J Infect Chemother xxx (xxxx) xxx

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Journal of Infection and Chemotherapy

journal homepage: http://www.elsevier.com/locate/jic

Original Article

Features predicting treatment failure in pediatric acute otitis media

Masamitsu Kono a, Kunihiro Fukushima b, Yosuke Kamide c, Masaru Kunimoto d,
Shigenori Matsubara e, Shoichi Sawada f, Tomoko Shintani g, Akihisa Togawa h,
Akihiro Uchizono i, Yoshifumi Uno j, Noboru Yamanaka k, Muneki Hotomi a, *
a
Department of Otorhinolaryngology-Head and Neck Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama-shi, Wakayama 641-8510,
Japan
b
Department of Dermatology & Otolaryngology, Hayashima Clinic, 1475-2 Hayashima, Hayashima-cho, Tokubo-gun, Okayama, 701-0304, Japan
c
Kamide ENT Clinic, 2433-4 Denbou, Fuji-shi, Shizuoka 417-0061, Japan
d
Kunimoto ENT Clinic, 5769-7 Tomo Aza Oohara, Numata-cho, Asa Minami-ku, Hiroshima -shi, Hiroshima 731-3161, Japan
e
Matsubara ORL Clinic, 100 Ikeda-cho, Seki-shi, Gifu 501-3247, Japan
f
Sawada Eye and Ear Clinic, 1734-5 Fukui-cho, Kochi-shi, Kochi, 780-0965, Japan
g
Tomo ENT Clinic, 1-246 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8611, Japan
h
Sunsun Clinic, 569-1 Nogawa, Wakayama-shi, Wakayama 640-8481, Japan
i
Sendai ENT Clinic, 1945-1 Taki-cho, Satsuma Sendai-shi, Kagoshima 895-0211, Japan
j
Uno ENT Clinic, 3702-4 Kita Tomihara, Okayama-shi, Okayama, 701-1153, Japan
k
Moriya Keiyu Hospital, 980-1 Tachizawa, Moriya-shi, Ibaraki, 302-0118, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: To facilitate better antibiotic stewardship, we conducted this clinical trial to identify the
Received 26 June 2020 prognostic features of treatment failure in pediatric acute otitis media (AOM).
Received in revised form Study: Design: This is a randomized, parallel-group, open-label, comparative clinical trial.
30 July 2020
Subjects and Methods: Children with AOM and aged between 1 month and 5 years were enrolled. Pa-
Accepted 3 August 2020
Available online xxx
tients were randomly assigned to receive either amoxicillin alone (70 mg/kg) for five days, or the same
with additional clarithromycin (15 mg/kg) for the initial three days. The clinical course of AOM was
evaluated based on tympanic membrane scores. Failure of treatment for AOM was confirmed on day 14.
Keywords:
Acute otitis media
Nasal conditions were also assessed by a clinical scoring system for acute rhinosinusitis.
Amoxicillin Results: Treatment failures occurred in 25 out of 129 (19.4%) children. The ratio of treatment failures by
Prognosis age was significantly higher in children younger than 2 years than in children older than 2 years. The
Acute rhinosinusits tympanic membrane scores on day 3 (P ¼ 0.0334) and day 5 (P < 0.0001) and acute rhinosinusitis scores
Tympanic membrane findings on day 5 (P ¼ 0.0004) were higher in failure cases than in cured cases. Multivariate logistic regression
Randomized clinical trial analysis indicated significant associations between the treatment failure with tympanic membrane
scores and acute rhinosinusitis scores on day 5, and the antimicrobial treatment regimen.
Conclusions: Improvement of acute rhinosinusitis and tympanic membrane scores on day five were
important predictive features in failure of treatment for pediatric AOM. These results will be useful when
discussing the treatment decisions with the patient's parents.
© 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.
Published by Elsevier Ltd. All rights reserved.

1. Introduction

Acute otitis media (AOM) is one of the most common infectious

Abbreviations: AOM, acute otitis media; NTHi, nontypeable H. influenzae; AMPC,
amoxicillin; CAM, clarithromycin; TM, tympanic membrane; ARhiS, acute rhinosi-
nusitis; OME, otitis media with effusion; RCT, randomized clinical trial; CI, confi-
dence intervals.
* Corresponding author. Department of Otorhinolaryngology-Head and Neck
Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama-shi,
Wakayama, 641-447-8510, Japan.
E-mail address: mhotomi@wakayama-med.ac.jp (M. Hotomi).
diseases during early childhood [1]. It is estimated that approxi-
mately 50% of children will have at least one occurrence of AOM in
their first year of life [2,3]. Non-typeable Haemophilus influenzae
(NTHi) and Streptococcus pneumoniae are considered to be the two
major causative pathogens responsible for AOM [4e6].
Amoxicillin (AMPC) is recommended as the first choice of drug
for the treatment of AOM and it has shown beneficial efficacy in

https://doi.org/10.1016/j.jiac.2020.08.003
1341-321X/© 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Please cite this article as: Kono M et al., Features predicting treatment failure in pediatric acute otitis media, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2020.08.003
2 M. Kono et al. / J Infect Chemother xxx (xxxx) xxx
randomized, double-blind, placebo-controlled studies [6e9]. This
treatment strategy is similar to the recommended treatment for
acute rhinosinusitis [10e15]. It is estimated, however, that up to
one-third of children with AOM present refractory and/or recurrent
clinical courses [1]. The risk factors for refractory AOM and their
management are important in a clinical setting.
Recently there has been an alarming increase in antimicrobial
resistance to H. influenzae and S. pneumoniae, complicating anti-
microbial treatment for AOM [16,17]. Antimicrobial tolerance due
to biofilm formation and antimicrobial resistance are two major
obstacles to treatment of this disease [18,19]. Recent studies
demonstrated that NTHi has the ability to form biofilm and it es-
capes antimicrobial sterilization. This may result in persistent
inflammation in the middle ear [20e23]. Risk factors for increased
occurrence of refractory AOM include inappropriate antimicrobial
treatment as a result of biofilm formation, as well as selection of
resistant pathogens [24e26]. Macrolides such as clarithromycin
(CAM) are an alternative candidate treatments to eradicate the
biofilm [27e29].
Appropriate usage of antibiotics based on stringent diagnostic
and treatment criteria is recommended. To facilitate better anti-
biotic stewardship, this randomized, double-blind prospective
clinical trial aims to identify the prognostic features of treatment
failures in pediatric AOM.
2. Materials and methods
2.1. Patients and diagnostic criteria
Children with AOM and aged between 1 month and 5 years were
eligible for enrolment to this study within 48 h of the onset of
symptoms, irrespective of gender. AOM was diagnosed on the basis
of acute onset of otalgia, fever and irritability and the presence of
bulging and erythema of the tympanic membrane and/or otorrhea.
The severity of AOM was assessed according to the criteria specified
by the Clinical Practice Guidelines for the Diagnosis and Management
of AOM in Children in Japan 2013 (Table 1) [30]. Exclusion criteria
were as follows: 1) history of AOM or otitis media with effusion
(OME) within 1 month before the onset of the current episode, 2)
placement of a tympanostomy tube, 3) craniofacial abnormalities
or immunodeficiency, 4) history of hypersensitivity to penicillin or
macrolide. Children with recurrent AOM were also excluded from
this study.
The protocol was approved by the Wakayama Medical Univer-
sity Institutional Ethical Review Board (UMIN no. 000015564).
Written informed consent was obtained from parents or guardians
Table 1
Clinical scoring system for defining severity of acute otitis media.
None Mild
Symptoms Otalgia 0: absent 1: present
Crying and/or 0: absent 1: present
Bad temper
Fever (axilla) 0: under 1: higher than 37.5  C but under 38.5  C
37.5  C
TM Bulging and/ 0: absent 4: present in a part of the tympanic membrane
findings or
Protrusion
Hyperemia 0: absent 2: present at the manubrium of malleus, or in a part of the ear
drum
Otorrhea 0: absent 4: present but the tympanic membrane is visible
The severity of acute otitis media was defined by patient symptoms and the appearance of the tympanic membrane based on Clinical Practice Guidelines for the Diagnosis and
Management of Acute Otitis Media (AOM) in Children in Japan, 2013 update.
TM: tympanic membrane.
Definition of severity of acute otitis media (total score): Mild (9), Moderate (10~15), Severe (16).
Please cite this article as: Kono M et al., Features predicting treatment failure in pediatric acute otitis media, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2020.08.003
prior to enrollment into this study following a precise explanation
of the objective and methods of this trial, expected effects and risks,
and other relevant matters.
2.2. Study design
This was a randomized, parallel-group, open-label, comparative
clinical trial (RCT). Eligible patients were randomly assigned to
treatment (1:1 allocation) using dynamic allocation with a minimi-
zation method with study center as allocation factors to minimize
bias. It was initiated by the investigators and conducted indepen-
dently of any commercial entities from November 1, 2014 through
August 31, 2015 at Wakayama Medical University Hospital and at
eight private clinics in Japan. Our objective was to examine any
features that would predict treatment failures in pediatric AOM.
On the enrollment visit (day 1), the patient's symptoms, medical
history and clinical characteristics were recorded. Either nasopha-
ryngeal swabs, otorrhea or middle ear fluids were obtained for
bacterial cultures with a small rayon-tipped flexible swab. The
severity of AOM was evaluated based on an AOM clinical scoring
system (Table 1) [30]. Eligible patients were randomly assigned to
receive either just AMPC (70 mg/kg) for five days (AMPC-only
group), or the same but with CAM (15 mg/kg) for the initial three
days (AMPC þ CAM group).
The first visit after the enrollment visit was scheduled for three
days after the initiation of the study drug (day 3). The second visit
was scheduled for two days after that (day 5). The clinical courses of
AOM by the two treatment arms were evaluated based on tympanic
membrane scores (TM scores) (Table 1). The cure of AOM was
confirmed on 14 days after starting the treatment. During the
course of the study, nasal symptoms and findings were also
assessed by a clinical scoring system for acute rhinosinusitis
(Table 2) [11]. At each visit, the attendant physician asked the
parents about their child's overall condition and if there had been
any adverse effects. At any visit, the physician could switch from the
study drug to rescue treatment if the child's overall condition or
tympanic membrane findings warranted the change.
2.3. Bacterial culture
Specimens of swabs were cultured on sheep blood agar, choc-
olate agar, and MacConkey agar at 37  C in 5% CO2 according to the
usual clinical laboratory procedures. We identified S. pneumoniae
by colonial morphology, the presence of alpha hemolysis, Gram-
stain characteristics, optochin disk susceptibility and bile solubil-
ity. We also identified H. influenzae by exclusive growth on
Severe
2: present-continuous severe pain
2: higher than 38.5  C
8: present in the whole tympanic membrane
4: present in the whole tympanic membrane
8: present and obstructing visibility of the tympanic
membrane
 M. Kono et al. / J Infect Chemother xxx (xxxx) xxx
Table 2
Clinical scoring system for defining severity of acute rhinosinusitis.
Symptoms and Nasal findings
Symptoms Rhinorrhea
Bad temper
Wet cough
Nasal Findings Nasal secretions
Post nasal discharge
Severity of acute rhinosinusitis was defined by patient symptoms and nasal findings by a clinical scoring system (ARhiS score) based on Japanese practical guidelines for
management of acute rhinosinusitis.
chocolate agar, colonial morphology, Gram-stain characteristics,
requirements for hemin and nicotinamide, and failure to group
with standard Haemophilus typing sera. M. catarrhalis were iden-
tified by colonial morphology, Gram-stain characteristics, and the
biochemical reaction of butyrate esterase. We graded bacterial
growth between 0 and þ 4 and considered only those species
with þ2 to þ4 growth to be significant enough to be potential
pathogens.
2.4. Outcomes
Treatment failure was assessed at follow up until day 14. It was
defined as any of the following: no improvement in symptoms and
TM score by day 14, requiring additional antimicrobial treatment by
worsening of conditions such as perforation of tympanic mem-
brane or development of severe infection. We evaluated the clinical
features that predict failure of treatment for AOM.
2.5. Statistical analysis
Comparisons between two groups were assessed by Chi-square
analysis. Absolute percentage differences in rates and 95% confi-
dence intervals (CI) are shown. Multivariable logistic regression
analysis was performed to estimate predicting factors associated
with failure of antimicrobial treatment. All reported P values are
two-sided and statistical significance was defined as P < 0.05.
Calculations were performed using the statistical software pack-
ages JMP (SAS Institute Inc., Cary, NC) and Prism (GraphPad, San
Diego, CA).
3. Results
3.1. Patients and characteristics
Enrolled in the study were 146 children. Seventeen children, 7 in
the AMPC-only group and 10 in the AMPC þ CAM group, were
excluded because assessment of the clinical course of AOM was not
available, or because they dropped out of follow-up (Fig. 1). Finally,
129 children ranging in ages between 4 and 60 months (median 27
months) were evaluated in this study. Patient characteristics are
listed in Table 3.
The enrolled children were randomly assigned to either AMPC-
only group (67 children) or AMPC þ CAM group (62 children),
respectively. Forty-six children (74.2%) in AMPC þ CAM group and
39 children (58.2%) in AMPC-only group attended day care centers
(P ¼ 0.01). There were no significant differences in other patient
characteristics such as age distribution, sex distribution, having
siblings, prior antimicrobial treatments within a month, past his-
tory of AOM, or bilateral AOM between the two treatment groups.
Please cite this article as: Kono M et al., Features predicting treatment failure in pediatric acute otitis media, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2020.08.003
3
None Mild Moderate or More severe
0 1 2
0 1 2
cough observed interfering with sleep
0 2 4
serous mucopurulent purulent, intermediate or large amount
small amount
3.2. Bacteriology
Bacterial cultures exhibiting S. pneumoniae were detected at
40.8%, H. influenzae at 62.6% and M. catarrhalis at 59.1%, respec-
tively. One or more of S. pneumoniae, H. influenzae, and
M. catarrhalis were detected in 118 children (83.1%). There were no
significant differences in the distribution of the three pathogens
between the AMPC-only group and the AMPC þ CAM group
(Table 4).
3.3. Treatment outcomes of AOM
Treatment failures occurred in 25 out of 129 (19.4%) children. In
subgroup analysis, treatment failures occurred in 16 of 58 (27.6%)
children younger than 2 years of age and in 9 of 71 children over 2
years of age (12.7%). The ratio of treatment failures by age was
significantly higher in children younger than 2 years than in chil-
dren older than 2 years (OR, 0.38; 95% CI, 0.15 to 0.95; P ¼ 0.044).
There were no significant differences in treatment failure ratio
between bacterial species.
Failure of treatment occurred in 7 of 62 (11.3%) children in
AMPC þ CAM group and in 18 of 67 children (26.9%) in AMPC-only
group. Treatment failure ratio of AOM in AMPC þ CAM group was
lower than those in AMPC-only group (odds ratio [OR], 2.89; 95%
confidence interval [CI], 1.11 to 7.50; P ¼ 0.025).
3.4. Predictive parameters associated with clinical failure of AOM
Predictive features of clinical failure of AOM were evaluated. We
examined improvement of clinical severity for tympanic mem-
brane (TM scores) and acute rhinosinusitis (ARhiS scores) on days 1,
3 and 5 during the course of treatment. The TM scores on day 3
(P ¼ 0.0334) and day 5 (P < 0.0001) and ARhiS scores on day 5
(P ¼ 0.0004) were worse in failure cases than in cured cases (Fig. 2).
Multivariate logistic regression analysis by stepwise method
indicated significant associations between the cure ratio with TM
scores on day 5 and ARhiS scores on day 5, and the antimicrobial
treatment regimen (Fig. 3).
4. Discussion
Although there has been tremendous success using amoxicillin
for treatment against pediatric simple AOM, there continue to be
intractable cases [8,9]. Predisposing factors have been discussed,
including age younger than 2 years, rhinosinusitis, and others.
There are increasing demands to establish useful parameters for
predicting treatment failure to encourage appropriate antimicro-
bial usage based on AMPC. We reported the parameters for pre-
dicting antimicrobial treatment failure against pediatric AOM.
Improvement of TM scores at five days and acute rhinosinusitis
after the initial AMPC treatments were important clinical features
for predicting treatment failures of pediatric AOM.
4 M. Kono et al. / J Infect Chemother xxx (xxxx) xxx

Fig. 1. Enrollment, random assignment, and follow-up of the study patients. A total 144 cases of acute otitis media were initially enrolled in this study and randomly assigned to
either amoxicillin-only (AMPC) group or to amoxicillin þ clarithromycin (AMPCþCAM) group. Fifteen cases were excluded, so 129 cases (67 cases in amoxicillin-only group and 62
cases in amoxicillin þ clarithromycin group) could be followed.

Table 3 Amoxicillin is recommended as the drug of the first choice

Clinical characteristics of the children by treatment group. against simple AOM in children in accordance with the antimi-
All (n ¼ 129) AMPC þ CAM (n ¼ 62) AMPC only (n ¼ 67) P value
crobial treatment guidelines for AOM in Japan, US and across
Europe [30]. Intensive studies have been concerned with either the
Age
clinical courses of AOM after treatments with AMPC, or the risk
Median 27 27 26 ns
Max 60 60 60 factors for refractory AOM [31,32].
Min 4 4 4 The current study indicated the improvement of TM on day 5 of
Sex no. (%) treatments related to the cure of AOM. We could not identify any
Male 61 (47.3) 30 (48.4) 31 (46.3) ns
significant associations between the improvement of AOM and
Female 68 (52.7) 32 (51.6) 36 (53.7)
Daycare attendance no. (%)
bacterial species, although treatment failures were usually related
Yes 85 (65.9) 46 (74.2) 39 (58.2) 0.01 to antimicrobial resistant pathogens. Yano et al. reported that the
No 44 (34.1) 16 (25.8) 28 (41.8) improvement rate of the severity score of AOM caused by NTHi on
Sibling no. (%) week 1 of the treatment course was significantly associated with
Yes 73 (56.6) 33 (53.2) 40 (59.7) ns
the time to recovery [26]. If the prognosis of AOM could be pre-
No 56 (43.4) 29 (46.8) 27 (40.3)
Prior antimicrobial treatment no. (%) dicted during the course of the antimicrobial treatment, it would be
Yes 41 (31.8) 19 (30.6) 22 (32.8) ns valuable to physicians and patients alike. Physicians can make de-
No 88 (68.2) 43 (69.4) 45 (67.2) cisions on changing the treatment strategy based on improvement
Past history of AOM no. (%)
of TM findings on day 5. Clinicians can utilize the current study
Yes 35 (27.1) 13 (21.0) 22 (32.8) ns
No 94 (72.9) 49 (79.0) 45 (67.2)
findings to practice improved antibiotic stewardship.
Bilateral AOM no. (%) Previous studies indicated that AOM related to biofilm formed
Yes 46 (35.7) 24 (38.7) 22 (32.8) ns NTHi that were not cured by just AMPC [23,24]. Although the
No 83 (64.3) 38 (61.3) 45 (67.2) recognition of the roles of biofilm in AOM has improved our un-
There were no significant differences between AMPC-only and AMPC þ CAM study derstanding of the reason why persistent clinical courses occur, it
groups by Chi-square test except for daycare attendance. offers little guidance regarding successful treatment. Moreover,
ns; not significant, AOM; acute otitis media, AMPC; amoxicillin, CAM;
AMPC is ineffective against NTHi invasion into host cells [22,33,34].
clarithromycin.

Table 4
Bacteriology.

S. pneumoniae S. pneumoniae S. pneumoniae H. influenzae S. pneumoniae H. influenzae M. catarrhalis others negative

H. influenzae H. influenzae M. catarrhalis M. catarrhalis
M. catarrhalis

All 19.7% 7.7% 9.9% 22.5% 3.5% 12.7% 7.0% 6.3% 10.6%
AMPC only 20.3% 9.5% 8.1% 21.6% 4.1% 13.5% 5.4% 8.1% 9.5%
AMPC 19.1% 5.9% 11.8% 23.5% 2.9% 11.8% 8.8% 4.4% 11.8%
þCAM

S. pneumoniae, H. influenzae and M. catarrhalis were identified at 40.8%, 62.6%, and 59.1%, respectively.
AMPC; amoxicillin, CAM; clarithromycin.

Please cite this article as: Kono M et al., Features predicting treatment failure in pediatric acute otitis media, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2020.08.003
 M. Kono et al. / J Infect Chemother xxx (xxxx) xxx 5

Fig. 2. Parameters associated with treatment failure of acute otitis media. Severity of acute otitis media and TM scores were defined according to a clinical scoring system of acute
otitis media (Table 1). The differences between cure cases and failure cases of acute otitis media were evaluated for severity of acute otitis media on day 1, TM scores (days 3 and 5)
and ARhiS scores (days 1, 3 and 5). ARhiS: acute rhinosinusitis. TM: tympanic membrane. *: P < 0.05, ***: P < 0.001.

Fig. 3. Logistic regression analysis of parameters associated with treatment failure of acute otitis media. Factors that significantly associate the treatment failure of acute otitis
media. ARhiS: acute rhinosinusitis. TM: tympanic membrane.

Iino et al. reported that CAM could resolve persistent inflammation
in AOM by elimination of both intracellular NTHi and biofilms [35].
Acute rhinosinusitis is closely related with AOM and is an impor-
tant risk factor for developing refractory AOM [36,37]. Nasopha-
ryngeal colonization with NTHi has an important role in
development of AOM because it becomes the reservoir of causative
pathogens [38e41]. Biofilm-producing pathogens were isolated
more frequently from the nasopharynx in the recurrent AOM group
than in the control group [20]. Based on these findings, concurrence
of acute rhinosinusitis with AOM is thought to be an important
prognostic factor for resistance against treatment with just AMPC.
In the current study, there was no difference in bacterial
distribution between the two treatment groups. CAM improves the
acute rhinosinusitis, which acts as a reservoir of biofilm-related
pathogens, so there will be improvement of AOM with acute
rhinosinusitis.
The current study highlights objective clinical features that
predict risk of treatment failure. Generalizability of results is
limited, however, due to the single geographic location of study
participants. Moreover, the current results do not indicate that
combination therapy was recommended over standard AMPC
treatment. Myringotomies were performed in some cases on day 1,
so we could not rule out the possibility that this accelerated the
improvement of AOM. We did not directly observe evidence of

Please cite this article as: Kono M et al., Features predicting treatment failure in pediatric acute otitis media, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2020.08.003
6 M. Kono et al. / J Infect Chemother xxx (xxxx) xxx
biofilm in this study, so further investigation is needed to clarify
this aspect of disease resolution.
In conclusion, our results emphasize the importance of accurate
assessment of clinical features of AOM; children seem to benefit
most from further treatment if they have not had improvement of
TM scores by day 5 and/or if they have acute rhinosinusitis. Clini-
cians can use these results in their every-day practice when dis-
cussing the treatment decisions with the parents.
ICMJE statement
Contributors MH and NY was responsible for the organization
and coordination of the trial. AT was the chief investigator. MH and
MKa were responsible for the data analysis. MH and NY developed
the trial design. All authors contributed to the writing of the final
manuscript. All members of the Study Team contributed to the
management or administration of the trial.
Conflict of interest disclosure
The authors declare financial support from Taisho Toyama
Pharmaceutical Company. The funder had no role in the experi-
mental design, implementation of the study, interpretation of the
data or decision to submit the manuscript for publication. This does
not alter the authors’ adherence to any publication policies on
sharing data and materials.
Acknowledgements
We acknowledge editing and proofreading by Benjamin Phillis
from the Clinical Study Support Center at Wakayama Medical
University. There are no conflicts of interest.
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Please cite this article as: Kono M et al., Features predicting treatment failure in pediatric acute otitis media, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2020.08.003