Drugs 42 (Suppl.

4): 25-29, 1991

0012-6667/91/0400-0025/$2.50/0
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DRSUP3254

Cefixime vs Amoxicillin in the Treatment of Acute

Otitis Media in Infants and Children
Nicola Principi and Paola Marchisio
Pediatric Department, University of Milan, Milan, Italy

Summary Cefixime is a new oral cephamycin antibiotic with a broad spectrum of antibacterial activity
in vitro. It is resistant to hydrolysis by most {1-lactamases and has pharmacokinetic characteristics
which allow administration in a single daily dose for the treatment of some bacterial infections.
The aim of this study was to compare the clinical efficacy of cefixime with that of amoxicillin
in the treatment of acute otitis media in 40 children. Cefixime 8 mg/kg was given once daily at
bedtime, whereas amoxicillin 50 rug/kg/day was administered in 3 divided doses; both drugs
were given for 10 days. IS days after starting the trial, a favourable clinical response was dem-
onstrated in 18 of 20 children in both treatment groups. Cure rates, recurrences and persistent
middle ear effusions were not significantly different in the 2 study groups during a 3-month
follow-up. It was concluded that cefixime is clinically effective and well tolerated in the treatment
of children with acute otitis media.

Acute otitis media (AOM) is one of the com-
monest diseases of infants and children. A study
by Teele and associates (1989) is the most repre-
sentative of several different epidemiological stud-
ies demonstrating that only about 20%of the paed-
iatric population do not experience an episode of
AOM in the first 3 years of life, while almost 50%
experience 3 or more episodes. Although it is re-
cognised that 20% of episodes of AOM are caused
by viruses, nearly all children with AOM are treated
with an antibiotic. Reasons for this decision in-
clude both the difficulty of identifying the aetiology
of the single episode at the time of diagnosis (Blue-
stone 1989) and the possibility that viral AOM can
be complicated by superimposed bacterial infec-
tions (Chonmaitree et al. 1990).
The choice of the best antibacterial drug for
treating AOM depends on several factors, the most
important being knowledge of the bacterial species
commonly responsible for the disease and their
susceptibility to commonly used antibiotics.
Studies performed in both the USA and Europe
have demonstrated that Streptococcus pneumon-
iae, Haemophilus injluenzae and Branhamella
(Moraxella) catarrhalis account for over two-thirds
of the bacteria recovered from middle ear fluid
during AOM (Bluestone 1989;Francois et al. 1988;
Karma et a1. 1987). As a consequence, amoxicillin
has been considered the drug of choice, while ce-
faclor and cotrimoxazole have been proposed in
cases in which amoxicillin cannot be used. How-
ever, recent microbiological research, particularly
that conducted in the USA, has demonstrated an
increasing prevalence of isolates of {1-lactamase-
producing strains of H. injluenzae and B. catar-
rhalis from children with AOM. In the Scottsdale
region, for example, in the period 1981 to 1990,
the percentages of {1-lactamase-producing strains
26
of H. influenzae and B. catarrhalis have increased
from 17 to 40% and from 67 to 95%, respectively
(McLinn 1990). In Italy, the incidence of i3-lacta-
rnase-producing strains of bacteria responsible for
AOM varies considerably between different geo-
graphical areas where middle ear fluids were ob-
tained and cultured. In our experience of children
living in Milan, the problem still seems to be of
limited importance. However, the availability of
drugs active against i3-lactamase-producing bacte-
ria may be very important.
Cefixime, an orally absorbed broad spectrum
bactericidal o-lactam antibiotic, is a compound ex-
hibiting both a pharmacokinetic profile and micro-
biologicalactivity that are of great interest for AOM
therapy. This agent can be administered once daily
and is resistant to hydrolysis by a wide range of 13-
lactamases, For these reasons, it has the potential
to become a first-line treatment for AOM.
This paper reports the results of an open label
randomised prospective trial comparing cefixime
with amoxicillin in Italian children with AOM.
1. Materials and Methods
Children with clinical signs and symptoms of
AOM were enrolled in the study. The diagnosis of
AOM was based on clinical data (fever or otalgia
or both), pneumatic otoscopy (hyperaemia or
opacity, accompanied by fullness or bulging of the
tympanic membrane, immobility) and tympano-
metric findings (a flat, type B curve and absent sta-
pedial reflex). Children with otorrhoea were in-
cluded only if the ear had been draining for no
longer than 12 hours.
Patients were assigned in an open label fashion
to receive treatment with either cefixime or amox-
icillin according to a table of random numbers. Ce-
fixime dosage was 8 mg/kg administered once daily
at bedtime and amoxicillin 50 rug/kg/day was given
in 3 divided doses for to days. No other medica-
tion was administered except for antipyretics if
needed.
Laboratory evaluations were performed at the
time of enrolment and at the end of treatment.
Blood tests consisted of a complete blood count
Drugs 42 (Suppl. 4) 1991
with differential and platelet evaluation and a bio-
chemistry profile including urea nitrogen, serum
creatinine, and aspartate aminotransferase. Patients
with apparently clinically significant results were
repeatedly retested until either normal laboratory
values were noted or it was concluded that treat-
ment was unsuccessful, Tympanocentesis was not
performed because it was considered not justifiable
on ethical grounds except for specific clinical sit-
uations in selected patients.
Early therapeutic efficacy was evaluated from
clinical, otoscopic and tympanometric findings
midtreatment and 5 days after the completion of
therapy. Particular attention was also given to the
evaluation of adverse reactions strictly related to
antibiotic administration, such as nausea, vomit-
ing, diarrhoea and skin rashes.
Early outcome was defined as follows:
• Cure: normalisation of clinical, otoscopic and
tympanometric findings.
• Improvement: relief of acute signs and symp-
toms of AOM with persistent unilateral or bilateral
middle ear effusion demonstrated by otoscopy (ab-
normalities of the tympanic membrane, i.e. dif-
fusely opaque or presence of air-fluid level) and
tympanometric findings (flat, type B curve and ab-
sent stapedial reflex).
• Failure: persistence of signs and symptoms of
AOM midtreatment and/or need for discontinua-
tion of treatment because of adverse effects. Child-
ren in whom treatment was considered to be a fail-
ure were discharged from the study and treated with
other antibiotics. The other children were sched-
uled to be re-examined 30, 60 and 90 days after
entering the study and at any time during the study
period if symptoms of disease recurred. Each visit
included an interval history and physical exam-
ination with pneumatic otoscopy and tympano-
metry. On the basis of the data collected during
these visits, late outcome was defined as follows:
• Cure: resolution of otitis media with effusion
demonstrated by normalisation of otoscopic tym-
panometric findings.
• Recurrence: a new episode of AOM.
• Persistence of effusion: either unilateral or bi-
lateral middle ear effusion.
Cefixime and Acute Otitis Media in Children 27

Table I. Demographic details of infants and children with 40 300/mm 3, SD ± 6400) in the amoxicillin group.
acute otitis media enrolled in a randomised comparison Pretreatment mean CRP serum level was 43.3 mg/
of cefixime and amoxicillin L (range 5 to 159 mg/L, SD ± 41.8) in the cefixime
group and 43.6 mg/L (range 6 to 189 mg/L, SD ±
Cefixime Amoxicillin
42.0) in the amoxicillin group. The differences were
(n = 20) (n = 20)
not statistically significant.
n % n %
2.2 Early Outcome
Age (years)
0.5 1 5 1 5
0.5-1.9 6 30 8 40 Two of20 (10%) children treated with cefixime
2.0-6.0 9 45 8 40 were considered cured compared with 4 (20%) of
6.0-12.0 4 20 3 15 those given amoxicillin (table II). Improvement was
noted in 16 (80%) of the children treated with ce-
Sex
Male 11 55 13 65
fixime, compared with 14 (70%) of those in the
Female 9 45 7 35 amoxicillin group. Two patients in each treatment
group (10%) were considered treatment failures. Of
Prior otitis media
those treated with cefixime, 1 had a suppurative
None 8 40 7 35
complication (mastoiditis), caused by Pseudo-
Prior episodes 12 60 13 65
monas aeruginosa resistant to cefixime, while
Laterality of disease treatment was discontinued in the other because of
Unilateral 10 50 10 50 vomiting. Both children who failed amoxicillin
Bilateral 10 50 10 50
therapy had persistent signs and symptoms of AOM
after 5 days of therapy. Laboratory investigations
performed 5 days after the end of treatment showed
The results were statistically analysed using the that all the patients, excluding failures, had WBC
Student's paired t-test and x 2 analysis with Yates counts and CRP serum levels within the normal
correction unless the sample size was too small, in range.
which case Fisher's exact test was used. All re-
ported p values were 2-sided. The level of signifi- 2.3 Late Outcome
cance selected was p < 0.05.
Cure rates and frequency of persistence of ef-
2. Results fusion at 30, 60 and 90 days after the acute episode
2.1 Group Comparability and Laboratory were similar in both groups (table II), showing an
Values upward trend in cure rate and a concomitant
downward trend in persistence of effusion.
A total of 40 patients entered the study, 20 for Adverse reactions were infrequent with only one
each treatment group. Children treated with cefix- cefixime-treated child requiring withdrawal of the
ime and amoxicillin were similar with respect to drug because of vomiting, and 3 patients in each
age, sex, prior history of AOM and laterality of dis- group experiencing mild diarrhoea, which did not
ease (table I). Moreover, most patients in each require withdrawal of therapy.
group had high white blood cell (WBC) counts and
C-reactive protein (CRP) serum levels, possibly in- 3. Discussion
dicative of a bacterial aetiology of the episode. Pre-
treatment mean WBC count was 12600/mm 3 This study confirms data reported by Howie and
(range 7700 to 19900/mm 3, SD ± 3800) in the Owen (1987), Kenna et al. (1987) and McLinn
cefixime group and 12 500/mm 3 (range 5700 to (1987), who demonstrated that cefixime is at least
28
Table II. Clinical outcome (no. of patients) at different time intervals after beginning treatment with cefixime (C) or
amoxicillin (A) in 40 infants and children with acute otitis media
Clinical outcome Time after start of treatment
15 days 30 days
C A C A
Cure 2 4 3 5
Improvement 16 14
Persistent effusion 14
Failure 2 2
Recurrence
Lost to follow-up
as effective as, or superior to, the antibiotics tra-
ditionally employed in the treatment of AOM in
infants and children. In particular, our data dem-
onstrate that cefixime 8 mg/kg given once daily is
as effective as amoxicillin 50 rug/kg/day in 3 di-
vided doses. The normalisation of the clinical pic-
ture and of acute phase reactants in most patients
after 10 days' treatment with either antibiotic dem-
onstrates the efficacy of both cefixime and amox-
icillin in the treatment of AOM.
However, in contrast to other bacterial paedi-
atric infectious illnesses, in which the therapeutic
goal is to resolve the acute phase of the disease,
children with ADM require long term monitoring
of middle ear condition. In fact, it has been dem-
onstrated that the persistence of effusion in the
middle ear cavity for a long period of time (more
than 3 to 6 months) causes a conductive hearing
loss and may result in language, behavioural and
learning defects (Marchant et al. 1984; Teele et al.
1984). Rates of persistence of middle ear effusion
were similar in both treatment groups, although
somewhat higher than in other reports. The differ-
ence may be related to the time of year in which
the study was conducted (winter) and to the high
proportion of children who had experienced pre-
vious episodes of ADM.
We conclude that cefixime is effective and well
tolerated when used in the treatment of ADM both
in infants and children. An antibiotic requiring only
once daily administration and with activity against
Drugs 42 (Suppl. 4) /99/
60 days 90 days
C A C A
5 7 7 9
13 8 10 5 7
0 3 4 2
2
[1-lactamase-producing strains of common patho-
gens is undoubtedly a suitable alternative to
traditional therapy.
References
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Chonmaitree T, Owen MJ, Howie VM. Respiratory vi-
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Howie VA, Owen MJ. Bacteriologic and clinical efficacy
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Teele DW, Klein JO, Rosner B, et al. Otitis media with
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29
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Correspondence and reprints: Prof. Nicola Principi, Pediatric De-
partment IV, University of Milan, via GBGrassi 74,20157 Milan,
Italy.