International Journal of Pediatric Otorhinolaryngology 86 (2016) 183–188

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International Journal of Pediatric Otorhinolaryngology

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / i j p o r l

Topical versus oral antibiotics, with or without corticosteroids, in the

treatment of tympanostomy tube otorrhea
Jeremy Chee a,*, Khang Wen Pang a, Jui May Yong b, Roger Chun-Man Ho c, Raymond Ngo b
a National University Health System, Singapore
b Department of Otolaryngology–Head and Neck Surgery, National University Health System, Singapore
c
Department of Psychological Medicine, University Medicine Cluster, National University Health System, Singapore

A R T I C L E I N F O A B S T R A C T

Article history: Objective: Antibiotic treatment is the standard of care for tympanostomy tube otorrhea. This meta-
Received 16 March 2016 analysis aims to evaluate the efficacy of topical antibiotics with or without corticosteroids versus oral
Received in revised form 21 April 2016 antibiotics in the treatment of tube otorrhea in children.
Accepted 5 May 2016
Data Sources: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and ProQuest.
Available online 11 May 2016
Review Methods: The above databases were searched using a search strategy for randomized controlled
trials for optimal treatment of tube otorrhea in the pediatric population. PRISMA (Preferred Reporting
Keywords:
Items for Systematic reviews and Meta-Analyses) guidelines were followed. Primary outcome was cure
Tympanostomy
Tube otorrhea (i.e. clearance of otorrhea) at 2–3 weeks. Secondary outcomes were microbiological eradication and com-
Otitis media plications such as dermatitis and diarrhea. The incidence of these events was defined as dichotomous
variables and expressed as a risk ratio (RR) and number needed to benefit (NNTB) in a random-effects
model.
Results: We identified 1491 articles and selected 4 randomized controlled trials which met our inclu-
sion criteria. Topical treatment had better cure (NNTB = 4.7, pooled RR = 1.35, p < 0.001) and microbiological
eradication (NNTB = 3.5, pooled RR = 1.47, p < 0.001 among 3 of the studies) than oral antibiotics. Oral
antibiotics had higher risk of diarrhea (pooled RR = 21.5, 95% CI 8.00–58.0, p < 0.001, Number needed to
harm (NNTH) = 5.4) and dermatitis (pooled RR = 3.14, 95% CI 1.20–8.20, p = 0.019, NNTH = 32). The use
of topical steroids in addition to topical antibiotics was associated with a higher cure rate (pooled RR = 1.59,
p < 0.001 vs pooled RR = 1.57, p = 0.293).
Conclusion: Topical antibiotics should be the recommended treatment for management of tympanostomy
tube otorrhea in view of its significantly improved clinical and microbiological efficacy with lower risk
of systemic toxicity as compared to oral antibiotics. Further research is necessary to confirm the ben-
efits of topical corticosteroids as an adjunct to topical antibiotics.
© 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Tympanostomy tube insertion is the most common
otolaryngologic day-surgery procedure performed in the pediatric
population. In the US, nearly 1 in 15 children would have under-
gone a tympanostomy tube insertion by 3 years of age [1]. Indications
for tube insertion include persistence of middle ear effusion, re-
current middle ear infections, or infections recalcitrant to oral
antibiotic therapy [2]. It has been shown to significantly restore
hearing, reduce effusion prevalence, reduce incidence of recur-
rence of otorrhea, and improve disease-specific quality of life for
* Corresponding author at: Department of Otolaryngology–Head and Neck Surgery,
National University Health System, 1E Kent Ridge Road, NUHS Tower Block Level 7,
119228, Singapore. Tel.: +65 6772 5555; fax: +65 6779 5678.
E-mail address: cheejeremy@gmail.com (J. Chee).
children with otitis media with effusion or recurrent acute otitis
media [3].
Acute otorrhea is the most common observed complication of
tympanostomy tube, with a mean incidence of 26% (range, 4%–
68%) in observational studies and up to 83% with prospective
surveillance [4,5]. Tube otorrhea is usually sporadic and painless [6],
but may be accompanied with foul odor, pain and pyrexia [3]. It is
postulated to be a manifestation of a recurrent acute otitis media,
with bacterial superinfection or infection. Streptococcus pneumoniae,
Haemophilus influenzae, and Moraxella catarrhalis [7,8] are often im-
plicated as the predominant bacteria. Treatment is usually with
broad-spectrum antibiotics, which can be delivered either orally or
with topical eardrops.
Trials comparing topical and oral antibiotics in children with tube
otorrhea have had relatively small sample sizes. But indepen-
dently they suggest that otic drops are as effective as, or more
effective than, oral treatment. Despite these evidence in the

http://dx.doi.org/10.1016/j.ijporl.2016.05.008
0165-5876/© 2016 Elsevier Ireland Ltd. All rights reserved.
184 J. Chee et al. / International Journal of Pediatric Otorhinolaryngology 86 (2016) 183–188
literature, a survey conducted in 2013 showed that 54% of sur-
veyed emergency medicine physicians used oral antibiotics to treat
tube otorrhea, as compared to 9% of surveyed otolaryngologists [9].
A systemic search identified randomized controlled trials (RCTs)
that directly compared topical and oral antibiotics in the treat-
ment of acute tube otorrhea, and a meta-analysis was conducted.
2. Methods
The reporting of our systemic review was guided by the PRISMA
Statement [10].
2.1. Systematic search strategy and study selection
Studies were selected and screened according to the research
question and PICO criteria. We sought all RCTs that studied the ef-
ficacy of topical versus oral antibiotics in pediatric patients with acute
tube otorrhea. The PICO criteria used were: pediatric humans with
acute tube otorrhea; topical antibiotics with or without topical cor-
ticosteroids versus oral antibiotics; cure rates at specific time
intervals, microbiological eradication as well as median time to ces-
sation where possible; and RCTs only.
Initial database searches were conducted in August 2015. PubMed,
EMBASE, Cochrane Central Register of Controlled Trials and ProQuest
were searched using the terms as shown below. Search results were
screened to remove duplicate, non-peer reviewed, and review ar-
ticles. All articles were de-identified (blinded title, authors, journal
name, and year of publication) before selection. Two authors in-
dependently selected abstracts according to the research question
and PICO criteria. Disagreements between the authors were re-
solved by consensus. The stages and reasons for exclusions are
presented in Fig. 1.
2.2. Data extraction
The extracted data comprised the year of publication, partici-
pant numbers, the two intervention arms, the study design, and
study findings. The outcomes investigated included cure (defined
as the absence of otorrhea), microbiological eradication and any com-
plications or treatment-related adverse effects. For all studies, data
were extracted independently by two authors (JC, KWP). Any dif-
ferences in reporting were reconciled by jointly revisiting the relevant
publication.
2.3. Statistical analysis
All statistical analyses were performed with STATA Version 13.0.
Meta-analysis of binomial data using the random-effects model was
performed to derive a summary estimate of relative risks. The
random-effects model was used because it takes into account both
variation caused by sampling error and also random variation of the
underlying effect sizes between studies. The effect of topical versus
oral antibiotics in terms of cure rates and microbiological eradica-
tion were calculated using relative risks with its p-value. Significant
difference was set at p < 0.05 for all analyses. A fixed-effects
(weighted with inverse variance) or a random-effects model was
used where appropriate, after computing the chi-squared and I2 sta-
tistics. When p < 0.05 or I2 > 50%, the assumption of homogeneity
was rejected and a random effects model was adopted. Random-
effect estimates were used when there was significant between-
study heterogeneity. Peter’s test was used to test for evidence of
publication bias when the heterogeneity variance tau-squared was
less than 0.1.
3. Results
We found 1360 potentially relevant articles after duplicates were
removed. Of these, only 4 [11–14] fulfilled the inclusion criteria.
These 4 studies were published between years 1998 and 2014. These
studies were analyzed as intention to treat. Patient with negative
microbiology at baseline were excluded from analysis of efficacy of
microbiological eradication.
The 4 studies included 560 subjects with tube otorrhea (277 re-
ceived topical antibiotics while 283 received oral antibiotics). Other
study design characteristics are summarized in Table 1. The Jadad
score is summarized in Table 2. All studies were single blinded as
the intervention was the route of administration of medications,
which made patient-blinding not feasible.
Data from the four eligible studies were pooled for meta-
analysis. Results showed that patients who received topical treatment
demonstrated a statistically significant improvement in resolu-
tion rates at the defined endpoint of 2–3 weeks (pooled relative risk
[RR] = 1.35, 95% Confidence Interval [CI] 1.21–1.50, p < 0.001, Number
needed to benefit [NNTB] = 4.7). Fig. 2 shows the Forest plot and
the standard relative risk for patients who received topical versus
oral antibiotics. There was little evidence for publication bias for
small-study effects (intercept = 73.9, 95% CI −363 to 511, t = 0.73,
p = 0.542). However, heterogeneity was high (I2 = 80.8%). Sub-
group analysis showed that patients who used topical antibiotics
with steroids (pooled RR = 1.59, 95% CI 1.34–1.89, p < 0.001,
NNTB = 3.0) reported significantly improved cure rates at 2–3 weeks
(I2 = 5.3%). However, patients who used topical antibiotics alone had
a statistically non-significant improvement (pooled RR = 1.57, 95%
CI = 0.68–3.67, p = 0.293, I2 = 82.4%).
Microbial eradication results were included in 3 of the above 4
studies. Topical treatment was also shown to have improved erad-
ication rates compared to oral antibiotics (pooled RR = 1.47, 95% CI
1.27–1.70, p < 0.001, NNTB = 3.5) (Fig. 3). There was similarly little
evidence for publication bias for small-study effects (intercept = −55.3
95% CI −911 to 801, t = −0.82, p = 0.562).
In addition, side effects were much less common with topical
antibiotics than with oral antibiotics. Three of the above studies re-
ported numbers in terms of side effects. The two most common
adverse reactions reported were gastrointestinal disturbances (i.e.
diarrhea) and dermatitis. Oral antibiotics carried a significantly higher
risk of diarrhea (pooled RR = 21.5, 95% CI 8.00–58.0, p < 0.001, number
needed to harm (NNTH) = 5.4) and dermatitis (pooled RR = 3.14, 95%
CI 1.20–8.20, p = 0.019, NNTH = 32).
4. Discussion
Antibiotics reduce otorrhea, fever and pain from otitis media. A
meta-analysis performed by Rovers et al concluded that oral anti-
biotics were more effective than placebo in the treatment of children
with acute otitis media and otorrhea (NNTB = 3) [15] with regard
to the above outcomes. In adults with chronic suppurative otitis
media, topical antibiotics are more efficacious in reducing otor-
rhea than either oral [16] or intramuscular [17]antibiotics, possibly
because the tympanic membrane perforation permits a higher local
drug concentration to be achieved with topical antibiotic therapy.
For pediatric patients with tube otorrhea, studies have shown failure
rates of between 10% and 23% with ciprofloxacin-containing ear
drops versus 20%–70% with oral antibiotics alone [12,13,18–20].
The most recent clinical practice guidelines by the American
Academy of Otolaryngology-Head and Neck Surgery suggest a strong
recommendation for topical antibiotics over oral antibiotics based
on Grade B aggregate evidence [21], based on 3 RCTs performed
between 1998 and 2010. We included a fourth well-designed study
which was recently published, and conducted a meta-analysis to
statistically analyze the utility of topical versus oral antibiotics in
 J. Chee et al. / International Journal of Pediatric Otorhinolaryngology 86 (2016) 183–188 185

PRISMA 2009 Flow Diagram

Identification Records identified through Additional records identified

database searching through other sources
(n = 1491 ) (n = 0 )

Records after duplicates removed

(n = 1360 )
Screening

Records screened Records excluded

(n = 1360) (n = 1333 )

Full-text articles assessed Full-text articles excluded,

for eligibility with reasons
Eligibility

(n = 27 ) (n = 23 )

Studies included in
qualitative synthesis
(n = 4 )
Included

Studies included in
quantitative synthesis
(meta-analysis)
(n = 4 )

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-
Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit www.prisma-statement.org.

Fig. 1. PRISMA 2009 flow diagram.

order to achieve better evidence for topical antibiotics. There was
some heterogeneity in terms of study enrollment, inclusion and ex-
clusion criteria. Subgroup analysis was difficult given the small
number of trials. In two of the included trials, children who were
pre-treated were allowed to participate, and group A strep and Pseu-
domonas infections were excluded [11,12]. There was also some
variation in terms of time of measurement of outcomes, as well as
ototopic solutions used (i.e. different classes of antibiotics as well
as usage of steroids). In light of this high degree of heterogeneity
(I2 = 80.8%), a random effects model was utilized in our analysis.
However, the general outcomes were similar and we believe that
the results of the analysis remain clinically significant.
Our meta-analysis showed a convincing benefit of topical over
oral antibiotics in achieving cessation of otorrhea, microbiological
eradication and in the side-effect profile. Unfortunately, in view of
a lack of well-reported data, it was not possible to statistically analyze
the difference in time to resolution of otorrhea. However, the studies
which included a patient diary as part of its methodology (3 of 4)
did report a significant improvement in median time to cessation
of otorrhea in the topical arm. Although patients with negative
cultures at the outset were excluded from the analysis for micro-
biological eradication, the calculated RR was similar for both cure
and microbiological eradication. This excluded group is unlikely to
have a large effect on the effect size calculated.
It has been postulated that there are three main reasons for the
efficacy of topical ear drops in the treatment of tube otorrhea. First,
the mechanical removal or dilution of bacterial load may augment
the efficacy of local antimicrobial activity for topical ear drops. This
was seen in the study by Heslop et al [13] where mechanical saline
rinsing had a lower failure rate as compared to oral amoxicillin (58%
186 J. Chee et al. / International Journal of Pediatric Otorhinolaryngology 86 (2016) 183–188

Table 2

ITT (microbiology)

ITT (microbiology)

ITT (microbiology)
Intention-to-treat
Quality of the 4 studies as assessed by Jadad score.
Analysis type References Year Randomization Blinding Description Quality

(ITT) (cure)
of dropouts score

ITT (cure)

ITT (cure)
ITT (cure)
Goldblatt et al 1998 2 0 1 3
Dohar et al 2006 2 0 1 3
Heslop et al 2010 2 0 0 2
van Dongen et al 2014 2 0 1 3
of cure (days)
assessment
Timing of

18–21
17–20

vs 70%) [13]. Second, the drug concentration achieved in the middle

14
14
ear mucosa will be higher with topical antibiotics as compared to
oral antibiotics. The middle ear mucosa is traditionally considered
Duration of
treatment

as a non-specialized site that is not highly perfused by blood flow

(days)

[22]. Oral antibiotics rely on passive diffusion to penetrate inter-

10

10

7
7

stitial fluid, and tend to reach lower peak concentrations than in

serum [23] especially with variable intestinal absorption and hepatic-
8.3–16.7 mg/kg TID

first pass effects. Studies have shown up to 1000-fold increases in

13.3 mg/kg TID

tissue concentration for topical versus oral ciprofloxacin [24]. Third,

45 mg/kg BID

10 mg/kg TID

it has been shown that topical antibiotics reduces tympanostomy

tube biofilm formation [25]. Given the incidence of Pseudomonas
Dose

aeruginosa in middle ear infections and its predisposition to for-

mation of biofilm, localized therapy which targets this biofilm would
be advantageous in achieving source clearance.
Amoxicillin/

Amoxicillin/

Amoxicillin/
Type of oral

Amoxicillin
clavulanate

clavulanate

clavulanate

Sub-group analysis showed that the addition of steroids to topical

antibiotic

solutions was associated with a higher and statistically significant

cure rate as compared to those who used topical antibiotic ear drops
without steroids. Van Dongen et al reported a 5% treatment failure
rate with antibiotic-steroid ear drops [14], while Heslop et al [13]
4 drops BID

4 drops BID
0.25 ml BID

5 drops TID

and Goldblatt et al [11] reported a 23% and 24% treatment failure

rate respectively with antibiotic-only ear drops. Experimental animal
Dose

studies showed otorrhea in a primate model of chronic suppura-

tive otitis media resolved more quickly when steroids was given as
Dexamethasone 0.1%

part of the therapy [26]. Another study showed that the addition
Ciprofloxacin 0.3%

Ciprofloxacin 0.3%

of steroids helps to prevent persistent middle ear mucosal changes

Type of ototopic

0.8%–colistin 2%
Hydrocortisone
Ofloxacin 0.3%

1%–bacitracin

[27]. Two separate human RCTs [18,19] comparing topical antibi-

otics with and without steroids similarly showed an overall
solution

improvement in cure rate, as well as time-to-cessation with the ad-

dition of steroids.
While the anti-inflammatory effect of steroids likely helps to
otorrhea that had lasted for up to 7 days at
a clinical diagnosis of uncomplicated AOM

reduce middle ear mucosal secretions, there exists a concern re-

6 months to 12 years, with patent TTs and

months or recurrent AOM, first episode of

parent or guardian) of ≤3 weeks’ duration

otorrhea after TT insertion, TT in situ, and

Caucasian, <10 years, TT insertion due to
presumed bacterial origin for <3 weeks;

1–10 years of age with symptoms of TT

1–12 years; premenarche (in females);

garding associated effects of impaired wound healing and local

mucopurulent or purulent otorrhea of

secretory otitis media for more than 3

with otorrhea (drainage visible to the

immunosuppression resulting in superinfection. In our study, sub-

group analysis showed that efficacy in terms of microbiological
patent TT in the infected ear(s);

eradication was similar between both arms. A recent review also

concluded that microbiological eradication was in fact enhanced with
the addition of a steroid to fluoroquinolone ear drops [28]. Rat model
the time of screening

studies have also shown that while tympanic membrane healing

Study population

in 1 or both ears

no comorbidity.

was transiently modulated by treatment with antibiotic-steroid ear

drops, this may conversely enhance middle ear drainage and middle
ear concentrations of the antibiotic solutions, thus potentially re-
ducing otorrhea and preventing or treating infection. There was also
no adverse effect on normal healing of the tympanic membrane [29].
Systemic antibiotics are associated with complications such as
1998

2014
2006

2010
Year

dermatitis, gastrointestinal disturbances, and allergic reactions [11]

which topical antibiotics avoid. Our meta-analysis revealed a higher
Number of

incidence of diarrhea and dermatitis in patients who took oral an-

patients/

140/146
controls
treated

76/77
39/40

22/20

tibiotics. Side-effects affect compliance, and while no formal analysis

was conducted, previous study authors have suspected a higher com-
pliance rate in patients who received local rather than oral therapy
Study characteristics.

[13]. Furthermore, topical antibiotics have not been shown to induce

van Dongen et al
Goldblatt et al

microbiological resistance [8], which is a worry in widespread usage

Heslop et al
Dohar et al
References

of systemic antibiotics.
There are concerns of ototoxicity with topical therapy in the
Table 1

context of tube otorrhea. Several studies suggest a risk of ototox-

icity in usage of aminoglycoside-based ear drops [30]. In contrast,
 J. Chee et al. / International Journal of Pediatric Otorhinolaryngology 86 (2016) 183–188
Fig. 2. Forest plot of otorrhea cure rates in ototopical versus oral antibiotics.
Fig. 3. Forest plot of microbiological eradication rates in ototopical versus oral antibiotics.
fluoroquinolones have been shown to have very limited to no oto-
toxic effects [31,32]. Furthermore, steroids have been shown to have
a protective effect on potential ototoxic effects of otic drops [33].
There were no reports of patients who complained of hearing loss
after starting ear drops in the 4 studies we analyzed.
This meta-analysis incorporates a small number of studies with
a small pooled sample size. Heterogeneity in study design and
conduct and variations in choice of topical antibiotic and steroids
has resulted in relatively large study heterogeneity and broad con-
fidence intervals. We have attempted to adjust for this via the
utilization of random effects models as well as via subgroup anal-
ysis. While the studies were not double-blinded, we believe that
the difference in delivery is one of the reasons why topical antibi-
otics is more efficacious than oral antibiotics (as seen in the study
by Heslop et al [13] where patients randomized to receive topical
saline had a lower failure rate as compared to oral amoxicillin [58%
vs 70%]). This effect would not surface if a true double blind study
had been performed. Last but not least, the study done by Dohar
et al [12] and Goldblatt et al [11] are indeed prone to inherent bias
due to industry sponsorship and potential conflict of interest.
However, we note that the effect sizes of these two studies are in
fact smaller than those by Heslop et al [13] and van Dongen et al
[14] as seen in Figs. 2 and 3 – suggesting that the advantage of topical
treatment is indeed real.
We feel that the improvement in side-effect profile, coupled with
the increase in efficacy, provides reasonably strong evidence that
187
topical treatment should be the first choice in treatment of tube otor-
rhea. In terms of healthcare economics, treatment of tube otorrhea
with topical antibiotics has been shown to have up to 12% savings
as compared to oral antibiotics [34].
5. Conclusion
Ototopical therapy should be the first choice in the treatment
of acute tube otorrhea in view of its excellent cure rates and mi-
crobiological eradication coupled with a safe side-effect profile. The
addition of steroids appears to confer an advantage for both cure
rates as well as microbiological eradication. Further research is
needed to identify which subsets of children are most likely to benefit
from topical steroids in addition to topical antibiotics.
Conflict of interest
No sponsorships or competing interests have been disclosed for
this article.
References
[1] M.D. Kogan, M.D. Overpeck, H.J. Hoffman, M.L. Casselbrant, Am. J. Public Health
90 (2000) 245–250.
[2] G.G. Browning, M.M. Rovers, I. Williamson, J. Lous, M.J. Burton, Cochrane
Database Syst. Rev. (10) (2010) CD001801.
188 J. Chee et al. / International Journal of Pediatric Otorhinolaryngology 86 (2016) 183–188
[3] R.M. Rosenfeld, M.H. Bhaya, C.M. Bower, P.E. Brookhouser, M.L. Casselbrant, K.H.
Chan, et al., Arch. Otolaryngol. Head Neck Surg. 126 (2000) 585–592.
[4] C. Ah-Tye, J.L. Paradise, D.K. Colborn, Pediatrics 107 (2001) 1251–1258.
[5] M.M. Rovers, N. Black, G.G. Browning, R. Maw, G.A. Zielhuis, M.P. Haggard, Arch.
Dis. Child. 90 (2005) 480–485.
[6] D.J. Kay, M. Nelson, R.M. Rosenfeld, Otolaryngol. Head Neck Surg. 124 (2001)
374–380.
[7] J. Dohar, Int. J. Pediatr. Otorhinolaryngol. 67 (2003) 1317–1323.
[8] P.S. Roland, D.A. Parry, D.W. Stroman, Otolaryngol. Head Neck Surg. 133 (2005)
585–595.
[9] V. Badalyan, R.H. Schwartz, S.L. Scwhartz, P.S. Roland, Pediatr. Emerg. Care 29
(2013) 203–208.
[10] D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, P. Group, BMJ 339 (2009) b2535.
[11] E.L. Goldblatt, J. Dohar, R.J. Nozza, R.W. Nielsen, T. Goldberg, J.D. Sidman, et al.,
Int. J. Pediatr. Otorhinolaryngol. 46 (1998) 91–101.
[12] J. Dohar, W. Giles, P. Roland, N. Bikhazi, S. Carroll, R. Moe, et al., Pediatrics 118
(2006) e561–e569.
[13] A. Heslop, T. Lildholdt, N. Gammelgaard, T. Ovesen, Laryngoscope 120 (2010)
2516–2520.
[14] T.M. van Dongen, G.J. van der Heijden, R.P. Venekamp, M.M. Rovers, A.G. Schilder,
N. Engl. J. Med. 370 (2014) 723–733.
[15] M.M. Rovers, P. Glasziou, C.L. Appelman, P. Burke, D.P. McCormick, R.A.
Damoiseaux, et al., Lancet 368 (2006) 1429–1435.
[16] S. Esposito, G. D’Errico, C. Montanaro, Arch. Otolaryngol. Head Neck Surg. 116
(1990) 557–559.
[17] S. Esposito, S. Noviello, G. D’Errico, C. Montanaro, Arch. Otolaryngol. Head Neck
Surg. 118 (1992) 842–844.
[18] P.S. Roland, J.B. Anon, R.D. Moe, P.J. Conroy, G.M. Wall, S.J. Dupre, et al.,
Laryngoscope 113 (2003) 2116–2122.
[19] P.S. Roland, L.S. Kreisler, B. Reese, J.B. Anon, B. Lanier, P.J. Conroy, et al., Pediatrics
113 (2004) e40–e46.
[20] L. Vaile, T. Williamson, A. Waddell, G. Taylor, Cochrane Database Syst. Rev. (2)
(2006) CD001933.
[21] R.M. Rosenfeld, S.R. Schwartz, M.A. Pynnonen, D.E. Tunkel, H.M. Hussey, J.S.
Fichera, et al., Otolaryngol. Head Neck Surg. 149 (2013) 8–16.
[22] Y. Huang, Z. Yang, L. Cartier, B. Cheung, R.J. Sawchuk, Antimicrob. Agents
Chemother. 51 (2007) 4336–4341.
[23] B. Barry, M. Muffat-Joly, P. Gehanno, Clin. Microbiol. Infect. 3 (Suppl. 3) (1997)
S37–S42.
[24] D.M. Campoli-Richards, J.P. Monk, A. Price, P. Benfield, P.A. Todd, A. Ward, Drugs
35 (1988) 373–447.
[25] R.G. Thomas, C. Ojano-Dirain, P.J. Antonelli, Laryngoscope 121 (2011) 1067–
1071.
[26] C.M. Alper, J.E. Dohar, M. Gulhan, A. Ozunlu, D. Bagger-Sjobak, P.A. Hebda, et al.,
Arch. Otolaryngol. Head Neck Surg. 126 (2000) 165–173.
[27] S.N. Park, S.W. Yeo, Acta Otolaryngol 121 (2001) 808–812.
[28] J.W. Kutz Jr., P.S. Roland, K.H. Lee, Expert Opin. Pharmacother. 14 (2013)
2399–2405.
[29] P.A. Hebda, S. Yuksel, J.E. Dohar, Laryngoscope 117 (2007) 522–528.
[30] G. Matz, L. Rybak, P.S. Roland, M. Hannley, R. Friedman, S. Manolidis, et al.,
Otolaryngol. Head Neck Surg. 130 (2004) S79–S82.
[31] K.R. Kavanagh, K. Parham, S.R. Schoem, Arch. Otolaryngol. Head Neck Surg. 135
(2009) 238–241.
[32] R. Samarei, Glob. J. Health Sci. 6 (2014) 144–149.
[33] S.K. Park, D. Choi, P. Russell, E.O. John, T.T. Jung, Laryngoscope 114 (2004)
768–771.
[34] T.M. van Dongen, A.G. Schilder, R.P. Venekamp, G.A. de Wit, G.J. van der Heijden,
Pediatrics 135 (2015) e1182–e1189.