Research Article

High-Dose Amoxicillin with Clavulanate for the Treatment of

Acute Otitis Media in Children
Chia-Huei Chu,
1,2
Mao-Che Wang,
1,2
Liang-Yu Lin,
3,4,5
Tzong-Yang Tu,
1,2
Chii-Yuan Huang,
1,2
Wen-Huei Liao,
1,2
Ching-Yin Ho,
1,2
and An-Suey Shiao
1,2
1
Department of Otorhinolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, No. 201, Section 2,
Shih-Pai Road, Taipei 11217, Taiwan
2
Department of Otorhinolaryngology, National Yang-Ming University School of Medicine, No. 155, Section 2, Li-Nong Street,
Taipei 11217, Taiwan
3
Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, No. 201, Section 2,
Shih-Pai Road, Taipei 11217, Taiwan
4
Department of Medicine, National Yang-Ming University School of Medicine, No. 155, Section 2, Li-Nong Street, Taipei 11172, Taiwan
5
Institute of Pharmacology, National Yang-Ming University School of Medicine, No. 155, Section 2, Li-Nong Street, Taipei 11217, Taiwan
Correspondence should be addressed to An-Suey Shiao; asshiao@gmail.com
Received 23 November 2013; Accepted 22 December 2013; Published 6 January 2014
Academic Editors: J. M. Coticchia, R. Matalon, C. OMorain, and P. A. Schachern
Copyright 2014 Chia-Huei Chu et al. Tis is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objective. Tis study uses the acute otitis media clinical practice guideline proposed in 2004 as a reference to evaluate whether
antibiotics doses that are in line with the recommendations lead to better prognosis. Te study also attempts to clarify possible
factors that infuence the outcome. Study Design. Retrospective cohort study. Subjects and Methods. A total of 400 children with
acute otitis media were enrolled. Te dosage of amoxicillin was considered to be appropriate when in accord with clinical practice
guidelines, that is, 8090 mg/kg/day. Te outcome was defned according to the description of tympanic membrane on medical
records. Multivariate logistic regression was used to analyze the relationship between antibiotic dosage and prognosis afer adjusting
for baseline factors. Results. Te majority of prescriptions were under dosage (89.1%) but it was not noticeably associated with
outcome ( = 0.41). Te correlation between under dosage and poor prognosis was signifcant in children below20 kg with bilateral
acute otitis media (odds ratio 1.63; 95% CI 1.022.59, = 0.04). Conclusion. Treating acute otitis media in children, high-dose
amoxicillin with clavulanate as recommended in the clinical practice guideline was superior to conventional doses only in children
under 20 kg with bilateral diseases.
1. Introduction
Acute otitis media (AOM) is one of the common childhood
infections, occurring ofen afer acute upper respiratory tract
infections. It is also the leading cause of clinic visits by
children and the most frequent reason that doctors prescribe
antibiotics [13]. According to insurance statistics, AOM-
related outpatient services in the US were as high as 16
million in 2000, and 80% of the cases were prescribed with
antibiotics. It had been reported that the estimated annual
medical expenditure related to AOM is about $3.8 billion
to $5.3 billion in the US [4, 5]. Te total cost per AOM
episode ranged from C332.00 to C752.49 in several European
countries [6]. Inadditionto medical expense fromphysicians
consultation and medications, AOM indirectly causes the
loss of childrens school time and caregivers work time and
income [7].
To reduce medical costs while maintaining high stan-
dards of medical quality, the American Academy of Pedi-
atrics, the American Academy of Otolaryngology-Head and
Neck Surgery, and the American Academy of Family Physi-
cians endorsed an evidence-based comprehensive review, the
AOM Clinical Practice Guidelines: Diagnosis and Manage-
ment of AOM, which was published in May 2004 [8]. Te
guidelines emphasize the importance of correct diagnosis and
Hindawi Publishing Corporation
e Scientic World Journal
Volume 2014, Article ID 965096, 6 pages
http://dx.doi.org/10.1155/2014/965096
2 Te Scientifc World Journal
provide suggestions for initial treatment of children between
the age of 2 months and 12 years with uncomplicated AOM.
Amoxicillin with or without -lactamase inhibitor is the
mainstreamchoice in the treatment of AOM, but information
on dosage comparisons of antibiotics and research on true
clinical outcome is limited [911]. In the past, most studies
on AOM focused on epidemiological surveys, laboratory
bacteriological reports, and the therapeutic efects of diferent
antibiotics [12, 13]. Experts have published diferent view-
points on the suggestions in the clinical practice guidelines,
such as when to provide antibiotic treatment, how to give
an adequate dose, and the proper duration of treatment. As
most of the evidence comes from bacteriological research in
laboratories and a small number of samples inclinical studies,
higher level evidence is lacking [1417]. Terefore, doctors
still do not have a consensus on these issues [18].
Tis study aimed to evaluate whether physicians pre-
scriptions are in accordance with the dosage guidelines and
whether high-dose amoxicillin with clavulanate is associated
with better outcomes in pediatric AOM.
2. Subjects and Methods
2.1. Subjects. We conducted a retrospective cohort study
from January 1, 2005, to December 31, 2008. Children aged
2 months to 12 years who were diagnosed with acute otitis
media according to the diagnosis code (382.00) in the Inter-
national Classifcation of Diseases, Ninth Revision, Clinical
Modifcation (ICD-9-CM), were enrolled. Tose who had
been coded with any anatomic or genetic abnormalities, such
as craniofacial anomalies or Down syndrome, or immune
defciencies were excluded. Children with histories of recur-
rent AOM (three or more previous episodes of AOM within
12 months), those who had undergone any middle ear or
inner ear procedure, those who had only one visit, or those
missing records were excluded. Teir age, gender, weight,
diagnosis date, unilateral or bilateral disease, and details in
antibiotic prescriptions were reviewed.
2.2. Methods. Antibiotics prescriptions that contained amox-
icillin with clavulanate (amoxicillin 400 mg with clavulanate
57 mg/5 mL) were reviewed in detail. Dosage was considered
to be correct, that is, high dose, if the amoxicillin component
was within 10% of the guideline suggestions. If the dosage
was outside the 10% range, it was considered either over-
or under dose. Te recommended dose of the amoxicillin
component is 8090 mg/kg/day. However, for children over
20 kg, this might correspond to a dosage that surpasses the
common clinical dosage for adults of 1500 mg/day. Terefore,
a daily dosage of 1500 mg amoxicillin for children over 20 kg
was considered to be acceptable.
To evaluate the relationship betweenamoxicillindose and
AOMprognosis, study analysis focused on the comparison of
two groups: those who were prescribed with an amoxicillin
dose that was in agreement with the guideline recommenda-
tions (8090 mg/kg/day) those who were not.
Te assessment of treatment outcome was based on med-
ical records within 14 days afer the antibiotic prescription
expiry date. In our institute, the middle ear status in children
was mainly evaluated by telescope examination by a licensed
otology specialist which had been demonstrated to have
the highest sensitivity (97.8%) and specifcity (100.0%) [19].
Successful control was defned as a medical record of an
eardrum that either was normal or showed otitis media with
efusion (OME). Failed control was defned as improvement
in only one of two afected ears or a change in antibiotics
before the end of the treatment period (with the reason for
changing antibiotics being failure to control illness rather
than side efects).
3. Statistical Analysis
Continuous variables such as age and body weight are pre-
sented as mean and standard deviation. Gender, single-ear or
bilateral disease, and illness season were categorical variables
and represented as numbers and percentages. To analyze
the possible prognostic factors, we used a t-test and chi-
square test for univariate analysis. All covariates in univariate
analyses along with the two basic demographic variables
(gender and weight) were then included in a binary logistic
regression model. All statistical analyses were carried out
with IBM SPSS statistical sofware version 14.0 for Windows
(IBM Corp., New York, USA). Statistical signifcance was
defned as a P value of less than 0.05.
4. Results
4.1. Clinical Characteristics of the Study Population. A total
of 400 medical records with diagnosis code 382.00 were
reviewed. Tere were 94 children with complicated AOM
(i.e., clinical recurrence of AOM within 30 days, histories of
recurrent AOM, AOM with underlying chronic otitis media
with efusion, any underling anomalies that may alter the
course of AOM such as clef palate, genetic problems such
as Down syndrome, immunodefciencies, and status afer any
middle or inner ear surgery); 59 had only one visit, 40 had
incomplete record, 15 were prescribed with cephalosporin or
sulfa drugs, and 27 were prescribed with amoxicillin. One
hundred and sixty fve children treated with amoxicillin with
clavulanate were included into analysis. Te average age of the
165 enrolled patients was 4.91 years old (0.2811.72 years old),
the average weight was 19.36 kg (7.5048.0 kg), and 94 were
boys (57%). Most illnesses occurred in spring (31.5%) and
autumn (28.5%). Single-ear AOM occurred in 81 participants
(49.1%) (Table 1).
4.2. Antibiotic Dosage. Eighteen in 165 (10.9%) prescriptions
were in accord with the recommendations of the clinical
practice guidelines. Underdosage was extremely common
(89.1%). None of the prescriptions exceeded the upper limit
of 90 mg/kg/day. Overall, the average dose of the amoxicillin
component was 45.5 mg/kg/day, which was far lower than the
guideline suggestion. However, 86 (52.1%) prescriptions were
within the range of 4050 mg/kg/day, the traditional usage
for amoxicillin. In other words, half of the physicians indeed
followed the conventional dosage.
Te Scientifc World Journal 3
Table 1: Demographic data of 165 children.
Characteristic Number (%)
Age: mean 4.91 2.52 (y/o)
Body weight: mean 19.36 7.52 (kg)
Gender
Boy 94 (57.0)
Girl 71 (43.0)
Illness season
Spring 52 (31.5)
Summer 28 (17.0)
Autumn 47 (28.5)
Winter 38 (23.0)
Single or bilateral disease
Single-sided AOM 81 (49.1)
Bilateral AOM 84 (50/9)
Abbreviations: AOM: acute otitis media.
Table 2: Treatment outcome of acute otitis media.
Overall High dose Underdose
(%) (%) (%)
Successful control 121 (73.3) 15 (83.3) 106 (72.1)
Eardrum normal 75 (45.5) 10 (55.6) 51 (34.7)
OME 70 (42.4) 5 (27.8) 55 (37.4)
Failed control 44 (26.7) 3 (16.7)

41 (27.9)

Sum 165 18 147

Abbreviations: OME: otitis media with efusion.

Fisher exact test, = 0.41.
4.3. Antibiotic Dosage and Treatment Outcome. Successful
control was achieved in 121 patients (73.3%) while the
remaining 26.7%had failed control. Fewer patients who were
given the correct dose (i.e., high-dose amoxicillin) had poor
AOM prognosis (16.7% versus 27.9%), but this result was not
signifcant (Fisher exact test, = 0.41) (Table 2).
4.4. Factors Afecting Treatment Outcome. In univariate anal-
ysis, only disease in autumn/winter was associated with a
poor prognosis ( = 0.03). Age ( = 0.22), gender ( =
0.07), and body weight ( = 0.25) were not associated
with treatment outcome. Bilateral AOM was borderline
signifcantly correlated with poor disease control ( = 0.05).
Since antibiotics prescribed in children are based on body
weight, the age and weight are highly correlated (Spearmans
rho = 0.88, < 0.001); thus body weight was chosen instead
of age in the following analyses. Using multivariate analysis,
we analyzed relevant factors that infuenced AOM prognosis
(Table 3); it is found that, compared to patients with AOM
in the spring/summer, the odds ratio (OR) of autumn/winter
patients who failed control was 2.47 (95%confdence interval
(CI): 1.175.23, = 0.02).
4.5. Subgroup Analysis. According to the newest interna-
tional growth standards for infants and children from the
World Health Organization (2007) [20], with 50% percentile
estimation, children weigh about 20 kg at 6 years of age.
Table 3: Factors relevant to poor outcome of acute otitis media ( =
165) by multivariate analysis (binary logistic regression model).
Variables value OR of failed control (95% CI)
Girls 0.21 1.61 (0.773.36)
Weight

0.48 0.98 (0.931.04)

Autumn/winter 0.02

2.47 (1.175.23)
Bilateral AOM 0.09 1.96 (0.914.19)
Underdose 0.58 1.45 (0.385.53)
Abbreviations: AOM: acute otitis media; OR: odds ratio; CI: confdence
interval. Reference groups inmodel: boys, illnesses inspring/summer, single-
sided AOM, or high dose.

Age showed high collinearity with body weight in

the model. Since antibiotics were given mainly based on body weight, weight
was chosen instead of age in the regression model.

< 0.05.
Table 4: Factors relevant to poor outcome of acute otitis media:
subgroup analysis of children <20 kg ( = 110) and binary logistic
regression model II.
Variables value
OR of failed control
(95% CI)
Girls 0.84 1.10 (0.442.74)
Weight

0.07 0.89 (0.781.01)

Autumn/winter 0.001

4.90 (1.8712.89)
Bilateral AOM and
underdose
0.04

1.63 (1.022.59)
Abbreviations: AOM: acute otitis media; OR: odds ratio; CI: confdence
interval. Reference groups inmodel: boys, illnesses inspring/summer, single-
sided AOM, or high dose.

Age showed high collinearity with body weight in

the model. Since antibiotics were given mainly based on body weight, weight
was chosen instead of age in the regression model.

< 0.05.
Since the daily dosage for children over 20 kg might sur-
pass the equivalent common clinical dosage for adults of
1500 mg/day, we performedsubgroupanalysis for 110 children
who weighed less than 20 kg (details not shown). Among
this subgroup, illness in autumn/winter was consistently a
strong factor for poor prognosis (OR 4.80; 95% CI 1.8212.67,
= 0.002). In addition, the risk of failed control in bilateral
AOM patients was 2.43 times more than single-sided AOM
children although it was not statistically signifcant (95% CI
0.906.53, = 0.08). No obvious association was observed
between under dose and AOM prognosis (OR 2.18; 95% CI
0.3812.48, = 0.38).
When bilateral AOM and under dose were taken
together, their correlation with treatment failure was evident
(OR 1.63; 95% CI 1.022.59, = 0.04). Again, AOM
in autumn/winter was consistently associated with a poor
prognosis (OR 4.90; 95% CI 1.8712.89, = 0.001). Te
results implied that the beneft of high-dose amoxicillin
with clavulanate as recommended in the guidelines was
more noticeable in children under 20 kg with bilateral AOM
(Table 4).
5. Discussion
Our study found no signifcant correlation between high-
dose amoxicillin and better disease control when treating
AOM with amoxicillin-clavulanate combination. Although
4 Te Scientifc World Journal
fewer patients who were given the high dosage failed to
control AOM (16.7% for high dose versus 27.9% for under
dose), the correlation was not evident. A signifcant asso-
ciation could be seen only in children below 20 kg with
bilateral AOM when they were given insufcient dosages
of amoxicillin. Te OR for these children having a poor
prognosis was 1.63 (95% CI 1.022.59, = 0.04) in contrast
to those who weighed more than 20 kg or with single-
ear disease. Illness in autumn and winter had a strongly
negative impact on AOM recovery. For physicians behavior,
underdosage was extremely common (89.1%), refecting that
the debates on dosage indeed exist even several years afer the
launch of the clinical practice guidelines. To a certain extent,
our results were consistent with the latest guidelines revisions
[21].
Many scholars questioned about guidelines recommen-
dations being based on reports of bacterial drug resistance.
Since laboratory bacteriological studies may be diferent
from clinical trials with patients that evaluate a drugs
curative efect, researchers suggest more studies evaluating
clinical outcomes should be taken into consideration [14
17]. Tere was limited evidence based solely on dosage.
Tis study is one of the few reports that simply investigated
the relationships between amoxicillin dosage and clinical
outcomes. Additional strength of our research was the precise
determination of therapeutic efect. Te treatment outcome
(documented on medical records) regarding the eardrum
status was evaluated by an otology specialist using video-
telescopy coupled with a bright xenon light source which had
been demonstrated to have the highest sensitivity (97.8%) and
specifcity (100.0%) [19].
Schrags study in South America in 2001 concluded
that treatment with short-course high-dosage amoxicillin
(5 days, 90 mg/kg/day) reduced drug-resistant Streptococcus
pneumonia (S. pneumoniae) with a probability of 8% and
relative risk (RR) of 0.8 (0.600.97) compared with more
days with a low dosage (10 days, 40 mg/kg/day). Te short-
course high-dosage amoxicillin was especially helpful for
families with 3 or more children [10]. Garrison compared
the curative efect of high-dosage (8090 mg/kg/day) and
standard-dosage (4045 mg/kg/day) amoxicillin, fnding that
the two treatments had close rates of failure (11% versus 12%,
= 0.78). In addition, the side efects of medication, number
of parents inquiry calls, parents subjective assessment of
treatment days, and number of AOM reoccurrences were not
signifcantly diferent for the two treatments [9]. Our results
were relatively close to Garrisons research. However, the chil-
dren enrolled herein were older than the above-mentioned
two reports and only prescriptions with amoxicillin with
clavulanate were included into analysis.
Te clinical practice guidelines recommendation on
amoxicillin dosage is controversial. Te main reasons for
the higher doses (8090 mg/kg/day) in the guidelines are
reports of penicillin-resistant S. pneumoniae. Before 2004, the
prevalence rate of penicillin nonsusceptible S. pneumoniae
(including intermediate and resistant strains) in the US had
been increasing [2224]. Te resistance rate increased from
21%in1995 to 25%in1998 with a highest reported rate of 33%.
Strain resistant to three or more antibiotics also increased
from 10% to 14%. Terefore, the commonly used conven-
tional amoxicillin dosage (4050 mg/kg/day) was thought
to be insufcient for controlling infection by drug-resistant
bacteria. Te committee therefore suggested that physicians
should give higher doses of amoxicillin to AOM patients.
Previous studies had reported that 30% (1550%) of
dissociated S. pneumoniae from upper respiratory tract
is not susceptible to penicillin, with a medium or high
drug-resistance level. Only S. pneumoniae highly resistant
to penicillin has no response to conventional dosages of
amoxicillin (4050 mg/kg/day). About half of nonsuscep-
tible S. pneumoniae has a medium drug resistance level
to penicillin (minimal inhibitory concentration (MIC): 0.1
1.0 g/mL), and the other half has a high drug-resistance
level to penicillin(MIC2.0 g/mL). Appropriately elevating
dosages increase the drug concentration in middle ear fuid;
theoretically, if this concentration surpasses the MIC of S.
pneumoniae with a medium resistance level to penicillin,
most cases of S. pneumoniae related AOM are responsive to
amoxicillin treatment [25, 26].
As to other common pathogens in AOM, about 50% of
Haemophilus infuenza (H. infuenza) and 100% of Moraxella
catarrhalis (M. catarrhalis) are -lactamase positive [25,
26]. In contrast to penicillin-resistant S. pneumoniae, AOM
caused by H. infuenza or M. catarrhalis requires a -
lactamase inhibitor such as clavulanic acid, a second- or
third-generation cephalosporin, or other types of antibiotics.
A sufcient dose of amoxicillin combined with clavulanic
acid is efective for susceptible-to-medium-resistant S. pneu-
moniae and is also efective against -lactamase-positive
bacteria. For these reasons, the frst choice of a majority of
clinicians is oral amoxicillin with or without a -lactamase
inhibitor (unless patients are allergic to penicillin). In our
hospital, a tertiary referral center as well as a teaching hospi-
tal, some of the specialists prescribed high-dose amoxicillin
with clavulanate at the childs frst visit unless patients were
allergic to penicillin at the era of pneumococcal conjugate
vaccination.
Another important factor that infuenced prognosis was
season. Illnesses in autumn and winter were constant
strongly associated with a poor prognosis in this retrospec-
tive cohort study. Both univariate and multivariate analysis
showed that outcome in autumn/winter patients was poorer
than spring/summer patients (OR 2.47; 95%CI 1.175.23, =
0.02). Te result was even more obvious in children <20 kg
(OR 4.80; 95% CI 1.8212.67, = 0.002). Tis result may
be explained by a high prevalence for upper respiratory tract
infections seen in autumn and winter, and people usually
have several cold episodes. A child attends day care center
or with siblings is likely to have multiple upper respiratory
tract infections before resolution of a previous AOM, leading
to more complicated disease course and poorer prognosis.
Reviewing the English literature, some reported that boys
have poorer AOM prognosis than girls [27]. In our study, the
ratio of boys who failed AOMprimary control was lower than
girls (21.3% versus 33.8%) but was not signifcant ( = 0.07).
Female gender was not an independent risk factor for poor
AOMcontrol either inunivariate or multivariate analysis (OR
1.61; 95% CI 0.773.36, = 0.21). It had been reported that
Te Scientifc World Journal 5
bilateral infection gave rise to poor prognosis [27]. Our study
concluded that patients who had single-ear AOM initially
had 19.8% failed control, as opposed to 33.3% for bilateral
infection patients, although it was borderline signifcant ( =
0.05). Tis may be explained by insufcient samples ( = 165)
in this research. Other parameters related to illness severity
such as body temperature and earache, or infant crying, could
not be comprehensively collected during the process of chart
reviewand were thus not incorporated into outcome analysis.
Patients in medical centers might have diferent or
complicated pathogens causing AOM more than patients
fromcommunity groups, and the possibility of drug-resistant
bacteria could be higher. Children enrolled in this study were
from the ENT Department in our hospital, a medical center.
Besides, the average age in our cohort was 4.88 years old,
which is somewhat older than the commonly seen age for
AOM. Older children should have a lower chance of AOM
[28] because of relative maturity of the Eustachian tube-
middle ear ventilation system; but on the contrary, patients
who are over the common age and had middle ear infections
might have more complex illnesses. Tese two perspectives
could have led to the result of a comparable curative efect of
regular-dose and high-dose amoxicillin with clavulanate.
In real-world settings, physicians prescribe antibiotics
based on their understanding of the pathogenesis, course of
disease, severity of the illness, pathogens causing the illness,
and pharmacological knowledge. Other factors including
physicians personal preference, bacterial drug-resistance
reports from diferent areas or medical associations, care-
givers attitude, and insurance benefts may also play a role.
Our study has limitations. Tis is a retrospective cohort
study; some of the possible risk factors such as past AOM
history, previous visit to primary physicians, medication
that had been used, day care attendance, siblings number,
smoking in the household, and breast milk feeding could not
be fully collected while doing chart review. Te compliance
for antibiotics was not known clearly either.
6. Conclusion
Our study demonstrated that high-dose amoxicillin with
clavulanate as recommended in AOM clinical practice
guidelines provided signifcant benefts only in children
under 20 kg with bilateral illnesses. Te question of how
amoxicillin (amoxicillin-potassium clavulanate combina-
tion) dosage afects the prognosis of AOM needs more
prospective controlled studies that comprehensively collect
common prognostic factors with a large number of samples
and laboratory bacteriological analyses.
Abbreviations
AOM: Acute otitis media
CI: Confdence interval
H. infuenza: Haemophilus infuenza
M. catarrhali: Moraxella catarrhalis
MIC: Minimal inhibitory concentration
OME: Otitis media with efusion
OR: Odds ratio
S. pneumonia: Streptococcus pneumonia.
Conflict of Interests
All authors have no fnancial relationships relevant to this
paper to disclose. All authors report no confict of interests.
Acknowledgment
Te study project was approvedby Institutional ReviewBoard
of Taipei Veterans General Hospital (VGHIRB no. 2012-09-
027B).
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