ORGNAL RESEARCH ARTCLE

Adls 2012 Springer international Publishing AG. All rights reserved.

Comparison of Amoxicillin/Clavulanic
Acid High Dose with Cef dinir in the
Treatment of Acute Otitis Media
Janet R. Casey} Stan Block^ Jim Hedrick^ Anthony Almudevar^ and Michael E.
1 Legacy Pediatrics, Rochester, NY, USA
2 Kentucky Pdiatrie Research, Bardstown, KY, USA
3 Department of Biostatistics & Computational Biology, University of Rochester, Rochester, NY, USA
4 Rochester General Hospital Research Institute, Center for Irvfectious Diseases and Immunology, Rochester,
NY, USA
Abstract Background: 10 days of amoxicillin/clavulanic acid high dose and 5 days of
cefdinir have been the preferred first- or second-line antibiotics for treatment
of children with acute otitis media (AOM) since 2004, as recommended by the
American Academy of Pediatrics in the USA, but no head-to-head compar-
ison study has been done.
Objective: The purpose of the study was to compare the clinical efficacy of
amoxicillin/clavulanic acid high-dose therapy for 10 days with cefdinir ther-
apy for 5 days for AOM at recommended doses.
Methods: This was an investigator-blind trial in young children 6-24 months
old with no history of rectirrent AOM who were randomly assigned to amoxicillin/
clavulanic acid (80 mg/kg/day amoxicillin) or cefdinir (14 mg/kg/day), both in
two divided doses.
The diagnosis of AOM was based on specific clinical criteria by validated
otoscopists at two AOM research centres. The outcome measure for clinical
cure was resolution of all symptoms and signs of AOM except for persistence
of middle-ear effusion at test-of-cure (TOC) 11-14 days after initiation of
antibiotic treatment. Clinical failure was defined as persistence of symptoms
and signs of AOM and the need for additional antibiotic therapy. Subjects
lost to follow up or who had not taken at least 80% of the prescribed med-
ication were classified as having an indeterminate response. Compliance was
monitored using Medical Electronic Monitoring System (MEMS) caps and
antibiotic bottle volume measurement at the TOC visit. A logistic regression
model was used to estimate the association of age with cure rate. Full inter-
actions in terms of age with treatment were included to estimate any age
gradient differential.
Results: A total of 330 children (average age 13.1 months) with AOM were
studied. At TOC, 256 children had clinical cure, 69 had clinical failure, and
1992
Casey et al.
5 were lost to follow-up. High-dose amoxicillin/clavulanic acid-treated chil-
dren had a better cure rate (86.5%) than cefdinir-treated patients (71.0%;
p = 0.001). Cefdinir was correlated with less frequent cure outcomes as chil-
dren increased in age between 6 and 24 months. The odds ratios for clinical
cure per increasing month of age estimated from a logistic regression model
for amoxicillin/clavulanic acid high dose and cefdinir treatment groups was
0.992 (95% CI 0.932, 1.056), p>0.05 and 0.932 (95% CI 0.881, 0.986),
p = 0.01. The differences in the odds ratios are significant at p< 0.002, in-
dicating a stable clinical cure rate across the ages of children studied for
amoxicillin/clavulanic acid and decreasing clinical cure rates as children in-
creased in age for cefdinir.
Conclusion: In children with bonafide AOM for whom clinical outcomes are
assessed by validated otoscopists, 10 days of high-dose amoxicillin/clavulanic
acid is significantly more effective than 5 days of cefdinir as therapy for
AOM. Because of the identified age effect (correlated to child weight), higher
doses of cefdinir may have led to a different conclusion; 10 days of cefdinir
may also have led to a different conclusion.
Background
In 2004, the American Academy of Pediatrics
(AAP) and the American Academy of Family
Physicians (AAFP) recommended amoxicillin/
clavulanic acid high dose and cefdinir as pre-
ferred antibiotics for treatment of children with
acute otitis media (AOM).['l The forthcom-
ing 2012 AAP/AAFP guidelines will make the
same recommendation.
In this paper, we describe a head-to-head com-
parison of amoxicillin/clavulanic acid high dose
versus cefdinir as 10- and 5-day treatments, re-
spectively, for AOM in children. Both are ap-
proved antibiotic treatments for AOM, and the
studied durations and dosages of treatment are
approved US FDA regimens.
Methods
Study Setting
The study took place at Legacy Pediatrics,
Rochester, NY, USA, and Kentucky Pdiatrie
Research, Bardstown, KY, USA. Both sites had
two investigators who are validated expert otos-
copists. The sociodemographics of the patient
populations of the two sites differ. Legacy Pe-
diatrics cares for a predominantly suburban, higher
socioeconomic status population, while the Bards-
town Kentucky Pdiatrie Research group cares for
a predominantly rural, lower socioeconomic sta-
tus population.
Study Design and Patient Population
This was a prospective, randomized, investigator-
blind trial that included children aged 6-24 months
with AOM enrolled from the above-mentioned
two sites. The study was conducted from January
2003 to May 2005.
The diagnosis of AOM was based on exami-
nation with pneumatic otoscopy that identified a
bulging or full tympanic membrane; and the
presence of purulent middle-ear effusion, and
reduced tympanic membrane mobility as docu-
mented by both pneumatic otoscopy and an
abnormal tympanogram (as evidenced by a ' B' or
' C curve). Symptoms of otalgia, irritabihty, and
fever were assessed at diagnosis and test-of-cure
(TOC). Four of the authors (JC, SB, JH and MP)
were the clinical investigators (validated otosco-
Adls 2012 Springer internationai Pubiishing AG. Aii rights reserved.
Drugs 2012; 72 (15)
Amoxicillin/Clavulanic Acid vs Cefdinir in AOM 1993
pists) who made the diagnosis of AOM on study
entry and determined clinical outcome (see the
Interventions and Assessments section).
Exclusion criteria were children with chronic
otitis media, chronic middle-ear effusion, venti-
lation tubes, perforated tympanic membranes or
otorrhea, and patients with 'A' or 'B' curves with
obvious dry perforation (high volume).
The stucly was approved by an investigational
review board (Western IRB, Seattle, WA, USA),
and written informed consent was obtained.
Interventions and Assessments
Antibiotic treatment consisted of amoxicillin/
clavulanic acid high dose (80 mg/kg/day amoxicillin
divided twice daily) or cefdinir (14 mg/kg/day di-
vided twice daily). High-dose amoxicillin/clavulanic
acid was given for 10 days and cefdinir for 5 days.
Each AOM research site used an independent
computer-generated random number table to al-
locate subjects.
Symptoms and signs were recorded at two as-
sessment visits: one at the time of diagnosis and
a second at the TOC visit 11-14 days later. The
same otoscopist carried out both assessments for
each child using 10- and 30-point symptom
scoring systems at each visit.'^'
The determination of compliance was mon-
itored by use of a Medical Electronic Monitoring
System (MEMS) cap dispenser and measurement
of antibiotic volume remaining at the TOC visit.
The per protocol analysis required a minimum of
80% compliance with the prescribed dosing regimen.
Outcome
Subjects were classified as having clinical cure,
failure, or an indeterminate outcome at TOC
based upon symptoms and examination findings.
Clinical Cure
Participants were considered to have clinical
cure if they met the following criteria:
they received the prescribed dosing regimen
during the first 72 hours of the study and met
the following;
their body temperature at the TOC visit was
<38C if the temperature was measured rectally
or aurally, <37.5C if measured orally, or
<37.3C if measured at the axilla;
otoscopic examination of the tympanic mem-
brane was rated as improved by the investi-
gator at the visit, with no evidence of fullness
or bulging of the tympanic membrane (the
presence of middle-ear effusion was acceptable);
no antibiotic was given for AOM and no
surgical procedure was performed for AOM
on or before the TOC visit;
no indeterminate criteria applied.
Clinical Failure
Subjects were considered to have clinical failure
at the TOC visit if they had received the prescribed
dosing regimen during the first 72 hours of the
study, did not meet any other indeterminate cri-
teria, and one of the following conditions were
met:
an additional antibiotic was prescribed for
AOM on or before the TOC visit;
a surgical procedure was performed for AOM
on or before the TOC visit;
there was evidence of fullness or bulging of the
tympanic membrane;
perforation of the tympanic membrane on or
before the TOC visit;
the subject had unsatisfactory resolution of
signs and symptoms of AOM according to the
investigator.
Indeterminate Outcome
A participant was classified as having an in-
determinate outcome at the TOC visit and dropped
from the analysis at TOC if <80% of the prescribed
treatment was taken, or there were inadequate
data to assess clinical outcome due to lack of
follow-up.
Statistics
Association of cure rate and age, and any in-
teraction with treatment was quantitatively esti-
mated using a fully determined logistic regression
model, permitting the estimation-specific age
gradients, as well as formal statistical tests for
treatment differences in age gradients. Estimates
of the age gradient are given in the form of odds
ratios (ORs) for cure rates associated with an
Adls 2012 Springer Internotionoi Publishing AG. Aii rights reserved. Drugs 2012; 72 (15)
1994
Casey et ai.
increase in age of 1 month, and are obtainable
directly from model parameters.
Results
A total of 330 children were enrolled in the
study, and their average age was 13.1 months
(SD4.9); 105 and 225 children were enrolled at
the New York and Kentucky sites, respectively.
There were 165 children in each treatment group;
325 children were evaluated at the TOC visit and
five subjects were lost to follow-up.
Table I shows the overall assessment of clinical
outcome for the two antibiotic regimens. The clini-
cal cure rate with amoxicillin/clavulanic acid high
dose (86.5%) was significantly higher than that
with cefdinir (71.0%) [p = 0.001].
Figure 1 shows an analysis of the variation in
cure rate of amoxicillin/clavulanic acid high dose
and cefdinir according to the age of the child.
There is a significant difference between the two
antibiotics (p< 0.002). The difference in efficacy
with high-dose amoxicillin/clavulanic acid be-
tween the ages of 6 and 24 months in the children
treated did not impact the overall cure rate (OR
0.87 [95% CI 0.28, 2.69]; p = 0.8). In contrast, the
difference in efficacy with cefdinir between the
ages of 6 and 24 months in the children treated
did adversely impact the overall cure rate (OR
0.28 [95% CI 0.10, 0.78]; p = 0.01).
In table II, the ORs of clinical cure as esti-
mated from a logistic regression model are pre-
sented. For each increasing month of age, the OR
for cure remained stable for treatment with high-
dose amoxicillin/clavulanic acid but significantly
Table I. Clinical outcomes with amoxicillin/clavulanic acid high
dose versus cefdinir
Outcome
Clinical cure (no. of pfs)
Clinical failure (no. of pts)
Indeterminate (no. of pis)
Cure rale (%)
High-dose amoxicillin/
clavulanic acid
N = 165
141
22
3
86.5
Cefdinir
N = 165
115
47
3
71.0
a Chi-square = 10.8, degrees of freedom = 1, p-value = 0.001.
pts = patients.
declined for treatment with cefdinir (p = 0.01).
Thus, if the odds of cure were considered to be
100% at age 6 months, then 1 month later the
odds for cure would decrease to 93.2% (95% CI
88.1, 98.6), and for each subsequent month the
odds of cure would decrease by another 93.2%
compared with the prior month.
Table III shows the symptoms and otoscopic
signs at both the initial and the TOC visits at the
two study sites. Given the age of the study
participants, at enrollment approximately half
could not complain of ear pain but more than
half had a history of irritability. Nearly 100%
of subjects had tympanic membrane erythema,
decreased tympanic membrane mobility, abnor-
mal effusion colour, and a full/bulging tym-
panic membrane. Nearly all signs of AOM were
absent at the TOC visit in the cured children, with
the exception of decreased tympanic membrane
mobility, reflecting persistence of middle-ear
effusion.
CompUance exceeded 80% for valuable sub-
jects per protocol. Details of the compliance
aspect of the study and use of MEMS cap mon-
itoring will be published elsewhere (Block et al.,
unpublished results).
Discussion
Amoxicillin/clavulanic acid high dose and
cefdinir are recommended as first- and/or second-
line antibiotic choices for AOM in children accord-
ing to the recommendations of the AAP/AAFP
guidelines for AOM management. Although there
have been prior studies of amoxicilhn/clavulanic
acid and cefdinir as treatment of AOM,'^-''' this is
the first study to compare amoxicillin/clavulanic
acid high dose for 10 days versus cefdinir for
5 days, both of which are approved regimens for
AOM in children.
The superior outcome with 10 days of amox-
icillin/clavulanic acid high dose compared with
5 days of cefdinir could be predicted by in vitro
testing of the drugs against the dominant oto-
pathogens of AOM.'^^ Although tympanocentesis
was not performed in this trial, the pathogen mix
in children with AOM in this age group and the
antibiotic susceptibility of those pathogens has
Adis 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012; 72 (15)
Amoxicillin/CIavulanic Acid vs Cefdinir in AOM 1995
1.0 -
0.8 -
0.6
3
-^ 0.4
0.2
0
o
AmoxiCillih/clavulaniC acid HD
Cefdinir
10 15 20
Age (mo)
25
Fig. 1. Predicted cure rates from the logistic regression model (with separate age slopes for each drug). Sample estimates of cure rate
grouped into four age categories are superimposed. HD = high dose.
been extensively characterized over long time
periods at both centres, including the contempo-
raneous time period of the current study.^^^'
The better efficacy observed with high-dose
amoxicillin/clavulanic acid must be taken in the
context that these children were in a clinical trial
where compliance was very high. In comparison, in
everyday clinical practice, the greater incidence of
adverse events such as gastrointestinal upset and
diarrhoea with amoxicillin/clavulanic acid high
dose compared with cefdinir, as well as the marginal
taste of amoxicillin/clavulanic acid high dose should
be factors considered when prescribing amoxicillin/
clavulanic acid high dose for children.'''^1
Our study has strengths and limitations. The
study design was prospective, randomized and
investigator blinded. The four participating clini-
cians in this study are highly skilled, validated
otoscopists; therefore clinical diagnosis at study
entry and at TOC would Ukely have a high
correlation (>90% for all four investigators, data
not shown) with tympanocentesis results. Entry
into AOM clinical trials based on a clinical
diagnosis and outcome assessment has the po-
tential to result in the 'Pollyanna phenomena'.t'l
Indeed, such a study design has the potential
to disguise true differences in antibiotic com-
parative trials when sample sizes are small.
However, in our study, the sample size proved
adequate to show a statistically significant dif-
ference between the two treatments. We contend
that this may have occurred because of the diag-
nostic skill of the otoscopists at study entry and
at TOC. Furthermore, a multicentre, open-label,
non-comparator, tympanocentesis study of AOM
of 447 children at risk for persistent and recur-
rent AOM treated with a higher dosage of
cefdinir (25 mg/kg/day once daily) for a longer
duration than our trial (10 days) was described by
Arguedas et al.I"' They found that, at higher
doses administered for 10 days, the bacteriological
eradication rate, based on repeat tympanocent-
esis, was 91%, 67% and 43% for Streptococcus
Table II. Odds ratios for clinical cure per increasing month of age
estimated from a logistic regression model for amoxicillin/clavulanic
acid high dose and cefdihir treatment groups
Treatment Odds ratio (95% CI) p-Value
High-dose amoxicillin/
clavulanic acid
Cefdinir
0.992(0.932,1.056)
0.932 (0.881, 0.986)
>0.05
0.01
Adis 2012 Springer internationai Pubiishing AG. Aii rights reserved. Drugs 2012: 72 (15)
1996
Casey et al.
Table III. Percentage of patients
study sites
Symptom or otoscopic sign
with symptoms and
Initiai visit
NY site
otoscopic signs at the initiai
KYsite
[n=225(%))
diagnosis visit and at the
TOO visit
NY site
test-of-cure visit at the two
KY site
[n = 223(%)]
History ot fever
Otaigia
irritabiiity
Fever >38C (at visit)
TM erythema
Reduced TM mobiiity
Abnormai effusion coiour
TM fuil/buiging
Otorrhoea
Perforation
37
42
53
9
80
98
97
99
2
0
23
47
63
11
96
100
99
96
5
1
5
5
12
4
6
48
16
9
0
0
8
11
18
1
22
38
24
21
2
0
KY=Kentucky; NY = New York; TM=tympanic membrane; TOC=test of cure.
pneumoniae that were penicillin susceptible,
penicillin intermediate and penicillin resistant,
respectively.
Conciusion
Our results show that 10 days of treatment
with high-dose amoxicillin/clavulanic acid is a
more effective antibiotic regimen than 5 days of
cefdinir for AOM in young children. Our findings
also show that the efficacy of cefdinir decreases as
a child ages between 6 and 24 months and, since
age of children predicts weight of the child, this
observation suggests higher doses of cefdinir
might produce higher clinical cure rates. We em-
phasize that, in clinical practice (unlike in a con-
trolled chnical trial), the efficacy of an antibiotic
also depends on comphance and that the com-
pliance features of cefdinir are superior to those
of high dose amoxicillin/clavulanic acid. Because
of the identified age effect (correlated to child
weight), higher doses of cefdinir may have led to a
different conclusion; 10 days of cefdinir may also
have led to a different conclusion.
Acicnowiedgements
Janet Casey and Michael Pichichero were supported
in part by NIH NIDCD ROl 08671. Abbott Laboratory
(Chicago, IL) provided an investigator-initiated grant to
Dr Stan Block to conduct the study. Michael Pichichero re-
ceived honoraria and grants from Abbott Laboratories from
2001 to 2005. This work would not have been possible without
assistance from medical students Mark Sakr, Jim Woods and
Sam Horr.
References
1. American Academy of Pediatrics Subcommittee on Man-
agement of Acute Otitis Media. Diagnosis and man-
agement of acute otitis media. Pediatrics 2004; 113:
1451-65
2. Casey JR, Block S, Puthoor P, et al. A simple scoring system
to improve clinical assessment of acute otitis media. Clin
Pediatr (Phila) 2011 Jul; 50 (7): 623-9
3. Block SL, McCarty JM, Hedrick JA, et al. Comparative
safety and efficacy of cefdinir vs. amoxicillin/clavulanate
for treatment of suppurative acute otitis media in children.
Pediatr Infect Dis J 2000; 19; S159-65
4. Block SL, Busman TA, Paris MM, et al. Comparison of five-
day cefdinir treatment with ten-day low dose amox-
icillin/clavulanate treatment for acute otitis media. Pediatr
Infect Dis J 2004; 23 (9): 834-8
5. Jacobs MR, Felmingham D, Appelbaum PC, et al. The
Alexander Project 1998-2000; susceptibility of pathogens
isolated from community-acquired respiratory tract infec-
tion to commonly used antimicrobial agents. J Antimicrob
Chemother 2003; 52 (2): 229-46
6. Casey JR, Pichichero ME. Changes in frequency and path-
ogens causing acute otitis media in 1995-2003. Pediatr In-
fect Dis J 2004; 23; 824-8
7. Block SL, Hedrick J, Harrison CJ, et al. Community-wide
vaccination with heptavalent pneumococcal conjugate
significantly alters the microbiology of acute otitis media.
Pediatr Infect Dis J 2004; 23 (9): 829-33
8. Casey JR, Adlowitz DG, Pichichero ME. New patterns in
the otopathogens causing acute otitis media six to eight
Adis 2012 Springer International Publishing AG. All rights reserved.
Drugs 2012. 72 (15)
Amoxicillin/clavulanic Acid vs Cefdinir in AOM 1997
years after introduction of pneumococcal conjugate vac- II. Arguedas A, Dagan R, LeibovitzE, et al. A multicenter, open
cine. Pediatr Infect Dis J 2010; 29 (4): 304-9 label, double tympanocentesis study ofhigh dose cefdinir in
9. Cifaldi MA, Paris MM, Devcich KJ, et al. Parent-reported children with acute otitis media at high risk of persistent or
outcomes for treatment of acute otitis media with cefdinir recurrrent infection. Pediatr Inf Dis J 2006; 25: 211-8
or amoxicillin/clavulanate oral suspensions. Pediatr Drugs
2004; 6 (6): 387-93 ~ ~ " ^ " ^ " ^ ~ ~ ^ ~ ~ " ~ " ~ " ~ ^ " ~ ~ ~ ~ ~ ~ ~ " ~ ~ '
. . . . , r^ ,. o A T 1 ,-.r- 1 .t u Correspondence: Dr Micitael E. Pichichero, Rochester
10. Marchant CD, Carlin SA, Johnson CE, et al. Measuring the ^^
comparative efficacy of antibacterial agents for acute otitis General Hospital Research InsUtute, 1425 Portland Avenue,
media; the "Pollyanna phenomenon." J Pediatr 1992; 120: Rochester, NY 14621, USA.
72-7 E-mail: michael.pichicheroQrochestergeneral.org
Adis 2012 Springer internationai Pubiishing AG. Aii rights reserved. Drugs 2012; 72 (15)
Copyright of Drugs is the property of ADIS International Limited and its content may not be copied or emailed
to multiple sites or posted to a listserv without the copyright holder's express written permission. However,
users may print, download, or email articles for individual use.