Research

JAMA Otolaryngology–Head & Neck Surgery | Original Investigation

Efficacy and Safety of Ciprofloxacin Plus Fluocinolone

in Otitis Media With Tympanostomy Tubes in Pediatric Patients
A Randomized Clinical Trial
Zorik Spektor, MD; Felix Pumarola, MD; Khaleed Ismail, MD; Brent Lanier, MD; Iftikhar Hussain, MD; John Ansley, MD; Henry F. Butehorn III, MD;
Kenneth Esterhuizen, MD; John Byers, MD; Franklin Douglis, MD; Bryan Lansford, MD; F. Javier Hernández, MD

Supplemental content
IMPORTANCE Acute otitis media with tympanostomy tubes (AOMT) in children commonly
presents with otorrhea and negatively affects their daily activities.

OBJECTIVE To evaluate the efficacy and safety of topical ciprofloxacin, 0.3%, plus
fluocinolone acetonide, 0.025%, otic solution relative to ciprofloxacin, 0.3%, otic solution
alone and fluocinolone acetonide, 0.025%, otic solution alone in the treatment of AOMT in
children.

DESIGN, SETTING, AND PARTICIPANTS Two twin multicenter, randomized, double-blind clinical
trials with identical designs were conducted from June 24, 2011, through June 23, 2014, at
ear, nose, and throat pediatric practices, general practices, hospitals, and clinical research
centers. The study population comprised 662 children (331 in each trial) with AOMT in at least
1 ear who presented with moderate or severe purulent otorrhea for 3 weeks or less. Data
analyses were performed on an intention-to-treat basis.

INTERVENTIONS Patients were randomly assigned to receive ciprofloxacin plus fluocinolone,

ciprofloxacin alone, or fluocinolone alone twice daily for 7 days and were evaluated on days 1
(baseline), 3 to 5 (undergoing therapy), 8 to 10 (end of therapy), and 18 to 22 (test of cure).

MAIN OUTCOMES AND MEASURES The primary efficacy measure was time to cessation of
otorrhea. The principal secondary end point was sustained microbiological cure, defined as
eradication or presumed eradication at end-of-therapy and test-of-cure visits.

RESULTS A total of 662 children participating in the 2 studies were randomized to receive
ciprofloxacin plus fluocinolone (n = 223), ciprofloxacin alone (n = 221), or fluocinolone alone
(n = 218). The median age was 2.5 years (range, 0.6-12.7 years). The median time to cessation
of otorrhea was 4.23 days (95% CI, 3.65-4.95 days) in patients receiving ciprofloxacin plus
fluocinolone compared with 6.95 days (95% CI, 5.66-8.20 days) in those receiving
ciprofloxacin and not estimable findings in those receiving fluocinolone alone (P < .001).
The clinical cure rate at the test-of-cure visit was 80.6% in the ciprofloxacin plus fluocinolone
group, 67.4% in the ciprofloxacin group (difference, 13.2%; 95% CI, 5.0%-21.4%; P = .002),
and 47.6% in the fluocinolone group (difference, 33.0%; 95% CI, 24.0%-42.0%; P < .001).
The sustained microbiological cure rate was 79.7% in the ciprofloxacin plus fluocinolone
group vs 67.7% in the ciprofloxacin group (difference, 12.0%; 95% CI, 0.8%-23.0%; P = .04)
and 37.6% in the fluocinolone group (difference, 42.1%; 95% CI, 29.3%-54.8%; P < .001).
Only 7 (3.1%) of the patients receiving ciprofloxacin plus fluocinolone, 8 (3.6%) of the
patients receiving ciprofloxacin, and 10 (4.7%) of the patients receiving fluocinolone
presented with adverse events related to study medication.

CONCLUSIONS AND RELEVANCE The combination of ciprofloxacin plus fluocinolone is more Author Affiliations: Author
affiliations are listed at the end of this
effective than treatment with ciprofloxacin or fluocinolone alone for AOMT, and it is safe and article.
well tolerated in children. Corresponding Author: Zorik
Spektor, MD, Center for Pediatric
TRIAL REGISTRATION clinicaltrials.gov Identifiers: NCT01395966 and NCT01404611 ENT–Head and Neck Surgery,
10150 Hagen Ranch Rd, Ste 100,
JAMA Otolaryngol Head Neck Surg. doi:10.1001/jamaoto.2016.3537 Boynton Beach, FL 33437
Published online December 22, 2016. (zspektor@comcast.net).

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 Research Original Investigation
A
cute otitis media (AOM) is an inflammation of the
middle ear that usually results from an upper respira-
tory tract infection. When fluid accompanies the in-
flammation, the condition is known as otitis media with effu-
sion. The most common surgery performed on children for the
treatment of recurrent AOM and otitis media with effusion is
the insertion of tympanostomy tubes (TTs) into the eardrum,
which produces a decrease in the frequency of ear infections,
allows drainage of effusion, and permits topical administra-
tion of antibiotics to the middle ear1-4 when infection occurs.
In the United States, almost 700 000 children receive TTs ev-
ery year.5 Placement of TTs significantly improves hearing, re-
duces effusion, and is associated with improvement in qual-
ity of life for children with recurrent AOM, otitis media with
effusion, or both.6-8 Otorrhea is the most frequent complica-
tion after the insertion of the TTs and may occur immediately
after surgery or during the time the TTs remain in place. Early
postoperative otorrhea occurs in approximately 10% to 20%
of children, whereas published rates of delayed tube otor-
rhea range from 4% to 83%.9-16 Acute otitis media with tym-
panostomy tubes (AOMT) differs clinically and microbiologi-
cally from AOM in that AOMT frequently presents with sudden
onset of purulent otorrhea.17 Bacteria commonly isolated from
children with AOMT include Streptococcus pneumoniae, Hae-
mophilus influenzae, and Moraxella catarrhalis as well as patho-
gens associated with acute otitis externa infections, such as
Staphylococcus aureus and Pseudomonas aeruginosa.17,18
Treatment options for AOMT include systemic and topi-
cal antibiotics with or without corticosteroids.17 The selec-
tion of the proper agent should be based on a consideration
of benefits and risks, including the development of bacterial
resistance to antibiotics and the ototoxicity related to the
treatment. Clinical trials have revealed the superiority of
topical treatment with fluoroquinolones, used alone or in
combination with a corticosteroid, compared with oral
amoxicillin and clavulanate. 1,19 Other studies 18,20 have
found that topical ciprofloxacin-dexamethasone combina-
tion improves resolution of AOMT compared with cipro-
floxacin or ofloxacin alone. These studies18,20 indicate that
an effective and safe treatment option for AOMT is the use of
a topical fluoroquinolone with the addition of a corticoste-
roid. Topical ciprofloxacin has been used in combination
with fluocinolone acetonide for the treatment of diffuse oti-
tis externa. This combination has proved to be a safe and
effective treatment, with superior levels of clinical efficacy
and bacteriologic response to those obtained with cipro-
floxacin alone.21
This article presents the results of 2 clinical studies
(Clinical Study to Assess the Efficacy and Safety of DF289
Plus DF277 Otic Solution in the Treatment of Middle Ear
Infections in Pediatric Patients [CIFLOTIII/10IA02] and Efficacy
and Safety of DF289 Plus DF277 Otic Solution in the Treatment
of Middle Ear Infections in Pediatric Patients [CIFLOTIII/
10IA04]) designed to evaluate the efficacy and safety of topi-
cal ciprofloxacin, 0.3%, plus fluocinolone acetonide,
0.025%, otic solution relative to ciprofloxacin, 0.3%, otic
solution alone and fluocinolone acetonide, 0.025%, otic
solution alone in children with AOMT.
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Ciprofloxacin Plus Fluocinolone in Otitis Media With Tympanostomy Tubes
Key Points
Question Is the combination of ciprofloxacin plus fluocinolone
acetonide otic solution more effective and safer than ciprofloxacin
alone and fluocinolone alone to treat acute otitis media with
tympanostomy tubes in children?
Findings In 2 randomized clinical trials with identical designs,
which included 662 children with acute otitis media with
tympanostomy tubes, ciprofloxacin plus fluocinolone
administered for 7 days was compared with their components
alone. The cessation of otorrhea occurred 2.7 days sooner with the
combination, and the number of related adverse events was small.
Meaning Ciprofloxacin plus fluocinolone is more effective than
treatment with either of the components alone for acute otitis
media with tympanostomy tubes and is well tolerated.
Methods
Study Design and Participants
Two identical multicenter, randomized, double-blind clini-
cal trials approved by the US Food and Drug Administration
were performed. Figure 1 shows the CONSORT flow diagrams
for the trials. The trial protocol can be found in Supplement 1.
These studies were undertaken as part of the development of
a combination of ototopical ciprofloxacin and fluocinolone for
the treatment of AOMT and conducted at multiple sites in the
United States, Canada, South Africa, and Europe. The proto-
cols were approved by the corresponding central or institu-
tional independent review boards specific to each site
(eMethods in Supplement 2). Written informed consent was
obtained from each patient’s parent or legally authorized rep-
resentative. Written informed assent was obtained from older
children when required. A total of 331 patients were enrolled
in each study. Included in the studies were children of either
sex between 6 months and 12 years of age with AOMT in at least
1 ear who presented with otorrhea for 3 weeks or less and with
moderate or severe purulent otorrhea at inclusion. Purulent
otorrhea was defined as a thin hazy or cloudy outpouring dis-
charge (a puslike liquid); otorrhea was defined as moderate
when the anterior sulcus was full and the fluid came up to the
edge of the TT, which should be totally or partly visible; otor-
rhea was defined as severe when copious discharge pre-
vented visualization of the TT unless the fluid was suctioned
from the ear canal. In cases of blocked TTs, the assessments
were performed after unblocking the TT with a small suc-
tion. Exclusion criteria included TT placement 3 days or less
before study entry; TT containing antiseptic or antibacterial
activity; T-type tubes; otitis externa; suspected viral, fungal,
or mycobacterial ear infection; craniofacial anomalies; oto-
logic surgery (other than TTs) within the previous year;
mastoiditis; known or suspected quinolone and/or cortico-
steroid hypersensitivity; use of topical or systemic antimi-
crobial, antifungal, or steroid agents within the 7 days
preceding study entr y; and conc urrent use of anti-
inflammatory agents.
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 Ciprofloxacin Plus Fluocinolone in Otitis Media With Tympanostomy Tubes Original Investigation Research

Figure 1. CONSORT Flow Diagrams

A CIFLOT/10IA02

335 Children screened for eligibility

4 Excluded (registered by mistake)

331 Randomized

112 Randomized to receive 109 Randomized to receive 110 Randomized to receive

ciprofloxacin plus fluocinolone ciprofloxacin fluocinolone

104 Completed the study 99 Completed the study 91 Completed the study
8 Discontinued 10 Discontinued 19 Discontinued
2 Adverse events 3 Adverse events 5 Adverse events
2 Lack of efficacy 4 Lack of efficacy 8 Lack of efficacy
4 Other 3 Other 6 Other

112 Included in the analysis of the
primary outcome (cessation
of otorrhea)
113 Included in safety analysis a
65 Included in the analysis
of microbiological cure
109 Included in the analysis of the
primary outcome (cessation
of otorrhea)
108 Included in safety analysis
70 Included in the analysis
of microbiological cure
110 Included in the analysis of the
primary outcome (cessation
of otorrhea)
106 Included in safety analysis
60 Included in the analysis
of microbiological cure

B CIFLOT/10IA04

336 Children screened for eligibility

5 Excluded (registered by mistake)

331 Randomized

CIFLOTIII/10IA02 indicates Clinical

111 Randomized to receive
ciprofloxacin plus fluocinolone
106 Completed the study
5 Discontinued
0 Adverse events
0 Lack of efficacy
5 Other
111 Included in the analysis of the
primary outcome (cessation
of otorrhea)
111 Included in safety analysis
60 Included in the analysis
of microbiological cure
112 Randomized to receive
ciprofloxacin
104 Completed the study
8 Discontinued
2 Adverse events
4 Lack of efficacy
2 Other
112 Included in the analysis of the
primary outcome (cessation
of otorrhea)
112 Included in safety analysis
65 Included in the analysis
of microbiological cure
108 Randomized to receive
fluocinolone
89 Completed the study
19 Discontinued
3 Adverse events
10 Lack of efficacy
6 Other
108 Included in the analysis of the
primary outcome (cessation
of otorrhea)
107 Included in safety analysis
62 Included in the analysis
of microbiological cure
Study to Assess the Efficacy and
Safety of DF289 Plus DF277 Otic
Solution in the Treatment of Middle
Ear Infections in Pediatric Patients;
CIFLOTIII/10IA04, Efficacy and Safety
of DF289 Plus DF277 Otic Solution in
the Treatment of Middle Ear Infections
in Pediatric Patients.
a
One patient was mistakenly treated
with ciprofloxacin plus fluocinolone
instead of fluocinolone alone
because of a site operation mistake.
That patient, having already taken
the ciprofloxacin plus fluocinolone,
was included in the ciprofloxacin
plus fluocinolone safety analysis.

Sample Size
Analyses were performed on an intention-to-treat basis. To
evaluate otorrhea using the clinical intention-to-treat (CITT)
population and the microbiological outcome using the micro-
biological intention-to-treat (MITT) population,22 a power analy-
sis was conducted to estimate the appropriate sample size based
on the results of the study reported by Roland et al18 compar-
ing ciprofloxacin plus dexamethasone with ciprofloxacin alone
in pediatric patients with AOMT. The difference in the time to
cessation of otorrhea (TCO) between these 2 groups for the MITT
population (absolute effect size) was 1.1 days. A total of 90 mi-
crobiological patients per group would be necessary for a 2-sided
log-rank test stratified by age (<3 years old or ≥3 years old) at a
significance level of P ≤ .05 to have 90% power. Considering
CITT as all randomized patients to be approximately 20% larger
than MITT (includes CITT patients whose baseline microbio-
logical culture yielded ≥1 pathogen), a sample size of 330 chil-
dren (110 per treatment group) was established.
Randomization
All patients were centrally randomized through an interac-
tive web response system, which assigned a number to iden-

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 Research Original Investigation
tify each patient throughout the duration of the study (June
24, 2011, through June 23, 2014). At randomization, patients
were stratified by age to ensure adequate representation of
each age group in the study. At randomization, patients were
assigned a unique medication kit number. For patients who
had bilateral AOMT, a second kit containing the same treat-
ment was provided. The most affected ear was considered
the evaluable ear. If the disease severity was identical in
both ears, the investigator selected the evaluable ear. In
either case, the nonevaluable ear would receive the same
treatment as the evaluable ear.
Study Medication and Study Conduct
All patients were assigned to 1 of the 3 cohorts in a 1:1:1 ratio
to receive topical treatment with ciprofloxacin plus fluocino-
lone, ciprofloxacin alone, or fluocinolone alone. The medica-
tion was provided in blue translucent, single-use vials of the
same characteristics, which were wrapped in a foil pouch to
ensure protection from light. The patients, caregivers, and in-
vestigators did not know which treatment was assigned. The
studies lasted approximately 3 weeks and included 4 sched-
uled visits on day 1 (visit 1: baseline visit), days 3 to 5 (visit 2:
undergoing therapy visit), days 8 to 10 (visit 3: end-
of-therapy visit), and days 18 to 22 (visit 4: test-of-cure visit).
At baseline, once the informed consent was obtained, care-
givers were taught to administer study medication and in-
structed to instill it twice daily for 7 days. A patient diary was
provided to each caregiver with detailed instructions to com-
plete it daily during the study period. This information was
used to evaluate patient adherence and presence of otorrhea
on each day during the study. The OM6 quality-of-life
questionnaire23 was also given to the caregivers, who were
asked to complete it during each visit. Medical history and con-
current symptoms and conditions were registered by each in-
vestigator. Before the first study dose and at visit 4, an audio-
metric evaluation was performed in all patients who were able
to participate in it. At visit 1, a sample of middle ear exudate
was obtained. At each of the 4 visits, a detailed otologic his-
tory and physical examination were conducted, and concomi-
tant medications and adverse events were recorded. Clinical
response was evaluated at visits 2, 3, and 4. If middle ear exu-
date was present at visits 3 and 4, then exudate was collected
and submitted for a microbiological evaluation. Used and un-
used study medication containers and patient diaries were col-
lected from the caregivers at visits 3 and 4, respectively.
Clinical Efficacy Parameters
The primary efficacy variable for these studies was TCO, de-
fined as the first day on which the otorrhea was absent and re-
mained absent until the completion of the study. Cessation of
otorrhea was ascertained by evaluating caregiver diaries and
confirmed by the otoscopic examination performed by the in-
vestigators at each study visit. Other clinical parameters as-
sessed throughout the study included volume, type or color
of otorrhea, otalgia, eardrum edema, granulation tissue, ec-
zema, and status of the TT. The volume of otorrhea, otalgia,
eardrum edema, granulation tissue, and eczema was mea-
sured on a 4-point scale, in which 0 indicates absent; 1, mild;
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Ciprofloxacin Plus Fluocinolone in Otitis Media With Tympanostomy Tubes
2, moderate; and 3, severe. Additional information on otalgia
was also collected from the AOM severity of symptoms
scale24,25 questionnaires. Type and color of otorrhea were as-
sessed as serous, mucoid, or purulent, wich each described as
sanguineous or nonsanguineous. The TT status was recorded
by determining the presence or absence of the TT and its func-
tionality (open vs closed). Clinical success was defined as com-
plete resolution of clinical signs (otorrhea, eardrum edema,
otalgia, and eczema) that were present at baseline and ab-
sence of any new findings (granulation tissue is no worse than
at baseline), whereas clinical failure was indicative of wors-
ened, lack of change, or some improvement.
Microbiological Efficacy Parameters
The middle ear exudate was obtained at visits 1, 3, and 4 by
aspirating through the TT using a syringe or a cannula (Juhn
Tym–Tap; Medtronic), after previous cleansing, suctioning, or
dry mopping of the ear canal of each patient. Samples were sub-
mitted for analysis to the central laboratory. The following spe-
cies were considered pathogens: S pneumoniae, H influenzae,
M catarrhalis, S aureus, and P aeruginosa. Microbiological out-
come was determined for each patient at visits 3 and 4. Sus-
tained microbiological cure was defined as eradication (if the
culture did not reveal growth of any pathogen) or presumed
eradication (if there was no material to culture and clinical re-
sponse was clinical cure) in the bacteriological response at vis-
its 3 and 4.
Safety Parameters
Safety was assessed by incidence of adverse events (AEs). All
AEs reported by the patient or caregiver spontaneously, ob-
served by the investigator, and elicited in response to ques-
tions from the study staff were recorded. The severity of each
AE (mild, moderate, or severe) and its association with study
medication (not related, possibly related, probably related, or
definitely related) were assessed and recorded by the inves-
tigators. The audiometric examinations performed at visits 1
and 4 were evaluated to determine any significant change in
hearing.
Statistical Analysis
Because CIFLOTIII/10IA02 and CIFLOTIII/10IA04 were iden-
tical in design and methods and each trial individually also ob-
tained statistically significant results, data were pooled to as-
sess the efficacy and safety outcomes. Kaplan-Meier estimates
were applied to evaluate the TCO in the CITT population. For
statistical calculations, the maximum length of TCO (maxi-
mum study duration of 22 days) was assigned to those pa-
tients without an observed value of cessation of otorrhea (pa-
tients with otorrhea still present at the end of the study visit and
those who discontinued prematurely for any reason or took res-
cue medication). Those patients were called censored patients.
The differences among treatments were assessed with a 2-sided
log-rank test, stratified by age group. The proportion of pa-
tients with sustained microbiological cure was compared among
treatment groups with a Cochran-Mantel-Haenszel test, strati-
fied by age. The same analysis was performed on the MITT popu-
lation. For the analyses of the secondary variables, compari-
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 Ciprofloxacin Plus Fluocinolone in Otitis Media With Tympanostomy Tubes Original Investigation Research

Table 1. Time to Cessation of Otorrhea in the Clinical Intention-to-Treat Population

CIFLOTIII/10IA02 CIFLOTIII/10IA04 Pooled

Ciprofloxacin Ciprofloxacin Ciprofloxacin
Plus Plus Plus
Fluocinolone Ciprofloxacin Fluocinolone Fluocinolone Ciprofloxacin Fluocinolone Fluocinolone Ciprofloxacin Fluocinolone
Variable (n = 112) (n = 109) (n = 110) (n = 111) (n = 112) (n = 108) (n = 223) (n = 221) (n = 218)
Patients with 88 (78.6) 73 (67.0) 53 (48.2) 87 (78.4) 77 (68.8) 47 (43.5) 175 (78.5) 150 (67.9) 100 (45.9)
TCO, No. (%)
Censored 24 (21.4) 36 (33.0) 57 (51.8) 24 (21.6) 35 (31.2) 61 (56.5) 48 (21.5) 71 (32.1) 118 (54.1)
patients,
No. (%)a
TCO, median 3.75 7.69 NE 4.94 6.83 NE 4.23 6.95 NE
(95% CI), d (3.04-4.39) (4.78-11.44) (7.43-NE) (3.74-5.52) (5.49-7.74) (13.93-NE) (3.65-4.95) (5.66-8.20) (16.67-NE)
P valueb NA <.001 <.001 NA .02 <.001 NA <.001 <.001
Abbreviations: CIFLOTIII/10IA02, Clinical Study to Assess the Efficacy and Safety of DF289 Plus DF277 Otic Solution in the Treatment of Middle Ear Infections in
Pediatric Patients; CIFLOTIII/10IA04, Efficacy and Safety of DF289 Plus DF277 Otic Solution in the Treatment of Middle Ear Infections in Pediatric Patients;
NA, not applicable; NE, not estimable; TCO, time to cessation of otorrhea.
a
Patients without an observed value, consisting of those with otorrhea still present at the end of study and those who discontinued for any reason or took rescue
medication.
b
P value is obtained from the log-rank test stratified on age (patients <3 years old vs ⱖ3 years old): pairwise comparisons vs the ciprofloxacin plus fluocinolone group.

sons between the treatment groups were assessed with the χ2
test. Safety end points were summarized by treatment group
using summary statistics or frequency counts, as appropriate.
Statistical significance was defined as P < .05. Statistical analy-
ses were performed using SAS statistical software, version 9.3
(SAS Institute Inc).
Results
Demographics and Participant Flow
A total of 662 children participating in the 2 studies were ran-
domly assigned to ciprofloxacin plus fluocinolone (n = 223),
ciprofloxacin alone (n = 221), or fluocinolone alone (n = 218).
There were 69 withdrawals, 13 (8 in the CIFLOTIII/10IA02 study
and 5 in the CIFLOTIII/10IA04 study) from the ciprofloxacin
plus fluocinolone group, 18 (10 in the CIFLOTIII/10IA02 and
8 in the CIFLOTIII/10IA04) from the ciprofloxacin group, and
38 (19 in each study) from the fluocinolone group. The me-
dian age was 2.5 years (range, 0.6-12.7 years), 391 (59.1%) were
male, and 511 (77.2%) were white. No relevant differences in
demographic and baseline characteristics were found be-
tween the treatment groups and among the CIFLOTIII/
10IA02 and CIFLOTIII/10IA04 studies.
Clinical Efficacy Outcomes
Main Variable
The main variable was TCO for the CITT population (223 were
treated with ciprofloxacin plus fluocinolone, 221 with cipro-
floxacin, and 218 with fluocinolone). Analysis of TCO for each
study revealed similar statistically significant differences
among treatments (Table 1). Considering both studies, the over-
all median TCO in patients receiving ciprofloxacin plus fluo-
cinolone was 4.23 days (95% CI, 3.65-4.95 days) compared with
6.95 days (95% CI, 5.66-8.20 days) in those receiving cipro-
floxacin alone (P < .001). Although the median TCO for the fluo-
cinolone group was not estimable because the number of cen-
sored patients was greater than the number of patients with
cessation of otorrhea, the comparison vs ciprofloxacin plus
fluocinolone revealed a statistically significant difference
in favor of the combination (P < .001). In Figure 2, the
Kaplan-Meier estimates illustrate the faster cessation of otor-
rhea and the greater proportion of otorrhea-free patients over
time for the ciprofloxacin plus fluocinolone group.
Secondary Variables
There were statistically significant differences in the clinical
responses reported at visits 3 and 4 when comparing cipro-
floxacin and fluocinolone alone against the ciprofloxacin plus
fluocinolone groups. Results of the overall analyses are given
in the eTable in Supplement 2. The clinical cure rate at visit 3
was significantly higher with ciprofloxacin plus fluocinolone
(176 [79.6%]) than with ciprofloxacin (136 [62.4%]) (differ-
ence, 17.2%; 95% CI, 8.8%-25.7%) and with fluocinolone (94
[44.3%]) (difference, 35.3%; 95% CI, 26.2%-44.4%). At visit 4,
clinical cure was achieved in 179 patients (80.6%) in the cip-
rofloxacin plus fluocinolone group vs 147 (67.4%) in the cip-
rofloxacin group (difference, 13.2%; 95% CI, 5.0%-21.4%;
P = .002) and 101 (47.6%) in the fluocinolone group (differ-
ence, 33.0%; 95% CI, 24.0%-42.0%; P < .001).
Microbiological Efficacy Outcomes
Of 382 patients in the MITT population, 125 were treated with
ciprofloxacin plus fluocinolone, 135 with ciprofloxacin, and 122
with fluocinolone. The principal secondary variable was sus-
tained microbiological cure. A statistically significantly higher
number of patients receiving ciprofloxacin plus fluocinolone
had sustained microbiological cure (94 [79.7%]) than in the
other groups: 84 (67.7%) in the ciprofloxacin group (differ-
ence, 12.0%; 95% CI, 0.8%-23.0%) and 41 (37.6%) in the fluo-
cinolone group (difference, 42.1%; 95% CI, 29.3%-54.8%)
(Table 2). At visit 3, the number of children with a favorable
microbiological outcome was higher in the ciprofloxacin plus
fluocinolone group (103 [83.1%]) compared with the other
groups: 91 (68.9%) with ciprofloxacin (difference, 14.2%; 95%
CI, 3.6%-24.6%; P = .002) and 48 (40.3%) with fluocinolone
(difference, 42.8%; 95% CI, 30.5%-54.9%; P < .001) (Table 2).
At visit 4, a favorable microbiological response was achieved

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 Research Original Investigation Ciprofloxacin Plus Fluocinolone in Otitis Media With Tympanostomy Tubes

Figure 2. Kaplan-Meier Estimates for the Time to Cessation of Otorrhea in the Clinical
Intention-to-Treat Population

100

Patients With Cessation of Otorrhea, %

Ciprofloxacin and fluocinolone
80

60 Ciprofloxacin

Fluocinolone
40

20

0
0 2 4 6 8 10 12 14 16 18 20 22
Time, d

No. of patients at risk

Ciprofloxacin and fluocinolone 223 181 115 81 60 55 55 54 52 48 47 47
Ciprofloxacin 221 200 154 122 96 87 82 81 78 76 73 70
Fluocinolone 218 194 175 150 136 129 127 125 123 121 117 117

Table 2. Microbiological Response in the Microbiological Intention-to-Treat Population

Ciprofloxacin
Plus Fluocinolone Ciprofloxacin Fluocinolone
Variable (n = 125) (n = 135) (n = 122)
Sustained Microbiological Cure (at Visits 3 and 4)
Success, No. (%)a 94 (79.7) 84 (67.7) 41 (37.6)
Failure, No. (%)b 24 (20.3) 40 (32.3) 68 (62.4)
Missing, No. 7 11 13
Difference vs ciprofloxacin plus NA 12.0 (0.8 to 23.0) 42.1 (29.3 to 54.8)
fluocinolone, % (95% CI)
P valuec NA .03 <.001
Microbiological Response at Visit 3 Abbreviation: NA, not applicable.
a
Success, No. (%) a
103 (83.1) 91 (68.9) 48 (40.3) Eradication or presumed
b
eradication.
Failure, No. (%) 21 (16.9) 41 (31.1) 71 (59.7) b
Unfavorable and indeterminate
Difference vs ciprofloxacin plus 14.2 (3.6 to 24.6) 42.8 (30.5 to 54.9) responses.
fluocinolone, % (95% CI)
c
P value is obtained from
P valued NA .002 <.001
Cochran-Mantel-Haenszel test
Microbiological Response at Visit 4 stratified on age (patients <3 years
Success, No. (%)a 96 (85.7) 88 (87.1) 47 (72.3) old vs ⱖ3 years old): pairwise
comparisons vs the ciprofloxacin
Failure, No. (%)b 16 (14.3) 13 (12.9) 18 (27.7)
plus fluocinolone group.
Difference vs ciprofloxacin plus −1.4 (−7.8 to 10.6) 13.4 (1.4 to 25.5) d
fluocinolone, % (95% CI) P value is obtained from χ2 test vs
d the ciprofloxacin plus fluocinolone
P value NA .86 .005
treatment group.

in 96 patients (85.7%) in the ciprofloxacin plus fluocinolone No significant differences were found in the audiometric as-
group, 88 (87.1%) in the ciprofloxacin group (difference, −1.4%; sessment. The audiometric evaluation improved or did not
95% CI, −7.8% to 10.6; P = .86), and 47 (72.3%) in the fluocino- change at the end of the study in 49 patients (98.0%) receiving
lone group (difference, 13.4%; 95% CI, 1.4%-25.5%; P = .005). ciprofloxacin plus fluocinolone, 62 patients (98.4%) receiving
ciprofloxacin, and 52 patients (96.3%) receiving fluocinolone.
Safety Results
Analyses of AEs were performed on 224 children treated with cip-
rofloxacin plus fluocinolone, 220 treated with ciprofloxacin, and
213 treated with fluocinolone. Only 7 patients (3.1%) in the cip-
Discussion
rofloxacin plus fluocinolone group, 8 (3.6%) in the ciprofloxa- The use of topical ciprofloxacin when administered in combina-
cin group, and 10 (4.7%) in the fluocinolone group presented with tion with a corticosteroid for the treatment of AOMT has been
AEs related to study medication (Table 3). Overall, AEs were mild previously investigated.18 These are the first randomized stud-
to moderate and led to few patients discontinuing the study. The ies, to our knowledge, in which ciprofloxacin has been admin-
most commonly reported AEs were otic events. istered in combination with fluocinolone for AOMT. Fluocino-

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 Ciprofloxacin Plus Fluocinolone in Otitis Media With Tympanostomy Tubes Original Investigation Research

Table 3. Treatment-Related Adverse Events in the Safety Population

No. (%) of Adverse Eventsa

Ciprofloxacin
Plus Fluocinolone Ciprofloxacin Fluocinolone
Adverse Event (n = 224) (n = 220) (n = 213)
Otic events
Ear pain 1 (0.4) 1 (0.5) 2 (0.9)
Ear pruritus 1 (0.4) 1 (0.5) 0
Otorrhea 1 (0.4) 1 (0.5) 2 (0.9)
Ear edema 1 (0.4) 0 1 (0.5)
Eardrum edema 1 (0.4) 0 0
Granulation tissue 1 (0.4) 0 1 (0.5)
Contralateral otitis media 1 (0.4) 0 0
Eczema 0 1 (0.5) 1 (0.5)
Ear discomfort 0 1 (0.5) 0
Deafness neurosensory 0 1 (0.5) 0
Otitis externa 0 1 (0.5) 0
Otitis externa candida 0 1 (0.5) 0
Ear infection fungal 0 0 1 (0.5)
Ear hemorrhage 0 0 1 (0.5)
Nonotic events
Rash 1 (0.4) 0 2 (0.9)
Dermatitis 0 1 (0.5) 0
a
Some patients experienced more
Sinusitis 0 0 1 (0.5)
than 1 event.

lone, like other topical corticosteroids, has anti-inflammatory,
antipruritic, and vasoconstrictive properties. The principal aim
of these studies was to evaluate the efficacy and safety of cipro-
floxacin plus fluocinolone compared with ciprofloxacin alone and
fluocinolone alone in patients with AOMT.
The primary efficacy variable evaluated was TCO. The results
indicate that topical treatment with ciprofloxacin plus fluocino-
lone was statistically superior to ciprofloxacin alone and fluo-
cinolone alone in children aged 6 months to 12 years with AOMT.
Resolution of otorrhea occurred at 4.23 days in patients receiv-
ing ciprofloxacin plus fluocinolone compared with 6.95 days in
patients receiving ciprofloxacin alone, revealing the superiority
of ciprofloxacin plus fluocinolone in the treatment response
(P < .001). This difference (2.7 days) in favor of ciprofloxacin plus
fluocinolone is clinically meaningful because it represents a 64%
improvement in clinical response and an important advantage
over ciprofloxacin as a single-agent antibiotic therapy. Although
the median TCO for the fluocinolone group was not estimable,
the comparison vs the ciprofloxacin plus fluocinolone combina-
tion revealed a significant difference in favor of the combination.
A significant reduction of otorrhea with ciprofloxacin plus fluo-
cinolone was recorded at visit 2.
The clinical cure was achieved in a greater percentage of
children in the ciprofloxacin plus fluocinolone group than in
other study groups. Results obtained at the end-of-treatment
and test-of-cure visits revealed statistically significant differ-
ences between ciprofloxacin plus fluocinolone compared with
either treatment alone (P < .001 in all cases). The use of cipro-
floxacin with the addition of a corticosteroid has been previ-
ously studied for AOMT. 1,18,20 Two studies revealed the
superiority of topical treatment with ciprofloxacin and
d ex a m e t h a s o n e c o m b i n at i o n c o m p a re d w it h o r a l
amoxicillin-clavulanate1 and topical ofloxacin.21 A previously
published trial18 also confirmed an overall clinical cure rate ad-
vantage and a shorter TCO when comparing the topical admin-
istration of ciprofloxacin and dexamethasone combination with
ciprofloxacin alone in children with AOMT. That study found
a 1-day difference in reduction of otorrhea when a combina-
tion of antibiotic and steroid medication was used. It did not
find a significant clinical difference between the 2 treatment
groups at the test-of-cure visit. Our studies found a signifi-
cant and consistent benefit of ciprofloxacin plus fluocinolone
combination throughout the study period to the test-of-cure
visit. This outcome suggests that the addition of fluocinolone
to ciprofloxacin may offer a more sustained treatment for AOMT
than the addition of dexamethasone.
We compared the sustained microbiological cure and the
microbiological response to topical therapy with ciprofloxa-
cin plus fluocinolone vs ciprofloxacin alone and fluocinolone
alone. Our results revealed that sustained microbiological cure
was better with ciprofloxacin plus fluocinolone (94 [79.7%])
than in the ciprofloxacin alone (84 [67.7%]; P = .04) and fluo-
cinolone alone (41 [37.6%]; P < .001) groups. The number of
children with a favorable microbiological response at the end
of treatment was higher in the combined therapy group (103
[83.1%] vs 91 [68.9%] in the ciprofloxacin alone group [P = .002]
and 48 [40.3%] in the fluocinolone alone group [P < .001]). At
visit 4, the microbiological response was similar with cipro-
floxacin alone and ciprofloxacin plus fluocinolone (88 [87.1%]
vs 96 [85.7%], P = .86), whereas it differed between cipro-
floxacin plus fluocinolone and fluocinolone alone (96 [85.7%]
vs 47 [72.3%], P = .005).
Most treatment-emergent AEs were mild or moderate, and
investigators considered most treatment-emergent AEs to be

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 Research Original Investigation Ciprofloxacin Plus Fluocinolone in Otitis Media With Tympanostomy Tubes

unrelated to study medication in each treatment group. The
frequency of AEs associated with the 3 treatments was low: less
than 5% in each of the 3 groups and none of severe intensity.
No deaths or related serious AEs were reported during the con-
duct of both studies. These results agree with the low inci-
dence of drug-related AEs reported previously,21,26 thus con-
firming the high tolerability of the combination. The data
presented in this work indicate that ciprofloxacin plus fluo-
cinolone is clinically and microbiologically superior to cipro-
floxacin alone in the treatment of children with AOMT.
Conclusions
Our studies indicate that topical treatment with ciprofloxa-
cin in combination with fluocinolone constitutes a safe and
effective treatment for children with AOMT and allows for
superior levels of clinical efficacy than treatment with
either component alone. The cessation of otorrhea occurred
2.72 days sooner with the combination than with ciprofloxa-
cin alone. This result may represent an important advantage
of this combination over other ototopical therapies. A sus-
tained clinical improvement was achieved with the combi-
nation treatment relative to ciprofloxacin alone through the
end-of-treatment and the test-of-cure visits. The microbio-
logical cure rate was also greater with the combination than
with antibiotic alone at the end of treatment. The combina-
tion of ciprofloxacin, 0.3%, and fluocinolone acetonide,
0.025%, for 7 days is more effective than treatment with
either of the components alone for post-TT otorrhea, and it
is well tolerated as evidenced by the small number of
related AEs recorded in these studies.

ARTICLE INFORMATION Alcon, other support from Cellceutix, and grants, Schane, MD; Diana H. Henderson, MD, CPI; and
Accepted for Publication: September 29, 2016. personal fees, and other support from Medtronic. Justin Gull, MD.

Published Online: December 22, 2016.
doi:10.1001/jamaoto.2016.3537
Author Affiliations: Center for Pediatric ENT–Head
and Neck Surgery, Boynton Beach, Florida
(Spektor); Otolaryngology Department, Hospital
Vall d’Hebron, Barcelona, Spain (Pumarola); private
practice, Johannesburg, South Africa (Ismail);
Central California Clinical Research, Fresno (Lanier);
Vital Prospects Clinical Research Institute PC, Tulsa,
Oklahoma (Hussain); Carolina ENT Clinic (Centri
Inc), Orangeburg, South Carolina (Ansley);
Spartanburg Ear Nose & Throat, North Grove
Medical Park, Spartanburg, South Carolina
(Butehorn); Ear, Nose, and Throat, Constantiaberg
Medi-Clinic, Cape Town, South Africa (Esterhuizen);
Greensboro Ear, Nose & Throat, Greensboro, North
Carolina (Byers); private practice, Conroe, Texas
(Douglis); Ear, Nose, and Throat Department, NEA
Baptist Clinic, Jonesboro, Arkansas (Lansford);
Otolaryngology Department, Hospital Quirón,
Madrid, Spain (Hernández).
Author Contributions: Dr. Spektor had full access
to all the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Pumarola, Hernández.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Spektor, Lansford,
Hernández.
Critical revision of the manuscript for important
intellectual content: Spektor, Pumarola, Ismail,
Lanier, Hussain, Ansley, Butehorn, Esterhuizen,
Douglis.
Statistical analysis: Hussain, Hernández.
Administrative, technical, or material support:
Pumarola, Lansford.
Study supervision: Spektor, Hernández.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest.
Dr Douglis reported receiving personal fees from
Laboratorios SALVAT SA, Otonomy, and Alcon.
Drs Esterhuizen, Ismail, and Lanier reported
receiving personal fees from Laboratorios SALVAT
SA. Dr Spektor reported receiving personal fees and
other support from Laboratorios SALVAT SA and
Funding/Support: This report represents the
results of the clinical trials sponsored by
Laboratorios SALVAT SA as part of the US Food and
Drug Administration approval of the ciprofloxacin
plus fluocinolone combination for the treatment of
otitis media with tympanostomy tubes.
Role of the Funder/Sponsor: Laboratorios SALVAT
SA contributed to the study design, analyzed the
data, reviewed and revised the manuscript, and
approved the final manuscript as submitted.
Meeting Presentation: This paper was presented
at the 2016 National Conference and Exhibition
Meeting of the American Academy of Pediatrics;
October 24, 2016; San Francisco, California.
Additional Contributions: Enrique Jimenez, MD,
and Patricia Lois from the Medical Department at
Laboratorios SALVAT SA contributed to the study
design, analysis of the data, and revision of the
manuscript. The following investigators
participated in the trial: Scott Charlton, MD; Ismail
H. Mitha, MD; Laurance Chu, MD; James Hedrick,
MD; Joshua Gottschall, MD; Edward Goldblatt, MD;
Nancy Appelblatt, MD; Oliver H. Haag, MD; Ann
Edmunds, MD; Richard Glover, MD; Lars
Mortensen, MD; John Morris, MD; Richard Van
Leeuwen, MD; Jeffrey Rosenbloom, MD; Kirk
Coverston, MD; Jennifer Mijares-Zimmerman, MD;
Gavin Setzen, MD; Jonathan Moss, MD; Jaco
Jurgens, MD; Jeff Hunt, MD; Steven Miller, MD;
William Johnston, MD; Farid Marquez, MD; Keith
Ramsey, DO; Steven Goudy, MD; Dale Ehmer Jr,
MD; Ronald Fischler, MD; Mitzie Hewitt, DO; Shelley
Weiss, MD; Thomas Andrews, MD; Michelle Bosch,
MD; Richard DeMaio, MD; Frank A. Calcagno, MD;
Carlos Martin, MD, PhD; Jonathan Lee, MD; Isaac
Melamed, MD; Alan Garcadden, MD; Bryan Harvey,
MD; Matthew R. Brown, MD; Jay Chavda, MD;
Marcus Fietchner, MD; Willard R. Thompson Jr, MD;
AntonioE. Collazo, MD; Ronald B. Shealy, MD;
Alejandro Colls, MD, PhD; James D. Sidman, MD;
Mark B. DiDea, MD; Don S. Respler, MD; Montserrat
Droguet, MD, PhD; Peter Spafford, MD; Naeem
Moosa, MD; J. Lewis Romett, MD; Matti Penttila,
MD; Karel Pokorný, MD, PhD; Naresh Aggarwal, MD;
Chad McDuffie, MD; Heikki O. Valkama, MD; Simon
I. Angeli, MD; Julian S. Trokis, MD; Serge Padoan,
MD; Rosa Rosell, MD, PhD; Carlos Asensio, MD;
Henry Lipps, DO; Maryam Taghadosi, MD; Mark D.
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