Journal of Antimicrobial Chemotherapy (1996) 37, Suppl.

C, 63-69

An open study to compare azithromycin with cefaclor in the treatment of

children with acute otitis media

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A. F. Rodriguez

Juan Pablo II Children's Hospital, Guatemala City, Guatemala

An open, multicentre study involving 259 children between 6 months and 13 years
of age was performed to assess the efficacy and safety of azithromycin and to
compare it with cefaclor as treatment of acute otitis media. Patients were randomized
to receive either azithromycin 10 mg/kg once daily for 3 days or cefaclor 40 mg/kg
daily in divided doses every 8 h for 10 days. Cure or improvement in signs and
symptoms was observed in 112/114 (98%) evaluable azithromycin-treated patients
and 116/120 (97%) evaluable cefaclor-treated patients on days 11-15. In contrast to
cefaclor, however, azithromycin was associated with a significantly (P = 0.033)
higher cure rate 1 month after completion of treatment. In those patients who were
followed up to days 25—30, the response was satisfactory (cure or improvement) in
31/32 (97%) patients who had received azithromycin and in 31/36 (86%) to whom
cefaclor had been administered. Patients tolerated both treatments well and no severe
adverse events related to therapy were recorded in either group. The results of this
study show that a 3-day, once-daily regimen of azithromycin has comparable clinical
efficacy and tolerability to a thrice-daily course of cefaclor administered for 10 days,
but the azithromycin is associated with a lower incidence of relapse.

Introduction
Acute otitis media affects children of all ages and socio-economic backgrounds and is
one of the commonest infectious diseases in childhood (Klein & Bluestone, 1982; Lim,
1989). If untreated, the sequelae, particularly loss of hearing, are frequent and may
persist for life (Holm & Kunze, 1969; Teele, Klein & Rosner, 1984). Otitis media is
predominantly of bacterial aetiology and, if middle ear fluid is examined, bacterial
pathogens are isolated in about two-thirds of cases. Streptococcus pneumoniae is the
most frequently recognized pathogen, followed by Haemophilus influenzae (Klein &
Bluestone, 1982), although Moraxella catarrhalis is becoming increasingly important,
particularly in younger children (Bulmer, Bertino & Husak, 1984; Harrison, Marks
& Welch, 1985; Gehanno et al., 1992).
The penicillins, especially ampicillin or amoxycillin, are extensively prescribed for
this infection. However, the increasing incidence of /Mactamase-producing strains of
H. influenzae and M. catarrhalis has undermined their efficacies in some countries
(Machka, 1990). As a result, a variety of other therapeutic agents, including cefaclor,
cefuroxime, trimethoprim/sulphamethoxazole (co-trimoxazole) and co-amoxiclav, have
been employed. These alternative agents have broadly similar activities to those of
ampicillin against most ampicillin-susceptible pathogens causing otitis media, but
63
0305-7453,96/37CO63 + 07 $12.00/0 £ 1996 The British Society for Antimicrobial Chemotherapy
64 A. F. Rodriguez

have the added advantage of superior activity against /Mactamase-producing strains

(Bluestone, 1990).
The macrolide erythromycin is sometimes prescribed for patients with otitis media
caused by ampicillin-resistant strains and is a frequent choice in those allergic to
/Mactams. Erythromycin, however, is less than optimal therapy because its activity
against H. influenzae is marginal (Washington & Wilson, 1985). As a result, the
empirical use of erythromycin should be restricted to cases where pathogens other than

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H. influenzae are suspected. Alternatively, the pathogen should be obtained by
myringotomy, identified and its antibiotic susceptibility determined, although in
many countries, this procedure is not routinely performed. Furthermore, to await
susceptibility data before the administration of therapy may lead to unnecessary
delay.
The semi-synthetic azalide, azithromycin, is similar in structure to erythromycin, but
has a methyl-substituted nitrogen at position 9a of the lactone ring. It thus possesses
a 15- as opposed to a 14-membered macrocyclic lactone ring (Bright et al., 1988). This
structural modification confers upon azithromycin a wider spectrum of antibacterial
activity than that of erythromycin. As well as being active against Gram-positive
pathogens, including S. pneumoniae, azithromycin is highly effective against
Gram-negative pathogens such as H. influenzae, including /Mactamase-producing
strains, and M. catarrhalis (Aronoff, Laurent & Jacobs, 1987; Retsema et al., 1987;
Dunkin, Jones & Howard, 1988; Hardy et al., 1988). A further advantage of
azithromycin is its unique pharmacokinetic profile, with its ability to achieve high
concentrations in tissues and body fluids (Foulds, Shepard & Johnson, 1990). In a gerbil
model of middle ear infection caused by H. influenzae Girard, Faiella & Cimochowski
(1991) demonstrated that after a single oral dose of azithromycin lOOmg/kg, the
antibacterial agent was still present in the bulla wash, the site of infection, 48 h later
at a concentration of 0.49 mg/L, although the serum concentration had declined
markedly to 0.25 mg/L. The high tissue concentrations of azithromycin were associated
with good clinical efficacy in this in-vivo model and azithromycin was superior to other
macrolides, including clarithromycin, roxithromycin and erythromycin. A study in
children with otitis media scheduled to undergo surgery has also shown that
concentrations of azithromycin in middle ear fluid far exceed those in simultaneous
serum samples and that concentrations in the fluid remained elevated for 48 h after a
course of therapy (Pukander & Rautianen, 1996).
The current study was carried out with the aim of evaluating the efficacy and safety
of azithromycin given once daily for 3 days, compared with cefaclor administered three
times daily for 10 days in the treatment of acute otitis media in children.

Patients and methods

Study design
Approval of the design and conduct of this study, which was carried out according to
the Declaration of Helsinki, was obtained from local ethics committees. Written consent
from the patients' parents or legal guardians was obtained before participation in the
study.
Boys and girls, between 6 months and 12 years of age, with acute otitis media were
eligible for enrolment. The diagnosis was made on the basis of the following symptoms:
 Azithromycin vs cefaclor in otitis media 65

pain in one or both ears; erythema, fullness or bulging of the tympanic membrane; loss
of tympanic membrane landmarks; fever; lethargy; and/or irritability. Children with
chronic otitis media (i.e. those in whom symptoms had persisted for more than 4 weeks)
and those with a perforated ear drum were not enrolled. Any child who was terminally
ill or had an illness or other condition that might prevent completion of the study was
excluded. Also children were not included if they had a gastrointestinal tract
disturbance, such as chronic diarrhoea, that could affect drug absorption, or had a
concurrent infection that required treatment with an antimicrobial agent other than the

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study drug. Concurrent treatment with ergotamine or digitalis glycosides was not
permitted and children were excluded if they were known to be allergic to macrolide
or /Mactarn antibiotics. Other reasons for exclusion from the study were treatment with
another antimicrobial agent in the previous 72 h, receipt of another investigational drug
during the previous month or previous enrolment in the study. Bacteriological sampling
was not performed.

Treatment schedule
Patients were randomly allocated to oral treatment with either azithromycin or
cefaclor. Azithromycin suspension was administered, starting on day 1, as a single
oral dose equivalent to 10 mg/kg once daily for 3 days; doses were administered either
1 h before or 2 h after a meal. Cefaclor suspension was given orally in divided doses
every 8 h (i.e. thrice daily) to give a total daily dosage of 40 mg/kg for 10 days.
All dosages were calculated from the child's weight at enrolment and each child's
parent or guardian was provided with a calibrated spoon or dropper to ensure accurate
dosing.

Evaluation of clinical response

All patients were assessed at visit 3 (day 10-14) for overall changes in the signs and
symptoms recorded before treatment on day 1 and were classified as cured, improved
or failing to respond to therapy according to whether there was complete, partial or
no disappearance, or worsening, of the pretreatment signs and symptoms. The severity
of each of the signs and symptoms (fever, irritability, malaise/lethargy, earache,
reddened eardrum, diminished light reflex) used to assess clinical response to treatment
were recorded on a four-point scale (0, absent; 1, mild; 2, moderate; 3, severe). There
was also an optional follow-up visit between days 25 and 30.

Evaluation of safety
Adverse events, whether observed by the investigators, or volunteered by the children,
their parents or guardians, were recorded at visits 2 (day 4-6) and 3 (day 10-14)
for all patients who received at least one dose of either study drug. The severity
and causal relationship to the study drug were recorded for all such
events.
Samples of blood and urine for laboratory safety testing were taken at enrolment
before the start of treatment (visit 1) and at visits 2 (day 4-6) and 3 (day 10-14). If an
abnormal laboratory value was recorded, the patient was monitored until the variable
had returned to its baseline value or the normal range.
66 A. F. Rodriguez

Statistical analysis
Comparison of clinical responses to azithromycin and cefaclor were performed by the
Cochran-Mantel-Haenszel test based on Ridit scores. Safety data for the two treatment
groups were compared with the chi-squared or Fisher's exact test as appropriate. The
statistical tests were all two-tailed and were performed at the 0.05 significance level.

Results

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A total of 259 children between approximately 5 months and 13 years of age were
enroled; 125 children were randomly assigned to receive treatment with azithromycin
and 134 to receive cefaclor. There were no significant differences in demographic
variables (i.e. sex distribution, age and body weight) between the two treatment groups
(Table I). In the azithromycin group, 11 patients were excluded from clinical evaluation
(three violated the protocol, two were lost to follow-up and six were not evaluated at
the end of therapy), as were 14 patients treated with cefaclor (the protocol was violated
in two patients, one was lost to follow-up and 11 were not assessed at the end of
therapy).
At the assessment between days 10 and 14, 114 azithromycin-treated patients and 120
patients in the cefaclor group were clinically evaluable. The clinical response was classed
as satisfactory (cure or improvement) for 112 (98%) children treated with azithromycin
and for 116 (97%) who had received cefaclor (Table II). Two azithromycin- and four
cefaclor-treated patients were considered to be clinical failures.
The clinical response was assessed on day 25-30 in 32 patients from the azithromycin
group and 36 treated with cefaclor (Table II). At this time, a significantly (P = 0.033)
larger percentage of patients treated with azithromycin were classed as having
responded satisfactorily—31 (97%) who received azithromycin and 31 (86%) in the
cefaclor group were either cured or improved; relapse was recorded in one azithromycin
and five cefaclor treated patients.
All 259 patients who were enroled in the trial and who had received a study
drug were included in the safety analysis. A total of six adverse events possibly
or probably related to antibiotic treatment were noted in six (5%) patients who
received azithromycin (Table III). In the cefaclor-treated group, each of eight patients

Table I. Baseline characteristics of patients in the

treatment groups
Azithromycin Cefaclor
Characteristic (n= 125) (n= 134)
Gender
male (%) 59 (47.2) 73 (54.5)
female (%) 66 (52.8) 61 (45.5)
Age (years)
mean (±S.D.) 4.3 ±2.5 3.6 ±2.7
range 0.5-13.2 0.4-12.1
Weight (kg)
mean (±S.D.) 17.0 ±9.9 16.0 ±7.7
range 7.0-53.0 6.0-59.0
 Azithromycin vs cefaclor in otitis media 67

Table II. Clinical reponse to treatment with

azithromycin or cefaclor on completion of therapy (day
10-14) and at the follow-up assessment (day 25-30)

No. (%) of patients

Clinical response azithromycin cefaclor

End of therapy 114 120

cure 97 (85%) 86 (72%)

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improvement 15 (14%) 30 (25%)
failure 2 (2%) 4 (3%)
Follow-up 32 36
cure 29 (91%) 27 (75%)
improvement 2 (6%) 4(11%)
relapse 1 (3%) 5 (14%)

experienced an adverse event. In neither of the treatment groups were any of the events
considered to be severe. All adverse events experienced by patients in the azithromycin
group involved the gastrointestinal tract, vomiting being the commonest (three events).
Among the cefaclor-treated patients, the most frequent event was diarrhoea which
occurred in seven; the other patient had an erythematous rash. No persistent
abnormalities in laboratory safety data were noted in any of the evaluable patients in
either the azithromycin or cefaclor treatment groups.

Discussion
The azalide azithromycin was shown in the present study to be as effective as the
cephalosporin cefaclor as treatment of acute otitis media in children. This finding is
consistent with the results of previous studies that have demonstrated good clinical
efficacy with azithromycin and comparability with established therapies, such as
amoxycillin (Mohs et al., 1993) and co-amoxiclav (Daniel, 1993; Schaad, 1993), in this
clinical setting.
In the current study, at the end of treatment, satisfactory clinical responses were
recorded in similar percentages of patients, whether they were treated with azithromycin
or cefaclor. There was, however, a significant difference between the treatment groups

Table HI. Adverse events probably or possibly related to treatment

No. (%) of patients

azithromycin cefaclor
System/adverse events (n =125) (n = 134)

Gastrointestinal
diarrhoea 1 (1) 7 (5)
nausea 3 (2) 0
abdominal pain 1 (1) 0
enteritis 1 (1) 0
Dermatological
rash 0 1 (1)
Total no. of patients with adverse events 6 (5) 8 (6)
68 A. F. Rodriguez

in terms of those patients who were successfully followed up 25-30 days after the start
of treatment. At this stage, a significantly higher percentage of patients who had
received azithromycin were deemed to have been cured or to have experienced
improvement in their signs and symptoms, whereas in the cefaclor-treated group there
was a relatively high incidence of relapse at this time. This finding suggests that there
may be an advantage in using azithromycin, thus confirming the preliminary results of
Pestalozza, Cioce & Facchini (1992) who found that the early cure achieved with
azithromycin was maintained at 30 days.

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Azithromycin has another advantage. The dosing regimen for cefaclor involves the
administration of a total of 30 doses given over a 10-day period. In contrast, with
azithromycin, because of its ability to achieve high concentrations in tissues (Foulds
el al., 1990), only three doses given once daily over 3 consecutive days are required to
maintain concentrations in tissues in excess of the MICs of many common pathogens
and to produce a satisfactory clinical response. As all parents know from experience,
it is difficult to administer medication to children. The problem is exacerbated if
treatment has to be given several times each day over a period of a week or more
(Bergman & Werner, 1963). The consequence is that a course of therapy is often not
completed, sometimes resulting in relapse and the need for additional antibiotic
treatment. Gehanno et al. (1990) recognized the problems encountered when dosing
regimens are complex and acknowledged that a short, simple regimen could make an
important contribution to therapy. A three-dose course of azithromycin, therefore,
provides a useful alternative to established antibacterial therapy for the treatment of
otitis media in children.

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