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A Placebo-Controlled Trial of Antimicrobial

Treatment for Acute Otitis Media (N Engl J Med
2011;364:116-126.)

Paula A. Thtinen, M.D., Miia K. Laine, M.D., Pentti Huovinen, M.D., Ph.D.,
Jari Jalava, Ph.D., Olli Ruuskanen, M.D., Ph.D., and Aino Ruohola, M.D., Ph.D.

Introduction
Acute otitis media is the most common bacterial infection during early childhood. 1
Antimicrobial agents have been the primary treatment for this infection since the
1950s, when the first studies showed that antimicrobial therapy improved the
outcome.2,3 Nevertheless, there is no consensus regarding the optimal management
of acute otitis media.1 Because the treatment of acute otitis media is a major
reason for the use of antimicrobial agents in the outpatient setting, experts have
called for these agents to be used judiciously. 4,5 Several guidelines for the
management of acute otitis media recommend an observation period before
antimicrobial therapy is even considered. 6-10 These recommendations are based
largely on meta-analyses that concluded that for 1 child to have relief of symptoms,
7 to 17 children must be treated with antimicrobial agents. 11-15 However, some
experts have suggested that the original studies included in the meta-analyses had
important limitations, such as biases in patient selection, varying diagnostic criteria,
and suboptimal spectrum or dosage of antimicrobial agents. 1,16-20 We conducted a
randomized, double-blind, placebo-controlled study of the efficacy of antimicrobial
therapy in the age group with the highest incidence of acute otitis media. Our aim
was to assess the efficacy of antimicrobial treatment for acute otitis media when
strict diagnostic criteria are used and the antimicrobial coverage and dosage of the
active treatment are adequate.

Discussion
The study was done to assess the efficacy of antimicrobial treatment (amoxicillinclavulanate) with respect to the resolution of symptoms of acute otitis media. The
study type was randomized, double-blind, placebo-controlled study that was
initiated by the investigators and was conducted independently of any commercial
entities. There are primary and secondary outcomes. The primary outcome was the
time to treatment failure from the first dose until the end-of-treatment visit on day
8. The definition of treatment failure was based on the overall condition of child
(including adverse events) and otoscopic signs of acute otitis media. Secondary
outcome was the time to initiation rescue treatment (rescue treatment was an
open-label antimicrobial treatment, primarily amoxicillin-clavulanate 40/5.7
mg/kg/day divided into two daily doses for 7 days) and the development of
contralateral acute otitis media.
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The study factor of the primary outcome is composed of six independent

components:
No improvement in overall condition by the first scheduled visit (day 3) (i.e.,
unless parent thought that their childs overall condition was improving, the case
was categorized as treatment failure)
A worsening of the childs overall condition at any time
No improvement in otoscopic signs by the end-of-treatment visit on day 8
Perforation of the tympanic membrane at any time
Severe infection (e.g., mastoiditis or pneumonia) necessitating systemic openlabel antimicrobial treatment at any time
Any other reason for stopping the study drug (e.g., an adverse event or nonadherence to the study drug) at any time
The first two components were based on parents assessment of the childs overall
condition (including adverse events; healthy, better, no improvement, or worse) as
reported to the study physician while the four other components were measured by
physicians. The time of treatment failure was the study on which the study
physician confirmed any one of the components for the first time. At the enrollment
visit (Day 1), the patients symptoms, medical history, and demographic and clinical
characteristics were recorded, a nasopharyngeal sample was obtained, and other
clinical examination was performed, including thorough otoscopic and
tympanometric examination. At the first day, parents were given a diary to record
the symptoms (fever was defined as a body temperature of 38 oC or higher; the
writer encouraged the use of analgesic and antipyretic agents), doses of study
drugs and any other medications (the use of analgesic ear drops and decongestant
nose drops or sprays were allowed), absenteeism of the child from day care and of
the parent from work, and adverse events. The recording was used as the data for
the study factors of secondary outcomes.
There were no important confounders considered in this study, because the study
has proven that children with acute otitis media benefit from antimicrobial
(amoxicillin-clavulanate) treatment as compared with placebo, although they have
more side effects on the children. The inclusion criteria of the sampling were:
Children 6 to 35 months of age with acute symptoms
Children in whom acute otitis media was diagnosed per protocol; 3 overall criteria
were required for diagnosis of acute otitis media:
Middle-ear fluid had to be detected by means of pneumatic otoscopic
examination that showed at least two of the following tympanic-membrane
findings: bulging position, decreased or absent mobility, abnormal color or
opacity not due to scarring, or air-fluid interfaces.
At least one of the following acute inflammatory signs in the tympanis
membrane had to be present: distinct erythematous patches or streaks or
increased vascularity over full, bulging, or yellow tympanic membrane.
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The child had to have acute symptoms, such as fever, ear pain, or respiratory
symptoms.
The exclusion criteria were:
Ongoing antimicrobial treatment: If antimicrobial treatment had ceased according
to prescription the day before the enrollment visit, patient was eligible.
Acute otitis media with spontaneous perforation of tympanic membrane: Acute
otitis media with spontaneous perforation of tympanic membrane has been
shown to benefit from antimicrobial treatment. (21) Further, Streptococcus
pyogenes is common in cases with acute otorrhea and this pathogen carries an
increased risk of mastoiditis.(22)
Systemic or nasal steroid therapy within the 3 preceding days: Systemic or nasal
steroids may affect the outcome of acute otitis media. (23-25)
Antihistamine therapy within the 3 preceding days: Antihistamines may affect the
outcome of acute otitis media.(25)
Oseltamivir therapy within the 3 preceding days: Oseltamivir may affect the
outcome of acute otitis media.(26)
Allergy to penicillin or amoxicillin: The active treatment was amoxicillinclavulanate; penicillin and amoxicillin may have allergic cross-reactivity.
Tympanostomy tube present in tympanic membrane.
Severe infection requiring systemic antimicrobial treatment.
Documented Epstein-Barr virus infection within the 7 preceding days.
Down syndrome or other condition affecting middle ear diseases (e.g. cleft
palate): These patients belong to special populations and their acute otitis media
should be treated with antimicrobials.
Known immunodeficiency: As above.
Severe vomiting or another symptom to violate per oral dosage.
Poor parental co-operation due to language or other reasons: Only patients whose
parents could understand, speak, and read Finnish sufficiently were eligible. This
was an important ethical principle because the study physician had to make sure
that the parents understood and accepted that their child could also receive
placebo.
Use of any investigational drugs during the 4 preceding weeks: A common
principle to avoid unknown interactions.
In this study, the eligible patients were randomly assigned to receive amoxicillinclavulanate (40 mg of amoxicillin per kilogram of body weight per day plus 5.7 mg
of clavulanate per kilogram per day, divided into two daily doses) or placebo for 7
days. The random allocation sequence was done with a computerized randomnumber generator by the Department of Biostatistics, University of Turku, Turku,
Finland. The statistician gave the allocation list to the Hospital Pharmacy of Turku
University Hospital, Turku, Finland. The pharmacist concealed the allocation by
labeling the identical opaque study drug containers with allocation numbers.
Another allocation list without the randomization code was given to the Pediatric
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Infectious Disease Ward in Turku University Hospital, Turku, Finland. The ward served
as a call-center where the allocation list was kept. The wards nursing staff assigned
the study participants to their groups by providing the study personnel by phone
the next allocation number in the list.
In this study, from 322 patients who underwent the randomization, 162 were
assigned to receive amoxicillin-clavulanate and 160 were assigned to receive
placebo. From 162 patients that were basically assigned to receive antimicrobial
treatment, only 161 patients received amoxicillin-clavulanate; 1 did not receive
amoxicillin-clavulanate and did not come to any follow-up visits. The 161 patients
who received amoxicillin-clavulanate treatment were all included in the analysis, 1
was included until withdrawn by parent on 3 rd day. From 160 patients that were
assigned to receive placebo, only 159 patients received placebo and 1 did not
receive placebo and did not come to any follow-up visits. From 159 patients who
received placebo, 1 was withdrawn on day 1 and only 158 were included in the
analysis (1 was included until withdrawn by parent on 3 rd day).
The study considered the statistical test by using the Kaplan-Meier method to
analyze time-to-event data with use of the log-rank test; hazard ratios and
confidence intervals (95% confidence intervals were provided in this study) were
calculated on the basis of a Cox regression model. Categorical outcomes were
compared with the use of the chi-square test. All analyses were performed on data
from the intention-to-treat population. All reported P values are two-sided and the
analyses were performed with the uses of SPSS software, version 16.0. The study of
placebo-controlled trial of antimicrobial treatment for acute otitis media is known to
be clinically and socially significant. The development of bacterial resistance is
related to an unnecessary antimicrobial treatment. This has been a problem for
many years that more and more bacteria are developing resistance to antimicrobial
treatment and when it comes to an end, there would be no appropriate drug that
could be used to treat bacterial infection. So, the study of placebo-controlled trial of
antimicrobial treatment is actually needed for another bacterial infection disease in
order to ensure that an appropriate antimicrobial treatment is given to patient and
to minimize the unnecessary use of antimicrobial drugs to treat patients illness.
The study was ethical because there were no children harmed from the study; the
side effects caused by the antimicrobial treatment, for example, were able to be
treated by the use of other medications; parents also had a right to withdraw their
child from the study, so this study was considered as ethical.

Conclusion
The study provides evidence that in children 6 to 35 months of age, the treatment
of acute otitis media with an antimicrobial agent that gives adequate coverage
such as amoxicillin-clavulanate is beneficial. Treatment failure occurred less in
children who received amoxicillin-clavulanate (18.6%) as compared with the
children who received placebo (44.9%). Overall, amoxicillin-clavulanate reduced the
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progression to treatment failure by 62% and the need for rescue treatment by 81%.
Antimicrobial treatment has been proven to be effective in reducing the risk of
treatment failure by improving both overall condition and otoscopic signs, although
children who received antimicrobial treatment developed more side effects (i.e.,
diarrhea, eczema) compared to children who received placebo.

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