Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Dohar, 2006

Type of study: RCT

Setting and country: randomized, observer-masked, parallel-group, multicenter trial in the USA.

Funding and conflicts of interest:

This study was supported by a grant from Alcon Research

Ltd (Fort Worth, TX).

Financial Disclosure: Drs Dohar, Giles, Bikhazi, Carroll, Moe, and Reese are independent physicians who received compensation from the sponsor for the study expenses but received no other financial

incentives. Dr Roland is an independent physician who is paid by the sponsor for services as a medical monitor and consultant.

Inclusion criteria:

Aged 6 months to 12 years with patent TTs and a clinical diagnosis of uncomplicated AOM with otorrhea of <= 3 weeks duration in 1 or both ears.

Exclusion criteria:

otorrhea present for >=3 weeks and

those with acute or malignant otitis externa. In addition:

known or suspected fungal or mycobacterial ear infections, a history of or active viral infections of the tympanic membrane, mastoiditis,

or infections requiring systemic antibiotic therapy.

Patients were also excluded for otologic surgery

(except that confined to the tympanic membrane) in the

previous year or if they presented with or had a history of diabetes, immunosuppressive disorders, acute or

chronic renal disease, active hepatitis, chronic nasal obstruction and/or persistent rhinorrhea, complicating

structural abnormalities, known or suspected quinolone

hypersensitivity, and, in girls, menarche.

Patients were

not permitted to receive topical (otic or ophthalmic)

corticosteroids or antibiotics concurrently or within the preceding 3 days, systemic corticosteroids within the preceding 7 days, inhaled corticosteroids at doses

>= 800 g/day, topical antibiotics for skin infections within the

preceding 7 days, topical otic analgesics/anesthetics or antiseptic washes, or nonsteroidal anti-inflammator drugs, with the exception of oral acetaminophen for relief of pain.

Additional exclusions associated with

amoxicillin/clavulanic acid included previous history of chronic diarrhea or pseudomembranous colitis, current

diagnosis of mononucleosis, current or previous history of cholestatic jaundice or hepatic dysfunction, or con

current

administration of allopurinol or probenecid.

N total at baseline:

Intervention: 39

Control: 41

Important prognostic factors²:

Man age was 1.88 years (ITT dataset), range 6 months to 8 years.  

Sex:

I: 51% M

C: 54% M

Groups comparable at baseline? No statistically significant differences were identified between the 2 groups with respect to age, gender, ethnicity,

or affected ear(s).

Describe intervention (treatment/procedure/test):

topical CIP/DEX (Ciprodex Sterile Otic Suspension, manufactured by Alcon Laboratories Inc, Fort Worth, TX) dosed 4 drops twice daily for 7 days

In both treatment groups, the ear canal was cleaned

of all fluid and debris via suction (aural toilet) at baseline (and possibly during follow up

visits)

Describe  control (treatment/procedure/test):

AMOX/CLAV (Augmentin ES-600 Oral Suspension,

manufactured by GlaxoSmithKline, Research Triangle Park, NC) dosed 90 mg/kg per day divided every 12 hours for 10 days.

In both treatment groups, the ear canal was cleaned

of all fluid and debris via suction (aural toilet) at baseline (and possibly during follow up

visits).

Length of follow-up:

18+3 days

Loss-to-follow-up:

Not reported, all patients were analysed.

Incomplete outcome data:

One patient in each treatment group discontinued the study because of related adverse

event(s).

A 1-year-old male receiving CIP/DEX discontinued

the study because of tube obstruction in the study

ear, and a 1-year-old male receiving AMOX/CLAV dis

continued the study because of dermatitis and diarrhea.

Outcome measures and effect size (include 95%CI and p-value if available):

Presence of otorrhea

The median time to absent otorrhea for CIP/DEX was 4.0

days (ITT) compared with 7.0 days (ITT) for AMOX/CLAV.

Clinical cure at TOC:

CIP/DEX: 84.6% (33/39)

AMOX/CLAV: 58.5% (24/40)

Number of otorrhea recurrences during 6 month follow-up

Not reported.

Quality of life

Not reported.

Serious complications

Not reported.

Treatment-related adverse events (suspected ototoxicity)

Treatment-related adverse

events were reported in 12.8% of patients receiving

CIP/DEX compared with 29.3% of patients receiving

AMOX/CLAV.

These adverse events were nonserious, mild to moderate, and generally resolved with or without treatment.

Neither treatment group had any negative effect on patient

audiometry.

Conclusion: Topical otic treatment with ciprofloxacin/ dexamethasone otic suspension is superior to treatment with oral amoxicillin/clavulanic acid suspension and results in more clinical cures and earlier cessation of otorrhea with fewer adverse effects in children with acute otitis media with otorrhea through tympanostomy tubes.

Van Dongen, 2014

Type of study: parallel, open-label RCT

Setting and country: primary and secondary care, NL

Funding and conflicts of interest: The study was supported by a grant from Netherlands Organization for Health Research and Development. No conflicts of interest are reported.

Inclusion criteria:

children aged 1 to 10 yearswith a clinical diagnosis of uncomplicated

ear discharge through a grommet of <= 7 days duration in one or both ears

Exclusion criteria:

body temperature of more than 38.5 °C, antibiotics during the

previous 2 weeks, grommets placed within the previous 2 weeks, episode of ear discharge in the previous 4weeks, 3 ormore episodes in the previous 6 months or 4 or more episodes

in the previous year, Down syndrome, craniofacial anomaly, known immunodeficiency

allergy to the medications used in this study.

N total at baseline:

Intervention: 76

Control (oral antibiotics): 77

Control (initial observation): 77

Important prognostic factors²:

For example

age ± SD:

Intervention: 4.6, 2.1

Control (oral antibiotics): 4.4, 2.0

Control (initial observation):4.4, 2.0

Sex:

I: 66% M

C oral: 52% M

C obs: 56% M

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

hydrocortisone–bacitracin–colistin ear drops

(Bacicoline-B, Daleco Pharma) (administered

as five drops, three times daily, in the discharging ear or ears for 7 days),

Describe  control (treatment/procedure/test):

Oral antibiotics:

oral amoxicillin–

clavulanate suspension (30 mg of amoxicillin

and 7.5 mg of clavulanate per kilogram of body

weight per day, divided into three daily doses ad

ministered

orally for 7 days)

initial observation:

initial observation for 2 weeks (no assigned medication prescription

to fill).

Length of follow-up:

6 months

Loss-to-follow-up:

Intervention: 5/76

Reasons (describe): 3 stopped early, 1 received additional oral antibiotics, 1 stopped early and used oral antibiotics.

Control oral: 9/77

Reasons (describe): 3 stopped early, 5 received additional antibiotic, 1 stopped early and used antibiotics

Control obs: 16/77

Reasons (describe)

6 received oral antibiotics, 7 received antibiotic eardrops, 2 received both and 1 was lost-to-follow-up.

Incomplete outcome data:

Intervention: 10%

Control oral: 5%

Control obs: 5%

Otorrhea status not filled out in available parental diaries.

Outcome measures and effect size (include 95%CI and p-value if available):

Presence of otorrhea

Antibiotic versus observation

RR: 0.10 (0.04 to 0.26)

RD: 49% (37 to 62%)

Antibiotic versus oral antibiotics

RR: 0.12 (0.04 to 0.32)

RD: 39% (26 to 59%)

Number of otorrhea recurrences during 6 month follow-up (median)

I: 0 (range 0 to 9)

C oral: 1 (range 0 to 6)

C init: 1 (range 0 to 5)

Quality of life

At 2 weeks of follow-up, the change in the generic

health-related quality-of-life scores did not differ significantly among the study groups.

The changes in the disease-specific health-related

quality-of-life scores at 2 weeks were small but

consistently favored eardrops (supplemental data).

Serious complications 

No serious adverse events were reported in the three groups within 2 weeks.

Treatment-related adverse events

Antibiotic versus observation

RD: NA for all outcome measures.

Antibiotic versus oral antibiotics

Local discomfort:

RD: 21% (95%CI 12 to 30)

Gastrointestinal discomfort:

RD 23% (14 to 33%)

Rash:

RD 1% (-4 to 7%)

Oral candidiasis:

RD: 0)

Conclusion: In this pragmatic, randomized, controlled trial,

we found that antibiotic–glucocorticoid eardrops

were superior to oral antibiotics and to initial

observation with respect to the primary outcome of otorrhea at 2 weeks, as assessed otoscopically in children with tympanostomy tubes and acute otorrhea.

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Brennan-Jones, 2020

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs.

Literature search up to march 2020.

Topical antibiotics plus steroids versus placebo or no intervention

A: Browning, 1988

B: Eason, 1986

C: Picozzi, 1983

Study design: RCT (parallel)

Setting and Country:

A: two-arm, single-blind, parallel-group RCT, UK

B: five-arm, non-blinded, parallel-group RCT, Solomon Islands, Munda

C: two-arm, double-blind, parallel-group RCT, Scotland

Source of funding and conflicts of interest:

non-commercial

This project was supported by the National Institute for Health

Research, via Cochrane Infrastructure, Cochrane Programme Grant

or Cochrane Incentive funding to Cochrane ENT. The views and

opinions expressed therein are those of the authors and do not

necessarily reflect those of the Systematic Reviews Programme,

NIHR, NHS or the Department of Health.

Inclusion criteria SR: RCT’s with a follow-up for at least one week. Patients (adults and children) who had chronic ear discharge of unknown cause or chronic suppurative otitis media.

Exclusion criteria SR: cross-over trials, studies that randomized participants by ear for those that compared topical antibiotics plus steroids against systemic antibiotics. Studies were the majority (more than 50%) of participants had an alternative diagnosis to CSOM (e.g. otitis externa), underlying cholesteatoma, ear surgery within the last six weeks.

We did not include studies designed to evaluate interventions

in the immediate peri-surgical period, which were focused on

assessing the impact of the intervention on the surgical procedure

or outcomes.

4 studies included

Important patient characteristics at baseline:

N, mean age

A: 64 intervention, mean age 51 years 59 placebo, mean age 47 years

B: 134 children (184 ears) mean age 5.4 years

C: 37, age not reported.

Sex:

A: 46% Male

B:  63.4%

C: not reported

Main diagnosis

A: adults with active mucosal chronic otitis media.

B: chronic suppurative otitis media with presence of otorrhoea for more than 3 months and tympanic membrane perforation.

C: active chronic otitis media

Groups comparable at baseline? Yes

Describe intervention:

We have included any combinations of topical antibiotic plus

topical steroids, whether formulated as a single formulation or

applied separately.

At least five days of treatment with antibiotics was required, except

for antibiotics where a shorter duration has been proven to be

equivalent (e.g. azithromycin for systemic antibiotics).

A: gentamicin/ hydrocortisone, ear drops, no dose given except to say "highest recommended

daily dose" (4 drops/6 hours), duration of treatment = 4 to 6 weeks depending on success

B: Sofradex eardrops (0.5% w/v of framycetin sulphate, 0.050% w/v of dexamethasone and 0.005% w/v of gramicidin) (no details of volume or frequency of administration), PLUS

aural toilet 4 times per day using cotton wool wisps twisted on to orange sticks. Treatment duration = 6

weeks.

All treatments administered by parents.

C: gentamicin plus hydrocortisone ear drops, no information on dose,

frequency of administration, treatment duration = 4 weeks

Describe  control:

A: initially placebo ear drops were used (0.9% sterile saline, 1 drop/8 hours)

but this was changed in the second stage of the study to placebo tablets. It was not clear how many patients

were in both groups. Duration of treatment = 4 to 6 weeks depending on success.

The patients on placebo therapy also performed regular aural toilet with cotton buds.

B: no treatment

All treatments administered by parents.

C: placebo (no further information given), ear drops, treatment

duration = 4 weeks

End-point of follow-up:

A: 4 to 6 weeks of treatment and follow-up

B: 3 to 6 weeks duration of treatment and 6 weeks duration of follow-up

C: 4 week duration of treatment and follow-up.

For how many participants were no complete outcome data available?

(intervention/control)

A: low dropout rate. 24/187 (12.8%) of participants were lost to follow-up but no information is provided about the reasons or to which group

they were allocated

B: no dropouts or missing data reported; no statements about missing data

C: 16% (6/37) were not included in the analysis.

Outcome measure-1: Defined as presence of otorrhea / resolution of ear discharge

Effect measure: RR, RD, mean difference [95% CI]:

A: -

B: study conducted in 'high-risk' children reported this outcome by ear at 6 weeks and found that 58% of 41 ears were improved with topical antibiotics (framycetin sulphate, dexamethasone and gramicidin) with steroids compared with 50% of 26 ears with no topical treatment.

C: -

Outcome measure-2: Defined as number of otorrhea recurrences during 6-month follow-up

The outcome measure was not included in the SR of Brennan-Jones (2020).

Outcome measure-3: Defined as quality of life

None of the studies reported this outcome meausure.

Outcome measure-4: Defined as (serious) complications

A: reported that no side effects occurred in any participants, which would include the defined serious complications.

B: reported one case of mastoiditis and one case of meningitis with focal encephalitis. It is not clear which group these patients were from, or whether the complications occurred pre- or post-treatment.

Outcome measure-5: Defined as treatment related adverse events (suspected ototoxicity)

A: One study reported that "in the majority there was no change in [bone conduction] thresholds and if a change did occur it was as likely to reflect

an improvement as a deterioration…". The study also reported "no

increased incidence of otological symptoms, in particular of tinnitus

or vertigo, was detected in patients complying to antibiotic-steroid ear

drops compared with the pre-management incidence or against that in patients after placebo management".

Facultative:

Topical antibiotics plus steroid versus systemic (oral) antibiotics

D: Ramos, 2003

Excluded as the study did not include ACMOM patients.

Risk of bias

A: unclear risk of bias

B: high risk of bias

C: unclear risk of bias

High risk population:

A: no

B: yes (indigenous groups) – study noted prevalence is 3.8%.

C: no

GRADE conclusions:

Very low (all outcome measures).

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Dohar, 2006

Definitely yes

Reason: sequentially assigned to treatment according to a randomization code provided by the Alcon Biostatistics Department. The randomization was blocked within center to ensure balanced treatment groups within each center.

Unclear

Reason: The randomisation was blocked within a

centre to ensure balanced treatment groups

within each centre. It is, however, unclear

how large these blocks were and therefore it is unclear if the person performing the randomization could predict treatment allocation.

Definitely no

Reason: Because of the differences between a topically and an orally administered medication, as well as the difference in the dosing regimens, this

study was considered observer masked. That is, the investigator

conducting the clinical evaluations had no

knowledge of the patient’s treatment assignment. Dosing

assignments were provided to the study coordinator who was responsible for dispensing and providing dosing

instructions to the patient (parent/guardian).

Definitely yes

Reason: One patient in each treatment group discontinued the study because of related adverse event(s).

Unclear

Reason: protocol was not available. All outcome measures reported in the methods section are reported in the results.

Definitely no

Reason: The study sponsor is the provider of the medication under study. The influence of the study sponsor on the publication is not clearly described.

Low risk (objective outcomes)

High risk (subjective outcomes)

Reason: the study was not blinded, impact of the sponsor is unknown and the allocation concealment is not described.

Van Dongen, 2014

Definitely yes

Reason: An independent data manager generated a randomization

sequence (with the use of block sizes

of six), with stratification according to age (<4 years

vs. =4 years). The study physician accessed the

trial randomization website at the conclusion of the home visit to obtain the study-group assignment.

Definitely yes

Reason: The randomization assignment was concealed and could not be predicted in advance of or during enrollment.

Definitely no

Reason: the study was a pragmatic, non-blinded trial design to enhance the applicability of our findings to daily practice.

Definitely yes

Reason: lost-to-follow-up was infrequent (1 in the initial observation control group).

Definitely yes

Reason: Trial registered before start of trial; Netherlands

Trial Register number, NTR1481 Full protocol available on NEJM.org; outcomes listed atNTR and protocol reported

in paper.

Probably yes

Reason:

Baseline characteristics are balanced, ITT is performed, sample size calculations were performed, co-interventions were not reported.

Low risk (objective outcomes)

Some concerns (subjective outcomes)

Reason: the study was not blinded (open-label study).

Brennan-Jones, 2020

Yes

To assess the eFects of adding a topical steroid to topical antibiotics in the treatment of people with chronic suppurative otitis media (CSOM).

Yes

Different databases were searched up to march 2020.

Yes

Yes

Not applicable

Yes

Risk of bias and GRADE conclusions are formulated.

No

Meta-analyses are therefore not performed.

Yes

Yes

Of both the SR and the individual studies (if available).