a proper intake of such drug
must be observed. In addition, diagnoses of hypoglycemia, spasm, renal
disorder, anaphylaxis, Steven-Johnson syndrome, toxic epidermal necrolysis are
made within seven days of antimicrobial prescription. That is why the study aims
to provide an appropriate antimicrobial usage for treating pediatric acute otitis
media through examining the Real World Data(RWD) administered by the
Health, Clinic, and Education Information Evaluation Institute. The acute otitis
media patients from the period of January 1, 1985 to March 21, 2019 were
analyzed to produce a Manual of Antimicrobial Stewardship that is considered as
a clinical practice guideline for diagnosing and managing AOM. There are three
published manuals where it started from Period 1, a study from 2001-2006, while
Period 2 for 2007-2015. Lastly, Period 3 for the span of 2016-2019.

As the manuals were published in a different period, changes in antimicrobial

prescription rates were significantly evident. The antimicrobial prescription rate
alone during 2001 was 91% but declined to 40% by 2019. In addition, the use of
penicillins increased from 0% to 75%, whereas the use of cephalosporins
decreased from 84% to 10%, and acetaminophen increased from 33% to 58%.
In 2019, penicillins were prescribed in approximately 80% of AOM cases; thus,
the appropriate use of penicillins as the first choice treatment was established
with AOM.

As the first study to examine annual changes in the actual use of

antimicrobials in pediatric AOM patients using RWD, it shows that efforts to
promote the proper use of antimicrobials have led to fruition. The results imply
that physicians are following the clinical practice manual and more-carefully
prescribing antimicrobials after each manuals are published.

Reaction:

The article stressed the importance of proper drug prescription to the

patients, which must constantly be considered essential because it can hugely
affect an individual's health, and I truly agree with that. After reading the entire
analysis, it provides pieces of information that indicate the danger of an intake of
drugs that are not appropriate. Thus, I agree with the article's point because it
definitely aids the children to prevent from being drug-resistant and undergo
adverse effects due to regular intake of a specific drug. On the other hand, it
relates not only to otitis media but also to all other diseases where its medication
prescribed still needs to be improved.

Moreover, I grasped the purpose of prohibiting individuals who use

medicines without a physician's prescription. I admit that there are certain times
wherein I use drugs to ease light pain without a doctor's order. From now on, I
deeply understood that this action must be stopped because it will not benefit
me; rather, it will just harm me. Also, I must warn my family who does the same,
which was only a passed practice on me. I figured out that research-based
articles make the community absorb and follow its content, for it hits a huge
difference and effect when truth with evidence is presented before you. As of
today, I recognized the value of updated articles; although it takes time, but they
can surely put my health into a safe space.

As a nursing student, I firmly saw the beauty of being detailed in learning the
pharmacology and proper administration of drugs to the patients. I perceived that
the right administration of medicine is vital to the nursing profession and must
not be taken lightly. The article itself conveys an enormous impact on the
medical field, for it gives an impression to the physicians that the drugs we think
are the cure of a particular illness today might not be the fit for the disease.
Meanwhile, it proposes that with patience, perseverance, and hard work, it is not
impossible to achieve extensive research that will be significant to medical care.

As a conclusion in relation to nursing context, critical thinking is necessary to

obtain the best nursing care we can provide to our patients and we must not limit
our care on what's already given. Instead we must broaden our knowledge
through reading and show our capability to contribute. It must be notable that
changes in drugs prescribed are constant as an example to otitis media which
shows that penicillin is the most effective drug for it. That’s why it is necessary to
consider the balance between possible side effects and efficacy in evaluating the
proper use of antimicrobials.
 Journal of Infection and Chemotherapy 27 (2021) 1413–1422

Contents lists available at ScienceDirect

Journal of Infection and

Chemotherapy
Original Article

Improvement in the appropriate antimicrobial usage for treating pediatric

acute otitis media in Japan: A descriptive study using nation-wide electronic medical
record data
a a b c c
Masamitsu Kono , Gen Sugita , Koju Itahashi , Yuji Sasagawa , Yasuhiro Iwama ,
b a, Muneki Hotomi a,*
Shuichi Hiraoka , Makiko Ohtani
a
Department of Otorhinolaryngology-Head and Neck Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama-shi, Wakayama, Wakayama, 641-8510,

Japan

b
Medical Affairs Department, Meiji Seika Pharma Co., Ltd., 2-4-16 Kyobashi Chuo-ku, Tokyo, 104-8002, Japan

c
Regulatory Affairs & Clinical Data Science Department, Meiji Seika Pharma Co., Ltd., 2-4-16 Kyobashi Chuo-ku, Tokyo, 104-8002, Japan

ARTICLEINFO Methods: A descriptive study using an electronic medical record database. Of 199,896 patients enrolled
between 2001 and 2019, a total of 10,797 were aged <16 years and had AOM as their first and primary
disease (overall pediatric AOM cohort). In addition, 4786 patients with AOM without other comorbidities
(pediatric AOM cohort)

Keywords: were included.

Real-world data
Results: In the overall pediatric AOM cohort, the age distribution ranged from 11% to 23% for those younger
than 2 years and from 66% to 77% for those younger than 6 years, with no change over time. In the pediatric
Pediatric acute otitis media
AOM cohort, the antimicrobial prescription rate was 91% in 2001 but declined to 40% by 2019. Antimicrobial
Guidelines for diagnosis and management use increased from 0% to 75% for penicillins, whereas use of cephalosporins decreased from 84% to 10%. The
Pneumococcal conjugate vaccine
prescription rate for acetaminophen alone increased from 33% to 58%. There were no differences in the inci-
dence of adverse reactions among the prescribed antimicrobials.
Antimicrobial stewardship

Conclusions: Due to education efforts and promotion of the proper use of antimicrobials through means such
ABSTRACT as the Clinical practice guidelines for the diagnosis and management of acute otitis media in children (2006)
and the Manual of Antimicrobial Stewardship (2016), a change in the use of antimicrobials occurred, leading to

Objectives: We investigated changes a trend to more proper use of these agents.

in prescriptions for antimicrobial
agents to treat children with acute
otitis media (AOM).

1. Introduction tries [9–11].

Acute otitis media (AOM) is one of the most common infections for
which antimicrobials are prescribed [1,2]. Sixty-two percent of children
will have AOM at least once by 1 year of age and 17% will have it at
least three times, and 83% will have it at least once by 3 years of age
[3]. AOM accounts for ~16.8% of pediatric patients [4]. In Japan,
~4.3% of children visiting medical facilities have AOM [5,6]. AOM
can cause hearing loss in infants and toddlers and delay speech and/or
voice acquisition and development of cognitive functions [7,8].
Given the
Advocates called for a clinical practice guideline for the diagnosis
and management of AOM in Japan in 2006, and a fourth revision de-
tailing recommended antimicrobial treatment based on disease severity
was published in 2018 [12]. First-line therapy with amoxicillin (60–90
mg/kg) is recommended in moderate or severe cases, whereas no anti-
microbial therapy is recommended in mild cases. Evaluating the tym-
panic membrane is a useful index for predicting the prognosis of infants

high prevalence and developmental impact of AOM, evidence-based

guidelines for pediatric patients have been advocated in many coun-
 Abbreviations: AOM, acute otitis media; BLNAR, β-lactamase non-producing ampicillin-resistant; EMR, electronic medical record; PCV, protein-conjugated
pneumococcal vaccine; RIHDS, Research Institute of Healthcare Data Science; RWD, real-world data.

* Corresponding author.

E-mail address: mhotomi@wakayama-med.ac.jp (M. Hotomi).

https://doi.org/10.1016/j.jiac.2021.05.013

Received 1 February 2021; Received in revised form 28 April 2021; Accepted 14 May 2021

Available online 26 June 2021

1341-321X/© 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. This is

an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

M. Kono et al.
with AOM, as it promotes the proper use of antimicrobials [13–15].
Regular antibiotic use increases the risk of inducing drug resistance
in causative pathogens. On contrary, antibiotics can also cause side ef-
fects such as diarrhea, vomiting, and rashes, making their proper use
important [16,17]. A 2016 WHO alert regarding the increase in drug-
resistant microbes included recommendations for the appropriate use of
antimicrobial agents. In Japan, a national action plan on anti- microbial
resistance was established in 2016, and Manual of Antimi- crobial
Stewardship (1st edition) were published [18]. In epidemiologic
surveillances of AOM completed after the introduction of protein-
conjugated pneumococcal vaccine (PCV) in Japan, increased
rates of β-lactamase non-producing ampicillin-resistant (BLNAR)
Hae-
mophilus influenzae were reported [19,20].
The effects of a clinical practice guideline for the diagnosis and
management of AOM in Japan and Manual of Antimicrobial Steward-
ship, promoting the appropriate use of antimicrobial agents, and the
introduction of PCVs on actual prescription rates for antimicrobial
agents have not been adequately evaluated. In this study, a large-scale
medical care information database derived from electronic medical re-
cords was examined to determine changes over time in the actual use of
antimicrobial agents in children with AOM.
2. Materials and methods
2.1. Clinical information database
This population-based, retrospective, observational cohort study
used a real-world data (RWD) database administered by the Health,
Clinic, and Education Information Evaluation Institute (HCEI; Kyoto,
Japan) with the support of Real World Data, Co., Ltd. (Kyoto, Japan).
The RWD database consists of 20 million electronic medical records
(EMRs) collected from 186 health institutions nationwide and contains
information on patient statistics, diagnostics, prescribing, treatment
modalities, and tests. Data are anonymized, with unique identifiers
assigned to each patient within the same institution.
The RIHDS research ethics committee (https://rihds.org/ethic/)
approved this study in March 2019 (reception number RI2018018).
2.2. Pediatric AOM cohort
EMRs including patient-related data spanning the period January 1,
1985, to March 21, 2019, were examined. The first diagnostic infor-
mation in each EMR was analyzed.
The overall pediatric AOM cohort included 199,896 patients diag-
nosed with otitis media who met the following criteria: (1) younger
than 16 years of age; (2) primary medical condition assigned code
3829027 (AOM) as per the Master of Standardized Diseases developed
at the Medical Information System Development Center; and (3)
patient pre- scription information was available. Exclusion criteria
included diag- nosis of AOM but no record of previous prescriptions.
In addition, patients without other disease diagnoses among all
pediatric AOM pa- tients were categorized into the pediatric AOM
cohort.
2.3. Study design
For the all pediatric AOM cohort, we analyzed annual changes in
age at first presentation among patients under 16 years of age selected
141
Journal of Infection and Chemotherapy 27 (2021) 1413–1422
with pediatric AOM as the primary disease. In addition, we analyzed the
prescription rates of acetaminophen over time for patients with un-
complicated AOM without diagnoses of other diseases. Antimicrobials
included systemic antimicrobial agents (ATC code J01) analyzed by
antimicrobial lineage. Regarding adverse reactions, diagnoses of hypo-
glycemia, spasm, renal disorder, anaphylaxis, Stevens-Johnson syn-
drome, rash, toxic epidermal necrolysis, or diarrhea made within 7 days
of antimicrobial prescription were extracted from the EMRs.
The analysis period was defined as follows. With regard to the timing
of introduction of the guideline/manual, the period before a clinical
practice guideline for the diagnosis and management of AOM in
Japan were published was defined as the first period of
antimicrobial stew-
ardship (period 1, 2001–2006). The second period of antimicrobial
stewardship (period 2, 2007–2015) was defined as the period after
publication of the clinical practice guidelines for pediatric AOM until
Manual of Antimicrobial Stewardship was published, and the third period
spanned 2016–2019 (period 3). With regard to the timing of introduction
of PCV, time prior to the clinical introduction of PCV in
Japan was defined as the pre-PCV period and spanned 2001–2010,
whereas the post-PCV period spanned 2011–2019, as clinical use of 7-
valent PCV began in 2010 and 13-valent PCV in 2013. During the third
period (2016–2019) both the guideline/manual and PCV were available.
2.4. Statistical analysis
Statistical analysis was performed using GraphPad Prism software,
version 8.4.3. Significant differences were determined with Fisher’s
exact test (between two groups) or Kruskal-Wallis test with Dunn’s
multiple comparisons post-test (more than two groups), with a two-
tailed significance level of less than 5%.
3. Results
3.1. Subjects
Among 199,896 individuals with a diagnosis of otitis media during
the period January 1, 2001, to March 21, 2019, a total of 10,797 patients
met the inclusion criteria and formed the all pediatric AOM cohort. In
addition, 4786 pediatric patients with AOM without concomitant dis-
eases were selected as the pediatric AOM cohort (Fig. 1).
Regarding the background of patients included in the all pediatric
AOM cohort, 5885 (54.5%) were male and 4912 (45.5%) were female,
and the gender ratio remained unchanged each year. For the overall
pediatric AOM cohort, the median age was 4.0 years, and the mean age
was 4.4 years. Regarding the background of patients included in the
pediatric AOM cohort, 2655 (55.5%) were male and 2131 (44.5%) were
female, and the gender ratio remained unchanged each year. For the
pediatric AOM cohort, the median age was 4.0 years, and the mean age
was 4.7 years (Fig. 2).
The number of patients in the overall pediatric AOM cohort increased
on a year-to-year basis during 2001–2010 (pre-PCV period), during
which popularity of EMRs increased in Japan. Meanwhile, the number of
patients with AOM decreased during 2011–2013 and leveled
off during 2014–2018 (Fig. 2a). When comparing the number of patients
M. Kono et al. Journal of Infection and Chemotherapy 27 (2021) 1413–1422
with AOM in the pre- and post-PCV periods, there was a significant
reduction in the number of patients with AOM in the post-PCV period
compared to the pre-PCV period, particularly the 4-year period during

2007–2010 (median number of AOM patients: pre-PCV vs. post-PCV,

1038 vs. 436; p < 0.0001).

There was no significant change over time in the age distribution of

patients at first episode of AOM (Fig. 2b). Each year, the median age
of

patients at their first episode was 3–4 years. Patients <2 years old
comprised 11–23%, whereas those <6 years old comprised 66–77% of
the cohort, and there was no yearly difference in age distribution.

3.2. Changes in antimicrobial and analgesic prescribing rates

The change in prescription rates of antimicrobials at the time of the

first episode of AOM in the 4786 children with AOM without concom-
itant diseases was shown in Fig. 3. The antimicrobial prescription rate
was 90.5% in 2001 but decreased over time to 62.8% in 2006, 35.8% in

2016, and 28.9% in 2017. In contrast, the rate increased slightly to

40.0% during 2018–2019 (Fig. 3a). The median antimicrobial pre-
scription rates during the first (2001–2006), second (2007–2015), and

141

third (2016–2019) periods of antimicrobial stewardship were 66.5%,
47.3%, and 33.6%, respectively. The rate of prescriptions for
antibiotics was significantly lower in the second and third periods of
antimicrobial
stewardship than in the first period (Fig. 3b, Table 1). There was no
significant difference in the prescription rate of antimicrobials between
the second and third periods of antimicrobial stewardship.
Annual changes in antimicrobial prescribing rates were compared
with changes in acetaminophen prescribing rates (analgesic prescribing
rates). The rate of prescriptions for antimicrobial agents alone declined
over time, whereas the rate of co-prescriptions for antimicrobial agents
and acetaminophen tended to increase during 2006–2009 and then
declined after 2010 (Fig. 4a). The median rate of a single antibiotic
prescription was 33.9%, 15.8%, and 15.0% in period 1, period 2, and
period 3, respectively. Compared with period 1, the rate of single anti-
biotic prescriptions was significantly lower in period 2 and period 3
(Fig. 4b, Table 2). In contrast, the rates of combined prescriptions for
Fig. 1. Process for selecting the study cohorts.
antimicrobials and acetaminophen decreased significantly in the second
and third periods of antimicrobial stewardship (second period vs. third
period: 34.8% vs. 18.0%).
The rate of single acetaminophen prescriptions increased over time
(Fig. 4c). The median rates of prescriptions for an acetaminophen alone
were 7.9%, 37.5%, and 44.1% in the first, second, and third periods of
antimicrobial stewardship, respectively. The rates of prescriptions for an
acetaminophen alone were significantly higher in the second and third
periods compared with the first period (Fig. 4d, Table 2). The proportion
of cases in which neither antimicrobials nor acetaminophen were pre-
scribed also changed over time.
3.3. Changes in prescribing rates by antimicrobial type
 Changes in the prescription rates of antimicrobial agents over time
were further examined by types of antimicrobials (Fig. 5). The pre-
scription rates of oral penicillins increased from 0% to 75% during

2001–2019. In contrast, the prescription rates of oral cephalosporins

declined over time, from 84.2% in 2001 to 10.0% in 2019 (Fig. 5a).
Oral macrolides were prescribed at a rate of 15.8% in 2001, but the rate
declined thereafter. Similarly, prescription rates were extremely low for
oral carbapenem and oral quinolones. The prescription rates for inject-
able antibiotics were low, ranging from 0 to 15%. The median pre-
scription rates of oral penicillins were 6.1%, 58.9%, and 67.6% in
period 1, period 2, and period 3, respectively. The prescription rates of
oral penicillins increased significantly in the period 2 and period 3
compared
 Fig. 2. Populations and age distributions. a: Distribution of the numbers of patients with AOM by year. b: Distribution of ages of patients with AOM by year.
to period 1 (Fig. 5b, Table 3). In contrast, prescription rates of oral
cephalosporins were 84.8% in the period 1, 33.3% in period 2, and
21.5% in period 3 with a significant decrease in period 2 and period 3
compared to period 1 (Fig. 5b, Table 3).
3.4. Changes in antimicrobial use following the introduction of PCVs
Changes in antimicrobial use associated with the introduction of
PCVs were examined as antimicrobial switch rates for changes within
14 days of initial prescription of antimicrobials in the pre- and post-
PCV periods (Fig. 6). For oral penicillins, antimicrobial non-switch
rates remained unchanged in the pre- and post-PCV periods (pre-PCV vs.
post- PCV: 77% vs. 85%). In contrast, the antimicrobial non-switch rate
for oral cephalosporins was 72% in the pre-PCV period and significantly
higher (92%) in the post-PCV period.
3.5. Incidence of adverse reactions to antimicrobials
Regarding the incidence of adverse reactions associated with the use
of antimicrobials, diarrhea was the most common side effect. The inci-
dence of diarrhea associated with oral antibiotics was 0.23% for peni-
cillins, 0.19% for cephalosporins, 0.66% for carbapenems, 0.23% for
macrolides, and 0.69% for quinolones (Table 4).
4. Discussion

Appropriate antimicrobial use has been promoted as a countermea-

sure for the increased prevalence of drug-resistant microbes. Prophy-
lactic administration of PCVs and the promotion of antimicrobial
stewardship have been implemented in the treatment of AOM. Our
study is the first to examine annual changes in actual use of
antimicrobials in pediatric AOM patients using RWD and to describe
how social medicine
Fig. 3. Annual changes in antimicrobial prescription rates. a: The annual change in prescription rates of antimicrobials at the time of the first episode of AOM.
b: The changes in antimicrobial prescription rates during the three periods of antimicrobial stewardship. The box shows median, 25 percentile and 75 percentile.
Whiskers show 5 and 95 percentile. *p < 0.05, **p < 0.01.

Table 1

Changes in antimicrobial prescription rates over time.

Total antimicrobial prescription Median 25 percentile 75 percentile 95% CI Mean Standard deviation Standard error vs. Period 1 vs. Period 2
Period 1 (2001–2006) 66.5 59.3 79.8 56.9–82.5 69.7 12.2 5.0 – –

Period 2 (2007–2015) 47.3 38.6 55.0 40.1–54.1 47.1 9.1 3.0 p < 0.05 –

Period 3 (2016–2019) 33.6 29.5 39.0 26.2–41.8 34.0 4.9 2.5 p < 0.01 ns
efforts to promote the proper use of antimicrobials have led to changes
in antimicrobial prescription rates.

The antimicrobial prescribing rate was approximately 90% in 2001

and then decreased over time to 40% in 2019. Two major guideline/
manual have been published over that period regarding the promotion

of antimicrobial stewardship in Japan. The first edition of Clinical

Practice Guidelines for the Diagnosis and Management of Acute Otitis
Media (AOM) in Children was published in 2006, and the first edition
of Manual of Antimicrobial Stewardship were proposed as an AMR
Action Plan by the Ministry of Health, Labour and Welfare in 2016
[12,18].
Fig. 4. Annual changes in antimicrobial and acetaminophen prescription rates. a: The annual change in prescription rates of antibiotics alone and antibiotics
with acetaminophen at the time of the first episode of AOM. b: The changes in prescription rates of antibiotics alone and antibiotics with acetaminophen during
the three periods of antimicrobial stewardship. c: The annual change in rates of prescription of acetaminophen alone and in rates of prescription of neither
antimicrobials nor analgesics at the time of the first episode of AOM. d: The changes in rates of prescription of acetaminophen alone and in rates of prescription
of neither antimicrobials nor analgesics during the three periods of antimicrobial stewardship. The box shows median, 25 percentile and 75 percentile. Whiskers
show 5 and 95 percentile. *p

< 0.05, **p < 0.01.

Table 2

Changes in rates of antimicrobial and analgesic prescriptions over time.

Median 25 percentile 75 percentile 95% CI Mean Standard deviation Standard error vs. Period 1 vs. Period 2

Antibiotics alone

Period 1 (2001–2006) 33.9 28.3 52.7 25.4–52.0 38.7 12.7 5.2 – –

Period 2 (2007–2015) 15.8 11.8 16.5 12.0–17.3 14.6 3.4 1.1 p < 0.01 –

Period 3 (2016–2019) 15.0 12.0 18.8 9.2–21.3 15.3 3.8 1.9 p < 0.05 ns

Antibiotics with acetaminophen

Period 1 (2001–2006) 31.6 29.4 33.3 27.7–34.2 31.0 3.1 1.3 – –

Period 2 (2007–2015) 34.8 25.7 40.7 26.1–38.9 32.5 8.3 2.8 ns –

Period 3 (2016–2019) 18.0 16.9 21.3 14.9–22.5 18.7 2.4 1.2 ns p < 0.05

None
 Period 1 (2001–2006) 24.5 16.6 30.7 14.7–31.6 23.2 8.0 3.3 – –

Period 2 (2007–2015) 16.8 15.6 19.1 15.5–19.2 17.3 2.4 0.8 ns –

Period 3 (2016–2019) 23.5 17.8 24.1 15.6–28.0 21.8 3.9 1.9 ns ns

Acetaminophen alone

Period 1 (2001–2006) 7.9 3.6 10.6 2.5–11.8 7.1 4.4 1.8 – –

Period 2 (2007–2015) 37.5 29.7 41.0 28.8–42.3 35.6 8.8 2.9 p < 0.05 –

Period 3 (2016–2019) 44.1 37.0 51.8 32.1–56.5 44.3 7.7 3.8 p < 0.01 ns

Following the publication of the guideline/manual, antimicrobial pre-

scribing rates have decreased significantly compared with antimicrobial

prescribing rates in the first period (2001–2006), the second period
(2007–2015), and the third period (2016–2019). Similarly, in Korea it

was reported that the prescription rates of antimicrobials for AOM

decreased by 12.5% during 2009–2017 due to recommendations in
AOM clinical practice guidelines [21]. Following publication of the

2004 guidelines for AOM care in the United States, antimicrobial

Fig. 5. Annual changes in antimicrobial prescription rates based on type of antimicrobial. a: Annual changes in prescription rates of antimicrobial agents by
antimicrobial type over time. b: Annual changes in prescription rates of oral penicillins and cephalosporins during the three periods of antimicrobial stewardship.
The box shows median, 25 percentile and 75 percentile. Whiskers show 5 and 95 percentile. *p < 0.05, **p < 0.01, ***p < 0.001.

Table 3

Changes over time in prescription rates according to antimicrobial type.

Median 25 percentile 75 percentile 95% CI Mean Standard deviation Standard error vs. Period 1 vs. Period 2

Penicillin

Period 1 (2001–2006) 6.1 1.2 16.5 -3.2–22.4 9.6 12.2 5.0 – –

Period 2 (2007–2015) 58.9 48.1 64.9 49.0–64.6 56.8 10.2 3.4 p < 0.05 –
Period 3 (2016–2019) 67.6 60.4 74.0 56.1–78.6 67.3 7.1 3.5 p < 0.01 ns

Cephalosporin

Period 1 (2001–2006) 84.8 76.6 93.9 70.7–96.1 83.4 12.1 4.9 – –

Period 2 (2007–2015) 33.3 29.6 47.6 29.8–45.3 37.6 10.0 3.3 p < 0.05 –

Period 3 (2016–2019) 21.5 12.5 24.1 9.0–29.8 19.4 6.5 3.3 p < 0.001 ns
 Fig. 6. Antimicrobial switch ratio. Changes in antimicrobial use associated with the introduction of PCVs were examined as antimicrobial switch rates for changes
within 14 days of initial prescription of antimicrobials in the pre- and post-PCV periods. *p < 0.05.

Table 4

Adverse effects of antimicrobial agents.

Adverse event Oral formulation Injectable formulation Non-

Penicillin (n Cephalosporin (n Carbapenem (n Macrolide (n Fluoroquinolone (n Penicillin (n Cephalosporin (n (n =

antibiotic
= 13,503) = 19,728) = 757) = 3011) = 721) = 1209) = 2034) 23,371)

Hypoglycemia (%) 9 (0.07) 10 (0.05) 3 (0.40) 0 (0.00) 1 (0.14) 4 (0.33) 1 (0.05) 10 (0.04)

Spasm (%) 2 (0.01) 2 (0.01) 0 (0.00) 0 (0.00) 0 (0.00) 2 (0.17) 0 (0.00) 6 (0.03)

Renal disorder (%) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 1 (0.00)

Anaphylactic (%) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 1 (0.08) 1 (0.05) 3 (0.01)

Stevens-Johnson 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 1 (0.05) 0 (0.00)

a
p < 0.05 vs. Non-antibiotic. prescription rates for AOM in children (aged 3 months to 12 years)
decreased from 66.0% in 2005 to 51.9% in 2007 [22]. In the United
p < 0.01 vs. Non-antibiotic.
b
Kingdom, antimicrobial prescribing rates for AOM in children (aged 3
months to 15 years) declined from 77% in 1990 to 58% in 2006 [23]. It
is thought that clarification of treatment recommendations for AOM in
children through the medical care guidelines and increased awareness of
1420
the appropriate use of antimicrobial agents had a significant effect on
lowering prescription rates of antimicrobial agents for treating pediatric
AOM in Japan.
The rates for antimicrobials alone declined over the years, whereas
the prescription rates of acetaminophen alone increased. Addressing
earache, a major symptom of AOM, is an important challenge [24].
Non-medical factors, such as parents’ desire for pain relief for their
child, also affect antimicrobial prescriptions [25]. Changes in the rates
1420
of antimicrobial prescriptions are thought to have resulted from a greater
emphasis on the proper use of these agents based on criteria for accurate
diagnosis through evaluation of the tympanic membrane, as
recommended in the clinical guidelines for pediatric AOM.
The frequency of oral penicillin use increased, whereas that of oral
cephalosporins use decreased. McGrath reported that rates of cephalo-
sporins prescriptions for childhood AOM in the United States began
increasing from 12.3% in 2001, peaked in 2007, and remained at 17.4%
in 2011, increasing by 41.5% over 11 years [22]. A survey conducted
over 2002–2006 in the United States reported that the overall rate of
antimicrobial prescriptions for AOM decreased, amoxicillin use
increased, and cephalosporins use increased immediately after the
AAP/AAFP Guidelines for the Treatment of Acute Otitis Media were
advocated [26]. In Japan, the frequency of penicillins use increased and
 decreased. These results suggest that clinicians are following clinical
that of cephalosporins use decreased following publication of the pedi- practice guideline/manual and more-carefully prescribing antimicrobials.
atric AOM clinical practice guidelines in 2006. The appropriate use of
antimicrobials was promoted by the Manual of Antimicrobial Steward- Funding
ship published in 2016. In 2019, penicillins were prescribed in
approximately 80% of AOM cases; thus, the appropriate use of penicil-
lins as the first-choice treatment was established with AOM.
This work was supported by Meiji Seika Pharma.
Antimicrobial treatment failure is also believed to affect
prescription rates, particularly those of cephalosporins [22,27,28]. As
Ubukata et al. demonstrated, the introduction of PCVs has alerted
clinicians to the increased prevalence of BLNAR H. influenzae as a Compliance with ethics guidelines
causative agent of childhood otitis media. It was predicted that future
positioning of a second-choice drug for treating H. influenzae will be
problematic [29]. In this study, the incidence of adverse effects caused This study was conducted with approval from RIHDS research ethics
by antimicrobials, particularly diarrhea, was low, irrespective of the committee (https://rihds.org/ethic/) in March 2019 (reception number
type of antimicrobial prescribed, so it is necessary to consider the RI2018018).
balance between possible side effects and efficacy in evaluating the
proper use of antimicrobials [30].
Data availability
The incidence of AOM has decreased since 2010, and it has been
reported that the incidence of tympanotomy has decreased in children
with AOM, although no clear protective effect of PCVs on AOM in These analyses were conducted on medical records data provided by
children has been observed in Japan [31,32]. It was also reported that HCEI under a commercial license, which the authors are unable to share.
pneumococcal serotypes that cause AOM in children have changed
with the introduction of PCVs [20]. It is difficult to conclude from Authors’ contributions/ICMJE statement
RWD that the use of carbapenems or quinolones, which are positioned
as novel antibiotics for treating AOM in children, has been very
Contributors MH and KI were responsible for the organization and
infrequent and that the use of these antibiotics has reduced the
coordination of the trial. MH and KI were the chief investigators and
incidence of AOM, which is thought to be strongly affected by PCV
responsible for the data analysis. MH, KI, YS, YI and SH developed the
administration. In addition, there was no change in the antimicrobial
trial design and analysis. All authors contributed to the writing of the
change rate (switch ratio) for penicillin as the first-choice drug
final manuscript. All authors of this Study Team contributed to the
following the introduction of PCVs. However, the antimicrobial change
management or administration of the trial.
rate of cephalosporin as the first-choice drug decreased after the
introduction of PCVs compared with the pre-PCV period. Amoxicillin
or amoxicillin/clavulanate is an established treatment regimen with a
low failure rate [33,34]. In addi- tion, PCVs reduce the relative risk of Declaration of competing interest
pneumococcal AOM, suggesting that the clinical application of PCVs
has influenced the change in the incidence of AOM in children and that
treatment failure has decreased [28].
Koju Itahashi, Yuji Sasagawa, Yasuhiro Iwama, and Shuichi Hiraoka
The study had some limitations. First, common limitations of are employees of Meiji Seika Pharma. Muneki Hotomi has received
lecture fees from Meiji Seika Pharma and research grants from Pfizer.
observational studies apply, including selection bias and an inability to
This does not alter the authors’ adherence to any publication policies.
confirm efficacy in the absence of a placebo group. Second, they are
limited in that they primarily include hospital-based cohorts. Patient
References
information from clinics that are not registry facilities was not included
in this study. In this regard, it was challenging that the database con-
sisted of a limited number of hospitals and clinics and did not cover all [1] Schilder AG, Chonmaitree T, Cripps AW, Rosenfeld RM, Casselbrant ML,
regions of Japan. Third, incomplete adherence may have affected the Haggard MP, et al. Otitis media. Nat Rev Dis Primers 2016;2:16063.
accuracy and certainty of the results, as follow-up of patients [2] Marchisio P, Tagliabue M, Klersy C, Mira E, Pagella F, Baggi E, et al. Patterns
transferred to other medical institutions was not possible and the data in acute otitis media drug prescriptions: a survey of Italian pediatricians and
were based on prescriptions. As HCEI databases contain data registered otolaryngologists. Expert Rev Anti Infect Ther 2014;12:1159–63.
at the time [3] Teele DW, Klein JO, Rosner B. Epidemiology of otitis media during the first
seven
the contract sites introduced EMRs, the yearly increase in the number years of life in children in greater Boston: a prospective, cohort study. J Infect Dis
of patients diagnosed with AOM during 2001–2010 may have 1989;160:83–94.
been
[4] Marchisio P, Cantarutti L, Sturkenboom M, Girotto S, Picelli G, Dona D, et al.
affected by the prevalence of EMRs; therefore, it was not possible to Burden of acute otitis media in primary care pediatrics in Italy: a secondary data
draw conclusions about the increasing number of cases. Finally, labo- analysis from the Pedianet database. BMC Pediatr 2012;12:185.
ratory results are not reflected, and the severity of childhood AOM and [5] Otsuka T, Kitami O, Kondo K, Ota H, Oshima S, Tsuchiya A, et al. Incidence
its relationship to the causative organism could not be demonstrated. survey of acute otitis media in children in sado island, Japan–Sado otitis media study
Further epidemiologic studies of trends in medical care of AOM are (SADOMS). PloS One 2013;8:e68711.
expected to provide more reliable information in the future. [6] Monasta L, Ronfani L, Marchetti F, Montico M, Vecchi Brumatti L, Bavcar A,
et al. Burden of disease caused by otitis media: systematic review and global estimates.
In conclusion, there were significant changes in prescription rates of PloS One 2012;7:e36226.
therapeutic agents, with decreases in antimicrobial prescription rates
and increases in acetaminophen prescription rates. Rates of penicillin
[7] Cordeiro FP, da Costa Monsanto R, Kasemodel ALP, de Almeida Gondra L, de
Oliveira Penido N. Extended high-frequency hearing loss following the first episode of
prescriptions increased, whereas rates of cephalosporin prescriptions otitis media. Laryngoscope 2018;128:2879–84.

142
[8] Kasemodel ALP, Costa LEM, Monsanto RDC, Tomaz A, Penido NO.
[24] van Uum RT, Venekamp RP, Zuithoff NP, Sjoukes A, van de Pol AC, Schilder
Sensorineural
hearing loss in the acute phase of a single episode of acute otitis media. Braz J AG, et al. Improving pain management in childhood acute otitis media in general
Otorhinolaryngol 2020;86:767–73. practice: a cluster randomised controlled trial of a GP-targeted educational
intervention. Br J Gen Pract 2020;70:e684–95.

[9] Lieberthal AS, Carroll AE, Chonmaitree T, Ganiats TG, Hoberman A,

Jackson MA, et al. The diagnosis and management of acute otitis media. Pediatrics
2013;131:
e964–99.

[10] Siddiq S, Grainger J. The diagnosis and management of acute otitis media:
American Academy of Pediatrics Guidelines 2013. Arch Dis Child Educ Pract Ed
2015;100:193–7. https://doi.org/10.1136/archdischild-2013-305550 [PubMed:

25395494].

[11] Marchisio P, Bortone B, Ciarcia` M, Motisi MA, Torretta S, Castelli Gattinara

G, et al. Updated guidelines for the management of acute otitis media in children by
the Italian society of pediatrics: prevention. Pediatr Infect Dis J 2019;38(12S
Suppl):
S22–36.

[12] Hayashi T, Kitamura K, Hashimoto S, Hotomi M, Kojima H, Kudo F, et al.

Clinical
practice guidelines for the diagnosis and management of acute otitis media in
children-2018 update. Auris Nasus Larynx 2020;47:493–526.

[13] Kono M, Fukushima K, Kamide Y, Kunimoto M, Matsubara S, Sawada S, et

al.
Features predicting treatment failure in pediatric acute otitis media. J Infect
Chemother 2021;27:19–25.

[14] Hotomi M, Yamanaka N, Shimada J, Ikeda Y, Faden H. Factors associated

with clinical outcomes in acute otitis media. Ann Otol Rhinol Laryngol 2004;113:
846–52.

[15] Hotomi M, Yamanaka N, Samukawa T, Suzumot M, Sakai A, Shimada J, et

al.
Treatment and outcome of severe and non-severe acute otitis media. Eur J
Pediatr 2005;164:3–8.

[16] Venekamp RP, Sanders SL, Glasziou PP, Del Mar CB, Rovers MM.
Antibiotics for acute otitis media in children. Cochrane Database Syst Rev
2015;2015:Cd000219.

[17] Costelloe C, Metcalfe C, Lovering A, Mant D, Hay AD. Effect of antibiotic

prescribing in primary care on antimicrobial resistance in individual patients:
systematic review and meta-analysis. BMJ 2010;340:c2096.

[18] Manual of antimicrobial stewardship (1st edition).

https://www.mhlw.go.jp/file/0 6-Seisakujouhou-10900000-
Kenkoukyoku/0000193504.pdf. [Accessed 18 April 2021].

[19] Ubukata K, Morozumi M, Sakuma M, Adachi Y, Mokuno E, Tajima T, et al.

Genetic characteristics and antibiotic resistance of Haemophilus influenzae isolates
from
pediatric patients with acute otitis media after introduction of 13-valent
pneumococcal conjugate vaccine in Japan. J Infect Chemother 2019;25:720–6.

[20] Ubukata K, Morozumi M, Sakuma M, Takata M, Mokuno E, Tajima T, et

al. Etiology of acute otitis media and characterization of pneumococcal isolates
after introduction of 13-valent pneumococcal conjugate vaccine in Japanese
children.
Pediatr Infect Dis J 2018;37:598–604.

[21] Kim SH, Kim JR, Song JJ, Chae SW. Trend and patterns in the antibiotics
prescription for the acute otitis media in Korean children. Int J Pediatr
Otorhinolaryngol 2020;130:109789.

[22] McGrath LJ, Becker-Dreps S, Pate V, Brookhart MA. Trends in antibiotic

treatment of acute otitis media and treatment failure in children, 2000-2011. PloS
One 2013; 8:e81210.

[23] Thompson PL, Gilbert RE, Long PF, Saxena S, Sharland M, Wong IC. Has
UK guidance affected general practitioner antibiotic prescribing for otitis media in
children? J Public Health (Oxf) 2008;30:479–86.

142
[25] Damoiseaux RA, de Melker RA, Ausems MJ, van Balen FA. Reasons for
non-
guideline-based antibiotic prescriptions for acute otitis media in The Netherlands.
Fam Pract 1999;16:50–3.

[26] Coco A, Vernacchio L, Horst M, Anderson A. Management of acute otitis

media after publication of the 2004 AAP and AAFP clinical practice guideline.
Pediatrics
2010;125:214–20.

[27] Grubb MS, Spaugh DC. Treatment failure, recurrence, and antibiotic
prescription rates for different acute otitis media treatment methods. Clin Pediatr
2010;49:
970–5.

[28] Sox CM, Finkelstein JA, Yin R, Kleinman K, Lieu TA. Trends in otitis
media
treatment failure and relapse. Pediatrics 2008;121:674–9.

[29] Pichichero ME. A review of evidence supporting the American Academy of

Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-
allergic patients. Pediatrics 2005;115:1048–57.

[30] Block SL, Schmier JK, Notario GF, Akinlade BK, Busman TA,
Mackinnon 3rd GE, et al. Efficacy, tolerability, and parent reported outcomes for
cefdinir vs. high-dose amoxicillin/clavulanate oral suspension for acute otitis
media in young children.
Curr Med Res Opin 2006;22:1839–47.

[31] Sugino H, Tsumura S, Kunimoto M, Noda M, Chikuie D, Noda C, et al.

Influence of pneumococcal conjugate vaccine on acute otitis media with severe
middle ear inflammation: a retrospective multicenter study. PloS One
2015;10:e0137546.

[32] Sasaki A, Kunimoto M, Takeno S, Sumiya T, Ishino T, Sugino H, et al.

Influence of pneumococcal conjugate vaccines on acute otitis media in Japan.
Auris Nasus
Larynx 2018;45:718–21.

[33] T¨ahtinen PA, Laine MK, Huovinen P, Jalava J, Ruuskanen O, Ruohola A. A

placebo-
controlled trial of antimicrobial treatment for acute otitis media. N Engl J Med
2011;364:116–26.

[34] Hoberman A, Paradise JL, Rockette HE, Shaikh N, Wald ER, Kearney DH, et
al. Treatment of acute otitis media in children under 2 years of age. N Engl J Med

142