Study ID

Sequence generation

Alloc. concealment

Balance at baseline?

Blinding

Follow‐up

Browning 1983a

Unclear

Treatment allocation described as random, using random numbered list kept by the pharmacist, who dispensed the medication, but method of sequence code generation was not stated.

The choice of antibiotic depended on sensitivity results of ear discharge isolates.

Participants with Pseudomonas species isolated were randomised to topical antibiotics or antiseptics only ‐ not to oral antibiotics due to resistance.

Did not discuss whether randomisation was stratified by the different diagnostic groups (and results not reported separately in trial report).

Unclear

Medication was supplied in the clinic by the pharmacist using the random numbered list, after eligibility assessments by the clinicians, who were blinded (except for antiseptic). Whether treatment was concealed from the pharmacist is not discussed.

Unclear Baseline characteristics (including the distribution of participants with and without modified radical mastoidectomy) not reported.

Single blind

Allocation was kept blinded from the clinicians, with the necessary exception of antiseptic, given by the otologist after aural toilet.

Inadequate

32% dropout: 24/75 participants were defaulters or non‐compliers (ie used <75% of the medication).
(Numbers excluded not given by treatment group or diagnosis).

Results given for the 51 participants who complied with treatment only (38 on topical antibiotics or antiseptics, included in this review).

Clayton 1990

Unclear

Treatment allocation described as random, with medication codes; but no further details of sequence generation method were given.

Did not discuss whether randomisation was stratified by the different diagnostic groups ‐ therefore included all participants in this review.

Adequate

Patients were randomly allocated treatment in a double‐blind fashion.

Medication codes were known only by the pharmacy.

No

The following imbalances were reported for analysed participants, after exclusions (due to failure to attend clinic or comply with treatment; exclusions were not reported by treatment group):

Significant bias (P=0.0002) for more mildest disease score (score 1) in the antiseptic group (1/60) than antibiotic (11/42) ‐ scores not presented by diagnosis;

More ears with otitis externa (significant) and central perforations (not reported as significant) were analysed in the antibiotic group than antiseptic (see Table 02 for numbers).

Double blinded

Inadequate

Dropout rates (numbers of randomised ears that were excluded; not reported by treatment group):

25% (5/20) central perforations;
30% (9/30) mastoid cavity infections;
25.8% (23/89) otitis externa ;
26.6% (37/139) total.

Patients who failed to attend clinics or to comply with treatment were excluded.

Fradis 1997

Unclear

Participants were randomised to treatment, with coded bottles, but method of sequence code generation not described.

Participants with otorrhoea in both ears were given two different bottles.

Adequate

All numbered treatment bottles were similar in appearance.

Treatment bottles and code were retained in the hospital pharmacy; only the pharmacy department head knew what each bottle contained.

Yes

Groups comparable for age and bacteriology (although slight imbalance in numbers of positive cultures: 18 ciprofloxacin, 16 tobramycin, 12 antiseptic/placebo).

No information was given for treatment groups of cases of surgical perforation or where no perforation could be seen.

Double blind

The treating physician and participants were blinded to treatment.

The treatment code was only broken at the end of the study to summarise the results of the investigation.

Adequate

Adequate for ears, which were the unit of analysis, but slightly inadequate for participants:

6/60 (10%) randomised ears (6/51 participants, ie 12%) were unavailable for follow‐up after three weeks.

Excluded numbers by treatment group:
Ciprofloxacin: 1/20 ears (5%)
Tobramycin: 2/20 ears (10%)
1% Burow aluminium acetate: 3/20 ears (15%)

Gyde 1978

Adequate

Used Taves' method of minimisation, with type of infection as the principal criteria.

Minimisation is an alternative method to stratified randomisation for treatment allocation. It is sometimes recommended for small sample sizes, and can incorporate more prognostic factors (Scott 2002).

Unclear whether 'type of infection' relates to diagnosis or bacteriology ‐ therefore included all participants in this review.

Unclear

Allocation concealment not mentioned, except that solutions were called 'A' (TSP) and 'B' (gentamicin) (trial was described as double blind).

Taves' minimisation approach can lead to predictability of treatment allocation in some situations.

Yes

Ears were balanced accross treatments for diagnosis (equal numbers per treatment) before and after crossover.

Balanced for age, sex, and diagnosis, with no great differences betwen the seriousness of infections in the two groups, according to the trialists.
These results are for all ears including crossed‐over cases, so some participants are counted twice (bilateral disease or crossover) and 1 was counted 4 times (bilateral disease and crossed over).

But there was more bilateral disease in the TSP group (7/43 participants = 16.3%) than on gentamicin (2/48=4.2%), for all participants before crossover.

Double‐blind

The solutions were called 'A' (TSP) and 'B' (gentamicin) to conserve the double blind.

The treatment provider/outcome assessor was blinded until after the analysis of the results. Participants were also blinded.

Unclear

No withdrawal was reported ‐ numbers analysed are the same as the reported numbers eligible for the study.

But participants unable to continue the proposed length of treatment or return for follow‐up visits were excluded.

Appears to be only per protocol population reported and analysed; number of excluded noncompliers was not reported.

Gyde 1981

Unclear

Participants were randomly assigned to one treatment group using coded medications, but method of generation of random codes was not described.

Did not discuss whether randomisation was stratified by the different diagnostic groups ‐ therefore included all participants in this review.

Adequate

Medications were coded and identically labelled, and used sequentially starting with the lowest number; no number was skipped or used more than once.

Mostly

Comparable across treatment groups (for ears) for diagnosis.

Overall results for age and bacteria were also comparable (not broken down by diagnosis).

But there was a slightly higher proportion of males in the TP group (17/33 ears, 51.5%) than the TSP group (25/35 ears, 71.4%).

Double blind

Unclear

No withdrawal was reported ‐ number analysed is the same as the reported number of ears eligible for the study.

But participants unable to continue the proposed length of treatment or return for follow‐up visits were excluded.

Appears to be only per protocol population reported and analysed; number of excluded noncompliers was not reported.

Jaya 2003

Unclear

Treatment allocation described as random, with coded bottles, but method of generation of random codes was not described.

Adequate

Both drugs were coloured identically and were dispensed in identical bottles, labelled with code numbers only ‐ given to participants after baseline assessments.

Mostly

Comparable for a range of demographic and disease related (prognostic) factors, except more participants receiving PVP‐I were male (10/19, 52.6%), than on ciprofloxacin (4/21, or 19.0%).

Other prognostic criteria were assessed and found to have no significant effect on the outcomes for the compared treatments.

Double blinded

The randomisation code was only decoded at the end of the study.

Adequate

10% dropout rate: 4/40 randomised participants were excluded by week 4 (1/21 ciprofloxacin; 3/19 PVP‐I ).

Reasons for exclusion from the analysis were not given.

Kasemsuwan 1997

Unclear

Treatment allocation was described as random, with coded medications, but method of generation of random codes was not specified.

Adequate

Participants were randomly allocated treatment in a double blind method. The medication codes were known only in the pharmaceutical laboratory.

Unclear

Baseline characteristics not reported for each group.

Double blind

Inadequate

30% dropout: 15/50 participants were excluded due to lack of attendance.

Participants who received other antibiotics during the trial were also excluded.

Kaygusuz 2002

Unclear

Treatment allocation described as random, but randomisation method was not stated.

Unclear

Allocation concealment not reported ‐ nor was blinding.

Yes for bacteriology

Baseline characteristics only reported for infective organism, which was comparable accross groups.

Unclear

Blinding not mentioned.

Adequate

No loss to follow‐up or exclusions were reported.

80 participants were reported as included in the study and analysed.

Lorente 1995

Unclear

Treatment allocation described as randomised, but randomisation method was not stated.

Unclear

Allocation concealment methods were not stated ‐ but trial was double blind.

Yes

Comparable for age sex, otorrhoea, itching, stinging, pain, irritation, and tinnitus.

Double‐blind

Unclear

Not clear how many people were originally randomised into the trial. (No exclusion was reported.)

Macfadyen 2005

Adequate

Treatment was prepared according to computer generated block randomisation schedule, stratified by school.

Adequate.

Treatment was identical in appearance, and identically labeled and packaged in treatment boxes, identifiable by school name and trial number only.
Treatment packs remained sealed until sequentially allocated to a child.

Yes

Comparable for age*, sex, duration of current episode*, proportion of bilateral cases*, size of perforation*, cause of current episode, whether previous ear treatment had ever been used, and hearing level.

* Logistic regression adjusting for these factors did not significantly alter the treatment effect.

Double blind

Participants, care‐givers, and outcome assessors remained blind to the treatment allocated throughout the study.

Adequate

Number with missing data and so excluded from analysis for resolution of discharge at four weeks:
33/427 (7.7%) total;
20/216 (9%) ciprofloxacin;
13/211 (6%) boric acid.

Some of these were due to missing data for participants seen at that visit.

The rest were due to withdrawals or lost to follow up:
25/427 (5.9%) total;
16/216 (7.4%) ciprofloxacin (15 lost to follow‐up; 1 consent withdrawn);
9/211 (4.3%) boric acid (all lost to follow‐up).

All analyses followed the Intention To Treat principle.

Tutkun 1995

Unclear

Participants were randomly divided into two groups but randomisation method was not stated.

Unclear

Allocation concealment not reported ‐ nor was blinding.

Unclear?

Only reported baseline data for bacteriology ‐ comparable apart from "normal flora" isolated in the ciprofloxacin group only (4 cases; excluded from hearing analyses in Ozagar 1997.

Unclear

Blinding not mentioned.

Unclear

It is not clear how many people were originally randomised into the trial ‐ an unreported number of non‐compliers (participants who did not use the topical solutions regularly and those who had taken any other medication during the study period) were excluded from study.

4 participants were excluded from the hearing analysis (and clinical response in Ozagar 1997).

van Hasselt 1997

Unclear

Described as a randomised trial in 2002 paper, but randomisation method was not stated.

Unclear

Allocation concealment not reported ‐ nor was blinding.

Unclear

Baseline characteristics were not provided.

Unclear

Blinding not mentioned.

Inadequate

28% dropout: 27/96 participants did not complete the trial.
Ofloxacin: 8% dropout (1/12 participants)
Neomycin/polymyxin B: 21% dropout (8/38 participants)
Acetic acid/spirit: 39% dropout (18/46 participants)

Only children completing the trial fully (ie attended at both review dates) were included in the analysis.

van Hasselt 1998

Unclear

Described as a randomised trial, but randomisation method was not stated.

Unclear

Allocation concealment not reported ‐ but trial was double‐blind.

Unclear

Baseline characteristics were not provided.

Double‐blind

Adequate (except week 8)

Number excluded from the analysis:
Week 1: 12/151 ears (8%);
Week 2: 13/151 ears (9%) ;
Week 8: 23/151 ears (15%).

'Defaulting ears' were excluded.

van Hasselt 2002

Unclear

Described as a randomised trial, but randomisation method was not stated.

Unclear

Allocation concealment not reported ‐ but trial was double‐blind.

Unclear

Baseline characteristics were not provided.

Double‐blind

Unclear

Not clear how many people were originally randomised into the trial.

Study ID

CSOM diagnosis

Otitis exclusions

Other elig criteria

Disease duration

Bacteriology?

Mucosal appearance?

Other diagnoses?

Other diags: sep?

Browning 1983a

Active chronic otitis media including previous modified radical mastoidectomy participants.

1) Cholesteatoma 2) Aural polyp

Non‐otitis inclusion criteria: 1) Over 16 years old Exclusions ‐ see otitis exclusions; no other exclusions were specified.

Not specified ‐ but all participants were secondary referrals

Yes. Sensitivity of isolated aerobic flora determined the choice of antibiotic. Participants with Pseudomonas spp were not randomised to oral (systemic) antibiotic.

Not reported

19/51 (i.e. 37%) analysed participants had previously undergone modified radical mastoidectomy (not provided by treatment group).

NB: only 38/51 on topical antibiotics or antiseptics included in this review (2 of 3 treatment groups)

No

Clayton 1990

Otorrhoea caused by:
a) discharging central perforation;
b) mastoid cavity;
c) otitis externa.

1) Acute middle ear disease
2) Cholesteatoma
3) Clinical evidence of fungal ear infection

Exclusion criteria ‐ treatment related:
1) Topical or systemic antibiotic use in previous three weeks;
2) History of drug sensitivity to any of the agents used in the study.

Not specified ‐ but excluded acute middle ear disease

Indicated;
Not required for inclusion:
11.7% had no bacteria isolated.

Yes: scoring system of severity included presence and degree of oedema obscuring the tympanic membrane or mastoid cavity, or of oedematous mucosa lining the mastoid cavity.

Included otorrhoea from mastoid cavity and otitis externa.

a) Discharging central perforation: 15 ears + 5 excluded
b) Mastoid cavity: 21 ears + 9 excluded
c) Otitis externa: 66 ears + 23 excluded

Participants who failed to attend clinic or comply with treatment were excluded (numbers not given by treatment group).

Not separate in review: randomisation not reported to stratify by diagnosis.

But results were given by diagnosis separately in trial publication.

Fradis 1997

CSOM was defined as a chronic inflammation of the middle ear and mastoid process with a perforated tympanic membrane and discharge.

All cases had purulent disease.

1) Prior middle‐ear surgery
2) Suspected cholesteatoma

Other inclusion criteria:
1) Signed consent
2) Discontinued all other medications two weeks before study entry.

Exclusion criteria ‐ treatment related
1) History of allergy to aminoglycosides or fluoroquinolone derivatives.

Exclusion criteria ‐ other
1) General health problems
2) Younger than 18 years (range was 18 to 73 years)

Disease duration: mean (range): 24 months (1 to 240 months).

Indicated;
Not required for inclusion:
23/60 cultures were negative for organisms before treatment.

In 8/60 ears granulation tissue meant no perforation could be seen

a) 3/60 ears: surgical perforations;
b) 8/60 ears: no perforation seen due to granulation tissue

No

Gyde 1978

1) Otorrhoea from:
a) recurrent benign chronic otitis media with tympanic membrane perforation (CSOM);
b) postoperative infections (mastoidectomy or tympanoplasty) and mastoid cavity infections;
c) subacute otitis media (with small or medium perforation);
d) external otitis.

1) Otorrhoea not caused by bacteria
2) 'Unsafe' ears (active atticoantral disease, accompanied by cholesteatoma with adjacent area extension)

Inclusion criteria ‐ other:
1) Adults or children ‐ includes paediatric cases (under 12 years old), and geriatric cases (over 60 years old).
2) Informed consent

Exclusion criteria ‐ treatment related:
1) Known allergy to any components of the trial drugs.
2) Use of high doses of local (topical) corticosteroid preparations.
3) Previous use of ototoxic drug therapy.
4) Use of general or topical antibiotics within two weeks before study entry.
5) Unable to continue the proposed length of treatment or return for follow‐up visits due to distance or inconvenience.

Exclusion criteria ‐ other:
1) Pregnant or lactating.
2) Infants under 2 months old.

Not specified

Indicated with results;
Required for inclusion.

Not reported

Total 100 analysed ears before crossover;
12 ears crossed over to the alternative treatment (8/50 TSP to gentamicin; 4/50 gentamicin to TSP):

a) 50 CSOM (25 TSP, 25 gentamicin);
7 ears then crossed over (2 from gentamicin to TSP, 5 from TSP to gentamicin)

b) 10 postoperative and mastoid cavity infections (5 TSP, 5 gentamicin);
3 ears then crossed over (3 from TSP to gentamicin)

c) 16 subacute otitis media (8 TSP, 8 gentamicin);
2 ears then crossed over (2 from gentamicin to TSP)

d) 24 external otitis (12 TSP; 12 gentamicin)
0 ears crossed over.

Not separate in review: type of infection was the principal criteria for randomisation (minimisation), but unclear whether this relates to diagnosis or bacteriology.

But results were given by diagnosis separately in trial publication (for number of ears).

Gyde 1981

1) Otorrhoea from
a) recurrent otitis media with tympanic membrane perforation (CSOM);
b) infected mastoid cavities and post‐operative tympanoplasties;
c) subacute otitis media;
d) external otitis.

2) Presence of gram‐negative or gram‐positive organisms from a specified list.

1) Acute otitis media
2) 'Unsafe' ears (active atticoantral disease, with adjacent area extension)

13/68 ears were paediatric (< 12 years old), 12/68 ears were geriatric (> 70 years old).
Concurrent medications, such as analgesics and decongestants etc were allowed.

Exclusion criteria ‐ treatment related:
1) History of sensitivity to any components of the trial drugs.
2) Use of extensive ototopical corticosteroid preparations within the past four weeks.
3) Previous use of ototoxic drug therapy.
4) Use of oral or parenteral antibiotics within two weeks before study entry.
5) Unable to continue the proposed length of treatment or return for follow‐up visits due to distance or inconvenience.

Exclusion criteria ‐ other:
1) Pregnant or lactating.
2) Tuberculosis, fungal or viral diseases.

Disease duration (for all diagnoses) ranged from just under 1 month to 5 years.

Indicated;
Required for inclusion:
Presence of gram‐negative or gram‐positive organisms from a specified list.

Not reported

Numbers for analysed ears (68 total: 35 TSP, 33 TP)
a) 27 CSOM (13 TSP, 14 TP);
b) 6 infected mastoid cavities and post‐operative tympanoplasties (2 TSP, 4 TP);
c) 4 subacute otitis media (2 TSP, 2 TP);
d) 31 external otitis (18 TSP, 13 TP).

Not separate in review: randomisation not reported to stratify by diagnosis.

But results were given by diagnosis separately in trial publication.

Jaya 2003

Actively discharging CSOM with moderate to large central perforation (i.e. active CSOM‐tubotympanic disease).

1) Cholesteatoma
2) Aural polyp
3) Impending complications of CSOM

Other inclusion criteria:
1) Older than 10 years

Exclusion criteria ‐ treatment related:
1) Known allergy to iodine or fluoroquinolone
2) Prior systemic or topical antibiotic therapy within 10 days of study entry

Exclusion criteria ‐ other
1) Debilitating illness (e.g. diabetes mellitis, tuberculosis, renal failure or AIDS)

Total duration of disease:
</= 5 years: n = 13
> 5 years: n = 27

Current episode of discharge was < 2 weeks for many participants:
<1 week: n = 15
1 to 4 weeks: n = 20
> 4 weeks: n = 5

The trialists reported that this duration did not significantly alter the outcome in both treatment groups.

Indicated;
Not required for inclusion:
8/40 swabs did not yield potential bacterial pathogen

Status of middle ear at baseline (number of participants):
20 hyperemic
18 pale and edematous
2 granular

None specified ‐ see otitis exclusions

n/a

Kasemsuwan 1997

1) Perforated tympanic membrane for longer than 3 months;
2) Mucopurulent otorrhoea

(Assessed on microscopic examination)

1) Cholesteatoma
2) Underlying diseases

Other inclusion criteria:
1) Adult (age range was 21 to 66)

Exclusion criteria ‐ treatment related:
1) Receiving antibiotics in the previous two weeks and during the study.

Exclusion criteria ‐ other:
1) Pregnant women
2) Underlying diseases

Perforated tympanic membrane for longer than 3 months

Indicated;
Not required for inclusion:
no bacteria were isolated for 26% of participants

Not reported

Not specified ‐ see otitis exclusions

n/a

Kaygusuz 2002

Chronic suppurative otitis media with:
1) perforated eardrum, and
2) discharge in the ears for > 3 months

1) Suspected or confirmed cholesteatoma (on otoscopy)
2) Previous history of ear surgery

Other inclusion criteria:
None reported other than adults with CSOM (age range was 18 to 60 years, mean, (SD) 31 (+/‐11.5) years)

Exclusion criteria ‐ treatment related:
1) Allergy to aminoglycosides or fluoroquinolones

Exclusion criteria ‐ other:
1) Under 18 years old
2) General health problems

Discharge for > 3 months (average duration was 44.4 years +/‐ 40.9 months; range 3 to 10 years)

Indicated;
Not required for inclusion:
5.8% of pre‐treatment cultures were negative

Not reported

Not specified ‐ see otitis exclusions.

n/a

Lorente 1995

Simple chronic otitis media in the suppurative phase (CSOM): purulent otitis of > 3 months duration, with perforated tympanic membrane.

1) Cholesteatoma or attic disease
2) Otomycosis
3) Bilateral hypoacusia higher than 60 dB

Inclusion criteria ‐ other:
1) Age 18 to 65 (mean 42 years)
2) Either gender
3) No evidence of physical or psychological (psychiatric) illness, with laboratory tests (biochemical and haematological) within reference ranges
4) Consent to participate

Exclusion criteria ‐ treatment related:
1) Topical or systemic antibiotic use in the previous 48 hours
2) Allergy to quinolones or aminoglycosides

Exclusion criteria ‐ other:
1) Pregnant or breast feeding
2) Severe kidney or liver deficiency

Purulent otitis of > 3 months duration

Indicated:
Not specified in inclusion criteria:
304 microorganisms isolated before treatment were reported

Not reported

Not specified ‐ see otitis exclusions

n/a

Macfadyen 2005

1) Purulent aural discharge for 14 days or longer, with pus seen in the external canal on otoscopy
2) Perforated tympanic membrane (on otoscopy)

Other ear problems:
1) Pre‐existing disease, e.g. otomycosis, polyp, impacted foreign body, or previous ear surgery
2) Complicated otitis media, e.g. cholesteatoma, mastoiditis, requires treatment other than study treatment
3) Anatomical abnormalities

Inclusion criteria ‐ other:
1) School children (enrolled at Kisumu rural primary schools visited)
2) Age five years or older (range was 4 to 19 years)
3) Informed consent (parental consent for affected children; school staff and parent‐teacher‐association representatives consented to school participation).

Exclusion criteria ‐ treatment related:
1) Treated for ear infection or received antibiotics for any other disorder in the previous 2 weeks
2) Allergy to study drugs.

Purulent aural discharge for 14 days or longer

Assessed but results not provided
Not required for inclusion

Not assessed

No ‐ see otitis exclusions

n/a

Tutkun 1995

History of purulent otorrhoea lasting > 1 year

Cholesteatoma

Inclusion criteria ‐ treatment related:
1) All participants stopped taking any medication at least 10 days prior to treatment.

Inclusion criteria ‐ other:
1) Informed consent.

Exclusion criteria ‐ treatment related:
1) History of allergy to fluoroquinolone derivatives or aminoglycosides, or to topical agents

2) Did not use the topical solutions regularly, or had taken any other medication during the study.

Exclusion criteria ‐ other:
1) Younger than 9 years
2) History of general health problems.

History of purulent otorrhoea lasting > 1 year

Indicated
Not specified in inclusion criteria:
4 participants had normal flora

Not reported

Not specified

n/a

Van Hasselt 1997

CSOM ('typically... affected ears were filled with mucoid pus.... Most perforations were medium or large. Granulations were present in most cases')

Not reported

Inclusion criteria ‐ other:
Children

Exclusion criteria:
Not reported.

Not specified

Not specified

Not reported

Not specified

n/a

Van Hasselt 1998

> 2 months CSOM for inclusion as an active ear (CSOM not described)

Not reported

Participants were mainly children.

Exclusion criteria:
1) Uncooperative with suction cleaning

> 2 months CSOM

Not specified

Not reported

Not specified

n/a

Van Hasselt 2002

CSOM (not described)

Not reported

Other eligibility criteria:
Not reported

Not specified

Not specified

Not reported

Not specified

n/a

Study ID

# of particpants

# of ears

% bilateral cases

Handling bilat cases

Results: pt or ears?

Browning 1983a

75 randomised ‐ all treatments; not reported by group

51 analysed:
18 topical antibiotics
20 topical antiseptics
* 13 systemic antibiotics; not included in this review *

19/51 (37%) were post modified radical mastoidectomy ‐ numbers and results were not presented separately.

Not reported

Not reported

One ear was chosen at random by the pharmacist (method of choice unknown).

Participants

Clayton 1990

Not reported

Randomised ears:
139 total: 20 central perforation; 30 mastoid cavity; 89 otitis externa

Completed (analysed) + excluded cases:

Total: 102 completed (42 antiseptic; 60 antibiotic) +37 excluded;

Central perforation: 15 completed (4 antiseptic; 11 antibiotic) + 5 excluded;

Mastoid cavity: 21 completed (13 antiseptic; 8 antibiotic) + 9 excluded;

Otitis externa: 66 completed (25 antiseptic; 41 antibiotic) + 23 excluded

Not reported

Unclear ‐ report for ears only, but baseline characteristics table uses term 'patients' instead, although totals match number of ears reported in text.

Ears?

But baseline characteristics table uses term 'patients' (text uses 'ears').

Fradis 1997

51 randomised participants; 45 analysed

60 randomised ears (20 per treatment group)

54 analysed ears:
19 ciprofloxacin
18 tobramycin
17 Burow aluminium acetate

Randomised bilateral rates: 9/51 (17.6%)

Analysed bilateral rates: 9/41 (20.0%).

Treated both ears (each ear given a different bottle in bilateral cases), and report number of ears.

Ears

Gyde 1978

Randomised participants: not reported

Analysed participants before crossover (all diagnoses reported only):
91 total; 43 TSP; 48 gentamicin.

Analysed participants crossed over to other treatment (all diagnoses):
11/91 total;
7/43 from TSP to gentamicin;
4/48 from gentamicin to TSP.

NB the trialists reported the combined crossover plus pre‐crossover numbers.

Randomised ears: not reported

Analysed ears before crossover:

100 total (50 TSP; 50 gentamicin);

50 CSOM (25 TSP; 25 gentamicin);

10 post‐operative and mastoid cavity infections (5 TSP; 5 gentamicin);

16 subacute otitis media (8 TSP; 8 gentamicin);

24 otitis externa (12 TSP; 12 gentamicin).

Analysed ears crossed over to other treatment:

12/100 total (8/50 from TSP to gentamicin; 4/50 from gentamicin to TSP);

7/50 CSOM (5/25 from TSP to gentamicin; 2/25 from gentamicin to TSP);

3/10 post‐operative and mastoid cavity infections (3/5 from TSP to gentamicin);

2/16 subacute otitis media (2/8 from gentamicin to TSP);

0/24 otitis externa.

NB the trialists reported combined pre‐ plus post‐crossover numbers. Where possible, we have used pre‐crossover cases only.

Randomised participants: rates not reported

Analysed participants bilateral rates (all diagnoses only):

Before crossover:
Total: 9/91 (9.9% bilateral);
TSP: 7/43 (16.3% bilateral);
Gentamicin: 2/48 (4.2% bilateral).

Crossed over to alternative treatment:
Total: 1/11 (9% bilateral);
TSP to gentamicin: 1/7 (14% bilateral);
Gentamicin to TSP: 0/4 (0% bilateral).

ie this crossover participant is counted 4 times in the combined figures presented by the trialists (twice per treatment).

Both ears treated and analysed separately ‐ reported number of ears

Ears

Gyde 1981

60 participants were eligible and included in the analyses

Not available by treatment group or diagnosis.

Eligible ears included in the analyses:

68 total (35 TSP; 33 TP);

27 CSOM (13 TSP; 14 TP);

6 post‐operative and mastoid cavity infections (2 TSP; 4 TP);

4 subacute otitis media (2 TSP; 2 TP);

31 otitis externa (18 TSP; 13 TP)

Total: 8/60 (13.33%)

Not available by treatment group or diagnosis.

Treated both eligible ears and report number of ears.

Ears

Jaya 2003

40 randomised participants
(21 ciprofloxacin; 19 PVP‐I )

36 assessed at week 4
(20 ciprofloxacin; 16 PVP‐I)

Not reported; but only 40 ear swabs taken at baseline

Not reported

Unclear ‐ reported at participant level.

Participants

Kasemsuwan 1997

Main text states participants:
50 randomised

35 completed study and analysed (19 ciprofloxacin; 16 normal saline)

Abstract states ears:
50 ears randomised
35 completed study and analysed

Not reported

Unclear ‐ used term 'ears' in abstract, but mostly 'patients' in main text.

Participants?

'Participant' in main text, but used term 'ears' in abstract.

Kaygusuz 2002

80 participants included and analysed (20 per treatment group; i.e. 40 for this review)

103 ears included (not reported by treatment group)

23/80 (28.75%)

Appears to have taken success when both ears had resolved only (treatment was successful when there was no discharge).

Participants

Lorente 1995

308 analysed participants
(159 ciprofloxacin; 149 gentamicin)

Numbers originally randomised, not provided

Not reported

Not reported

Not reported

Participants

Macfadyen 2005

427 randomised participants
(216 ciprofloxacin; 211 boric acid)

394 analysed for resolution at four weeks
(196 ciprofloxacin; 198 boric acid)

533 randomised ears
(264 ciprofloxacin; 269 boric acid)

Rates for randomised participants:
Total: 106/427 (25%)
Ciprofloxacin: 48/216 (22%)
Boric acid: 58/211 (27%)

Report at participant level.

Both ears treated and assessed for bilateral cases ‐ success when both ears had resolved or healed.

Sensitivity analysis conducted ‐ success for bilateral cases when either or both ears resolved or healed.

Audiometry results were averaged over the study ear(s) for one overall reading.

Participants

Tutkun 1995

44 analysed participants
(24 ciprofloxacin; 20 gentamicin)

40 analysed for hearing
(20 ciprofloxacin; 20 gentamicin) (Ozagar 1994)

Not reported

Not reported

Unclear ‐ reported at participant level; bilateral disease or numbers of ears not discussed

Participants

van Hasselt 1997

96 children randomised:
12 ofloxacin;
38 neomycin/polymyxin B
46 acetic acid/spirit

69 children completed and included in analysis:
11 ofloxacin
30 neomycin/polymyxin B
28 acetic acid/spirit

Number ears randomised: not reported

93 ears included in analysis: (or 88?)
14 ofloxacin
40 neomycin/polymyxin B (35 in Van Hasselt 2002 paper)
39 acetic acid/spirit.

Randomised rates: not available

Analysed participants:
Total: 24/69 (34.78%)
Ofloxacin: 3/11 (27.27%)
Neomycin/polymyxin B: 10/30 (33.33%) (or 5/30, 16.67% from Van Hasselt 2002 publication)
Acetic acid/spirit: 11/28 (39.29%)

Treated both ears and report % ears dry.

CBM Report: provided number and proportion of ears dry and wet at each visit.

2002 paper: reported proportion of ears dry at two weeks.

Ears

van Hasselt 1998

107 participants randomised

Number analysed: not reported

151 randomised ears

Analysed ears:
139 ears at week 1

138 ears at week 2:
32 ofloxacin twice daily;
39 ofloxacin once weekly;
36 neomycin polymyxin B twice daily;
31 neomycin polymyxin B once weekly.

128 ears at week 8.

Total randomised: 44/107 (41.12%)

Analysed participants: not available

Report proportion of analysed ears dry; numbers of ears per group reported for week two only.

Ears

van Hasselt 2002

Not reported

253 analysed ears:
79 ofloxacin + HPMC
91 povidone iodine + HPMC
83 HPMC

Not reported

Reported % of number of ears dry.

Ears

Study ID

Intervention

Strength

Dose and frequency

Duration

Ear Toilet

Concurrent meds

Do topical antibiotic eardrops work?

Quinolone versus placebo:

Kasemsuwan 1997

1) Quinolone: ciprofloxacin in saline solution

2) Placebo: normal saline solution

1) Ciprofloxacin: 250 microgram/mL

2) Saline: n/a

Both treatments:
5 drops three times daily.

Both treatments:
At least 7 days.

Both groups:
Ear cleaning at each visit (treatment days 1, 4 and 7).

Excluded if received antibiotics in the previous two weeks or during the study.

van Hasselt 2002

1) Quinolone: ofloxacin in HPMC

2) Placebo: HPMC

HPMC = hydroxypropyl methyl‐cellulose (hypromellose) ‐ a treatment delivery vehicle.

1) 0.075% Ofloxacin in 1.5% HPMC

2) 1.5% HPMC

All treatments:
1 single topical application after suction cleaning.

Both treatments:
Once only.

Both groups:
Suction cleaning once.

Not reported.

Which antibiotic eardrops work best?

Non‐quinolone versus non‐quinolone

Gyde 1978

1) Non‐quinolone: trimethoprim‐sulfacetamide‐polymyxin B (TSP) (Burroughs Wellcome Ltd).

2) Non‐quinolone: gentamicin sulphate (Garamycine)

1) 0.1% TSP
(Trimethoprim 1 mg/mL; Polymyxin B 10,000 U/mL; Sulfacetamide 5mg/mL).

2) 0.3% gentamycin sulphate

Both treatments:
8 drops twice daily (morning and evening).

Both treatments:
Depended on clinical and bacteriological response:
Up to 3 weeks initially, plus 3 weeks if required.

Failed ears or not dry at 6 months crossed over to the other treatment for 3 weeks; 6 month follow‐up as before: 11 participants (12 ears; 7 CSOM ears).

Average duration (including crossovers) (days):

All successfully treated ears:
TSP 19.3 days (range 7 to 32) (N = 46);
gentamicin 21.7 days (range 10 to 37) (N = 51).

CSOM: TSP 16.4, gentamicin 22.8;

Post‐operative or mastoid infections: TSP 24.0, gentamicin 24.3;

Subacute otitis media: TSP 21.3, gentatmicin 22.7

Otitis externa: TSP 17.1, gentamicin 17.5.

Both groups:
Suction and dry mopping before each treatment application.

Pneumatic otoscope sometimes also used to ensure the eardrops reached the middle ear and mastoid cavity.

Two‐week washout period if used any antibiotics before study entry.

Excluded if used high doses of ototopical corticosteroids, or ever used ototoxic drug therapy.

Gyde 1981

1) Non‐quinolone: Trimethoprim‐ sulfacetamide‐ polymyxin B (TSP)

2) Non‐quinolone: Trimethoprim‐ polymyxin B (TP)

1) 0.1% TSP

2) 0.1% TP

Concentrations of treatment components: Trimethoprim 1 mg/mL; Polymyxin B 10,000 U/mL; Sulfacetamide 5 mg/mL.

Both treatments:
8 drops twice daily (morning and night).

Both treatments:
Up to 14 days maximum, depending on response to treatment and bacterial culture results.

Both groups:
Suction and dry mopping before each treatment application.

Pneumatic otoscope sometimes also used to ensure the eardrops reached the middle ear and mastoid cavity.

Two week washout period if used any antibiotics before inclusion.

Excluded if used extensive ototopical corticosteroids within 4 weeks, or ever used ototoxic drug therapy.

Concurrent medications such as analgesics and decongestants etc were allowed.

Quinolone versus non‐quinolone

Fradis 1997

1) Quinolone: ciprofloxacin hydrochloride solution

2) Non‐quinolone: tobramycin

1) Ciprofloxacin: Not specified

2) Tobramycin: Not specified

All treatments:
5 drops, 3 time daily.

All treatments:
3 weeks.

Not specified.

All other medication discontinued two weeks before study entry.

(34 participants previously received systemic antibiotics; 12 had used neomycin‐polymyxin B eardrops without success).

Kaygusuz 2002

1) Quinolone: ciprofloxacin hydrochloride

2) Non‐quinolone: tobramycin

1) 0.3% Ciprofloxacin hydrochloride

2) 0.3% Tobramycin

All treatments:
2 drops 3 times daily.

All treatments:
3 weeks.

All groups:
Aspiration once daily.

Not reported.

Lorente 1995

1) Quinolone: ciprofloxacin

2) Non‐quinolone: gentamicin

1) 0.3% Ciprofloxacin

2) 0.3% Gentamicin

Both treatments:
5 drops (0.75 mg) 3 times daily.

Both treatments:
8 days (awaiting confirmation that this was not continued to day 30).

Not specified.

Excluded if received antibiotic treatment (topical or systemic) in the last 48 hours.

Tutkun 1995

1) Quinolone: ciprofloxacin hydrochloride

2) Non‐quinolone: gentamicin sulfate

1) Ciprofloxacin hydrochloride: 200 microgram/mL

2) Gentamicin sulfate: 5 mg/mL

Both treatments:
5 drops 3 times daily.

Both treatments:
10 days.

Not specified.

All other medication stopped at least 10 days prior to treatment.

Excluded if used any other medication during the study.

van Hasselt 1997

1) Quinolone: ofloxacin (Exocin R from Allergan)

2) Non‐quinolone: neomycin‐polymyxin B

1) 0.3% Ofloxacin;

2) 0.5% Neomycin, 0.1% polymyxin B

All treatments:
3 drops, 3 times daily.

All treatments:
2 weeks.

All groups:
Suction cleaning at the beginning of the trial, and at weeks 1 and 2 visits.

Not reported.

VH 1998 daily

1) Quinolone: ofloxacin

2) Non‐quinolone: neomycin‐ polymyxin B

1) 0.3% Ofloxacin

2) Neomycin‐ polymyxin B: not specified

Both treatments:
6 drops twice daily.

All treatments:
2 weeks.

All groups:
Once weekly suction cleaning.

Not reported.

VH 1998 weekly

1) Quinolone: ofloxacin

2) Non‐quinolone: neomycin‐ polymyxin B

1) 0.3% Ofloxacin

2) Neomycin‐ polymyxin B: not specified

Both treatments:
Once weekly.

All treatments:
2 weeks.

All groups:
Once weekly suction cleaning.

Not reported.

Do topical antibiotics work better than topical antiseptics?

Non‐quinolone versus antiseptic

Browning 1983a

1) Non‐quinolone: chloramphenicol (Chloromycetin), or gentamicin (Genticin) (self treated).
Choice of antibiotics depended on sensitivity of bacterial isolated at baseline.

2) Antiseptics: insufflation of boric acid and iodine powder after aural toilet (otologist treated).

1) Antibiotics: not specified

2) Antiseptic: not specified

1) Topical Antibiotics (self treat):
a) Chloramphenicol: 1 or 2 drops, 3 times daily;
b) gentamicin: 3 or 4 drops, 4 times daily.

2) Antiseptic: once weekly (insufflation after aural toilet, by otologist) (dose not reported).

All treatments:
4 weeks.

All groups:
Weekly aural toilet by otologist, using microscopic vision and suction aspiration when necessary.

Not reported.

Clayton 1990

1) Non‐quinolone: gentamicin sulphate

2) Antiseptic: aluminium acetate

1) 0.3% Gentamicin sulphate

2) 8% Aluminium acetate

All treatments:
5 drops, 3 times daily.

All treatments:
3 weeks.

All groups:
Self mopping before each treatment administration.

No antibiotics in the preceding 3 weeks.

Fradis 1997

2) Non‐quinolone: tobramycin

3) Antiseptic: Burow aluminium acetate solution

2) Tobramycin: Not specified

3) 1% Aluminium acetate
(weak antiseptic, used as a "placebo" by the trialists).

All treatments:
5 drops, 3 times daily.

All treatments:
3 weeks.

Not specified.

All other medication discontinued two weeks before study entry. (34 participants previously received systemic antibiotics; 12 had used neomycin‐polymyxin B eardrops without success).

van Hasselt 1997

2) Non‐quinolone: neomycin‐polymyxin B

3) Antiseptic: acetic acid in spirit and glycerin

2) 0.5% Neomycin, 0.1% polymyxin B

3) 2% Acetic acid in 25% spirit and 30% glycerin

All treatments: 3 drops, 3 times daily.

All treatments:
2 weeks.

All groups: Suction cleaning at the beginning of the trial, and at weeks 1 & 2 visits.

Not reported.

Quinolone versus antiseptic

Fradis 1997

1) Quinolone: ciprofloxacin hydrochloride solution

3) Antiseptic: Burow aluminium acetate solution

1) Ciprofloxacin: Not specified

3) 1% Aluminium acetate (weak antiseptic, designated as the "placebo group" by the trialists).

All treatments:
5 drops, 3 time daily.

All treatments:
3 weeks.

Not specified.

All other medication discontinued two weeks before study entry. (34 participants previously received systemic antibiotics; 12 had used neomycin‐polymyxin B eardrops without success).

Jaya 2003

1) Quinolone: ciprofloxacin hydrochloride

2) Antiseptic: povidone (polyvinyl pyrrolidone)‐ iodine (PVP‐I, Betadine)

1) 0.3% Ciprofloxacin hydrochloride

2) 5% Povidone iodine

All treatments:
3 drops three times daily.

All treatments:
10 days.

Both groups:
Dry mopping before each treatment occasion.

Aural suctioning performed before initial treatment for all participants, and at subsequent weekly visits if discharge was present.

No prior systemic or topical antibiotic therapy within 10 days of study entry.

Macfadyen 2005

1) Quinolone: ciprofloxacin hydrochloride (Ciloxan, from Alcon)

2) Antiseptic: boric acid in alcohol
(powder from UK but manufactured locally)

1) 0.3% Ciprofloxacin hydrochloride

2) 2% Boric acid in 45% alcohol

Both treatments:
Drops given twice daily (morning registration and lunch time).

Child‐to‐child treatment: older children trained to clean and treat infected ears (at school), under supervision of trained teachers.

Both treatments:
10 consecutive school days (ie excluding weekends).

Both groups:
Dry mopping before each treatment administration.

Dry mop only for weeks 2‐4 if persistent discharge at week 2.

Excluded if treated for ear infection or received antibiotics for any other disorder in the previous 2 weeks.

van Hasselt 1997

1) Quinolone: ofloxacin (Exocin R, from Allergan)

3) Antiseptic: acetic acid in spirit and glycerin

1) 0.3% Ofloxacin

3) 2% Acetic acid in 25% spirit and 30% glycerin

All treatments: 3 drops, 3 times daily.

All treatments:
2 weeks.

All groups: Suction cleaning at the beginning of the trial, and at weeks 1 & 2 visits.

Not reported.

van Hasselt 2002

1) Quinolone: ofloxacin in HPMC

2) Antiseptic: povidone iodine in HPMC

HPMC = hydroxypropyl methyl‐cellulose (hypromellose) ‐ a treatment delivery vehicle.

1) 0.075% Ofloxacin in 1.5% HPMC

2) 1% Povidone iodine in 1.5% HPMC

All treatments: 1 single topical application after suction cleaning.

Both treatments:
Once only.

All groups:
Suction cleaning once.

Not reported.

Study ID

CSOM Resolution

Healing

Time to resolution

Time to reappearance

Hearing improvement

Safety

Other outcomes?

Other notes

Participant or ears?

Browning 1983a

1) Participants with active, mucoid or inactive ears after 4 weeks of treatment.

Participant

Clayton 1990

1) Improved ears (i.e. dry or discharge improved by a score of 2 or more) at treatment days 9 and 21.

Scoring system for severity of infection: degree of otorrhoea and of oedema or oedematous mucosa.

Numbers with complete cure not reported.

Presented results for day 21 only.

1) Antibiotic or antiseptic resistant bacterial strains at treatment days 9 and 21.
(Reported resistant strains for 21 days.)

2) Compliance to treatment, monitored at assessments every 3 days.

Resolution reported as 'improved' or 'not improved'; complete cure not reported.

Excluded participants who failed to attend clinics or failed to comply with treatment (exclusions per diagnosis reported but not by treatment group).

Unclear ‐ ears?

Fradis 1997

1) Clinical efficacy: cessation of otorrhoea on microscopic examination 24 hours after end of 3 weeks treatment.

Reported as cure, improvement or failure ‐ improvement has been grouped with failure for this review.

** 1) Hearing assessment: audiology assessed before and 24 hours after 3 weeks treatment.
Results were not reported. **

1a) Bacteriological efficacy: eradication, persistence or superinfection, 24 hours after end of treatment;
Reported pre and post‐treatment microorganisms isolated (including fungi, Candida).

1b) Sensitivity of pre and post (24 hrs)‐treatment bacteria to ciprofloxacin and tobramycin.

Ears

Gyde 1978

1) Ears with clinical cure or failure at 6 months:

Success: dry ear within 3 weeks of treatment, or sufficiently improved after 3 weeks that 3 weeks further therapy allowed the discharge to stop; with negative post‐treatment culture; and no return of the same strain of causative organism within 6 months of stopping treatment.

Failure: evidence of exudate after 3 weeks, with a positive culture and little hope of further improvement. Failures at 6 months were allocated the alternative treatment, and followed‐up for 6 months as before.

Results at 6 months, before crossover, have been taken for this review.

1) Mean duration of treatment (days).
Reported for successful ears only; includes crossed over treatment times.

1) Relapse

1) Hearing assessment in 50 participants: pre and post‐treatment audiometry, with a follow‐up audiogram by a certified audiologist.

Results for average hearing loss before and after treatment, average improvement, and variation in improvement, are reported for each treatment group and treatment + 'intervention' (unclear what this is ‐ possibly surgery).

Post‐treatment observations were 3 to 12 months after medical treatment or surgery, to detect any delayed ototoxicity.

Audiometry (or an assessment of impedence, or both) assessed for a subset of 50 subjects only.

Results were not reported separately by diagnosis; all analysed cases are included in this review.

1) Ototoxicity: pre and post‐treatment audiometry, with a follow‐up audiogram by a certified audiologist.
Post‐treatment observations were 3 to 12 months after medical treatment or surgery, to detect any delayed ototoxicity.

Audiometry (or an assessment of impedence, or both) assessed for a subset of 50 subjects only (not reported separately by diagnosis).

2) Adverse reactions: open‐ended question with further questioning for intensity of reaction. No specific or suggestive questions were asked.

1) Bacteriology ‐ reported cure, improvement or failure according to pre‐treatment bacteria cultured;
Results include crossed over cases.

Negative bacterial culture was included in the definition of cure.

Ears

Gyde 1981

1) Ears with clinical cure or failure at 3 months:

Success: dry ear clinically within 3 weeks of treatment, with negative post‐treatment culture, and no return of the same strain of causative organism within 3 months of stopping treatment.

Failure: evidence of exudate after 3 weeks, with a positive culture and little hope of further improvement.

** 1) Hearing assessment: pre and post‐treatment audiometry, with a follow‐up audiogram by a certified audiologist.
Only reported negative findings in relation to ototoxicity ‐ see safety column.**

1) Ototoxicity: pre and post‐treatment audiometry, with a follow‐up audiogram by a certified audiologist.

2) Adverse reactions: open‐ended question with further questioning for intensity of reaction. No specific or suggestive questions were asked.

1) Bacteriology ‐ reported cure or failure according to pre‐treatment bacteria cultured.

Negative bacterial culture was included in the definition of cure.

Participants were examined at Days 7 and 14, and 3 months after completing therapy to detect any delayed toxicity.

Clarification has been sought regarding the timings of the outcomes (2 weeks, 3 weeks or 3 months).

Ears

Jaya 2003

1) State of discharge (actively discharging or inactive) on microscopy.

Assessed at study start and weeks 1, 2, 3, and 4 (results presented for all 4 weeks)

** 1) Hearing assessment: pure tone audiometry (PTA) measured at study start and week 4.
Only stated a lack of cases with deteriorated hearing on PTA; improvement not reported **

1) Pure tone audiometry (PTA) measured at study start and week 4.
Reported lack of cases with deteriorated hearing on PTA only.

2) Ototoxic effects or allergy to the drug: specific inquiries for symptoms at weeks 1, 2, 3, and 4.

1) Bacteriology and sensitivity of pus culture at study start, and week 4 (if still discharging).

Participant

Kasemsuwan 1997

1) Clinical response (no discharge on microscopic examination) after 7 days.

** 1) Hearing assessment: audiometric measurements before treatment and within 48 hours post therapy.
Only presented results in relation to ototoxicity, and not improvement in hearing.**

1) Adverse effects of medication: recorded at each visit (treatment days 1, 4 and 7)

2) Ototoxicity: audiometric measurements assessed before treatment and within 48 hours post‐treatment.

1) Bacteriological response after 7 days (eradication; only performed aerobic culture).
Sensitivity analysis also conducted.

Unclear ‐ participants?

Kaygusuz 2002

1) Clinical response ‐ subjective assessment according to scale of discharge: complete improvement (no discharge); partial improvement (moist/wet); or unsuccessful (discharge filled the middle ear or external canal).

Partial improvement has been classified as failure for this review.

Participants were assessed daily for three weeks. Results were reported for Days 7, 14 and 21.

** Not reported as an outcome, although a lack of additional side‐effects when adding steroid to treatment, was reported in the discussion.**

1) Bacteriology before and after treatment, and resistance of pre‐treatment cultures to ciprofloxacin and tobramycin.

Participant

Lorente 1995

1) Number and proportion of participants with dry ears (presence or absence of otorrhoea, assessed on otoscopy) at Day 8.

**1) Hearing assessment: audiometry to detect deterioration in hearing in relation to ototoxicity;
Not reported improvement or degree of change. **

1) Ototoxicity: assessment of audiometry results and report of tinnitus to detect deterioration in hearing, and of balance to detect damage to the labyrinth.

2) Adverse events: local (pain, pruritis, stinging etc) and general.

1) Participants with negative bacterial cultures (pre and post‐treatment bacteriology assessed); only reported proportions, not numbers.

2) Changes in mean scores for otorrhoea, pruritus (itching), stinging, pain, irritation and tinnitus at days 8 and 30. Scoring was on a scale of 0 (absent) to 3 (severe).

All outcomes were assessed at visits on Days 0 (before treatment), 8 and 30.

Telephone contact on Day 3, to collect details of adverse events only.

Participant

Macfadyen 2005

1) Resolution of aural discharge on otoscopy at two and four weeks (resolution at two weeks was the primary outcome).

1) Healing of the tympanic membrane on otoscopy at 2 and 4 weeks.

1) Change in hearing threshold (pure tone audiometry) from baseline at 2 and 4 weeks.

Hearing threshold in dB HL was averaged across 0.5, 1, 2 and 4 kHz.

Unilateral cases: 1 single reading taken from the diseased ear;
Bilateral disease: calculated average across both ears.

Presented results for mean improvements in hearing threshold, and the difference in improvement between treatments, controlling for baseline threshold with analysis of covariance (ANCOVA).
Adding background noise as an additional covariate did not change the conclusions.

Also described hearing impairment levels using WHO classifications; considered changes between levels using Fishers exact test.

1) Adverse event probe ‐ reported adverse events of interest only (local symptoms of pain, irritation and bleeding on mopping) at weeks 2 and 4.

Participants were followed‐up at weeks 2 and 4; reported results for both visits.

All analyses followed the intention‐to‐treat principle.

For bilateral cases, success was defined as when both ears resolved or healed; sensitivity analysis used success for bilateral cases when either or both ears resolved or healed.

Participant

Tutkun 1995

1) Clinical success 24 hours after 10 days treatment: cessation of otorrhoea on otoscopy and eradication of microorganisms in post‐treatment culture (aerobic culture only).

Differences between average pre‐treatment and post‐treatment (24 hours after 10 days treatment) mean values of:
1) speech reception thresholds;
2) speech discrimination scores;
3) pure tone thresholds for air conduction (dB HL, at 250 to 8000 Hz);
4) pure tone thresholds for bone conduction (dB HL, at 500 Hz to 4000 Hz).

Also:
6) Pre‐treatment and post‐treatment air‐bone gaps (dB HL at 500 Hz to 4000 Hz (dB HL).

For all hearing analyses, only averages have been reported, with no standard deviation or other indicators of variation or range of results.

1) Ototoxicity: pure tone threshold, and speech discrimination scores assessed before and 24 hours post‐treatment.

2) Safety: absence of side‐effects reported in results but not specified as an outcome for assessment.

1) Sensitivity to gentamicin and ciprofloxacin of aerobic culture taken 24 hours before treatment and 24 hours after completing treatment.

Participants were assessed on Days 2, 5, 7 and 10. Final assessment 24 hours after completing 10 days treatment.

Negative bacterial culture was included in the definition of cure.

Participant

van Hasselt 1997

1) Dry or wet ear after 1 and 2 weeks.

Results for cure at week 2 were discrepant between the 1997 CBM report (see figures and results text) and 2002 paper (see results text) for acetic acid and neomycin‐ polymyxin B.

Ears

van Hasselt 1998

1) Resolution of otorrhoea at weeks 1, 2 (end of treatment) and week 8: inactive when completely dry middle ear; active when otorrhoea still present.

Presented % ears cured at each visit, but only reported numbers per group at week 2.

1) Medicine cost per healed ear after week 8.

Ears

van Hasselt 2002

1) Dry ears after 1 week.

Ears

Intervention

Number examined

Number improved

Ave dB loss before

Ave dB loss after Rx

Average hearing gain

dB variation in gain

Topical non‐quinolone antibiotic:

Trimethoprim‐polymyxin‐B‐sulfacetamide (TSP)

19 (any diagnosis)

17

31.3

13.5

17.8

? to 43

TSP + intervention (not specified)

25 (any diagnosis)

24

35.7

16.1

20.0

‐6 to 53

Topical non‐quinolone antibiotic:

Gentamicin

26 (any diagnosis)

23

35.9

19.6

16.4

0 to 35

Gentamicin + intervention (not specified)

22 (any diagnosis)

20

37.9

19.6

18.2

‐3 to 34

Frequency

Ciprofloxacin ‐ air

Ciprofloxacin ‐ bone

Gentamicin ‐ air

Gentamicin ‐ bone

250 Hz

Difference (dB HL)

‐1.2

2.0

500 Hz

Pre‐treatment (dB HL)

38.3

14.5

34.8

11.8

Post‐treatment (dB HL)

35.4

12.7

31.7

13.3

Difference (dB HL)

+2.9

+1.8

+3.1

‐1.5

1000 Hz

Pre‐treatment (dB HL)

32.3

13.3

35.8

10.1

Post‐treatment (dB HL)

31.7

10.4

30.3

14.0

Difference (dB HL)

+0.6

+2.9

+5.5

‐3.9

2000 Hz

Pre‐treatment (dB HL)

30.5

13.1

31.5

12.5

Post‐treatment (dB HL)

29.5

14.0

27.5

14.6

Difference (dB HL)

+1.0

‐0.9

+4.0

‐2.1

4000 Hz

Pre‐treatment (dB HL)

36.0

22.2

37.6

23.9

Post‐treatment (dB HL)

31.3

19.5

40.6

24.6

Difference (dB HL)

+4.7

+2.7

‐3.0

‐0.7

8000 Hz

Difference (dB HL)

+7.7

+4.0

Group

500 Hz

1000 Hz

2000 Hz

4000 Hz

Ciprofloxacin

Pre‐treatment (dB HL)

25.0

23.0

18.0

15.7

Post‐treatment (dB HL)

24.5

18.2

15.7

12.3

Gentamicin

Pre‐treatment (dB HL)

21.4

25.7

17.1

15.1

Post‐treatment (dB HL)

22.5

20.0

16.4

17.8

Assessment

Ciprofloxacin

Gentamicin

student's t‐test p

Speech Reception Threshold (SRT) (dB HL)

Pre‐treatment

34.3

34.4

Post‐treatment

30.8

30.2

Difference (dB HL)

+3.5

+4.2

P > 0.01

Speech Discrimination Score (SDS)

Pre‐treatment

96.3%

96.0%

Post‐treatment

96.6%

98.4%

Difference (%)

‐0.3%

‐2.4%

P > 0.01

Week

Treatment Group

N

dB Mean Improve (SD)

Dif 95%CI: cip‐boric

p

(ANCOVA controlling for baseline audio level)

(ANCOVA controlling for baseline audio level)

2 weeks

Ciprofloxacin
Boric acid

201
202

4·32 (11·18)
2·69 (11·67)

2·17 (0·09 to 4·24)

0·0410

4 weeks

Ciprofloxacin
Boric acid

196
194

5·42 (11·03)
2·63 (12·18)

3·43 (1·34 to 5·52)

0·0014

Study ID

Treatment comparison

Allergic reaction

Ototoxicity

Other AE

Gyde 1978

1) Topical non‐quinolone antibiotic: trimethoprim‐polymyxin B‐sulfacetamide eardrops.

2) Topical non‐quinolone antibiotic: gentamicin 0.3% eardrops

The treatments did not cause any allergic reactions.

The results of audiometry (tested on 50 subjects, 3 to 12 months after treatment or additional surgery) showed no signs of ototoxicity either immediatly after the treatment , or later on, for either treatments (see separate table for results).

The majority of the participants tested showed an improvement of the auditory acuteness, and hearing results remained stable in all cases examined during the 3 to12 month post‐observation period.

There were no unfavourable reactions nor side effects following the administration of either treatment.

The participants did not complain about pain, itching or of burn.

The treatment did not cause allergic reactions not excessive fungal growth.

Gyde 1981

1) Topical non‐quinolone antibiotic: trimethoprim‐polymyxin B‐sulfacetamide eardrops.

2) Topical non‐quinolone antibiotic: trimethoprim‐polymyxin B eardrops.

There were no signs of ototoxicity.

[From abstract only ‐ data not presented]

There were no incidences of side‐effects/local sensitivity, or fungal infection overgrowth.

[From abstract and discussion only ‐ data not presented]

Jaya 2003

1) Topical quinolone: 0.3% ciprofloxacin hydrochloride eardrops.

2) Topical antiseptic: 5% povidone‐iodine eardrops.

No patients developed allergic manifestations.

No patients developed ototoxic effects.

There was no deterioration of hearing as assessed by pure‐tone audiometry.

Kasemsuwan 1997

1) Topical quinolone: ciprofloxacin in saline eardrops.

2) Topical placebo: normal saline eardrops.

No worsening of audiological measurements (taken 24 hours after completing treatment) was detected.

No medical side‐effects related to the topical medication were detected in the study.

Lorente 1995

1) Topical quinolone: ciprofloxacin eardrops 0.3%

2) Topical non‐quinolone: gentamicin 0.3%

One case (on gentamicin) of slight auditory disorder was detected on audiometry; the loss was considered to be only slight and without clinical relevance by the trialists.

One case of loss of balance was reported before treatment in a patient randomised to ciprofloxacin; this disappeared during the course of treatment.

A joint analysis of the action of both treatments showed no statistically significant effects on the audiometry results (P = 0.21).

Both treatments were reported to be very well tolerated with respect to general side effects.

No cases of superinfection with fungus (Candida albicans or Aspergillus) were observed.

Macfadyen 2005

1) Topical quinolone: ciprofloxacin eardrops (after dry mopping)

2) Topical antiseptic: boric acid in alcohol eardrops (after dry mopping)

For adverse events of ear pain, irritation and bleeding on mopping, there was a higher frequency in the boric acid group (30/206) than in the ciprofloxacin group (17/210).

Tutkun 1995

1) Topical quinolone: ciprofloxacin eardrops

2) Topical non‐quinolone: gentamicin eardrops

Audiometric evaluation yielded no evidence of ototoxicity as reflected by the pure tone threshold and speech discrimination scores in either group.

Instead, hearing thresholds were slightly better than pre‐treatment levels in both groups (Ozagar 1997).

There were no side effects.