Indian Journal of Pediatrics, Volume 72March, 2005 233

Special Article
Correspondence and Reprint requests : Dr. Mukesh Aggarwal,
Head of Unit, Pediatric Department, B.Y. Nair Hospital, Mumbai,
India.
Acute Otitis media (AOM) is the most frequent
respiratory tract infection of infancy and childhood that is
treated with antimicrobial agents.
1,2
Complications of
untreated AOM include mastoiditis, meningitis, lateral
sinus thrombosis and chronic suppurative otitis media.
3
Earlier, the complications of untreated AOM were
infrequent in developed countries because of the efficacy
of orally administered antibiotics. However, with the
emergence of multidrug resistance among all the major
bacterial pathogens, serious complications can occur.
The most common causative pathogens include
Streptococcus pneumoniae, Haemophilus influenzae and
Moxarella catarrhalis, and therefore antibacterial
management should target against these isolates.
4
Increased incidence of beta-lactamase-producing strains
of H.influenzae and M.catarrhalis in acute otitis media
reinforces the fact that beta-lactamase stable drugs such as
Comparative Efficacy and Safety Evaluation of Cefaclor
VS Amoxycillin + Clavulanate in Children with Acute
Otitis Media (AOM)
Mukesh Aggarwal, Ramanuj Sinha
1
, M. Vasudeva Murali
2
, Prita Trihan
1
and P.K. Singhal
3
Pediatric Department, B.Y. Nair Hospital, Mumbai,
1
National Medical College, Kolkata,
2
Gandhi Medical College
and Hospital, Secunderabad, Andhra Pradesh,
3
Apollo Hospital, New Delhi, I ndia.
Abstract. Acute Otitis Media (AOM) is the most frequent respiratory tract infection of infancy and childhood that is treated
with antimicrobial agents. The most common causative pathogens include Streptococcus pneumoniae, Hemophilus influenzae
and Moxarella catarrhalis, and therefore antibacterial management should target against these isolates. Cefaclor, a congener
of cephalexin monohydrate, is a semisynthetic cephalosporin antibiotic. It is an orally active cephalosporin which has
demonstrated activity against a wide range of organisms in vitro. Present study is designed as a multicentric prospective trial
to study and compare the efficacy and safety of cefaclor versus amoxicillin+clav in children with acute otitis media. One hundred
and sixty seven patients were evaluated for efficacy endpoints in the cefaclor arm comprised of 104 males and 63 females with
a mean age of 5.742.80 years and 185 patients in the amoxy-clav group comprised of 118 males and 67 females with a mean
age of 4.932.92 years. Both cefaclor and amoxy-clav caused a significant improvement in all the signs and symptoms after
a 10-day treatment period. However, between-the-group comparisons showed that the reduction in most of the symptoms was
significantly more in cefaclor arm as compared to amoxicillin-clav arm. The clinical success (clinical cure + improvement) at
the end of therapy was significantly more in cefaclor arm: 98% with cefaclor versus 85% with amoxicillin+clav, p<0.05 (Table
3). Failure cases were prescribed other antibiotics according to the culture sensitivity reports, as rescue medication. Bacterial
eradication rates were largely consistent with clinical responses. Bacteriological eradication was seen in 95% of patients in
cefaclor group and 78% of patients in amoxicillin+clav group. In conclusion, cefaclor is a well tolerated and effective antibacterial
option for acute otitis media in children and it is superior to the combination of amoxicillin+clav in efficacy and tolerability in acute
AOM. Moreover, its expanded spectrum of activity, ability to achieve adequate concentrations in tissues, suitability for twice-
daily dosing, and proven tolerability suggest that it is a good alternative to agents traditionally used in acute otitis media.
[Indian J Pediatr 2005; 72 (3) : 233-238] E-mail: ashok.moharana@ranbaxy.com
Key words: Acute Otitis Media (AOM); Cephalosporins; Antibacterial therapy
second and third generation oral cephalosporins and
amoxicillin/clavulanate have become alternative
therapies, particularly for patients with recurrent otitis
media.
5
Resistance to penicillins is also of increasing
concern particularly among strains of S. pneumoniae and
AOM patients are more likely to be penicillin-resistant
than isolates from any other source. Persistent and
recurrent AOM more frequently involves pathogens with
increased resistance to antimicrobials.
5
Cefaclor, a congener of cephalexin monohydrate, is a
semisynthetic cephalosporin antibiotic. It is an orally
active cephalosporin which has demonstrated activity
against a wide range of organisms in vitro. It is well
absorbed when given orally on an empty stomach.
Although metabolism may play a role in the disposition
of cefaclor, elimination is primarily renal. Cefaclors
spectrum of activity is better than the commonly used
first-generation cephalosporins, including a wide range of
gram-negative and gram-positive bacteria; in particular,
Escherichia coli, Klebsiella spp. Proteus mirabilis,
Mukesh Aggarwal et al
234 Indian Journal of Pediatrics, Volume 72March, 2005
Salmonella spp. and Haemophilus influenzae are more
susceptible to clinically achievable concentrations of
cefaclor than cephalexin. Cefaclor has been demonstrated
to be effective against beta-lactamase-producing H.
influenzae resistant to ampicillin. Efficacy of cefaclor has
been demonstrated in urinary tract, upper and lower
respiratory tract, and skin and soft tissue infections in
adults and children as well as in pediatric otitis media.
Adverse reactions, mostly gastrointestinal, are generally
mild and occur in few patients.
6
Combination of
amoxycillin and clavulanate (a beta-lactamase inhibitor)
have been used in various respiratory tract infections
including Otitis media.
On this background present study is designed as a
multicentric prospective trial to study and compare the
efficacy and safety of cefaclor versus amoxicillin+clav in
children with acute otitis media.
MATERIALS AND METHODS
Study Design
Under a prospective, open, comparative and multicentric
study patients were treated as out-door patients or
hospitalized during the treatment period and this was at
the discretion of the investigator. All participating
patients or their legal guardians provided consent prior to
enrollment. And the Institutional Review Board or
Independent Ethics Committee of each site approved the
study protocol.
Patients
In the study only the patients aged 6 months to 12 years
with clinical symptoms and tympanic membrane signs of
AOM, otoscopic evidence of acute inflammation
(dullness,

cloudiness, erythema or bulging, perforation)
plus tympanometric-confirmed middle ear effusion in at
least 1 ear were enrolled. Both fresh and recurrent cases
(without complications like mastoiditis) were included.
Eligible patients were not on any other antibiotic therapy
when enrolled in the study.
The study excluded the patients with appearance and
history more

suggestive of chronic otitis media with
effusion, ventilation tube, perforated tympanic
membrane, and chronic suppurative

otitis media; serious
chronic disease (for example, cystic fibrosis,

valvular heart
disease); previous complications (septic

complications,
hearing impairment); children with complicated AOM
(eg. mastoiditis), facial abnormalities, that would
confound evaluation of the therapeutic response; known
severe renal disease; patients hypersensitive/contra-
indicated to study drug.
Study procedure
Either cefaclor 20 mg/kg 40-mg/kg per day in 3
divided doses for 10 days (cefaclor arm) or Amoxycillin
+ clavulanate 45mg/kg every 12hrly or 40mg/kg every
8hrly for 10 days (amoxycillin arm) was administered to
those patients fulfilling the inclusion criteria of the study.
No topical aural antibacterial within 2 days before the
study or any systemic antibacterial within 2 days before
the study or during the study were allowed. Before
initiating the antibiotic therapy, the ear canal was
cleansed with an antibiotic and tympanocentesis was
performed in order to obtain middle ear fluid for isolation
of bacterial pathogens as well as determination of
antibiotic susceptibilities.
From the first day upto the end of therapy (on 10
th
day)
the patients were evaluated. Wherever possible,
tympanocentesis was repeated if there was no clinical
improvement after 72 hour of treatment or as clinically
indicated. Patients requiring antacids containing
aluminium and magnesium salts were administered 8
hours before or after cefaclor/amoxy-clav administration.
If the symptoms were not controlled or worsened,
additional medications could be given depending at the
discretion of the investigator and this rescue medication
was recorded in the CRF. Patients were considered to be
compliant with the study medication if at least 80% of
study medications were taken according to the prescribed
regimen (as judged by the investigator by asking
questions to the patient and/or their parents/guardian.
Otherwise patient was considered to be normal.
Evaluation Visits
After keen observation of the patient the physician
recorded for adherence to therapy, any adverse drug
reactions and the clinical response on the following days:
Visit 0: Day 0 (inclusion w.r.t. eligibility criteria)
Visit 1: Day 1, start of study medications
Visit 2: Day 10, end of therapy.
In order to assess the tympanic membrane for severity
of erythema, opacification, loss of light reflex, fullness or
bulging, drainage, perforation, mobility and middle ear
effusion autopsy was performed at each visit.
Tympanometry was interpreted to confirm the presence
(abnormal) or absence (normal) of middle ear effusion.
At each visit symptoms of otalgia, irritability, anorexia,
lethargy, decreased hearing, vertigo and fever were
assessed. For any complications patients were also
monitored.
Efficacy Assessment
Primary outcome measures were listed as follows
1. At the end of the therapy clinical resolution of
tympanic membrane (otoscopic) signs and
symptoms of AOM determined.
2. No. of cases in which change of antibiotics was
needed
3. Physician Global Evaluation of patient condition
(using a 5-point scale)
1=Excellent, 2=Very Good, 3 = Good, 4= Fair, 5
=Poor
4. Clinical Outcome was defined as follows:
Clinical Cure: Defined as absence of fever, otalgia,
Comparative Efficacy and Safety Evaluation of Cefaclor vs Amoxycillin + Clavulanate
Indian Journal of Pediatrics, Volume 72March, 2005 235
irritability and otoscopic signs of AOM for patients who
did not require additional antibiotics, regardless of the
presence of residual middle ear effusion.
Improved: If clinical signs and symptoms including
otoscopic findings diminished but did not completely
resolve i.e persistence of otitis media with effusion.
Relapse/Recurrence: Reappearance of signs and
symptoms during treatment.
Failure: Unsatisfactory remission of tympanic
membrane signs or symptoms of AOM requiring
additional antimicrobial therapy.
5. Bacteriological Outcome was defined as follows :
Cure: Pathogen eradicated from post treatment
cultures.
Presumed Cure: No subsequent culture but no signs or
symptoms of acute infection with or without persistence
of middle ear effusion.
Cure with Reinfection: New pathogen isolated following
cure, requiring continued or alternate therapy.
Failure: No clearance of initial pathogen following > 3
days of treatment.
Recurrence: eradication and then reisolation of initial
pathogen).
Safety Assessment
After the close observation of the patients the severity of
clinically adverse events was categorized by the
investigators as mild, moderate or severe. It is also
classified the relationship of adverse events to the study
drugs as either certainly, probably, or possibly drug
related; not drug related; or with an unknown
relationship to the study drug.
Global assessment of overall tolerability was also
recorded on a 5-point scale (1=excellent, 2 =very good,
3=good, 4=fair, 5=poor).
Statistical Analysis
Symptom assessment was done with actual patient
numbers. Age is presented as mean + SD. Rest of the data
is presented as percentages. Comparison of signs and
symptoms of disease before and after therapy and
comparisons between the two groups was done by Paired
t-test. The limit of significance was set at p value < 0.05.
RESULTS
Patient Characteristics
One hundred and sixty seven patients were evaluated for
efficacy endpoints in the cefaclor arm comprised of 104
males and 63 females with a mean age of 5.742.80 years
and 185 patients in the amoxy-clav group comprised of
118 males and 67 females with a mean age of 4.932.92
years (Table 1). These excluded those sixteen patients in
the cefaclor group and twenty one patients in the amoxy+
clavulanate group who were dropped from the study
mostly because of lost to follow up. All children had one
or more pretreatment symptoms of AOM; the most
frequent were earache, irritability, lethargy), infection and
exudation. In most children the severity of symptoms was
classified as moderate. All children had one or more
abnormal otoscopy findings; the most frequent were
bulging tympanic membrane, erythema and loss of light
reflex. Many children also had signs of systemic infection:
cough, vomiting and diarrhea and fever.
TABLE 1. Demographic Profile and Baseline Characteristics of
Patients Evaluated for Efficacy end Points and Safety
Profile.
Cefaclor Group Amoxy+ Clav Group
Total Patients 167 185
Male Female Male Female
104 63 118 67
Mean Age (Years) 5.742.80 4.93 2.92
Overall Clinical Response
Both cefaclor and amoxy-clav caused a significant
improvement in all the signs and symptoms after a 10-day
treatment period (Table 2). However, between-the-group
comparisons showed that the reduction in most of the
symptoms was significantly more in cefaclor arm as
compared to amoxicillin-clav arm (Table 2). The
percentage decrease in signs and symptoms at the end of
therapy in the two treatment groups is shown in Fig 1.
The clinical success (clinical cure + improvement) at
the end of therapy was significantly more in cefaclor arm:
98% with cefaclor versus 85% with amoxicillin+clav,
p<0.05 (Table 3). Failure cases were prescribed other
antibiotics according to the culture sensitivity reports, as
rescue medication.
Bacteriological Outcome
Pretreatment pathogens were isolated from 233 (70%)
patients. The most common pathogens isolated were S.
pneumoniae, H. influenzae and M. catarrhalis. Bacterial
eradication rates were largely consistent with clinical
responses. Bacteriological eradication was seen in 95% of
patients in cefaclor group and 78% of patients in
amoxicillin+clav group (Table 3).
Global Assessment
94% physicians rated treatment with cefaclor as excellent
to good versus 80% with amoxicillin+clav (Fig. 2)
Adverse Effect Profile
Table 4 summarizes the drug-related adverse events.
Gastrointestinal side effects were the only adverse events
reported, and were significantly more in amoxy-clav
group compared to cefaclor. Most of the adverse effects
were mild and self-limiting in nature. None of the patients
withdrew from the study due to these adverse events.
At the end of the study overall tolerability of study
medications was assessed by the physicians. 95% rated
the tolerability of cefaclor as excellent to good versus 72%
Mukesh Aggarwal et al
236 Indian Journal of Pediatrics, Volume 72March, 2005
TABLE 2. Comparison of Change in Symptom Scores in the Two Groups
Cefaclor Group Amoxy + Clav Group
% Change p-value* % Change p-value*
Symptoms
Earache/Otalgia -97.87% p<0.001 -74.61%
a
p<0.001
Irritability -93.33% p<0.001 -77.77%
b
p<0.001
Lethargy -88.28% p<0.001 -66.14%
a
p<0.001
Infection -92.77% p<0.001 -80.68%
b
p<0.001
Exudation -85.6% p<0.001 -67.97%
a
p<0.001
Tympanic Membrane Signs
Bulging (Otoscopy) -93.33% p<0.001 -75.84%
a
p<0.001
Erythema -90.98% p<0.001 -78.33%
b
p<0.001
Loss Of Light Reflex -92.94% p<0.001 -83.78%
c
p<0.001
Systemic Infection
Presence of Cough, Vomiting & Diarrhea -85.39% p<0.001 -73.4%
b
p<0.001
Fever -90% p<0.001 -76.54%
a
p<0.001
*p value is compared to baseline value.
a
p < 0.001 , comparison between two drugs
b
p < 0.05 , comparison between two drugs
c
p < 0.01 , comparison between two drugs
of amoxy-clav. Similarly, 93% of the patients rated
tolerability of cefaclor as excellent to good versus 68% in
amoxy-clav group. (Figs. 3 and 4)
DISCUSSION
A common medical problem like acute otitis media is also
very familiar to pediatricians who attend children with
this condition on a regular basis and to childrens
caretakers, whose normal routine is so often disrupted as
a result. Adequate treatment on time is desirable in order
to relieve the childs immediate discomfort. Likelihood of
long-term sequelae, such as hearing loss or permanent
middle ear damage should be lessened with the help of an
effective antibacterial treatment in AOM.
7
Factors influencing the successful management of
acute otitis media, include the knowledge of the
etiological organisms, primarily S. pneumoniae, H.
influenzae and M. catarrhalis and their particular
susceptibilities to antimicrobial agents.
8
Due to the
increasing isolates with -lactamase-producing capability,
use of amoxicillin and ampicillin has decreased in favor of
drugs with greater -lactamase stability. Thus, the oral
cephalosporins cefaclor and oral third generation
TABLE 3. Clinical and Bacteriological Outcomes in the Two Groups
Cefaclor Group Amoxy+Clav. Group
Clinical outcome
Cure 96.6% 80%
Improvement 2.4% 5%
Failure 1% 15%
Bacteriological outcome
Cure/ Presumed Cure 95% 78%
Failure/ Presumed failure 5% 16%
Recurrence 0% 6%
TABLE 4. Number of Patients with Most Frequently Reported
Adverse Events in Each Group
Adverse event Cefaclor group Amoxy + Clav group
Diarrhea 3 20*
Nausea 1 9*
Vomiting 1 9*
Bloating 1 3
P < 0.05, comparison between two groups
cephalosporins, as well as amoxicillin/clavulanate and
cotrimoxazole are now frequently prescribed.
4,5
Cefaclor is an oral cepahalosporin with good
antibacterial activity against these common pathogens
involved in acute otitis media. Its efficacy has been seen to
be similar to cefuroxime axetil and azithromycin.
9,10
Cefaclor is effective in vitro against the organism most
commonly associated with the otitis media including S.
pneumoniae and -lactamase-positive and negative strains
of H. influenzae.
This multicenter study reveals that cefaclor is an
effective antimicrobial agent for acute AOM and its
efficacy is significantly superior to that of the combination
of amoxicillin+clav. There was a marked improvement in
all the signs and symptoms associated with acute AOM
over 10 days of the study. Clinical success was obtained in
98% of patients in cefaclor group versus 85% with
amoxicillin+clav.
The results of this study are in line with those of earlier
multicentre, randomized, comparative clinical trials
carried out to assess the efficacy of cefaclor in the
treatment of children with acute and uncomplicated otitis
media with effusion. Cefaclor produced a statistically
higher response rate than amoxycillin (p=0.03) in a
double-blind randomized clinical trial in 110 children
suffering from acute AOM with effusion.
11
The most common pathogens isolated from patients in
the present study were S. pneumoniae, H. influenzae and M.
Comparative Efficacy and Safety Evaluation of Cefaclor vs Amoxycillin + Clavulanate
Indian Journal of Pediatrics, Volume 72March, 2005 237
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-100.00%
-80.00%
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Cefaclor
Amoxy+Clav
Fig. 1. Change in symptoms score in each group
50%
33%
11%
6%
0%
35%
20%
25%
18%
2%
0%
10%
20%
30%
40%
50%
60%
Excellent Very good Good Fair Poor
Grading of efficacy
%

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cefaclor
amoxy+clav
Fig 2. Global efficacy assessment by physicians
29.20%
10.20%
32.30%
21.50%
33.80%
39.90%
3.80%
16.50%
0.80%
11.80%
0.00%
25.00%
50.00%
Excellent
Assessment Of Overall
Tolerability
Good Poor
Cefaclor Group Amoxy+Clav Group
Fig 3. Analysis of Physicians Overall Tolerability of Drugs
Fig. 4. Analysis of Patients Overall Tolerability of Drugs
23.80%
13.50%
31.50%
20.20%
37.70%
34.60%
5.80%
19.80%
0.80%
11.90%
0.00%
25.00%
50.00%
Excellent
Assessment Of Overall
Tolerability
Very Good Good Fair Poor
Cefaclor Group Amoxy+Clav Group
Mukesh Aggarwal et al
238 Indian Journal of Pediatrics, Volume 72March, 2005
catarrhalis. Cefaclor eradicated pathogens in 95% of the
patients compared to 78% in amoxy-clav group. The
clinical effectiveness of cefaclor may be related to its
excellent in vitro activity against a wide range of
organisms. Its spectrum of activity is wider than that of
cephalexin.
Cefaclor was better tolerated by our study population
compared to amoxicillin+clav. The side effects observed
in both groups were of mild intensity and no patient
withdrew from the study due to adverse events.
CONCLUSION
For acute otitis media in children, cefaclor is a well
tolerated and effective antibacterial option. It is superior
to the combination of amoxicillin+clav in efficacy and
tolerability in acute AOM. Moreover, its expanded
spectrum of activity, ability to achieve adequate
concentrations in tissues, suitability for twice-daily
dosing, and proven tolerability suggest that it is a good
alternative to agents traditionally used in acute otitis
media.
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